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hodgkin lymphoma ( hl ) is a highly curable lymphoma with overall cure rates exceeding 80% and over 90% with limited stage disease . the improved survival has led to the concern about long - term effects of cancer therapy adversely affecting the quality of life of these children . computerized tomography ( ct ) scan is currently the recommended modality in the staging and assessment of response at the end of therapy in patients with hl . the drawbacks of ct scan include its failure to differentiate areas of necrosis and fibrosis in residual masses from viable tumor thus , creating a therapeutic dilemma whether the patient requires further treatment or not . it also fails to identify tumor deposits in unenlarged nodes thus , underestimating the stage of the disease before starting therapy . fluorine-18 fluorodeoxyglucose ( 18f - fdg ) positron emission tomography ( pet ) has been widely established in the treatment protocol of non - hodgkin lymphoma ( nhl ) . in recent times it is being used with in hl , for staging at the time of diagnosis , to differentiate persistent , active disease from residual , but inactive masses at the completion of therapy as well as for monitoring for relapse . however , pet alone has lower specificity because of poor localization details . introduction of combined pet and ct ( 18f - fdg - pet / ct ) technology has revolutionized imaging by fusing functional and anatomical data . it is being routinely used for staging , response monitoring and prognostication of a wide array of tumors . this study describes our experience with nine patients of hl where fdg - pet - ct scan helped us to decide further management after completion of planned chemotherapy . this is a retrospective review of the records of all children aged less than 12 years , diagnosed with hl on biopsy enrolled in pediatric oncology clinic at the all india institute of medical sciences between october 2005 and may 2010 . patients with post - treatment ct scan showing evidence of residual disease , who underwent fdg - pet - ct for deciding further management , were included for the study . those with concurrent hiv infection , any pre - existing severe organ ( kidney , liver , cardiac , and cerebral ) dysfunction were excluded . a baseline hemogram and serum biochemistry including lactate dehydrogenase ( ldh ) was obtained . a chest x - ray and contrast enhanced computerized tomographic scan ( cect ) of chest , abdomen and pelvis were carried out in all patients . a bone marrow aspiration / biopsy was carried out in all except in stage ia - iia patients . splenic involvement was defined as clinically detectable splenomegaly or presence of hypodense lesions on abdominal cect in patients without clinically detected splenomegaly bulky disease was defined as presence of lymph nodal mass of at least 6 cm diameter or a mediastinal mass with a diameter exceeding one - third of the maximum intra - thoracic cavity width on an upright postero - anterior chest radiograph . patients treated at our center received either 4 alternate cycles of adriamycin , bleomycin , vinblastine , dacarbazine / cyclophosphamide , oncovin , procarbazine , prednisone ( abvd / copp ) or 4 - 6 cycles of abvd as initial therapy . patients were reassessed for residual disease and need for radiotherapy / escalated chemotherapy at end of chemotherapy with ct scan of the site of disease . fdg - pet scan was carried out whenever there was a discordance of clinical evaluation and ct findings . after fasting for at least 4 h and with patients in a resting state , in a quiet room , a dose of 5.3 mbq / kg ( 0.14 mci / kg ) of fdg was injected intravenously . sedation was carried out when needed using 0.1 mg / kg midazolam to avoid motion artifacts . pet - ct scan was acquired on a dedicated pet - ct scanner approximately 60 min after intravenous injection of radiotracer on a biograph scanner ( siemens , germany ) . nine of these patients underwent pet scans at the end of treatment and were found to be eligible . clinical profile of patients in all nine patients , ct scan evaluation after completion of chemotherapy revealed residual disease . as there was discrepancy between clinical and radiological findings , the patients underwent a fdg - pet scan . computerized tomography and fluorodeoxyglucose - positron emission tomography - computerized tomography findings in 8 out of 9 patients , fdg - pet showed no scan evidence of active disease . in one patient , fdg - pet carried out after completion of chemotherapy showed evidence of active disease in spleen and retroperitoneal lymphnodes . follow - up fdg - pet performed . after completion the chemotherapy , showed no scan evidence of active disease . the patient continues to be in remission at a follow - up of 20 months . recent changes in the treatment protocols for over the past two decades have resulted in improved survival among patients of hl . ct scan is the recommended imaging modality at the end of therapy and often detects residual disease based on persistence of sizeable lymphadenopathy / organ enlargement / hypoechoic lesions in patients who are clinically well . there is thus , a need for an imaging modality to differentiate residual but inactive / inert masses from active lesions that require further treatment . the use of pet in detection of cancer cells employing fdg as the tracer molecule is based on warburg 's demonstration that malignant cells show accelerated glucose metabolism . as early as 7 days after first administration of chemotherapy and in most patients after 2 cycles of chemotherapy , there is shutdown of cellular metabolic and chemokine - synthetic machinery . in contrast , in patients not responding to chemotherapy , the cellular metabolic activity persists and is evidenced by increased uptake . this sensitivity of pet holds promise for extensive use in both response assessments during chemotherapy , as well as in cases with discordant clinical and ct findings after therapy completion . pet scan has widespread use among nhl patients in staging , post - therapy assessments and evaluation of residual masses . teresawa , et al . in a systemic review found varying sensitivities from 0.33 to 0.77 and specificity from 0.82 to 1.00 in post - therapy evaluation of nhl patients . , pet has been evaluated in the context of staging , response assessment and end - therapy assessment in hl but pediatric data is scarce . though , pet scan detects smaller lymph node involvement and elucidates bone marrow , splenic and liver involvement , it is not the standard in hl staging due to high sensitivity and false positivity rates . the main utility of fdg - pet in hl is post - treatment assessment . but studies in this regard have produced conflicting results . terasawa , et al . in a systemic review reported sensitivity between 0.50 and 1.00 and specificity between 0.67 and 1.00 for post - treatment evaluations . juweid reported a consistently high negative predictive value averaging about 90% and exceeding 80% , which is similar to that of ct . the positive predictive value while being more variable ( averaging approximately 65% with most studies reporting values exceeding 50% ) , was higher than that of ct ( about 20% ) . however , these data primarily reflects that of adult patients of hl . fdg - pet has also been studied as a predictor of outcome in hl . a negative interim pet after 2 cycles of chemotherapy was associated with an increased 2 year progression free survival rate compared to the pet positive group . furth et al . in a prospective study demonstrated that pediatric hl patients with a negative pet during early response assessment ( after 2 cycles of chemotherapy ) have an excellent prognosis while pet - positive patients have an increased risk for relapse . they also demonstrated that a standardized uptake value ( suv)max reduction of < 58% was associated with an increase in risk of relapse . the present studied demonstrated the role of pet - ct in resolving therapeutic dilemmas in 29% of patients which are common after therapy for hl . though , doing a pet - ct in all such patients involves lot of cost , the cost of further chemo / radiotherapy and its side - effects outweigh the monetary burden . however , this modality of investigation has the potential as a baseline evaluation to detect small areas of disease involvement not detected by ct and as a prognostic marker for predicting disease free interval . pet - ct scan is a promising modality in deciding further management when faced with situations where there is discordance between the post - treatment ct scan and the clinicalcondition of patient with hodgkin lymphoma , thus , avoiding unnecessary chemotherapy / radiotherapy .

introduction : hodgkin lymphoma ( hl ) is a highly curable lymphoma with cure rates of over 80% and even higher with limited stage disease . computerized tomography ( ct ) scan is currently the recommended modality in staging and assessment of response to therapy in patients with hl . however , ct has its limitations . this study describes our experience with patients of hl where fluorodeoxyglucose positron emission tomography ( fdg - pet)-ct scan helped decide further management , after completion of chemotherapy.methodology:this is a retrospective review of the records of children diagnosed with hl at our center . patients with post - treatment ct scan showing evidence of residual disease , who underwent fdg - pet - ct for deciding further management , were included in the study.results:thirty one patients were diagnosed with hl during this period . nine patients were eligible and underwent pet - ct . in 8 out of 9 patients , pet - ct showed no scan evidence of active disease . in one patient , fdg - pet - ct carried out after completion of chemotherapy showed evidence of active disease and was given radiotherapy.conclusion:fdg-pet-ct is a promising modality in deciding further management when there is discordance between the post - treatment ct scan and clinical condition of the patient with hl thus avoiding unnecessary chemotherapy / radiotherapy .

the existence of nonlamellar structures of biological membranes , such as inverted hexagonal ( hii ) or cubic ( qii ) phases , has long been a matter of dispute . the major experimental limitations of identifying 2d periodic hexagonal or 3d periodic cubic membrane morphologies in ( living ) cells are caused by the dimensions of these structures and by limited analysis tools at this size range in vivo . in vitro , complex lyotropic liquid crystalline phases , i.e. , lamellar ( l ) , hii , or qii structures , are readily amenable to a range of experimental techniques , such as nuclear magnetic resonance , small - angle x - ray scattering , and differential scanning calorimetry . these techniques , however , are not feasible in whole cells because of limited resolution power and background noise . thus , the experimental approach to uncover nonlamellar membrane structures in ( fixed ) cells is restricted to em , leaving a wide range of interpretations for 3d structures between fact and artifact . transmission em ( tem ) images are 2d projections of ( ultra ) thin , yet finitely thick ( typically 7090 nm ) , sections cut randomly through a 3d specimen . the comprehension of 3d structures based on 2d tem projections is , thus , extremely difficult , particularly if the lattice size of the observed structure is in the same order of magnitude as the section thickness . in recent years , tremendous progress has been made based on electron tomography ( et ) that allows 3d reconstruction of sections that are up to 400 nm thick , with a resolution of 5 nm , i.e. , approaching the molecular level ( for review see lucic et al . , specifically , cryo - et from specimens in vitreous ice provides an excellent means to preserve cellular structure , which avoids artifacts found in conventional em preparation techniques , and is also good for high - resolution analysis of membrane - bound organelles ( lucic et al . 2005 ; hsieh et al . , 2006 ) . despite the technological advantages of cryo - et , most of the depictions of biological membranes that appeared in the literature during the past decades are derived from tem of fixed and thin - sectioned cells and tissues . dependent on the thickness and orientation of the ultrathin section , relative to the coordinates of an ordered 3d structure , various types of projection patterns are observed . thus , for the past five decades , frequent misinterpretations of tem micrographs of membrane - based cell ultrastructure were inescapable , particularly for the highly folded and interconnected cubic membrane morphologies . extensive membrane proliferations leading to unusual and highly convoluted depictions in tem have been observed in numerous cell types from all kingdoms of life and in virtually any membrane - bound cell organelles , especially smooth er , plasma membrane , inner nuclear membrane , mitochondrial inner membrane , and chloroplast thylakoid membranes ( landh , 1996 ; federovitch et al . , not surprisingly , the er was found to be the most prominent target of morphological alterations because of its highly convoluted structure and central functions in membrane lipid synthesis , assembly , secretion of membrane and secretory proteins , ion homeostasis , and membrane quality control . thus , these morphologies appear under numerous nicknames in the literature , such as undulating membranes cotte de mailles ( franke and sheer , 1971 ) , membrane lattice ( linder and staehelin , 1980 ) , crystalloid membranes ( yamamoto et al . , 1996 ) , paracrystalline er ( wolf and motzko , 1995 ) , and tubuloreticular structures ( grimley and schaff , 1976 ; landh , 1995 , 1996 ) . the so - called organized smooth er ( oser ) that is formed in response to elevated levels of the membrane - resident protein cytochrome b(5 ) has recently been added to this list ( snapp et al . , 2003 ) . quite remarkably , the most prominent examples of er expansion are related to lipid synthesis , viral infection , and drug detoxification . for example , cells of the adrenal cortex or leydig cells of the testes , which synthesize large amounts of sterol , display dramatic proliferations of crystalloid er ( sisson and fahrenbach , 1967 ; black , 1972 ) . several studies directly correlate overexpression of certain er - resident proteins with 2d and 3d ( cubic ) periodic symmetry transition of the er , implying a specific structure function relationship of cubic membrane formation as a consequence of an altered protein or lipid inventory of the membrane . overexpression of hmg - coa reductase isozymes induces assembly of nuclear and cortical er stacks with 2d symmetry , termed karmellae , in yeast ( wright et al . , 1988 ; profant et al . , 2000 overexpression of this enzyme in ut-1 ( chin et al . , 1982 ) or cho cells ( jingami et al . , 1987 ; roitelman et al . , 1992 ) induces formation of crystalloid er , which houses most of the hmg - coa reductase protein ( anderson et al . , 1983 ; orci et al . , 1984 ) . the crystalloid er membrane contains reduced levels of free cholesterol ; sterol supplementation of these cells results in accelerated degradation of hmg - coa reductase and the disappearance of the crystalloid er ( orci et al . , 1984 ) . however , the enzymatic activity may not be the key factor in inducing er structure alteration , as nonfunctional subdomains of er - resident proteins also result in crystalloid er formation . for instance , yamamoto et al . ( 1996 ) reported that at least two regions of msaldh , but not the entire enzymatically active protein , may be required for the formation of the crystalloid er in transfected cos-1 cells . as a common theme , membrane rearrangements resulting in cubic morphologies may be a consequence of various cellular stresses , and may occur , e.g. , as a response to hypoxia stress ( takei et al . , 1994 ) , drug treatment ( feldman et al . , 1981 ) , tumors ( schaff et al . , 1976 ) , or specifically , upon stimulation of b lymphocytes with lipopolysaccharide ( federovitch et al , 2004 ) and , indeed , were subsequently identified to resemble cubic membrane architecture ( almsherqi et al . , 2005 ) . tubuloreticular structures , therefore , have significant potential as ultrastructural markers in pathology ( ghadially , 1988 ) . possibly the best - characterized cubic membrane transition was observed in the mitochondrial inner membranes of the free - living giant amoeba ( chaos carolinensis ) . in this organism , mitochondrial inner membranes undergo dramatic changes in 3d organization upon food depletion , providing a valuable model system with which to study induced membrane reorganization . within 1 d of starvation , 70% of mitochondria undergo this morphological transition , which after 7 d of starvation is observed in virtually all mitochondria ( daniels and breyer , 1968 ) . intriguingly , this process is fully reversible to wild - type morphology upon refeeding ( deng and mieczkowski , 1998 ) . using et , we have unequivocally demonstrated that inner mitochondrial membranes in c. carolinensis cells adopt cubic morphology . this starvation - triggered transition is accompanied by alterations in cellular oxidative stress response , which led us to speculate that cubic membrane formation may be related to oxidative stress ( deng et al . , 2002 ) . whether cubic membrane formation is solely a result of aberrant membrane protein and/or lipid interactions in infected or pathological states , or is a specific cellular response to these pathologies remains unclear . to some extent , regular 3d folding appears to be an intrinsic property of membranes that is enhanced under certain conditions ; however , the specific mechanisms leading to cubic membrane formation are not known . recently , voeltz et al . ( 2006 ) discovered a novel class of proteins , termed reticulons , which are involved in shaping the highly curved tubular er membrane . it is tempting to speculate that cubic membrane inducing conditions may also interfere with reticulon function . however , the potential role of reticulons , or related proteins , in supporting or preventing the formation of karmellae , whorls , hexagonal , or cubic membrane structures remains to be determined . nonlamellar arrangements of lipids in aqueous dispersions are well characterized in vitro and are of significant technological interest as biomimetics , matrices for membrane protein crystallization , and drug delivery systems ( barauskas et al . among these nonlamellar lipid mesophases , cubic phases attract great attention because of their unique feature of 3d periodicity . these highly curved 3d periodic ( n)-parallel membrane bilayers represent infinite periodic minimal surfaces ( hyde , 1996 ) that divide space into ( n + 1 ) independent aqueous subcompartments . the type of surface symmetry may change , for instance , depending on the water content , giving rise to cubic structures with gyroid ( qg ) , double diamond ( qd ) , or primitive ( qp ) types of symmetry ( luzzati and husson , 1962 ; landh , 1995 ; de kruijff , 1997 ; hyde et al . , 1997 ) . whereas infinite periodic minimal surfaces are extensively studied and applied in material sciences , structures in biological systems , such as cubic cell membranes , are obviously much less characterized and understood . two principal approaches are feasible to unequivocally determine cubic membranes in biological specimens based on em . in em tomography , a thicker sectioned specimen ( up to 400 nm ) is analyzed by intermediate voltage tem at multiple tilted angles , yielding a large number of projections that are reconstructed by computational image analysis into a 3d representation of the object ( lucic et al . , 2005 ) . em tomography has previously been successfully applied to determine cubic membrane transition of the inner mitochondrial membrane morphology in c. carolinensis upon starvation ( deng et al . , 1999 ) . alternatively , because cubic membrane morphologies adopt mathematically well defined 3d configurations ( fig . 1 a ) , images resulting from tem of ultrathin sections can be matched to theoretical computer - generated projections ; direct template correlative matching ( dtc ; landh , 1995 , 1996 ; deng and mieczkowski , 1998 , almsherqi et al . , 2005 ) is a method based on pattern and symmetry recognition . with dtc , the electron density of the tem image is correlated to a library of computer - generated 2d projection maps ( cubic membrane simulation projection software ; deng and mieczkowski , 1998 ; fig . these 2d projection catalogs represent cubic symmetries of gyroid g- , double diamond d- , and primitive p - surfaces , simulating various surface parameters , projection directions , and section thicknesses of a tem specimen ( deng and mieczkowski , 1998 ) . ( a ) a pair of 3d periodic cubic surfaces illustrates the structure and symmetry of the cubic regions of oser membranes . each surface shown represents the center of a membrane bilayer , indicating the close proximity of two bilayer membranes in that model . ( b ) examples of computer - simulated 2d projections for the respective g- and d - type cubic surfaces , at different viewing angles . these simulated 2d projection maps form a library that is used to match the membrane patterns of interest , as observed by tem . oser was observed in cos-7 and cv-1 cells , having formed as a consequence of overexpression of cytochrome b(5 ) tagged with gfp ( snapp et al . , 2003 ) . oser consists of a network of membranes that are arranged in a nonrandom order and display an equally spaced pattern with cubic symmetry . comparison of the 2d tem images with the fingerprints of the projection library suggested gyroid and double diamond cubic membrane configurations . indeed , superimposition of computer - generated projections with subdomains of the tem images match perfectly . subdomains of tem micrographs correlate precisely with the computer - simulated 2d projection of a balanced double - membrane gyroid ( g)-type ( fig . the exact matching of the intricate , fine details of the projection map , such as the appearance of the dashed straight line , and of material density with the theoretical computer - generated projections ( fig . 2 , b and c ) can be taken as additional evidence of the cubic nature of oser . although oser displays diverse patterns in the 2d tem micrographs , they are all derived from exactly the same mathematically well defined 3d structures , but at varying sectional thicknesses and viewing directions . to further confirm the identity of the patterns beyond visual inspection , fast fourier transform calculations were performed on the pattern of the membrane subdomain , in comparison to projections derived from the computer - generated library and the background of pattern - free membrane regions . the chosen domains typically showed reflection of at least the second order , and they support the identity of the image projections with the calculated data ( unpublished data ) . these analyses strongly support the notion of the formation of a true cubic membrane morphology in cv-1 and cos-7 cells upon cytochrome b(5 ) overexpression . the controlled induction of oser formation in an experimental system that is amenable to genetic manipulation may , indeed , open new perspectives for analyzing and understanding cubic membrane formation and its potential biological functions . identification of cubic membrane morphologies in tem micrographs . two examples of the dtc method , applied to tem images of oser ( adopted from snapp et al . , ( a ) the original tem micrograph ( snapp et al . , 2003 fig . 2 c ) matches perfectly to the theoretical superimposed projections of balanced ( 2-parallel surfaces ) gyroid cubic membranes , as depicted in b. asterisks indicate one of the multicontinuous , yet distinct , subvolumes of cubic membrane architecture . a double diamond projection ( c ) the arrows in a and d indicate the continuity of one cubic membrane subvolume ( between closely arranged bilayers ) and the cytoplasm ( cy ) . signature patterns of the theoretical projection are indistinguishable to the electron density pattern of the tem micrographs . the simulated projections are generated from sections with a thickness of 1/4 of a unit cell , viewed along the direction [ 36 , 30 , 17 ] for gyroid ( b ) and [ 28 , 16 , 5 ] for double diamond - type ( c ) . the unit cell is the smallest structural unit that possesses the symmetry and properties of cubic membranes . bars : ( a ) 100 nm ; ( d ) 160 nm . an important implication of snapp et al . ( 2003 ) is related to the ease with which lamellar and bicontinuous cubic phases are interconverted . this conclusion is inferred from the fact that weakly dimerizing gfp and chimeric er proteins with gfp on their cytoplasmic tails could induce oser formation , but similar proteins with nondimerizing gfp tags could not . a previous work suggested that crystalloid er biogenesis entailed a tight , zipperlike dimerization of the cytoplasmic domains of certain er - resident proteins ( yamamoto et al . , 1996 ) . however , snapp et al . ( 2003 ) found that oser - inducing proteins can diffuse freely between oser and the other ordinary lamellar er , indicating that they may not be tightly bound in zipper structures . the low - affinity interaction between cytoplasmic domains of oser - inducing proteins could explain phenomena such as ( a ) the heterogeneity of er membrane structures observed , ( b ) the high rate of ( reversible ) lamellar cubic phase transition , and ( c ) the technical difficulties and limitations in isolating intact cubic membranes from biological samples for studies in vitro . the weak molecular interaction that results in er transformation could be attributed to the electrostatic interaction between the corresponding cytoplasmic domains of specific membrane - resident proteins ( masum et al . , 2005 ) . in vitro studies using monoolein membranes containing negatively charged dioleoylphosphatidic acid have shown that electrostatic interactions caused by surface charge of the membranes ( li et al . , 2001 ) , charged short peptides such as poly - l - lysine ( masum et al . , 2005 ) , and ca concentration ( awad et al . , 2005 ) play an important role in phase transition between lamellar and cubic phases and in the stability of cubic phases . as electrostatic interactions in the membrane interface are altered either by the increase in surface charge density of the membrane or by the decrease in salt concentration , the lipid membrane phase may change from lamellar to cubic phase . such cubic lipid phases may not only form to adapt altered membrane proteins or charge distribution , but may also provide the means to rapidly adjust cellular physiology to the changing environmental conditions , such as temperature . i.e. , the changes in lattice size as demonstrated in vitro ( de campo et al . , 2004 ) , may represent an immediate biophysical response , which may allow for a rapid adaptation in water content and ion concentration / charge distribution in a given membrane compartment . in conclusion , cubic membrane formation in biological systems , which are induced by lipid and protein alterations , drug intervention , or stress , is a widespread phenomenon that is only poorly understood . the apparent relation to pathological states will clearly spark more interest in investigating and understanding these intriguing membrane arrangements . however , novel techniques are required to address membrane transitions in living specimens and to understand the function of these membrane arrangements in the biological context . extensive membrane proliferations leading to unusual and highly convoluted depictions in tem have been observed in numerous cell types from all kingdoms of life and in virtually any membrane - bound cell organelles , especially smooth er , plasma membrane , inner nuclear membrane , mitochondrial inner membrane , and chloroplast thylakoid membranes ( landh , 1996 ; federovitch et al . , not surprisingly , the er was found to be the most prominent target of morphological alterations because of its highly convoluted structure and central functions in membrane lipid synthesis , assembly , secretion of membrane and secretory proteins , ion homeostasis , and membrane quality control . thus , these morphologies appear under numerous nicknames in the literature , such as undulating membranes cotte de mailles ( franke and sheer , 1971 ) , membrane lattice ( linder and staehelin , 1980 ) , crystalloid membranes ( yamamoto et al . , 1996 ) , paracrystalline er ( wolf and motzko , 1995 ) , and tubuloreticular structures ( grimley and schaff , 1976 ; landh , 1995 , 1996 ) . the so - called organized smooth er ( oser ) that is formed in response to elevated levels of the membrane - resident protein cytochrome b(5 ) has recently been added to this list ( snapp et al . , quite remarkably , the most prominent examples of er expansion are related to lipid synthesis , viral infection , and drug detoxification . for example , cells of the adrenal cortex or leydig cells of the testes , which synthesize large amounts of sterol , display dramatic proliferations of crystalloid er ( sisson and fahrenbach , 1967 ; black , 1972 ) . several studies directly correlate overexpression of certain er - resident proteins with 2d and 3d ( cubic ) periodic symmetry transition of the er , implying a specific structure function relationship of cubic membrane formation as a consequence of an altered protein or lipid inventory of the membrane . overexpression of hmg - coa reductase isozymes induces assembly of nuclear and cortical er stacks with 2d symmetry , termed karmellae , in yeast ( wright et al . , 1988 ; profant et al . , 2000 ) . overexpression of this enzyme in ut-1 ( chin et al . , 1982 ) or cho cells ( jingami et al . , 1987 1992 ) induces formation of crystalloid er , which houses most of the hmg - coa reductase protein ( anderson et al . , 1983 ; orci et al . , 1984 ) the crystalloid er membrane contains reduced levels of free cholesterol ; sterol supplementation of these cells results in accelerated degradation of hmg - coa reductase and the disappearance of the crystalloid er ( orci et al . , 1984 ) . however , the enzymatic activity may not be the key factor in inducing er structure alteration , as nonfunctional subdomains of er - resident proteins also result in crystalloid er formation . for instance , yamamoto et al . ( 1996 ) reported that at least two regions of msaldh , but not the entire enzymatically active protein , may be required for the formation of the crystalloid er in transfected cos-1 cells . as a common theme , membrane rearrangements resulting in cubic morphologies may be a consequence of various cellular stresses , and may occur , e.g. , as a response to hypoxia stress ( takei et al . , 1994 ) , drug treatment ( feldman et al . , 1981 ) , tumors ( schaff et al . , 1976 ) , or specifically , upon stimulation of b lymphocytes with lipopolysaccharide ( federovitch et al tubuloreticular structures are also formed in sars - infected cells ( goldsmith et al . , 2004 ) and , indeed , were subsequently identified to resemble cubic membrane architecture ( almsherqi et al . , 2005 ) . tubuloreticular structures , therefore , have significant potential as ultrastructural markers in pathology ( ghadially , 1988 ) . possibly the best - characterized cubic membrane transition was observed in the mitochondrial inner membranes of the free - living giant amoeba ( chaos carolinensis ) . in this organism , mitochondrial inner membranes undergo dramatic changes in 3d organization upon food depletion , providing a valuable model system with which to study induced membrane reorganization . within 1 d of starvation , 70% of mitochondria undergo this morphological transition , which after 7 d of starvation is observed in virtually all mitochondria ( daniels and breyer , 1968 ) . intriguingly , this process is fully reversible to wild - type morphology upon refeeding ( deng and mieczkowski , 1998 ) . using et , we have unequivocally demonstrated that inner mitochondrial membranes in c. carolinensis cells adopt cubic morphology . this starvation - triggered transition is accompanied by alterations in cellular oxidative stress response , which led us to speculate that cubic membrane formation may be related to oxidative stress ( deng et al . , 2002 ) . whether cubic membrane formation is solely a result of aberrant membrane protein and/or lipid interactions in infected or pathological states , or is a specific cellular response to these pathologies remains unclear . to some extent , regular 3d folding appears to be an intrinsic property of membranes that is enhanced under certain conditions ; however , the specific mechanisms leading to cubic membrane formation are not known . ( 2006 ) discovered a novel class of proteins , termed reticulons , which are involved in shaping the highly curved tubular er membrane . it is tempting to speculate that cubic membrane inducing conditions may also interfere with reticulon function . however , the potential role of reticulons , or related proteins , in supporting or preventing the formation of karmellae , whorls , hexagonal , or cubic membrane structures remains to be determined . nonlamellar arrangements of lipids in aqueous dispersions are well characterized in vitro and are of significant technological interest as biomimetics , matrices for membrane protein crystallization , and drug delivery systems ( barauskas et al . , cubic phases attract great attention because of their unique feature of 3d periodicity . these highly curved 3d periodic ( n)-parallel membrane bilayers represent infinite periodic minimal surfaces ( hyde , 1996 ) that divide space into ( n + 1 ) independent aqueous subcompartments . the type of surface symmetry may change , for instance , depending on the water content , giving rise to cubic structures with gyroid ( qg ) , double diamond ( qd ) , or primitive ( qp ) types of symmetry ( luzzati and husson , 1962 ; landh , 1995 ; de kruijff , 1997 ; hyde et al . , 1997 ) . whereas infinite periodic minimal surfaces are extensively studied and applied in material sciences , structures in biological systems , such as cubic cell membranes , are obviously much less characterized and understood two principal approaches are feasible to unequivocally determine cubic membranes in biological specimens based on em . in em tomography , a thicker sectioned specimen ( up to 400 nm ) is analyzed by intermediate voltage tem at multiple tilted angles , yielding a large number of projections that are reconstructed by computational image analysis into a 3d representation of the object ( lucic et al . , 2005 ) . em tomography has previously been successfully applied to determine cubic membrane transition of the inner mitochondrial membrane morphology in c. carolinensis upon starvation ( deng et al . , 1999 ) . alternatively , because cubic membrane morphologies adopt mathematically well defined 3d configurations ( fig . 1 a ) , images resulting from tem of ultrathin sections can be matched to theoretical computer - generated projections ; direct template correlative matching ( dtc ; landh , 1995 , 1996 ; deng and mieczkowski , 1998 , almsherqi et al . , , the electron density of the tem image is correlated to a library of computer - generated 2d projection maps ( cubic membrane simulation projection software ; deng and mieczkowski , 1998 ; fig . these 2d projection catalogs represent cubic symmetries of gyroid g- , double diamond d- , and primitive p - surfaces , simulating various surface parameters , projection directions , and section thicknesses of a tem specimen ( deng and mieczkowski , 1998 ) . ( a ) a pair of 3d periodic cubic surfaces illustrates the structure and symmetry of the cubic regions of oser membranes . each surface shown represents the center of a membrane bilayer , indicating the close proximity of two bilayer membranes in that model . ( b ) examples of computer - simulated 2d projections for the respective g- and d - type cubic surfaces , at different viewing angles . these simulated 2d projection maps form a library that is used to match the membrane patterns of interest , as observed by tem . oser was observed in cos-7 and cv-1 cells , having formed as a consequence of overexpression of cytochrome b(5 ) tagged with gfp ( snapp et al . , 2003 ) . oser consists of a network of membranes that are arranged in a nonrandom order and display an equally spaced pattern with cubic symmetry . comparison of the 2d tem images with the fingerprints of the projection library suggested gyroid and double diamond cubic membrane configurations . indeed , superimposition of computer - generated projections with subdomains of the tem images match perfectly . subdomains of tem micrographs correlate precisely with the computer - simulated 2d projection of a balanced double - membrane gyroid ( g)-type ( fig . the exact matching of the intricate , fine details of the projection map , such as the appearance of the dashed straight line , and of material density with the theoretical computer - generated projections ( fig . 2 , b and c ) can be taken as additional evidence of the cubic nature of oser . although oser displays diverse patterns in the 2d tem micrographs , they are all derived from exactly the same mathematically well defined 3d structures , but at varying sectional thicknesses and viewing directions . to further confirm the identity of the patterns beyond visual inspection , fast fourier transform calculations were performed on the pattern of the membrane subdomain , in comparison to projections derived from the computer - generated library and the background of pattern - free membrane regions . the chosen domains typically showed reflection of at least the second order , and they support the identity of the image projections with the calculated data ( unpublished data ) . these analyses strongly support the notion of the formation of a true cubic membrane morphology in cv-1 and cos-7 cells upon cytochrome b(5 ) overexpression . the controlled induction of oser formation in an experimental system that is amenable to genetic manipulation may , indeed , open new perspectives for analyzing and understanding cubic membrane formation and its potential biological functions . identification of cubic membrane morphologies in tem micrographs . two examples of the dtc method , applied to tem images of oser ( adopted from snapp et al . , 2003 fig . 2 c ) matches perfectly to the theoretical superimposed projections of balanced ( 2-parallel surfaces ) gyroid cubic membranes , as depicted in b. asterisks indicate one of the multicontinuous , yet distinct , subvolumes of cubic membrane architecture . a double diamond projection ( c ) the arrows in a and d indicate the continuity of one cubic membrane subvolume ( between closely arranged bilayers ) and the cytoplasm ( cy ) . signature patterns of the theoretical projection are indistinguishable to the electron density pattern of the tem micrographs . the simulated projections are generated from sections with a thickness of 1/4 of a unit cell , viewed along the direction [ 36 , 30 , 17 ] for gyroid ( b ) and [ 28 , 16 , 5 ] for double diamond - type ( c ) . the unit cell is the smallest structural unit that possesses the symmetry and properties of cubic membranes ( 2003 ) is related to the ease with which lamellar and bicontinuous cubic phases are interconverted . this conclusion is inferred from the fact that weakly dimerizing gfp and chimeric er proteins with gfp on their cytoplasmic tails could induce oser formation , but similar proteins with nondimerizing gfp tags could not . a previous work suggested that crystalloid er biogenesis entailed a tight , zipperlike dimerization of the cytoplasmic domains of certain er - resident proteins ( yamamoto et al . , 1996 ) . however , snapp et al . ( 2003 ) found that oser - inducing proteins can diffuse freely between oser and the other ordinary lamellar er , indicating that they may not be tightly bound in zipper structures . the low - affinity interaction between cytoplasmic domains of oser - inducing proteins could explain phenomena such as ( a ) the heterogeneity of er membrane structures observed , ( b ) the high rate of ( reversible ) lamellar cubic phase transition , and ( c ) the technical difficulties and limitations in isolating intact cubic membranes from biological samples for studies in vitro . the weak molecular interaction that results in er transformation could be attributed to the electrostatic interaction between the corresponding cytoplasmic domains of specific membrane - resident proteins ( masum et al . , 2005 ) . in vitro studies using monoolein membranes containing negatively charged dioleoylphosphatidic acid have shown that electrostatic interactions caused by surface charge of the membranes ( li et al . , 2001 ) , charged short peptides such as poly - l - lysine ( masum et al . , 2005 ) , and ca concentration ( awad et al . , 2005 ) play an important role in phase transition between lamellar and cubic phases and in the stability of cubic phases . as electrostatic interactions in the membrane interface are altered either by the increase in surface charge density of the membrane or by the decrease in salt concentration , the lipid membrane phase may change from lamellar to cubic phase . such cubic lipid phases may not only form to adapt altered membrane proteins or charge distribution , but may also provide the means to rapidly adjust cellular physiology to the changing environmental conditions , such as temperature . i.e. , the changes in lattice size as demonstrated in vitro ( de campo et al . , 2004 ) , may represent an immediate biophysical response , which may allow for a rapid adaptation in water content and ion concentration / charge distribution in a given membrane compartment . in conclusion , cubic membrane formation in biological systems , which are induced by lipid and protein alterations , drug intervention , or stress , is a widespread phenomenon that is only poorly understood . the apparent relation to pathological states will clearly spark more interest in investigating and understanding these intriguing membrane arrangements . however , novel techniques are required to address membrane transitions in living specimens and to understand the function of these membrane arrangements in the biological context .

cubic membranes represent highly curved , three - dimensional nanoperiodic structures that correspond to mathematically well defined triply periodic minimal surfaces . although they have been observed in numerous cell types and under different conditions , particularly in stressed , diseased , or virally infected cells , knowledge about the formation and function of nonlamellar , cubic structures in biological systems is scarce , and research so far is restricted to the descriptive level . we show that the organized smooth endoplasmic reticulum ( oser ; snapp , e.l . , r.s . hegde , m. francolini , f. lombardo , s. colombo , e. pedrazzini , n. borgese , and j. lippincott - schwartz . 2003 . j. cell biol . 163:257269 ) , which is formed in response to elevated levels of specific membrane - resident proteins , is actually the two - dimensional representation of two subtypes of cubic membrane morphology . controlled oser induction may thus provide , for the first time , a valuable tool to study cubic membrane formation and function at the molecular level .

a 52-year - old caucasian woman was admitted to our hospital from the nursing home due to refusal of percutaneous endoscopic gastrostomy tube feeding and altered mental status , which was attributed to hypoglycemia and urinary tract infection . her medical history was significant for long - standing severe anorexia nervosa , depression and recent percutaneous endoscopic gastrostomy tube placement for nutritional support at another hospital . she was allergic to ciprofloxacin and penicillin and her nursing home medications included multivitamin , megestrol , ferrous sulfate , calcium carbonate , ranitidine , thiamine , folic acid , and olanzapine . upon admission , her weight was 21 kg and her bmi was 7.9 , which amounted to approximately 40%percnt ; of her ideal body weight . the physical exam revealed dry skin , excoriations all over the body , brittle nails , pallor and profound emaciation with bitemporal wasting . her abdomen was scaphoid without organomegaly , and she had a percutaneous endoscopic gastrostomy tube with granulation tissue surrounding the stoma . laboratory investigations revealed hemoglobin of 8.4 g / dl , white cell count of 3.5 k/l , platelet count of 230 k/l , prothrombin time of 12 s and activated partial thromboplastin time of 29 s , normal serum electrolytes except for a blood sugar level of 56 . her liver function tests showed serum alanine aminotransferase of 32 units / l , serum aspartate aminotransferase of 32 units / l and serum total bilirubin of 0.6 mg / dl . she continued to refuse oral and tube feeding and she had intermittent episodes of hypoglycemia . after consultation with the nutritional team , tube feeding was begun at 400 kcal / day and advanced gradually over the next 5 days to 900 kcal / day . five days after the initiation of feeding , she developed tachycardia and lab work revealed electrolyte abnormalities such as hypophosphatemia ( phosphorus 0.8 mg / dl ) and hypokalemia ( potassium 2.9 meq / l ) ( fig . an electrocardiogram was done , which showed sinus tachycardia with some premature ventricular complexes and prolonged qt interval ( qtc 472 ) . she was then evaluated by cardiologists and nutritional teams . a diagnosis of refeeding syndrome was made , and the patient was transferred to the telemetry unit for further management . further laboratory tests revealed elevated transaminases ( alanine aminotransferase 193 units / l , aspartate aminotransferase iu / l ) and bilirubin ( 1.4 mg / dl ) , which were normal upon admission ( fig . viral hepatitis was excluded by serological tests and autoimmune workup , including anti - smooth muscle antibody , anti - liver / kidney microsomal antibody , antinuclear antibody and antimitochondrial antibody , was negative . an abdominal ultrasound revealed normal echotexture of the liver without intra- or extrahepatic biliary dilatation and normal doppler evaluation of the hepatic and portal vein blood flow . infusions of potassium phosphate and magnesium sulfate were administered in addition to oral potassium phosphate supplements . her enteral intake was reduced and daily electrolyte levels were obtained along with regular monitoring of the liver function tests . the liver enzymes started improving after reduction of the tube feeding rate . anorexia nervosa is characterized by severe protein energy malnutrition , abnormally low body weight and is often accompanied by additional psychopathological disorders . several studies and case reports have highlighted increases in serum liver enzymes in patients with anorexia nervosa or extreme malnutrition . the majority of them have reported abnormal liver function test results occurring prior to the initiation of any nutritional supplementation and improvement of enzymes upon feeding . hepatocellular injury in such patients has sometimes been called starvation hepatitis and is attributed to several mechanisms triggered by malnutrition including apoptosis / autophagy , hypoperfusion of the liver , hypoxia , oxidative stress , and iron deposition [ 3 , 4 ] . rarely , there have been reports of anorexic patients with rapid and profound elevations in liver enzymes , specifically transaminases upon initial refeeding associated with refeeding syndrome [ 5 , 6 ] . a medline search using the key words refeeding syndrome and abnormal liver function tests revealed two case reports from 2000 to 2014 [ 7 , 8 ] . refeeding syndrome is a potentially lethal condition , which is broadly defined as severe electrolyte and fluid shifts associated with metabolic abnormalities in malnourished patients undergoing refeeding either orally , enterally , or parenterally . a hepatic manifestation as part of metabolic abnormalities can occur during the initial few weeks of refeeding . they are more common in those patients being refed enterally or with total parenteral nutrition . usually , elevations in aspartate aminotransferase and alanine aminotransferase are noted and may sometimes be followed by a rise in alkaline phosphatase and bilirubin . usually , these abnormalities revert to normal levels upon reduction of the rate of feeding . the pathophysiology of this has not been clarified , but a few hypotheses have been postulated and out of them refeeding steatosis / steatohepatitis has gained the most attention . it is attributed to fat accumulation in the hepatocytes secondary to excessive dextrose and carbohydrate supplementation in a severely malnourished patient during the refeeding phase [ 10 , 11 , 12 ] . we conclude that the development of refeeding syndrome may manifest as abnormal liver function along with electrolyte abnormalities . we recommend close monitoring of liver function tests in patients who are being refed after a long period of starvation as abnormal liver chemistry values may be a harbinger of the refeeding syndrome . on behalf of all authors , the corresponding author states that there is no conflict of interest .

refeeding syndrome is defined as electrolyte and fluid abnormalities that occur in significantly malnourished patients when they are refed orally , enterally , or parenterally . the principal manifestations include hypophosphatemia , hypokalemia , vitamin deficiencies , volume overload and edema . this can affect multiple organ systems , such as the cardiovascular , pulmonary , or neurological systems , secondary to the above - mentioned abnormalities . rarely , patients may develop gastrointestinal symptoms and show abnormal liver function test results . we report the case of a 52-year - old woman with anorexia nervosa who developed refeeding syndrome and simultaneous elevations of liver function test results , which normalized upon the resolution of the refeeding syndrome .

the accretion process can occur onto the neutron star in the case of relatively slowly rotating objects even if the neutron stars are characterized by a super - strong surface magnetic field ( so called magnetars ) . up to now , magnetars have not been observed inside the binary systems . however , very recently it was claimed that x - ray emission characteristic for magnetars has been observed from the object lsi + 61 303 , which belongs to the rare class of massive binary systems emitting tev @xmath1-rays ( dubus & giebels 2008 ) . the observed outburst of thermal x - ray emission might be due to the transient accretion of matter onto the surface of the neutron star . moreover , quasi - periodic x - ray emission , with the frequency of 0.2 hz , has been reported from the direction of this binary ( ray , hartman et al . whether this emission is in fact related to this massive binary , it is at present an open issue ( see rea & torres 2008 ) . however , if it is true , then it makes sense to speculate that the compact object inside the lsi + 61 303 is an accreting magnetar . the aim of this paper is to investigate such a hypothesis . we apply the general scenario for the @xmath1-ray production similar to that one recently proposed for accreting classical and millisecond neutron stars ( bednarek 2008 ) . it is shown that also accreting magnetars can accelerate electrons in the magnetized , turbulent region inside the ns magnetosphere when the gravitational pressure of the accreting matter is balanced by the magnetic pressure of the rotating ns magnetosphere . we calculate the high energy radiation produced in the synchrotron and inverse compton processes by primary electrons and secondary @xmath2 cascade pairs immersed in the magnetic fields of the magnetar and the massive star , and in the thermal radiation from the massive star surface . we consider a compact binary system containing rotating strongly magnetized neutron star ( magnetar ) and a massive companion of the o , b type star . it is assumed that a mass from the stellar wind is effectively captured by the strong gravitational potential of the neutron star ( ns ) . depending on its period and surface magnetic field , the accretion process onto ns can occur in different phases . according to the classification scheme of lipunov ( 1992 ) , the accretion process can occur in the phase of accretor ( for relatively slow rotators ) or in the phase of propeller . the accretor phase in the case of classical and millisecond pulsars has been recently discussed by bednarek ( 2008 ) . in this paper we concentrate on the propeller phase for the strongly magnetized neutron stars , i.e. magnetars . in this case , the matter from the stellar wind can penetrate below the light cylinder radius of the rotating ns magnetosphere . this matter extracts rotational energy from the ns as a result of interaction of the free falling matter with the rigidly rotating inner ns magnetosphere . as a result of this interaction , a very turbulent and magnetized transition region is formed . we consider possible acceleration of electrons in such a medium . the distance at which the magnetic field starts to dominate the dynamics of the in - falling matter ( the alfven radius ) can be estimated by comparing the magnetic field energy density with the kinetic energy density of the wind , @xmath3 where @xmath4 is the magnetic field in the inner neutron star magnetosphere , @xmath5 is the density of the accreting matter , @xmath6 is the free fall velocity of the accreting matter , @xmath7 is the alfven radius , and g is the gravitational constant . the matter in this transition region is very turbulent and strongly magnetized providing good conditions for acceleration of particles to high energies . let us estimate the location of this region from the surface of the neutron star . by applying eq . [ eq1 ] , and assuming that the magnetic field in the neutron star magnetosphere is of the dipole type , i.e. @xmath8 , we obtain @xmath9 where the magnetic field at the neutron star surface is @xmath10 g and the accretion rate is @xmath11 g s@xmath12 ( see also baan & treves 1973 ) . then , we can estimate the magnetic field strength at the transition region , @xmath13 the accretion according to the propeller scenario can occur provided that some conditions are fulfilled . at first , the radius of the transition region has to lay inside the light cylinder radius of the neutron star , i.e @xmath14 , where @xmath15 s is the rotational period of the neutron star , and @xmath16 is the velocity of light . the above condition is fulfilled when , @xmath17 at second , the rotational velocity of the magnetosphere at @xmath7 has to be longer than the keplerian velocity of the accreting matter . the rotational velocity , @xmath18 is larger than the keplerian velocity , @xmath19 for the ns with the rotation periods , @xmath20 this last condition on the ns period separates the propeller phase ( lower periods ) from the accretor phase ( larger periods ) . the third condition relates the alfven radius , @xmath7 , to the capturing radius of the matter from the stellar wind by the ns . it is determined by the balance between the kinetic energy of wind with its potential energy in the gravitational field of the ns , @xmath21 where @xmath22 cm s@xmath12 is the velocity of the surrounding matter measured in respect to the ns . the accretion from the stellar wind occurs when @xmath23 , which happens for , @xmath24 this condition is not restrictive even for magnetars in the case of the accretion rates considered below . in the conditions expected for the transition region ( strongly magnetized and very turbulent medium ) , particles should be efficiently accelerated . in this paper we consider only acceleration of electrons . the acceleration rate of electrons with energy @xmath25 ( and the lorentz factor @xmath1 ) can be parametrized by , @xmath26 where @xmath27 is the acceleration parameter , @xmath16 the velocity of light , @xmath28 the larmor radius , and @xmath29 electron charge . during the acceleration process electrons suffer energy losses mainly on the synchrotron process and on the inverse compton scattering of radiation from the massive star . electrons lose energy on ic process in the thomson ( t ) and the klein - nishina ( kn ) regimes . let us estimate the photon energy densities from the massive star ( @xmath30 ) in the location of the ns , @xmath31 where @xmath32 k and @xmath33 is the stefan - boltzmann constant , and @xmath34 is the distance of the ns from the massive star . let us also estimate the energy density of the magnetic field at the transition region ( see eq . [ eq3 ] ) , @xmath35 the energy losses for each process ( synchrotron and ic in the t regime ) can be calculated from , @xmath36 where @xmath37 is the thomson cross section . the energy losses of electrons at large energies are dominated by the synchrotron process since the ic losses in the radiation field of the massive star decline due to the klein - nishina cross section . therefore , the maximum energies of accelerated electrons are determined by the balance between energy gains ( eq . [ eq10 ] ) and energy losses on synchrotron process ( eq . [ eq13 ] ) . they can be expressed by , @xmath38 it is clear that for the realistic parameters of the model electrons can reach tev energies . the maximum power available for acceleration of electrons is limited by the energy extracted from the rotating neutron star by the in - falling matter . this matter from the stellar wind is accelerated to the velocity of the magnetic field lines at @xmath7 . the power which has to be transfered from the rotating ns to the matter can be estimated from @xmath39 by using eq . [ eq4 ] , we can estimate the maximum power which can be extracted in terms of such a model in the propeller stage , @xmath40 a part of this maximum possible power , @xmath41 , can go on acceleration of electrons . the total rotational energy of the magnetar is , @xmath42 where @xmath43 is the angular momentum of inertia of rotating ns calculated for its mass equal to 1.4@xmath44 and the radius of 10 km , and @xmath45 is its angular velocity . this energy reservoir is enough to provide sufficient power to the accreting matter for a time of the order of thousand of years . note that a neutron star in a specific binary system can come through the cycles of rotational energy losses ( during the propeller phase ) and energy gains ( during the accretor phase ) . these phases depend on the accretion rate from the massive star which can change due to the stellar variability or evolution . so then , the angular velocity of magnetars may also increase at some periods as in the case of millisecond pulsars . for the known parameters of the binary system , we can estimate the accretion rate onto the magnetar , @xmath46 where the capturing radius is given by eq . [ eq8 ] , @xmath47 cm is the separation of the stars inside binary system , @xmath48 m@xmath49 yr@xmath12 is the mass loss rate of the massive star , and @xmath22 denotes the wind velocity and/or the ns velocity on its orbit around the massive star @xmath50 . for the luminous stars , the wind velocity , of the order of @xmath51 km s@xmath12 , is usually larger than the ns velocity . the b type stars , present inside the tev @xmath1-ray binaries , have typical mass loss rate in the range @xmath52 m@xmath49 yr@xmath12 and stellar wind velocities @xmath53 km s@xmath12 . then , the typical accretion rates onto the ns are in the range @xmath54 g s@xmath12 , for the separation of the companion stars below 10 radii of the massive star . in this model , radiation is produced by electrons in the synchrotron and ic process . we assume that primary electrons in the transition region reach the power law spectrum , @xmath55 up to @xmath56 . the energy losses of electrons are dominated at the highest energies ( close to @xmath57 ) by the synchrotron process occurring in the magnetic field of the transition region . the @xmath1-ray production at these highest energies in the ic scattering of thermal radiation from the massive star occurs typically at a lower rate than the synchrotron process but at lower energies ic process can dominate . the ic @xmath1-rays have large enough energies that in some cases they can initiate ic @xmath2 pair cascades in the radiation of the massive star . such cascade can develop provided that the optical depths for electrons in the anisotropic radiation of the massive star are large enough . these optical depths have been calculated in the most general case of the anisotropic radiation of the massive star by e.g. bednarek ( 1997 , 2000 ) . they can be easily scaled for the case of the massive star with the arbitrary parameters ( see bednarek 2008 ) . we developed the monte carlo code which is able to calculate the synchrotron radiation from the primary electrons ( magnetic field of the transition region ) , the secondary cascade @xmath2 pairs ( in the magnetic field of the massive star ) , and the @xmath1-ray spectra produced in ic @xmath2 pair cascade occurring in the anisotropic radiation of the massive star . this code base on the earlier code discussed for the binary systems ( e.g. bednarek 2000 ) . in order to calculate the synchrotron spectrum produced by @xmath2 pairs inside the volume of the binary system , we have to define the distribution of the magnetic field around the massive star . the strength of the magnetic field as a function of distance from the center of the massive star can be described by the following equations ( usov & melrose , 1992 ) , @xmath58 where @xmath59 is the surface magnetic field of the massive star , @xmath60 is the alfven radius within the massive star wind which can be derived by solving the equation , @xmath61 . it has simple approximate solution , @xmath62 where @xmath63 , @xmath64 is the mass loss rate , and @xmath65 is the stellar wind velocity . this approximation for the magnetic field structure is satisfactory inside the most important part of the binary system ( i.e. within @xmath66 ) for the stars which typical rotation velocity is lower than @xmath67 of their wind velocity . note that the larger values of the surface magnetic field of the massive star do not necessary mean larger values of the magnetic field at some distance from the stellar surface ( as would be expected from the simple analysis of eq . [ eq19 ] ) since b(r ) depends also on the alfven radius which in turn depends on the surface magnetic field and the mass loss rate of the massive star . as an example , we apply the model for the massive binary system lsi + 61 303 which has been discovered as a tev @xmath1-ray source by the magic collaboration ( albert et al . 2006 ) and confirmed by the veritas collaboration ( acciari et al . the tev @xmath1-ray emission from this binary system is observed only at a specific range of phases close to the apoastron . no any tev @xmath1-ray emission ( above @xmath68 gev ) has been observed up to now close to the periastron passage . the multi - wavelength observations of lsi + 61 303 show a hint of correlation between x - ray and tev @xmath1-ray emission ( albert et al . lsi + 61 303 belongs to the rare class of sources observed in the whole high energy range from x - rays up to tev @xmath1-rays ( tavani et al . 1996 , van dijk et al . 1996 , kniffen et al . 1997 ) . the massive star in this binary system belongs to a class b0 v. it is characterized by the surface temperature @xmath69 k and the radius @xmath70 ( see e.g. harmanec 1988 ) . the basic parameters of the binary system are not exactly known . two sets of parameters have been proposed by casares et al . ( 2005 ) and grundstrom et al . ( 2007 ) . the semimajor axis , @xmath71 , the eccentricity , @xmath29 , the angle of periastron passage , @xmath72 , the phase of the observer , @xmath73 , the inclination angle , @xmath74 , the distance at periastron and apoastron , @xmath75 and @xmath76 , are shown in table 1 . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [ cols= " < , < , < , < , < , < , < , < , < , < " , ] [ tab1 ] _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ we perform the calculations of the synchrotron x - ray and the cascade ic @xmath1-ray spectra for the location of the magnetar at the periastron and the apoastron passages for both sets of parameters . the surface magnetic field of the massive star is investigated in the range @xmath77 g and the surface magnetic field of the magnetar is fixed to @xmath78 g. electrons are accelerated in the transition region with the differential power law spectrum extending to the maximum energies given by eq . [ eq14 ] . for the illustration we chose the spectral index equal to -2 and the acceleration parameter @xmath79 . the power in relativistic electrons is estimated from eq . [ eq15 ] , applying specific energy conversion efficiency @xmath41 . note , that this power scales with the product of @xmath80 which is taken in our calculations to be equal to @xmath81 . we apply the inclination angles of the binary system to be consistent with other basic parameters ( see table 1 ) and assume the mass loss rate of the massive star equal to @xmath82 yr@xmath12 ( model i ) and @xmath83 yr@xmath12 ( model ii ) . the results of the example calculations with the parameters mentioned above are shown in fig . for all considered model parameters , the @xmath1-ray spectra change drastically between the periastron and apoastron passages . no any emission above @xmath01 tev is observed at the periastron due to the inefficient acceleration of electrons . the tev @xmath1-ray emission clearly extends through the tev energy range at the apoastron , in agreement with the magic and veritas observations . note that @xmath1-ray spectra depend also on the surface magnetic field of the massive star . for larger @xmath59 , secondary @xmath2 pairs from the ic cascade lose more energy on the synchrotron process . that s way , the synchrotron x - ray spectra are on the higher level for larger @xmath59 . 12.2truecm the distances of the periastron passage , @xmath75 , for both models are very similar ( table 1 ) , but distances of the apoastron passage , @xmath76 , differ significantly . this can explain the stronger absorption features in the case of the ic cascade spectrum at the apoastron in the case of parameters proposed by grundstrom et al . . however the steeper cascade ic spectra obtained at the periastron for the casares et al . ( 2005 ) parameters has to be related to the differences in the angle of the periastron passage in respect to the location of the observer . note , that in most of the considered cases ( e.g. figures a , c , e , f ) , the gev @xmath1-ray fluxes does not change drastically between the periastron and apoastron passages . therefore , it is likely that observed strong modulation of the tev @xmath1-ray emission with the period of the binary system may not be observed by the _ lat detector in the gev energies . the synchrotron spectra have more complicated shape due two the components produced by primary electrons and secondary @xmath2 pairs . the strength of the component produced by secondary @xmath2 pairs strongly depends on the surface magnetic field of the massive star , @xmath59 , and on the distribution of the magnetic field around the star . in general , for stronger @xmath59 , the synchrotron spectrum from secondary @xmath2 pairs is stronger ( see dashed curves in fig . [ fig1 ] ) , reaching saturation for @xmath84 g. at the apoastron passage , the second synchrotron bump becomes comparable to the first bump only for the largest considered values of the surface magnetic field of the massive star , i.e. @xmath85 g. note that a part of primary electrons can likely escape from the transition region with the matter which can be expelled along the rotational axis of the magnetar , i.e. within the possible transient jet which is sometimes expected in the case of the accretion process occurring in the propeller regime . the synchrotron emission of these electrons in the jet is not taken into account in this calculations . in this simple model , the conversion coefficient of energy from the transition region to relativistic electrons , @xmath41 , is kept independent on the phase of the binary system . however , @xmath41 may also depend on the accretion rate ( i.e. a distance between the stars ) in the way which is at present unknown . therefore , any absolute normalization of the spectra is problematic since it may vary with the phase of the binary system , e.g. as observed in the hard x - rays ( chernyakova et al . only detailed phase dependent multi - wavelength observations can put constraints on the injection details of electrons at different phases of the binary system . we show that strongly magnetized , accreting neutron stars ( magnetars ) close to the massive stars inside the binary systems can be responsible for the acceleration of electrons up to tev energies . these electrons interact with the magnetic field of the inner magnetosphere of the magnetar and with the soft radiation field from the massive companion producing x - rays ( synchrotron process ) and @xmath1-rays ( inverse compton process ) . a part of injected @xmath1-rays can be absorbed in the radiation of massive star developing ic @xmath2 pair cascade . secondary @xmath2 pairs lose significant part of their energy on the synchrotron emission . the @xmath1-ray spectra produced in such scenario can extend up to tev energies and the synchrotron spectra can extend up to mev energies . the processes discussed above concern to a specific stage in the evolution of the binary system , when the accretion rate onto the neutron star is at the range which guarantee the propeller phase . in fact , this phase may be short lived due to the variable wind from the massive star . when the accretion rate is different , the magnetar can move to the ejector or the accretor phase during which different scenarios should be considered . for example in the accretor phase the magnetar can gain angular momentum with the accreting matter and decrease its rotational period as expected in the case of the millisecond pulsars . we expect ( based on the comparison of eq . [ eq16 ] and [ eq17 ] ) that the propeller phase of the accretion onto the neutron star , in which observable fluxes of @xmath1-rays can be detected , is relatively short lived . this may explain a small number of massive binaries discovered up to now in the tev @xmath1-rays . applying the parameters of the binary system lsi + 61 303 , we show that such a model can explain the tev @xmath1-ray emission observed close to the apoastron passage of the neutron star . the lack of observable tev emission from the parts of the orbit close to the periastron is due to the inefficient acceleration of electrons and the suppression of the tev @xmath1-rays in the ic @xmath2 cascade process in which also the synchrotron energy losses play an important role . this work is supported by the polish mniszw grant n n203 390834 . acciari , v.a . 2008 , apj 679 , 1427 albert , j. et al . 2006 , science 312 , 1771 albert , j. et al . 2008 , apj 684 , 1351 baan , w.a . , treves , a. 1973 , a&a 22 , 421 bednarek , w. 1997 , mnras 285 , 69 bednarek , w. 2000 , a&a 362 , 646 bednarek , w. 2008 , arxiv0806.3616 casares , j. , ribas , i. , paredes , j.m . , marti , j. , allende prieto , c. 2005 , mnras 360 , 1105 chernyakova , m. , neronov , a. , walter , r. 2006 , mnras 372 , 1585 dubus , g. , giebels , b. 2008 , atel # 1715 grundstrom , e.d . 2007 , apj 656 , 437 harmanec , p. 1988 , 39 , 329 kniffen , d.a . et al . 1997 , apj 486 , 126 ray p.s . , hartman , j.m . 2008 , atel # 1730 rea , n. , torres , d.f . 2008 , atel # 1731 smith , a.w . 2008 , arxiv00810.0668 tavani , m. et al . 1996 , a&as 120 , 243 van dijk , r. et al . 1996 , a&a 315 , 485 usov , v.v . , melrose , d.b . 1992 , apj 395 , 575

we consider the neutron star ( ns ) of the magnetar type inside the massive binary system . we determine the conditions under which the matter from the stellar wind can penetrate the inner magnetosphere of the magnetar . at some distance from the ns surface , the magnetic pressure can balance the gravitational pressure of the accreting matter creating very turbulent , magnetized transition region . it is suggested that this region provides good conditions for acceleration of electrons to relativistic energies . these electrons lose energy on the synchrotron process and the inverse compton ( ic ) scattering of the radiation from the nearby massive stellar companion , producing high energy radiation from the x - rays up to @xmath0tev @xmath1-rays . the primary @xmath1-rays can be farther absorbed in the stellar radiation developing the ic @xmath2 pair cascade . we calculate the synchrotron x - ray emission from primary electrons and secondary @xmath2 pairs and the ic @xmath1-ray emission from the cascade process . it is shown that the quasi - simultaneous observations of the tev @xmath1-ray binary system lsi + 61 303 in the x - ray and the tev @xmath1-ray energy ranges can be explained in such an accreting magnetar model . [ firstpage ] stars : binaries : close stars : individual : ls i + 61 303 stars : neutron radiation mechanisms : non - thermal gamma - rays : theory

AFP Copyright: AFP The claim of the lorry attack in Berlin by so-called Islamic State (IS) does not prove much in terms of the attack. The group often refers to individuals who carry out attacks as its "soldiers" but the crucial question is firstly whether the individual had any form of direct contact with IS. Face-to-face or online communication are possible but far from certain. If there was no direct contact, it could still be the case that an individual was inspired rather than directed by the group. In this case, an individual may leave his or her own pledge of allegiance in written form or online or in a video. But until such evidence emerges, it remains hard to know if this is just an opportunistic claim by the group rather than one based on real substance. ||||| Firefighters attend an injured person after a truck ran into crowded Christmas market in Berlin, Germany, Monday, Dec. 19, 2016. Police said that several people have been killed. (AP Photo/Michael Sohn) (Associated Press) Firefighters attend an injured person after a truck ran into crowded Christmas market in Berlin, Germany, Monday, Dec. 19, 2016. Police said that several people have been killed. (AP Photo/Michael Sohn) (Associated Press) BERLIN (AP) — Police said Tuesday that the driver who rammed a truck into a crowded Christmas market in the heart of the German capital, killing at least 12 people and injuring nearly 50, did so intentionally and that they are investigating a suspected "terror attack." The truck struck the popular Christmas market filled with tourists and locals outside the Kaiser Wilhelm Memorial Church near Berlin's Zoo station late Monday. "Our investigators are working on the assumption that the truck was intentionally driven into the crowd at the Christmas market on Breitscheidplatz," Berlin police said on Twitter. "All police measures concerning the suspected terror attack at Breitscheidplatz are being taken with great speed and the necessary care," they said. Numerous German media reported that the suspect, who was picked up about 2 kilometers (1½ miles) from the crash site, was a Pakistani citizen. Footage showed the suspect, his head covered in a white sheet, being pushed into a police car shortly after the attack. Berlin's public radio station RBB-Inforadio cited security sources saying the man entered Germany on Dec. 31, 2015. News agency dpa, also citing unnamed security sources, said he came to Germany as a refugee in February 2016. Berlin's Tagesspiegel newspaper reported that the man was known to police for minor crimes. Police declined to comment on the reports, referring questions to federal prosecutors who said they would hold a news conference Tuesday afternoon. A spokesman for Berlin's office for refugee affairs said police conducted a large-scale search overnight at a large shelter for asylum-seekers at the city's now-defunct Tempelhof airport overnight. Four men in the late 20s were questioned but nobody was arrested, Sascha Langenbach told The Associated Press. Among the dead was a man in the truck, who succumbed as paramedics treated him, Berlin police spokesman Winfried Wenzel said. Police said later that the man was a Polish national, but didn't give further details of who he was or what happened to him. The Polish owner of the truck said he feared the vehicle may have been hijacked. Ariel Zurawski said he last spoke with the driver, his cousin, around noon, and the driver told him he was in Berlin and scheduled to unload Tuesday morning. "They must have done something to my driver," he told TVN24. In the immediate aftermath of the attack German officials were cautious in characterizing what had happened. "I don't want to use the word 'attack' yet at the moment, although a lot speaks for it," Interior Minister Thomas de Maiziere told ARD television late Monday. "There is a psychological effect in the whole country of the choice of words here, and we want to be very, very cautious and operate close to the actual investigation results, not with speculation." Germany has not experienced any mass-casualty attacks by Islamic extremists, but has been increasingly wary since two attacks by asylum-seekers in the summer that were claimed by the Islamic State group. Five people were wounded in an ax rampage on a train near Wuerzburg and 15 in a bombing outside a bar in Ansbach, both in the southern state of Bavaria. Both attackers were killed. Those attacks, and two others unrelated to Islamic extremism in the same weeklong period, contributed to tensions in Germany over the arrival last year of 890,000 migrants. Far-right groups and a nationalist party seized on Monday's attack, blaming German Chancellor Angela Merkel for what had happened. "Under the cloak of helping people Merkel has completely surrendered our domestic security," Frauke Petry, the co-chairwoman of the Alternative for Germany party, wrote. Manfred Weber, a member of Merkel's conservative party and leader of the European Parliament's biggest political grouping, cautioned against sweeping verdicts but said it was important to ensure that extremists didn't enter the country. "The state must be able to check every refugee who comes here," he told German public broadcaster ARD. French Interior Minister Bruno Le Roux expressed his sympathy after the attack. "We are all Berliners today," he told Europe-1 radio Tuesday. "In this type of situation, we need unity to face down terrorists, and on this occasion we need European unity. It must be strong, particularly strong." The White House condemned "what appears to have been a terrorist attack." It came less than a month after the U.S. State Department warned that extremist groups including Islamic State and al-Qaida were focusing "on the upcoming holiday season and associated events" in Europe. The Islamic State group and al-Qaida have both called on followers to use trucks in particular to attack crowds. On July 14, a truck plowed into Bastille Day revelers in the southern French city of Nice, killing 86 people. Islamic State claimed responsibility for that attack, which was carried out by a Tunisian living in France. Federal prosecutors, who handle terrorism cases, took over the investigation, according to German Justice Minister Heiko Maas. In Washington, White House National Security Council spokesman Ned Price said the United States was ready to help in the investigation and response. U.S. President-elect Donald Trump Islamic extremists must be "eradicated from the face of the earth" and pledged to carry out that mission with all "freedom-loving partners." Berlin's mayor, Michael Mueller, planned to hold a news conference on the attack at 1 p.m. (1200 GMT). The archbishop of Berlin, Heiner Koch, said he would hold prayers for the victims at the St. Hedwig Cathedral at noon. ___ Associated Press writers David Rising and Geir Moulson in Berlin and Angela Charlton in Paris contributed to this report. ||||| President-elect Donald Trump condemned the attack in Berlin, after a driver ploughed a lorry through a crowded Christmas market in the centre of Berlin. At least 12 people died in the alleged attack, while almost 50 others sustained injuries. The driver fled the scene, but police say they have arrested a suspect they believe was at the wheel. The passenger in the vehicle died at the scene. The incident was reminiscent of an attack in Nice, France, when a lorry driver drove through a crowded outdoor celebration for Bastille Day on 14 July. Isis later claimed responsibility for the attack, calling the truck driver a “soldier”. Follow the latest updates here But the motivation behind Monday’s deadly episode remains unclear. Still, the President-elect was quick to blame Isis and radical Islamist groups – before investigators could issue any confirmation. Berlin Christmas market lorry attack 18 show all Berlin Christmas market lorry attack 1/18 Several people have been killed after a lorry drove into crowds at a Christmas market in Berlin REUTERS/Fabrizio Bensch 2/18 'At least nine' people have been killed and more than 50 injured. AP 3/18 Emergency Services rush a Berlin market victim to an ambulance Associated Press 4/18 Police cordoned off the square at Kaiser Wilhelm Memorial Church following the incident REUTERS 5/18 Rescue workers inspect the lorry that crashed into a Christmas market close to the Kaiser Wilhelm memorial church in Berlin EPA 6/18 Emergency crews inspect the lorry that ploughed into a Berlin Christmas market, killing at least nine people AFP 7/18 Fire crews attend the scene of the attack AFP/Getty 8/18 Armed police secure the site of a lorry attack at a Christmas market in Berlin REUTERS 9/18 Crushed debris is visible beneath the wheels of the vehicle REUTERS 10/18 An injured man is pushed to an ambulance REUTERS 11/18 Medics attend an injured person after the lorry attack which killed at least nine and injured more than 50 people AFP/Getty 12/18 Firefighters examine the lorry which was rammed into a Berlin Christmas market REUTERS 13/18 A person is carried into an ambulance REUTERS 14/18 View of the lorry that crashed into a Christmas market in Berlin, killing at least nine and injuring at least 50 people AFP/Getty 15/18 Rescue workers push a person on a stretcher to an ambulance Getty 16/18 Firefighters assess the damage after the lorry rammed the Christmas market, killing 'at least nine', and injuring more than 50 people AP 17/18 Firefighters stand beside a toppled Christmas tree at the site of the suspected terrorist attack in a Berlin Christmas market AP 18/18 Damaged stalls at the scene of the incident at a Berlin Christmas market where at least nine people have been killed EPA “Our hearts and prayers are with the loved ones of the victims of today's horrifying terror attack in Berlin,” Mr Trump said. “Innocent civilians were murdered in the streets as they prepared to celebrate the Christmas holiday.” He added: “Isis and other Islamist terrorists continually slaughter Christians in their communities and places of worship as part of their global jihad. Berlin attack leaves 12 dead at Christmas markets “These terrorists and their regional and worldwide networks must be eradicated from the face of the earth, a mission we will carry out with all freedom-loving partners.” On Twitter, he elaborated on his warning. “Today there were terror attacks in Turkey, Switzerland, and Germany – and it is only getting worse,” he wrote. “The civilised world must change thinking!" But German officials have warned against using such extreme language before police could confirm the reason behind the incident. "I don't want to use the word 'attack' yet at the moment, although a lot speaks for it," said Germany's interior minister Thomas de Maizière. "There is a psychological effect in the whole country of the choice of words here, and we want to be very, very cautious and operate close to the actual investigation results, not with speculation." ||||| 06:56 De Maizière also confirms that the man who has been arrested on suspicion of carrying out the attack has denied the charges. The arrested man is from Pakistan, and arrived in Germany on 31 December 2015. He arrived in Berlin in February. The suspect spoke a dialect for which no translator could be found, the minister said. De Maizière says he is not giving much attention to the Isis message claiming responsibility for the attack. He confirms he will attend the vigil for the victims at 6pm in the memorial church on the square where the attack took place. De Maizière said police will not rest until they have completed their investigation into the attack. He urged once again for Christmas markets to remain open, but warned people to remain vigilant. He said it would be “a lovely idea to go to a Christmas market and buy a crib”. ||||| Are you in the area? Did you see what happened? You can WhatsApp us on +44 7435 939 154 to share your experiences and images. Please tag #CNNiReport in your message. Berlin (CNN) German authorities released a man and intensified their manhunt for the person who plowed a tractor-trailer truck into a crowd at a Berlin Christmas market , even as ISIS claimed Tuesday that it inspired the attack. Police said they didn't have enough evidence to hold a man they'd earlier described as a suspect in the Monday night truck assault that left 12 people dead and 48 injured. The dead include a man found shot inside the truck. There may be more than one suspect at large, armed and dangerous, Peter Frank, general prosecutor at Germany's Federal Court of Justice, told journalists. The ISIS-affiliated Amaq news agency released a statement saying Monday night's attack was carried out by "a soldier of the Islamic State" in response to calls by the group's leadership to target citizens of international coalition countries. CNN terrorism analyst Paul Cruickshank said ISIS often uses this terminology to refer to attacks by alleged sympathizers in the West. "This should not be taken to mean the group is claiming it directed this attack," Cruickshank said. "Investigators have not uncovered any links to ISIS." German authorities are investigating the attack as an act of terror. Chancellor Angela Merkel told journalists that we must "assume this is a terrorist attack." Latest developments Prosecutor: Forensic tests haven't confirmed man was in truck's cabin. Mourners pack nearby church at memorial for victims. Officials say several people could have been involved in the attack. A weapon used in the attack has not yet been found. Chancellor Angela Merkel visited the site where 12 people died. Attacker at large? Berlin police called on the public to remain alert as confusion swirled over who was driving when the truck barreled over a curb into the crowded market. "They're really back to square one in terms of this investigation. ... It may well be a scenario of a manhunt, a race against time to arrest this individual before they can strike again," Cruickshank said. German authorities released the man they'd detained after the attack. "The results of the investigation thus far have not produced imminent suspicion against the accused," the general prosecutor said in a statement. Investigators had initially described the asylum seeker they detained as a suspect. But a day later, they seemed to be backing off that claim. "We possibly need to assume that we have not arrested the right one," Frank said. "We do not know if there was one perpetrator or several perpetrators yet. We do not know if there was support given to the perpetrator." Authorities didn't release the identity of the man they detained. De Maiziere said earlier that the man was "probably from Pakistan." He entered Germany on December 31, 2015, Interior Minister Thomas De Maiziere said, and his application for asylum had stalled. So far, forensic tests haven't linked the man to the truck's cabin, the prosecutor said. Berlin police turned to the public for help and tweeted that they'd received 508 leads. Police also asked citizens to upload any digital video and photos of the incident or possible suspects. Bitte übersenden Sie Ihre Bild- und Videohinweise zum Ereignis #Breitscheidplatz an folgendes Upload-Portal:https://t.co/VgRGAV8AJB#Danke — PolizeiBerlinEinsatz (@PolizeiBerlin_E) December 20, 2016 Stalls shuttered at normally busy market While investigators searched for clues, the usually bustling Christmas market was eerily quiet, with stalls shuttered and nearby roads blocked off. The sounds of a choir singing rang out as a terrorism expert spoke to CNN near the market. "You have peace concerts, you have people laying down wreaths, you have people writing cards and people speaking silent prayers. This is completely unprecedented," said Peter Neumann, director of the International Center for the Study of Radicalization. "I don't think a lot of people are aware there's an attacker on the loose, potentially." Those unable to enter the packed building waited outside in the winter air, many hugging each other, crying, or silently clutching candles. Polish citizen found dead Police identified the man found shot to death inside the truck as the original driver from Poland, reported German state media ARD. He was not driving when the truck came through the market, police said. The gun has not been recovered, De Maiziere said. The truck, which was owned by a Polish company, "was steered deliberately into the crowd," police said. It was carrying 25 tons of steel, according to Ariel Zurawski, the owner of the truck company. Zurawski told CNN affiliate TVN 24 the vehicle may have been hijacked. Zurawski identified the slain man as his cousin, ARD said. Photos: Truck plows through Berlin Christmas market Authorities examine a truck Tuesday, December 20, that crashed into a crowded Christmas market in Berlin the night before. At least 12 people were killed and 48 injured in what police are investigating as a likely terrorist attack. Hide Caption 1 of 18 Photos: Truck plows through Berlin Christmas market Emergency responders tow the truck's cab away from the crash site on December 20. Ariel Zurawski, owner of the truck company, said the truck may have been hijacked as it was transporting 25 tons of steel. Hide Caption 2 of 18 Photos: Truck plows through Berlin Christmas market An overview of the crash site on December 20 shows where the tractor-trailer drove over the sidewalk and into market stalls near the Kaiser Wilhelm Memorial Church. Hide Caption 3 of 18 Photos: Truck plows through Berlin Christmas market A rescue worker stands beside Christmas decorations that were scattered by the crash. Hide Caption 4 of 18 Photos: Truck plows through Berlin Christmas market Members of the press crowd around the crash site on December 20. Hide Caption 5 of 18 Photos: Truck plows through Berlin Christmas market A rescue worker looks at destroyed market stalls near the truck's trailer. Hide Caption 6 of 18 Photos: Truck plows through Berlin Christmas market Authorities investigate the crash site on December 20. Hide Caption 7 of 18 Photos: Truck plows through Berlin Christmas market Emergency responders treat an injured person on Monday, December 19. Hide Caption 8 of 18 Photos: Truck plows through Berlin Christmas market German police shine a flashlight onto the back of the truck. Hide Caption 9 of 18 Photos: Truck plows through Berlin Christmas market Emergency crews work near the crash site on December 19. Hide Caption 10 of 18 Photos: Truck plows through Berlin Christmas market Police officers stand next to the truck. Hide Caption 11 of 18 Photos: Truck plows through Berlin Christmas market Ambulances are seen where the incident happened in western Berlin. Hide Caption 12 of 18 Photos: Truck plows through Berlin Christmas market Police stand beside the damaged truck that crashed into the market. Hide Caption 13 of 18 Photos: Truck plows through Berlin Christmas market First responders load an injured person into an ambulance. Hide Caption 14 of 18 Photos: Truck plows through Berlin Christmas market A Christmas tree lies next to the truck. Hide Caption 15 of 18 Photos: Truck plows through Berlin Christmas market Police take someone into custody near the market. Hide Caption 16 of 18 Photos: Truck plows through Berlin Christmas market Police stand guard at the market after the crash. Hide Caption 17 of 18 Photos: Truck plows through Berlin Christmas market An armed police officer stands near the scene. Hide Caption 18 of 18 Scene of the Christmas market attack in Berlin. Zurawski said that his cousin was happy to be finishing his route from Italy to Berlin and was looking forward to returning to Poland after one last leg to Denmark. "He was asking if he should be back home by Thursday night because he still needed to buy a Christmas gift for his wife," he said. Merkel: 'Hard to bear' saying earlier it would be "especially disgusting" if anyone in the attack had been given asylum. Merkel visited the scene of the attack,saying earlier it would be "especially disgusting" if anyone in the attack had been given asylum. Dressed in black and making her first public comments about the incident late Tuesday morning, she called for unity in the country. "I know that it would be especially hard to bear for us if it was to be confirmed that a person (who) committed this act ... was given protection and asylum in Germany," Merkel said. "This is a very difficult day. I, like millions of people in Germany, am horrified and deeply sad about what happened yesterday in Berlin." German Chancellor Angela Merkel arrives to give a statement the day after the Berlin attack. Monday's attack could cause further political upheaval for Merkel, who has come under criticism over her government's generous acceptance of refugees. Germany has taken in more than 890,000 asylum-seekers in the past year, a much higher number than other European nations. But a backlash has been growing, fueled in part by Islamist terror attacks in Germany and across the continent. World leaders, including US President Obama and French President Francois Hollande, expressed support for Merkel and the German people. 'It felt like slow motion' Before the attack on Monday evening it was a quintessential German Christmas scene at Breitscheidplatz: Trees strung with lights, vendors serving candied fruit and waffles, the smell of gluhwein -- German mulled wine -- wafting through the cold December air. Authorites inspect a truck that sped into a Christmas market in Berlin. American Shandana Durrani was at the market, at the foot of the Keiser Wilhelm Memorial Church, and had stopped to reply to a text message when the truck rammed into the crowd at around 8 pm. She was lucky to have stopped, she said, as the truck mounted the curb, mowing people and stalls down just 20 feet in front of her, sending everyone "running, scurrying, screaming." "I heard some popping and thought maybe there was a guy with a gun," she told CNN. "People just started running and dropping their gluhwein." View of the truck that crashed into a Christmas market at Gedächtniskirche church in Berlin. She said that it looked as if the driver had just mounted the curb and lost control, and that the whole thing probably lasted a mere 10 seconds. "It probably didn't last very long, but it felt like it was in slow motion (as I ) tried to get away from it." Security concerns De Maiziere said that Christmas markets would be closed Tuesday for a day of mourning. "But to cancel them would be wrong," he said, adding they would hopefully reopen the following day. Münch, of the Federal Criminal Office, said that authorities had assessed the likelihood of an attack at Christmas markets recently. Security officers guard the area after the Berlin Christmas market attack. The attack is similar to one in Nice, France, in July, when a truck rammed into a crowd gathered to see Bastille Day fireworks, killing 86 and injuring more than 200 people Terror groups including ISIS and a branch of al Qaeda have encouraged their followers to use vehicles to stage attacks The US and UK governments had warned their citizens of potential security threats in Germany. ||||| Image copyright AP Image caption Police have been patrolling other Christmas markets across Germany such as this one in Frankfurt The German authorities say they cannot be sure if a man in custody was behind Monday's lorry attack on a Berlin Christmas market that killed 12 people. "We have to entertain the theory that the detainee might possibly not have been the perpetrator," federal prosecutor Peter Frank told reporters. The style of attack and the target suggested Islamic extremism, he said. A vigil has been held at the Kaiser Wilhelm Memorial Church, right next to the scene of the attack. The man detained, who has denied involvement, arrived in Germany from Pakistan at the end of last year. He was captured in a park after reportedly fleeing the scene. Before attending the vigil, German Chancellor Angela Merkel vowed to punish those responsible for the attack "as harshly as the law requires". Media playback is unsupported on your device Media caption Berlin resident Ibrahim Colak: "I saw whole bodies being twisted" Her open-door policy on migration, which saw 890,000 asylum seekers arrive in Germany last year, has divided the country, with critics calling it a security threat. US President Barack Obama has called Mrs Merkel to offer his condolences and American assistance in defeating "terrorism in all of its forms". At about 20:14 local time (19:14 GMT) on Monday, the lorry ploughed through the popular market at Breitscheidplatz, near west Berlin's main shopping street, the Kurfuerstendamm. Along with the dead, 49 people were injured, 14 of them seriously. As of Tuesday afternoon, 24 of the injured had been released from hospital. The interior ministry said Christmas markets in Berlin would remain closed on Tuesday but other markets outside of the capital would operate as normal. Media playback is unsupported on your device Media caption The BBC's Jenny Hill: "What's really eerie is that the lights are still twinkling in what remains of the market" What do we know about the suspect? German media have identified him as Naved B, 23, who was reportedly known to police for minor crimes, but not terrorist links. He arrived in Germany on 31 December of last year and his asylum application was still in progress. Image copyright Reuters Image caption The asylum shelter at Berlin's former Tempelhof airport was raided He was seized near the Victory Column monument, 2km (1.2 miles) from the lorry attack scene, after fleeing towards the Tiergarten park. A bystander had been tracking the driver of the lorry after seeing him jump out of the cabin, and had led police to the suspect. Special forces on Tuesday stormed a hangar at Berlin's defunct Tempelhof airport, where they believed he had been living in a shelter with other migrants. Police are examining a mobile phone they seized during the search there. Who was the first known victim? The usual driver of the lorry, Polish citizen Lukasz Urban, was found dead on the passenger seat of the lorry, reportedly with gunshot and stab wounds to his body. No gun was recovered. Image copyright AFP Image caption The lorry ploughed through the market, destroying Christmas trees and stalls Image copyright AFP Image caption The popular market is near the historic Kaiser Wilhelm Memorial Church Mr Urban, 37, had been working for his cousin Ariel Zurawski, the Polish owner of the lorry, who said he had last been in contact at 16:00 (15:00 GMT) on Monday. Lukasz Wasik, the manager of the transport company, told Polish TV Mr Urban had been a "good, quiet and honest person'' devoted to his work. "I believe he would not give up the vehicle and would defend it to the end if were attacked," Mr Wasik said. How has Germany responded to the attack? Chancellor Merkel expressed her concern that the attacker might turn out to be an asylum seeker. Image copyright PA Image caption People gathered near the attack site with candles on Tuesday to mourn the victims Image copyright Reuters Image caption Mrs Merkel (centre) and other politicians attended a commemoration in the Kaiser Wilhelm Memorial Church "I know that it would be particularly difficult for us all to bear if it turned out that the person who committed this act was someone who sought protection and asylum in Germany," she said. The co-leader of Germany's anti-immigration AfD party, Frauke Petry, blamed Mrs Merkel's liberal policy on migrants. "The milieu in which such acts can flourish has been negligently and systematically imported over the past year and a half," she said. Horst Seehofer, the leader of Mrs Merkel's sister party in Bavaria, urged the chancellor "to rethink our immigration and security policy and to change it". Media playback is unsupported on your device Media caption Vice chair of German right wing party tells The World at One that Chancellor Merkel is to blame for attack Your questions on security in public spaces Is this attack unprecedented? Monday's incident mirrored the lorry attack on Bastille Day crowds in the French city of Nice on 14 July, claimed by so-called Islamic State (IS). A year of terror in Germany Both IS and al-Qaeda have urged their followers to use vehicles as a means to attack crowds. At the end of 2014, a van was driven into pedestrians at a Christmas market in the French city of Nantes, injuring 10 people. Last week, German prosecutors said a 12-year-old German-Iraqi boy was in custody on suspicion of plotting to blow up a Christmas market in the western town of Ludwigshafen.

– Police said Tuesday that the driver who rammed a truck into a crowded Christmas market in the heart of the German capital, killing at least 12 people and injuring nearly 50, did so intentionally and that they are investigating a suspected terror attack, the AP reports. The truck struck the popular Christmas market filled with tourists and locals outside the Kaiser Wilhelm Memorial Church near Berlin's Zoo station late Monday. On Tuesday, conflicting reports emerged about the suspected driver, and whether police had the right man. The latest: The BBC reports that the suspect in custody has been identified in German media reports as a 23-year-old Pakistani man named "Naved B" who entered Germany as a refugee in December 2015. After fleeing the scene of the attack on foot, he was captured more than a mile away. Police say a witness followed him. He has reportedly denied involvement. But according to German newspaper Die Welt's unnamed senior security sources, he's not the right guy. Reuters has this translation: "We have the wrong man ... the true perpetrator is still armed, at large and can cause fresh damage." German Chancellor Angela Merkel says it would be "particularly repugnant" if the attacker came to the country as a refugee, the Guardian reports. "We have to assume we are dealing with a terrorist attack," she said in a statement, promising that the perpetrators would be severely punished. Police say that an injured Polish man found in the truck died as he was being treated for his wounds. He is believed to have been the original driver of the truck, whose owner, his cousin, told authorities the truck must have been hijacked, the AP reports. Donald Trump blamed the attack on "Islamist terrorists," the Independent reports. "ISIS and other Islamist terrorists continually slaughter Christians in their communities and places of worship as part of their global jihad," he said. "These terrorists and their regional and worldwide networks must be eradicated from the face of the Earth, a mission we will carry out with all freedom-loving partners." American witness Shandana Durrani tells CNN that she was in the market when the truck started mowing down people as they were "running, scurrying, screaming" just 20 feet in front of her. "I heard some popping and thought maybe there was a guy with a gun," she says. "People just started running and dropping their gluehwein."

SECTION 1. SHORT TITLE. This Act may be cited as the ``Orphan Products Extension Now Accelerating Cures and Treatments Act of 2017'' or the ``OPEN Act''. SEC. 2. EXTENSION OF EXCLUSIVITY PERIODS FOR A DRUG APPROVED FOR A NEW INDICATION FOR A RARE DISEASE OR CONDITION. (a) In General.--The Federal Food, Drug, and Cosmetic Act is amended by inserting after section 505F of such Act (21 U.S.C. 355g) the following: ``SEC. 505G. EXTENSION OF EXCLUSIVITY PERIODS FOR A DRUG APPROVED FOR A NEW INDICATION FOR A RARE DISEASE OR CONDITION. ``(a) Designation.-- ``(1) In general.--The Secretary shall designate a drug as a drug approved for a new indication to prevent, diagnose, or treat a rare disease or condition for purposes of granting the extensions under subsection (b) if-- ``(A) prior to approval of an application or supplemental application for the new indication, the drug was approved or licensed under section 505(c) of this Act or section 351(a) of the Public Health Service Act but was not so approved or licensed for the new indication; ``(B)(i) the sponsor of the approved or licensed drug files an application or a supplemental application for approval of the new indication for use of the drug to prevent, diagnose, or treat the rare disease or condition; and ``(ii) the Secretary approves the application or supplemental application; and ``(C) the application or supplemental application for the new indication contains the consent of the applicant to public notice under paragraph (4) with respect to the designation of the drug. ``(2) Revocation of designation.-- ``(A) In general.--Except as provided in subparagraph (B), a designation under paragraph (1) shall not be revoked for any reason. ``(B) Exception.--The Secretary may revoke a designation of a drug under paragraph (1) if the Secretary finds that the application or supplemental application resulting in such designation contained an untrue statement of material fact. ``(3) Notice to public.--The Secretary shall provide public notice of the designation of a drug under paragraph (1). ``(b) Extension.-- ``(1) In general.--If the Secretary designates a drug as a drug approved for a new indication for a rare disease or condition, as described in subsection (a)(1)-- ``(A)(i) the 4-, 5-, and 7\1/2\-year periods described in subsections (c)(3)(E)(ii) and (j)(5)(F)(ii) of section 505, the 3-year periods described in clauses (iii) and (iv) of subsection (c)(3)(E) and clauses (iii) and (iv) of subsection (j)(5)(F) of section 505, and the 7-year period described in section 527, as applicable, shall be extended by 6 months; or ``(ii) the 4- and 12-year periods described in subparagraphs (A) and (B) of section 351(k)(7) of the Public Health Service Act and the 7-year period described in section 527, as applicable, shall be extended by 6 months; and ``(B)(i) if the drug is the subject of a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of section 505 or a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of section 505, the period during which an application may not be approved under section 505(c)(3) or section 505(j)(5)(B) shall be extended by a period of 6 months after the date the patent expires (including any patent extensions); or ``(ii) if the drug is the subject of a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certification the court determines that the patent is valid and would be infringed, the period during which an application may not be approved under section 505(c)(3) or section 505(j)(5)(B) shall be extended by a period of 6 months after the date the patent expires (including any patent extensions). ``(2) Relation to pediatric and qualified infectious disease product exclusivity.--Any extension under paragraph (1) of a period shall be in addition to any extension of the periods under sections 505A and 505E of this Act and section 351(m) of the Public Health Service Act, as applicable, with respect to the drug. ``(c) Limitations.--Any extension described in subsection (b)(1) shall not apply if the drug designated under subsection (a)(1) has previously received an extension by operation of subsection (b)(1). ``(d) Definition.--In this section, the term `rare disease or condition' has the meaning given to such term in section 526(a)(2).''. (b) Application.--Section 505G of the Federal Food, Drug, and Cosmetic Act, as added by subsection (a), applies only with respect to a drug for which an application or supplemental application described in subsection (a)(1)(B)(i) of such section 505G is first approved under section 505(c) of such Act (21 U.S.C. 355(c)) or section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)) on or after the date of the enactment of this Act. (c) Conforming Amendments.-- (1) Relation to pediatric exclusivity for drugs.--Section 505A of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355a) is amended-- (A) in subsection (b), by adding at the end the following: ``(3) Relation to exclusivity for a drug approved for a new indication for a rare disease or condition.--Notwithstanding the references in paragraph (1) to the lengths of the exclusivity periods after application of pediatric exclusivity, the 6-month extensions described in paragraph (1) shall be in addition to any extensions under section 505G.''; and (B) in subsection (c), by adding at the end the following: ``(3) Relation to exclusivity for a drug approved for a new indication for a rare disease or condition.--Notwithstanding the references in paragraph (1) to the lengths of the exclusivity periods after application of pediatric exclusivity, the 6-month extensions described in paragraph (1) shall be in addition to any extensions under section 505G.''. (2) Relation to exclusivity for new qualified infectious disease products that are drugs.--Subsection (b) of section 505E of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355f) is amended-- (A) by amending the subsection heading to read as follows: ``Relation to Pediatric Exclusivity and Exclusivity for a Drug Approved for a New Indication for a Rare Disease or Condition.--''; and (B) by striking ``any extension of the period under section 505A'' and inserting ``any extension of the periods under sections 505A and 505G, as applicable,''. (3) Relation to pediatric exclusivity for biological products.--Section 351(m) of the Public Health Service Act (42 U.S.C. 262(m)) is amended by adding at the end the following: ``(5) Relation to exclusivity for a biological product approved for a new indication for a rare disease or condition.--Notwithstanding the references in paragraphs (2)(A), (2)(B), (3)(A), and (3)(B) to the lengths of the exclusivity periods after application of pediatric exclusivity, the 6-month extensions described in such paragraphs shall be in addition to any extensions under section 505G.''.

Orphan Products Extension Now Accelerating Cures and Treatments Act of 2017 or the OPEN Act This bill amends the Federal Food, Drug, and Cosmetic Act to require the Department of Health and Human Services (HHS) to extend by six months the exclusivity period for a drug or biological product approved by the Food and Drug Administration (FDA) when the product is additionally approved to prevent, diagnose, or treat a new indication that is a rare disease or condition (also known as an orphan disease). HHS may revoke an extension if the application submitted to the FDA for the new indication contained an untrue material statement. HHS must notify the public of products that receive this extension and patents related to those products. Products may receive only one extension under this bill. Extensions under this bill are in addition to other extensions. The bill applies only to products approved after enactment of this bill for a new indication that is a rare disease or condition.

after the invention of the monte carlo ( mc ) paradigm by s. ulam in the late 1940s , it has become extremely popular in numerous application areas such as physics , biology , economics , social sciences , and other areas . as far as mathematics is concerned , monte carlo methods showed themselves exceptionally efficient in the simulation of various probability distributions , numerical integration , estimation of the mean values of the parameters , etc . @xcite . the salient feature of this approach to solution of various problems of this sort is that `` often , '' it is dimension - free in the sense that , given @xmath0 samples , the accuracy of the result does not depend on the dimension of the problem . on the other hand , applications of the mc paradigm in the area of optimization are not that triumphant . in this regard , problems of global optimization deserve special attention . as explained in @xcite ( see beginning of chapter 1.2 ) , `` _ _ in global optimization , randomness can appear in several ways . the main three are : ( i ) the evaluations of the objective function are corrupted by random errors ; ( ii ) the points @xmath1 are chosen on the base of random rules , and ( iii ) the assumptions about the objective function are probabilistic . _ _ '' pertinent to the exposition of this paper is only case ( ii ) . monte carlo is the simplest , brute force example of randomness - based methods ( in @xcite it is referred to as `` pure random search '' ) . with this method , one samples points uniformly in the feasible domain , computes the values of the objective function , and picks the record value as the output . of course , there are dozens of more sophisticated stochastic methods such as simulated annealing , genetic algorithms , evolutionary algorithms , etc . ; e.g. , see @xcite for an incomplete list of relevant references . however most of these methods are heuristic in nature ; often , they lack rigorous justification , and the computational efficiency is questionable . moreover , there exist pessimistic results on `` insolvability of global optimization problems . '' this phenomenon has first been observed as early as in the monograph @xcite by a. nemirovskii and d. yudin , both in the deterministic and stochastic optimization setups ( see theorem , section 1.6 in @xcite ) . specifically , the authors of @xcite considered the minimax approach to the minimization of the class of lipschitz functions and proved that , no matter what is the optimization method , it is possible to construct a problem which will require exponential ( in the dimension ) number of function evaluations . the `` same '' number of samples is required for the simplest mc method . similar results can be found in @xcite , theorem 1.1.2 , where the construction of `` bad '' problems is exhibited . below we present another example of such problems ( with very simple objective functions , close to linear ones ) which are very hard to optimize . concluding this brief survey , we see that any advanced method of global optimization can not outperform monte carlo when optimizing `` bad '' functions . this explains our interest in the mc approach as applied to the optimization setup . in spite of the pessimistic results above , there might be a belief that , if monte carlo is applied to a `` good '' optimization problem ( e.g. , a convex one ) , the results would not be so disastrous . the goal of the present paper is to clarify the situation . we examine the `` best '' optimization problems ( the minimization of a linear function on a ball or on a cube ) and estimate the accuracy of the monte carlo method . unfortunately , the dependence on the dimension remains exponential , and practical solution of these simplest problems via such an approach is impossible for high dimensions . the second goal of the paper is to exhibit the same situation with multiobjective optimization @xcite . we treat methods for the pareto set discovery via the monte carlo technique and estimate their accuracy , which happens to be poor for large dimensions . these results are instructive for multiobjective optimization , because there exist many methods based on a similar approach ( with regular grids instead of random grids ) , see @xcite . an intuitive explanation of the effects under consideration can rely on the geometric nature of multidimensional spaces . numerous facts of this sort can be found in chapter 2 of the book @xcite , which is available in the internet . the titles of sections in @xcite are very impressive : `` the volume is near the equator , '' `` the volume is in a narrow annulus , '' `` the surface area is near the equator . '' some of the results in the present paper clarify these statements by providing rigorous closed - form estimates for the minimum number of random points in the ball - shaped sets required to assess , with a given probability , the optimum of a linear function with given accuracy . these estimates are based on our previous results on the properties of the uniform distribution over a ball , @xcite ( see section 2.2 ) . as far as the geometry of many - dimensional spaces is concerned , the highly advanced monograph @xcite is worth mentioning ; it deals with the geometrical structure of finite dimensional normed spaces , as the dimension grows to infinity , and presents numerous deep mathematical results in the area . the rest of the paper is organized as follows . in section [ s : statement ] , we propose a motivating example , formulate the two optimization problems , scalar and multiobjective , considered within the monte carlo setup , and present two known theorems on the uniform distribution over the @xmath2-norm ball . these theorems will be used in section [ s : ball ] to derive new results related to the two optimization problems of interest for the case of the @xmath2-norm ball . section [ s : box ] deals with the scalar optimization problem for the case where @xmath3 is a box ; use of various deterministic grids are also discussed . brief concluding remarks are given in the last section . a preliminary version of this paper is @xcite . several refinements are performed in the current text ; first , we changed the overall structure of the exposition ; then , we provide a new result on the probability of the empirical maximum of a linear function on a ball ( section [ ssec : scalar ] ) , next , we add a result on the expected value ( end of section [ ssec : multiobj ] ) , present closed - form results for the @xmath4- and @xmath5-norm balls ( section [ ssec : boxmc ] ) , discuss deterministic grids over a box ( section [ ssec : lptau ] ) , and accompany these new results with numerical illustrations . finally , the introduction section and the bibliography list are considerably modified and extended and various typos and inaccuracies are corrected . in this section , we propose a motivation for the research performed in this paper , formulate the problems of interest , and present two known facts which form the basis for deriving the new results in section [ s : ball ] . to motivate our interest in the subject of this paper , we present a simple example showing failure of stochastic global optimization methods in high - dimensional spaces . this example is constructed along the lines suggested in @xcite ( also , see @xcite , theorem 1.1.2 ) and is closely related to one of the central problems discussed below , the minimization of a linear function over a ball in @xmath6 . consider an unknown vector @xmath7 , @xmath8 , and the function @xmath9 to be minimized over the euclidean ball @xmath10 of radius @xmath11 centered at the origin . obviously , the function has one local minimum @xmath12 , with the function value @xmath13 , and one global minimum @xmath14 , with the function value @xmath15 . the objective function is lipschitz with lipschitz constant equal to @xmath16 , and @xmath17 . any standard ( not problem - oriented ) version of stochastic global search ( such as multistart , simulated annealing , etc . ) will miss the domain of attraction of the global minimum with probability @xmath18 , where @xmath19 is the volume of the ball @xmath3 , and @xmath20 is the volume of the set @xmath21 . in other words , the probability of success is equal to @xmath22 where @xmath23 is the regularized incomplete beta function with parameters @xmath24 and @xmath25 ( for use of this function , also see theorem [ th : ball_maxlin ] in section [ s : ball ] ) , and @xmath26 is the height of the spherical cap @xmath27 ; in this example , @xmath28 . this probability quickly goes to zero as the dimension of the problem grows ; say , for @xmath29 it is of the order of @xmath30 . hence , any `` advanced '' method of global optimization will find the minimum with relative error not less @xmath31 ; moreover , such methods are clearly seen to be no better than a straightforward monte carlo sampling . the same is true if our goal is to estimate the minimal value of the function @xmath32 ( not the minimum point @xmath33 ) . various methods based on ordered statistics of sample values ( see section 2.3 in @xcite ) fail to reach the set @xmath27 with high probability , so that the prediction will be close to @xmath13 instead of @xmath15 . these observations motivate our interest in the analysis of the performance of the mc schemes in optimization . let @xmath34 denote a unit ball in one or another norm and let @xmath35 be a multisample of size @xmath0 from the uniform distribution @xmath36 . we are targeted at solving the problems of the following sort . .1 in * i. scalar optimization : * given the scalar - valued linear function @xmath37 defined on the unit ball @xmath34 , estimate its maximum value from the multisample . more specifically , let @xmath38 be the true maximum of @xmath39 on @xmath3 and let @xmath40 be the empirical maximum ; we say that @xmath41 approximates @xmath38 _ with accuracy at least @xmath42 _ if @xmath43 then the problem is : _ given a probability level @xmath44 and accuracy @xmath45 , determine the minimal length @xmath46 of the multisample such that , with probability at least @xmath47 , the accuracy of approximation is at least @xmath42 ( i.e. , with high probability , the empirical maximum nicely evaluates the true one ) . _ these problems are the subject of discussion in sections [ ssec : scalar ] and [ ssec : boxmc ] . , 1 in * ii . multiobjective optimization : * consider now @xmath48 scalar functions @xmath49 , and the image of @xmath3 under these mappings . the problem is to `` characterize '' the boundary of the image set @xmath50 via the multisample @xmath51 from @xmath3 . in rough terms , the problem is : _ determine the minimal sample size @xmath46 which guarantees , with high probability , that the image of at least one sample fall close to the boundary of @xmath52_. for the case where @xmath3 is the euclidean ball , the mappings @xmath53 are linear , and @xmath54 , this problem is discussed in section [ ssec : multiobj ] ; various statistics ( such as the cumulative distribution function , mathematical expectation , mode ) of a specific random variable associated with image points are evaluated . the results presented in section [ s : ball ] below are based on the following two facts established in @xcite ; they relate to the probability distribution of a specific linear or quadratic function of the random vector uniformly distributed on the euclidean ball . * fact 1 * @xcite . _ let the random vector @xmath55 be uniformly distributed on the unit euclidean ball @xmath34 . assume that a matrix @xmath56 has rank @xmath57 . then the random variable @xmath58 has the beta distribution @xmath59 with probability density function @xmath60 where @xmath61 is the euler gamma function . _ .1 in alternatively , the numerical coefficient in writes @xmath62 , where @xmath63 is the beta function . .1 in the second fact is an asymptotic counterpart of fact 1 . .1 in * fact 2 * @xcite . _ assume that for every @xmath64 , the matrix @xmath65 has rank @xmath66 , and @xmath67 is a random vector uniformly distributed over the unit ball @xmath3 in @xmath68 . then , as @xmath69 , the random vector @xmath70 tends in distribution to the standard gaussian vector @xmath71 , where @xmath72 is the identity @xmath73-matrix . _ note that for @xmath74 fixed , we have @xmath75 i.e. , facts 2 and 1 characterize the asymptotic distribution of the vector @xmath76 and exact distribution of its squared norm ( normalized by the dimension ) . in this section we analyse the two optimization settings formulated in section [ two_settings ] for @xmath3 being the @xmath74-dimensional unit @xmath2-ball . we consider the scalar case and discuss first a qualitative result that follows immediately from fact 1 . without loss of generality , let @xmath77 , so that the function @xmath78 takes its values on the segment @xmath79 $ ] , and the true maximum of @xmath39 on @xmath3 is equal to @xmath16 ( respectively , @xmath80 for the minimum ) and is attained with @xmath81 ( respectively , @xmath82 ) . let us compose the random variable @xmath83 which is the squared first component @xmath84 of @xmath85 . by fact 1 with @xmath86 ( i.e. , @xmath87 ) , for the probability density function ( pdf ) of @xmath88 we have @xmath89 straightforward analysis of this function shows that , as dimension grows , the mass of the distribution tends to concentrate closer the origin , meaning that the random variable ( r.v . ) @xmath88 is likely to take values which are far from the maximum , equal to unity . to illustrate , fig . [ fig : pdf_rho ] depicts the plot of the pdf for @xmath90 . .,width=264 ] we next formulate the following rigorous result . [ th : ball_maxlin ] let @xmath85 be a random vector uniformly distributed over the unit euclidean ball @xmath3 and let @xmath78 , @xmath91 . given @xmath92 and @xmath93 , the minimal sample size @xmath46 that guarantees , with probability at least @xmath47 , for the empirical maximum of @xmath39 to be at least a @xmath42-accurate estimate of the true maximum , is given by @xmath94}\,,\ ] ] where @xmath23 is the regularized incomplete beta function with parameters @xmath24 and @xmath25 . .1 in clearly , a correct notation should be @xmath95 , i.e. , rounding toward the next integer ; we omit it , but it is implied everywhere in the sequel . .1 in _ proof _ we specify sample size @xmath0 , and let @xmath51 be a multisample from the uniform distribution on @xmath3 ; also introduce the random variable @xmath96 the empirical maximum of the function @xmath97 , @xmath98 , from this multisample . we now estimate the probability @xmath99 . by fact 1 , the pdf of the r.v . @xmath100 is given by , and its cumulative distribution function ( cdf ) is known to be referred to as the _ regularized incomplete beta function _ @xmath101 with parameters @xmath102 and @xmath103 , @xcite . due to the symmetry of the distribution of @xmath84 , we have @xmath104 , so that @xmath105 . respectively , @xmath106 and @xmath107^n$ ] , so that finally @xmath108^n.\ ] ] letting @xmath109 and inverting the last relation , we arrive at . .1 in numerical values of the function @xmath23 can be computed via use of the matlab routine betainc . for instance , with modest values @xmath110 , @xmath111 , and @xmath112 , this gives @xmath113 , and this quantity grows quickly as the dimension @xmath74 increases . since we are interested in small values of @xmath42 , i.e. , in @xmath114 close to unity , a `` closed - form '' lower bound for @xmath46 can be computed as formulated below . in the conditions of theorem [ th : ball_maxlin ] @xmath115}\,,\ ] ] where @xmath116 . _ proof _ we have @xmath117}\\ & = & 1 - \beta_n x^{-1/2}\int_0^{1-x}v^{(n-1)/2}{\rm d}v \qquad\quad \mbox { [ $ v=1-t$ ] } \\ & = & 1 - \beta_n\frac{2}{n+1}x^{-1/2}(1-x)^{(n+1)/2},\end{aligned}\ ] ] so that from we obtain @xmath118^n\ ] ] and @xmath119 } < n_{\min}.\ ] ] proof is complete . .1 in further simplification of the lower bound can be obtained : @xmath120 this is doable by noting that @xmath121 for small @xmath122 and using the approximation @xmath123 for the beta function with large @xmath25 . these lower bounds are quite accurate ; for instance , with @xmath110 , @xmath111 , and @xmath112 , we have @xmath124 , while @xmath125 and @xmath126 . consider a ( possibly nonlinear ) mapping @xmath127 , @xmath128 ; the goal is to characterize the boundary of the image of a set @xmath34 under the mapping @xmath129 . apart from being of independent interest , this problem emerges in numerous applications . in particular , if a special part of the boundary , the _ pareto front _ @xcite is of interest , we arrive at a multiobjective optimization problem . numerous examples ( e.g. , see @xcite ) show that , for @xmath74 large , the images of the points sampled randomly uniformly in @xmath3 may happen to fall deep inside the true image set , giving no reasonable description of the boundary and the pareto front of @xmath52 . we first present a qualitative explanation of this phenomenon by using the setup of fact 2 ; i.e. , the set @xmath3 is the unit euclidean ball and the mappings are linear . since the squared norm of a standard gaussian vector in @xmath130 has the @xmath131-distribution @xmath132 with @xmath66 degrees of freedom @xcite , from fact 2 and we obtain @xmath133 in distribution as @xmath134 . this is in compliance with the well - known result in the probability theory , namely , @xmath135 in distribution as @xmath136 , @xcite ; here , @xmath137 stands for the r.v . having the beta distribution with shape parameters @xmath138 . for @xmath139 ( i.e. , @xmath54 , the case most relevant to applications ) , fig . [ fig : beta_distr ] depicts the plots of the cumulative distribution functions @xmath137 ( see below for the explicit formula ) for @xmath140 ( i.e. , @xmath141 ) . for @xmath140.,width=340 ] hence , fact 2 immediately implies the following important conclusion : linear transformations essentially change the nature of the uniform distribution on a ball . namely , as the dimension of the vector @xmath85 grows , with the rank of the transformation matrix @xmath142 being unaltered , the distribution of the vector @xmath143 tends to `` concentrate closer the center '' of the image set . we now turn to fact 1 and provide quantitative estimates ; to this end , consider the simple case where @xmath54 and the two mappings are linear : @xmath144 ( i.e. , @xmath145 in the notation of fact 1 ) ; for instance , @xmath146 may be any two different unit coordinate vectors , so that @xmath147 and @xmath148 , @xmath149 , are the two different components of @xmath114 . then the image of @xmath3 is the unit circle centered at the origin . introduce now the random variable @xmath150 the squared norm of the image of @xmath151 under mapping ( i.e. , @xmath152 ) . then , by fact 1 with @xmath54 , we have the closed - form expressions for the cdf @xmath153 and pdf @xmath154 of the r.v . @xmath88 : @xmath155 @xmath156 with these in mind , let us evaluate the minimal length @xmath0 of the multisample that guarantees a given accuracy with a given probability . to this end , recall that , given a multisample @xmath157 from the scalar cdf @xmath158 with pdf @xmath159 , the random variable @xmath160 has the cumulative distribution function @xmath161 with pdf @xmath162 which is , in our case writes @xmath163 we next evaluate several statistics of the r.v . @xmath164 . the theorem below determines the minimal sample size @xmath46 that guarantees , with high probability , that a random vector @xmath36 be mapped close to the boundary of the image set . [ th : mapping_prob ] letting @xmath85 be the random vector uniformly distributed over the unit euclidean ball @xmath34 , consider the linear mapping @xmath165 as in . given @xmath92 and @xmath93 , the minimal sample size @xmath46 that guarantees , with probability at least @xmath47 , that at least one sample be mapped at least @xmath42-close to the boundary of the image set , is given by @xmath166 for small @xmath42 we have @xmath167 _ proof _ let us specify sample size @xmath0 and estimate the probability for a sample to be mapped close to the boundary of the image set . to this end , denote the image of @xmath36 under mapping by @xmath168 and introduce the r.v . @xmath169 the maximum of @xmath170 over the multisample @xmath51 . also , consider the r.v . @xmath171 for which we have @xmath172 and the r.v . @xmath173 , the maximum of @xmath88 over the multisample @xmath51 , for which we have @xmath174 hence , noting that @xmath175 , for a small @xmath176 ( i.e. , letting @xmath177 ) , we see that the probability for at least one sample @xmath178 to be mapped at least @xmath42-close to the boundary is equal to @xmath179 let @xmath92 be a desired confidence level ; then , letting @xmath180 and inverting the last relation , we obtain the minimal required length of the multisample . the simple approximation for @xmath46 follows from the fact that @xmath121 for small @xmath122 . @xmath181 .1 in to illustrate , for modest dimension @xmath110 , accuracy @xmath111 , and probability @xmath112 , one has to generate approximately @xmath182 random samples to obtain , with probability @xmath183 , a point which is @xmath42-close to the boundary of the image set . a sharper illustration of this phenomenon for @xmath184 is given in fig . [ fig : twodmap ] , which depicts the images of @xmath185 samples of @xmath36 under mapping . none of them falls closer than @xmath186 to the boundary of the image set . -dimensional ball and the result of the monte carlo sampling , width=302 ] qualitatively , such a behavior can be explained by using geometric considerations and simple projection - type arguments discussed in @xcite . the pdf can be shown to be unimodular , and we find its mode by straightforward differentiating . letting @xmath187 , for the pdf we have @xmath188 then @xmath189 writes @xmath190 simplifying , we obtain @xmath191 hence , @xmath192 we thus arrive at the following result . [ th : mode ] letting @xmath85 be the random vector uniformly distributed over the unit euclidean ball @xmath34 , consider the linear mapping @xmath165 as in and the random variable @xmath193 the empirical maximum of the function @xmath194 from the multisample @xmath51 of size @xmath0 . the mode of the distribution of @xmath41 is given by @xmath192 for large @xmath74 we have an approximation @xmath195 the quantity @xmath196 is seen to be essentially less than unity for large @xmath74 , even if the sample size @xmath0 is huge . this means the r.v . @xmath41 takes values far from the boundary of the image . and @xmath197 , @xmath198,width=302 ] for instance , let @xmath90 ; then , to `` obtain a point in the @xmath199 vicinity of the boundary , '' one has to generate @xmath200 random samples in @xmath3 . the family of the pdfs is plotted in fig . [ fig : eta_pdf ] . we now estimate the mathematical expectation @xmath201 of the empirical maximum . [ th : expect ] under the conditions of theorem [ th : mode ] we have @xmath202 where @xmath63 is the beta function . _ proof _ if a r.v . @xmath203 is positive and defined on @xmath204 $ ] , then the expectation @xmath205 where @xmath158 is the cdf of @xmath203 . hence , having @xmath0 samples @xmath178 of @xmath36 and the respective r.v . @xmath171 with support @xmath206 $ ] , for the r.v . @xmath207 we have @xmath208 where @xmath209 is given by . by change of variables @xmath210 , we arrive at .@xmath181 for large @xmath74 and @xmath0 , numerical values of the expectation are close to those observed for the mode ; this is seen from the shape of the pdf depicted in fig . [ fig : eta_pdf ] . more formally , having the approximation @xmath211 for large @xmath0 , from we obtain @xmath212 for instance , with @xmath90 and @xmath213 , we have @xmath214 for the expectation and @xmath215 for the mode . in this section , we consider the scalar optimization problem , however , for box - shaped sets , i.e , , not related to facts 1 and 2 . we consider the scalar setup described in section [ two_settings ] along with the deterministic approach based on use of regular grids . consider the linear scalar optimization problem for the case where @xmath216^n$ ] . clearly , the results heavily depend on the vector @xmath217 in the optimized function @xmath218 ; we consider two extreme cases . .1 in * case 1 . * first , let @xmath219 and consider the empirical maximum @xmath220 where @xmath221 is the first component of the random vector @xmath151 . specifying @xmath93 , we obtain @xmath222 this quantity is seen to be independent of the dimension ( which is obvious as it is ) . now , specifying a probability level @xmath223 $ ] , we obtain that the minimal required sample size that guarantees accuracy @xmath42 with probability @xmath47 is equal to @xmath224 for instance , with @xmath225 and @xmath226 , one has to generate just @xmath227 points to obtain a @xmath228-accurate estimate of the maximum with probability @xmath183 , independently of the dimension . .1 in * case 2 . * now let @xmath229 ; i.e. , the optimized function is @xmath230 , so that the maximum is attained at @xmath231 and is equal to @xmath232 . in contrast to case 1 , monte carlo sampling exhibits a totally different behavior . below , @xmath233 stands for the volume of a set . [ th : box_diag ] letting @xmath85 be the random vector uniformly distributed over the unit @xmath4-norm ball @xmath234^n$ ] , consider the linear function @xmath230 . given @xmath92 and @xmath93 , @xmath235 , the minimal sample size @xmath46 that guarantees , with probability at least @xmath47 , for the empirical maximum of @xmath39 to be at least a @xmath42-accurate estimate of the true maximum , is given by @xmath236 for small @xmath42 and large @xmath74 we have @xmath237 _ proof _ let us specify a small @xmath238 and define @xmath239 so that the maximum of @xmath39 , over @xmath240 is equal to @xmath241 . for @xmath235 , the set @xmath242 is seen to be the simplex with @xmath243 vertices at the points @xmath244 and @xmath245 with @xmath246 . since @xmath247 , for @xmath36 we have @xmath248 so that @xmath249 equating this probability to @xmath47 and inverting this relation leads to . the lower bound follows immediately from stirling s formula and the fact that @xmath121 for small @xmath122.@xmath181 for @xmath110 and the same values @xmath250 and @xmath112 , we obtain a huge @xmath251 . even for @xmath252 , an `` unexpectedly '' large number @xmath253 of samples are to be drawn . .1 in * @xmath5-norm ball : * the setup of case 2 is of the same flavor as the one where the set @xmath3 is the unit @xmath5-norm ball , and the optimized function is @xmath254 with @xmath255 . we have a result similar to those in theorems [ th : ball_maxlin ] and [ th : box_diag ] . [ th : l_one_ball ] letting @xmath85 be the random vector uniformly distributed over the unit @xmath5-norm ball @xmath256 , consider the linear function @xmath257 . given @xmath92 and @xmath93 , the minimal sample size @xmath46 that guarantees , with probability at least @xmath47 , for the empirical maximum of @xmath39 to be at least a @xmath42-accurate estimate of the true maximum , is given by @xmath258 for small @xmath42 we have @xmath259 _ proof _ the true maximum of @xmath39 on @xmath3 is equal to unity ; we specify accuracy @xmath93 and consider the set @xmath260 we then have @xmath261 so that for @xmath36 we obtain @xmath262 and the rest of the proof is the same as that of the previous theorem . @xmath181 .1 in to compare complexity associated with evaluating the optimum of a linear function over the @xmath2- , @xmath4- , and @xmath5-balls , we present a table showing the minimal required number of samples for @xmath111 , @xmath112 and various dimensions , as per formulae , , and , respectively . .@xmath263-balls : minimal required number of samples for @xmath111 and @xmath112 . [ cols="^,^,^,^,^,^,^,^",options="header " , ] [ t : box ] it is seen that the uniform mesh exhibits a very poor relative performance as dimension grows , while the results of @xmath264 and monte carlo approaches are much better and similar to each other . clearly , the absolute values are very far from the true maxima equal to @xmath74 , since @xmath265 samples are not sufficient to obtain reasonable accuracy for dimensions @xmath266 . instead of computing the sample size for fixed values of the accuracy @xmath42 as in table 1 , here we fix the sample size and compute the empirical maxima . the reason for such an `` inversion '' is that , given @xmath42 and the specific linear function @xmath39 , it is not quite clear how to estimate the required length of the @xmath264-sequence . to overcome this problem , one might fix a reasonable value of accuracy , compute the minimal sample size @xmath46 required for monte carlo , run the @xmath264-approach with this length , and compare the results . however , for large dimensions @xmath74 , the values of @xmath46 are huge , leading to very large computation times or even memory overflow . the values obtained for the uniform mesh were computed by inverting relation and using the actual grid with cardinality @xmath267 , so the quantities presented in row `` uniform grid '' of table 2 are overly optimistic . more importantly , the routine sobolset has several parameters , such as @xmath268 ( choice of the initial point in the sequence ) and @xmath269 ( selection of every @xmath270th point ) . these play the similar role as the seed value in matlab pseudorandom number generators does , and may happen to be crucial for the quality of the resulting @xmath264 sequence . in the experiments , we used the default values @xmath271 ( i.e. , the first @xmath0 points ) , though for different values of @xmath272 , the respective estimates of the empirical maximum may differ a lot . for instance , adopting @xmath273 , for @xmath274 we obtain a much better estimate @xmath275 , while taking ( intentionally bad ) @xmath276 leads to very poor @xmath277 . finally , note that applications of uniform grids and @xmath264 sequences are limited to box - shaped sets . sets different from boxes can in principle be embedded in tight enclosing boxes with subsequent use of rejection techniques ; however , the rejection rate usually grows dramatically as the dimension increases . the main contribution of the paper is a rigorous explanation of the reason why does a direct monte carlo approach show itself inefficient in high - dimensional optimization problems when estimating the maximum value of a function from a random sample in the domain of definition . first , attention was paid to linear functions and ball - shaped sets ; using known results on the uniform distribution over the ball , we characterized the accuracy of the estimates obtained via a specific random variable associated with the function value . also , a multiobjective optimization setup was discussed . the results obtained testify to a dramatic growth of computational complexity ( required number of samples ) as the dimension of the ball increases . same flavor results are obtained for box - shaped sets ; these also include analysis of deterministic grids . deb , k. : multiobjective optimization . in : burke , e.k . and kendall , g. ( eds . ) : search methodologies : introductory tutorials in optimization and decision support techniques , pp . 444-463 . springer science+business media , new york ( 2014 ) polyak , b.t . , shcherbakov , p.s . : failure of the monte carlo methods in optimization problems of high dimensions . in : granichin , ( ed . ) : stochastic optimization in informatics , vol . 10 , no . 1 , 89100 ( in russian ) . petersburg state university ( 2014 ) polyak , b. , shcherbakov , p. , khlebnikov , m. : quadratic image of a ball : towards efficient description of the boundary . in : international conference on system theory , control , and computing ( icstcc 2014 ) , pp . ieee css ( 2014 )

the paper proposes an answer to the question formulated in the title . .2 in institute for control science , ras , moscow , russia + e - mails : [email protected] ; [email protected] july 5 , 2016

soft @xmath0-ray repeaters ( sgrs ) and anomalous x - ray pulsars ( axps ) are peculiar classes of high energy sources which share a number of properties ( among others , the emission of short bursts , slow rotation periods in a narrow range , secular spin down and a x - ray luminosity of @xmath2@xmath3erg s@xmath4 , see e.g. woods & thompson 2006 for a recent review ) . sgrs and axps are believed to be powered by ultra - magnetic neutron stars ( magnetars " ; duncan & thompson 1992 ; thompson & duncan 1995 ) . spectral analysis is an important tool in magnetar astrophysics since it can provide key information on the emission mechanism(s ) . the first attempts at modelling the spectra of axps were based on soft x - ray data ( @xmath5 kev ) only . it was found that a blackbody ( @xmath60.30.6kev ) plus a power - law ( photon index @xmath724 ) or , limited to a few cases , two blackbodies ( @xmath80.1 and @xmath90.8kev ) could successfully model the 0.510kev emission . even though the blackbody plus power - law spectral model has been frequently applied to the x - ray spectra of magnetar candidates , a convincing physical interpretation is still missing ( for the power - law component in particular ) . recent studies have attempted to overcome this limitation . thompson , lyutikov & kulkarni ( 2002 ) proposed that magnetars have twisted magnetospheres threaded by currents , which can efficiently boost via resonant cyclotron scattering the soft thermal photons emitted by the star surface . recent investigations ( lyutikov & gavriil 2006 ; fernandez & thompson 2006 ) showed that such a process may lead to the formation of the power - law tail observed in the soft x - rays . rea et al . ( 2006 , 2007 ) presented an application of the lyutikov & gavriil ( 2006 ) resonant cyclotron scattering model ( rcs model in the following ) to sgrs and axps , showing that in a few sources this component alone can explain the x - ray spectrum below @xmath10kev . more recently , hard x ray observations have shown that in some magnetar candidates ( namely , , , , , ; kuiper , hermsen & mndez 2004 ; kuiper et al . 2006 ; mereghetti et al . 2005 ; gtz et al . 2006 ) a large fraction of the total flux is emitted at energies well above @xmath11 kev . the origin of these `` hard '' tails , that have so far been detected up to energies of @xmath12 kev , is still debated ( see beloborodov & thompson 2006 and baring & harding 2006 for possible interpretations ) . axps and sgrs have been discovered to emit also at optical and/or nir wavelengths ( e.g. hulleman et al . 2000 ; israel et al . 2004 ; durant & van kerkwijk 2006b ) . their optical / nir flux represents a small fraction of the bolometric flux , but still can place important constraints on models . several axps , have exhibited long term variability both in their optical / infrared emission and in the x - rays ( oosterbroek et al . 1998 ; israel et al . 2002 ; hulleman et al . 2004 ; rea et al . unavoidably this introduces additional uncertainties in the modelling of broad band spectra , based on observations at different wavelengths taken at different times . the axp 4u0142 + 61 has been recently observed quasi - simultaneously in the hard x - rays ( with integral , see den hartog et al . 2006 ) , soft x - rays ( with swift xrt , see [ obs ] ) , radio , nir and optical ( with the westerbork synthesys radio telescope and gemini north ; see den hartog et al . 2006 and durant & van kerkwijk 2006b for all details ) . data from this and other campaigns show that most of the bolometric emission ( @xmath13% ) revealed so far from this object lies in the x/@xmath0ray energy range . motivated by this we present here an empirical modelling of the 0.5250kev spectrum of 4u0142 + 614 obtained during this quasi - simultaneous campaign ( see [ spectra ] ) . in [ discussion ] we discuss how the extrapolation of different models match the flux measured at other wavelengths . in particular , we note that only the fit with two absorbed log - parabolic functions is consistent with the @xmath0-ray upper limits and does not overestimate the observed optical / infrared emission . some physical implications of our study are then briefly discussed . lrlrlr & & + @xmath14 & @xmath15 & & @xmath16 & & @xmath17 + constant & 0.96 & & 0.90 & & 0.87 + + kt(kev ) & @xmath18 & kt(kev ) & @xmath19 & @xmath20(kev ) & @xmath21 + bbflux & @xmath22 & @xmath23 & @xmath24 & @xmath25 & @xmath26 + @xmath27 & @xmath28 & @xmath29 & @xmath30 & @xmath31 flux & @xmath32 + @xmath33 & @xmath34 & @xmath33 & @xmath35 & @xmath36(kev ) & @xmath37 + pl@xmath38flux & @xmath39 & rcsflux & @xmath40 & @xmath41 & @xmath42 + pl@xmath43flux & @xmath44 & pl@xmath45flux & @xmath46 & @xmath47 flux & @xmath48 + + total abs . flux & @xmath49 & & @xmath50 & & @xmath51 + total flux & @xmath52 & & @xmath53 & & @xmath54 + @xmath55 ( d.o.f . ) & 1.04 ( 48 ) & & 1.01 ( 48 ) & & 1.00 ( 48 ) + we used swift x - ray telescope ( xrt ) data obtained on 2005 july 1112th for an on source exposure time of 7400s in photon counting ( pc ) mode ( that produced a standard 2d image ) . the data were analysed with the ftool task xrtpipeline ( version build-14 under headas 6.0 ) . we applied standard screening criteria to the data , and hot and flickering pixels , high background intervals and bright limb were removed . screened event files were then used to derive light curves and spectra . we included data between 0.58kev , where the pc response matrix is well calibrated ( we used the latest v.8 response matrices ) . we extracted photons from an annular region ( 3 pixels inner radius , 30 pixel outer radius ) in order to avoid pile - up contamination and we considered standard grades for the pc mode 012 . for the hard x - ray part of the spectrum , we used integral data taken by the ibis / isgri instrument ( 20250kev energy range ) quasi - simultaneously with the swift xrt ones . these consist of 868ks divided in 265 science windows , collected between 2005 june 29th and july 17th , in a pointed observation ( see den hartog et al . we fitted ( making use of xspec 11.3 and 12.1 ) the x/@xmath0ray spectrum of by using any combination of the following components : a ) for the soft x - ray part two blackbodies , a blackbody plus a power - law , a neutron star atmosphere model ( nsa model , only available for a maximum magnetic field of b=@xmath56 g ) , a comptonized blackbody ( compbb ) , a disk blackbody ( diskbb ) , a log - parabolic function , a rcs model ( as in rea et al . 2006 , 2007 ) , and b ) for the hard x - ray part a power - law , a bremsstrahlung model ( bremss ) , a log - parabolic function . in all cases we included photoelectric absorption ( abundances set to solar values from lodders 2003 ) and a constant to account for cross - calibration uncertainties in the two instruments all combinations , except for the three models discussed below ( see also fig.1 , 2 , and tab.1 ) , gave unsatisfactory reduced @xmath57 values ( @xmath58 ) . all the three models that successfully reproduce the spectrum require 8 free parameters . of course , we found that other models , involving components not listed above ( e.g. a cut - off power - law instead of the hard x - ray power - law ) , gave satisfactory results . however , in all cases more than 8 free parameters were required . this is the empirical model which is usually adopted for axp spectra and consists of a single blackbody and two power - laws . for the best fit gave a blackbody temperature of @xmath59kev , a very steep power - law below @xmath11 kev with @xmath60 , and a flatter power law for the high - energy part of the spectrum , @xmath61 ( see also kuiper et al . 2006 ; den hartog et al . we tried also a slightly more general model which includes a cut - off around 300kev in the attempt to make the extrapolation of the canonical model compatible with the existing upper limits above @xmath62 mev ( note that we did not include the mev upper limits in the fit ) . we found that the quality of the fit did not improve much , despite the addition of one more free parameter in this modelling . note that the model consisting of two blackbodies plus a power - law did not provide a good fit , mainly because the two blackbodies alone can not account for the soft x - ray part of the emission . this combination makes use of the rcs model , based on the spectra computed by lyutikov & gavriil ( 2006 ) and recently implemented in xspec by rea et al . ( 2006 ) . as shown by rea et al . ( 2006 , 2007 ) , this component can explain well the soft x - ray emission of a few magnetars , whereas an additional power - law is required for sources of this class that have a strong hard x - ray emission . the model parameters , together with the ranges over which each parameter was allowed to vary , are : the velocity of the magnetospheric @xmath63 currents ( in units of @xmath64 ) @xmath65 ; their ( thomson ) scattering optical depth , @xmath66 ; and the temperature of the seed surface emission ( assumed to be a blackbody ) , @xmath67 kev@xmath68 kev . the efficiency of rcs drops above @xmath10kev , but even in the 610kev energy range the addition of another model component is required to fit the x - ray spectrum of . we find a best fit of the whole 0.5250 kev spectrum with a rcs plus power - law model with a surface temperature of @xmath69kev , magnetospheric plasma parameters of @xmath70 and @xmath71 , and a power law index of @xmath72 . the rcs component dominates the emission below 6 kev . the log - parabolic model is an empirical model commonly used to fit blazars spectra , but also successfully applied to a few radio pulsars displaying hard x - ray emission , e.g. the crab and the vela pulsars ( kuiper et al . 2001 ; massaro et al . 2006a , b ) . we applied this model to our data and found that it fits well the soft and hard x - ray spectrum of ( see also kuiper et al . log - parabolic spectra ( landau et al . 1986 ) can be obtained when relativistic electrons are accelerated by a statistical acceleration mechanism in which the probability of acceleration depends on energy , and cool via synchrotron losses ( landau et al . 1986 ; massaro et al . 2004 ) or by inverse compton scattering of synchrotron seed photons . the log - parabolic spectral distribution can be regarded as the simplest generalization of a power - law distribution , as it comprises a mild symmetric spectral curvature . we adopted the following expression , @xmath73 , where @xmath74 is the energy in kev , @xmath75 is the photon index at 1 kev energy and @xmath76 controls the curvature of the parabola in a log - log representation . the log - parabola peaks at @xmath77 ; its free parameters , besides the normalization constant @xmath78 , are @xmath75 and @xmath76 or , equivalently , @xmath79 and @xmath76 . the two log - parabolae we fitted have peaks at @xmath80 1.32 and 412kev , and curvatures of @xmath812.52 and 0.7 . they provide a very good fit to the data , and have the same number of free parameters as the models discussed above ( see fig . 1 and tab.1 ) . we have shown that among spectral models with a relatively limited number of free parameters ( @xmath82 ) , only three successfully fit the x - ray spectrum of ( see [ spectra ] ) . the 0.5250 kev fluxes we derived , are consistent among all the three best models . @xmath14 in the rcs and log - parabolic models is closer to the value measured for this source using x - ray edges in grating spectra ( @xmath83@xmath84 ; see durant & van kerkwijk 2006a ) . comparing the extrapolations of these models with the radio , infrared and optical fluxes measured from quasi - simultaneous observations ( durant & van kerkwijk 2006b , den hartog et al . 2006 ) , as well as @xmath0-ray upper limits obtained around 0.2 mev by comptel ( kuiper et al . 2006 ) , we found that the canonical model ( 3.1 ) overpredicts all of them . the rcs model ( 3.2 ) and the two log - parabolae ( 3.3 ) improve over the canonical model since they do not overpredict the low energy emission . in any case , the optical / nir emission of 4u0142 + 614 ( and likely of other magnetar candidates ) accounts for only less than 5% of the overall source luminosity , and might be due to secondary processes as compared to those responsible for the x/@xmath0ray flux . the optical emission is pulsed , so it is likely to be non - thermal in origin ( kern & martin 2000 ) . on the contrary , the ir emission can be ascribed to a fossil disk ( see e.g. wang et al . 2006 ) , reprocessing a fraction of the soft / hard x - ray emission of the magnetar . the two log - parabolae ( 3.3 ) are the only model that naturally accounts for the fast decline of the spectrum in the @xmath0-rays , implied by the comptel upper limits . nevertheless , in the other two models these limits would not be violated if the hard x - ray power law were characterised by a cut - off at @xmath85kev ( though this would require an additional free parameter in the fit ) . note that in a more detailed physical model the high - energy power law required to fit the integral data may quickly decline around @xmath85 kev , e.g. as a result of the maximum energy up to which the spectrum of the emitting particles extends . thompson & belobodorov ( 2005 ) recently proposed that the hard x - ray magnetar emission may be attributed to bremsstrahlung photons emitted by a thin surface layer heated up to @xmath86 kev by returning currents . however , we find that the spectrum is harder at high energies than envisaged this scenario ( fig.2 ) . a bremsstrahlung model seems hardly compatible with the hard x - ray spectrum of this source and the comptel upper limits . although two log parabolic functions are often used to model a synchrotron self compton ( ssc ) emission , in the case at hand this interpretation appears unlikely for several reasons . first , it is difficult to reconcile the soft part of the x - ray spectrum with synchrotron emission , since the low energy log - parabola has a curvature @xmath87 which translates in a curvature of @xmath88 for the e@xmath89 spectrum . this is very close to the cut - off curvature of the high energy synchrotron emission of a single particle . moreover , we performed detailed simulations ( see tramacere 2002 ; tramacere & tosti 2003 for details ) in order to infer which local magnetic field and electron density is needed to power the emission by a ssc mechanism . we obtained @xmath90 g and @xmath91@xmath92 , respectively . a charge density of the same order is predicted in the simple twisted magnetosphere model by thompson , lyutikov & kulkarni ( 2002 ) , but close to the neutron star surface . instead , the low value of the magnetic field requires that such e@xmath89 are located at an altitude of several hundred kms in the magnetosphere . we may speculate that inverse compton scattering by a population of relativistic particles high up in the magnetosphere may explain the hard x ray emission of magnetars , for other ( than synchrotron ) spectral distributions of seed photons , e.g. that produced by the rcs model . interestingly , the presence of highly relativistic particles well above the star surface has been also suggested by thompson & beloborodov ( 2005 ) . these authors pointed out that seed positrons injected at @xmath86 km above the surface can undergo runaway acceleration and upscatter x - ray photons above the threshold for pair production . in their model , the @xmath93 pairs would then be responsible for efficient synchrotron emission in the 20 - 200 kev band . in this letter we introduced and fitted spectral models , as purely empirical laws . as in many other studies where the total emission of x ray pulsars is modelled , no attempt was made to fit separately the spectral behaviour of the pulsed and the non pulsed components . a more extensive study based on data of other magnetar candidates and attempting a more detailed physical interpretation of these results is in progress and will be reported elsewhere . nr acknowledges support from an nwo - postdoctoral fellowship and a short term visiting fellowship awarded by the university of sydney , and sz thanks pparc for financial support . this work was partially supported through asi and miur funds . nr thanks s. campana and v. mangano for a preliminary help with the swift analysis , m. van kerkwijk , m. durant , w. hermsen , l. kuiper , p. den hartog , m. mndez , j. schuurmans , m. baring , l. burderi , s. markoff and e. massaro for useful discussions . we also thank n. gehrels for approving the swift observation within the director time and the referee , feryal ozel , for useful suggestions . durant , m. & van kerkwij , m. h. , 2006a , apj , 650 , 1082 durant , m. & van kerkwijk , m. h.2006b , apj 652 , 576 duncan , r.c . , & thompson , c. 1992 , apj , 392 , l9 fernandez , r. & thompson , c. 2006 , apj submitted , astro - ph/0608281

we present an empirical spectral modelling of the high energy emission of the anomalous x - ray pulsar 4u 0142 + 614 , based on simultaneous swift and integral observations from x to @xmath0-ray energies . we adopted models contained in the xspec analysis package , as well as models based on recent theoretical studies , and restricted ourselves to those combinations of up to three components which produce a good fit while requiring the lowest number of free parameters . only three models were found to fit satisfactorily the 0.5250 kev spectrum of 4u 0142 + 614 : i ) a @xmath1kev blackbody and two power - laws , ii ) a resonant cyclotron scattering model plus a power - law and iii ) two log - parabolic functions . we found that only the latter two models do not over - predict the infrared / optical emission observed simultaneously from this axp , and only the log - parabolic functions can naturally account for the upper limits set by comptel in the @xmath0-ray range . a possible interpretation of the two log - parabolae in terms of inverse compton scattering of soft x - ray photons by very energetic particles is discussed .

nonmotor symptoms have a strong impact on the prognosis and quality of life in patients with multiple system atrophy ( msa ) . patients with msa often have evidence of compromised gastrointestinal motility [ 1 , 2 ] , which may be caused by disruptions in the autonomic nervous system . however , it remains unclear whether neurohormonal function contributes to compromised gastrointestinal motility in msa . ghrelin is a gut hormone that acts as a natural ligand for the growth hormone secretagogue receptor . it plays an important role in the neurohormonal interaction between the gastrointestinal tract and the central nervous system . ghrelin has been reported to influence gastrointestinal motility in humans [ 4 , 5 ] . the aim of the present study was to determine whether ghrelin secretion is affected in patients with msa , and to investigate the relation between ghrelin secretion and gastrointestinal symptoms in these patients . subjects were 30 patients with probable msa ( 21 patients with msa - c and 9 patients with msa - p ) , 24 patients with other atypical parkinsonian disorders ( 13 patients with progressive supranuclear palsy - richardson syndrome and 11 patients with corticobasal syndrome ) , and 24 control subjects ( 16 patients with non - neurodegenerative diseases and 8 healthy individuals ) . the 16 subjects with non - neurodegenerative diseases consisted of three patients with peripheral neuropathy , three patients with idiopathic normal pressure hydrocephalus , four patients with cervical spondylosis , and six post - stroke patients undergoing rehabilitation . neurologists specialized in movement disorders clinically diagnosed the patients with msa and other atypical parkinsonian disorders in accordance with established or proposed diagnostic criteria for the diseases [ 68 ] . the levodopa - equivalent daily dose of anti - parkinsonian medication was calculated as described previously . none of the patients with msa or other atypical parkinsonian disorders were receiving anticholinergic therapies . dementia was not a criterion for exclusion , because patients with other atypical parkinsonian disorders may have associated dementia . no drugs that are known to affect ghrelin secretion in human , namely , olanzapine , flutamide , estrogen , somatostatin , growth hormone , insulin - like growth factor - i , and rikkunshito , were administered to the subjects before blood sampling . none of the subjects had alcoholism , diabetes mellitus , inflammatory bowel diseases , or cancer - induced cachexia . the protocol of this study was approved by the ethics committee at niigata university school of medicine , and was carried out in accordance with the declaration of helsinki . the gastrointestinal domain of the scales for outcomes in parkinson s disease - autonomic ( scopa - aut ) was used to assess gastrointestinal symptoms . this is composed of seven questions about gastrointestinal symptoms , namely , swallowing / choking , sialorrhea , dysphagia , early abdominal fullness , constipation , straining for defecation , and fecal incontinence . a symptom was considered present ( gaining 1 point ) if the patient reported that it had occurred regularly or often in the past month , and the severity of gastrointestinal symptoms was rated by the total scopa - aut gastrointestinal score ( range 07 points ) . on the day prior to blood sampling dinner was served at 1800 h and the time of lights out was set at 2100 h. subjects were asked to stay in bed from lights out until the time of blood sampling the next morning , except for visits to the toilet . bedrooms used in this study were in quiet surroundings and set at a comfortable room temperature between 18 and 25 c throughout the night . blood samples were obtained from subjects the morning after a 12 h fast . to avoid the influence of food intake and visual or olfactory stimulus of food on ghrelin secretion , subjects were not permitted to eat between meals and breakfast was served after blood sampling . to avoid the effect of alcohol intake on ghrelin secretion , subjects were instructed to abstain from drinking beverages that contained alcohol during the study period . blood samples were immediately transferred to polypropylene tubes containing na2edta and aprotinin , and then centrifuged at 3,500 rpm for 10 min . immediately after centrifugation , one - tenth of the volume of 1 n hcl was added to the separated plasma . there are two circulating forms of ghrelin , acylated ( active ) ghrelin with n - octanoylation at serine three and unacylated ghrelin . the plasma levels of active ghrelin and unacylated ghrelin were measured using commercially available enzyme - linked immunosorbent assay kits according to the manufacturer s instructions ( active ghrelin and desacyl - ghrelin elisa kit , mitsubishi kagaku iatron inc . , the sensitivity of the applied methods was 4 fmol / ml for active ghrelin and 14 fmol / ml for unacylated ghrelin . the intra- and interassay coefficients of variation were 5.5 and 4.9 % respectively for active ghrelin , and 4.7 and 8.6 % respectively for unacylated ghrelin . the ratio of active ghrelin to total ghrelin in the plasma ( active ghrelin ratio ) was obtained using the following formula:\documentclass[12pt]{minimal } \usepackage{amsmath } \usepackage{wasysym } \usepackage{amsfonts } \usepackage{amssymb } \usepackage{amsbsy } \usepackage{mathrsfs } \usepackage{upgreek } \setlength{\oddsidemargin}{-69pt } \begin{document}$$ { \text{active ghrelin } } /\left ( { { \text{active ghrelin } } + { \text { unacylated ghrelin } } } \right ) \times { 1}00 \ , \left ( \% \right ) . $ $ \end{document } one - way analysis of variance was used to compare variables across the three groups . pearson s correlation coefficient was used to quantify the relation between the scopa - aut gastrointestinal score and the active ghrelin ratio in each group . subjects were 30 patients with probable msa ( 21 patients with msa - c and 9 patients with msa - p ) , 24 patients with other atypical parkinsonian disorders ( 13 patients with progressive supranuclear palsy - richardson syndrome and 11 patients with corticobasal syndrome ) , and 24 control subjects ( 16 patients with non - neurodegenerative diseases and 8 healthy individuals ) . the 16 subjects with non - neurodegenerative diseases consisted of three patients with peripheral neuropathy , three patients with idiopathic normal pressure hydrocephalus , four patients with cervical spondylosis , and six post - stroke patients undergoing rehabilitation . neurologists specialized in movement disorders clinically diagnosed the patients with msa and other atypical parkinsonian disorders in accordance with established or proposed diagnostic criteria for the diseases [ 68 ] . the levodopa - equivalent daily dose of anti - parkinsonian medication was calculated as described previously . none of the patients with msa or other atypical parkinsonian disorders were receiving anticholinergic therapies . dementia was not a criterion for exclusion , because patients with other atypical parkinsonian disorders may have associated dementia . no drugs that are known to affect ghrelin secretion in human , namely , olanzapine , flutamide , estrogen , somatostatin , growth hormone , insulin - like growth factor - i , and rikkunshito , were administered to the subjects before blood sampling . none of the subjects had alcoholism , diabetes mellitus , inflammatory bowel diseases , or cancer - induced cachexia . the protocol of this study was approved by the ethics committee at niigata university school of medicine , and was carried out in accordance with the declaration of helsinki . the gastrointestinal domain of the scales for outcomes in parkinson s disease - autonomic ( scopa - aut ) was used to assess gastrointestinal symptoms . this is composed of seven questions about gastrointestinal symptoms , namely , swallowing / choking , sialorrhea , dysphagia , early abdominal fullness , constipation , straining for defecation , and fecal incontinence . a symptom was considered present ( gaining 1 point ) if the patient reported that it had occurred regularly or often in the past month , and the severity of gastrointestinal symptoms was rated by the total scopa - aut gastrointestinal score ( range 07 points ) . on the day prior to blood sampling dinner was served at 1800 h and the time of lights out was set at 2100 h. subjects were asked to stay in bed from lights out until the time of blood sampling the next morning , except for visits to the toilet . bedrooms used in this study were in quiet surroundings and set at a comfortable room temperature between 18 and 25 c throughout the night . blood samples were obtained from subjects the morning after a 12 h fast . to avoid the influence of food intake and visual or olfactory stimulus of food on ghrelin secretion , subjects were not permitted to eat between meals and breakfast was served after blood sampling . to avoid the effect of alcohol intake on ghrelin secretion , subjects were instructed to abstain from drinking beverages that contained alcohol during the study period . blood samples were immediately transferred to polypropylene tubes containing na2edta and aprotinin , and then centrifuged at 3,500 rpm for 10 min . immediately after centrifugation , one - tenth of the volume of 1 n hcl was added to the separated plasma . there are two circulating forms of ghrelin , acylated ( active ) ghrelin with n - octanoylation at serine three and unacylated ghrelin . the plasma levels of active ghrelin and unacylated ghrelin were measured using commercially available enzyme - linked immunosorbent assay kits according to the manufacturer s instructions ( active ghrelin and desacyl - ghrelin elisa kit , mitsubishi kagaku iatron inc . the sensitivity of the applied methods was 4 fmol / ml for active ghrelin and 14 fmol / ml for unacylated ghrelin . the intra- and interassay coefficients of variation were 5.5 and 4.9 % respectively for active ghrelin , and 4.7 and 8.6 % respectively for unacylated ghrelin . the ratio of active ghrelin to total ghrelin in the plasma ( active ghrelin ratio ) was obtained using the following formula:\documentclass[12pt]{minimal } \usepackage{amsmath } \usepackage{wasysym } \usepackage{amsfonts } \usepackage{amssymb } \usepackage{amsbsy } \usepackage{mathrsfs } \usepackage{upgreek } \setlength{\oddsidemargin}{-69pt } \begin{document}$$ { \text{active ghrelin } } /\left ( { { \text{active ghrelin } } + { \text { unacylated ghrelin } } } \right ) \times { 1}00 \ , \left ( \% \right ) . one - way analysis of variance was used to compare variables across the three groups . pearson s correlation coefficient was used to quantify the relation between the scopa - aut gastrointestinal score and the active ghrelin ratio in each group . age at the time of evaluation , sex distribution , and body mass index were matched across the three groups , and disease duration and levodopa equivalent daily doses were matched for the two patient groups ( table 1 ) . the scopa - aut gastrointestinal score was significantly higher in the msa group than in the other two groups ( table 1 ) . although the levels of plasma active ghrelin and unacylated ghrelin did not differ between the three groups , the active ghrelin ratio was significantly lower in the msa group than in other two groups ( table 1 ) . the active ghrelin ratio was very similar in the atypical parkinsonian and control groups ( table 1 ) . in the control group , there was no difference in active ghrelin ratio between the 16 patients with non - neurodegenerative diseases ( mean : 13.6 % ) and 8 healthy individuals ( mean : 14.4 % , p = 0.7).table 1subjects demographic characteristics and state of ghrelin secretionmsaother apdcontrol p valuenumber of cases302424age ( years)67.5 ( 1.6)73.1 ( 1.3)67.5 ( 3.0)0.1male : female16:1415:915:9>0.5disease duration ( years)4.3 ( 0.5)3.9 ( 0.7)not applicable0.64levodopa equivalent daily doses ( mg / day)130.6 ( 40.0)135.0 ( 38.4)not applicable0.93body mass index ( kg / m)21.2 ( 0.6)21.5 ( 0.8)22.1 ( 0.6)0.6scopa - aut gastrointestinal score3.8 ( 0.3)2.1 ( 0.2)0.5 ( 0.1)0.001*active ghrelin ( fmol / ml)6.9 ( 0.9)10.2 ( 1.3)11.2 ( 1.7)0.05unacylated ghrelin ( fmol / ml)102.2 ( 15.8)69.9 ( 10.3)66.8 ( 8.1)0.08active ghrelin ratio ( % ) 8.0 ( 0.8)13.7 ( 1.1)13.9 ( 0.9)0.001**data are n or mean ( standard error ) msa multiple system atrophy , apd atypical parkinsonism disorder , scopa - aut scales for outcomes in parkinson s disease - autonomic * post - hoc p values ( after bonferroni correction ) : msa vs. other apd ; p = 0.001 , msa vs. control ; p = 0.001 , other apd vs. control ; p = 0.002 * * post - hoc p values ( after bonferroni correction ) : msa vs. other apd ; p = 0.001 , msa vs. control ; p = 0.001 , other apd vs. control ; p = 1.0 subjects demographic characteristics and state of ghrelin secretion data are n or mean ( standard error ) msa multiple system atrophy , apd atypical parkinsonism disorder , scopa - aut scales for outcomes in parkinson s disease - autonomic * post - hoc p values ( after bonferroni correction ) : msa vs. other apd ; p = 0.001 , msa vs. control ; p = 0.001 , other apd vs. control ; p = 0.002 * * post - hoc p values ( after bonferroni correction ) : msa vs. other apd ; p = 0.001 , msa vs. control ; p = 0.001 , other apd vs. control ; p = 1.0 in the msa group , the active ghrelin ratio was significantly correlated with the scopa - aut gastrointestinal score ( r = 0.5 , p = 0.004 ; fig . 1 ) , there was no correlation between the active ghrelin ratio and the scopa - aut gastrointestinal score in the atypical parkinsonian group ( p = 0.6 ) or the control group ( p = 0.9).fig . 1the relation between the ratio of active ghrelin to total ghrelin in the plasma ( active ghrelin ratio ) and the scales for outcomes in parkinson s disease - autonomic ( scopa - aut ) gastrointestinal score in patients with msa ( r = 0.5 , p = 0.004 ) the relation between the ratio of active ghrelin to total ghrelin in the plasma ( active ghrelin ratio ) and the scales for outcomes in parkinson s disease - autonomic ( scopa - aut ) gastrointestinal score in patients with msa ( r = 0.5 , p = 0.004 ) in the present study , patients with msa showed aberrant ghrelin secretion that was characterized by a low active ghrelin ratio . furthermore , there was a significant correlation between the reduced active ghrelin ratio and the severity of gastrointestinal symptoms in patients with msa , indicating that a lower active ghrelin ratio was associated with more gastrointestinal symptoms in msa . this phenomenon was not observed in patients with progressive supranuclear palsy - richardson syndrome or corticobasal syndrome . experimental data have shown that dopamine and dopamine agonists stimulate the release of active ghrelin from a ghrelin - producing cell line in vitro , therefore stimulatory effects of these drugs on ghrelin secretion should be considered in patients with msa and other atypical parkinsonian disorders . however , levodopa equivalent daily doses were matched for msa and other atypical parkinsonian groups , thereby controlling for the possibility that anti - parkinsonian medications influenced the results of this study . previous studies have shown that patients with msa frequently exhibit delayed gastric emptying and slow colonic transit . accumulating evidence suggests that active ghrelin facilitates motility of the gastric antrum [ 4 , 5 ] and colorectum , and unacylated ghrelin may counteract the effects of active ghrelin [ 22 , 23 ] . therefore , the reduced active ghrelin ratio presented in this study may contribute to compromised motilities of the gastric antrum and colorectum in patients with msa . postmortem examination of msa patients has revealed that neurodegeneration occurs in vagal autonomic nuclei , which provide extrinsic cholinergic innervation to the gastrointestinal tract . therefore , there may be a link between disruption of the vagal pathway to the gastrointestinal tract and aberrant ghrelin secretion in patients with msa . our observation that the active ghrelin ratio was similar in the atypical parkinsonian and control groups suggests that cholinergic innervation to the gastrointestinal tract is relatively well preserved in patients with progressive supranuclear palsy - richardson syndrome and corticobasal syndrome . these findings are the first to show that reduced active ghrelin ratio may contribute to the pathogenic mechanism of compromised gastrointestinal motility in patients with msa . pharmacological interventions that have therapeutic value in relation to increasing plasma active ghrelin should be considered for gastrointestinal symptoms in patients with msa .

patients with multiple system atrophy ( msa ) often have evidence of compromised gastrointestinal motility . ghrelin is a gut hormone that influences gastrointestinal motility in humans . the aim of this study was to determine whether ghrelin secretion is affected in msa patients , and to investigate the relation between ghrelin secretion and gastrointestinal symptoms . plasma levels of active ghrelin and unacylated ghrelin were measured in patients with msa ( n = 30 ) , other atypical parkinsonian disorders including progressive supranuclear palsy - richardson syndrome and corticobasal syndrome ( n = 24 ) , and control subjects ( n = 24 ) using enzyme - linked immunosorbent assays . gastrointestinal symptoms were quantified in all subjects using a self - report questionnaire . the ratio of active ghrelin to total ghrelin in the plasma ( active ghrelin ratio ) was lower in patients with msa ( mean : 8.0 % ) than in patients with other atypical parkinsonian disorders ( mean : 13.7 % , p = 0.001 ) and control subjects ( mean : 13.9 % , p = 0.001 ) . the active ghrelin ratio was correlated with the severity of gastrointestinal symptoms in msa ( r = 0.5 , p = 0.004 ) . our observations indicate that ghrelin secretion is affected in patients with msa . the low active ghrelin ratio may contribute to gastrointestinal symptoms in msa .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Community Foreclosure Assistance Act of 2007''. SEC. 2. ADDITIONAL EMERGENCY CDBG FUNDING. (a) Appropriation.--There are authorized to be appropriated, and shall be appropriated, $1,000,000,000, to remain available until expended, for assistance to States, metropolitan cities, and urban counties (as those terms are defined in section 102 of the Housing and Community Development Act of 1974 (42 U.S.C. 5302)) in carrying out the community development block grant program under title I of the Housing and Community Development Act of 1974 (42 U.S.C. 5301 et seq.)-- (1) for necessary expenses related to the impact of housing foreclosures, and other related economic and community development activities; and (2) to provide foreclosure-based rental assistance for individual renters in the form of relocation assistance. (b) Limitation.-- (1) In general.--Except for counseling services none of the amounts appropriated under subsection (a) may be provided, directly or indirectly, to an individual homeowner for foreclosure prevention purposes, including for refinancing assistance, loans, or any other form of financial assistance. Such funds may be provided directly to a certified housing counseling service, which shall be considered as a subrecipient of such grant amounts. (2) Definition.--For purposes of paragraph (1), the term ``certified housing counseling service'' means a housing counseling agency approved by the Secretary of Housing and Urban Development pursuant to section 106(d) of the Housing and Urban Development Act of 1968 (12 U.S.C. 1701x(d)). SEC. 3. INCREASED PUBLIC SERVICES REQUIREMENT CAP. For purposes of this Act, paragraph (8) of section 105(a) of the Housing and Community Development Act of 1974 (42 U.S.C. 5305(a)) shall apply to the use of all funds appropriated or otherwise made available under this Act by substituting-- (1) ``25 per centum'' for ``15 per centum'' each place that term appears; and (2) ``25 percent'' for ``15 percent'' each place that term appears. SEC. 4. LOW AND MODERATE INCOME REQUIREMENT. At least 50 percent of the funds appropriated or otherwise made available under this Act shall benefit primarily persons of low- and moderate-income. SEC. 5. PLANS AND REPORTS. (a) Comprehensive Plan.--None of the funds appropriated or otherwise made available under this Act shall be used by any State, metropolitan city, or urban county until such time as that State, metropolitan city, or urban county submits to the Secretary of Housing and Urban Development, for approval by the Secretary, a comprehensive plan detailing the proposed use of all such funds. (b) Report on Use of Funds.--During the period of time that funds are being expended under this Act, each State, metropolitan city, or urban county receiving funds under this Act shall submit, on a quarterly basis, a report to the Secretary of Housing and Urban Development describing and accounting for the use of all such funds expended during the applicable period. SEC. 6. WAIVERS. (a) General Waiver.--In administering funds appropriated or otherwise made available under this Act, the Secretary of Housing and Urban Development shall waive, or specify alternative requirements for, any provision of any statute or regulation that the Secretary administers in connection with the obligation by the Secretary or the use by the recipient of such funds (except for requirements related to fair housing, nondiscrimination, labor standards, and the environment), upon a request by a State, metropolitan city, or urban county that such waiver is required to facilitate the use of such funds, and a finding by the Secretary that such waiver would not be inconsistent with the overall purpose of the statute. (b) Low and Moderate Income Requirement Waiver.--The Secretary of Housing and Urban Development may waive, upon the request of a State, metropolitan city, or urban county, the 50 percent requirement described under section 4. Such waiver shall, in the discretion of the Secretary, only be granted if a compelling need is demonstrated. (c) Public Services Cap.--The Secretary of Housing and Urban Development may waive, upon the request of a State, metropolitan city, or urban county, the public service requirement cap described under section 3. Such waiver shall, in the discretion of the Secretary, only be granted if a compelling need is demonstrated. (d) Other Waiver Provisions.-- (1) Publication in the federal register.--The Secretary of Housing and Urban Development shall publish in the Federal Register any waiver of any statute or regulation authorized under this section not later than 5 days before the effective date of such waiver. (2) Review of waiver.--Each waiver granted under this section by the Secretary of Housing and Urban Development shall be reconsidered, and if still necessary reauthorized by the Secretary, not later than 2 years after the date on which such waiver was first published in the Federal Register pursuant to paragraph (1). (3) Notification of committees.--The Secretary of Housing and Urban Development shall notify the Committee on Appropriations of the Senate and the Committee on Appropriations of the House of Representatives of any waiver granted or denied under this section not later than 5 days before such waiver is granted or denied. SEC. 7. NONCOMPLIANCE WITH COMMUNITY DEVELOPMENT REQUIREMENTS. For purposes of this Act, the provisions of section 111 of the Housing and Community Development Act of 1974 (42 U.S.C. 5311)(relating to noncompliance) shall apply to the use of all funds appropriated or otherwise made available under this Act. SEC. 8. GAO AUDIT. The Comptroller General of the United States shall-- (1) conduct an audit of the expenditure of all funds appropriated under this Act in accordance with generally accepted government auditing standards; and (2) submit a report detailing such audit to the Committee on Banking, Housing, and Urban Affairs of the Senate and the Committee on Financial Services of the House of Representatives. SEC. 9. REPORTS. The Secretary of Housing and Urban Development shall report, on a quarterly basis, to the Committee on Appropriations of the Senate and the Committee on Appropriations of the House of Representatives on-- (1) the use of funds appropriated or otherwise made available under this Act, including-- (A) the number of households receiving counseling and rental assistance; (B) the outcomes of such assistance activities; (C) the names of those certified housing counseling service providing counseling assistance pursuant to this Act; and (D) such other information as the Secretary may deem appropriate; and (2) all steps taken by the Secretary to prevent fraud and abuse of such funds.

Community Foreclosure Assistance Act of 2007 - Makes appropriations for additional emergency Community Development Block Grant (CDBG) assistance to states, metropolitan cities, and urban counties to carry out CDBG programs under the Housing and Urban Development Act of 1974: (1) for necessary expenses related to the impact of housing foreclosures, and other related economic and community development activities; and (2) to provide foreclosure-based rental assistance for individual renters in the form of relocation assistance. Prohibits the direct or indirect provision of such funds, except for certified housing counseling services, to an individual homeowner for foreclosure prevention purposes, including refinancing assistance, loans, or any other form of financial assistance. Increases from 15% to 25% the maximum amount of CDBG funds a local government may use for public services under the Housing and Urban Development Act of 1974, including those concerned with employment, crime prevention, child care, health, drug abuse, education, energy conservation, welfare or recreation needs. Requires at least 50% of CDBG funds appropriated or otherwise made available under this Act to benefit primarily persons of low- and moderate-income.

stochastic optimization algorithms play an important role in optimization problems involving objective functions that can not be computed analytically . these schemes are extensively used in discrete event systems , such as queuing systems , for obtaining optimal or near - optimal performance measures . gradient descent algorithms are used for stochastic optimization by estimating the gradient of average cost in the long run . methods for gradient estimation by random perturbation of parameters have been proposed in @xcite . the smoothed functional ( sf ) scheme , described in @xcite , approximates the gradient of expected cost by its convolution with a multivariate normal distribution . based on all the above schemes , two - timescale stochastic approximation algorithms have been presented in @xcite , which simultaneously perform cost averaging and parameter updation using different step - size schedules . the main issue with such algorithms is that , although convergence to a local optimum is guaranteed , the global optimum can not achieved in practice . hence , new methods are sought . in this paper , we propose a new sf technique based on @xmath0-gaussian distribution , which is a generalization of the gaussian distribution . we show that @xmath0-gaussian satisfies all the conditions for smoothing kernels proposed by rubinstein @xcite . we illustrate a method for gradient estimation using @xmath0-gaussian . we also present a two - timescale algorithm for stochastic optimization using @xmath0-gaussian based sf , and show the convergence of the proposed algorithm . the rest of the paper is organized as follows . the framework for the optimization problem and some of the preliminaries are presented in section [ background ] . gradient estimation using @xmath0-gaussian sf has been derived in section [ validity ] . section [ algorithm ] presents the proposed algorithm . numerical experiments comparing our algorithm with a previous algorithm is presented in section [ results ] . an outline of convergence analysis of our algorithm is discussed in section [ convergence ] . finally , section [ conclusion ] provides the concluding remarks . most of the distributions , like normal , uniform , exponential etc . , can be obtained by maximizing shannon entropy functional defined as @xmath1 , where @xmath2 is a pdf defined on the sample space @xmath3 . other entropy functions have also been proposed as generalized information measures . one of the most popular among them is nonextensive entropy , first introduced in @xcite , and later studied by tsallis @xcite . its continuous form entropy functional , which is consistent with the discrete case @xcite , is defined as @xmath4^q\mathrm{d}x}{q-1 } , \qquad{q\in\mathbb{r}}.\ ] ] this entropy functional produces shannon entropy as @xmath5 . corresponding to this generalized measure , @xmath0-expectation of a function @xmath6 can be defined as @xmath7^q\mathrm{d}x } { \displaystyle\int\limits_{\mathbb{r}}[p(x)]^q\mathrm{d}x}.\ ] ] maximizing tsallis entropy under the following constraints : @xmath8 results in @xmath0-gaussian distribution @xcite , which is of the form @xmath9 where @xmath10 is called tsallis cut - off condition , and @xmath11 is the normalizing constant , which depends on the value of @xmath0 . the function defined in is not integrable for @xmath12 , and hence , @xmath0-gaussian is a probability density function only for @xmath13 . multivariate form of the @xmath0-gaussian distribution @xcite is defined as @xmath14 where @xmath15 is the normalizing constant . it is easy to verify that the multivariate normal distribution is a special case of as @xmath16 . a similar distribution can also be obtained by maximizing rnyi entropy @xcite . let @xmath17 be a parameterized markov process , depending on a tunable parameter @xmath18 , where @xmath19 is a compact and convex subset of @xmath20 . let @xmath21 denote the transition kernel of @xmath22 when the operative parameter is @xmath18 . let @xmath23 be a lipschitz continuous cost function associated with the process . [ ergodic ] the process @xmath22 is ergodic for any given @xmath24 as the operative parameter , _ i.e. _ , @xmath25 \text { as } l\to\infty,\ ] ] where @xmath26 is the stationary distribution of @xmath22 . our objective is to minimize the long - run average cost @xmath27 by choosing an appropriate @xmath18 . the existence of the above limit is given by assumption [ ergodic ] . in addition , we assume that the average cost @xmath28 satisfies the following condition . [ differentiable ] @xmath29 is continuously differentiable with respect to any @xmath30 . we also assume the existence of a stochastic lyapunov function through the following assumption . [ lyapunov ] let @xmath31 be a sequence of random parameters , obtained using an iterative scheme , controlling the process @xmath22 , and @xmath32 @xmath33 , @xmath34 denote the sequence of associated @xmath35-fields . + there exists @xmath36 , @xmath37 compact , and a continuous @xmath38-valued function @xmath39 , with @xmath40 , such that under any non - anticipative @xmath31 , a. @xmath41 < \infty$ ] and b. @xmath42 \leqslant v(y_n ) - \epsilon_0 $ ] , when @xmath43 , @xmath34 . assumption [ differentiable ] is a technical requirement , whereas assumption [ lyapunov ] is used to show the stability of the scheme . assumption [ lyapunov ] will not be required , for instance , if the single - stage cost function @xmath44 is bounded in addition . given any function @xmath45 , its smoothed functional is defined as @xmath46 = \int\limits_{-\infty}^{\infty}g_{\beta}(\eta)f(\theta-\eta)\mathrm{d}\eta = \int\limits_{-\infty}^{\infty}g_{\beta}(\theta-\eta)f(\eta)\mathrm{d}\eta,\ ] ] where @xmath47 is a kernel function . the idea behind using smoothed functionals is that if @xmath48 is not well - behaved , _ i.e. _ , it has a fluctuating character , then @xmath49 $ ] has less fluctuations for appropriate values of @xmath50 . this ensures that any optimization algorithm with objective function @xmath48 does not get stuck at any local minimum , but converges to the global minimum . the parameter @xmath50 controls the degree of smoothness . rubinstein @xcite has shown that the sf algorithm achieves these properties if the kernel function satisfies the following sufficient conditions : 1 . @xmath51 , + where @xmath52 . 2 . @xmath53 is piecewise differentiable in @xmath54 . 3 . @xmath53 is a probability distribution function , + _ i.e. _ , @xmath49 = \mathbb{e}_{g_{\beta}(\eta)}[f(\theta-\eta)]$ ] . @xmath55 , the dirac delta function . @xmath56 = f(\theta)$ ] . the normal distribution satisfies the above conditions , and has been used as a kernel by katkovnik @xcite . based on , a form of gradient estimator has been derived in @xcite which is given by @xmath57\approx\frac{1}{\beta ml}\sum_{n=0}^{m-1}\sum_{m=0}^{l-1}{\eta(n)h(y_m)}\ ] ] for large @xmath58 , @xmath59 and small @xmath50 . the process @xmath60 is governed by parameter @xmath61 , where @xmath62 is obtained through an iterative scheme . @xmath63 is a @xmath64-dimensional vector composed of i.i.d . @xmath65-distributed random variables . the @xmath0-gaussian distribution satisfies the kernel properties ( p1 ) ( p5 ) for all @xmath13 , @xmath66 . 1 . from , it is evident that @xmath67 . 2 . for @xmath68 , @xmath69 , for all @xmath70 . @xmath71 for @xmath72 , when @xmath73 , we have @xmath74 so , holds . on the other hand , when @xmath75 , we have @xmath76 , which implies @xmath77 and , @xmath78 . + thus , @xmath79 is differentiable for @xmath80 , and piecewise differentiable for @xmath72 . 3 . @xmath79 is a distribution for @xmath13 and hence , the corresponding sf @xmath81 , which is parameterized by both @xmath0 and @xmath50 can be written as @xmath82 = \mathbb{e}_{g_{q,\beta}(\eta)}[f(\theta-\eta)].\ ] ] 4 . as @xmath83 , @xmath84 . but , we have @xmath85 for @xmath13 . so , @xmath86 . it follows from dominated convergence theorem that @xmath87 & = \int\limits_{-\infty}^{\infty}{\lim_{\beta\to0}g_{q,\beta}(\eta)f(\theta-\eta)d\eta } \\&=\int\limits_{-\infty}^{\infty}{\delta(\eta)f(\theta-\eta)\mathrm{d}\eta } = f(\theta ) . \end{aligned}\ ] ] @xmath88 our objective is to estimate @xmath89 using the sf approach . the existence of @xmath89 is due to assumption [ differentiable ] . now , @xmath90^t.\ ] ] + let us define , @xmath91 for @xmath72 , and @xmath92 for @xmath68 . it is evident that @xmath93 is the support set for the @xmath0-gaussian distribution with @xmath0-variance @xmath94 . + define the sf for gradient of average cost as @xmath95 & = \big[s_{q,\beta}[\nabla_{\theta}^{(1)}j(\theta ) ] \quad\ldots\quad s_{q,\beta}[\nabla_{\theta}^{(n)}j(\theta ) ] \big]^t \\&=\int\limits_{\mathbb{r}^n}g_{q,\beta}(\theta-\eta){\nabla_{\eta}j(\eta)}\mathrm{d}\eta \;.\end{aligned}\ ] ] it follows from integration by parts and the definition of @xmath93 , @xmath95&=\int\limits_{\omega_q}\nabla_{\eta}g_{q,\beta}(\eta)j(\theta-\eta)\mathrm{d}\eta \;.\end{aligned}\ ] ] substituting @xmath96 , we have @xmath95 & = \int\limits_{\omega_q}{\frac{2}{(3-q)\beta}}\frac{\bar{\eta}j(\theta+\beta\bar{\eta})}{\left(1-\frac{(1-q)}{(3-q ) } \vert\bar{\eta}\vert^2\right)}g_q(\bar{\eta})\mathrm{d}\bar{\eta } \nonumber \\&=\frac{2}{\beta(3-q)}\mathbb{e}_{g_q(\bar{\eta})}\left[\frac { \bar{\eta}j(\theta+\beta\bar{\eta})}{\left(1-\frac{(1-q)}{(3-q)}\vert\bar{\eta}\vert^2\right)}\right]\enspace . \label{d : formula } \end{aligned}\ ] ] we first state the following lemma which will be required to prove the result in proposition [ d : convergence ] . [ q - expect ] let @xmath97 be a function defined over a standard @xmath0-gaussian distributed random variable @xmath98 , @xmath99 @xmath100\enspace,\quad\qquad\ ] ] where @xmath101^q\mathrm{d}x\right]$ ] , @xmath15 being the normalizing constant for n - variate @xmath0-gaussian . from @xmath102^q\mathrm{d}x } { \displaystyle\int_{\mathbb{r}^n}[g_{q}(x)]^q\mathrm{d}x } \\&= \frac{1}{\lambda_q k_{q , n}}\int\limits_{\mathbb{r}^n}{f(x ) } \left(1-\frac{(1-q)\vert{x}\vert^2}{(3-q)}\right)_+^{\frac{q}{1-q}}\mathrm{d}x \quad \\&= \frac{1}{\lambda_q}\int\limits_{\omega_q}\frac{f(x)}{\left(1-\frac{(1-q)}{(3-q ) } \vert{x}\vert^2\right)}g_q(x)\mathrm{d}x \\&= \frac{1}{\lambda_q}\mathbb{e}_{g_q(x ) } \left[\displaystyle\frac{f(x)}{1-\frac{(1-q)}{(3-q ) } \vert{x}\vert^2}\right]\enspace.\end{aligned}\ ] ] @xmath88 [ d : convergence ] for a given @xmath13 , @xmath66 , as @xmath83 , sf for the gradient converges to a scaled version of the gradient , @xmath103-\frac{2\lambda_q}{(3-q)}\nabla_{\theta}j(\theta ) \right \vert \to 0 \text { as } \beta \to 0.\ ] ] for small @xmath50 , using taylor series expansion , @xmath104 by lemma [ q - expect ] , @xmath105 = \frac{2\lambda_q}{\beta(3-q)}\bigg\langle\bar{\eta}j(\theta+\beta\bar{\eta})\bigg\rangle_q \\&= \frac{2\lambda_q}{\beta(3-q)}\bigg[\big\langle{\bar{\eta}}\big\rangle_q{j(\theta ) } + \beta\big\langle{\bar{\eta}\bar{\eta}^t}\big\rangle_q{\nabla_{\theta}j(\theta ) } + \\&\qquad\qquad\qquad\qquad\qquad\frac{1}{2}\beta^2\big\langle{\bar{\eta}\bar{\eta}^t{\nabla_{\theta}^2j(\theta)}\bar{\eta}}\big\rangle_q + o(\beta^2)\bigg ] \\&= \frac{2\lambda_q}{(3-q)}\left[{\nabla_{\theta}j(\theta ) } + \beta\left(\frac{1}{2}\big\langle{\bar{\eta}\bar{\eta}^t{\nabla_{\theta}^2j(\theta)}\bar{\eta}}\big\rangle_q + o(\beta)\right)\right]\end{aligned}\ ] ] thus , @xmath106\to\left(\displaystyle\frac{2\lambda_q}{(3-q)}{\nabla_{\theta}j(\theta)}\right)$ ] as @xmath83 . as a consequence of the proposition [ d : convergence ] , for large @xmath58 and small @xmath50 , the form of gradient estimate suggested by is @xmath107\approx\frac{1}{\lambda_q\beta m}\sum_{n=0}^{m-1}\left[\frac{\bar{\eta}(n ) j(\theta(n)+\beta\bar{\eta}(n))}{\left(1-\frac{(1-q)}{(3-q)}\vert\bar{\eta}(n)\vert^2\right)}\right].\ ] ] using an approximation of , for large @xmath59 , we can write the above equation as @xmath108\approx\frac{1}{\lambda_q\beta ml}\sum_{n=0}^{m-1}\sum_{m=0}^{l-1 } \frac{\bar{\eta}(n)h(y_m)}{\left(1-\frac{(1-q)}{(3-q)}\vert\bar{\eta}(n)\vert^2\right)},\ ] ] where @xmath60 is governed by parameter @xmath109 . however , since @xmath110 , @xmath111 need not be explicitly determined as estimating @xmath112 $ ] instead of @xmath89 does not affect the gradient descent approach . as a special case , for @xmath113 , we have @xmath114 from definition . hence , we obtain the same form as in . in this section , we propose a two - timescale algorithm corresponding to the estimate obtained in . the @xmath0-gaussian distributed parameters ( @xmath54 ) have been generated in the algorithm using the method proposed in @xcite . + let \{@xmath115 } , \{@xmath116 } be two step - size sequences satisfying [ stepsize ] @xmath117 , @xmath118 , and @xmath119 . for @xmath120 , let @xmath121 @xmath122 represent the projection of @xmath24 onto the set @xmath19 . \{@xmath123}@xmath124 are quantities used to estimate @xmath112 $ ] via the recursions below . fix @xmath58 , @xmath59 , @xmath0 and @xmath50 . set @xmath125 . fix parameter vector @xmath126 . generate i.i.d . standard @xmath0-gaussian distributed random variables @xmath127 and set + @xmath128 . generate the simulation @xmath129 governed with parameter @xmath61 . + @xmath130 $ ] . . set @xmath131 . output @xmath132 as the final parameter vector . we consider a two - node network of @xmath133 queues with feedback . the setting here is somewhat similar to that considered in @xcite . nodes 1 and 2 are fed with independent poisson external arrival processes with rates @xmath134 and @xmath135 , respectively . after departing from node-1 , customers enter node-2 . once the service at node-2 is completed , a customer either leaves the system with probability @xmath136 or joins node-1 . the service time processes of the two nodes , @xmath137 and @xmath138 , respectively , are defined as @xmath139 where @xmath140 and @xmath141 are constants . here , @xmath142 and @xmath143 are independent samples drawn from uniform distribution on ( 0,1 ) . service time of each node depends on the @xmath144-dimensional tunable parameter vector @xmath145 , whose individual components lie in a certain interval @xmath146 $ ] , @xmath147 , @xmath148 . @xmath149 represents the @xmath150 update of parameter vector at node-@xmath151 , and @xmath152 represents the target vector . the cost function is chosen to be the sum of the two queue lengths at any instant . for the cost to be minimum , @xmath153 should be minimum , and hence , we should have @xmath154 , @xmath148 . we denote @xmath155 , and @xmath156 , where @xmath64=@xmath157+@xmath158 . for the simulations , we use the following values of parameters : + ( 1 ) @xmath159 , + ( 2 ) @xmath160 , @xmath161 for all @xmath162 , _ i.e. _ , @xmath163^n$ ] . + ( 3 ) @xmath164 , @xmath165 for @xmath166 , + ( 4 ) @xmath167 , @xmath168 , + ( 5 ) @xmath169 , @xmath170 . simulations are performed by varying the parameters @xmath0 and @xmath50 . we compare the performance of our algorithm with the sf algorithm proposed in @xcite , which uses gaussian smoothing . the euclidian distance between @xmath171 and @xmath172 is chosen as the performance measure as this gives the proximity of the updates to the global optimum . for each case , the results are averaged over @xmath173 independent trials . figure 1 shows that with same @xmath50 , @xmath0-sf converges faster than sf algorithm for some @xmath0 s . table i presents a detailed comparison for different values of @xmath0 and @xmath50 . .,height=136 ] [ gqsf1_error ] .performance ( mean distance from optimum ) . [ cols="^,^,^,^,^,^,^,^,^,^,^,^,^,^,^,^",options="header " , ] the cases where @xmath0-sf outperforms sf are highlighted , and for each @xmath50 , the best result is underlined . it can be observed that for smaller @xmath50 , @xmath0-sf with @xmath80 performs better than sf , but for larger @xmath50 , better performance can be obtained with @xmath72 . so , as @xmath50 increases , smaller @xmath0 s prove to be better . as per observations , @xmath174 performs better than gaussian in 63% cases , and also gives the least distance in most of the cases ( 50% ) . the results show that there are some values of @xmath66 for which we can reach closer proximity of the global minimum with the proposed algorithm than the sf case . this can be contributed to the power - law tail of @xmath0-gaussian which allows better control over the level of smoothing . there is an additional improvement provided by @xmath111 , which can be expressed as @xmath175\enspace.\ ] ] for @xmath80 , the term inside bracket is always less than 1 , which implies @xmath176 , whereas @xmath177 for @xmath72 . thus the gradient descent is faster for @xmath72 , which leads to faster convergence . we also note that for high @xmath0 , the algorithm does not converge for larger @xmath50 . so we may claim that the region of stability of @xmath0-sf , given by @xmath178 ( see theorem [ thm ] ) , decreases as @xmath0 increases . here , we give a sketch of the proof of convergence of the proposed algorithm . we just state the important results . the proofs will be given in a longer version of the paper . let @xmath179 , @xmath180 denote the @xmath35-fields generated by the above mentioned quantities , where @xmath181 and @xmath182 for @xmath183 , @xmath184 . define @xmath185 such that @xmath186)$ ] , where @xmath187 $ ] is the integer part of @xmath188 . thus , @xmath189 , @xmath190 and @xmath191 . with the above notation , substituting @xmath192 we can rewrite step 9 of our algorithm in terms of @xmath193 , @xmath194 and @xmath195 . we define the sequences @xmath196 , @xmath183 , @xmath197\right)\end{aligned}\ ] ] the sequences @xmath198 , @xmath199 @xmath200 are almost surely convergent martingale sequences . consider the following ordinary differential equations : @xmath201 - z(t).\end{aligned}\ ] ] [ lem ] the sequence of updates @xmath202 is uniformly bounded with probability 1 . [ z2d ] for a given @xmath13 , @xmath66 , with probability 1 @xmath203 \right\vert \to 0 $ ] as @xmath204 . the following corollary follows directly from proposition [ d : convergence ] and lemma [ z2d ] by triangle inequality . given a particular @xmath13 , with probability 1 , as @xmath204 and @xmath205 , @xmath206 now , finally considering the ode corresponding to the slowest timescale recursion : @xmath207 where @xmath208 for any bounded , continuous function @xmath209 . the stable points of lie in the set @xmath210 . given @xmath211 , we define @xmath212 . [ thm ] under assumptions [ differentiable ] [ stepsize ] , given @xmath13 , @xmath66 and @xmath211 , @xmath213 such that for all @xmath214 $ ] , the sequence @xmath31 obtained using the @xmath0-sf algorithm converges to a point in @xmath215 with probability @xmath216 as @xmath204 . the @xmath0-gaussian exhibits power - law behavior , which gives a better control over smoothing of functions as compared to normal distribution . we have extended the gaussian smoothed functional gradient estimation approach to @xmath0-gaussians , and developed an optimization algorithm based on this . we have also presented results illustrating that for some values of @xmath0 , our algorithm performs better than the sf algorithm @xcite .

the @xmath0-gaussian distribution results from maximizing certain generalizations of shannon entropy under some constraints . the importance of @xmath0-gaussian distributions stems from the fact that they exhibit power - law behavior , and also generalize gaussian distributions . in this paper , we propose a smoothed functional ( sf ) scheme for gradient estimation using @xmath0-gaussian distribution , and also propose an algorithm for optimization based on the above scheme . convergence results of the algorithm are presented . performance of the proposed algorithm is shown by simulation results on a queuing model .

Two female Democrats walked out of a House oversight committee hearing on the contraceptive coverage rule Thursday morning, accusing Chairman Darrell Issa (R-Calif.) of manipulating committee rules to block female witnesses from testifying. "What I want to know is, where are the women?" asked Rep. Carolyn Maloney (D-N.Y.) before walking out. "I look at this panel [of witnesses], and I don't see one single individual representing the tens of millions of women across the country who want and need insurance coverage for basic preventive health care services, including family planning." Text Size - + reset Female Democrats on why they walked out of hearing The five witnesses on the first panel were all male religious leaders or professors, including a Catholic bishop. Two women were listed on the committee website as witnesses for a second, later panel, also dominated by conservatives. The first panel, however, tends to draw the most attention at hearings. Democrats withdrew the name of a witness Issa had accepted, Barry Lynn of Americans United for Separation of Church and State, because they wanted a woman to testify. Lynn submitted a written statement instead. Maloney pressed Issa to allow Sandra Fluke, a law student from Georgetown University, to testify about the impact of the new requirement that most health plans offer contraceptive coverage with no co-pay. Issa shot back that Fluke was rejected because she was "not found to be appropriate or qualified" to testify about religious liberty. He said liberty, not contraception, was the topic of the hearing. Rep. Ann Marie Buerkle (R-N.Y.), the only female Republican lawmaker at the hearing, agreed with Issa. "I really find it so objectionable that my colleagues on the other side of the aisle would characterize this as something so narrow as being about contraception," she said. "This is a fundamental assault on one’s conscience." Ranking Democrat Elijah Cummings (D-M.D.) also accused the Republican majority of silencing women in the discussion even though they are most affected by the policy. "This committee commits a massive injustice by trying to pretend that the views of millions of women across this country are meaningless, or worthless, or irrelevant to this debate,” he said. Del. Eleanor Holmes Norton (D-D.C.) attempted to force a vote on seating Fluke, saying the chairman was breaking committee rules. When he ignored her motion, Norton and Maloney walked out. Maloney later returned. Norton did not. Norton accused Issa of "pretzel turning of the rules so as to deny us a witness" in a press conference convened in the hallway. She said the hearing was "the kind you expect in an autocratic regime." Fluke told the gathered reporters about a friend’s experience that she had hoped to include in her testimony. The woman had lost an ovary to an illness that could have been treated with contraceptives that she couldn't access and now was facing the possibility of infertility, Fluke said. "It's striking that the chairman would say that the reason I cannot speak is that I'm not qualified to speak on the matter," she said. "I feel that the women this affects are the most qualified to speak on this matter." ||||| ABC News A Capitol Hill hearing that was supposed to be about religious freedom and a mandate that health insurers cover contraception in the United States began as an argument about whether Democrats could add a woman to the all-male panel. "Where are the women?" the minority Rep. Carolyn Maloney, D-N.Y., asked early in the hearing. She criticized the Republican committee chairman, Rep. Darrel Issa, for wanting to "roll back the fundamental rights of women to a time when the government thought what happens in the bedroom is their business." "We will not be forced back to that primitive era," she said. Issa bristled at the charge and said Democrats could not add their witness because she was not a member of the clergy, but a student at Georgetown. He also faulted Democrats for not submitting the name of the witness, Sandra Fluke, in time. Fluke would have talked about a classmate who lost an ovary because of a syndrome that causes ovarian cysts. Georgetown, which is affiliated with the Catholic Church, does not insure birth control, which is also used to treat the syndrome. Issa said the hearing is meant to be more broadly about religious freedom and not specifically about the contraception mandate in the Health Reform law. The congressional hearing suggested that the Obama administration went too far with its mandate that all insurers except churches - including non-church religious affiliated organizations - must offer health insurance. It's titled "Lines Crossed: Separation of Church and State. Has the Obama Administration Trampled on Freedom of Religion and Freedom of Conscience?" Among the witnesses invited by Issa to attend the hearing was a representative of the Catholic bishops, who oppose the Obama administration "accommodation" on birth-control coverage. Joining them are many other men of other religions. Not invited, complained Democrats, were representatives from the Catholic Health Association, which is run by a woman and actually runs the Catholic hospitals, nor Catholic Charities, both of which said Friday they supported the president's plan. Ranking committee member Rep. Elijah Cummings, D-Md., wanted to invite third-year Georgetown Law Center student Sandra Fluke to testify, telling Issa it was important to have at least one woman at the witness table because the issue involved health repercussions for women. Read Fluke's full testimony here. Issa's staff sent a letter to the Democrats, saying, "As the hearing is not about reproductive rights but instead about the administration's actions as they relate to freedom of religion and conscience, he believes that Ms. Fluke is not an appropriate witness." "It was just crushing to hear the chairman's reason to not allow my testimony," Fluke told ABC News. "I can understand that [the issue] is connected to religion, but I don't understand how you can have an open conversation without hearing from the women who have been personally affected by this." Cummings, the ranking Democrat, and Maloney asked Issa to reconsider and let Fluke testify, noting she was in the audience, when the hearing got underway Thursday. "It was staggering to sit there and feel like this panel of men was going to talk about my health and women like me," Fluke said. "It felt so very wrong." Rep. Cummings accused Issa of creating "conspiracy hearing" and stacking the witness list by refusing to allow women "commits a massive injustice by trying to pretend that the views of millions of women across the country are meaningless." A terse back and forth followed between Issa, Maloney and Delegate Eleanor Holmes Norton of Washington, D.C., about what the true purpose of the hearing was and whether a violation of rules existed. Issa pointed out that Democrats barred Republican witnesses when they were in the majority. Two women were featured on the second panel, one a female physician. In what seemed like a move to drive home his point, Issa's first witness used a hypothetical example of the government forcing a Jewish orthodox-owned deli to serve pork, as a comparison to the Health and Human Services' mandate for religious employers. The next three witnesses asked why the government was getting involved in the conscience of the American people. "Religious people determine what violates their conscience, not the federal government," the Rev. Jonah Paffhausen, Washington archbishop of the Orthodox Church in America, said. "Please get the federal government, Mr. Chairman, out of our consciences." Congressman Danny K. Davis asked the witnesses about their position regarding the ability of birth control to offer other preventative care for woman (such as ovarian cancer prevention) offered and endorsed by groups such as the American Academy of Pediatrics and American Public Health Association. Rabbi Meir Soloveichik responded for the group. "If that was the focus, none of us would be here today," he said. "We are not here because we seek to hurt preventative care of anybody. We are here today because the administration is showing insensitivity to the liberty of conscience." Rep. Gerry Connolly accused the witnesses of "being used for a political agenda" and that the "hearing is a sham." "I think it taints the value of this panel that could have been a thoughtful discussion," he said referring to the fact that the minority was denied their requested additional witnesses. "This is a panel designed to embarrass the president of the United states and his administration." All the witnesses defended their presence on the commitment to religious freedom. Connolly also criticized the use of quotes and images of democratic presidents, such as john F. Kennedy, by Issa to demonstrate the administrations subversion of first amendment rights. "In an almost Stalinist like fashion have signs of democratic icons," he said. The witnesses often emphasized they would not violate their "liberty of conscience." "If there is real religious liberty in our country," said Roman Catholic Bishop William Lori, "then churches have the god given right to run their own institutions and own internal affairs according to their teachings. Fluke sat directly behind the bishop. "He spent his entire testimony talking about a hypothetical story," she said. "It was very difficult to hear his testimony about a hypothetical story and not about the real stories, about the women in my story." ABC News' Alexa Keyes contributed to this report.

– Two female lawmakers made a point today on Capitol Hill: In a debate concerning birth control, let some women talk. Carolyn Maloney and Eleanor Holmes Norton, both Democrats, walked out of Darrell Issa's hearing on contraceptive coverage because all five witnesses were men, including a Catholic bishop, reports Politico. "What I want to know is, where are the women?" asked Maloney. "I look at this panel [of witnesses], and I don't see one single individual representing the tens of millions of women across the country who want and need insurance coverage for basic preventive health care services, including family planning." Democrats asked Issa to allow a female law student from Georgetown to speak, noting that Sandra Fluke was already in the audience. Issa, however, responded that the hearing's focus was on religious liberty, not contraception, and that Fluke was therefore unqualified, notes ABC News. The only female Republican on the panel backed him up. "I really find it so objectionable that my colleagues on the other side of the aisle would characterize this as something so narrow as being about contraception," said Ann Marie Buerkle. "This is a fundamental assault on one’s conscience."

SECTION 1. SHORT TITLE. This Act may be cited as the ``Workforce Housing Construction for the GO Zone Act of 2007''. SEC. 2. EXTENSION OF PLACED-IN-SERVICE DATE REQUIREMENT FOR LOW-INCOME HOUSING CREDIT BUILDINGS IN GULF OPPORTUNITY ZONE. Section 1400N(c) of the Internal Revenue Code of 1986 is amended-- (1) by striking ``or 2008'' in paragraph (3)(A) and inserting ``2008, 2009, or 2010'', (2) by striking ``during such period'' in paragraph (3)(B)(ii) and inserting ``during the period described in subparagraph (A)'', and (3) by striking ``or 2008'' in paragraph (4)(A) and inserting ``2008, 2009, or 2010''. SEC. 3. PRESERVATION OF PREVIOUS LOW-INCOME HOUSING CREDIT BUILDINGS IN GULF OPPORTUNITY ZONE. (a) In General.--If an owner of a qualified low-income building (as defined in section 42(c)(2) of the Internal Revenue Code of 1986) located in the GO Zone (as defined in section 1400M(1) of such Code) in the second taxable year or later of the credit period (as defined in section 42(f)(1) of such Code) for such building-- (1) suffers a reduction in the qualified basis (as determined under section 42(b)(1) of such Code) of such building (hereinafter referred to as the ``lost qualified basis'') as a result of a disaster that caused the President to issue a major disaster declaration as a result of Hurricanes Katrina and Rita, but under subsection (j)(4)(E) of section 42 of such Code avoids recapture or loss of low-income housing credits previously allowed under such section with respect to such building (hereinafter referred to as the ``existing credits'') by restoring the lost qualified basis by reconstruction, replacement, or rehabilitation within a reasonable period established by the Secretary of the Treasury, and (2) obtains an allocation of additional low-income housing credits under such section to fund, in whole or in part, the reconstruction, replacement, or rehabilitation of such building (hereinafter referred to as the ``new credits''), then the qualified basis of such building for purposes of determining the new credits shall equal the excess (if any) of such building's qualified basis as of the close of the first taxable year of the credit period (as so defined) with respect to the new credits (assuming such reconstruction, replacement, or rehabilitation expenditures meet the requirements for treatment as a separate new building), over such building's qualified basis with respect to the existing credits as determined immediately prior to the disaster referred to in paragraph (1). (b) Special Rule for Time for Making Allocations of Credits.--For purposes of section 42(h)(1)(E)(ii) of the Internal Revenue Code of 1986, buildings described in subsection (a) shall be deemed to be qualified buildings. (c) Avoidance of Recapture of Credit.--For purposes of section 42(j)(4)(E) of the Internal Revenue Code of 1986, qualified low-income housing projects (as defined in section 42(g)(1) of such Code) suffering casualty as a result of a disaster that caused the President to issue a major disaster declaration for the Go Zone (as defined in section 1400M(1))shall be deemed to have restored any casualty loss by reconstruction or replacement within a reasonable period if such loss is restored before January 1, 2011. SEC. 4. CREDIT ALLOWABLE FOR CERTAIN BUILDINGS ACQUIRED DURING 10-YEAR PERIOD IN THE KATRINA, RITA, AND WILMA DISASTER AREAS. Section 1400N(c) of the Internal Revenue Code of 1986 is amended by redesignating paragraph (5) as paragraph (6) and by inserting after paragraph (4) the following new paragraph: ``(5) Credit allowable for buildings acquired during 10- year period.--A waiver may be granted under section 42(d)(6)(A) (without regard to any clause thereof) with respect to any building in the Gulf Opportunity Zone, the Rita GO Zone, or the Wilma GO Zone.''. SEC. 5. INCLUSION OF BASIS OF PROPERTY FOR MIXED INCOME HOUSING IN KATRINA, RITA, AND WILMA DISASTER AREAS. Section 1400N(c) of the Internal Revenue Code of 1986, as amended by this Act, is amended by redesignating paragraph (6) as paragraph (7) and by inserting after paragraph (5) the following new paragraph: ``(6) Increase in applicable fraction for mixed income projects.-- ``(A) In general.--In the case of any qualified low-income housing project under section 42(g) which is located in the Gulf Opportunity Zone, the Rita GO Zone, or the Wilma GO Zone and in which the applicable fraction for any building of such qualified low-income housing project is not less than 20 percent and not more than 60 percent but for the provisions of this subparagraph, the numerator of the applicable fraction under section 42(c)(1)(B) shall be increased by-- ``(i) one or 5 percent of the total number of units (whichever adjustment provides the largest unit fraction) for each building in the qualified low income housing project in the case of the unit fraction under section 42(c)(1)(C), and ``(ii) five percent of the total floor space in the case of the floor space fraction under section 42(c)(1)(D). ``(B) Application.--Subparagraph (A) shall apply to-- ``(i) housing credit dollar amounts allocated after December 31, 2007, and ``(ii) buildings placed in service after such date to the extent paragraph (1) of section 42(h) does not apply to any building by reason of paragraph (4) thereof, but only with respect to bonds issued after such date.''. SEC. 6. OVER INCOME LOANS FOR KATRINA, RITA, AND WILMA DISASTER AREAS. (a) In General.--Section 1400N(a)(5)(B) of the Internal Revenue Code of 1986 is amended by adding ``and'' at the end of clause (ii), by striking clause (iii), and by redesignating clause (iv) as clause (iii). (b) Mortgage Revenue Bonds.--Section 1400T(a) of the Internal Revenue Code of 1986 is amended by adding ``and'' at the end of paragraph (1), by striking paragraph (2), and by redesignating paragraph (3) as paragraph (2). (c) Effective Date.--The amendments made by this section shall apply to bonds issued after the date of the enactment of this Act. SEC. 7. COMMUNITY DEVELOPMENT BLOCK GRANTS NOT TAKEN INTO ACCOUNT IN DETERMINING IF BUILDINGS ARE FEDERALLY SUBSIDIZED. Section 1400N(c) of the Internal Revenue Code of 1986, as amended by this Act, is amended by redesignating paragraph (7) as paragraph (8) and by inserting after paragraph (6) the following new paragraph: ``(7) Community development block grants not taken into account in determining if buildings are federally subsidized.-- For purpose of applying section 42(i)(2)(D) to any building which is placed in service in the Gulf Opportunity Zone, the Rita GO Zone, or the Wilma GO Zone during the period beginning on January 1, 2006, and ending on December 31, 2010, a loan shall not be treated as a below market Federal loan solely by reason of any assistance provided under section 106, 107, or 108 of the Housing and Community Development Act of 1974 by reason of section 122 of such Act or any provision of the Department of Defense Appropriations Act, 2006, or the Emergency Supplemental Appropriations Act for Defense, the Global War on Terror, and Hurricane Recovery, 2006.''. SEC. 8. APPLICATION OF THE DEFINITIONS AND SPECIAL RULES UNDER SECTION 42(I) OF THE INTERNAL REVENUE CODE OF 1986 FOR BOND- FINANCED PROJECTS. (a) In General.--For purposes of qualifying as a qualified residential rental project under section 142(d)(1) of the Internal Revenue Code of 1986 [in the Gulf Opportunity Zone, the Rita GO Zone, or the Wilma GO Zone], the special definitions and special rules for low-income units in section 42(i)(3) of such Code shall apply. (b) Effective Date.--This section shall take apply to bonds issued after the date of the enactment of this Act. SEC. 9. SPECIAL TAX-EXEMPT BOND FINANCING RULE FOR REPAIRS AND RECONSTRUCTIONS OF RESIDENCES IN THE GO ZONES. Section 1400N(a) of the Internal Revenue Code of 1986 is amended by adding at the end the following new paragraph: ``(7) Special rule for repairs and reconstructions.-- ``(A) In general.--For purposes of section 143 and this subsection, any qualified GO Zone repair or reconstruction shall be treated as a qualified rehabilitation. ``(B) Qualified go zone repair or reconstruction.-- For purposes of subparagraph (A), the term `qualified GO Zone repair or reconstruction' means any repair of damage caused by Hurricane Katrina, Hurricane Rita, or Hurricane Wilma to a building located in the Gulf Opportunity Zone, the Rita GO Zone, or the Wilma GO Zone (or reconstruction of such building in the case of damage constituting destruction) if the expenditures for such repair or reconstruction are 25 percent or more of the mortgagor's adjusted basis in the residence. For purposes of the preceding sentence, the mortgagor's adjusted basis shall be determined as of the completion of the repair or reconstruction or, if later, the date on which the mortgagor acquires the residence. ``(C) Termination.--This paragraph shall apply only to owner-financing provided after the date of the enactment of this paragraph and before January 1, 2011.''.

Workforce Housing Construction for the GO Zone Act of 2007 - Amends the Internal Revenue Code to: (1) extend through 2010 the placed-in-service date requirement for buildings in the Gulf Opportunity Zone (GO Zone) for purposes of the low-income housing tax credit; (2) allow a low-income housing tax credit for buildings in the GO Zone, the Rita GO Zone, or the Wilma GO Zone (GO Zones) during a specified 10-year period; (3) provide a basis adjustment for low-income housing projects in the GO Zones; (4) exclude Community Development Block Grant funds from consideration in determining whether GO Zone buildings are federally subsidized; and (5) modify certain rules relating to tax-exempt financing of GO Zone buildings.

Chyna had been taking the legally prescribed pills over the course of three weeks, but wasn't using them properly, he said. Her death was the result of an accidental overdose, Anzaldo insisted, not suicide. ||||| Chyna, the former wrestling champion, died from a cocktail of prescription pills, her manager revealed. The former WWE intercontinental champion, whose real name is Joanie Laurer, had unintentionally overdosed on a deadly combination of Valium and Ambien, her manager, Anthony Anzaldo, told the Daily News. FORMER WWE WRESTLER CHYNA'S BRAIN TO BE DONATED TO SCIENCE, WILL BE EXAMINED FOR SIGNS OF CTE Chyna died from an accidental overdose on Valium and Ambien, not a suicide attempt, her manager said. (Spencer Platt/Getty Images) “She was inappropriately taking her legally prescribed medication over the course of two to three weeks,” Anzaldo said. “On Sunday night, her body had enough.” The manager doesn’t believe that Chyna had purposely taken a deadly number of pills in a suicide attempt, as there weren’t any illegal drugs or alcohol around the apartment when he found her. Chyna had been taking Ambien and Valium for years, but had steadily upped her intake to a dangerous amount, leading up to her death, Anzaldo said. “Her normal amount was one thing, but over the course of time she was increasing, and not properly,” he told the News. Chyna had been taking Valium and Ambien for several years, but rapidly increasing her dosage to dangerous amounts, her manager siad. (Dan Callister/Getty Images) Joanie Laurer, better known by her in-ring name Chyna, was found dead in her California apartment on April 21. (Lawrence Lucier/Getty Images) Chyna’s toxicology report will not return for another eight months, but her manager predicted the prescription drugs would be behind the wrestler’s death. “They’re not going to find 60 pills in her stomach,” Anzaldo explained. Chyna's brain will be donated for research to examine for any signs of CTE from her wrestling career. (Yukio Hiraku/ZUMAPRESS.com) The 45-year-old wrestling star, had been dead for days before Anzaldo found her body on April 21. Her brain will be turned over to the doctor played by Will Smith in “Concussion,” to examine for any signs of chronic traumatic encephalopathy (CTE). Anzaldo claimed Chyna would be an interesting subject for Dr. Bennet Omalu because of her history with the WWE and domestic violence. Before her death, she posted a 13-minute video on YouTube in a haunting final message. She told her fans: "I hope you have a beautiful day. Wake up, wake up, wake up. Or sleep in. Or stay in bed all damn day today. It's Sunday, right? Love you all, peace."

– With toxicology reports still months away, Chyna's manager says he knows what killed the former professional wrestler, the New York Daily News reports. Anthony Anzaldo, who found Chyna's body in her California home last Wednesday, says she was killed by an unintentional overdose of legally prescribed Ambien and Valium. “She was inappropriately taking her legally prescribed medication over the course of two to three weeks,” Anzaldo says. “On Sunday night, her body had enough.” According to the Los Angeles Times, Anzaldo denies the death of the 46-year-old wrestler—real name Joanie Laurer—was a suicide attempt. “You are not going to find 60 pills in her stomach,” he says.

pituitary carcinoma is a rare disorder accounting for 0.10.5% of pituitary adenomas [ 14 ] . it is believed that pituitary carcinomas arise from the transformation of benign invasive macroadenomas [ 14 ] , and the process of this transformation takes place slowly . a large majority of pituitary carcinomas preserves a capacity for producing anterior pituitary hormones [ 14 ] , most notably acth and prolactin . however , a definite distinction between pituitary carcinoma and adenoma is impossible on the basis of endocrinological , neuroradiological , and histological criteria . the presence of cns and/or distant metastases is a prerequisite to establishing the diagnosis of this clinical entity [ 14 ] . the most common is corticotroph carcinoma , representing 42% of pituitary carcinomas [ 14 ] , and 53 cases of corticotroph carcinoma have been described in the english literature so far [ 545 ] . at the time of diagnosis , 32 ( 60% ) of the 53 cases presented with symptoms and signs of chronic hypercortisolemia characteristic of cushing 's disease [ 59 , 1218 , 2022 , 2732 , 34 , 35 , 38 , 39 , 43 ] , while 15 ( 28% ) of the 53 cases developed these features 6 months to 12 years after an initial presentation as a pituitary mass compressing the surrounding tissues [ 10 , 11 , 19 , 2326 , 33 , 36 , 37 , 39 , 40 , 42 , 44 , 45 ] . although very rarely , silent corticotroph carcinoma has also been recognized by the presence of metastatic lesions in the absence of clinical features associated with chronic hypercortisolemia [ 27 , 41 ] . a case of corticotroph carcinoma , which displayed aggressive behavior resulting in multiple cranial nerve palsies , invasive petrosal bone destruction , and liver metastasis , is reported . this carcinoma presented initially as an invasive macroadenoma causing double vision and asymptomatic cushing 's disease , despite active hormone production . a 52-year - old japanese woman suddenly developed double vision on the way to her office and was referred to our university hospital by an ophthalmologist . she gained 10 kg in weight after menopause at the age of 50 years . on physical examination , the patient 's height was 151 cm , and her weight was 63.5 kg , with a body mass index of 27.8 kg / m . the patient presented with no signs indicative of cushing 's syndrome , such as moon face , truncal obesity , buffalo hump , purple striae cutis , skin atrophy , or hirsutism . she had a history of two normal deliveries at ages 26 and 28 years . routine blood tests revealed no abnormalities in serum electrolytes , lipid profile , or glucose level . magnetic resonance imaging ( mri ) revealed a pituitary macroadenoma ( height 22 mm ; width 25 mm ; depth 21 mm ) that extended suprasellarly compressing the optic chiasm , infrasellarly into the sphenoid sinus , and laterally invading into the right cavernous sinus ( fig . on gadolinium - enhanced t1-weighted coronal images , tumoral invasion into the right cavernous sinus was evident at its inferior portion along the inferior arterial wall of the intracavernous internal carotid artery ( ica ; fig . 1b ) and at its middle portion through a space between the intra- and supracavernous icas ( fig . endocrine investigation with the use of the irma kit ( mitsubishi chemical yatron , tokyo , japan ) for acth and the tfb ria kit ( immunotec , prague , czech republic ) for cortisol measurement revealed a concomitant elevation of morning acth ( 293 pg / ml ; normal range , 7.455.7 pg / ml ) and cortisol ( 24.6 g / dl ; normal range , 4.018.3 g / dl ) levels in blood and a complete loss of the diurnal change in both hormones ( table 1 ) . both elevated acth and cortisol levels did not respond to an intravenous injection of a 100-g dose of human corticotropin - releasing hormone ( crh ; sumitomo pharmaceutical co. ltd , osaka , japan ) or to orally administered low - dose ( 1 mg ) or high - dose ( 8 mg ) dexamethasone sodium phosphate in an overnight suppression test ( table 1 ) . for the hormonal systems other than the acth - cortisol axis , growth hormone response to l - arginine hydrochloride ( 30 g ) infusion was impaired , with a peak value of 0.12 g / l ( normal range , > 3.0 basal gonadotropins were diminished below normal postmenopausal levels , while baseline prolactin and thyroid function were normal . the search for mass lesions producing acth ectopically within the patient 's double vision worsened progressively , and the patient underwent transsphenoidal surgery 8 days after the first visit . histologically , the excised specimens were typical pituitary adenoma on hematoxylin eosin staining ( fig . 2a ) and were diffusely immunostained with mouse monoclonal anti - human acth antibody ( dako uk ltd , cambridgeshire , uk ; fig . the adenoma showed strong nuclear pleomorphism , hyperchromasia , and enlarged nucleoli ( fig . 2a ) , but it did not exhibit crooke 's hyaline change in the cytoplasm , a histological feature characteristic of crooke cell adenoma . were positively stained for a proliferation marker , ki-67 antigen , with mouse monoclonal anti - human mib-1 antibody ( dako uk ltd . ; 1radiographic presentation of a pituitary invasive macroadenoma in a patient who presented with multiple cranial nerve palsies at different stages . upper two films are conventional gadolinium - enhanced t1-weighted 3-mm coronal slices ( a , b ) , 6 mm apart in an anterior to posterior direction , at initial presentation with a right abducens nerve palsy . arrows indicate cavernous sinus invasion . lower two images are axial ( c ) and coronal ( d ) images of contrast - enhanced , 1-mm slices of bone ct at the time of lower cranial nerve palsies ( c ) and t1-weighted , 2-mm slices of high - resolution mri at the time of a right oculomotor nerve palsy ( d ) , both obtained under stereotactic conditions . the recurrence occurred twice within the right cavernous sinus but not within the sella : at the first recurrence the tumor destructively invades the petrosal bone and has destroyed the jugular foramen ( arrow ) ( c ) , and at the second , the tumor is seen to have recurred at the superior posterior portion of the cavernous sinus ( d ) . color line - circled areas indicate the area irradiated with the same dose of gkr ; the outer area was irradiated at a lower dosagetable 1acth and cortisol measurementdiurnal changeovernight dexamethasone suppression testhuman corticotropin - releasing hormone ( crh ) testtime of day ( h)dosetime ( min)8:0023:001 mg8 mg0306090acth ( pg / ml)293307307258270321310cortisol ( g / dl)24.636.235.829.026.230.930.2fig . 2photomicrographs of the histological and immunohistochemical features of the primary pituitary tumor and the metastasized liver tumor . pituitary tumor : a , c , e , and g ; liver tumor : b , d , and f. both pituitary and liver tumors show nuclear pleomorphism , hyperchromasia , and enlarged nucleoli ( arrow heads ) on hematoxylin numerous tumor cell nuclei are positive for ki-67 , and the proportion of cells with positive ki-67 staining accounts for 15% and 35% of the primary ( e ) and metastasized ( f ) tumor cells , respectively . immunoreactive nuclear protein p53 examined in the primary pituitary tumor is stained in almost all cells ( g ) . original magnification 400 ( a , b ) , 200 ( c g ) radiographic presentation of a pituitary invasive macroadenoma in a patient who presented with multiple cranial nerve palsies at different stages . upper two films are conventional gadolinium - enhanced t1-weighted 3-mm coronal slices ( a , b ) , 6 mm apart in an anterior to posterior direction , at initial presentation with a right abducens nerve palsy . lower two images are axial ( c ) and coronal ( d ) images of contrast - enhanced , 1-mm slices of bone ct at the time of lower cranial nerve palsies ( c ) and t1-weighted , 2-mm slices of high - resolution mri at the time of a right oculomotor nerve palsy ( d ) , both obtained under stereotactic conditions . the recurrence occurred twice within the right cavernous sinus but not within the sella : at the first recurrence the tumor destructively invades the petrosal bone and has destroyed the jugular foramen ( arrow ) ( c ) , and at the second , the tumor is seen to have recurred at the superior posterior portion of the cavernous sinus ( d ) . color line - circled areas indicate the area irradiated with the same dose of gkr ; the outer area was irradiated at a lower dosage acth and cortisol measurement photomicrographs of the histological and immunohistochemical features of the primary pituitary tumor and the metastasized liver tumor . pituitary tumor : a , c , e , and g ; liver tumor : b , d , and f. both pituitary and liver tumors show nuclear pleomorphism , hyperchromasia , and enlarged nucleoli ( arrow heads ) on hematoxylin eosin staining , but neither tumor shows mitotic figures ( a , b ) . numerous tumor cell nuclei are positive for ki-67 , and the proportion of cells with positive ki-67 staining accounts for 15% and 35% of the primary ( e ) and metastasized ( f ) tumor cells , respectively . immunoreactive nuclear protein p53 examined in the primary pituitary tumor is stained in almost all cells ( g ) . original magnification 400 ( a , b ) , 200 ( c g ) following the transsphenoidal surgery , morning acth decreased to 47.9 pg / ml , accompanied by a decline in cortisol to 2.94.5 g / dl ( fig . 3 ) . in an overnight dexamethasone suppression test , however , serum cortisol was not suppressed to a normal level of < 1.0 g / dl with the high 8-mg dose . the abducens nerve palsy remained , though improved , leaving a moderate degree of double vision with lateral gaze to the right . two months postoperatively , the patient was treated with -knife radiosurgery ( gkr ; marginal dose , 25 gy ; maximum dose , 50 gy ) using the leksell gamma knife model c with automatic positioning system ( elekta instruments ab , stockholm , sweden ) , which ameliorated diplopia completely by 3 months ( fig . eight months after gkr , acth and cortisol increased to 244 pg / ml and 26.9 g / dl , respectively , and the patient developed a swallowing disturbance and hoarseness due to the lower cranial nerve palsies on the right side . 1c ) and high - resolution mri within the right cavernous sinus at a site not previously irradiated but not within the sella . the recurrent tumor invaded destructively into the whole right petrosal bone and destroyed the jugular foramen ( fig . one month later , the second gkr ( marginal dose , 15 gy ; maximum dose , 30 gy ) was carried out , resulting in complete disappearance of the lower cranial nerve palsies within 1 month and normalization of the cortisol but not the acth level ( fig . 3 ) . three months after the second gkr , acth and cortisol rose to 146 pg / ml and 20.5 g / dl , respectively , and the patient again developed double vision , but this time with left lateral gaze due to the right oculomotor palsy . recurrence of the tumor was again identified with mri in the superior posterior part of the right cavernous sinus ( fig . 1d ) , and 1 month after the appearance of double vision , the patient received the third gkr ( marginal dose , 15 gy ; maximum dose , 30 gy ) . the diplopia resolved completely within 1 month , and cortisol declined to an upper normal level of 16.1 g / dl , but the elevated acth remained unchanged ( fig . 3 ) . upper panel shows sequential change in blood acth and cortisol levels along with the timing ( arrows ) of therapeutic interventions that included transsphenoidal surgery ( tss ) , -knife radiotherapy ( gkr ) , and partial right - lobe hepatectomy ( hepatex ) . the occurrence and resolution of cranial nerve palsies are shown by black bars , in which the width indicates the duration of palsy and the height indicates its severity . broken and straight lines indicate the upper normal limit of cortisol ( 18.3 g / dl ) and acth ( 55.7 pg / ml ) , respectively . shown over the upper panel are medications with daily dose in parentheses and their duration of use and dosage in black bars . lower panel shows the same time course for serum potassium concentration with a broken line indicating the lower limit of normal ( 3.4 meq / l ) clinical course as a function of time ( months ) after transsphenoidal surgery . upper panel shows sequential change in blood acth and cortisol levels along with the timing ( arrows ) of therapeutic interventions that included transsphenoidal surgery ( tss ) , -knife radiotherapy ( gkr ) , and partial right - lobe hepatectomy ( hepatex ) . the occurrence and resolution of cranial nerve palsies are shown by black bars , in which the width indicates the duration of palsy and the height indicates its severity . broken and straight lines indicate the upper normal limit of cortisol ( 18.3 g / dl ) and acth ( 55.7 pg / ml ) , respectively . shown over the upper panel are medications with daily dose in parentheses and their duration of use and dosage in black bars . lower panel shows the same time course for serum potassium concentration with a broken line indicating the lower limit of normal ( 3.4 meq / l ) four months after the third gkr , both acth and cortisol began to rise rapidly , and 3 months later , they reached unusually high levels of 534 pg / ml and 52.0 g / dl , respectively ( fig . 3 ) . the patient 's condition deteriorated , accompanied by rapid weight gain ( 7 kg ) , generalized skin pigmentation , severe hypokalemia ( 2.8 meq / l ) , and hypertension ( 170/110 mmhg ) , all of which were uncontrollable with administration of spironolactone ( 50100 mg / day ) and metyrapone ( 1.52.25 g / day ) and supplementation with slow - release potassium chloride ( 1.87.2 g / day ; fig . 3 ) . because acth and cortisol levels continued to increase , reaching extremely high levels of 654 pg / ml and 84.7 g / dl , respectively ( fig . abdominal ct at 24 months postoperatively to evaluate the status of adrenal hypertrophy identified multiple space - occupying lesions in the liver . the patient underwent partial right - lobe hepatectomy , which removed all hepatic lesions and led to reduction of serum cortisol to 25.928.8 g / dl and normalization of hypokalemia ( fig . the excised hepatic lesions were histologically very similar to the in situ pituitary adenoma in terms of nuclear pleomorphism , increased nuclear chromatin , and prominent nucleoli on hematoxylin 2f ) with a value ( 35% ) approximately 2.4 times higher than that ( 15% ) of the primary tumor . in addition , the in situ adenoma retrospectively immunostained with monoclonal mouse antibody to p53 protein ( dako uk ltd ) was strikingly positive ( fig . following abdominal surgery , both the hypertension and hypokalemia became medically controllable , and the patient 's condition was improving . the metastasis usually takes place within the cns to the cerebral cortex , cerebellum or cerebellopontine angle , brainstem , and spinal cord , or outside the cns to the liver , lymph nodes , bone , lung , and other tissues [ 14 ] . in the absence of metastasis , it seems necessary to attempt screening for those pituitary tumors that might have an aggressive potential to transform into carcinomas , although there is no practical clinical guideline for their screening at present . in 1997 , pemicone et al . classified adenohypophysial tumors with respect to their aggressive potential and described seven tumor characteristics required for pituitary carcinoma . the present case fulfilled all of the characteristics that they described except for the presence of mitosis : high ki-67 immunoreactivity ( 15% ) , positive p53 immunoreactivity , macroadenoma tumor size ( 2 cm ) , gross invasion ( proven by surgery ) , metastasis ( liver ) , and high blood hormone levels ( acth and cortisol ) . in 2004 , the who introduced for pituitary tumors a new adenoma entity termed atypical adenoma , which was designated as an invasive tumor that exhibits an elevated mitotic index , a ki-67 labeling index greater than > 3% , and extensive nuclear staining for p53 immunoreactivity [ 48 , 49 ] . this definition denotes an aggressive potential for atypical adenoma and the possibility of its future malignant transformation . atypical adenoma differs from carcinoma only in the lack of metastasis . in keeping with the who classification in 2004 that atypical tumors and those with a ki-67 labeling index greater than 10% , regardless of p53 immunostaining , should be followed for early recurrence and/or development of metastases . the pituitary tumor of the present patient fulfills the definition of the atypical adenoma introduced by the who , except for the presence of mitosis , and is consistent with the adenomas with a very high ki-67 labeling index described by kaltsas . although there was no mitosis in either the primary or metastasized tumor in the present patient , it has been reported that mitoses were not demonstrated in all pituitary tumors , i.e. , positive in 21.4% of invasive pituitary adenomas and 66.7% of pituitary carcinomas . nonetheless , this can not explain why the primary adenoma cells did not show mitosis despite expressing ki-67 immunoreactivity in a very high proportion . the cell cycle - specific ki-67 antigen may not always reflect all of the proliferating abilities of individual adenomas that are turning over at different rates . otherwise , mitoses might have been obscured , though present , by tissue processing or technical artifacts . the latency period from the diagnosis of pituitary tumor to the demonstration of metastasis varied considerably among patients with corticotroph carcinomas [ 545 ] , which probably reflects the difference in the speed at which individual pituitary adenomas transform into carcinoma . in the 53 reported patients with corticotroph carcinomas [ 545 ] , the mean ( se ) latency period that we calculated was 93 10 months ( range , 3360 months ) . the latency period of the present patient was 24 months , which in the order of latency length , was ranked as the fourth shortest . no doubt , the latency period would have shortened if abdominal ct , which detected hepatic metastases , had been performed at an earlier stage . such clinically rapid progression of the disease , together with twice - repeated early recurrence within the cavernous sinus , is highly suggestive of an aggressive nature of the primary tumor from the beginning of its clinical manifestation . the aggressive , even malignant , nature of the tumor might be supported by its high radiosensitivity , as evidenced by rapid resolution of cranial nerve palsies within 13 months after gkr . three additional , unique behaviors of the present tumor became evident on neurological and radiological examinations . the first was a transient cystic enlargement of the irradiated residual tumor that was incidentally recognized on mri 1 month after the first gkr . the second was the occurrence of the lower cranial nerve palsies that caused swallowing difficulty and a husky voice , and the third was destructive bone invasion involving the unilateral whole petrosal bone , which was detected on bone ct at the time of the lower cranial nerve palsies . we have never observed any of these findings in a series of several hundreds of pituitary adenoma patients whom we treated with gkr . there is no description on clinical features of atypical adenoma because it was defined as a pathological , but not clinical , entity intermediate between adenoma and carcinoma . the present tumor pathologically accords well with atypical adenoma except absence of mitosis , and hence its unusual behaviors associated with repeated local recurrence within the cavernous sinus could represent some clinical features of atypical adenoma . it is likely that the patient 's tumor , which initially manifested as a clinically invasive macroadenoma or pathologically as an atypical adenoma , subsequently underwent malignant transformation presumably triggered by the surgery and/or irradiation , a main mechanism currently postulated to underlie the development of pituitary carcinoma ( 14 ) . the reason for initial lack of glucocorticoid excess symptoms may require some explanation . it might in part be due to partial cortisol resistance of unknown etiology , because the patient did not develop such hypercortisolemic signs / symptoms as systemic pigmentation and hypertension with hypokalemia until the last few months before death , at which time serum cortisol increased to an extraordinarily high level in parallel with acth . it is unlikely that the patient 's adenoma secreted a biologically inactive , c - terminally extended , big first , the irma used for our acth measurements does not recognize this high - molecular - weight form of acth - related peptide . second , a closely parallel change in acth and cortisol throughout almost the entire clinical course favors the view of tumor - secreted acth as a biologically active peptide . consistent with the present patient , a substantial proportion of previously reported patients with corticotroph carcinoma did not present initially with cushing 's disease . of the 53 reported patients , including 34 women and 19 men , only 32 subjects were diagnosed as having cushing ' syndrome or disease at initial presentation [ 59 , 1218 , 2022 , 2732 , 34 , 35 , 38 , 39 , 43 ] . the remaining 21 cases were endocrinologically asymptomatic , except for one case of galactorrhea amenorrhea syndrome , and presented with the pituitary mass compressing the adjacent tissues [ 10 , 11 , 19 , 23 , 24 , 26 , 27 , 33 , 36 , 37 , 4042 , 44 , 45 ] : visual disturbance in 13 cases , headache in one case , and visual impairment plus headache in five cases ( symptoms not described in one case ) . these 21 hormonally asymptomatic tumors , which were initially diagnosed as non - functioning adenomas , can be divided into two subgroups on the basis of the subsequent clinical course . one subgroup consisted of 15 adenomas that developed characteristic features of cushing 's disease 73 12 months ( range , 6144 months ) after initial diagnosis [ 10 , 11 , 19 , 2326 , 33 , 36 , 37 , 39 , 40 , 42 , 44 , 45 ] . of these 15 adenomas , only five tumors underwent initial immunohistochemical examination , and all were positive for acth , indicating that these 5 adenomas were silent corticotroph adenomas at the initial presentation . notably , 12 of the 15 adenomas metastasized within 12 years after manifesting as cushing 's disease , which suggests the possibility that these metastasized adenomas had already undergone malignant transformation at the time of their clinical manifestation as cushing 's disease . the other subgroup consisted of the remaining six of the 21 adenomas that were all initially diagnosed as silent corticotroph adenoma with acth immunostaining and continued to be clinically silent until they caused systemic or craniospinal metastasis [ 27 , 41 ] . it is likely that marginally hypercortisolemic or even eucortisolemic but endocrinologically abnormal subjects have been mixed in with these initially asymptomatic patients , because subjects with cushing 's disease often have upper normal levels of baseline acth and/or cortisol in blood . this is in contrast with prolactinomas , in which blood prolactin levels increase proportionally with the size of tumors , and macroadenomas usually have prolactin values more than ten times higher than the normal upper limit , thereby not requiring any dynamic test for diagnosis [ 14 , 52 ] . in clinically asymptomatic or subclinical cushing 's disease , however , it is often difficult to make an accurate diagnosis only with baseline cortisol and/or acth levels without measuring 24-h urinary free cortisol output or performing appropriate diagnostic tests , such as an overnight dexamethasone suppression test to demonstrate the abnormal glucocorticoid feedback regulation or determination of the morning and midnight cortisol levels to identify the abnormal diurnal rhythm of the acth - cortisol axis . the use of such diagnostic tests in patients with invasive macroadenoma will decrease the chance of misdiagnosing asymptomatic patients with cushing 's disease as having a non - functioning pituitary adenoma . in conclusion , this is the first case of pituitary carcinoma in our university hospital over the last 30 years , which is in accordance with the rarity of this clinical entity . the patient 's tumor differed from common invasive macroadenomas , clinically with repeated early recurrence and immunohistochemically with an extraordinarily high ki-67 labeling index . rapid aggressive progression of the disease from initial presentation suggests that the patient 's pituitary tumor might have emerged de novo as a corticotropinoma with high potential for malignant transformation . in our clinical experience , non - functioning adenomas , the majority of which is represented by gonadotropin - producing adenomas , rarely exhibit a high degree of cavernous sinus invasion , while often showing prominent suprasellar extension . adenomas , if they exhibit marked parasellar invasion , should be screened for adenomas of non - gonadotroph lineage . it is important to emphasize that all patients with invasive macroadenoma should be screened for cushing 's disease with an appropriate diagnostic test even if they are hormonally asymptomatic or eucortisolemic , and if they indeed represent cushing 's macroadenoma , they should be carefully followed for the future development of corticotroph carcinoma .

a 52-year - old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus . otherwise , she was asymptomatic despite marked elevation of acth ( 293 pg / ml ) and cortisol ( 24.6 g / dl ) levels . the patient underwent transsphenoidal surgery followed by -knife radiosurgery ( gkr ) , which healed the diplopia and ameliorated the hypercortisolemia . the excised tumor was diffusely stained for acth with a high ( 15% ) ki-67 labeling index . early tumor recurrence occurred twice thereafter , producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after gkr ; all palsies resolved completely with the second and third gkrs . hypercortisolemia worsened rapidly soon after the third gkr , and the patient developed marked weight gain , hypokalemia , and hypertension . multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry . an acth - producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level . the unique aggressive behavior and high potential for malignant transformation of this case are discussed .

our populations of interest are collectively referred to as inuit , which extend from the chukotka peninsula in russia across alaska and northern canada to greenland . they are known by a variety of self - designated names in different regions ( including yuit , yupik , inupiat , inuvialuit , inuit and kalaallit ) . our search revealed no english - language studies of obesity on inuit living in russia and they are excluded from our scoping review . in 2005 arksey and o'malley ( 15 ) published a methodological framework which presented 4 purposes for which a scoping review is appropriate : to examine the extent , range and nature of research activity.to determine the value of undertaking a full systematic review.to summarize and disseminate research findings.to identify research gaps in the existing literature.in a subsequent evaluation of the application of this framework , levac et al . ( 16 ) recommended that researchers add clarity and direction by clearly articulating research questions that guide the scope of the review , specifying concepts , target populations and health outcomes of interest , an approach which we have adopted in our study . to examine the extent , range and nature of research activity . to determine the value of undertaking a full systematic review . to summarize and disseminate research findings . to identify research gaps in the existing literature . the present study centres on the first purpose , namely to explore the extent , range and nature of research activity on obesity in the circumpolar inuit : to what extent has obesity research been undertaken in the circumpolar context ? are all subpopulations and geographic areas represented ? what methodologies are employed and are they sufficient to the task of describing risk factors , prevalence and health outcomes associated with obesity ? our study also addresses the third and fourth purposes : what is the prevalence of obesity ? what temporal trends , environmental risk factors and health outcomes are associated with obesity in this population ? finally , we undertake comprehensive assessment of the field as a whole and identify gaps in the existing literature : what subgroups of this population are under - researched , what methodologies are underutilized , and what further research is needed ? we operationalized obesity as a condition defined by direct or indirect assessment of excess body fat or adiposity , including body mass index ( bmi ) , various measures of abdominal obesity including waist circumference ( wc ) and waist - hip ratio ( whr ) , percent body fat and sum of skinfold thicknesses . both the dietitians of canada and the canadian pediatric society recommend the use of bmi to screen for overweight and obesity in children 2 or more years of age ( 17 ) , and a variety of guidelines exist for the identification of obesity in children 2 years and older ( 1821 ) . under the age of 2 years , rapid growth and variety in feeding practices make it difficult to identify children at risk of obesity ( 21 ) . the online databases cochrane library , jstor , medline , pubmed , science citation index , science direct and scopus were used to compile a list of english - language papers . search terms included a combination of medical subject headings and keywords related to the inquiry : greenlandic , inuit , eskimo , inupiat , alaska(n ) , aboriginal , indigenous , health , overweight , obesity , adiposity , body fat , body mass index , waist circumference , waist - hip ratio , diabetes , metabolic disease . the websites of national and regional governments and health agencies were searched for relevant published and unpublished documents . the publication records of authors and the reference lists of identified papers were combed for additional related resources . the search identified 115 citations which were assembled in an online refworks ( refworks - cos , bethesda , md ) file available to members of the team throughout the review . studies were included in the review on the following basis : the study was published during the 20-year period spanning 19922011.participants were age 2 years or greater.participants were identified in the study as greenlandic , inuit or eskimo or any of the regional self - designated terms.the study included 30 or more participants.obesity or abdominal obesity was a primary or secondary outcome variable or associated factor.the study was the result of primary research.studies on diabetes or cardiovascular diseases were included only if obesity was studied as a risk factor and assessed through direct or indirect means . participants were identified in the study as greenlandic , inuit or eskimo or any of the regional self - designated terms . obesity or abdominal obesity was a primary or secondary outcome variable or associated factor . 1 ) was conducted independently by both the principal reviewer ( tg ) and a second reviewer ( hb ) . the review team included authors of several of the papers identified in the literature search . these authors were excluded from selection , data extraction or quality assessment ( qa ) of their own papers . a customized data extraction instrument was developed to explore the scope of the available literature and to compare study design , methodology and results . the instrument summarizes study characteristics and findings , allows for expansion of sections relevant to each study under review , and permits comparisons across studies . we undertook qa of all selected studies using a modified version of the strobe instrument ( 22,23 ) ( strengthening the reporting of observational studies in epidemiology ) , a checklist of 22 items designed for cohort , case - control , and cross - sectional studies and intended as a tool to improve the consistency , quality and transparency of epidemiologic reporting . it is not designed to evaluate the quality of the research studies themselves ( 24,25 ) . a review of 86 published qa instruments yielded no clear candidate for a generic qa tool as the majority of reviewers develop subject - specific instruments ( 26 ) . ( 26 ) and used the comprehensive strobe statement as a starting point for our own qa instrument . however with its emphasis on reporting , strobe may inflate the quality of studies which are methodologically weak due to small sample size or lack of geographic representativeness . we therefore incorporated elements from the scottish intercollegiate guidelines network ( sign ) ( 27 ) methodology checklist in the development of our qa instrument . the resulting instrument yields a numeric qa score with maximum values that range from 27 to 29 depending on study design . we calculated percentage scores based on the maximum score for each category of study design and classified results as follows : a studies ( qa score > 85% ) ; b studies ( qa score 7685% ) ; c studies ( qa score 6175% ) ; and d studies ( qa score60% ) . in accordance with recommendations ( 28 ) , the qa was piloted prior to implementation . two reviewers ( tg and hb ) performed qa on 4 randomly - selected studies ( 11% of those selected ) and the results were compared using the k - statistic . then qa was performed by one of the reviewers ( either tg or hb ) on each of the studies reviewed . we use the term study in this paper to refer to journal articles and reports . these publications ultimately were based on a far smaller number of research studies or projects conducted in specific regions and are thus not independent . several publications from one study thus share the same methodological features of the parent study and only the reporting may differ . these publications may report on different cuts of the master dataset in terms of age furthermore , some publications report on the result of merging of the datasets of one or more of these studies . our populations of interest are collectively referred to as inuit , which extend from the chukotka peninsula in russia across alaska and northern canada to greenland . they are known by a variety of self - designated names in different regions ( including yuit , yupik , inupiat , inuvialuit , inuit and kalaallit ) . our search revealed no english - language studies of obesity on inuit living in russia and they are excluded from our scoping review . in 2005 arksey and o'malley ( 15 ) published a methodological framework which presented 4 purposes for which a scoping review is appropriate : to examine the extent , range and nature of research activity.to determine the value of undertaking a full systematic review.to summarize and disseminate research findings.to identify research gaps in the existing literature.in a subsequent evaluation of the application of this framework , levac et al . ( 16 ) recommended that researchers add clarity and direction by clearly articulating research questions that guide the scope of the review , specifying concepts , target populations and health outcomes of interest , an approach which we have adopted in our study . to examine the extent , range and nature of research activity . to determine the value of undertaking a full systematic review . to summarize and disseminate research findings . to identify research gaps in the existing literature . the present study centres on the first purpose , namely to explore the extent , range and nature of research activity on obesity in the circumpolar inuit : to what extent has obesity research been undertaken in the circumpolar context ? what methodologies are employed and are they sufficient to the task of describing risk factors , prevalence and health outcomes associated with obesity ? our study also addresses the third and fourth purposes : what is the prevalence of obesity ? what temporal trends , environmental risk factors and health outcomes are associated with obesity in this population ? finally , we undertake comprehensive assessment of the field as a whole and identify gaps in the existing literature : what subgroups of this population are under - researched , what methodologies are underutilized , and what further research is needed ? we operationalized obesity as a condition defined by direct or indirect assessment of excess body fat or adiposity , including body mass index ( bmi ) , various measures of abdominal obesity including waist circumference ( wc ) and waist - hip ratio ( whr ) , percent body fat and sum of skinfold thicknesses . both the dietitians of canada and the canadian pediatric society recommend the use of bmi to screen for overweight and obesity in children 2 or more years of age ( 17 ) , and a variety of guidelines exist for the identification of obesity in children 2 years and older ( 1821 ) . under the age of 2 years , rapid growth and variety in feeding practices make it difficult to identify children at risk of obesity ( 21 ) . the online databases cochrane library , jstor , medline , pubmed , science citation index , science direct and scopus were used to compile a list of english - language papers . search terms included a combination of medical subject headings and keywords related to the inquiry : greenlandic , inuit , eskimo , inupiat , alaska(n ) , aboriginal , indigenous , health , overweight , obesity , adiposity , body fat , body mass index , waist circumference , waist - hip ratio , diabetes , metabolic disease . the websites of national and regional governments and health agencies were searched for relevant published and unpublished documents . the publication records of authors and the reference lists of identified papers were combed for additional related resources . the search identified 115 citations which were assembled in an online refworks ( refworks - cos , bethesda , md ) file available to members of the team throughout the review . studies were included in the review on the following basis : the study was published during the 20-year period spanning 19922011.participants were age 2 years or greater.participants were identified in the study as greenlandic , inuit or eskimo or any of the regional self - designated terms.the study included 30 or more participants.obesity or abdominal obesity was a primary or secondary outcome variable or associated factor.the study was the result of primary research.studies on diabetes or cardiovascular diseases were included only if obesity was studied as a risk factor and assessed through direct or indirect means . participants were identified in the study as greenlandic , inuit or eskimo or any of the regional self - designated terms . obesity or abdominal obesity was a primary or secondary outcome variable or associated factor . 1 ) was conducted independently by both the principal reviewer ( tg ) and a second reviewer ( hb ) . the review team included authors of several of the papers identified in the literature search . these authors were excluded from selection , data extraction or quality assessment ( qa ) of their own papers . a customized data extraction instrument was developed to explore the scope of the available literature and to compare study design , methodology and results . the instrument summarizes study characteristics and findings , allows for expansion of sections relevant to each study under review , and permits comparisons across studies . we undertook qa of all selected studies using a modified version of the strobe instrument ( 22,23 ) ( strengthening the reporting of observational studies in epidemiology ) , a checklist of 22 items designed for cohort , case - control , and cross - sectional studies and intended as a tool to improve the consistency , quality and transparency of epidemiologic reporting . it is not designed to evaluate the quality of the research studies themselves ( 24,25 ) . a review of 86 published qa instruments yielded no clear candidate for a generic qa tool as the majority of reviewers develop subject - specific instruments ( 26 ) . ( 26 ) and used the comprehensive strobe statement as a starting point for our own qa instrument . however with its emphasis on reporting , strobe may inflate the quality of studies which are methodologically weak due to small sample size or lack of geographic representativeness . we therefore incorporated elements from the scottish intercollegiate guidelines network ( sign ) ( 27 ) methodology checklist in the development of our qa instrument . the resulting instrument yields a numeric qa score with maximum values that range from 27 to 29 depending on study design . we calculated percentage scores based on the maximum score for each category of study design and classified results as follows : a studies ( qa score > 85% ) ; b studies ( qa score 7685% ) ; c studies ( qa score 6175% ) ; and d studies ( qa score60% ) . in accordance with recommendations two reviewers ( tg and hb ) performed qa on 4 randomly - selected studies ( 11% of those selected ) and the results were compared using the k - statistic . then qa was performed by one of the reviewers ( either tg or hb ) on each of the studies reviewed . we use the term study in this paper to refer to journal articles and reports . these publications ultimately were based on a far smaller number of research studies or projects conducted in specific regions and are thus not independent . several publications from one study thus share the same methodological features of the parent study and only the reporting may differ . these publications may report on different cuts of the master dataset in terms of age furthermore , some publications report on the result of merging of the datasets of one or more of these studies . application of study selection criteria resulted in the inclusion of 38 studies in the review ( tables i and ii ) . the inter - rater reliability for the study selection was extremely strong ( weighted k=0.90 , p<0.001 ) . studies of adult circumpolar inuit included in the review by country of study , sample size , participants , study design and anthropometric measures / indices thirty - nine percent of studies examined obesity among canadian inuit ; 24% were set in alaska and 33% in greenland . the age range of adult participants tended to be broad , however , the lower age limit varied considerably ( table i ) . the study design was exclusively cross - sectional ; however , 19% of studies made comparisons to earlier research in order to report temporal trends in obesity metrics . there were 6 studies on children from canada and greenland , and none from alaska . three of these were retrospective cohorts constructed from greenland health surveillance data based on growth measures taken in doctors offices at age 2 years , at school entry and at various points during childhood and adolescence , which permitted the authors to examine the pattern of obesity onset in greenland inuit children and youth ages 217 years . studies of circumpolar inuit children included in the review by country of study , participants , study design and anthropometric indices all but one of the studies collected measured , rather than reported data . age - standardized prevalence of obesity was reported in 47% of studies ; the remainder reported only crude prevalence . bmi was used as an index of body size in all studies reviewed and was the only metric employed in studies in children . overall , the majority of studies ( 66% ) employed a combination of anthropometric markers ; the most common combinations were bmi+wc ( 17% ) and bmi+wc+whr ( 25% ) . no direct measures of adiposity , such as dual - energy x - ray absorptiometry or computerized tomography , were used . studies at the oldest end of the date range , prior to the publication of universal reference values for bmi , wc and whr , used a variety of reference standards , such as the 1987 us national center for health statistics standards for men and women ( 51,52,64 ) and bray 's bmi cutoff of 26 kg / m ( 28,65 ) the majority of studies of adults ( 63% ) employed bmi , wc and whr cutoffs defined by the world health organization ( who ) ( 6668 ) . all studies of children undertaken in greenland used the international obesity task force ( iotf ) reference values to define childhood obesity ( 18 ) . both the iotf and the 2000 centers for disease control ( cdc ) reference ( 20 ) were used in the 3 canadian publications derived from the nunavut inuit child health survey ( 5860 ) . during the qa pilot , raters subsequently reviewed the qa protocol together step - by - step to improve the consistency of rating prior to undertaking qa during the review . d . failure to achieve optimal quality scores resulted from a lack of clear definition of variables and data sources , in particular the failure to define obesity as a study variable . in 61% of studies , the authors did not provide adequate rationale for the obesity metric or the reference criteria used . a second major factor in study quality ranking was a lack of discussion of biases and limitations of the selected methodology ; this occurred in 76% of studies . we compared the obesity prevalence reported in studies of inuit adults ( table iii ) . this gender difference was particularly marked in studies reporting abdominal obesity , the sole exception being a greenland study of adults aged 3586 years ( 46 ) which employed lower wc cutoff values for abdominal obesity . prevalence ( % ) of obesity and abdominal obesity among inuit adults by sex and country of study obesity classified using who cutoff of bmi30 . eighty - two percent of studies analyzed risk factors associated with obesity , most commonly metabolic risk factors : lipid profile ( 44% ) ; serum glucose values ( 56% ) ; and either serum insulin or insulin resistance or both ( 13% ) . the tendency for obesity to be significantly associated with insulin resistance , impaired glucose metabolism , and unfavourable lipid profile was widely reported among adults . four studies examined the impact of variation in existing diagnostic criteria for mets ( 31,37,45,47 ) . among these studies , there was considerable discussion about whether abdominal obesity ( indicated by high wc ) had as deleterious an effect on metabolic risk relative to non - inuit populations . two papers called for improved diagnostic criteria for mets ( 31,45 ) and 2 others documented moderate agreement between who and national cholesterol education program diagnostic criteria for mets ( 37,47 ) . relatively few studies looked at diet and physical activity as risk factors for obesity among inuit . twenty - three percent of studies documented increased obesity prevalence in individuals with high energy intake , low physical activity measures , or some combination of both . the nunavut inuit child health survey was unable to establish a relationship between obesity risk and the consumption of market foods ( 59,60 ) . in greenland a study showed that overweight at school entry ( age 7 years ) predicted overweight in late childhood and adolescence ( 60 ) . the association between obesity and ses , specifically education , employment , job type and childhood socioeconomic conditions , was examined in 7 studies . two studies one in adults ( 58 ) and one in children ( 58 ) failed to find any association between household food insecurity and obesity outcomes . in greenland , westernization influenced the development of obesity and metabolic risk , although the processes differed among men and women . for men , risk of obesity and metabolic disease arose through a decrease in traditional hunting and fishing activities ; for women , the negative health consequences of westernization seem to be mediated through differences in ses , mainly educational attainment ( 47 ) . thirty - nine percent of studies examined obesity among canadian inuit ; 24% were set in alaska and 33% in greenland . the age range of adult participants tended to be broad , however , the lower age limit varied considerably ( table i ) . the exclusion of pregnant subjects was reported in 28% of studies . the study design was exclusively cross - sectional ; however , 19% of studies made comparisons to earlier research in order to report temporal trends in obesity metrics . there were 6 studies on children from canada and greenland , and none from alaska . three of these were retrospective cohorts constructed from greenland health surveillance data based on growth measures taken in doctors offices at age 2 years , at school entry and at various points during childhood and adolescence , which permitted the authors to examine the pattern of obesity onset in greenland inuit children and youth ages 217 years . studies of circumpolar inuit children included in the review by country of study , participants , study design and anthropometric indices age - standardized prevalence of obesity was reported in 47% of studies ; the remainder reported only crude prevalence . bmi was used as an index of body size in all studies reviewed and was the only metric employed in studies in children . overall , the majority of studies ( 66% ) employed a combination of anthropometric markers ; the most common combinations were bmi+wc ( 17% ) and bmi+wc+whr ( 25% ) . no direct measures of adiposity , such as dual - energy x - ray absorptiometry or computerized tomography , were used . studies at the oldest end of the date range , prior to the publication of universal reference values for bmi , wc and whr , used a variety of reference standards , such as the 1987 us national center for health statistics standards for men and women ( 51,52,64 ) and bray 's bmi cutoff of 26 kg / m ( 28,65 ) the majority of studies of adults ( 63% ) employed bmi , wc and whr cutoffs defined by the world health organization ( who ) ( 6668 ) . all studies of children undertaken in greenland used the international obesity task force ( iotf ) reference values to define childhood obesity ( 18 ) . both the iotf and the 2000 centers for disease control ( cdc ) reference ( 20 ) were used in the 3 canadian publications derived from the nunavut inuit child health survey ( 5860 ) . during the qa pilot , there was moderate inter - rater reliability ( k=0.43 , p=0.046 ) . raters subsequently reviewed the qa protocol together step - by - step to improve the consistency of rating prior to undertaking qa during the review . d . failure to achieve optimal quality scores resulted from a lack of clear definition of variables and data sources , in particular the failure to define obesity as a study variable . in 61% of studies , the authors did not provide adequate rationale for the obesity metric or the reference criteria used . a second major factor in study quality ranking was a lack of discussion of biases and limitations of the selected methodology ; this occurred in 76% of studies . we compared the obesity prevalence reported in studies of inuit adults ( table iii ) . in general , higher abdominal obesity prevalence was observed in women than in men . this gender difference was particularly marked in studies reporting abdominal obesity , the sole exception being a greenland study of adults aged 3586 years ( 46 ) which employed lower wc cutoff values for abdominal obesity . prevalence ( % ) of obesity and abdominal obesity among inuit adults by sex and country of study obesity classified using who cutoff of bmi30 . eighty - two percent of studies analyzed risk factors associated with obesity , most commonly metabolic risk factors : lipid profile ( 44% ) ; serum glucose values ( 56% ) ; and either serum insulin or insulin resistance or both ( 13% ) . the tendency for obesity to be significantly associated with insulin resistance , impaired glucose metabolism , and unfavourable lipid profile was widely reported among adults . four studies examined the impact of variation in existing diagnostic criteria for mets ( 31,37,45,47 ) . among these studies , there was considerable discussion about whether abdominal obesity ( indicated by high wc ) had as deleterious an effect on metabolic risk relative to non - inuit populations . two papers called for improved diagnostic criteria for mets ( 31,45 ) and 2 others documented moderate agreement between who and national cholesterol education program diagnostic criteria for mets ( 37,47 ) . relatively few studies looked at diet and physical activity as risk factors for obesity among inuit . twenty - three percent of studies documented increased obesity prevalence in individuals with high energy intake , low physical activity measures , or some combination of both . the nunavut inuit child health survey was unable to establish a relationship between obesity risk and the consumption of market foods ( 59,60 ) . in greenland a study showed that overweight at school entry ( age 7 years ) predicted overweight in late childhood and adolescence ( 60 ) . the association between obesity and ses , specifically education , employment , job type and childhood socioeconomic conditions , was examined in 7 studies . two studies one in adults ( 58 ) and one in children ( 58 ) failed to find any association between household food insecurity and obesity outcomes . in greenland , westernization influenced the development of obesity and metabolic risk , although the processes differed among men and women . for men , risk of obesity and metabolic disease arose through a decrease in traditional hunting and fishing activities ; for women , the negative health consequences of westernization seem to be mediated through differences in ses , mainly educational attainment ( 47 ) . in terms of overall scope , the literature on obesity in inuit populations is presently skewed toward studies of adults . this is likely due to the fact that obesity is a strong risk factor of diabetes and cardiovascular disease , which are primarily diseases of adults . there is strong evidence that obesity is increasing , that abdominal obesity is widely prevalent among inuit women , and that ( above a certain threshold not yet well - defined ) obesity has a deleterious effect on metabolic and cardiovascular health . in 1996 young observed that , in past studies , the low prevalence of obesity among inuit set them apart from other north american aboriginal populations ( 28 ) . studies published since 2000 document a consistent rise in obesity prevalence with increasing prevalence in the who class ii ( bmi 3539.9 ) and iii ( bmi40 ) categories of obesity ( 38,50,53,54,69 ) . many studies report disproportionately high prevalence of obesity ( measured by bmi ) and centripetal fat patterning ( measured by wc and whr ) among inuit women ( 11,30,32,37,38,52,55 ) . there is substantial evidence that obesity prevalence is increasing in children , which is particularly well documented in greenland ( 62,63 ) . the most recent data come from the nunavut inuit child health survey , where the prevalence of overweight and obesity ( using iotf cutoffs ) in this preschool age sample were 39 and 28% , respectively ( 58 ) . such high prevalence raises significant concern over future health and metabolic disease risk in children . there is also strong evidence from greenland and nunavut that the age of obesity onset is decreasing , such that obesity has emerged as a significant health concern in inuit preschoolers ( 59,62 ) . the decreasing age of onset of overweight is part of a constellation of biological processes ( including earlier skeletal maturity , earlier adolescent growth spurt , and decreasing age at menarche ) accompanying rapid acculturation to a western lifestyle ( 70,71 ) . there are pronounced gaps in our knowledge of obesity among inuit children , especially adolescents ( our review located only 2 studies ) ( 61,63 ) and no recent data on obesity prevalence among children aged 1012 years . it is increasingly recognized that many adult health problems have their origin in childhood , and socioeconomic factors operating during childhood has been shown to be associated with adult obesity among greenlanders ( 41 ) . prospective cohort studies offer the opportunity to examine associations between early childhood environment and obesity as well as the relative contribution of obesity and other risk factors to metabolic and cardiovascular health outcomes in inuit adults . in terms of international comparison , this review located only 2 studies that compared obesity prevalence in adult populations ( 56,57 ) . while it is likely that obesity and its concomitant health effects are influenced by processes particular to each country , there is nevertheless marked consistency in patterns of risk factors , prevalence and health - related outcomes among inuit . examples are changes in diet and physical activity patterns ( 9,50,58,72 ) and the role of a marine diet in mitigating some of the negative health effects of acculturation to a western lifestyle ( 32,7376 ) . we make several observations regarding the methodologies currently in use to assess obesity in the circumpolar inuit . first , while the link between obesity and metabolic / cardiovascular disease risk in this population is well established , there is evidence that current diagnostic thresholds may not reflect the levels of risk experienced by inuit . studies demonstrate that for given levels of obesity , inuit have lower blood pressure , lower levels of glucose , insulin , triglyceride and higher levels of hdl cholesterol than non - inuit subjects ( 31,44 ) , prompting some researchers to call for inuit - specific cutoffs for central obesity measures associated with diabetes and cardiovascular disease outcomes ( 31,44,57 ) . however , we find consistency in the relationship between rising adiposity and health risks . there is ample evidence that inuit mortality from cardiovascular disease is at least as high as in non - inuit populations and that inuit mortality from cerebrovascular disease is significantly higher ( 56 ) . rather than developing ethnic - specific cutoff values , we propose that researchers first undertake validation studies to determine the accuracy of indirect measures of adiposity in inuit adults and children . the accumulation of intra - abdominal or visceral fat is a marker of considerable metabolic risk . however without imaging studies ( e.g. dual x - ray absorptiometry , computerized tomography , ultrasonography and magnetic resonance imaging ) it is not known whether central obesity is predominantly intra - abdominal or subcutaneous . while attempts have been made to more accurately describe fat- and lean - mass distribution in inuit ( 77,78 ) we still know relatively little about fat distribution at various levels of bmi or waist circumference in this population . finally , we observe a general failure to define obesity as a variable . the quality of studies would be significantly improved by careful selection of metrics and reference standards and consistent reporting of limitations . our review found multiple metrics employed in 66% of studies however bmi was the sole indirect measure of adiposity employed in studies of children . there is evidence that methodologies such as wc , triceps skinfolds and mid - upper arm circumference ( muac ) may be effective tools for obesity screening in children ( 79,80 ) . inclusion of these methodologies may assist in the improvement of health surveillance programs for inuit children . standardized protocols incorporating hold - out samples and repeat measures would permit reporting of inter- and intra - observer error and technical error of measurement ( 81 ) , features which would improve both the rigour and comparability of anthropometric studies . given the logistical challenges of conducting obesity research in the north , it is likely that the majority of future studies will continue to employ indirect measures of adiposity . in order to improve consistency in the use of cutoffs for classifying body weight in inuit populations , we recommend the following : ( a ) the use and reporting of who cutoffs for adults ( 67,68 ) and ( b ) until international consensus is reached on the appropriate reference for children , the use and reporting of prevalence determined by both the iotf ( 18 ) and who growth standard and reference for children ( 19,21 ) . the results of this review indicate that concerted research effort has yielded substantial knowledge about the prevalence and factors associated with obesity in the circumpolar inuit . with the exception of inuit in chukotka , russia , there is broad geographic coverage of the regions where inuit reside . obesity prevalence is high among adults and has risen significantly in selected populations of preschool- and school - aged children . inuit women are at greater risk of abdominal obesity than inuit men however in both sexes obesity is associated with elevated metabolic risk factors such as insulin resistance , impaired glucose metabolism and negative trends in lipid profile . while the quality of studies is generally high and relies on measured , rather than reported , data , research on obesity among inuit would benefit from emphasis on several areas : careful selection of metrics and reference standards ; direct measures of adiposity in adults and children which can be used to determine accurate anthropometric markers of disease risk ; studies of preadolescent children ; and prospective cohort studies linking early childhood exposures with obesity outcomes throughout childhood and adolescence .

backgroundamong circumpolar populations , recent research has documented a significant increase in risk factors which are commonly associated with chronic disease , notably obesity.objectivethe present study undertakes a scoping review of research on obesity in the circumpolar inuit to determine the extent obesity research has been undertaken , how well all subpopulations and geographic areas are represented , the methodologies used and whether they are sufficient in describing risk factors , and the prevalence and health outcomes associated with obesity.designonline databases were used to identify papers published 19922011 , from which we selected 38 publications from canada , the united states , and greenland that used obesity as a primary or secondary outcome variable in 30 or more non - pregnant inuit ( eskimo ) participants aged 2 years or older.resultsthe majority of publications ( 92% ) reported cross - sectional studies while 8% examined retrospective cohorts . all but one of the studies collected measured data . overall 84% of the publications examined obesity in adults . those examining obesity in children focused on early childhood or adolescence . while most ( 66% ) reported 1 or more anthropometric indices , none incorporated direct measures of adiposity . evaluated using a customized quality assessment instrument , 26% of studies achieved an a quality ranking , while 18 and 39% achieved quality rankings of b and c , respectively.conclusionswhile the quality of studies is generally high , research on obesity among inuit would benefit from careful selection of methods and reference standards , direct measures of adiposity in adults and children , studies of preadolescent children , and prospective cohort studies linking early childhood exposures with obesity outcomes throughout childhood and adolescence .

After too many Caribbean vacations, Johnny Depp finally gets back down to some serious business in Black Mass, a major league real-life gangster film loaded with ripely presented murders, beatings, betrayals and vengeance-takings, all backed up by a deep-secret arrangement between Boston's top-dog criminal and the FBI. Even if director Scott Cooper's jump into big-time studio filmmaking feels familiar and derivative in some respects, he has taken care to borrow only from the best, and a top-notch cast socks over the many dramatic opportunities. Box-office prospects look potent. Long-time Depp fans who might have lately given up hope of his doing something interesting anytime soon will especially appreciate his dive into the deep end here to personify genuine perfidy in the guise of legendary hoodlum James "Whitey" Bulger, the crime kingpin of South Boston from the 1970s until 1994, when he was forced to go on the lam for what ended up being 16 years. For a dozen of them he was second only to Osama Bin Laden on the FBI's Ten Most Wanted list. What gave him such status provides the substance of this continually absorbing melodrama, one that scarcely glamorizes Bulger's complete allegiance to a life of crime. Bulger, to this day, denies that he was a rat for the Feds, the worst thing you could be in his world; to him it was an "alliance" to rid Boston of the Italian mafia. You can detect Depp behind the elaborate makeup job — the thinning, blondish, brushed back hair, the blue eyes, the rotten teeth. He may be better-looking than the real Bulger, but not by much. He's far from the biggest guy in the room, but he's plenty tough and has a Bloodhound's sense of smell for anyone who might be thinking of crossing him. He grew up in the slums of Southie and has known most of his cronies since playground days. In a nod to Citizen Kane, the script by Mark Mallouk and Jez Butterworth is structured around interview testimony given by some of Bulger's longtime henchmen after their arrest and their boss' disappearance. Their comments are revealing but not conflicting: Their boss was the thug of thugs, the baddest ass in Boston, a man who finally, in his 80s, was sentenced to two life terms plus five years after having been charged with murder (19 cases), extortion, racketeering, narcotics peddling and money laundering. Early scenes neatly establish the tough-guy ways of Bulger, recently sprung from nearly a decade in federal prison, including Alcatraz, and his underlings in the bars and cars of Southie. An escalation of war with the Angiulo family in North Boston seems inevitable, but Bulger's Winter Hill Gang isn't the only organization that wants to bring the Italians down: The FBI can't get anything on them, so the bureau's John Morris (David Harbour) and an agent who's known Bulger since boyhood times in the neighborhood, John Connolly (Joel Edgerton), eventually persuade Bulger that it's in his interest, as well as theirs, to secretly team up against their mutual enemy. Read more 'Spotlight': Venice Review This works out brilliantly, especially for Bulger, who now not only has Boston to himself by enjoys virtual carte blanche as far as the Feds are concerned; he can extort or kill essentially anyone he wants and knows he can get away with it. Turning a blind eye toward this as best he can is Bulger's upstanding brother Billy (Benedict Cumberbatch), who happens to be Massachusetts' most powerful state senator. The one thing Bulger can't control relates to his only child, a six-year-old boy who dies from an allergic reaction to an injection. He breaks down and argues with his wife (Dakota Johnson), after which we never see her again; maybe we don't want to know what happened to her. Where killings are concerned, sometimes Bulger does them himself, while on other occasions he lets one of his beefy goons handle them; Rory Cochrane, W. Earl Brown, Jesse Plemons and Scott Anderson are plenty convincing as his inner-circle boys. Cooper, who previously directed Crazy Heart and Out of the Furnace after working as an actor, times and stages the violence for sharp visceral impact and street realism, avoiding operatic extremes as well as trendy fast cutting and ridiculous forms of physicality. But especially in regard to some key interior dramatic sequences, Cooper would seem to have given the Godfather films some very close re-viewings, as his typical approach is much like Coppola's, starting with carefully composed and sometimes lengthily held master shots that are followed by unusually tight and sustained close-ups, which make the actors look really good. The performers return the favor with very strong, sometimes riveting work — and all with pretty passable Beantown accents. As Bulger's childhood crony who went straight only to make his bed with Bulger and then had to sleep in it, Edgerton is outstanding, painting a vibrant picture of an ambitious hustler who thinks he can talk his way into and out of anything but whose anxieties begin to show like cracks in melting ice. Peter Sarsgaard has some memorable moments as a drug-addled businessman who has the misfortune of ending up on Bulger's bad side; Harbour, Adam Scott and Kevin Bacon seethingly express, as federal agents, the FBI's growing frustration with the situation; Corey Stoll comes on strong as a federal prosecutor determined to nail Bulger, while Cumberbatch must go the other way to elegantly portray the distinguished brother who escaped the slums, had nine kids, served as longtime Massachusetts Senate president and then as president of the University of Massachusetts. Read more 'Beasts of No Nation': Venice Review In short, they all offer very strong support for Depp, who takes control of the proceedings from the outset and never yields it, except for when he disappears for a while in the second half. He's as charismatic as his character must be, fully convincing and frightening as his Bulger toys with friends and enemies alike to keep them guessing, hides his true intentions and dishes out punishment at an alarming rate. Depp's instinct for observing, underlaying and keeping things in, then letting it all out when required, pays big dividends here in a performance far more convincing than his previous big gangster role, John Dillinger in Michael Mann's Public Enemies; it's unexpected, very welcome at this point in his career and one of his best. The Boston locations are numerous and evocative, and production values are strong to to bottom, notably Masanobu Takayanagi's cinematography, Stefania Cella's production design and Kasia Walicka-Maimone's costumes. Production: Cross Creek Pictures Cast: Johnny Depp, Joel Edgerton, Benedict Cumberbatch, Rory Cochrane, Jesse Plemons, W Earl Brown, David Harbour, Dakota Johnson, Julianne Nicholson, Kevin Bacon, Corey Stoll, Peter Sarsgaard, Adam Scott, Juno Temple, Bill Camp Director: Scott Cooper Screenwriters: Mark Mallouk, Jez Butterworth, based on the book by Dick Lehr, Gerard O'Neill Producers: John Lesher, Brian Oliver, Scott Cooper, Patrick McCormick, Tyler Thompson Executive producers: Brett Ratner, James Packer, Steven Mnuchin, Peter Mallouk, Ray Mallouk, Christopher Woodrow, Brett Granstaff, Gary Granstaff, Phil Hunt, Compton Ross Director of photography: Masanobu Takayanagi Production designer: Stefania Cella Costume designer: Kasia Walicka Maimone Editor: David Rosenbloom Music: Tom Holkenborg Casting: Francine Maisler R rating, 123 minutes ||||| The icy blue eyes of notorious Boston crime boss James “Whitey” Bulger stare out from the screen in Scott Cooper’s “Black Mass” like the gaze of some confident jungle predator calmly lying in wait, holding his ground until the moment he moves in for the kill. And that same coolly calculated composure extends to every aspect of how the actor playing Bulger embodies the role, or rather disappears into it. But if Johnny Depp’s mesmerizing performance — a bracing return to form for the star after a series of critical and commercial misfires — is the chief selling point of “Black Mass,” there is much else to recommend this sober, sprawling, deeply engrossing evocation of Bulger’s South Boston fiefdom and his complex relationship with the FBI agent John Connolly, played with equally impressive skill by Joel Edgerton. Something of an anti-“The Departed” (which was partly inspired by the Bulger case), the movie has an intentionally muted, ’70s-style look and feel that may limit its appeal to the date-night multiplex crowd, but quality-starved adult moviegoers should flock to one of the fall’s first serious, awards-caliber attractions. Based on the exhaustively researched book of the same name by Boston Globe reporters Dick Lehr and Gerard O’Neill (who make cameo appearances in the film), “Black Mass” passed through the hands of several directors (including Jim Sheridan and Barry Levinson) on its way to the screen, and nearly fell apart entirely in 2013 when Depp briefly quit the picture over a reported salary dispute. But the project found the right steward in Cooper, who showed a sure hand with actors on his prior “Crazy Heart” and “Out of the Furnace,” and who here challenges Depp to give the kind of less-is-more performance the actor has scarcely been asked to deliver in the post-“Pirates of the Caribbean” era. And Depp more than rises to the occasion, doing career-best work as a man who might easily have been played for ghoulish caricature (a la Jack Nicholson in “The Departed”), but instead emerges as a complex, undeniably charismatic figure who draws other criminals and lawmen alike into his cult of sociopathic personality. Indeed, it takes a few moments to fully recognize Depp — transformed by latex, contacts and dramatically receding whitish-blond hair — in the film’s opening scenes, set in 1975, just as Bulger was beginning his ascent as the leader of the Winter Hill Gang, a loose confederacy of Irish- and Italian-American hoods vying for control of the South Boston streets against the mob-connected Angiulo brothers. Bulger’s turf war coincides with the homecoming of Connolly, who has established himself as a rising Bureau star on assignment in San Francisco and New York, and who has returned to Boston with the explicit task of taking down the Angiulos and their associates. To do this, he conceives of the plan that will ultimately lead to his undoing: recruiting his childhood friend, Bulger, to supply the Bureau with intel about his rivals in exchange for de facto immunity for his own dirty dealings. In Connolly’s logic, Bulger won’t be a “rat” per se, but rather will enter into an “alliance,” a quid pro quo of sorts that will also help him to rid himself of the competition. (Bulger, for his part, would later deny ever having served as an informant, claiming he paid the FBI for information and not the other way around.) “Black Mass” hinges on this increasingly compromising pas de deux, and Edgerton (sporting a flawless Boston accent) is superb at showing how the ambitious but straight-laced Connolly is ever more seduced by the decadent gangster lifestyle, his professional ethics muddied by the clan loyalty and street justice that, in some corners of Boston, are more sacred than the Constitution. But working from a script credited to Mark Mallouk and Jez Butterworth (other hands are also said to have been involved), Cooper enlarges the frame to give us a full-bodied portrait of both men’s worlds — in some ways diametrically opposed, in others oddly similar. Each has his own crew — the fellow thugs Bulger keeps close, and sometimes turns against in hair-trigger fashion (including the very good Jesse Plemons and Rory Cochrane as right-hand men Kevin Weeks and Steve Flemmi); the fellow agents (played by the likes of Kevin Bacon and Adam Scott) whom Connolly manipulates in an elaborate shell game designed to deflect attention from Bulger and himself. And though Connolly is the ostensible family man, with a concerned wife (Julianne Nicholson) who sees him changing in ways he doesn’t realize, we also experience an oddly tender side of Bulger himself — a devoted son to his elderly mother, loving sibling to his state-senator brother, Billy (an excellent Benedict Cumberbatch), and a protective father who indoctrinates his young son in the ways of the streets (“If nobody sees it, it didn’t happen”). The script compresses the potentially unwieldy narrative into three major acts, the second set in 1981 (when Bulger makes an ultimately ill-fated play to corner the Jai Alai gambling market in Florida), and the third in 1985, when the Bulger-Connolly alliance has so successfully eliminated Whitey’s competitors that the agent can no longer shield the Winter Hill Gang from the wrath of a dogged federal prosecutor (Corey Stoll). And at each step, Cooper stages taut, riveting setpieces that feel destined for the genre canon, including an unforgettable dinner scene (already revealed at some length in the film’s first trailer) in which Bulger turns a seemingly innocuous discussion of a “secret” family recipe into a blistering attack on the loyalty of Connolly’s supervisor, John Morris (David Harbour). The insidious cackle Bulger unleashes at the end of that rant is about the closest “Black Mass” ever comes to the grisly gallows humor that has become the lingua franca of the gangster movie in the post-“GoodFellas” era, but mostly Depp and Cooper play things in a more understated key. Depp hasn’t been this tamped down in a movie since he played second fiddle to Al Pacino in “Donnie Brasco”; even his Oscar-nominated J.M. Barrie in “Finding Neverland” seems a whirl of outsized tics and mannerisms by comparison. Even great actors (Nicholson and Pacino being among the perfect test cases) can fall back on indulgences and bad habits when they feel they’re giving the audience what it wants to see. But Depp is fully restored here to the daring, inspired performer of his early Tim Burton collaborations and “Dead Man,” knowing he is so deep inside the role that, whatever he does, we will come to him. The violence in “Black Mass,” when it comes, is swift and brutal, but nothing here is more startling than a single, sudden dart of Bulger’s eyes across a room. Working with a top-flight craft team that includes production designer Stefania Cella (“The Great Beauty”) and costume designer Kasia Walicka Maimone (“Foxcatcher”), Cooper bathes the film in a look that feels unfailingly true to the period without ever verging on kitsch; it’s a movie that isn’t just taking place in the late ‘70s and early ‘80s, but seems to have been made then. That feeling is further enhanced by the hard-edged elegance of cinematographer Masanobu Takayanagi’s 35mm widescreen lensing (which strongly recalls Gordon Willis’ work on “Klute” and the “Godfather” movies). In a complete about-face from his adrenaline-pumping “Mad Max: Fury Road” soundtrack, Dutch composer/producer Tom Holkenborg (aka Junkie XL) supplies an elegiac orchestral score that perfectly complements the film’s desperate, wintry mood.

– Yes, that's Johnny Depp in those eerie blue contacts and balding blonde wig. The actor transforms into gangster James "Whitey" Bulger in Black Mass, which follows the crimelord's remarkable rise in South Boston, with a strong supporting cast along for the ride. Here's what critics are saying: The movie's actors deliver "very strong, sometimes riveting work," writes Todd McCarthy at the Hollywood Reporter. Joel Edgerton is "outstanding" as FBI agent John Connolly, but it's Depp "who takes control of the proceedings from the outset and never yields it, except for when he disappears for a while in the second half," writes McCarthy. He's "fully convincing and frightening." Overall, it's "one of his best" performances. You certainly can't fault the acting, writes Moira Macdonald at the Seattle Times. Benedict Cumberbatch and Dakota Johnson each deliver alongside Depp. But the film "never quite seems to build to a peak," she says. "It's one of those movies that you don't exactly enjoy (so many guns, so many deaths), but you appreciate for its craft and tension, and for its cast's willingness to lose themselves in the darkness." Scott Foundas agrees with McCarthy. Depp is "mesmerizing" as he's restored "to the daring, inspired performer of his early Tim Burton collaborations." But there's a lot more to attract audiences, he writes at Variety. Director Scott Cooper also offers a wonderful portrait of Connolly, which results in a "sober, sprawling, deeply engrossing" picture. Foundas says it's "one of the fall's first serious, awards-caliber attractions." Rene Rodriguez couldn't disagree more. This is supposed to be Depp's comeback film, but "once again, he's playing a thinly written character who is all surface," he writes at the Miami Herald. Since "Depp never lets us inside Bulger's head," he appears only as "a two-dimensional boogeyman ... comprised of pieces from more memorable movie gangsters," Rodriguez says. "The only thing the film manages to do is remind us we've seen all this stuff done before—and done better."

failure rates as high as 40 to 70% have been reported following repeat fusion for pseudarthrosis.1 2 3 4 studies have also shown that patients with nonunion undergoing revision fusion surgery have worse outcomes compared with other indications for lumbar fusion.5 6 7 8 several surgical techniques exist for the treatment of nonunion , ranging from anterior - only and posterior - only procedures to combined anterior - posterior fusion . to our knowledge , there is no clear evidence in the literature as to which surgical technique is best suited for the treatment of symptomatic nonunion following attempted lumbar fusion . posterior spinal fusion ( psf ) and transforaminal lumbar interbody fusion ( tlif ) provide the advantage of a single approach with the ability to examine the previous fusion mass directly and address any possible hardware failure issues . although anterior - posterior ( ap ) approach probably affords the most reliable chance of fusion,2 4 6 it is associated with an increased complication rate.9 10 11 12 anterior lumbar interbody fusion ( alif ) alone can give the surgeon a large fusion surface area without further disruption of the paraspinal musculature . increasingly , treatment effectiveness for lumbar degenerative disorders is determined by improvements in health - related quality of life ( hrqol ) measures . the most commonly used disease - specific measure for low - back pain is the oswestry disability index ( odi),13 14 and a commonly used generic measures is the medical outcomes study short form-36 ( sf-36).15 therefore , the purpose of the current study was to examine if different surgical techniques used for the treatment of lumbar nonunion impacts 2-year postoperative hrqol measures . after receiving institutional review board approval , patients who underwent lumbar fusion surgery from 2002 to 2010 from a single institution for symptomatic nonunion who had preoperative and 2-year postoperative hrqol measures were identified . nonunion was diagnosed based on radiographs and computed tomography scans with sagittal and frontal reconstructions ( fig . hrqols evaluated included the sf-36,15 the odi,13 14 and numeric rating scales ( 0 to 10 ) for back and leg pain.16 patients were then grouped based on which surgical approach to treat their nonunion was used . of the 134 patients identified , 60 patients underwent instrumented posterolateral fusion ( psf ) , 18 patients underwent psf with tlif , 32 patients underwent ap spinal fusion , and 24 patients underwent alif . ( a ) frontal and ( b ) sagittal reconstructions of computed tomography axial scans of the 42-year - old man who had a transforaminal interbody fusion from l4 to s1 1 year prior showing lucency at the cage - end plate interface and lack of bridging trabeculation across the disk space . one - way analysis of variance was used to compare continuous variables , and the kruskal - wallis test was used to compare categorical variables among the four study groups . as the determination of which approach to use for the individual patients was based on physician preference , linear regression was also performed to control for confounders and selection bias . factors included age , gender , number of levels , body mass index , smoking , and workers ' compensation status as these factors have been previously shown to influence outcomes after lumbar fusion surgery . all statistical analyses were performed using statistical package for the social sciences version 21 ( ibm , somes , new york , united states ) . the percentage of patients reaching the minimum clinically important difference ( mcid ) was also examined for each group . this measure represents the minimum improvement in an outcome measure in which the patient perceives a worthwhile benefit.17 18 19 20 the mcid was defined as 12.8-point decrease in odi , 4.9-point increase in physical component summary ( pcs ) , 1.2-point decrease in back pain , and 1.6-point decrease in leg pain based on previously published thresholds.21 due to multiple concurrent analyses and relatively small sample size , threshold p value was set at 0.001 . the entire study cohort consisted of 65 male and 69 female patients with an average age of 50.4 years . thirty - eight ( 28.4% ) were smokers , and 17 ( 12.7% ) were involved in a workers ' compensation claim . the four groups were similar demographically in terms of age , sex distribution , smoking status , workers ' compensation status , and bmi . however , the tlif group had a greater blood loss and longer operative time , and the ap group had a longer length of hospital stay compared with the other groups ( table 1 ) . abbreviations : alif , anterior lumbar interbody fusion ; ap , anteroposterior fusion ; bmi , body mass index ; ebl , estimated blood loss ; psf , posterolateral fusion ; tlif , transforaminal lumbar interbody fusion . preoperative and 2-year hrqol measures and the pre- to 2-year postoperative change in hrqol measures for each of the surgical techniques are summarized in table 2 . there were no significant differences between the treatment groups with regard to preoperative and 2-year hrqol measures or the pre- to 2-year postoperative change in hrqol measures . although not statistically significant , psf demonstrated the greatest improvement in all of the hrqol measures at 2 years : 11.65-point improvement in odi , 3.36-point improvement in sf-36 pcs , 2.19-point decrease in back pain , and 1.74-point decrease in leg pain . abbreviations : alif , anterior lumbar interbody fusion ; ap , anteroposterior fusion ; hrqol , health - related qualify of life ; mcs , mental component summary ; odi , oswestry disability index ; pcs , physical component summary ; psf , posterolateral fusion ; sf-36 , short form-36 , tlif , transforaminal lumbar interbody fusion . we also examined the percentage of patients who reached the mcid for each surgical technique ( fig . only 17% of patients reached the mcid for odi when tlif or alif were used to treat the nonunion . the mcid for odi was reached in 25% of ap and 28% of psf techniques . the ap technique faired the best for all outcomes measured except for sf-36 pcs . bar graph showing proportion of patients in each group achieving minimum clinically important differences for each of the outcome measures.22 abbreviations : odi , oswestry disability index ; pcs , physical component summary ; sf-36 , short form-36 . after controlling for factors such as age , gender , bmi , smoking status , workers ' compensation status , number of levels fused , and preoperative hrqol measures , the linear regression analysis showed that the type of surgical approach was not predictive of the change in any of the hrqol scores ( table 3 ) . the primary goal of revision surgery for lumbar nonunion is to improve patients ' symptoms and their quality of life . however , improvement after lumbar fusion surgery has been shown to be influenced by numerous factors unrelated to the technical success of the surgery . albert et al found that the presence of abnormal neurologic findings , significant preoperative narcotic use , and workers ' compensation or legal status before surgery increased the chance of failure.6 although important , achieving a solid arthrodesis following pseudarthrosis may not be enough . the reported fusion rates after revision for nonunion have been highly variable , ranging from 40 to 100%.2 9 22 23 despite the radiographic evidence of fusion success of 100% at 2 years , adogwa et al found only a 4.01-point improvement in odi at 2 years after surgery.22 similarly , the study by gertzbein et al also found a 100% union rate after circumferential fusion , but the satisfactory outcome rate was slightly better than 50% based on intensity of pain , pain medication use , and work status.9 in a prospective study of 18 patients undergoing revision for pseudarthrosis following plif with stand - alone cages , cassinelli et al obtained a 94% fusion rate.23 however , 72% of these patients rated their musculoskeletal condition as the same or worse compared with preoperative condition . the mean odi improvement in the current study was 9.71 points , which is better than previously published results . a previous study at our institution found only 5.5-point improvement in odi at 2 years when treated with psf alone.5 cassinelli et al reported mean odi improvement of 5.3 points.23 in a subanalysis of their patients without a complication , odi improved 10.2 points . the purpose of this study was to determine if there was an optimal surgical treatment approach that not only achieves fusion after revision surgery for nonunion but also improves patient outcomes . unfortunately , the type of surgical approach did not seem to impact patient outcomes , whether interpreted as a mean change in outcome scores or the proportion of patients achieving mcid . even after controlling for possible confounding factors and selection bias , the type of surgical approach was not predictive of the change in any of the hrqol scores . although every patient included in this study had a lumbar pseudarthrosis , we did not stratify the different types of pseudarthrosis that may be encountered . for example , a patient might have had symptomatic adjacent - level stenosis but was found to have a pseudarthrosis intraoperatively . one could also argue that patients with gross instability and hardware failure might represent a subgroup of patients who are quite different from patients with a stable pseudarthrosis . there can be a host of confounding variables that are both patient- and surgeon - related . failed pseudarthrosis repair could potentially be due to improper diagnosis or indication for fusion in the first place . in conclusion , this study found no statistically significant difference in hrqol outcome measures between the four surgical techniques . all surgical approaches resulted in poor to modest improvement in odi with 17 to 28% of patients reaching mcid for odi . this study and previously published studies highlight the difficulty in achieving clinical success with revision surgery for lumbar pseudarthrosis , further emphasizing the importance of achieving a solid fusion with the index surgery .

study design retrospective comparative cohort . objective pseudarthrosis following fusion for degenerative lumbar spine pathologies remains a substantial problem . current data shows that patients who develop a pseudarthrosis have suboptimal outcomes . this study evaluates if treatment of pseudarthrosis can be affected by surgical approach . methods medical records of 63 female and 65 male patients ( mean age 50.37 ) who were treated for nonunion following lumbar fusion were reviewed . sixty patients underwent posterolateral fusion ( psf ) , 18 underwent psf with transforaminal interbody fusion ( tlif ) , 32 underwent anterior and posterior spinal fusion ( ap ) , and 24 underwent anterior lumbar interbody fusion ( alif ) . results significant differences between the treatment groups were observed in length of stay ( p = 0.000 ) , blood loss ( p = 0.000 ) , and operative time ( p = 0.000 ) . in the ap fusion group , minimal clinically important difference ( mcid ) was reached in 47% of patients for back pain , 28% for leg pain , and 28% for oswestry disability index ( odi ) . psf had the highest percentage of patients reaching mcid for short form-36 ( sf-36 ) physical composite score at 25% . alif and tlif subgroups reached mcid for odi in 17% of patients . linear regression analysis showed that type of surgical approach did not impact change in odi scores . conclusion although not statistically significant , the ap fusion group reached mcid more frequently in all outcomes except sf-36 physical component summary . all surgical approaches examined for treatment of lumbar pseudarthrosis resulted in only poor to modest improvement in odi . this result further emphasizes the importance of achieving a solid fusion with the index surgery .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Strict Liability for Safer Streets Act of 1993''. TITLE I--STRICT LIABILITY OF MANUFACTURERS AND IMPORTERS OF HANDGUNS AND ASSAULT WEAPONS SEC. 101. CAUSE OF ACTION; FEDERAL JURISDICTION. (a) In General.--Any person suffering bodily injury, death, or property damage, as a result of the discharge of a handgun or an assault weapon may bring an action in any United States district court against any permissible defendant for damages and such other relief as the court deems appropriate. (b) Permissible Defendants.--The following persons are permissible defendants in an action brought under subsection (a) with respect to a handgun or an assault weapon: (1) Any manufacturer of the handgun or assault weapon. (2) Any importer of the handgun or assault weapon. SEC. 102. STRICT LIABILITY. (a) In General.--Each defendant in an action brought under section 101(a) shall be held strictly liable in tort, without regard to fault or proof of defect, for all direct and consequential damages that arise from bodily injury, death, and property damage, proximately resulting from the discharge of the handgun or assault weapon with respect to which the defendant is a permissible defendant, except as provided in subsection (b) of this section. (b) Defenses.-- (1) Injury while committing a felony.--There shall be no liability under subsection (a) if it is established by a preponderance of the evidence that the plaintiff suffered the bodily injury, death, or property damage, while committing a crime punishable by death, or by imprisonment for life or for any term of years. (2) Self-inflicted injury.--There shall be no liability under subsection (a) if it is established by a preponderance of the evidence that the plaintiff's bodily injury or death was self-inflicted, or that the property damage was caused by the plaintiff. (3) Injury by law enforcement officer.--There shall be no liability under subsection (a) if it is established by a preponderance of the evidence that the injury was suffered as a result of the discharge, by a law enforcement officer in the performance of official duties, of a handgun or assault weapon issued by the United States or any department or agency thereof, or any State or any department, agency, or political subdivision thereof. (4) Injury by member of the united states armed forces.-- There shall be no liability under subsection (a) if it is established by a preponderance of the evidence that the injury was suffered as a result of the discharge, by a member of the Armed Forces of the United States in the performance of military duties, of a handgun or assault weapon issued by the United States or any department or agency thereof. (5) Injury by security guard.--There shall be no liability under subsection (a) if it is established by a preponderance of the evidence that the injury was suffered as a result of the discharge, by an individual within the scope of employment as a security guard, of a handgun or assault weapon issued by the employer of the individual. (c) Authority to Award a Reasonable Attorney's Fee.--In an action brought under section 101(a), the court may, in its discretion, allow the prevailing party a reasonable attorney's fee as part of the costs. SEC. 103. STATUTE OF LIMITATIONS. An action may not be brought under section 101(a) after the 2-year period that begins with the date the injury described therein is discovered. SEC. 104. APPLICABILITY. This title shall apply only to handguns and assault weapons manufactured in or imported into the United States after the effective date of this Act. SEC. 105. NO EFFECT ON OTHER CAUSES OF ACTION. This title shall not be construed to limit the scope of any other cause of action available to a person who suffers bodily injury, death, or property damage, as a result of the discharge of a handgun or an assault weapon. SEC. 106. DEFINITIONS. As used in this title: (1) Handgun.--The term ``handgun'' means a firearm which, at the time of manufacture, had a barrel of less than 12 inches in length. (2) Assault weapon.--The term ``assault weapon'' means-- (A) a firearm-- (i) which-- (I) has a barrel of 12 or more inches in length; and (II) is capable of receiving ammunition directly from a large capacity ammunition magazine; (ii) which is a semiautomatic firearm which is-- (I) not generally recognized as particularly suitable for, or readily adaptable to, sporting purposes; or (II) concealable on a person; or (B) a firearm which is substantially functionally equivalent to a firearm described by clause (i) or (ii) of subparagraph (A). (3) Large capacity ammunition magazine.--The term ``large capacity ammunition magazine'' means a detachable magazine, belt, drum, feed strip, or similar device which has, or which can be readily restored or converted to have, a capacity of 15 or more rounds of ammunition. (4) Semiautomatic firearm.--The term ``semiautomatic firearm'' means any repeating firearm which utilizes a portion of the energy of a firing cartridge to extract the fired cartridge case and chamber the next round, and which requires a separate pull of the trigger to fire each cartridge. (5) Law enforcement officer.--The term ``law enforcement officer'' means any officer, agent, or employee of the United States, or of a State or political subdivision thereof, who is authorized by law to engage in or supervise the prevention, detection, investigation, or prosecution of any violation of law. (6) Other terms.--The terms ``firearm'', ``importer'', and ``manufacturer'' shall have the meanings given such terms, respectively, in paragraphs (3), (9), and (10) of section 921(a) of title 18, United States Code. SEC. 107. EFFECTIVE DATE. This title shall apply to conduct occurring after the date of the enactment of this Act. TITLE II--REPORT TO VICTIMS ON FEDERAL CRIMES COMMITTED WITH FIREARMS SEC. 201. REPORT TO VICTIMS ON FEDERAL CRIMES COMMITTED WITH FIREARMS. Within 30 days after a conviction is obtained in any Federal court of a crime during or in relation to which an individual was injured or killed by a firearm (as defined in section 921(a)(3) of title 18, United States Code), the United States attorney prosecuting the case shall report, on whether title I of this Act applies to the firearm, to-- (1) the individual; or (2) if the individual is dead-- (A) the closest relative of the individual; or (B) if there is no such relative, the estate of the individual. TITLE III--REVENUE PROVISIONS SEC. 301. INCREASE IN TAX ON FIREARMS. (a) In General.--Section 4181 of the Internal Revenue Code of 1986 (relating to imposition of tax on firearms) is amended to read as follows: ``SEC. 4181. IMPOSITION OF TAX. ``There is hereby imposed a tax on the sale by the manufacturer, producer, or importer of any firearm, shell, or cartridge a tax equal to-- ``(1) in the case of firearms, 20 percent of the price for which so sold, and ``(2) in the case of shells and cartridges, 11 percent of the price for which so sold.'' (b) Effective Date.--The amendment made by subsection (a) shall take effect on the 1st day of the 1st calendar month beginning more than 30 days after the date of the enactment of this Act. (c) Floor Stocks Tax.-- (1) Imposition of tax.--In the case of any firearm on which tax was imposed under section 4181 of the Internal Revenue Code of 1986 before the tax-increase date and which is held on such date for sale by any dealer, there is hereby imposed a floor stocks tax on such firearm. (2) Amount of tax.--The amount of tax imposed by paragraph (1) with respect to any firearm shall be equal to the amount of tax imposed under section 4181 of such Code with respect to such firearm before the tax-increase date. (3) Liability for tax and method of payment.-- (A) Liability for tax.--Any dealer holding any firearm on the tax-increase date to which any tax imposed by paragraph (1) applies shall be liable for such tax. (B) Method of payment.--The tax imposed by paragraph (1) shall be paid in such manner as the Secretary of the Treasury or his delegate shall prescribe by regulations. (C) Time for payment.--The tax imposed by paragraph (1) shall be paid before the close of the 6-month period beginning on the tax-increase date. (4) Definitions.--For purposes of this subsection-- (A) Tax-increase date.--The term ``tax-increase date'' means the 1st day of the 1st calendar month beginning more than 30 days after the date of the enactment of this Act. (B) Firearm.--The term ``firearm'' has the same meaning as when used in section 4181 of such Code. (5) Other laws applicable.--All provisions of law, including penalties, applicable with respect to the taxes imposed by section 4181 of such Code shall, insofar as applicable and not inconsistent with the provisions of this subsection, apply to the floor stocks taxes imposed by paragraph (1), to the same extent as if such taxes were imposed by such section 4181. SEC. 302. HOSPITAL GUNSHOT COST RELIEF TRUST FUND. (a) In General.--Subchapter A of chapter 98 of the Internal Revenue Code of 1986 (relating to trust fund code) is amended by adding at the end thereof the following new section: ``SEC. 9512. HOSPITAL GUNSHOT COST RELIEF TRUST FUND. ``(a) Creation of Trust Fund.--There is established in the Treasury of the United States a trust fund to be known as the `Hospital Gunshot Cost Relief Trust Fund', consisting of such amounts as may be appropriated or credited to such Trust Fund as provided in this section or section 9602(b). ``(b) Transfers to Trust Fund.-- ``(1) In general.--There are hereby appropriated to the Hospital Gunshot Cost Relief Trust Fund amounts equivalent to 50 percent of the net revenues received in the Treasury from the firearms tax. ``(2) Net revenues.--For purposes of paragraph (1), the term `net revenues' means the amount estimated by the Secretary based on the excess of-- ``(A) the firearms taxes received in the Treasury, over ``(B) the decrease in the tax imposed by chapter 1 resulting from the firearms taxes. ``(3) Firearms tax.--For purposes of this section, the term `firearms tax' means the tax imposed by section 4181 with respect to firearms (within the meaning of such section). ``(c) Expenditures From Trust Fund.--Amounts in the Hospital Gunshot Cost Relief Trust Fund shall be available, as provided in appropriation Acts, only for purposes of making expenditures to assist hospitals located in urban areas in defraying the costs incurred in providing medical care to gunshot victims who are not covered under any health plan.'' (b) Clerical Amendment.--The table of sections for such subchapter A is amended by adding at the end thereof the following new item: ``Sec. 9512. Hospital Gunshot Cost Relief Trust Fund.''

TABLE OF CONTENTS: Title I: Strict Liability of Manufacturers and Importers of Handguns and Assault Weapons Title II: Report to Victims on Federal Crimes Committed With Firearms Title III: Revenue Provisions Strict Liability for Safer Streets Act of 1993 - Title I: Strict Liability of Manufacturers and Importers of Handguns and Assault Weapons - Authorizes any person suffering bodily injury, death, or property damage as a result of the discharge of a handgun or an assault weapon (weapon) to bring an action against any manufacturer or importer of such weapon for damages and such other relief as the court deems appropriate in U.S. district court. Specifies that each such defendant shall be held strictly liable in tort for all direct and consequential damages arising from bodily injury, death, and property damage proximately resulting from the discharge of the weapon, with exceptions for: (1) injury while committing a felony; (2) self-inflicted injury; (3) injury by a law enforcement officer; (4) injury by a member of the U.S. armed forces; and (5) injury by a security guard. Authorizes the court to allow the prevailing party to recover a reasonable attorney's fee. Sets a two-year statute of limitations that begins with the date the injury is discovered. Makes this title applicable only to weapons manufactured in or imported into the United States after the effective date of this Act. Title II: Report to Victims on Federal Crimes Committed with Firearms - Requires the U.S. attorney prosecuting a case, after a conviction is obtained in any Federal court of a crime during or in relation to which an individual was injured or killed by a firearm, to report on whether title I of this Act applies to the firearm, to the individual, or, if the individual is dead, to the closest relative of the individual (or, if there is no such relative, the estate of the individual). Title III: Revenue Provisions - Amends the Internal Revenue Code to increase the tax on firearms. Imposes a floor stock tax on specified firearms. Establishes in the Treasury a Hospital Gunshot Cost Relief Trust Fund to assist hospitals located in urban areas in defraying costs incurred in providing medical care to gunshot victims who are not covered under any health plan.

Big families are the happiest, while single dads struggle the most because they feel left out of their children's lives, a five-year study of family life satisfaction has found. Same-sex parents are the most resilient, have the highest self-esteem and the greatest social support of the eight family cohorts investigated by Edith Cowan University researcher Bronwyn Harman. Their satisfaction with their lives is only marginally less than that of parents with large families. Dr Harman spent five years interviewing hundreds of parents from a range of family set-ups to ascertain what life is like for different families, and how resilience, social support and self-esteem contribute to parents' happiness. Participants filled out questionnaires that scored their resilience, perceived social support, self-esteem and life satisfaction. Dr Harman then ranked the different groups of parents based on their scores. Parents with four or more children were the most satisfied with their lot, enjoying, rather than feeling overwhelmed by, the chaos of a big family. Although they said they have to deal with comments such as "are they all yours?" or "do they all have the same father?", large families benefit from lots of support from each other, and are rarely bored. Children learn responsibility from an early age, and older ones help out with their younger siblings. Advertisement "[The parents] usually say they always wanted a large family, it was planned that way, and it was a lifestyle they'd chosen," Dr Harman said. As the issue of gay marriage dominates political discussion, same-sex parents are also very happy with their lives, which Dr Harman attributes to greater social acceptance of lesbian, gay, bisexual and transgender people. "As we move towards the idea of same-sex marriage as something we should have, the stigma around [same sex] parents is being reduced," she said. Same sex parents have battled against stigma and discrimination because of their sexuality, which has made them less concerned about public perceptions and the most resilient of parents. "They have to go to a lot of effort to get these children, so these children are very, very much desired," Dr Harman said. "Often when same-sex parents do have a child they feel like they've hit the jackpot because they didn't think it was going to be possible because of their sexuality." Single fathers are the parents least satisfied with their lives because they feel like they're perceived to be the lesser parent. They can be blocked from seeing their children, left out of the loop with communication about school and medical matters, and excluded from family celebrations. Single dads said they were often mistakenly viewed as the instigator of the family break up, and they struggle to get time off work to look after their children because "a good father is a breadwinner not a homemaker". "There is this perception that mothers are the real parents and fathers just sort of help," Dr Harman said. "There is still no understanding in 2015 that fathers are co-parents that have just as much responsibility for kids." However single fathers whose children were now adults said it had been worth going through all the difficulties to maintain a strong relationship with their children. Dr Harman said government services for families did not take into account that not all families were the same. "We need to remember that different groups of parents have different needs to contribute to their life satisfaction," she said. "It would be much better if we were able to separate the needs of different families and tailor services towards those individual cohorts." Families speak: Single dad: "I am broken and struggling with bitterness - and I struggle daily with the hurt" Same-sex parents: "I feel more and more people are coming to realise that having same sex parents is not the worst a child could do in life" Large families: "Our house is a joyful house. Our children all bring unique skills and personalities to our family" ||||| Moms and dads with four or more kids — as well as gay and lesbian parents — were among the most satisfied with life overall, an Australian researcher has found. (Photo: Marcel Weber/Cultura/Getty Images) An Australian researcher has completed a five-year study of various types of families and which are the most content — and the results might catch you off-guard. Story: ‘Families Like Ours’: When Kids and Same-Sex Parents Come Together in One of America’s Gayest Towns “What surprised me the most, I think, was that parents who identify as LGBT — as well as mothers of large families — were the most satisfied with life,” Bronwyn Harman, a psychology and social science lecturer at the Edith Cowan University in Western Australia, tells Yahoo Parenting. “I thought mothers of large families [with four or more children] would be less satisfied because of the financial stress — in addition to the workload, ferrying kids around, noise factor, and so on,” she continued. But while they did acknowledge these issues, as well as point out that they must deal with frequent nosy comments (“Are they all yours?” “Do they have the same father?”), there was lots of happiness at home. “They said that they had planned a large family, it was a joyful experience for them, the house was often full of laughter, and there were many reasons to celebrate,” she says. Story: Do Kids Really Make Parents Happier? Regarding gay, lesbian, or transgender-identified parents, Harman says, “I thought their well-being would be lower, because of discrimination and lack of acceptance of diversity. However, they said that this was not the case. In fact, they are finding that society is becoming more accepting of diversity, and this is reflected in our current political climate in Australia, where there is a groundswell of support to legalize gay marriage.” For the study, which has not yet been published, Harman spent five years interviewing nearly 950 parents from different backgrounds to ascertain their level of happiness. Parents with four or more children were the most wholly satisfied, followed closely by LGBT parents. “These children are not accidents — the parents have to go to a lot of trouble and expense and forethought — so the child is very much desired,” Harman told ABC Australia, regarding the need for same-sex couples to use IVF, surrogacy, or adoption to become parents. “They see the child as an absolute blessing and something they may not have considered as being possible for them.” Regarding the larger families, she told the publication, “Parents accept that there is chaos in their lives, but it does not negate the happiness they get from their families.” In addition, she said, “With large families, we think they have social support within the family. The kids are never bored, they have someone to play with, and they get independence quite early on.” So which type of parent was the least satisfied with their lives? Single dads. “There is this perception that mothers are the real parents and fathers just sort of help,” Harman told the Sydney Morning Herald. “There is still no understanding in 2015 that fathers are co-parents that have just as much responsibility for kids.” Single fathers, the researcher found, feel like they’re seen as the lesser parent — especially since they can be kept from seeing their kids, not communicated with regarding their children’s school and medical issues, left out of family celebrations, and often seen, wrongly, as the cause of family breakups. In general, notes family therapist Lois Braverman, president and CEO of the Ackerman Institute for the Family in New York City, parental happiness often comes down to how much social support surrounds a family. “Parenting in isolation is the most difficult way to parent, whether you’re a straight or gay couple or a single parent,” Braverman tells Yahoo Parenting. She says it’s important for all moms and dads to feel supported in their decisions “either by their extended family or their family of choice within a community.” It’s why parents in large families — as well as the kids themselves — may do so well. “One of the things you learn when you’re one of many is to be very flexible and how different people’s temperaments are,” she says. “You grow up in a little community of many different personalities.” Read More ||||| The happiest parents are—drumroll, please—parents with four or more kids. Parents of large families were found to have the most life satisfaction, according to a study by Australia’s Edith Cowan University. Dr. Bronwyn Harman, of the psychology and social science school at the university, spent five years studying what types of families are most content. “[The parents] usually say they always wanted a large family, it was planned that way, and it was a lifestyle they’d chosen,” Harman told The Sydney Morning Herald. During her five-year study, Harman interviewed hundreds of parents from different family makeups. Her findings are based on resilience, social support, self-esteem, and life satisfaction. Her research points out that parental happiness relates to how much effort has been put into growing the family. “What is important for kids are things like consistency, boundaries and [to] know that they are loved, no matter what,” Harman tells ABC Australia. Prior to the study, Harman thought parents with more children would be less happy. Though larger families may have more chaos and expenses than a smaller family, Harman’s research shows that these issues are balanced by the amount of joy received from having more children. Her findings show that children who grow up in large families learn independence at a young age and always have someone to play with. ||||| Bigger is better: Parents with four or more children happiest despite chaos, research finds Updated Families with four or more children enjoy the greatest life satisfaction, a five-year study by Perth's Edith Cowan University has found. Bronwyn Harman, a lecturer in the School of Psychology and Social Science, asked parents from different family types about resilience, social support and self-esteem. She found that parents with four or more children had the best ratings in each of these areas. The second-highest life-satisfaction scores, separated by just 0.25 per cent, were parents who identified as lesbian, gay, bisexual, transgender or queer (LGBTQ). "With large families, we think they have social support within the family," Dr Harman said. "The kids are never bored, they have someone to play with and they get independence quite early on." Everyone — chill out. What is important for kids are things like consistency, boundaries and [to] know that they are loved, no matter what. Dr Bronwyn Harman Dr Harman's research revealed most big families were planned, but parents with many children described regularly being asked if they were Catholic, if they had a television and whether the children all had the same father. The disadvantages of having a larger family, such as the expense and time pressures, were balanced out by the joy their children gave them. "Parents accept that there is chaos in their lives but it does not negate the happiness they get from their families," Dr Harman explained. She said the effort it took for LGBTQ indentifying parents to have children, using IVF, surrogacy or adoption, could explain their high life-satisfaction rating. "These children are not accidents — the parents have to go to a lot of trouble and expense and forethought — so the child is very much desired," Dr Harman said. "They see the child as an absolute blessing and something they may not have considered as being possible for them." Mother of 16 children would like to have more Such parents were also facing few pressures from the wider community around their sexuality. "Stigma about same-sex parents is becoming lessened as we become more understanding of diversity," Dr Harman added. Jeni Bonell has 16 children, aged one to 25, and agreed that her extra large family had made her and her husband very happy. "I've just found over the years that I have truly loved having all these babies and watching them grow," Ms Bonell told 720 ABC Perth. "We try really hard to make sure everyone gets individual time with mum and dad. "They also have all this amazing support from their brothers and sisters as well." Life can be chaotic and the family's weekly food bill can be up to $700, but she said the older children did most of the cooking. "Every Sunday night, the older two that don't live here and my mum, come round for a roast dinner," Ms Bonell said, adding that she would like to have more children. "We have this great big mass of people and we just laugh and tell jokes and it is so much fun." Although Dr Harman's research found family type did affect parents' life satisfaction, it did not necessarily make a difference to a child's upbringing. "It's not the family make-up that makes a difference to how a child is parented, it is the family processes," Dr Harman said. People can parent well irrespective of their gender, age, relationship status, sexuality or income and the lesson was for parents to stop worrying about such things. "Everyone — chill out. It's not important," she said. "What is important for kids are things like consistency, boundaries and [to] know that they are loved, no matter what." Topics: parenting, perth-6000 First posted

– Parents with lots of kids running around doing God knows what, be thankful—you're the lucky ones. According to a new study in Australia, parents with at least four children get the most satisfaction out of life despite the chaos and higher expenses, the Daily Signal reports. "With large families, we think they have social support within the family," study lead Bronwyn Harman tells ABC News Australia. "The kids are never bored, they have someone to play with and they get independence quite early on." She interviewed 950 parents over a 5-year period to evaluate their happiness level, Yahoo reports, and asked them about self-esteem, social support, and resilience. While parents with big families did have issues—like people asking if the kids had multiple fathers—they were still the most satisfied. Harmon thought they'd be stressed out, but "they said that they had planned a large family, it was a joyful experience for them, the house was often full of laughter, and there were many reasons to celebrate," she says. Second-happiest (by a razor-thin margin of 0.25%) were LGBT parents, who also planned their families and went the extra mile of getting kids by surrogacy, IVF, or adoption. "These children are not accidents ... so the child is very much desired," says Harmon. The least happy in her still-unpublished study were single dads, who she says are often seen as lesser parents and struggle to play a role in their childrens' lives. "There is this perception that mothers are the real parents and fathers just sort of help," Harmon tells the Sydney Morning Herald. (Now see what 53,000 children have to say about happiness.)

in the wide and diverse field of biology , it is necessary to study fungi . fungi are an incredibly speciose , and biologically and morphologically diverse group , with estimates indicating at least a predicted 1.5 million species on earth . some of these fungi are visible to humans as larger fungi , such as mushrooms , but others are microbial with incredibly high numbers of species and individuals present in any substrate on earth , for instance soil , water , air , or in dead or living plants . they exist as saprotrophs that break down organic material , parasites causing diseases , and various types of symbionts of all types of larger organisms . it is evident that fungi play an irreplaceable role in the ecology and micro - ecology of any ecosystem , and contribute to the health of living organisms in either a positive or negative way . more directly in the lives of humans , fungi play an incredibly important role as sources of food or in processing food , novel sources of industrially important enzymes and compounds , human , animal and plant pathogens , spoiling or contaminating food with mycotoxins , agents for biological control , and ecological indicators . in africa that is endowed with high biodiversity and unique but vulnerable ecosystems , mycology is an endangered discipline . fungal components of any ecosystem are seldom characterised and almost never included in biodiversity data . proper fungal inventories and databases are largely non - existent , while those that exist contain only scanty and basic information . due to the lack of human capacities , national monographs of biodiversity in many african countries rarely encompass fungi . this not only leads to an unfortunate bias in the complete assessment of biodiversity , but also pertains to the unawareness of public and decision makers of fungi as important organisms . needless to say fungal biodiversity does not feature in biological checklists and red data listings of countries . the problem is worsened due to large numbers of new taxa still awaiting description and numerous areas and niches that are unexplored . in south africa alone , over 171 000 fungal species are estimated to exist based only on the modest assumption that an average of seven new fungal species are associated with each of the plant species known ( crous et al . 2006 ) . of these , only 780 represented new species ( crous et al . only 4.6% of the recorded fungi were newly described ( abdel - azeem 2011 ) . these have put excessive pressures on the environment and also on already limited food sources , compounded by threats of plant pathogens and pests . livestock and humans are equally threatened by fungal diseases or fungal toxins . even for quarantine purposes against plant pathogens , comprehensive lists of pathogens do not exist for most african countries . despite these threats , the study of pathogenic fungi is also generally neglected despite their importance , and again limited and pressured human and resource capacity exist to address this . sustainable ethnomycology provides valuable food and medicines and conserves such knowledge ( e.g. lowore & boa 2001 , bloesch & mbago 2008 ) . the cultivation of mushrooms on waste products such as straw is practised in numerous rural communities and provides valuable sources of protein and income . africa s fungal biodiversity represents potential opportunities to develop valuable products or by - products to address third world environmental and food security related problems , or to discover biological control methods to combat diseases . it can be broadly divided into medical mycology , food mycology , industrial mycology , aspects of plant pathology , symbioses , ecology , biodiversity , and systematics , with numerous overlaps between fields and expertise . specific fungi need to be collected and isolated using the specialised techniques known for the different groups of fungi and for different fields of mycology , unless these are obligate parasites that can not be cultured . collecting trips largely involve the same procedures as those for other organisms , but for many groups of fungi , a great deal of additional effort is necessary to first isolate and purify these fungi in culture before identification can be attempted . whereas the larger fungi , such as mushrooms , are more tangible and countable , it is especially these cultured fungi that are more numerous but difficult to comprehend by non - mycologists . furthermore , even with the larger fungi , the absence of fruiting bodies does not necessarily imply the absence of the fungus , but are merely tied to the absence of special environmental conditions conducive to the production of fruiting bodies . ideally , living isolates and biologically inactive herbarium specimens of fungi should be preserved in culture collections and herbaria , respectively , where these will continue to be available for study by other mycologists . the needs to do this are quite different from those of preserving various types of animals and plants , and in general are more costly , labour and time intensive , and specialised . sadly , very few such official collections exist , while large numbers of these fungi are kept in private research collections under immense financial pressure and largely linked to the presence of the particular researcher or the particular research project . various steps of identification and special expertise are necessary to either identify known fungi , for instance in the case of pathogens where the correct identity is vital , or to be able to obtain a sensible designation for unknown fungi . such identifications are often very difficult due to the large degree of variation in the fungal kingdom , the specialization and techniques required to identify different groups , and limited human expertise . even internationally , fewer mycologists and funding are available to actually identify and describe new fungi . several specific needs and resources have been identified for mycology in africa , although these may by no means be unique to this continent . physical needs such as funding and infrastructure are quite delimiting , and both are usually necessary for sustainable research . even with increasing interest from global funding organizations in africa , mycologists usually have to compete with other biologists working with more understandable and visible organisms . resources such as checklists are lacking . whereas physical needs can be met , human needs such as support by experts and mentors to provide guidance and training , and available students interested and funded to do projects , are more difficult to meet . experts willing to assist in identifications and coaching are difficult to find , usually overloaded themselves , and are often not on the african continent . the same problems existing in africa affecting diversity and numbers of animals and plants , apply to fungi . these problems include slash and burn , overgrazing , alien plant invasions , reforestations with non - native trees , encroachment , fragmentation , poor land management , degradation , and transformation ( gryzenhout et al . 2010 , ngala & gryzenhout 2010 ) . however , the difference is that fungi are not at all included in any such assessments , nor are the effects and impact on these fungi known . their diversity and functionality are understudied , and hence the impact of anthropogenic activities is unknown and the need for conservation overlooked . the invasiveness of non - native fungi is seldom studied , except for plant pathogens proven to be introduced , and the displacements of native fungi are thus unknown . numbers of microfungi and larger , visible fungi are disappearing without being noticed . due to pressures to produce food , indiscriminate spraying of especially non - selective fungicides by farmers africa prizes a number of local edible mushrooms , such as species of the truffle genus terfezia and chanterelles ( cantharellus ) , but these are occasionally overharvested or traded illegally . the loss of habitat due to deforestation for settlement and cultivation in africa is alarming and associated with the loss of local fungi . furthermore , trees are destroyed for firewood , the making of charcoal , timber , and tourist ornaments , and thus the fungi occurring with them as natural pathogens or endophytes inside plant tissues , also disappear . numerous fungal taxa are thus undergoing threats of extinction , along with their symbiotically associated plant species and generally in small sized hotspots . a recent red list of threatened larger fungi of benin totaling 30 species within two hotspots ( yorou & de kesel 2011 ) , gives evidence of the impact of human activities on fungal biodiversity and the need to elaborate ecosystems - based conservation strategies . africa has a rich tradition of ethnomycology that has not yet been documented in most parts . the traditional knowledge and practices are , however , declining from one generation to another , with older generations often still remaining the sole custodians . simultaneously , a number of negative or ignorant perceptions also exist , often among the public , other biologists or in government circles . these factors are compounded by poverty , land allocation , and land use practices , which usually take preference above the need to also study fungi . while funding is already difficult to obtain , funding for basic mycology is even scarcer , and can usually only be obtained for applied projects in fields where fungi play an important role , such as plant pathology , food microbiology , bioactive compounds , and/or applications in forest regeneration . herbaria and living culture collections are battling to maintain high standards or even to survive , due to lack of interest for investment and scarcity of funds . the large numbers of cultures also housed in private culture collections and that are carried by research funds and the dedication of the particular researchers , are also under threat . these collections are in danger of being lost when these funds become unavailable or the researchers discontinue their work . such private collections are not sponsored by government or other funding bodies . whereas institutes and research programmes with state - of - the - art infrastructure , capacity and excellence do exist in some african countries , all of these issues are usually the reasons for the brain drain of talented mycologists to other continents , from which some never return . there is a general consensus that there should be more scientific input by mycologists in political issues . this is difficult due to a lack of interest and ignorance in government , biodiversity , conservation , and public circles . legislation and permits are often very difficult for fungi due to ignorance of the special needs of mycologists and the lack of general checklists , and these processes are also often coupled with corruption by officials . political upheaval is a reality in many african countries , making the practice of any science difficult . moreover , inner politics within scientific communities are also debilitating for significant progress and large scale projects . the rich and unique biodiversity of africa and indigenous knowledge systems present numerous opportunities for fungal bio - exploration , characterization of species , bio - prospecting , and potential downstream applications paired with capacity building . for fungi , this biodiversity is virtually untapped . unlike the more developed , northern hemisphere countries with their extensive histories of mycology , africa in a sense can start with a clean slate with not too many problems , such as taxonomical ambiguities , to first resolve . the majority of biodiversity data can also immediately be fed to the current global biodiversity initiatives and need not be harvested first from previous and extensive lists . metagenetic approaches such as direct environmental sequencing or the use of other biochemical or molecular typing techniques of microbial communities , also present novel techniques to investigate these communities , albeit these are usually costly . although numerous challenges exist , incredibly talented , passionate and diverse mycologists are practising their science with few resources , and often at an international level . much of this is achieved through a system of african and global connections and collaborations . such expertise is actually playing a pioneering role to perpetuate mycological research and teaching locally . one most important but discrete opportunity is that numerous local students can be motivated and engaged to make a career in mycology , as fungal science is perceived to be a new and promising biological field for them . numerous students also do their pre- and postgraduate studies at african centres or abroad , and often at acclaimed research groups where they actually act to promote mycology ( brain gain ) and , if they return , the expertise they gained is brought back ( brain circulation ) . in some african countries , emerging good will towards biological sciences also may include more opportunities for mycology . the use of ethnomycology is promoted under communities in attempts not to lose those skills and knowledge , and these are useful initiatives to show the value of mycology for government officials and funders . a number of groups for communities and amateur mycologists are driven by individuals or groups of mycologists , who are usually already pressured . these are essential to nurture interest in this poorly represented field or to promote awareness of the importance of including fungi in biodiversity and conservation initiatives . these groups often include biologists from other disciplines , non - governmental organizations ( ngo s ) , nature conservationists , and from government , and thus play the important role of promoting mycology in the broader scientific community and disseminating interesting , useful or essential data . these include leading research , to promote the particular field of science across general scientific fields , to attract students with pertinent and stimulating teaching and research projects , and to build capacity through post - graduate training . due to relatively limited capacity in africa , a choice must be made if mycology in africa is to grow stronger and become more prominent , or if it will merely continue to exist . strong and continued action with clear goals will be necessary to build mycology in africa , and these must not be from a few individuals , but from numerous people and teams . common goals for groups of mycologists from several countries may be a way to stimulate this . in the open world we live in today , numerous ways of communicating , networking and collaborating is possible . novel , different ways of doing things must be sought if current systems are not working . this is especially true to retain young talent and to enable it to become able mycologists . these are difficult , but if even one of these challenges can be addressed and a solution established , it will make it possible to solve the next challenge and do more in future . for these , continuous advice is needed from fellow mycological societies , experienced mycologists , and those outside the field of mycology .

the african mycological association ( ama ) promotes mycology amongst members in africa and globally . the ama has about 200 members , mostly from african states but also with strong representation from europe and usa , amongst others . recent efforts by members of the ama focused on reviving and developing mycological research and networking in africa . a great deal must , however , still be done to promote the ama under african mycologists , and those elsewhere with interests in africa . african mycologists also experience challenges typical of the developing world and a great deal of fungi still needs to be discovered . this can also be seen as representing great opportunities for research and collaboration . several issues pertinent to mycology in africa were discussed during special interest group sessions of the 9th international mycological congress in 2010 , and through several opinion pieces contributed by ama members in the ama newsletter , mycoafrica . this contribution serves as a document to summarise these in a form that can be presented to fellow mycologists , biologists and other scientists , relevant government departments , funding bodies and non - governmental organizations and that pins down the importance of mycology , the status thereof in africa and the need to promote it more .

ATLANTIC CITY — Gov. Chris Christie announced today that he's signed an executive order to install an emergency management team in Atlantic City to help dig the financially strapped gambling resort out of what he called "an enormous hole." The initiative, which was balked at by some local officials, does not rule out the possibility of the city declaring bankruptcy. Christie tapped Kevin Lavin, a corporate finance attorney who specializes in helping troubled companies, as the emergency manager tasked with finding ways to overhaul the operations and finances of Atlantic City — which has seen four casinos close and more than 8,000 people lose their jobs over the last year. The Republican governor also named Kevyn Orr, a former corporate bankruptcy lawyer who led Detroit through the largest municipal bankruptcy filing in U.S. history last year, as a special counsel to Lavin. "I can't wait any longer," Christie said while making the announcement at the third summit he has held in Atlantic City with casino executives, business leaders, union leaders, and state and local officials to search for ways to revive the city. "We need more aggressive action. It's time to confront the dire circumstances with which we are confronted." The move comes as Christie considers whether to launch a bid for the 2016 Republican nomination for president and could have implications for his campaign. Officials stopped short of calling it a state takeover. Under the order, the team is expected to produce a plan within 60 days "to place the finances of Atlantic City in stable condition on a long-term basis by any and all lawful means." "What we're doing right now is getting information," said Lavin, who most recently worked for corporate turnaround firm FTI Consulting in New York. "That's all we're doing. Getting an understanding of the situation we're in. We need to delve into the details to see what's going on." Lavin and Orr said their salary and budget have not been ironed out, nor do they know where they'll be working in the city. They also stressed that it's premature to speculate if Atlantic City will declare bankruptcy as Detroit did. Orr took over Detroit's management in March of last year and resigned just as bankruptcy ended in December, with the city having shed $7 billion of its $18 billion debt. • OVERVIEW: What you need to know about the plan • 2016 IMPLICATIONS: Christie's last bet? A recent report said Atlantic City's property tax base is projected to fall from $11.3 billion this year to $8 billion by 2016. "This is urgent," Orr said at a news conference after Christie's announcement. "The trend lines for the city both on the revenue side and the cost side are not good." Asked whether bankruptcy is possible, Orr said: "We are going to be very candid with that discussion. That will be something we will decide in due course." Christie's order was issued through a longstanding state law that allows the state to step in to help financially ailing cities and towns. The idea of a management team was recommended by an advisory commission Christie formed in Atlantic City, a one-time premier gambling destination that has struggled over the last decade amid growing competition. Still, local officials have criticized the move. Mayor Don Guardian, a Republican who recently completed his first year in office, had said he was "100 percent opposed" to an emergency management team, fearing the city's staff would be replaced. Today, Guardian seemed more open to the move, saying it wasn't as drastic as he once expected. "It's cooperation that we need," he said. "It's working together.It's necessary for us to rethink how we are doing business in Atlantic City." But city council President Frank Gilliam was firm in his opposition today. "I don't believe it's necessary," said Gilliam, a Democrat. "I find it very imposing that we will basically have outsiders come into the city and dictate the direction of the city without sitting down with the city fathers and getting their input. We're open to working with them. But at the same time, any time that they usurp our power, we will definitely have problems with that." Christie said he is not trying to undermine Guardian, but instead wants the management team to work with the mayor and city council. "He has inherited an awful mess," the governor said of the mayor. "What we are doing is giving the mayor enhanced tools to be able to bring this to a successful resolution. This is not a move in any way to supplant the mayor's role here in the city." Orr agreed. "You still have a mayor, you still have a council," he said. "We want to work closely with them." Bill Dressel, director of the New Jersey League of Municipalities, said he will "watch the situation very carefully." "We were all anticipating a coup here, and it didn't turn out to be a coup," Dressel said. "It turned out to be a situation where the administration is bringing some real professional individuals in to provide more tools and resources to the mayor in making prudent decision and moving Atlantic City forward." But police and fire department leaders spoke out against the move, saying they're worried the team will try to alter union contracts. Patrick Colligan, president of the New Jersey Police Benevolent Association, called the move "unnecessary and disturbing." "Atlantic City does not need an emergency manager to guide it through this difficult period," Colligan said in a statement. "They have been appointed simply to slash the city budget and to give the governor the hatchet men he needs to further ruin anyone who dares to make working for the public their career." State lawmakers have also introduced dueling plans to help Atlantic City. The Democratic plan — led by state Senate President Stephen Sweeney (D-Gloucester) — is anchored by a proposal to have casinos make payments in lieu of taxes for 15 years to help cut down the city's debt. A Republican plan spearheaded by state Assemblyman Chris Brown (R-Atlantic) aims to give all Atlantic County property owners a five-year property tax freeze instead. NJ Advance Media staff writer Christopher Baxter contributed to this report. Brent Johnson may be reached at [email protected]. Follow him on Twitter @johnsb01. Find NJ.com Politics on Facebook. ||||| TRENTON — Gov. Chris Christie will appoint an emergency manager to take over the troubled resort town's daily operations, The Wall Street Journal reported early Thursday morning. The emergency manager position was one recommendation of an advisory commission Christie formed. The governor is expected to formally announce the move Thursday during the third summit he has held in an effort pull the city from economic hardship. "They're moving forward with an emergency manager," Atlantic City Council President Frank M. Gilliam Jr. told Philly.com. Christie is expected to name Kevin Lavin, a lawyer who worked for FTI Consulting Inc. in New York, a source told The Wall Street Journal. Another man, former Detroit emergency manager Kevyn Orr, will be brought on as a consultant to work with Lavin, the paper also reported. Orr controlled Detroit's finances beginning in March 2013. The two will begin immediately and will assume the powers now held by the mayor and council. They will also be free to consider a range of solutions — including renegotiating public-employee contracts, The Journal reported. "I've heard rumors to the same effect that other people have heard," state Sen. Jim Whelan (D-Atlantic) told NJ Advance Media, referring to Orr coming to the city. He added: "I wonder where the legal authority comes from for it, frankly, number one. Number two, I don't want to speak for the city or the mayor — I haven't been mayor for quite a while — but there's a philosophical question of we have an elected mayor and an elected council and we're just going to throw that out? On what basis? Detroit was in bankruptcy." Orr resigned from his post in December just as the city officially exited bankruptcy. Christie's office declined to comment. The advisory commission issued a report in November that recommended the state take an expanded oversight role in Atlantic City, including appointing an emergency manager. The report also recommended the creation of a public-private corporation for development and consolidation of services. The report came a day after Christie held his second Atlantic City summit. A spokesman for Atlantic City Mayor Don Guardian wouldn't confirm details of the emergency manager. Instead, Guardian's chief of staff, Chris Filiciello, said officials will "wait to see what the governor has to say tomorrow." Filiciello added: "The mayor is opposed to any and all emergency manager and overseers, no matter who it is, what their name is. The mayor will do everything he can to work with the governor. He's agreed with the governor on almost everything, but if there is an emergency manager appointed, he's going to disagree with the governor that it's the right action plan for Atlantic City." Atlantic City lost nearly half of its casino revenue over the past eight years and four of its 12 casinos closed in 2014. The closures put thousands out of work. The commission's report painted a striking picture of the city's finances, including a property tax base projected to fall from $11.3 billion this year to $8 billion by 2016, according to the commission's projections. It also outlined several "reforms" for Atlantic City's schools, pension system and city services and recommended regionalizing municipal services like police and fire departments. It pointed to consolidation in Camden County as a model that could create "significant cost savings and lower crime rates." Christie will meet with other officials in Atlantic City on Thursday afternoon. NJ Advance Media staff writers Claude Brodesser-Akner, Matt Friedman, and Paul Milo contributed to this report. Matt Arco may be reached at [email protected]. Follow him on Twitter @MatthewArco. Find NJ.com Politics on Facebook.

– This is why New Jersey can't have nice casino towns: financial woes, and Atlantic City's are so dire that Gov. Chris Christie has issued a state takeover of the city of 40,000, reports NJ.com. "I can't wait any longer," said Christie today in simultaneously announcing an emergency management team—which includes a veteran of Detroit's bankruptcy—to help pull the city out of "an enormous hole," he said. "We need more aggressive action." That team replaces Atlantic City's mayor and city council. Christie's move isn't without precedent: The state also stepped in 13 years ago with Camden. Unhappy with the move is Mayor Don Guardian, whose spokesman said last night that he is "opposed to any and all emergency manager and overseers, no matter who it is, what their name is." Today Guardian seemed more amenable, saying "cooperation" and "working together" are necessary, but the city council president is still unhappy. And, grumbled a state senator: "There's a philosophical question of we have an elected mayor and an elected council and we're just going to throw that out? On what basis? Detroit was in bankruptcy." Atlantic City's problems include: Four of its dozen casinos closed in the past year. More than 8,000 people lost jobs. A property tax base is poised to plunge from $11.3 billion this year to $8 billion next year.

numerous epidemiological and molecular biological studies have shown that inflammation greatly increases the risk of cancer . chronic inflammation can induce persistent tissue damage and changes in the inflammatory cells and cytokines present in the tissue microenvironment . these changes influence the eventual development of tumors , malignant invasion , and metastasis in inflammatory diseases such as ulcerative colitis , atrophic gastritis , barrett 's esophagus , colorectal cancer , and hepatocellular carcinoma [ 16 ] . the tumor microenvironment includes stromal cells , tumor - infiltrating immune cells , and a range of bioactive substances that suppress the immune response and protect the tumor from immune surveillance . regulatory t - cells ( tregs ) and tumor - associated macrophages ( tams ) comprise the majority of tumor - infiltrating cells associated with immune suppression in the tumor microenvironment [ 79 ] . the anti - inflammatory cytokines , interleukin-10 ( il-10 ) , il-4 , and transforming growth factor-1 ( tgf-1 ) , mediate local immune suppression and promote increased infiltration of tregs and tams . the inflammatory cytokines , interferon- ( ifn- ) and monocyte chemoattractant protein-1 ( mcp-1 ) , can either inhibit tumor angiogenesis by inducing cell apoptosis or act as negative regulators of tumor progression . chronic inflammation may thus influence tumor initiation , progression , invasion , and metastasis via changes in inflammatory - cell populations and cytokine levels in local tissues . oral squamous cell carcinoma ( oscc ) is the eleventh most prevalent solid tumor worldwide , responsible for approximately 4% of all malignancies . it is an aggressive , invasive epithelial malignancy and is always associated with premalignant oral lesions . oral leukoplakia ( olk ) , which appears as a white area or spot in the oral cavity , is the most common potentially malignant condition of the oral mucosa [ 1113 ] . oral lichen planus ( olp ) is a chronic t - cell - mediated mucocutaneous inflammatory condition of unknown etiology . it is described by the world health organization as potentially precancerous and has been associated with a significantly increased risk of oral cancer [ 14 , 15 ] . the majority of t - cells in the epithelium affected by olp and adjacent to damaged basal keratinocytes are activated cd8 lymphocytes , which are known to stimulate apoptosis of keratinocytes . the profile of inflammatory mediators in olk is also similar to that seen during the progression of oscc . the progression from premalignant lesions to oscc is a chronic , complex , multistep process . the key inflammatory mediator(s ) that influence the progression of olk and olp to oscc have not yet been identified . the aim of this study was to further elucidate the role of inflammatory mediators and infiltrating immunocytes in the pathogenesis of oscc . eighty - four specimens , including olk ( n = 44 ) , olp ( n = 19 ) , and oscc ( n = 21 ) , were evaluated by immunohistochemical ( ihc ) staining . all surgically resected tissue and biopsy specimens were obtained from the beijing stomatology hospital , beijing , china . olk specimens were subdivided into three groups , olk - i ( n = 20 ) , olk - ii ( n = 16 ) , and olk - iii ( n = 8) , by the extent of oral dysplasia . the olp lesions were not treated with steroids . the primary antibodies used in the ihc procedures were foxp3 ( 1 : 200 ) , il-10 ( 1 : 400 ) , il-4 ( 1 : 400 ) , ifn- ( 1 : 400 ) , mcp-1 ( 1 : 300 ; all from abcam , cambridge , uk ) , cd4 ( 1 : 300 , novocastra , newcastle , uk ) , cd68 ( kp-1 , 1 : 300 ; dako , glostrup , denmark ) , and tgf-1 ( 1 : 300 , santa cruz biotechnology , texas , usa ) . all were mouse monoclonal antibodies . endogenous peroxidase activity was blocked by incubation in 3% hydrogen peroxide for 10 min . antigen retrieval was performed by microwaving the samples in 10 mm tris base , 1 mm edta ( ph 9.0 ) buffer . nonspecific binding was blocked by incubation in 5% bovine serum albumin ( genview , usa ) for 20 min at room temperature . samples were washed with pbs ( ph 7.4 ) and staining was visualized by incubation with chenmate envision / hrp anti - rabbit / mouse reagent ( genetech , shanghai , china ) for 30 min at room temperature followed by incubation with 3,3-diaminobenzidine substrate following the instructions of the assay manufacturer . stained sections were rinsed gently with distilled water for 10 min , counterstained with hematoxylin and dehydrated through three increasing concentrations of alcohol , cleared in xylene , and mounted on slides . two pathologists independently counted the number of positively stained cells in five randomly selected fields of each specimen and noted the predominant location(s ) within the tissue . continuous variables were expressed as the means sd , and between - group differences were tested using one - way analysis of variance followed by scheff 's post hoc test . as shown in figure 1(a ) , cd4 t - lymphocytes were found predominantly in the superficial lamina propria of olp and olk samples or in interstitial tissue of the cancer nests . olp and olk contained fewer cd4 t - lymphocytes than oscc tissues did ( figure 1(b ) ) . the numbers of cd4 t - lymphocytes in olk - iii and oscc samples were comparable , and both were higher than the numbers seen in olk - i and olk - ii tissue samples . the ihc results thus suggested that cd4 t - lymphocytes increased gradually with the progression of oral dysplasia ( figure 1(b ) ) . ihc staining of foxp3 t - lymphocytes ( tregs ) revealed similar distributions of foxp3 and cd4 lymphocytes in all three groups ( figure 1(c ) ) , but there were significant differences in the number of foxp3 cells in oscc compared with olp or olk samples ( figure 1(d ) ) . no significant differences in the foxp3/cd4 ratio were seen in the three groups ( figure 1(e ) ) , but both the number of foxp3 t - lymphocytes and the foxp3/cd4 ratio increased gradually with the progression of oral dysplasia in olk samples ( figures 1(d ) and 1(e ) ) . similar to the pattern seen for cd4 t - lymphocytes , cd68 macrophages ( tams ) were observed predominantly in the superficial lamina propria of olp and olk tissues and/or the interstitial tissues of the cancer nests ( figure 2(a ) ) . there were significantly more tams in oscc than in olk ( p < 0.0001 ) and olp ( p = 0.0125 ) tissue . the number of infiltrating tams in olk tissues increased gradually with the progression of dysplasia to oscc ( figure 2(b ) ) , with maximum infiltration in oscc tissue ( figure 2(b ) ) . in olp and olk tissues , il-10 and il-4 macrophages were predominantly detected in the deep lamina propria as well as in all or part of the epithelial layers ; cells with positive tgf-1 staining were scattered throughout the lamina propria . in oscc tissues , il-10 and il-4 macrophages were predominantly seen in the cancer nests , and some positive signals were also found in cancerous epithelial tissues ( figures 3(a ) and 3(b ) ) . there were significantly more il-10 cells in oscc than in olk and olp tissues ( p < 0.001 , figure 3(d ) ) , suggesting that il-10 may contribute to immunosuppression in the cancer microenvironment . however , we did not observe a positive correlation between the number of il-10 cells and the progression of dysplasia in olk patients ( figure 3(d ) ) . significantly fewer il-4 cells were observed in oscc than in olp and olk tissues , suggesting that il-4 might not be a key factor for immunosuppression in the cancer microenvironment ( figure 3(e ) ) . however , the number of infiltrating il-4 macrophages increased gradually with the progression of dysplasia in olk tissue ( figure 3(e ) ) , suggesting that il-4 might be a key factor in oncogenesis . in contrast to il-10 , fewer tgf-1 macrophages were seen in oscc than in olk and olp tissues ( figure 3(f ) ) , and there was no correlation between tgf-1 macrophages and the progression of dysplasia in olk . ifn- macrophages were predominantly detected in olk ; very few were seen in olp and oscc tissues ( figure 4(a ) ) , and the number of ifn- cells was negatively correlated with the progression of oral dysplasia in olk ( figure 4(b ) ) . in olp , olk , and oscc , the distributions of mcp-1 and ifn- macrophages were similar ( figure 4(c ) ) , and no significant differences were observed in the number of mcp-1 macrophages in those tissues ( figure 4(d ) ) . these results suggest that ifn- rather than mcp-1 macrophages are involved in the progression from chronic inflammation to oscc . an association between chronic inflammation and tumor progression was proposed nearly 50 years ago . on the one hand , several pathogens , including candida , epstein - barr virus ( ebv ) , and human papilloma virus ( hpv ) , have been detected in the oral leukoplakia , which might initiate local inflammatory responses in precancerous lesions . on the other hand , cancer - associated toll - like receptor ( e.g. , tlr1 - 4 ) could be activated by mucosal bacteria , which would cause a carcinogenic process and oncogenic transformation through inducing inflammation . a number of studies published in the past decade have described interactions of solid tumors and the surrounding stroma that contributed to cancer growth , invasion , and metastasis . the evidence suggests that inflammatory cells and cytokines in the tissues that surround tumors contribute to tumor development and progression in spite of the antitumor responses of the host and that they increase the risk of chronic , inflammatory conditions progressing to cancer . the malignant transformation of olp and olk may thus be related to , or dependent on , a series of molecular stimuli originating with inflammatory infiltrate . we investigated key influences in the progression of chronic inflammation to malignant tumors , including tissue - infiltrating immune cells and anti- and proinflammatory cytokines in the olp , olk , and oscc tissue microenvironment . treg and tam cells are key components of the tumor microenvironment , but foxp3 is not expressed in normal oral mucosa . in keeping with that observation , we found that olp , olk , and oscc tissues contained inflammatory regions that were infiltrated to different extents by cd4 t - cells and cd68 macrophages and that oscc tissues contained more cd4 t - cells and cd68 macrophages than either olp or olk tissue . moreover , foxp3 , a marker specific for human cd4 cd25 treg cells , was expressed in olp , olk , and oscc tissues . our data indicate that these immune cells are involved in the regulation of local immune responses . gradual increases observed in the numbers of infiltrating cd4 t - cells , foxp3 t - lymphocytes , and cd68 macrophages in parallel with the progression of dysplasia in olk samples suggested that local changes in the population of immune suppressor cells are an important influence on the malignant progression of tumors . the finding that these immune cells were located close to the basement membrane of the superficial lamina propria in olk and olp and in the interstitial tissue of carcinoma nests is consistent with previous reports and suggests a potential possibility of an interaction between these cells . the infiltration of inflammatory cells during tumorigenesis is accompanied by changes in the local cytokine expression profile . studies in genetically modified mice and in human tumors found that altered expression of selected pro- ( mcp-1 , ifn- ) and/or anti - inflammatory cytokines ( il-4 , il-10 , and tgf-1 ) had a crucial role in the promotion of gastric , colorectal , liver , breast , and skin carcinoma development . il-10 is not expressed in epithelial cells of normal tissues [ 24 , 25 ] , but ihc analysis has demonstrated significantly stronger il-10 staining of epithelial cell cytoplasm in human oral and pharyngeal carcinomas compared with keratinocytes or inflammatory cells in normal epithelium [ 26 , 27 ] . growth of cancer cells is induced by il-4 via paracrine mechanisms , and the expression of il-4 has been reported in head and neck squamous cell carcinoma and oscc [ 28 , 29 ] . tgf-1 is a negative regulator of cell immune responses and is widely expressed in both normal and tumor cells . however , in squamous cell carcinoma , there is generally a negative correlation between tgf-1 expression and increased dysplasia , with no tgf-1 expression . interestingly , il-4 , il-10 , and tgf-1 had differing expression in olp , olk , and oscc tissue . oscc had significantly more il-10 , but not more il-4 cells , than olp and olk tissues , while the number of il-4 , but not il-10 cells , increased gradually with the progression of dysplasia in olk tissue . in contrast to the increased numbers of il-10 and il-4 in oscc compared with olk and olp tissues , fewer tgf-1 macrophages were detected in oscc tissues , and no correlation was found between tgf-1 macrophages and the progression of dysplasia in olk patients . the data thus suggested different roles for these anti - inflammatory cytokines . il-4 might be important for progression of olk to a precancerous oscc condition , but not for the immune evasion of oscc . il-10 might not be critical to the development of early - stage malignant dysplasia but contributes to tumor immune escape after progression to oscc , while tgf-1 might be less important for the development of oscc . in addition to anti - inflammatory cytokines , inflammatory cytokines also play an important role in tumor development and progression . ifn- is an important th1-type cytokine that is strongly induced by inflammatory stimuli that are also inhibited by il-4 . in chronic inflammation , infiltration of subepithelial tissue by ifn- cells , including macrophages , contributes to the maintenance of chronic inflammation in olp . . found that tumor - infiltrating macrophages were an important source of mcp-1 , resulting in recruitment of additional monocytes by positive feedback . in this study , the number of ifn- macrophages decreased with the degree of dysplasia in olk and was significantly deceased in oscc . these changes indicate that decreasing expression of ifn- plays an important role in the progression from olk to oscc . mcp-1 , a cytokine with a variety of biological activities , is secreted into the tumor microenvironment by tumor cells and stromal cells . however , no significant differences in the number of mcp-1 macrophages in olk , olp , and oscc tissues were seen in this study . previous studies have shown that interactions of cytokines and/or immune cells are important for the regulation of immune responses [ 3643 ] . we observed increases of cd4 t - cells , foxp3 t - lymphocytes , cd68 macrophages , and il-4 cells during the progression of dysplasia in olk and a parallel decrease in the expression of the inflammatory cytokine ifn-. these data indicate a shift toward immune suppression during the progression from mucocutaneous inflammatory disease to malignant cancer . moreover , as il-4 decreases in oscc , concomitant increase in il-10 expression may act to further inhibit immune responses . our study adds to what is known about how chronic inflammation can induce immune suppression and contribute to the occurrence of oscc . further studies should be performed to study the inhibition of the development of oscc by restoring immune homeostasis at the precancerous stage .

oral squamous cell carcinoma ( oscc ) is an aggressive , invasive malignancy of epithelial origin . the progression from premalignant lesions oral leukoplakia ( olk ) and oral lichen planus ( olp)to oscc involves complex inflammatory processes that have not been elucidated . we investigated the roles of inflammatory mediators and infiltrating immunocytes in the pathogenic progression of olk and olp to oscc . the occurrence of regulatory t - cells ( tregs ) and tumor - associated macrophages ( tams ) and the expression of anti - inflammatory cytokines and proinflammatory cytokines were investigated in olk , olp , and oscc tissues . immunohistochemical staining of cd4 , foxp3 , cd68 , tgf-1 , il-10 , il-4 , ifn- , and mcp-1 showed that the occurrence of tregs and tams increased in parallel with disease progression in olk and oscc . il-10 gradually increased during the early stages of olk and in oscc . infiltrating il-4 + macrophages were seen with increasing frequency in olk tissue during the progression of oral dysplasia . fewer tgf-1 + macrophages were seen in oscc than in olk and olp . the expression of ifn- decreased gradually with the olk development and had the lowest expression in oscc . mcp-1 expression did not change significantly during the development of oscc . the results suggested that the immunosuppression induced by chronic inflammation promotes tumorigenesis in oscc , rather than initiating it .

Now that the dust has settled on the scandal that pushed Anthony Weiner out of office, New York Democrats have made their choice for the Congressman to replace him: NY Assemblyman and former NYC City Councilman David Weprin. Weprin will be running against a yet-to-be-chosen Republican from the NY-9 seat, and would hold it until the end of 2012. The New York Times reported the New York Democrats’ announcement today, noting that, given the 2010 census, the Congressional seat may not even exist in the near future. “As a result of the 2010 census, New York must lose two Congressional seats, and some political observers believe that the Ninth District, which includes parts of Brooklyn and Queens, could be eliminated,” the Times reports. But for now, Weprin is going to campaign for the seat, based on his experience as an assemblyman and city councilman. The Times also notes that Weprin is an attorney from “a member of a prominent Queens political family.” Weprin also gave a statement to the New York Daily News: “This is an exciting opportunity and I’m looking forward to the campaign,” he said, adding: “I’ve never tweeted in my life and I don’t spend any time in the gym.” […] “I read the same things you read,” he said. “I’m not going in with any preconceived notion. I’m going to do the best job I can for as long as I can do it… The bottom line is I feel strongly that I can make a contribution now and now is the opportunity that may never arise ever again and sometimes you have to seize the opportunities when they arise. But more than that, I really feel that the district needs representation, whether for a short period of time or a long period of time.” The other tidbit of information out there is that Weprin has been known to do some public dancing– specifically, this YouTube video of Weprin getting down at a street festival. Not bad for a politician! Have a tip we should know? [email protected] ||||| Democrats tap David Weprin to run for seat vacated by Anthony Weiner Bryan Pace for News Assemblyman David Weprin is the Dems choice to run for Anthony Weiner's vacated seat. Assemblyman David Weprin, member of a powerful Queens political family, is the Democrats' choice to run for Anthony Weiner's vacant congressional seat. Weprin, who has close ties to the borough's political machine, will become the candidate to represent Congressional District 9, which spans sections of Queens and Brooklyn. He will face a yet-to-be-determined Republican in the Sept. 13 special election. "This is an exciting opportunity and I'm looking forward to the campaign," Weprin told the Daily News. "I've never tweeted in my life and I don't spend any time in the gym," Weprin added in a slap at Weiner, who was forced to resign last month amid a salacious sexting scandal - including nude workout pics. The winner of Weiner's seat may not be in Congress for long, since the seat has been eyed to be redistricted out of existence thanks to recent Census results. Weprin, 55, was picked by borough party boss Rep. Joe Crowley - who some political insiders feel valued loyalty over charisma when making the selection. "[Weprin] ain't exactly a powerhouse," said one prominent operative. "They wanted to pick somebody who wouldn't be dynamic enough to present a problem if he was redistricted out." Weprin - who lives in Holliswood, a few blocks outside of the district he hopes to represent - was a City Councilman for eight years and former finance chairman. Weprin's brother Mark is a City Councilman and their late father, Saul, was a legendary Assembly speaker. A source with knowledge of the selection process cited Weprin's fund-raising ability and the family's long history in Queens as selling points. He was deemed a "substantive guy, not the kind to be out tweeting." Other sources said Weprin pledged not to challenge any sitting congressman in 2012 - and may view this job as a stepping stone to a citywide office the following year. With Lisa L. Colangelo [email protected]

– New York Democrats have chosen their man to seek Anthony Weiner’s congressional seat: one David Weprin, an assemblyman from a powerful political family whose Queens home is just blocks from Weiner’s former district. The good: "I've never tweeted in my life and I don't spend any time in the gym," quipped Weprin. “This is an exciting opportunity and I'm looking forward to the campaign." But he "ain't exactly a powerhouse," an insider tells the New York Daily News. Instead of seeking a charming candidate, party leaders looked for a loyal one to run in the Sept. 13 special election, insiders say. That’s because census-based redistricting could soon remove the seat entirely. "They wanted to pick somebody who wouldn't be dynamic enough to present a problem if he was redistricted out," says the source. Others tell the Daily News that Weprin has promised not to take on any incumbent’s congressional seat in 2012; he’s focusing on New York City politics instead. Head to Mediaite to watch Weprin dance.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Commuter Bill of Rights Act of 2010''. SEC. 2. DEFINITIONS. For purposes of this Act the following definitions apply: (1) Eligible recipient.--The term ``eligible recipient'' means a provider of public transportation. (2) Public transportation.--The term ``public transportation'' means transportation by a conveyance that provides regular and continuing general or special transportation to the public, but does not include schoolbus, charter, sightseeing, or intercity bus transportation or intercity passenger rail transportation provided by the entity described in chapter 243 (or a successor to such entity). (3) Secretary.--The term ``Secretary'' means the Secretary of Transportation. SEC. 3. COMMUTER TRANSIT RIGHTS COMMISSION. (a) Establishment.--There is established an independent commission to be known as the ``Commuter Transit Rights Commission'' (hereinafter in this Act referred to as the ``Commission''). (b) Duties of the Commission.--The duties of the Commission shall be-- (1) to evaluate current Federal rules and regulations on commuter safety in emergency situations that govern transit providers; (2) to evaluate contingency plans that transit providers use across the United States and identify best practices; and (3) to make recommendations to the Secretary of Transportation (referred to in this Act as the ``Secretary'') pursuant to subsection (h). (c) Membership.-- (1) Number and appointment.--Not later than 60 days after the date of enactment of this Act, the Commission, which shall be composed of 12 members, shall be appointed by the Secretary as follows: (A) 2 members shall be commuters of public transportation. (B) 2 members shall be experts in rail safety. (C) 2 members shall be experts in water transportation. (D) 2 members shall be employees of State transportation agencies. (E) 2 members shall be experts in passenger safety. (F) 2 members shall be experts in emergency medicine. (2) Restriction.--No employee of the Department of Transportation may serve as a member of the Commission. (3) Chairperson.--The Chairperson of the Commission shall be elected by the members at the initial meeting. (d) Terms.-- (1) In general.--Each member shall be appointed for the life of the commission. (2) Vacancies.--A vacancy on the Commission shall be filled in the same manner as the original appointment. (3) Pay and travel expenses.-- (A) Pay.--Except as provided in subparagraph (C), each member of the Commission shall be paid at a rate equal to the daily equivalent of the minimum annual rate of basic pay for level IV of the Executive Schedule under section 5315 of title 5, United States Code, for each day, including travel time, during which he or she is engaged in the actual performance of duties vested in the Commission. (B) Travel expenses.--Members shall receive travel expenses, including per diem in lieu of subsistence, in accordance with subchapter I of chapter 57 of title 5, United States Code. (C) Prohibition of compensation of federal employees.--Members of the Commission who are full-time officers or employees of the United States or Members of Congress may not receive additional pay, allowances, or benefits by reason of their service on the Commission. (e) Meetings.-- (1) Initial meeting.--Not later than 30 days after the date on which all members of the Commission are appointed, the Commission shall hold its first meeting. (2) Subsequent meetings.--The commission shall meet monthly at the call of the Chairperson. (3) Quorum.--A majority of the Commission shall constitute a quorum but a lesser number may hold hearings. (f) Staff.--The Chairperson may appoint and fix the pay of additional personnel as the Chairperson considers appropriate. (g) Powers of the Commission.-- (1) Hearings and sessions.--The Commission may, for the purpose of carrying out this Act, hold hearings, sit and act at times and places, take testimony, and receive evidence as the Commission considers appropriate. (2) Powers of members and agents.--Any member or agent of the Commission may, if authorized by the Commission, take any action which the Commission is authorized to take by this section. (h) Recommendations.-- (1) Commuter bill of rights.--Not later than 160 days after its initial meeting, the Commission shall make recommendations to the Secretary that shall be known as the ``Commuter Bill of Rights''. The Commuter Bill of Rights shall include the following: (A) A list of situations in which a provider of public transportation shall implement its contingency plan. (B) Recommendations for the minimum standards that a contingency plan of a provider of public transportation must meet, including the following: (i) Provision of food, water, restrooms, ventilation, and medical services. (ii) Distribution of critical information to commuters on a disabled or delayed train or other transit vehicle, including a time frame for when commuters will be permitted to exit such disabled or delayed transit vehicle and how such commuters will be redirected to their final destinations in a timely manner. (C) Recommendations for Federal regulations on commuter safety in an emergency situation. (2) Procedure.--A majority of the Commission shall approve each recommendation before it is included in the Commuter Bill of Rights and submitted to the Secretary. (3) Supplemental report.--The Commission shall submit a supplemental report to the Secretary along with the Commuter Bill of Rights that contains all of the recommendations that the Commission considered, including those recommendations that did not receive a majority vote for inclusion in the Commuter Bill of Rights. (i) Termination.--The Commission shall terminate on the date that the Commission submits the Commuter Bill of Rights and supplemental report to the Secretary under subsection (h). SEC. 4. GRANT PROGRAM. (a) Authorization of Grant Program.--The Secretary may provide grants on a competitive basis to providers of public transportation to develop and implement contingency plans that fulfill the Commuter Bill of Rights. (b) Application.-- (1) In general.--To be eligible to receive a grant under this section, an eligible recipient shall submit an application not later than 90 days after the Secretary has issued a notice of availability at such time and in such manner as the Secretary may reasonably require. (2) Contingency plan implementation.--An eligible recipient shall include in its application a cost estimate of implementing the contingency plan to fulfill the Consumer Bill of Rights. (3) Certification.--When submitting an application, a provider of public transportation shall certify to the Secretary that the provider will implement its contingency plan not later than 90 days after receiving a grant under this section. (d) Amount of Grants.--An eligible recipient may only receive one grant under this section. The amount of such grant shall be the greater of $50,000 or 50 percent of the total amount of costs estimated in implementing the Commuter Bill of Rights as determined by the Secretary. SEC. 5. DUTIES OF THE SECRETARY. (a) In General.--The Secretary shall review the Commuter Bill of Rights submitted by the Commission under section 3 and issue regulations to require providers of public transportation to comply with the standards recommended by the Commuter Bill of Rights. (b) Federal Policies.--The Secretary shall use the Bill of Rights as recommended by the Commission to develop federal policies that will require compliance with the Bill of Rights by commuter transit providers. Such policies shall include-- (1) a requirement for providers of public transportation to submit for approval by the Secretary a proposed contingency plan meeting minimum standards according to the Bill of Rights; (2) a requirement that contingency plans be reviewed and updated as necessary and re-submitted to the Secretary every 5 years; and (3) a requirement that providers of public transportation comply with the final rule issued pursuant to subsection (a) not later than 180 days after the rule is issued under subsection (a). (c) Penalties and Sanctions.--The Secretary may assess appropriate penalties or sanctions for non-compliance as determined by the Secretary against providers of public transportation who fail to submit, obtain approval of, or adhere to its contingency plan. (d) Bill of Rights to Congress.--When the Secretary receives the Consumer Bill of Rights from the Committee, the Secretary shall forward a copy of such bill of rights to Congress. (e) Consumer Hotline.--The Secretary shall establish a consumer hotline telephone number for public transportation complaints in which the Secretary responds to consumer complaints not later than 30 days after submission of a complaint. SEC. 6. AUTHORIZATION OF APPROPRIATIONS. There are authorized to be appropriated to the Secretary, such sums as may be necessary to carry out this Act, to remain available until expended.

Commuter Bill of Rights Act of 2010 - Establishes the Commuter Transit Rights Commission. Requires the Commission to make recommendations to the Secretary of Transportation in the form of a Commuter Bill of Rights which includes: (1) a list of situations in which a provider of public transportation will implement its contingency plan during an emergency; (2) recommendations for minimum standards that a plan must meet, including the provision of food, water, restrooms, ventilation, and medical services, as well as the distribution of certain critical information to commuters on a disabled or delayed train or other transit vehicle; and (3) recommendations for federal regulations on commuter safety during emergencies. Authorizes the Secretary to provide competitive grants to providers of public transportation to develop and implement contingency plans that fulfill the Bill of Rights. Requires the Secretary to review the Bill of Rights and issue regulations to require providers of public transportation to comply with the Bill's recommended standards. Requires the Secretary to use the Bill of Rights to develop related federal policies. Authorizes the Secretary to assess penalties or sanctions against providers of public transportation who fail to submit, obtain approval of, or adhere to its contingency plan. Requires the Secretary to establish a consumer hotline telephone number for public transportation complaints.

forced - air patient warming systems , such as bair hugger ( augustine medical inc . , eden prairie , mn , usa ) , were developed in the 1980s and are acknowledged as being the most clinically effective patient warming modality . the advantages of avoiding hypothermia for patients undergoing major surgical procedures are well established , and include decreased blood loss ( with consequent reduction in blood product use ) , wound infection , duration of intensive care and hospital stay and cardiac ischaemia , and increased survival . however , a potential disadvantage is the risk for bacterial contamination of the operating theatre environment . prolonged exposure of the patient to the exhaust of the warming blanket could potentially mobilize their resident skin organisms into the theatre atmosphere , and thence into the surgical field , possibly increasing the risk for prosthetic material infection . we studied whether use of the bair hugger patient warming system increased bacterial contamination of the operating theatre and the surgical wound during prolonged surgery . the bair hugger upper body blanket ( model 522 ) was used for all patients . air samples were taken using standard techniques from the theatre atmosphere ( sites a1a3 ) and around the axillae ( sites b1 and b2 ) , where the exhaust air emerged , using the biotest rcs centrifugal air sampler and biotest hycon tc agar strips ( biotest uk ltd , solihull , west midlands , uk ) . a total of 160 l of air was sampled in 4 min from each of these sites . sterile swabs were used to take specimens from the warming unit and hose ( site c ) and immediately plated onto standard blood agar culture media . further specimens were taken from the wound edges with touch plates of blood agar ( site d ) . two readings were taken from each site , one when the warming blanket was first applied at the start of the operation and again at the end of the operation . the number of bacterial colonies visible to the naked eye on each of the agar strips and culture plates were then counted by hand and recorded . there were nine staff circulating in the operating theatre : three surgeons , two anaesthetists , one operating department assistant and three nurses . the mean duration of use of the warming blanket was 234 min ( range 180270 min ) . from each site , the number of bacterial colonies at the start of surgery was compared with that at the end of the operation . all operating theatre air specimens ( sites a1a3 ) exhibited a decrease in colony counts at the end of surgery ( mean reduction 36.4% ) . the exhaust air ( sites b1 and b2 ) colony counts also decreased at the end of surgery , although the size of the reduction was much less ( mean reduction 9.5% ) . in the wilcoxon matched pairs test , the test statistic t equalled 0 , because the rank difference was negative for all specimens from sites a1a3 , and b1 and b2 . this indicates that there was a significant decrease in the colony counts at the end of surgery as compared with the beginning ( p < 0.01 ) . all filter ( site c ) and wound specimens ( site d ) were sterile . none of the patients developed postoperative wound or prosthetic infections during a 6-month follow - up period . in the present study bacteria typing was to be done only if there was an increase in colony counts at the end of surgery , and this did not occur in any of the patients studied . as indicated above , the benefits of maintaining normothermia in surgical patients is well documented . it has been shown that the warming equipment itself does not cause bacterial dispersal but the role of patient flora was not investigated and the study was not conducted in a true surgical setting . this remained a concern in our unit , especially because some bacteria in wound infections originated from the patients ' skin . the present study did not show any increase in the mobilization and dispersal of patient resident skin organisms . the exhaust air from beneath the surgical drapes , which had passed over the patient 's skin , showed a decrease in the number of bacterial counts at the end of surgery , and this demonstrated that there was no increase in air contamination associated with the bair hugger patient warming system . furthermore , it indicated that the warm air stream did not force circulation of the patients ' skin organisms . if the bair hugger were affecting the atmosphere adversely , then the room air counts would also be expected to increase rather than decrease . in fact , the colony numbers in room air and system exhaust were reduced and this was consistent . although the study was not designed to evaluate other causes of bacterial presence in the operating theatre , we feel that the higher count at the beginning of surgery in room air may be due to the unrestricted movement of personnel in and out of the operating room , with opening and closing of doors , leading to increased air flow and turbulence . toward the end of surgery , movement of staff is much less and this may explain the fall in bacterial counts seen as the air turbulence decreases . we conclude that the use of the bair hugger patient warming system during prolonged abdominal surgery does not lead to increased bacterial contamination of the operating theatre atmosphere , and it is therefore unlikely to cause contamination of the surgical field . forced - air warming does not force patient 's resident skin organisms into and contaminate the operating theatre atmosphere such systems are unlikely to increase the incidence of wound and prosthetic infections a1a3 , room air ; b1 and b2 , exhaust from under drapes ; c , hose and filter of warming unit ; d , wound . comparison of the mean number of colonies values are expressed as mean ( range ) .

introductionuse of the bair hugger forced - air patient warming system during prolonged abdominal vascular surgery may lead to increased bacterial contamination of the surgical field by mobilization of the patient 's skin flora.methodsthis possibility was studied by analyzing bacterial content in air and wound specimens collected during surgery in 16 patients undergoing abdominal vascular prosthetic graft insertion procedure , using the bair hugger patient warming system . the bacterial colony counts from the beginning and the end of surgery were compared , and the data analyzed using the wilcoxon matched pairs test.resultsthe results showed not only that there was no increase in bacterial counts at the study sites , but also that there was a decrease ( p < 0.01 ) in air bacterial content around the patient and in the operating theatre after prolonged use of the patient warmer . no wound or graft infections occurred.conclusionthe use of this warming system does not lead to increased bacterial contamination of the operating theatre atmosphere , and it is unlikely to affect the surgical field adversely .

in the study of inflationary cosmology , it is often assumed that a classical inflaton field @xmath0 obeys a local equation of motion of the form @xmath1 where the friction term @xmath2 accounts for the loss of inflaton energy by radiation of particles . ( we omit the usual hubble damping term @xmath3 , for reasons discussed below . ) in particular , `` warm inflation '' scenarios ( see , for example , @xcite ) envisage a friction coefficient @xmath4 large enough for the inflaton motion to be perpetually overdamped , thus avoiding the usual process of reheating . however , an equation of this form does not arise automatically from quantum field theory . indeed , if the inflaton couples biquadratically to scalar fields @xmath5 , and via yukawa interactions to spin-@xmath6 fields @xmath7 , its equation of motion is generically of the form @xmath8 where the expectation values @xmath9 and @xmath10 are nonlocal functionals of @xmath0 . that is , they depend on the entire history of @xmath0 , at all times prior to the time @xmath11 at which the expectation values are evaluated . the issue we address here is whether these expectation values can be adequately approximated by a local friction term , together with a local correction to the effective potential @xmath12 , leading to the equation of motion ( [ localeom ] ) . to focus on this issue , which is substantially independent of the background metric , we simplify matters throughout by studying quantum field theory in minkowski spacetime , with @xmath13 . if the motion of @xmath0 is slow enough , it seems intuitively reasonable that suitable approximations to these expectation values can be obtained by considering the linear response of a state of thermal equilibrium to a time - dependent perturbation , @xmath14 . several implementations of this general idea can be found in the literature ( see , for example @xcite ) , and lead to well - defined estimates of the friction coefficient @xmath4 . however , the _ assumption _ that this problem can adequately be treated on the basis of linear perturbations about _ equilibrium _ thermal field theory deserves further investigation . if this assumption is valid , then the results should be reproduced in the slow evolution limit of _ nonequilibrium _ field theory . for the case of an inflaton coupled to a scalar field , this does not seem to be true @xcite . formally , one can derive approximate , local nonequilibrium evolution equations , but a time - derivative expansion of the solution to these equations , which is needed to arrive at ( [ localeom ] ) , does not exist . with the further approximation of replacing non - equilibrium self - energies with their equilibrium counterparts , a time - derivative expansion becomes possible , leading to what we call the _ adiabatic approximation _ , which essentially reproduces the results of linear response theory . however , numerical investigation shows that the motion generated by the nonequilibrium equations is not well approximated by the adiabatic approximation . these results might well be specific to the particular field theory considered . in this paper , we investigate this to some extent by extending the analysis of @xcite to the case of an inflaton that decays into spin-@xmath6 fermions . in principle , the calculations are quite similar , but the technicalities associated with spin-@xmath6 fields are slightly more complicated . in section [ freefer ] we derive exact evolution equations for the number densities @xmath15 , and auxiliary functions @xmath16 , which together specify the nonequilibrium state of fermions that are free , except for a @xmath0-dependent mass arising from a yukawa coupling to the classical inflaton . these are the fermionic analogues of the exact equations derived for scalar fields by morikawa and sasaki @xcite . as in the scalar - field case , they do not describe any significant frictional effect , because particles radiated by the inflaton motion can easily be reabsorbed . to achieve a permanent transfer of energy from the inflaton to the system of particles , these particles must interact with each other , and dissipate energy by scattering . an approximate set of nonequilibrium evolution equations is obtained in section [ interactions ] , by adapting the analysis described by lawrie and mckernan in @xcite . the closed - time - path methods used to develop this approximation are very different from the straightforward ( if long - winded ) operator methods available for free field theories , and the fact that the equations of section [ freefer ] are recovered in the free - field limit is a crucial check on this method of approximation . we again find that the nonequilibrium evolution equations do not admit a solution in the form of a time - derivative expansion ( in fact , this seems to be a general , model - independent result ) , but an adiabatic approximation can be devised , as explained in section [ adiabatic ] . numerical solutions to the nonequilibrium evolution equations , and to the adiabatic approximation to these equations , are described in section [ results ] . as in the previous case of an inflaton that decays into scalars , we find that these solutions do not agree well . in general , the adiabatic approximation appears to overestimate the damping effect of particle radiation on the inflaton motion ; in particular , we find that overdamping predicted by the adiabatic approximation , is not exhibited by the nonequilibrium evolution . a self - contained summary and discussion of these results is given in section [ conclusions ] . in this section , we derive a set of exact equations for the time evolution of a system of fermions that are free , apart from a coupling to the classical inflaton ; this gives rise to an effective time - dependent mass @xmath17 , where @xmath18 denotes the bare mass . these equations serve as a valuable check on the validity and interpretation of the approximate evolution equations we obtain in section [ interactions ] for the system of interacting fermions . we look for a formal solution of the dirac equation with time dependent mass , @xmath19\psi(x)=0\ ] ] by expanding the field @xmath20 in terms of two positive - energy spinors @xmath21 and their charge conjugates @xmath22 : @xmath23.\end{aligned}\ ] ] the spinors @xmath24 are helicity eigenstates , with helicity @xmath25 , @xmath26 , as indicated by the subscript and , at an arbitrary reference time @xmath27 , are solutions of the instantaneous dirac equation @xmath28u_\pm(\bm{k},\hat{t})=0,\ ] ] where @xmath29 and @xmath30 , normalized such that @xmath31 . dependence on the time @xmath11 is contained in the functions @xmath32 and these coefficients also depend on @xmath33 , in such a way that @xmath34 itself is independent of @xmath33 . by substituting the _ ansatz _ ( [ psiexpansion ] ) into the dirac equation ( [ dirac ] ) , we find equations for the @xmath11 dependence of @xmath35 . the change of variables @xmath36 with @xmath37 ( satisfying @xmath38 ) brings these equations into a standard form used in @xcite , namely @xmath39 the matrix @xmath40 ( with @xmath41 ) has eigenvalues @xmath42 , where @xmath43 . correspondingly , two orthogonal solutions to the equation @xmath44 can be written as @xmath45 where @xmath46 denotes time ordering . at the reference time @xmath33 , @xmath47 and @xmath48 are positive- and negative - energy solutions respectively ( that is , @xmath49 ) . the general solution for @xmath50 can thus be written as @xmath51 and the canonical equal - time anticommutator of @xmath34 and @xmath52 implies that the coefficients @xmath53 and @xmath54 have the usual anticommutator algebra @xmath55 for particle creation and annihilation operators . to find how these operators depend on @xmath33 we make use of the fact that @xmath56 . on substituting ( [ abcdtrans ] ) and ( [ abcdsolution ] ) into ( [ psiexpansion ] ) , we find ( after some algebra ) that @xmath57 where @xmath58 in a translation- and rotation - invariant state , expectation values of bilinear products of creation and annihilation operators are characterized by functions @xmath59 , @xmath60 and @xmath61 , defined by @xmath62 because the mode functions @xmath63 are positive - frequency only for times @xmath11 near @xmath33 , we can interpret @xmath59 as the number density of particles present _ at time _ @xmath33 with momentum @xmath64 and helicity @xmath65 , and @xmath60 as the corresponding density of antiparticles . the functions @xmath61 measure the off - diagonality of the density matrix in the basis specified by the modes @xmath66 , and have no classical analogue . the expectation value @xmath67 is conveniently expressed in terms of the number densities at time @xmath11 , and we achieve this by setting @xmath68 . we will restrict attention to states in which @xmath69 and @xmath70 are all equal , say to @xmath15 , while @xmath71 . it is easily checked using ( [ dbdthat ] ) that these equalities are preserved by the time evolution , and that the real number density @xmath15 and the complex function @xmath16 obey the evolution equations @xmath72,\nonumber\\ \label{dnudtferi}\end{aligned}\ ] ] where @xmath73 is the real part of @xmath74 . the expectation value of interest is given in terms of these functions by @xmath75,\ ] ] with all the quantities @xmath76 , @xmath77 , @xmath78 , @xmath79 evaluated at time @xmath11 . the evolution equations ( [ dndtferi ] ) and ( [ dnudtferi ] ) are the fermionic analogues of those derived by morikawa and sasaki @xcite for the case of the inflaton field coupled to a scalar field . the right - hand side of ( [ dndtferi ] ) is a particle ` creation ' term , proportional to @xmath80 , but it can be either positive or negative as @xmath81 oscillates , and a numerical solution shows that there is no permanent transfer of energy from the inflaton to the system of fermions . to see a frictional effect , it is necessary to introduce interactions between the fermions so that , roughly speaking , the created particles lose coherence with the inflaton , and a permanent dissipation of energy results . an approximation scheme for studying the non - equilibrium evolution of a system of interacting fermions was developed by lawrie and mckernan in @xcite . we follow their derivation closely , except that we introduce , as in section [ freefer ] , an evolving reference time @xmath33 , which allows us to make explicit the effect of particle creation . within the closed - time - path ( ctp ) formalism ( see , e.g. @xcite and references therein ) , we seek an approximation to the full two - point function @xmath82\rangle & -\langle \bar{\psi}_{\beta}(t',\bm{x}')\psi_{\alpha}(t,\bm{x})\rangle\\ \langle \psi_{\alpha}(t,\bm{x})\bar{\psi}_{\beta}(t',\bm{x}')\rangle & \langle \bar{\mathcal{t}}[\psi_{\alpha}(t,\bm{x})\bar{\psi}_{\beta}(t',\bm{x}'))]\rangle \end{pmatrix}\nonumber\\ \label{sdef}\end{aligned}\ ] ] from which the expectation value @xmath67 can be obtained as a special case . ( here , @xmath83 are dirac indices , while @xmath84 distinguish the indicated operator orderings . ) it is shown in @xcite that this can be expressed ( after a spatial fourier transform ) in terms of a single @xmath85 matrix @xmath86 as @xmath87 for any matrix @xmath88 , we define @xmath89 and @xmath90^t$ ] where @xmath91 is the charge conjugation matrix and @xmath92 indicates the transpose . as explained in detail in @xcite ( and in @xcite for the case of @xmath0 coupling to a scalar field ) , we construct a partially - resummed perturbation theory as follows . given a ctp action @xmath93 , where @xmath94 is quadratic in the fields and @xmath95 is of higher order , we take its lowest - order part to be @xmath96 where @xmath97 is a counterterm to be determined , and treat the remainder , @xmath98 as a perturbation . ( for @xmath99 , @xmath100 are the independent path - integration variables that inhabit the real - time branches of the closed time path ; we have indicated explicitly only the contribution of one spin-@xmath6 field . ) the lowest order propagator @xmath101 ( we suppress the momentum argument @xmath64 ) obeys the equation @xmath102 where the differential operator @xmath103 , defined by ( [ i0 ] ) , is @xmath104 and @xmath105 is the usual dirac operator . given suitable constraints on the form of the counterterm @xmath97 , the solution for @xmath106 can be written in the form ( [ propfourier ] ) in terms of a function @xmath107 which is the lowest - order approximation to @xmath108 . in this way , we obtain a reorganized perturbation theory , in which the vertices implied by @xmath95 are supplemented by the counterterm @xmath97 . in particular , self - energies have the form @xmath109 and we can optimize the propagators @xmath110 as an approximation to the full 2-point functions @xmath111 by choosing @xmath112 to cancel a local part of the loop diagrams in @xmath113 . the solution of ( [ diffop ] ) is explained in detail in @xcite . the matrix @xmath107 from which @xmath106 is built can be expressed in terms of the @xmath114 matrices , the mode functions @xmath115 introduced in section [ freefer ] , and two auxiliary functions @xmath116 and @xmath117 which , in the free - field limit , reduce to @xmath118 and @xmath119 respectively . these functions satisfy differential equations in the variable @xmath11 , which arise from ( [ diffop ] ) . in @xcite , the reference time @xmath33 was taken to be fixed at at the instant when an initial state is specified , but here we find it convenient to allow @xmath33 to vary , and eventually , as in section [ freefer ] , to set @xmath68 . the dependence of @xmath116 and @xmath117 on @xmath33 can be found from the fact that @xmath106 must be independent of @xmath33 . we now define @xmath120 evidently , we have @xmath121_{\hat{t}=t}\ ] ] and similarly for @xmath16 . applying the results of @xcite , we find that these two equations have the form @xmath122+\alpha_k(t)+ \frac{k\dot{m}(t)}{\omega_k(t)^2 } \nu_k^r(t)\nonumber\\ \label{dndtfermion}\\ \partial_{t}\nu_k(t)&=&-2[i\omega_k(t)+\gamma_k(t)]\nu_k(t)\nonumber\\ & & -\frac{k\dot{m}(t)}{2\omega_k(t)^2}\left[2n_k(t)- 1\right].\label{dnudtfermion}\end{aligned}\ ] ] the functions @xmath123 , which can be interpreted as a quasiparticle decay width , and @xmath124 appear in the counterterm @xmath97 and , according to the strategy outlined above , are to be determined from the self - energies @xmath113 . a concrete realization of this strategy is described in @xcite for the case that the fermions interact through a yukawa coupling to a scalar field @xmath125 of mass @xmath88 , @xmath126 and we consider the same model here , assuming for simplicity that @xmath5 does not couple to the inflaton , so @xmath88 is constant . evaluating the relevant self - energies to 1-loop order gives @xmath127\label{gammapsi}\\ \alpha_k(t)&=&\frac{g_\chi^2}{64\pi^2}(m^2 - 4m^2)\int d^3k'\frac{\delta(\omega_p-\omega_k-\omega_{k'})}{\omega_k\omega_{k'}\omega_p}\nonumber\\ & & \times\left[n_p(1-n_{k'})-(1+n_p)n_{k'}\right]\label{alphapsi}.\end{aligned}\ ] ] here , @xmath76 stands for the fermion mass @xmath128 , @xmath129 is ( approximately see below ) the number density of scalars , @xmath130 is the momentum of a scalar produced , say , by the collision of two fermions of momenta @xmath64 and @xmath131 , and @xmath132 . in this approximation , the first two terms in equation ( [ dndtfermion ] ) combine to give @xmath133+\alpha_k(t)\nonumber\\ & = & \frac{g_\chi^2}{32\pi^2}(m^2 - 4m^2)\int d^3k'\frac{\delta(\omega_p-\omega_k-\omega_{k'})}{\omega_k\omega_{k'}\omega_p}\nonumber\\ & \times&\left[n_p(1-n_k)(1-n_{k'})-(1+n_p)n_kn_{k'}\right]\end{aligned}\ ] ] which we recognize as the boltzmann scattering integral corresponding to the decay of a scalar into two fermions and the inverse production process . the evolution of @xmath129 is described by a similar boltzmann - like equation @xmath134,\label{chievolution}\end{aligned}\ ] ] where now @xmath135 . this contains no particle creation term ( analogous to the last term of ( [ dndtfermion ] ) ) owing to our assumption that @xmath125 does not couple to the inflaton . at this point , we have a closed system of evolution equations , consisting of ( [ dndtfermion ] ) , ( [ dnudtfermion ] ) , ( [ chievolution ] ) and the inflaton equation of motion , which we now take to have the form @xmath136 here , we have approximated @xmath67 by its lowest - order contribution , @xmath137 . it consists of a local function of @xmath138 , which contributes to the effective potential , together with the term @xmath139.\label{eomint}\ ] ] since we are concerned with the frictional effects arising from @xmath140 , we simplify matters by replacing the whole effective potential with @xmath141 . for later use , we observe that the total energy given by @xmath142\label{conservedenergy}\ ] ] is exactly conserved by this system of evolution equations . in the interest of accuracy , two remarks are in order . first , the representation ( [ propfourier ] ) of the full 2-point functions is valid for a cp - invariant theory . in practice , this means only that cp - breaking interactions will not be resummed by the counterterm @xmath97 . second , the quantities denoted in this section by @xmath15 , @xmath16 and @xmath129 are functions that arise in the process of solving the appropriate differential equations for spinor and scalar propagators . only in the free - field limit can they be unambiguously identified in terms of expectation values of creation and annihilation operators as in ( [ densities ] ) . the integral ( [ eomint ] ) that appears in the non - equilibrium equation of motion ( [ eomne ] ) has a divergent contribution from the term @xmath143 in the integrand . to isolate this divergence , consider the evolution equation ( [ dnudtfermion ] ) in the limit that @xmath144 is large . assuming that the thermal terms proportional to @xmath78 and @xmath145 can be neglected ( which is to be expected by analogy with equilibrium field theory , see e.g. section 3.5 of ref @xcite , but hard to prove here ) we find @xmath146 the solution can be written as @xmath147.\ ] ] and on repeatedly integrating by parts we find @xmath148\nonumber\\ & -&\frac{ig}{4k^2}\dot{\phi}(t)+\frac{g}{8k^3}\ddot{\phi}(t)+\cal{o}(k^{-4 } ) . \label{nuexp}\end{aligned}\ ] ] now , contributions to @xmath149 that vanish no faster than @xmath150 as @xmath151 will yield a divergent integral in ( [ eomint ] ) . to avoid this , we firstly choose initial conditions which have the form @xmath152 for large @xmath144 , so that the square bracket in ( [ nuexp ] ) vanishes . we are then left with the term @xmath153 which can be canceled by a wavefunction renormalization @xmath154 in the equation of motion ( [ eomne ] ) . this is , in fact , the same wavefunction renormalization that would be required in a zero - temperature quantum field theory with the yukawa coupling ( [ yukawa ] ) . with a suitable choice for @xmath155 , the renormalized integral is @xmath156,\end{aligned}\ ] ] where @xmath157 is a constant . the corresponding renormalized expression for the conserved total energy is @xmath158.\end{aligned}\ ] ] note that , since @xmath143 has a contribution of order @xmath150 , the spectrum of particles created by the last term in ( [ dndtfermion ] ) has a corresponding contribution of order @xmath159 , and so therefore does @xmath78 . this gives a convergent integral in ( [ renormpsi ] ) , but a divergent contribution to @xmath160 , which is cancelled by the last term in ( [ renormenergy ] ) . with the approximations developed above , the functions @xmath15 and @xmath16 that appear in @xmath140 obey local evolution equations ( [ dndtfermion ] ) and ( [ dnudtfermion ] ) , but the solution to these equations is non - local , i.e. @xmath140 evaluated at time @xmath11 depends on @xmath161 at all times @xmath162 prior to @xmath11 . one can attempt to derive a local approximation of the form @xmath163 which depends only on the values of @xmath0 and @xmath164 at time @xmath11 , by means of a time - derivative expansion , but we show below that , as in the case of an inflaton that decays into scalar particles @xcite , this does not work . to facilitate a time - derivative expansion , we introduce a formal expansion parameter @xmath165 multiplying time derivatives @xmath166\nu_k(t)\nonumber\\ & & -\epsilon\frac{gk\partial_t\phi(t)}{2\omega_k^2(t)}\left[2n_k(t)-1\right],\label{nandnu}\end{aligned}\ ] ] where we have also used @xmath167 . we now expand @xmath15 , @xmath129 and @xmath16 in powers of @xmath165 around the equilibrium distributions @xmath168 , @xmath169 and @xmath170 @xmath171 substituting this expansion into equations ( [ dndtfermions3])-([nandnu ] ) we find to leading order that @xmath172 , while @xmath173^{-1},\quad n_p^{\mathrm{eq}}=\left[e^{\beta\omega_p}-1\right]^{-1}\label{eqdist}\ ] ] for some inverse temperature @xmath174 are the usual fermi - dirac and bose - einstein distributions that make the boltzmann scattering integrals vanish . at order @xmath165 , @xmath175 and @xmath176 are solutions of the integral equations @xmath177 where @xmath178 means that we set @xmath179 and @xmath180 after differentiation . however , these equations are not self - consistent and therefore have no solution . it is easily seen from ( [ scatpsi ] ) and ( [ chievolution ] ) that @xmath181 this reflects the fact that if @xmath182 is the total number density of fermions of each helicity ( and also the number of antifermions of each helicity ) and @xmath183 is the total number density of scalars , then the quantity @xmath184 is conserved by the processes @xmath185 . ( for example , one fermion of a given helicity is produced , on average , in every two @xmath5 decays . ) in the presence of particle production , this conservation law no longer holds , but the scattering integrals still obey the sum rule ( [ sumrule ] ) . the integral equations ( [ dndtadiabatic ] ) therefore entail @xmath186 but this is not true for the equilibrium distributions ( [ eqdist ] ) . thus , although the evolution equations themselves are consistent ( albeit approximate ) , they do not admit a solution in the form of a time - derivative expansion . in principle , therefore , we can not approximate @xmath187 in the form ( [ tdexp ] ) or the inflaton equation of motion in the local form ( [ localeom ] ) by means of a time - derivative expansion . a local approximation to the equation of motion _ can _ however be obtained by resorting to a further approximation , which consists in replacing @xmath15 and @xmath129 with their equilibrium values ( [ eqdist ] ) for the purpose of evaluating the functions @xmath145 , which we then denote by @xmath188 , and @xmath189 . when this is done , the @xmath190 equations for @xmath175 and @xmath191 are @xmath192\delta\nu_k-\frac{gk\dot{\phi}}{2\omega_k^2 } \times\left[2n_k^{\mathrm{eq}}-1\right].\end{aligned}\ ] ] on rearranging these , we find that the inflaton equation of motion can be written as @xmath193 with @xmath194\nonumber\\ & = & \int\frac{dkk^2}{2\pi^2\omega_k(t)}\left(\frac{m(t)}{e^{\beta\omega_k(t)}+1}\right)\label{deltavad}\end{aligned}\ ] ] and @xmath195\nonumber\\ & = & \frac{g}{4\pi^2}\int\frac{dkk^2}{\omega_k(t)^2}\bigg\{\frac{\beta m(t)^2n_k^{\mathrm{eq}}(t)(1-n_k^{\mathrm{eq}}(t))}{\gamma_k^{\mathrm{eq}}(t)}\nonumber\\ & & + \frac{\gamma_k^{\mathrm{eq}}(t)}{[\omega^2_k(t ) + \gamma_k^{\mathrm{eq}2}(t)]}\frac{k^2}{2\omega_k(t)}\left[1 - 2n_k^{\mathrm{eq}}(t)\right]\bigg\}.\label{etaad}\end{aligned}\ ] ] in the zero temperature limit ( @xmath196 ) and taking @xmath197 this expression agrees with that found in @xcite ( apart from a factor of @xmath198 which we have not been able to account for ) . we refer to the approximation represented by ( [ eomad])-([etaad ] ) , together with a suitable prescription for determining the temperature @xmath199 , as the _ adiabatic approximation_. to estimate time evolution over any extended period of time within the adiabatic approximation , we must allow @xmath174 to change in an appropriate manner . we obtain a suitable prescription by requiring that the energy ( [ conservedenergy ] ) be conserved by the adiabatic evolution when @xmath200 and @xmath78 have their equilibrium values . the approximate nonequilibrium evolution equations developed in section [ deriv ] lead to the local equation of motion ( [ eomad ] ) only when we make the extra approximation of replacing self - energies ( from which the functions @xmath189 and @xmath145 are derived ) with their values in a state of thermal equilibrium , together with the time - derivative expansion which then becomes possible . on the face of it , one might expect these further approximations to be fairly harmless , at least for a system that does not evolve too fast , and does not stray too far from thermal equilibrium . however , the numerical calculations described in @xcite for the case of an inflaton coupled to scalar particles showed that the nonequilibrium evolution governed by a set of equations analogous to those of section [ deriv ] is not well represented by the corresponding adiabatic approximation , even under circumstances when that approximation might seem to be reasonably well justified . we therefore discuss in this section a similar numerical comparison of the time evolution generated by the nonequilibrium equations described in sections [ deriv ] and [ renorm ] , with that generated by the adiabatic approximation of section [ adiabatic ] . to discretize the nonequilibrium time evolution , we use a semi - implicit method defined schematically by @xmath201\frac{\delta t}{2},\ ] ] where @xmath202 represents the whole collection of variables @xmath0 , @xmath164 , @xmath78 , @xmath200 , and @xmath79 and @xmath203 labels time steps . in the absence of the @xmath204 interaction , it is straightforward to show that this method is stable for our problem . crucially , it is also simple enough that we can implement a discretized version of the renormalization scheme of section [ renorm ] that is exact up to rounding errors . when interactions are included , stability of the resulting set of integro - differential equations is very hard to analyse . we do in fact see evidence of instability when the calculations are pursued for sufficiently long times , but the results presented below are for periods of time for which the effects of this instability appear to be negligible . moreover , although the renormalized total energy ( [ renormenergy ] ) is exactly conserved in the continuum limit , there is no local discretized version of this expression that is exactly conserved by the discretized evolution equations . as a rough check on our computations , we have evaluated a discretized version of ( [ renormenergy ] ) , but we do not expect it to be exactly conserved . in particular , divergent contributions to the integral , which cancel by construction in the continuum limit , are not guaranteed to cancel when time evolution is discretized . in practice , all the initial conditions we have considered lead to an oscillatory solution for @xmath138 ; we find that energy acquires an oscillatory component ( with amplitude of order 5% of the total ) , consistent with incomplete cancellation of the divergent integral proportional to @xmath205 , together with a drift amounting to a few percent over the time intervals of interest . the adiabatic approximation is not affected by these issues . here , no renormalization is required ; semi - implicit discretization of the one remaining differential equation , the equation of motion ( [ eomad ] ) , leads to a stable problem ; and exact conservation of energy is imposed as the criterion for determining @xmath174 . intuitively , this approximation ought to be good when @xmath138 is slowly varying and thermalization of the created particles is efficient . a rough criterion for efficient thermalization is @xmath206 or , @xmath207 where @xmath208 is a relaxation time , which we take to be @xmath209 . to obtain slow variation in @xmath138 , we would ideally like to identify a set of parameters for which the motion is overdamped . within the adiabatic approximation , one way of achieving this is to make the first term in the friction coefficient ( [ etaad ] ) large , by making @xmath145 relatively small , but this tends to make thermalization slow , at least according to the criterion ( [ thermcrit ] ) . the parameter space of couplings , masses and initial conditions is , even for the simple model considered here , too large to permit a systematic exploration , but we have not succeeded in locating a set of parameter values that leads both to overdamped motion and to a very small value of @xmath210 . ( this was also true of the investigation reported in @xcite for an inflaton decaying into scalars ; in the context of warm inflation , it seems to be generally hard to devise simple field theory models that exhibit efficient thermalization as well as other desirable properties @xcite . ) nevertheless , we can find a situation in which the adiabatic approximation predicts overdamped motion , and @xmath210 is not too large . figure [ comparison ] shows the evolution of @xmath138 calculated from the nonequilibrium evolution equations and from the adiabatic approximation , with the parameter values @xmath211 , @xmath212 , @xmath213 , and initial conditions @xmath214 , @xmath215 , @xmath216 . the solid curve is the motion generated by the adiabatic approximation , which is indeed overdamped ; we see , however , that the motion generated by the non - equilibrium equations without the adiabatic approximation ( dashed curve ) although it exhibits some damping is far from overdamped . in both the adiabatic and non - equilibrium solutions . the initial conditions predict overdamping for the adiabatic solution . ] and @xmath210 for early times . the thermalization is relatively efficient in this period and the two solutions are still very different ] as in @xcite , this striking discrepancy does not seem to be accounted for by inefficient thermalization . in figure [ comparisontherm ] we show the early stages of the motion , along with the parameter @xmath210 as estimated within the adiabatic approximation . during this period of time , @xmath210 remains below 1 . thus , within the adiabatic approximation , one might well conclude that this approximation is reasonably self - consistent . while thermalization is not efficient enough to guarantee good accuracy , one would probably not anticipate the gross discrepancy between the two approximations for @xmath138 . at @xmath217 for both the adiabatic and the non - equilibrium solutions . ] moreover , we compare in figure [ gammacomp ] the function @xmath145 calculated at @xmath218 from the nonequilibrium number densities with that calculated in the adiabatic approximation from an exactly thermal distribution . while some difference is visible , it seems clear that the small quantitative difference can not in itself account for difference between the overdamped and oscillatory motions apparent in figure [ comparisontherm ] . in fact , the difference between these motions can be understood in the way suggested in @xcite . at @xmath219 , we chose an initial state of exact thermal equilibrium . denote by @xmath220 the integral ( [ eomint ] ) evaluated in this state , and let @xmath221 . at early times , when the value of @xmath0 has not changed by much , the nonequilibrium equation of motion ( [ eomne ] ) is given approximately by @xmath222 while the adiabatic approximation to this equation is @xmath223 as seen from figure [ comparisontherm ] , where @xmath224 , the velocity @xmath164 in the adiabatic approximation quickly approaches the `` terminal velocity '' @xmath225 and thereafter @xmath0 and @xmath164 evolve slowly , with @xmath226 . according to the original equation , by contrast , @xmath227 is still approximately equal to @xmath228 , leading to the dashed curve . clearly , in these circumstances , the original equation of motion is not well represented by the adiabatic approximation , and this is substantially independent of how well the number densities used to calculate @xmath229 and @xmath4 are thermalized . an example of the more generic case of underdamped motion is shown in figure [ underdamped ] . for both the adiabatic and non - equilibrium solutions ] we see that the nonequilibrium evolution shows significant damping , but that the rate of damping is overestimated by the adiabatic approximation . this differs somewhat from the case of inflaton decay into scalars @xcite . in that case , the adiabatic approximation leads to a friction coefficient roughly proportional to @xmath230 , and thus to an overestimate of damping at large amplitudes , but an underestimate at small amplitudes . in this paper , we have sought to address a very specific issue : can the expectation value @xmath231 appearing in the generic inflaton equation of motion ( [ phieom ] ) , which is a non - local functional of @xmath0 , be adequately approximated by a local function of @xmath138 and @xmath14 , leading to a local equation of motion such as ( [ localeom ] ) . the conclusion suggested by the results of the two preceding sections is that it can not be , but these results are neither exact nor wholly rigorous , so it is worthwhile to summarize carefully the line of argument we have adopted . derivations of the local friction coefficient @xmath4 to be found in the literature vary somewhat in the details of implementation , but generally involve the _ assumption _ , characteristic of linear response theory , that under suitable conditions the state of the particles can be treated according to _ equilibrium _ field theory . the possibility of obtaining a local equation of motion then depends on the behaviour of the relevant integral kernels , which can be investigated in perturbation theory for specific models ( see , for example @xcite and , for recent discussions @xcite ) . we seek to avoid this assumption by studying instead the slow - evolution limit of the _ nonequilibrium _ state . in principle , this is certainly the more correct procedure ; in practice , however , nonequilibrium evolution is extremely hard to deal with by analytic means . the approximation scheme sketched in sections [ deriv ] and [ renorm ] is the lowest non - trivial order of a partially resummed perturbation theory . it leads to a local set of evolution equations , but we find that these equations do not admit a solution in the form of a time - derivative expansion , which is needed to derive the local equation of motion ( [ localeom ] ) , and consequently that this local equation of motion does not , in principle , exist . we can not altogether rule out the possibility that this result is a feature of our approximation scheme , rather than of the exact dynamics . quantitatively , indeed , the accuracy of the approximation is likely to be quite modest , though we have no good way of assessing this . however , the fact that it reproduces the exact dynamics of section [ freefer ] in the free - field limit , and that the boltzmann - like scattering terms have a sensible kinetic - theory interpretation , offers some reassurance that the approximation captures essential features of the nonequilibrium dynamics . moreover , any improved method of studying nonequilibrium dynamics ( for example , the 2-particle - irreducible formalism developed by berges and coworkers ; see @xcite and references therein , especially @xcite ) is intrinsically non - local . it seems very likely that any attempt to derive a local equation of motion must follow a sequence of approximations more or less equivalent to that used here , and would fail at the same point . even if the local equation of motion is formally not valid , it might nevertheless be a good approximation under suitable circumstances . indeed , we can recover essentially the same result for @xmath4 as that given by linear response methods by taking the further step of replacing nonequilibrium self - energies with those calculated in a state of thermal equilibrium : we called this the adiabatic approximation to our non - equilibrium evolution equations . intuitively , this would seem to be a fairly innocuous step if the evolution is fairly slow , and thermalization is not too inefficient . to test this , we obtained numerically , in section [ results ] , solutions for the motion of @xmath0 both with and without the adiabatic approximation . in order to focus on the frictional effect ( and to simplify the numerical calculation somewhat ) we took the whole effective potential ( including the local part of @xmath231 ) to be approximated by the parabola @xmath232 . while this might significantly affect the actual motion obtained for @xmath138 , it is irrelevant for our purpose of assessing the effect of the extra adiabatic approximation . the results of this numerical comparison of the nonequilibrium and adiabatic approximations are broadly similar to those of the parallel calculations reported in @xcite for an inflaton decaying into scalars . in both cases , we find examples of conditions for which the adiabatic approximation predicts overdamped motion ( and so might seem , at least on the grounds of self - consistency , to be reliable ) , while the motion resulting from the `` full '' nonequilibrium evolution is oscillatory , with relatively little damping . ( in neither case did we find conditions under which the frictional effect generated by the nonequilibrium evolution is sufficient to cause overdamping ; however , we were unable to explore the large parameter space exhaustively . ) even with the adiabatic approximation , underdamped motion seems to be more typical of the model we studied , but the magnitude of the frictional effect seems to be significantly overestimated by this approximation . for the model studied in this work , indeed , it seems that friction is always overestimated by the adiabatic approximation . in the case of inflaton decay into scalars , the adiabatic approximation yields a friction coefficient that contains a factor @xmath230 , and appears to overestimate the frictional effect when @xmath0 is large , while underestimating it when @xmath0 is small . beyond the formal difficulty discussed in section [ adiabatic ] , the reasons for the failure of the adiabatic approximations are hard to identify in any detail . poor thermalization may be an issue , but as noted earlier , it seems implausible that the large discrepancies we observe are due merely to the quantitative effect of number densities that differ somewhat from a true thermal distribution . a more plausible possibility is that the discrepancies could be lessened simply by retaining more terms in the time - derivative expansion . comparison of ( [ od1 ] ) and ( [ od2 ] ) makes it rather obvious that , if the adiabatic motion is friction limited , so that @xmath225 and @xmath226 , and if the same value of @xmath0 and the same number densities are used to evaluate both the adiabatic and the `` full '' equation of motion , a large discrepancy is more or less inevitable . it could be , however , that this friction - limited motion does not lead to negligible values for higher - order terms in the time - derivative expansion , and that this accounts for the discrepancy . unfortunately , pursuing the adiabatic approximation to higher orders is rather complicated ( and not entirely unambiguous , in view of the evolving temperature we employed ) ; and to our knowledge , approximation schemes of this kind are not commonly used in the cosmological literature . the possibility of describing the dissipation of inflaton energy by a local friction term is primarily of interest in connection with warm inflation scenarios , and it should be emphasized that the results reported here and in @xcite do not in themselves determine whether or not such scenarios may be viable . to the extent that any generic result can be extracted , it seems that the adiabatic approximation overestimates the effects of dissipation : in particular , overdamped motion ( and hence warm inflation ) is apparently harder to achieve than the adiabatic approximation suggests . however , this may be true only of the simple models we have investigated . the somewhat discouraging conclusion is that no simple analytical approximation known to us represents dissipation reliably , and numerical investigations of the kind reported here offer a very inefficient tool for inflationary model building .

according to quantum field theory , the inflaton equation of motion does not have the local form that is generally assumed for cosmological purposes . in particular , earlier investigations of the nonequilibrium dynamics of an inflaton that decays into scalar particles suggest that the loss of inflaton energy is not well approximated by the local friction term derived from linear response theory . we extend this analysis to the case of an inflaton that decays into fermions , and reach broadly the same conclusion .

oxygen is the most abundant heavy element in the universe . due to its relatively high ionization potential , far - ultraviolet ( fuv ) photons ( 6ev@xmath16@[email protected] ) do not ionize it and thus a large fraction of atomic oxygen can be expected in the photodissociated gas interface between the ionized and the molecular gas before chemical species such as co , h@xmath18o or oh reach high abundances . the absorption of fuv photons by dust grains leads to the ejection of photoelectrons that heat the gas ( _ e.g. , _ draine 1978 ) as well as to intense fir dust continuum emission . the efficiency of this essential process can be estimated by comparing the luminosity of the main gas cooling lines ( _ e.g. , _ the fir fine structure lines of cii and oi ) with the luminosity of the dust emission . indeed , fir lines from abundant gas reservoirs are key players in the energy balance of the regions they trace ( from fuv illuminated interstellar clouds and protoplanetary disk surfaces to extragalactic starbursts ) . the oi(@xmath15 ) fine structure triplet system is formed by the @xmath1 ( ground state ) , the @xmath0 ( @xmath19@xmath20@xmath21/@xmath22=228k ) and the @xmath23 ( @xmath19@xmath20@xmath24/@xmath22=99k ) levels . radiative transitions between the @xmath0@xmath1 and @xmath23@xmath0 states lead to the widespread [ oi]63 and 145@xmath3 m line emission respectively . observations and models of such lines are crucial diagnostics of a broad range of galactic and extragalactic environments ( see hollenbach & tielens 1999 for a review ) . in this letter , we present the first detection of the [ oi]63@xmath3 m line toward the horsehead pdr ( @xmath25@xmath2400pc , edge - on ) , one of the most famous fuv - induced chemical laboratories in the sky . we analyze the fir line and continuum emission without strong simplifying assumptions in the excitation and radiative transfer treatment . the horsehead nebula was observed with the multiband imaging photometer for _ spitzer _ ( mips ) as part of our `` specpdr '' program ( id:20281 ; joblin et al . 2005 ) on 2006 april 3 using the spectral energy distribution mode ( hereafter mips / sed ) . mips / sed provided the capability of obtaining low resolution spectra ( @xmath26 ) in the fir range ( @xmath27 m ) using a slit spectrometer and the mips70 ge : ga detector array . the slit size has two detector pixels in width ( @xmath220@xmath28 ) and 12 pixels in length ( @xmath22@xmath29 ) . a reflective grating provides a spectral dispersion of 1.7@xmath3 m pixel@xmath30 . we used the `` spectral mapping '' mode and covered the horsehead with 14 pointings shifted by half the slit width in the direction perpendicular to the slit length . the exposure time was 10s per pointing . the `` chop distance '' for the off positions was set to + 3@xmath29 for each pointing . both on and off source areas are shown in fig.[fig : show_area]@xmath31 . we subtract the average off - source spectrum to every on - source spectra . we first retrieved the bcd data ( ver . s16.1.0 ) that we proceed with the _ mosaic_sed.pl _ script of mopex to obtain the post - bcd level data ( in intensity units of mjysr@xmath30 ) . we apply a flat correction to the spatial dimension on the detector ( _ i.e. _ detector columns relative gain correction ) at the bcd level . we compute the flat response of the detector columns using the off positions . we have developed a pipeline that builds spectral cubes ( two spatial dimensions and one spectral dimension ) from the post - bcd data . we work in the assumption that no spatial information is available in the slit width . thus , the @xmath32 rows of the detector can be seen as images of the sky through the slit for @xmath32 sampled wavelengths between 55 and 97@xmath3 m . for each wavelength , this image of the slit is reprojected into a @xmath33 spatial grid of the sky . the final cube then has @xmath34 pixels . the pixel size of the spatial grid is half of each detector pixel field of view , pfov ( 9.8/2 = 4.9 ) . nevertheless , due to dispersion , the light that falls on a pixel comes from the entire slit width , that is two times the pixel size , so that the pfov is rather @xmath35 . this leads to an overestimation of the intensity of a factor 2 that we take into account here . for extended sources , one also has to correct for the effect of the aperture used for the photometric calibration with point sources . we then divide the intensity by the 5 pixels aperture correction function ( see mips data handbook ) . the photometry of the resulting spectral cubes ( for all sources in our program ) were checked by cross - calibrating them with mips70 data when available . it appears that the mips / sed gain is 30% higher than the mips70 one . on the basis that the photometer calibration is more reliable , we apply this 30% correction to our mips / sed data and use the mips70 absolute calibration uncertainty of 7% . figure[fig : show_area]@xmath31 shows the on and off source areas of our _ spitzer _ observations plotted over the polycyclic aromatic hydrocarbon ( pah ) mid ir emission toward the horsehead ( abergel et al . 2003 ) . the pah band emission traces the fuv illuminated edge of the cloud ( compigne et al . 2007 , 2008 ; goicoechea et al . 2009 ) . mips spectra averaged over the on and off areas are shown as green and blue histograms ( fig.[fig : show_area]@xmath36 ) . the on off subtracted spectrum is shown as a black histogram . the [ oi]63@xmath3 m line is not present in the off spectrum , and therefore , the extended line emission can fully be attributed to the cloud . in order to have an approximate view of the spatial location of the oxygen emission , fig.[fig : show_area]@xmath37 displays the [ oi]63@xmath3 m line intensity measured in each pixel of the data cube ( gray scale ) . ortho_-h@xmath18 @xmath38=00 @xmath39(1 ) pure rotational line emission at @xmath217@xmath3 m , delineating the edge of the pdr , is shown as white contours . overall , the [ oi ] emission peaks in the warm cloud layers ( where h@xmath18 and pah emission are also bright ) directly exposed to the fuv radiation from @xmath40ori o9.5v star . although the excitation requirements of the _ ortho_-h@xmath18 @xmath38=00 @xmath39(1 ) ( @xmath20@xmath41/@xmath421015k ) and [ oi]63@xmath3 m ( @xmath20@xmath41/@xmath42228k ) lines are different , the apparent shift between both line emission peaks in fig.1@xmath37 may be marginal since mips / sed astrometry is not better than @xmath25@xmath28 . besides , cloud inclination variations ( relative to the line of sight ) from north to south , and thus differential line opacity effects , likely explain the brighter [ oi]63@xmath3 m emission observed toward the north of the filament . the [ oi]63@xmath3 m line intensity toward the emission peak , as measured over the @xmath215 full width at half maximum ( fwhm ) angular resolution of mips at 63@xmath3 m ( circle on fig.[fig : show_area]@xmath37 ) , is @xmath6=([email protected])@xmath810@xmath44 wm@xmath45sr@xmath30 ( @xmath24 times brighter than the h@xmath18 @xmath38=10 @xmath39(1 ) fluorescent emission at 2.12@xmath3 m ; see habart et al . the resulting mips spectrum is shown in fig.[fig : show_area]@xmath36 as `` peak '' . the [ oi]63@xmath3 m line is detected at a 10@xmath40 level . the fir thermal emission of dust raises from @xmath2155mjy sr@xmath30 ( at @xmath255@xmath3 m ) to @xmath2325mjy sr@xmath30 ( at @xmath285@xmath3 m ) . the continuum peaks at longer wavelengths and thus the temperature of the grains emitting in the fir ( @xmath14 ) can not be high ( @xmath14@xmath4635k ) , lower than the expected gas temperature ( @xmath13 ) . apart from this [ oi]63@xmath3 m bright emission toward the cloud edge , the mips data show a fainter level of widespread emission ( @xmath24 times weaker ) likely arising from the more diffuse cloud envelope , or halo , illuminated by the ambient fuv radiation field . in order to guide our interpretation of the [ oi]63@xmath3 m line toward the peak , fig.[fig : mtc_grid ] ( _ left _ ) shows the output of a photochemical model ( le petit et al . 2006 ; goicoechea & le bourlot 2007 ) adapted to the steep density gradient , @xmath10@xmath2@xmath47 ( habart et al . 2005 , goicoechea et al . 2009 ) and fuv illumination conditions in the horsehead edge ( @xmath48@xmath5100 , where @xmath48 is the fuv flux in habing units of the local interstellar value ) . we adopt an elemental oxygen abundance of 3@xmath810@xmath49 relative to h nuclei ( savage & sembach 1996 ) . taking into account that the gas temperature rapidly decreases from the low density pdr ( @xmath13@xmath5100k ; see also pety et al . 2005 ; habart et al . 2009 ) to the denser and shielded inner layers ( @xmath13@xmath4620k ; pety et al . 2007 ) , we predict that the [ oi]63@xmath3 m emission peak should occur at the surface of the molecular cloud between @[email protected] and 0.5 . due to the relatively low fuv radiation field impinging the cloud , dust grains are not expected to attain large temperatures ( @xmath14@xmath4630k ) . however , h@xmath18 photodissociation is still important in the cloud edge and a significant fraction of hydrogen is predicted to reside in atomic form in the same layers where [ oi]63@xmath3 m is bright . at extinction depths greater than @[email protected] , carbon monoxide starts to be protected against photodissociation and the gas temperature falls sharply . the formation of co ( and other o - rich gas and ice species ) decreases the abundance of atomic oxygen inward . observations of the [ oi]63@xmath3 m line and fir continuum emission constrain the mean gas density and both the dust and gas temperatures toward the pdr . in this work , we use a _ nonlocal _ and non - lte code that treats both the line and continuum radiative transfer and includes the radiative pumping of oi levels by absorption of fir dust photons ( see the appendix in goicoechea et al . almost all studies solving the excitation of atomic fine structure levels simplify the problem by assuming a _ local _ treatment of the excitation calculation : _ lvg _ or single - zone escape probability methods ( _ e.g. , _ rllig et al . 2007 ) , where the source function ( the line emissivity / absorption ratio ) is assumed to be constant , and the radiative coupling between different cloud positions is neglected . the effects of dust opacity are also generally omitted ( gonzlez garca et al . 2008 ) . their applications to the interpretation of [ oi]63,145@xmath3 m lines have been widely used by a number of authors in the past ( _ e.g. , _ tielens & hollenbach 1985 ; van dishoeck & black 1986 ; spaans et al . 1994 ; poglitsch et al . 1995 ; kaufman et al . 1999 ; vastel et al . 2001 ; liseau et al . 1999 , 2006 ) . nevertheless , elitzur & asensio ramos ( 2006 ) recently compared the exact solutions provided by their _ nonlocal _ method with those given by the _ local _ approximation and concluded that , for gas densities around 10@xmath5010@xmath11cm@xmath9 , the error in the predicted [ oi]63/145 line intensity ratio can be significant ( _ i.e. , _ comparable with the variation range of the ratio for different temperatures and densities ) . indeed , these are the densities expected in the outer layers of the horsehead nebula , _ i.e. , _ below the critical densities of oi fine structure transitions ( @xmath51@xmath55@xmath810@xmath52cm@xmath9 for oi(@xmath0@xmath1)h@xmath18 collisional ) used in this work are : oi collisions with _ ortho / para_h@xmath18 from jaquet et al . ( 1992 ) : note that for low energies ( @xmath13@xmath46300 - 400k ) , the @xmath53 and @xmath54 rates are slightly higher ( _ e.g. , _ by @xmath4610@xmath55 at 100k ) when _ para_-h@xmath18 is the perturber . otherwise , rate coefficients are slightly higher for _ ortho_-h@xmath18 collisions ; oi h collisions from abrahamsson et al . ( 2007 ) : at 100 k these excitation rate coefficients are a factor of @xmath24 larger than those by launay & roueff ( 1977 ) ; oi he collisions from monteiro & flower ( 1987 ) ; oi@xmath56 collisions from bell et al . ( 1998 ) and oi@xmath57 collisions from chambaud et al . ( 1980 ) . ] de - excitation ) . under these conditions , the determination of the @xmath15 level populations is a non - trivial problem and radiative and opacity effects ( fir pumping and line - trapping ) can play a role . besides , the [ oi]63@xmath3 m line becomes optically thick ( @xmath58 ) for low column densities , @xmath59(oi)@xmath6010@xmath61cm@xmath45 , and the [ oi]145@xmath3 m line can be suprathermal ( @xmath63@xmath64t@xmath65 ) or even inverted ( @xmath63@xmath160 ) and the emission amplified ( @xmath66@xmath160 ) by the maser effect ( see also liseau et al . 2006 ; elitzur & asensio ramos 2006 ) . in order to constrain the dust temperature , the fir dust luminosity and obtain an approximated value for the gas density in the [ oi]63@xmath3 m emitting region , we have first modeled the observed sed toward the peak position . we explicitly solve the continuum radiative transfer problem by taking a dust opacity @xmath67 proportional to @xmath68(100/@xmath69)@xmath70 , where @xmath68 is the dust opacity at 100@xmath3 m ( per gas+dust mass column density ) and @xmath71 is the dust spectral index . assuming a line - of - sight depth of 0.1pc ( uncertain within a factor of @xmath22 , see constraints by habart et al . 2005 ) , the best models of the continuum shape and absolute intensity level are obtained for @xmath14@xmath530k ( in agreement with the pdr model prediction ) and @xmath10=@xmath72(h)+2@xmath72(h@xmath18)@xmath510@xmath73cm@xmath9 ( with @[email protected] and @[email protected]@xmath74g@xmath30 ; _ e.g. , _ li & draine 2001 ) . integrating the resulting continuum intensity distribution from 40 to 500@xmath3 m we obtain @xmath75=2.5@xmath810@xmath76 wm@xmath45sr@xmath30 . the dust model is shown in fig.[fig : show_area]@xmath36 ( red dashed curve ) . we determine that the line - of - sight extinction depth toward the peak is @[email protected] , consistent with the expected values of a cloud edge . the fir dust continuum toward the region of bright [ oi ] , h@xmath18 , and pah emission is optically thin , with @xmath77@xmath52@xmath810@xmath9 . after modeling the fir radiation field in the pdr we now solve the oi @xmath15 populations adding radiative pumping by fir dust photons . we include collisional rate coefficients@xmath78 ( cm@xmath50s@xmath30 ) of atomic oxygen with _ ortho_ and _ para_h@xmath18 , h , he , electrons , and protons . h@xmath18 and h collisions dominate , but it is important to include their rates ( s@xmath30 ) with the most realistic h and h@xmath18 density contributions . note that , for example , @xmath80 collisional excitation can be neglected ( to first order ) if only oi h@xmath18 collisions apply ( monteiro & flower 1987 ) , but it does contribute if collisions with h are included ( abrahamsson et al . we adopt an _ ortho_-to-_para_h@xmath18 ratio@xmath78 ( otp ) of 3 , although , at the @xmath13 and @xmath10 considered in this work , our results do not change by taking an otp of 1 ( [ oi ] lines become @xmath22@xmath55 brighter ) . figure [ fig : mtc_grid ] ( right ) displays a grid of _ nonlocal _ models showing the emergent @xmath6 intensity as a function of @xmath59(oi ) column density . the lower panel shows the predicted @xmath6 for @xmath13=100k ( _ i.e. , _ roughly the gas temperature in the outermost cloud layers ) and varying h@xmath18 densities . guided by our pdr model ( figure [ fig : mtc_grid ] ( left ) ) , and in order to modify only one physical parameter in the grid , we take a fixed @xmath72(h ) density of 10@xmath81cm@xmath9 and a high ionization fraction : @xmath82/@xmath10=10@xmath49 ( see goicoechea et al . 2009 ) . our calculations include thermal , turbulent , and opacity line broadening with a turbulent velocity dispersion of @xmath40=0.225kms@xmath30 ( fwhm@xmath83 ) . this value is inferred from heterodyne interferometric observations of the hco radical toward the pdr ( gerin et al . the shaded regions show the observed [ oi]63@xmath3 m line intensity toward the peak position . for a line - of - sight depth of 0.1pc and taking oi / h@xmath53@xmath810@xmath49 in the pdr ( most oxygen in atomic form ) , our observations are reproduced with @xmath72(h@xmath18)@xmath55@xmath810@xmath50cm@xmath9 ( consistent with the dust model ) and @xmath59(oi)@xmath58.5@xmath810@xmath61cm@xmath45 ( best model shown in figure 1 ( b ) ) . the [ oi]63@xmath3 m opacity at line center is @xmath84@xmath56 ( due to saturation the width of the line profile is opacity broadened , [email protected]@xmath30 , _ i.e. , _ broader than the linewidth of an optically thin line affected only by turbulent and thermal dispersion ) . the predicted [ oi]63/145 line intensity ratio is @xmath515 . the required h@xmath18 density has to be multiplied ( divided ) by @xmath24 if the gas temperature is a factor of 2 lower ( higher ) ; line opacities and [ oi]63/145 intensity ratios change accordingly . future observations of both [ oi]63,145@xmath3 m lines will help to better constrain the density and the atomic oxygen abundance gradient . for @xmath13=100k , the [ oi]63@xmath3 m line emission is subthermal ( @xmath63@xmath16t@xmath65 ) which means that the @xmath0 level ( @xmath85 ) is much less populated than in lte ( _ i.e. , _ @xmath86@xmath87 ) . in fact we find that the @xmath23@xmath0 transition at 145@xmath3 m is suprathermal ( with @xmath88@xmath89 ) . this effect is produced by the larger radiative life time of the upper @xmath23 level compared to the lower @xmath0 level ( by a factor of @xmath25 ) . even more , the lack of significant @xmath23-@xmath0 collisional de - excitation for oi h@xmath18 collisions ( neglecting those with h ) can invert the level populations ( @xmath90 ) leading to a [ oi]145@xmath3 m maser line emission . high temperatures ( @xmath13@xmath60100k for a pure h@xmath18 gas and @xmath13@xmath60300k for a pure h gas ) together with relatively low @xmath84 opacities ( or @xmath10@xmath1610@xmath52cm@xmath9 ) are required to obtain the level inversion , otherwise line trapping in the [ oi]63@xmath3 m line increases the upper @xmath0 level population again . at such `` low '' gas densities ( @xmath91 ) the _ local _ treatment of oi excitation overestimates ( underestimates ) the @xmath85 ( @xmath92 ) level populations , leading to stronger ( weaker ) [ oi]63@xmath3 m ( 145@xmath3 m ) emission as long as @xmath84@xmath601 . the error made increases with @xmath59(oi ) ( see elitzur & asensio ramos 2006 ) . the fir continuum toward the horsehead is optically thin and radiative pumping does not play a significant role in the oi excitation ( it reduces @xmath6 by @xmath21@xmath55 ) . however , in more extreme sources ( with opaque continuum emission ) , fir pumping can reduce the @xmath63 of the oi @xmath0-@xmath1 transition ( @xmath63@xmath93 ) and increase the @xmath94 level population ratio . for the physical conditions treated here , the [ oi]63/145 ratio decreases by a factor of @xmath22 if the dust emission becomes optically thick at 63@xmath3 m . overall , neglecting fir pumping and using _ local _ approximations for the oi excitation overestimates the [ oi]63/145 ratio . once the non - lte level populations have been accurately computed , one can determine the appropriate [ oi]63@xmath3 m cooling rate per volume unit , @xmath95=@xmath96@xmath97 ( where @xmath98 are the collisional excitation and de - excitation rates in s@xmath30 ) . this relation takes into account that only line photons following collisional excitation and escaping the cloud are responsible of the gas cooling . we compute @xmath95@xmath55@xmath810@xmath99ergs@xmath30cm@xmath9 toward the peak position . our observations and models are consistent with the [ oi]63@xmath3 m line arising from the outer layers ( @[email protected] and 0.5 ) of the horsehead pdr ( @xmath48@xmath5100 and @xmath10@xmath510@xmath11cm@xmath9 ) where the gas is warm ( @xmath5100k ) and not all available hydrogen has converted into h@xmath18 yet . together with available [ cii]158@xmath3 m observations ( @xmath100 wm@xmath45sr@xmath30 , from _ kao _ at @xmath255 resolution ; zhou et al . 1993 ) , we find that the luminosity of the [ cii]158@xmath3 m + [ oi]63@xmath3 m lines represents @xmath21%-2% of the total fir dust luminosity . this fraction corresponds to a high efficiency of the photoelectric heating mechanism . in fact , due to the relatively low fuv field but moderate gas density in the pdr , the horsehead is a good source to investigate the grain populations that efficiently transform the incident fuv field into gas heating . _ herschel _ will allow us to map almost all relevant fir cooling lines at much higher spectral and angular resolutions . together with appropriate models of their excitation , it will then be possible to study the energy balance of interstellar clouds in greater detail . we thank the specpdr team for their contribution to the project , a. noriega - crespo and r. paladini for valuable discussions on mips / sed data reduction and m. gerin and the referee for helpful comments on the manuscript . jrg was supported by a _ ramn y cajal _ research contract from the spanish micinn and co - financed by the european social fund .

we present the first detection of neutral atomic oxygen ( @xmath0@xmath1 fine structure line at @xmath263@xmath3 m ) toward the horsehead photodissociation region ( pdr ) . the cloud has been mapped with the _ spitzer space telescope _ at far - ir ( fir ) wavelengths using the multiband imaging photometer for _ spitzer _ ( mips ) in the spectral energy distribution ( sed ) mode . the [ oi]63@xmath3 m line peaks at the illuminated edge of the cloud at @[email protected] - 0.5 ( inward the gas becomes too cold and outward the gas density drops ) . the luminosity carried by the [ oi]63@xmath3 m line represents a significant fraction of the total fir dust luminosity ( @xmath6/@xmath7@xmath54@xmath810@xmath9 ) . we analyze the dust continuum emission and the _ nonlocal _ oi excitation and radiative transfer in detail . the observations are reproduced with a gas density of @xmath10@xmath510@xmath11cm@xmath9 and gas and dust temperatures of @xmath13@xmath5100k and @xmath14@xmath530k . we conclude that the determination of the oi @xmath15 level populations and emergent line intensities at such `` low '' densities is a complex non - lte problem . fir radiative pumping , [ oi]63@xmath3 m subthermal emission , [ oi]145@xmath3 m suprathermal and even maser emission can occur and decrease the resulting [ oi]63/145 intensity ratio . the _ herschel space observatory _ , observing from @xmath255 to 672@xmath3 m , will allow us to exploit the diagnostic power of fir fine structure lines with unprecedented resolution and sensitivity .

apoptosis is the most common form of programmed cell death and its role in organ and tissue development and differentiation is well documented . however , apoptosis is also commonly encountered during pathophysiological processes . in the kidney , tubular apoptosis in fact , we have previously shown that tubular cell apoptosis contributes to kidney injury independently of inflammation . pathological apoptosis is a stochastic process that occurs randomly in space and time following injury . therefore , the quantitation of apoptosis in fixed tissue has always underestimated the magnitude of this form of cell death . this is further confounded by the short life of apoptotic tubular cells as they are shed into the lumen or cleared by phagocytic cells . hoechst easily detected condensed or fragmented nuclei and the vital probe propidium iodide excluded necrotic cells with damaged cell membranes . while this approach was successful in quantifying tubular apoptosis in kidney volumes of live animals , the inherent toxicity of hoechst and propidium iodide precluded imaging over prolonged periods of time . phiphilux is a new generation cell permeable probe which emits fluorescence in the red ( g2d2 ) or green ( g1d2 ) when cleaved by active caspase 3 . its appeal for imaging apoptosis stems from the important fact that it does not inhibit the subsequent activity of caspase 3 once cleaved . therefore , it offers a unique opportunity to follow the progress of apoptosis over time . we are aware of only one paper that describes the use of phiphilux with intravital 2-photon microscopy to image apoptosis in the gut villi . in that paper , we therefore report on the use of phiphilux to image caspase 3 activity and apoptosis in renal tubules in live mice with 2-photon intravital microscopy . eight week old c57bl/6j and b6129s1-casp3/j ( caspase 3 knockouts ) mice , weighing on average 20 g , were obtained from jackson labs . briefly , live animal imaging was performed using a bio - rad mrc-1024mp laser scanning confocal / multiphoton scanner attached to a nikon diaphot inverted microscope with a nikon 20 or 60 na 1.2 water - immersion objective . fluorescence excitation was provided by a titanium - sapphire laser ( spectraphysics , mountain view , ca ) 800 nm excitation . in some studies we used an olympus fv1000-mpe confocal / multiphoton microscope equipped with a spectra physics maitai deep see laser and gallium arsenide 12-bit detectors . the system is mounted on an olympus ix81 inverted microscope stand with a nikon 20 and 60 na 1.2 water - immersion objective . we estimate that the power at the surface of the kidney was between 2 and 28 mw . animals were placed on the stage with the exposed intact kidney placed in a coverslip - bottomed cell culture dish ( warner inst . , hamden , ct ) bathed in isotonic saline as we have described . in some animals , unilateral renal ischemia was induced with a 60 min clamp of the renal pedicle . phiphilux g2d2 ( calbiochem ) 570 l per mouse was injected iv through an external jugular line and the kidney was imaged for periods up to 2 hours . intravital 2-photon imaging of sham mouse kidneys reveals 2 populations of proximal tubules easily distinguished by their green autofluorescence ( fig . using freely filtered fluorescently labeled inulin , we have previously determined that the tubules with bright green autofluorescence are the downstream s2 . tubules with dim autofluorescence ( occasionally with a brown yellow hue ) are s1 ( fig . collecting ducts show minimal , if any , autofluorescence and have a bright nuclear hoechst signal . within 1 min after phiphilux injection , the probe exhibited significant red fluorescence exclusively in s1 tubules near the brush border ( fig . phiphilux fluorescence continued to increase in s1 tubules over a 30 min time period ( fig . phiphilux signal could be seen in a small punctate subapical pattern that partially co - localized with the green autofluorescence signal ( inset in fig . because the latter is thought to emanate from endosomes , this possibly indicates early endocytosis of the probe . to determine whether this activation of phiphilux was related to the presence of constitutionally active caspase 3 in s1 , we imaged the kidney of a sham caspase 3 ko mouse . as shown in figure 2 , phiphilux was also activated in s1 tubules . like in wild - type mice , the caspase 3-independent signal of phiphilux in s1 tubules was indicative of non - specific activation by protease activity in s1 during probe uptake in this highly endocytic tubular segment . in figure 3 , we followed the phiphilux signal in a sham wild - type kidney volume over a 2 hour time period , imaging intermittently every 30 minutes . we noted a decrease in the phiphilux signal in s1 and an increase in hoechst fluorescence in various tubules indicative of photodamage . s2 segments did not exhibit any phiphilux signal over that time period but also showed some photodamage as evidenced by a change in their typical autofluorescence pattern . at later time points , phiphilux signal could be easily detected in the lumen of collecting ducts . at no time ischemia reperfusion is known to induce caspase 3 activation and apoptosis in s2 and s3 renal tubules . to determine whether this can be detected by phiphilux , we imaged the kidney of a wild - type mouse after 40 minutes of ischemia . immediately following reperfusion , however , within 30 minutes after reperfusion , some phiphilux signal could be detected in s2 tubular cells ( fig . sixty minutes following reperfusion , phiphilux positive s2 cells with condensed nuclei suggestive of apoptosis could be easily detected in random fields ( fig . figure 4d shows the persistence of non - apoptosis - related phiphilux signal in s1 next to a clearly apoptotic phiphilux positive s2 cell . occasionally , phiphilux signal was detected in damaged s2 cells shed into the s2 lumen ( fig . interestingly , phiphilux signal ( presumably indicating caspase 3 activity ) preceded nuclear condensation in these early shed apoptotic cells . at no time most ischemia - induced apoptosis in the kidney is confined to s2 and s3 segments . the data presented above show that phiphilux should be used with caution when imaging renal apoptosis with intravital 2-photon microscopy . the non - specific activation of this probe in s1 segments was clearly not related to caspase 3 and can be confounding in the overall estimation of apoptosis . the mechanism of non - caspase 3 -related activation of phiphilux in s1 is unclear . non - caspase proteases such as calpains could be involved in this process . however , their distribution and activity in various tubular sub segments are unknown . in contrast , we believe that phiphilux detected true apoptosis in s2 cells following ischemia . that this phiphilux signal in apoptotic s2 cells is indeed a read - out of caspase 3 activity could theoretically be confirmed by performing the ischemia reperfusion experiment in caspase 3 ko mice . however , many groups have shown that with inhibition or absence of caspase 3 , apoptosis at these early time points is greatly reduced if present at all . the non - caspase 3 related activation of phiphilux in s1 tubules underscores this important segmental difference in the kidney . the utility of phiphilux in reporting caspase 3 activation with intravital microscopy in other organs and tissues remains to be determined .

tubular cell apoptosis is a major phenotype of cell death in various forms of acute kidney injury . quantifying apoptosis in fixed tissues is problematic because apoptosis evolves over time and dead cells are rapidly cleared by the phagocytic system . phiphilux is a fluorescent probe that is activated specifically by caspase 3 and does not inhibit the subsequent activity of this effector caspase . it has been used successfully to quantify apoptosis in cell culture . here we examined the feasibility of using phiphilux to measure renal tubular apoptosis progression over time in live animals using intravital 2-photon microscopy . our results show that phiphilux can detect apoptosis in s2 tubules but is activated non - specifically in s1 tubules .

laparoscopic liver resection ( llr ) for lesions located in the posterior segments ( pss ) , namely , segments 1 , 7 , 8 , and 4a , presents inherent technical challenges . even though appropriate adjustments and technical tricks have been described for safe and effective parenchyma - preserving surgery in pss , operating time , blood loss , and the rate of r1 resections remain higher with respect to both llr in the anterior segments and laparoscopic major hepatectomies . furthermore , studies investigating the role of laparoscopy for ps liver neoplasms revealed major hepatectomies to be the procedure of choice instead of segmentectomies and nonanatomic liver resections . this appears to be in contrast to the ongoing parenchyma - preserving management of liver malignancies in both the open setting and llr of malignancies located in the anterior segments . therefore , there is a general agreement to consider open liver resection ( olr ) the current standard of care for lesions located in pss , reserving llr for surgeons with wide experience in both liver and laparoscopic surgery . recently , robotics have been introduced in liver surgery , with the aim of overcoming some of the limitations of traditional laparoscopy , providing greater maneuverability with a set of articulated instruments and a tridimensional view . comparing llr with robot - assisted liver resection ( ralr ) , the latter allowed a more conservative approach , especially for lesions located in the pss , decreasing , in turn , the rate of major hepatectomies . however , the effectiveness and safety of rlr with respect to traditional open liver surgery for lesions in the pss have not yet been investigated . the aim of this study was to pinpoint the early outcomes of open and robotic liver resections in a subgroup of patients with liver lesions in the right posterior section , with special reference to lesions posterior to the right hepatic vein or superior to the right portal vein , excluding resections of the anterior aspect of segment 6 , which are considered straightforward laparoscopically . to address this issue , we retrospectively analyzed the differences in demographics , technical details , and outcomes of open and robotic liver resections for lesions in the right posterior section at 2 institutions , each with specific experience in open and minimally invasive liver surgery . the first group was a series of 19 consecutive patients who underwent ralr in segments 6 and 7 from january 2007 to june 2012 at a referral center for minimally invasive surgery ( division of general , minimally invasive and robotic surgery , spoleto , italy ) . all of these patients underwent macroscopic curative liver resection for primary or secondary liver tumors and benign conditions with a robot - assisted laparoscopic technique and were prospectively reviewed through a maintained nonselective liver surgery database . data for the second group were retrieved from the liver surgery database at a high - volume hepatobiliary center , the hepatobiliary unit , department of surgery , san raffaele scientific institute ( milan , italy ) . between january 2004 and december 2012 , 1416 consecutive liver resections were prospectively collected in a single database containing clinical , surgical , pathologic , and follow - up information for patients submitted to olr . a laparoscopic series was not considered , because of the purpose of the study . as first selection , the group of patients who underwent macroscopic curative olr in segments 6 and 7 from january 2007 to june 2012 was extrapolated to avoid bias due to the learning curve and the implementation of surgical techniques . on the basis of indications given in the operative report the period of recruitment was considered ended in june 2012 , enabling at least 6 months of follow - up for each enrolled patients . only those patients with completed a total of 102 patients met these criteria and formed the basis of the control group . as further assessment , a subgroup of patients was extrapolated among the control group according to an individually matched case - control design with ralr cases . the olr cases were individually selected as accurately as possible to exclude patients with extrahepatic disease ( 29 cases ) , patients in whom llr was attempted ( 2 cases ) , and patients who underwent concomitant radiofrequency ablation ( 2 cases ) . ultimately , a total of 69 patients were selected , with a ratio between the numbers of the 2 groups of 1:3.6 . clinical and pathologic characteristics , postoperative outcomes , hospital course , and postoperative morbidity and mortality were compared between the ralr and olr groups . demographic data , surgical procedures , postoperative course , and outpatient follow - up were reviewed . the following data were collected prospectively : age , sex , preoperative workup , type and location of the liver nodule , size , type of procedure , duration of surgery , blood loss , intraoperative complications , pathologic findings , postoperative complications , and hospital stay . operative time was calculated as the time between laparotomy and skin suture for olr and the time between pneumoperitoneum induction and port - site closure for ralr . all patients entered a protocol of follow - up and underwent periodic physical , biochemical , and radiologic examinations . prior consent was obtained , and full treatment options were offered to all patients treated . all procedures were carried out using the da vinci s surgical system ( intuitive surgical systems , sunnyvale , california ) , and ultrasound exploration was completed with an aloka prosound alpha 7 ( aloka , tokyo , japan ) . for lesions in segments 6 and 7 , the patient was rotated on the left flank to facilitate liver mobilization and inferior vena cava dissection . after 12 mm hg pneumoperitoneum was induced with a veress needle , the camera port and the left robotic trocars were placed at the level of the right costal margin , whereas the right robotic trocar was inserted in the intercostal space between the 10th and 11th ribs along the scapular line , as previously described . two accessory trocars can be placed along the midline and the anterior axillary line for suction and retraction . to control liver inflow , an extracorporeal tourniquet was used to encircle the liver pedicle and carry out the pringle maneuver in an intermittent fashion ( 10 minutes of ischemia , 5 minutes of reperfusion ) . moreover , a single dose of a medium - half - life steroid drug ( methylprednisolone 500 mg ; solu - medrol , pfizer , rome , italy ) was administered at the induction of anesthesia to reduce the oxidative parenchymal damage induced by the intermittent ischemia - reperfusion vascular control . the kelly - clamp crushing technique using endowrist bipolar precise forceps ( intuitive surgical systems ) was preferred for curved and angulated section lines and tumor dissection close to major liver vessels . to secure larger vessels on the transection line , we used hem - o - lock clips ( tfx medical ltd , durham , north carolina ) or ligatures with vicryl or prolene . the hepatic veins were usually divided with the laparoscopic linear stapler ( endo gia ; ethicon endo - surgery , cincinnati , ohio ) or sutured . abdominal incision consisted of a right angle laparotomy in the right upper quadrant , allowing favorable access to the posterior liver segments . intraoperative ultrasonography was used to plan the parenchymal transection , and the resection line was outlined on the liver surface with electrocautery marks . liver resection was performed using the sonosurg system ( olympus , tokyo , japan ) , which integrates an ultrasonic dissector and an ultrasonic coagulating cutter . the ultrasonic dissector was used to fracture hepatocytes along the proposed line of division , leaving intact the crossing arteries , veins , and bile ducts . thus , intraparenchymal vascular anatomy could be easily defined , and a decision on hemostatic technique could be made on the basis of vessel size . millimetric structures were effectively coagulated using the bipolar forceps , whereas larger vessels and biliary branches were sealed with titanium clips or sectioned between ligatures . the few larger vessels and portal triads were divided using vascular staplers ( ets - flex ; ethicon endo - surgery ) . considering the usual ineffectiveness of the ultrasonic dissector in cases of cirrhotic liver , the ultrasonic coagulating cutter was adopted in these cases as able to effectively transect fibrotic parenchyma . an argon beam coagulator was used to refine unsatisfactory hemostasis , possibly in addition to the application of hemostatic matrixes on the transection surface . a single flat jackson - pratt drain was placed in the posterior aspect of the resection bed . as a rule , the hepatic pedicle was encircled by a tourniquet before transection , allowing the pringle maneuver to be performed as needed in an intermittent fashion ( 10 minutes of ischemia , 5 minutes of reperfusion ) . moreover , a single dose of a medium - half - life steroid drug ( methylprednisolone 500 mg ; solu - medrol ) was administered at the induction of anesthesia to reduce the oxidative parenchymal damage induced by the intermittent ischemia - reperfusion vascular control . in both groups , continuous data are reported as mean sd ( range ) and were compared by using the 2-sided student t test . comparisons between groups for categorical variables were performed using the test with yates 's correction or the fisher exact test as appropriate . statistical analysis was performed with spss statistics version 19.0 ( ibm , armonk , new york ) . the first group was a series of 19 consecutive patients who underwent ralr in segments 6 and 7 from january 2007 to june 2012 at a referral center for minimally invasive surgery ( division of general , minimally invasive and robotic surgery , spoleto , italy ) . all of these patients underwent macroscopic curative liver resection for primary or secondary liver tumors and benign conditions with a robot - assisted laparoscopic technique and were prospectively reviewed through a maintained nonselective liver surgery database . data for the second group were retrieved from the liver surgery database at a high - volume hepatobiliary center , the hepatobiliary unit , department of surgery , san raffaele scientific institute ( milan , italy ) . between january 2004 and december 2012 , 1416 consecutive liver resections were prospectively collected in a single database containing clinical , surgical , pathologic , and follow - up information for patients submitted to olr . a laparoscopic series was not considered , because of the purpose of the study . as first selection , the group of patients who underwent macroscopic curative olr in segments 6 and 7 from january 2007 to june 2012 was extrapolated to avoid bias due to the learning curve and the implementation of surgical techniques . on the basis of indications given in the operative report the period of recruitment was considered ended in june 2012 , enabling at least 6 months of follow - up for each enrolled patients . only those patients with completed a total of 102 patients met these criteria and formed the basis of the control group . as further assessment , a subgroup of patients was extrapolated among the control group according to an individually matched case - control design with ralr cases . the olr cases were individually selected as accurately as possible to exclude patients with extrahepatic disease ( 29 cases ) , patients in whom llr was attempted ( 2 cases ) , and patients who underwent concomitant radiofrequency ablation ( 2 cases ) . ultimately , a total of 69 patients were selected , with a ratio between the numbers of the 2 groups of 1:3.6 . clinical and pathologic characteristics , postoperative outcomes , hospital course , and postoperative morbidity and mortality were compared between the ralr and olr groups . demographic data , surgical procedures , postoperative course , and outpatient follow - up were reviewed . the following data were collected prospectively : age , sex , preoperative workup , type and location of the liver nodule , size , type of procedure , duration of surgery , blood loss , intraoperative complications , pathologic findings , postoperative complications , and hospital stay . operative time was calculated as the time between laparotomy and skin suture for olr and the time between pneumoperitoneum induction and port - site closure for ralr . all patients entered a protocol of follow - up and underwent periodic physical , biochemical , and radiologic examinations . prior consent was obtained , and full treatment options were offered to all patients treated . all procedures were carried out using the da vinci s surgical system ( intuitive surgical systems , sunnyvale , california ) , and ultrasound exploration was completed with an aloka prosound alpha 7 ( aloka , tokyo , japan ) . for lesions in segments 6 and 7 , the patient was rotated on the left flank to facilitate liver mobilization and inferior vena cava dissection . after 12 mm hg pneumoperitoneum was induced with a veress needle , the camera port and the left robotic trocars were placed at the level of the right costal margin , whereas the right robotic trocar was inserted in the intercostal space between the 10th and 11th ribs along the scapular line , as previously described . two accessory trocars can be placed along the midline and the anterior axillary line for suction and retraction . to control liver inflow , an extracorporeal tourniquet was used to encircle the liver pedicle and carry out the pringle maneuver in an intermittent fashion ( 10 minutes of ischemia , 5 minutes of reperfusion ) . moreover , a single dose of a medium - half - life steroid drug ( methylprednisolone 500 mg ; solu - medrol , pfizer , rome , italy ) was administered at the induction of anesthesia to reduce the oxidative parenchymal damage induced by the intermittent ischemia - reperfusion vascular control . the kelly - clamp crushing technique using endowrist bipolar precise forceps ( intuitive surgical systems ) was preferred for curved and angulated section lines and tumor dissection close to major liver vessels . hemostasis of small vessels was obtained with monopolar or bipolar cautery . to secure larger vessels on the transection line , we used hem - o - lock clips ( tfx medical ltd , durham , north carolina ) or ligatures with vicryl or prolene . the hepatic veins were usually divided with the laparoscopic linear stapler ( endo gia ; ethicon endo - surgery , cincinnati , ohio ) or sutured . abdominal incision consisted of a right angle laparotomy in the right upper quadrant , allowing favorable access to the posterior liver segments . intraoperative ultrasonography was used to plan the parenchymal transection , and the resection line was outlined on the liver surface with electrocautery marks . liver resection was performed using the sonosurg system ( olympus , tokyo , japan ) , which integrates an ultrasonic dissector and an ultrasonic coagulating cutter . the ultrasonic dissector was used to fracture hepatocytes along the proposed line of division , leaving intact the crossing arteries , veins , and bile ducts . thus , intraparenchymal vascular anatomy could be easily defined , and a decision on hemostatic technique could be made on the basis of vessel size . millimetric structures were effectively coagulated using the bipolar forceps , whereas larger vessels and biliary branches were sealed with titanium clips or sectioned between ligatures . the few larger vessels and portal triads were divided using vascular staplers ( ets - flex ; ethicon endo - surgery ) . considering the usual ineffectiveness of the ultrasonic dissector in cases of cirrhotic liver , the ultrasonic coagulating cutter was adopted in these cases as able to effectively transect fibrotic parenchyma . an argon beam coagulator was used to refine unsatisfactory hemostasis , possibly in addition to the application of hemostatic matrixes on the transection surface . a single flat jackson - pratt drain was placed in the posterior aspect of the resection bed . as a rule , the hepatic pedicle was encircled by a tourniquet before transection , allowing the pringle maneuver to be performed as needed in an intermittent fashion ( 10 minutes of ischemia , 5 minutes of reperfusion ) . moreover , a single dose of a medium - half - life steroid drug ( methylprednisolone 500 mg ; solu - medrol ) was administered at the induction of anesthesia to reduce the oxidative parenchymal damage induced by the intermittent ischemia - reperfusion vascular control . in both groups , all procedures were carried out using the da vinci s surgical system ( intuitive surgical systems , sunnyvale , california ) , and ultrasound exploration was completed with an aloka prosound alpha 7 ( aloka , tokyo , japan ) . for lesions in segments 6 and 7 , the patient was rotated on the left flank to facilitate liver mobilization and inferior vena cava dissection . after 12 mm hg pneumoperitoneum was induced with a veress needle , the camera port and the left robotic trocars were placed at the level of the right costal margin , whereas the right robotic trocar was inserted in the intercostal space between the 10th and 11th ribs along the scapular line , as previously described . two accessory trocars can be placed along the midline and the anterior axillary line for suction and retraction . to control liver inflow , an extracorporeal tourniquet was used to encircle the liver pedicle and carry out the pringle maneuver in an intermittent fashion ( 10 minutes of ischemia , 5 minutes of reperfusion ) . moreover , a single dose of a medium - half - life steroid drug ( methylprednisolone 500 mg ; solu - medrol , pfizer , rome , italy ) was administered at the induction of anesthesia to reduce the oxidative parenchymal damage induced by the intermittent ischemia - reperfusion vascular control . the kelly - clamp crushing technique using endowrist bipolar precise forceps ( intuitive surgical systems ) was preferred for curved and angulated section lines and tumor dissection close to major liver vessels . hemostasis of small vessels was obtained with monopolar or bipolar cautery . to secure larger vessels on the transection line , we used hem - o - lock clips ( tfx medical ltd , durham , north carolina ) or ligatures with vicryl or prolene . the hepatic veins were usually divided with the laparoscopic linear stapler ( endo gia ; ethicon endo - surgery , cincinnati , ohio ) or sutured . abdominal incision consisted of a right angle laparotomy in the right upper quadrant , allowing favorable access to the posterior liver segments . intraoperative ultrasonography was used to plan the parenchymal transection , and the resection line was outlined on the liver surface with electrocautery marks . liver resection was performed using the sonosurg system ( olympus , tokyo , japan ) , which integrates an ultrasonic dissector and an ultrasonic coagulating cutter . the ultrasonic dissector was used to fracture hepatocytes along the proposed line of division , leaving intact the crossing arteries , veins , and bile ducts . thus , intraparenchymal vascular anatomy could be easily defined , and a decision on hemostatic technique could be made on the basis of vessel size . millimetric structures were effectively coagulated using the bipolar forceps , whereas larger vessels and biliary branches were sealed with titanium clips or sectioned between ligatures . the few larger vessels and portal triads were divided using vascular staplers ( ets - flex ; ethicon endo - surgery ) . considering the usual ineffectiveness of the ultrasonic dissector in cases of cirrhotic liver , the ultrasonic coagulating cutter was adopted in these cases as able to effectively transect fibrotic parenchyma . an argon beam coagulator was used to refine unsatisfactory hemostasis , possibly in addition to the application of hemostatic matrixes on the transection surface . a single flat jackson - pratt drain was placed in the posterior aspect of the resection bed . as a rule , the hepatic pedicle was encircled by a tourniquet before transection , allowing the pringle maneuver to be performed as needed in an intermittent fashion ( 10 minutes of ischemia , 5 minutes of reperfusion ) . moreover , a single dose of a medium - half - life steroid drug ( methylprednisolone 500 mg ; solu - medrol ) was administered at the induction of anesthesia to reduce the oxidative parenchymal damage induced by the intermittent ischemia - reperfusion vascular control . in both groups , continuous data are reported as mean sd ( range ) and were compared by using the 2-sided student t test . comparisons between groups for categorical variables were performed using the test with yates 's correction or the fisher exact test as appropriate . statistical significance was set at p < .05 . statistical analysis was performed with spss statistics version 19.0 ( ibm , armonk , new york ) . patient demographics , indications for liver surgery , and preoperative data are shown in table 1 . the comorbidity rate was similar as well , as demonstrated by the same patient stratification on the basis of american society of anesthesiologists score . the rate of previous abdominal surgery was significantly higher in the olr group ( 26.3% vs 66.7% ) . indications for surgery were similar , except for benign diseases and hepatocellular carcinoma , operated on at a higher rate in the olr group . ralr was characterized by a more liberal use of the pringle maneuver and longer operative times . even though a trend toward a shorter hospitalization was observed in the ralr group ( 6.7 vs 7.9 days ) , blood loss and intra- and postoperative transfusions did not differ between groups . patient demographics , indications for liver surgery , and clinical characteristics data are expressed as mean sd or as number ( percentage ) . abbreviations : asa , american society of anesthesiologists ; bmi , body mass index ; hcc , hepatocellular carcinoma . types of liver resections in both groups perioperative details data are expressed as mean sd or as number ( percentage ) . overall morbidity and mortality rates were similar , at 15.8% and 0% and 13% and 0% , in the ralr and olr groups , respectively ( table 4 ) . in the ralr group , a significantly higher rate of chest complications was registered , including both pleural effusion and pneumonia . in the olr group , sepsis was the main medical complication , with a rate significantly higher with respect to the ralr group ( p = .002 ) . overall specific morbidity and mortality according to clavien - dindo classification according to the clavien - dindo classification , major ( grades 24 ) complications were not significantly different between the 2 groups ( 5.3% vs 1.4% ; p = .80 ) . the 2 groups had similar total lesion numbers and mean nodule dimensions . in malignancies , tumor - free margin rates were similar in both groups ( 10.5% and 9% r1 resections , respectively , for ralr and olr , p > .05 ) . the 2 groups had similar total lesion numbers and mean nodule dimensions . in malignancies , tumor - free margin rates were similar in both groups ( 10.5% and 9% r1 resections , respectively , for ralr and olr , p > .05 ) . to date , llr is considered a safe option for the treatment of primary and secondary tumors of the liver as well as of benign conditions . however , laparoscopy is far from optimal for lesions located in the pss . when faced with posterior and deeply located lesions , laparoscopy is associated with a trend toward an increased rate of major hepatectomies , with the sacrifice of a large amount of healthy parenchyma . in a series reported by castaing et al comparing 2 matched groups of 60 patients , in the llr group , the rate of right hepatectomies was 35% higher than in the olr group ( 20 vs 7 ) . in a multicenter study by nguyen et al , similarly , in a series of llrs for right posterior lesions presented by cho et al , 5 of 40 patients underwent right hepatectomies ( 12.5% ) . these data are in net contrast with the actual trend of parenchymal preservation for both primary and secondary liver tumors . even when laparoscopic resections are performed in pss with attempted preservation of the parenchyma , they are poorly effective and generally associated with higher blood loss compared with resections of the anterior segments . recently , robotic surgical systems have been introduced to improve the surgical skills needed during demanding surgical procedures , including laparoscopic liver and biliary surgery . with regard to liver surgery , there is some evidence that the da vinci surgical system may facilitate biliary reconstruction , major hepatectomy , and resection of pss and reduce the conversion rate . recently , a comparative 2-institution study showed the possibility offered by robotic assistance in managing patients with larger numbers of lesions and limiting the rate of major hepatectomy at the same time . the numbers of subsegmentectomies and mixed resections were significantly higher in the robotic group with respect to the laparoscopic group ( 37% vs 16.1% ) , especially for lesions located in pss ( 55% vs 34.1% , p = .019 ) . on the basis of this study , the articulated robotic instruments may reproduce the kelly - clamp crushing technique , and the wrist - like movements allow challenging resections , even in pss . therefore , even if robotics seem to overcome some of the limitations of laparoscopy to approach pss , there is no evidence for the effectiveness of robotics with respect to open surgery that is widely accepted as the standard of care for patients with liver nodules in the pss . to the best of our knowledge , therefore , results from our study could elucidate whether robotics might offer early outcomes comparable with those attained by open surgery for patients eligible for liver resection in the pss . the most notable finding of the present study was that olr and ralr are equally safe and feasible , with minimal blood loss and acceptable morbidity that contributed to short patient hospitalizations in both groups . differences among patients affected by hepatocellular carcinoma and previous abdominal surgical procedures can be related to effects of center volume and/or referral patterns , but we believe that these data do not affect the peri- and postoperative outcome measures . types of resections were comparable between the 2 groups in terms of equal numbers , sizes , and locations of liver lesions , although a trend toward a larger number of right posterior sectionectomies was seen in the olr group . notwithstanding the similar distribution of type of resections , operating time was longer and the pringle maneuver was more extensively used in the ralr group . liver resection was carried out using articulated robotic instruments , reproducing the kelly - clamp crushing technique under intermittent inflow occlusions . this technique was initially developed to obviate the lack of specifically designed tools for parenchymal transection . because of extreme flexibility and versatility of the articulated bipolar forceps , the kelly - clamp crushing technique became the standard practice for liver resection , allowing challenging resections in pss and dissections close to the main liver vessels . it is likely that , with the introduction of articulated robotic devices specifically designed for liver transection , blood loss and transection time could be further reduced . even with a substantial difference in technical features , there were no differences between the ralr and olr groups in terms of overall postoperative morbidity . these data are particularly interesting considering the reported higher blood loss and the scarce performance of laparoscopic surgery to approach the pss . the higher rate of thoracic medical complications in the ralr group could be related to the prolonged left lateral decubitus position , with consequent difficulties in lung ventilation . the higher rate of biliary leaks in the ralr group could be related to the presence in this group of patients with hydatid cysts , which are traditionally associated with a high rate of postoperative biliary fistula . another factor that might influence the length of stay was the routine application of a fast - track protocol in the olr group . robotic surgery is not cost effective if not coupled with perioperative care aimed at fast recovery . the implementation of fast - track care has been demonstrated to significantly reduce hospital stays in patients who undergo laparoscopic colectomy , and if an open colectomy is undertaken , it is preferentially done coupled with fast - track care . in our study , there was consistent evidence that this role could also translate to liver resections in the pss . thus , future studies evaluating the cost - effectiveness of robotic liver resection on a prospective basis should also investigate the effects of postoperative fast - track care on total hospital costs . the comparable results of ralr and olr support the need for better refined studies on specific issues , other than cost - effectiveness . effects of magnification and 3-dimensional views on specific complications ( ie , biliary fistula ) , outcomes of robotic resections in specific subgroup of patients ( ie , those with cirrhosis ) , and postoperative quality of life need to be better clarified . ralr is a safe and feasible option for selective lesions in the right posterior section . although short - term postoperative outcomes of ralr for segments 6 and 7 are encouraging , further analysis is needed to determine the oncologic soundness of a robotic approach for malignant tumors . in addition , a randomized controlled study is needed to further demonstrate the efficacy and cost - effectiveness of ralr in the pss compared with open and laparoscopic hepatectomies . data from this study could be used as a baseline for future prospective studies investigating specific issues in liver resection in the pss .

background : open liver resection is the current standard of care for lesions in the right posterior liver section . the objective of this study was to determine the safety of robot - assisted liver resection for lesions located in segments 6 and 7 in comparison with open surgery.methods:demographics , comorbidities , clinicopathologic characteristics , surgical treatments , and outcomes from patients who underwent open and robot - assisted liver resection at 2 centers for lesions in the right posterior section between january 2007 and june 2012 were reviewed . a 1:3 matched analysis was performed by individually matching patients in the robotic cohort to patients in the open cohort on the basis of demographics , comorbidities , performance status , tumor stage , and location.results:matched patients undergoing robotic and open liver resections displayed no significant differences in postoperative outcomes as measured by blood loss , transfusion rate , hospital stay , overall complication rate ( 15.8% vs 13% ) , r0 negative margin rate , and mortality . patients undergoing robotic liver surgery had significantly longer operative time ( mean , 303 vs 233 minutes ) and inflow occlusion time ( mean , 75 vs 29 minutes ) compared with their open counterparts.conclusions:robotic and open liver resections in the right posterior section display similar safety and feasibility .

recently , there has been broad interest in the condensed matter physics community in the search for novel topological phases , as well as the tuning and understanding of the related phase transitions , aiming for both scientific explorations and potential applications @xcite . among these novel topological phases is the quantum anomalous hall ( qah ) phase @xcite , which is characterized by a finite chern number and chiral edge states in the bulk band gap , and maintains robust stability against disorder and other perturbations @xcite . although the first proposal appeared over twenty years ago , not until recently was the experimental evidence for qah phase reported within cr - doped ( bi , sb)@xmath3te@xmath4 at extremely low temperatures @xcite . some strategies to achieve qah effects at high temperatures in honeycomb materials are proposed @xcite , such as by transition - metal atoms adaption @xcite , magnetic substrate proximity effect @xcite , and surface functionalization @xcite . in honeycomb lattices , @xmath1 and @xmath2 valleys similar to real spin , provide another tunable binary degree of freedom to design valleytronics . by breaking the inversion symmetry , a bulk band gap can be opened to host a quantum valley hall ( qvh ) effect , which is classified by a valley chern number @xmath5 @xcite . for technological applications , it is important to find a novel topological state with a large gap that simultaneously shares the properties of both qah states and qvh states , i.e. valley - polarized qah ( vp - qah ) phases , on the one hand , and learn how to drive transitions among different phases , on the other . the element bismuth has the largest soc strength in the periodic table of elements except radioactive elements . the above exotic topological quantum phases can be expected to emerge notably in the bi - based materials . actually , the star materials for three - dimensional ( 3d ) ti are no other than the bi - based materials bi@xmath3se@xmath4 , and bi@xmath3te@xmath4 @xcite . bi - based material cu@xmath6bi@xmath3se@xmath4 is predicted as a 3d time - reversal - invariant topological superconductor @xcite . the honeycomb monolayer bi film is a two - dimensional ( 2d ) ti with the soc gap opened at @xmath7 point @xcite . a fully - hydrogenated ( f - h ) or halogenated bi honeycomb monolayer is predicted a 2d ti with a record bulk band gap ( > 1 ev ) at @xmath1 and @xmath2 points @xcite . for electron doping , the 2d ti f - h monolayer is predicted to host time - reversal - invariant @xmath8 topological superconductivity @xcite . and @xmath9 are the polar angles and magnitude of the spontaneous magnetization @xmath10 . @xmath11 is half the intrinsic soc strength . vp - qah1(2 ) corresponds to @xmath12(@xmath13 ) and @xmath14(@xmath14 ) . the two cases can be related by time reversal operation . the red dash line is the phase transition path occurred in the h - h bi monolayer . , width=336 ] here , we report the theoretical finding of two novel vp - qah topological phases , where qvh and qah effects coexist , and associated topological phase transitions caused by the magnetization orientation in a half - hydrogenated ( h - h ) bi honeycomb monolayer . the band gap of the vp - qah phases can reach 0.19 ev with an appropriate buckled angle . other phases , shown in fig . [ fig : phase_diagram ] , such as ferromagnetic ( fm)-metal and fm - insulator phases , are found in several regions with different magnetization orientations . the magnetization orientation can be tuned via an external magnetic field or proximity induction by different magnetic substrates . furthermore , these common experimental measures can be used to control the topological phase transitions in such a h - h bi monolayer . therefore , our findings provide an ideal platform for the design of dissipationless electronics and valleytronics in a robust and controllable manner . first - principles ( fp ) calculations are performed using the projector augmented wave method implemented in the vienna @xmath15 simulation package ( vasp ) @xcite . perdew - burke - ernzerhof parametrization of the generalized gradient approximation ( gga - pbe ) is used for the exchange correlation potential @xcite . the plane wave energy cutoff is set to 300 ev , and the brillouin zone is sampled by a @xmath16 mesh . the single layer structures were constructed with a vacuum layer of 20 to avoid the interactions between the layers . by using the wannier90 code , the maximally localized wannier functions are constructed and the berry curvature is obtained @xcite . based on the constructed wannier functions , we use an iterative method @xcite to obtain the surface green s function of the semi - infinite system , from which we can calculate the dispersion of the edge states . direction . ( c ) the projection band structures for the h - h bi monolayer . the color of the symbols labels the different atomic orbitals , and their size is proportional to the weight of the band eigenfunctions on these atomic orbitals . ( d ) the spin - polarized band structure for the h - h bi monolayer . ( e ) the soc band structure for the magnetization along @xmath0 axis . the red circle ( black line ) is for the bands from the wannier interpolation ( fp ) . both are in good agreement . ( f ) the berry curvature distribution along the line with high symmetry for the summation of all the valence bands . inset : the first brillouin zone and its points of high symmetry.,width=336 ] figure [ fig : structure](a ) plots the typical geometries for a f - h bi monolayer , with three - fold rotation symmetry and inversion symmetry , like for graphane . the h - h bi monolayer with a quasi - planar geometry can be obtained by removing half of the hydrogenation of the f - h bi monolayer @xcite . the lattice constant is 5.54 with the distance between bi and h atoms @xmath17=1.83 . its three - fold rotation symmetry remains but inversion symmetry broken , as shown in fig . [ fig : structure](b ) , similar to graphone . figures [ fig : structure](c - e ) plot the band structures for three cases within the gga , spin - polarized and soc calculations . as shown in fig . [ fig : structure](c ) , there is a flat band near the fermi level from the @xmath18 orbital of the bi atoms disconnected from the h atoms , since these bi atoms constitute a triangular lattice with large bond length . for spin - polarized calculations [ fig . [ fig : structure](d ) ] , a magnetic moment of approximately 1 @xmath19 per unit cell is induced with the spin - up @xmath18 band fully filled and the spin - down one almost empty . when spin - orbit coupling ( soc ) is taken into account , the h - h bi monolayer is a ferromagnetic insulator with the magnetization lying in the basal plane ( x - y ) . for the magnetization along + @xmath0 axis , an soc band gap of proximate 40 mev opens around the @xmath1 point , as shown in fig . [ fig : structure](e ) . using the wannier interpolation method , we can calculate the band structure and the berry curvature . the wannier band structure reproduces the fp one [ fig . [ fig : structure](e ) ] well . from the berry curvature distribution in fig . [ fig : structure](f ) , one can find an obvious dip around the valley @xmath1 and an imbalance between valley @xmath1 and @xmath2 , which indicates a nontrivial topological property of the bulk bloch wave - functions . after integration of the berry curvature throughout the whole brillouin zone as well as around each individual valley , we obtain the chern number @xcite @xmath12 as well as @xmath20 and @xmath21 , demonstrating its nontrivial topological features of simultaneously possessing both qah and qvh phases . this is further confirmed by the analysis of edge states , band evolution mechanism and spin texture , which will be discussed later . in addition to the chern number , the gapless edge mode inside the bulk energy gap provides a more intuitive picture to characterize the topological properties of the bulk . in fig . [ fig : edge_state ] , we plot the band structures with their orbital projected character and the corresponding edge states of zigzag semi - infinite systems for four different cases . for the f - h bi monolayer , the low - energy bands are dominated by the @xmath22 and @xmath23 orbitals of the bi atoms as shown in fig . [ fig : edge_state](a ) , and there are two helical edge states in the huge bulk gap of about 1 ev [ fig . [ fig : edge_state](e ) ] , which indicates a qsh phase . for the h - h bi monolayer , the two relevant flat bands mainly consist of the @xmath18 orbital from the dehydrogenated - site bi atoms , which are located in the original large qsh gap of the f - h monolayer . moreover , the orientation of the magnetization dramatically changes the relativistic band structures , especially the two relevant bands straddling the fermi level , as well as the size and the position of the gaps , as shown in fig . [ fig : edge_state](b - d ) . three typical insulating phases emerge for different orientation alignments of the magnetization . from the edge states of the zigzag semi - infinite systems and the direct calculations of chern number [ fig . [ fig : edge_state](f - h ) ] , we find the three typical insulating phases correspond to the vp - qah1 ( @xmath12,@xmath14 ) , ferromagnetic insulator , and vp - qah2 ( @xmath13,@xmath14 ) states , respectively . in order to obtain a physical picture of the nontrivial topological properties of vp - qah , we investigate the band structure evolution and the spin texture as shown in fig . [ fig : mechanism ] . without loss of generality , we analyze the case of the magnetization aligned along the + @xmath0 axis . the evolution is divided into three stages , as schematically plotted in fig . [ fig : mechanism](a - c ) . we start with the f - h bi monolayer , whose low - energy band structure has a huge qsh band gap opened by on - site soc @xcite . dehydrogenation from the a sublattice leads to a flat band mainly consisting of the @xmath18 orbital from bi atoms of the a - sublattice around the fermi level in the otherwise huge qsh gap [ fig . [ fig : structure](c ) ] . at the first stage of the band evolution , in fig . [ fig : mechanism](a ) , the internal spontaneous magnetization splits the flat @xmath24 bands into two bands , @xmath25 and @xmath26 , where @xmath24 means that the bands consist of the @xmath18 orbitals of the a - sublattice bi atoms . considering the electron filling , the fermi level is located slightly lower than the @xmath26 band . the intrinsic soc plays a role in the second stage . from the pervious work @xcite , it is known the bands with total angular momentum @xmath27 and @xmath28 constitute the low - energy valence and conduction bands for qsh states in the f - h bi monolayer respectively , as shown in [ fig : mechanism](a ) . the superscript @xmath29 indicates the bands mainly come from the @xmath30 orbitals . in the following , we will focus on the valence bands with @xmath31 , in view of that the total angular momentum conservation is required in the presence of soc and the two relevant flat @xmath18 bands likewise own @xmath32 . specifically , around the valley @xmath1 , the valence bands consist of @xmath33 ( @xmath34 ) and @xmath35 ( @xmath36 ) , while around the valley @xmath2 , the subscripts sublattice index a and b are exchanged , where @xmath37 . as shown in fig . [ fig : mechanism](b ) , the on - site ( a - sublattice ) soc brings about the level repulsion : @xmath33 is pushed downward and @xmath25 upward around valley @xmath1 , while @xmath38 is pushed downward and @xmath26 upward around valley @xmath2 . at the last stage , in fig . [ fig : mechanism](c ) , the intrinsic rashba soc breaks the band crossing and opens a gap around valley @xmath1 , and results in a nontrivial state , i.e. vp - qah state , which is validated from the spin texture for the relevant @xmath18 orbital valence band . as plotted in fig . [ fig : skyrmion ] , the skyrmion - type spin texture around valley @xmath1 can be mapped onto a whole spherical surface and thus gives rise to a nonzero winding number ( chern number ) in the momentum space . moreover , since there is only one skyrmion around valley @xmath1 , rather than valley @xmath2 , the imbalance leads to a qvh effect . consequently , a vp - qah state emerges sharing novel properties of both qah states and qvh states . for the relevant @xmath18 orbital valence band from the dehydrogenated bi atoms . @xmath39 , @xmath40 , and @xmath41 are expectations of the three components of the spin operator for the @xmath18 orbital . the arrows represent the orientation of the spin , which is rotated by the intrinsic rashba soc and generates a nontrivial skyrmion spin texture in the momentum space , i.e. , around @xmath1 point , the spin points down , while far from @xmath1 point the spin points up , as plotted in ( b ) . the only one skyrmion around @xmath1 results in a vp - qah1 phase.,width=336 ] the effective minimal two - band hamiltonian around two valleys @xmath1 and @xmath2 is given to demonstrate the low - energy properties of the h - h bi monolayer in the spin splitting basis @xmath42 , which are linear combinations of @xmath43 and @xmath44 ( for details see the appendix a ) @xmath45 where @xmath46 , and @xmath47 $ ] . @xmath48 , @xmath49 and @xmath50 are the lattice constant , the strength of intrinsic rashba soc , and the intrinsic soc strength , respectively . @xmath51 is the fermi velocity . @xmath9 , @xmath52 and @xmath53 are the respective strength , polar and azimuthal angles of the magnetization . @xmath54 is the angle between the vector @xmath55 and the @xmath56 axis . labels two valleys @xmath1 and @xmath2 . the last term is the intrinsic rashba soc term . by fitting the band structures using both fp and the above two - band model , these parameters can be determined as @xmath58 , @xmath59 , @xmath60 , and @xmath61 . in the second stage , for the + @xmath0 axial magnetization case , the crossing of the @xmath25 and @xmath26 bands around valley @xmath1 ( see fig . [ fig : mechanism](b ) ) is critical , which provides a pivot for the subsequent intrinsic rashba soc . both of these two constituents result in an inverted band gap as shown in fig . [ fig : mechanism](c ) . whether the two bands are crossing depends on the order of the eigenvalues in eq.(1 ) when it is considered without the rashba soc term . it leads to the relations between @xmath9 and @xmath11 , @xmath62 . when the magnetization deviates the + @xmath0 axial direction , the x and y components of the zeeman term will also break the above crossing , resulting in a trivial phase . however , the nontrivial properties remain unchanged as long as rashba soc dominates the x and y zeeman components . this requirement makes further restrictions on the ratio of @xmath9 and @xmath11 . for the case where the magnetization is along the negative @xmath0 axis , the spin splitting is reversed , and band evolution with similar mechanism takes place around the @xmath2 valley . . its value ( blue line - square ) changes from negtive to positive , which means the easy magnetization axis orientating from in - plane to out of plane . ( b ) the band for the vp - qah1 with the largest gap ( 0.19 ev ) , corresponding to the buckled angle @xmath63 case . , width=3 ] moreover , we find that the buckled degree of the h - h bi monolayer can enlarge the gap of the vp - qah phase significantly and change the magnetic anisotropy energy ( mae ) dramatically , as shown in fig . [ fig : gapbuckled](a ) . the largest gap of the vp - qah1 phase closes to 0.2 ev with the buckled angle @xmath63 , whose band is plotted in fig . [ fig : gapbuckled](b ) . here the mae is about 1 mev , hence the manipulation of orientation of magnetization is possible with an experimental accessible induced magnetic field ( 10 t ) . if we continue to increase the angle , the gap deceases . a insulator - metal phase transition takes place with the buckled angle @xmath64 ( see the appendix b ) . as one of the potential applications , it is possible to make a homogeneous junction by applying external magnetic fields with different orientations or by virtue of magnetic substrates at different regions of a h - h bi monolayer film sample , as shown in fig . [ fig : application ] . fully valley - polarized chiral edge states along these boundaries emerge and can be utilized as dissipationless conducting wires and chiral interconnects to lower the power consumption of devices in electronics and valleytronics . ( @xmath2 ) index moves downwards ( upwards ) with the external magnetic field in the left region pointing up ( down ) . such tunable valley - polarized chiral edge states can be used as dissipationless conducting wires for electronics and valleytronics.,width=3 ] on the experimental side , bi monolayers with a buckling honeycomb lattice and films have been manufactured via molecular beam epitaxy @xcite . on the other hand , chemical functionalization of such 2d materials is a powerful tool to create new materials with desirable features , such as modifying graphene into graphone ( semihydrogenated graphene ) , graphane and fluorinated graphene using h and f , respectively @xcite . the buckled honeycomb geometry of the bi monolayer makes it possible to saturate the chemical bonds of bi atoms on only one sublattice . therefore , it is a very promising that a h - h bi honeycomb monolayer may be synthesized by chemical reaction in solvents or by exposure of a bi monolayer or ultrathin film to atomic or molecular gases . an candidate substrate here could be layer materials such as transition metal dichalcogenides ( e.g. mos@xmath3 ) and @xmath65-bn , which stabilize and weakly interact with the h - h bi honeycomb monolayer through van der waals interaction and thus do not alter the band topology of the monolayer . in summary , we find topological phase transitions in a h - h bi honeycomb monolayer via tuning the orientation of the magnetization . depending the orientation of the magnetization , there are four different phases , i.e. vp - qah1 , vp - qah2 , fm - insulator , and fm - metal , as shown in fig . [ fig : phase_diagram ] . the mechanism for the nontrivial topological phase is given and a low - energy effective hamiltonian is provided to capture the essential physics . further , the low buckled geometry prominently increases the size of the gap by several times . fully valley - polarized chiral edge states can be utilized as dissipationless conducting wires and chiral interconnects for the lower power - consumption devices in electronics and valleytronics . these make the hydrogenated bi honeycomb monolayers an ideal platform to investigate soc relevant physics , novel topological states and the related phase transitions , and indicate great potential for the practical applications in a controllable manner . this work was supported by the most project of china ( nos . 2014cb920903 , 2013cb921903 , and 2011cba00108 ) , the national natural science foundation of china ( grant nos . 11404022 , 11225418 , and 11174337 ) , the specialized research fund for the doctoral program of higher education of china ( grant no . 20121101110046 ) , and excellent young scholars research fund of beijing institute of technology ( grant no . 2014cx04028 ) . from the first - principles ( fp ) calculations in the main text , the basis @xmath66 are relevant . the lattice hamiltonian reads @xmath67 the first two terms represent the quantum spin hall phase lattice hamiltonian for the fully - hydrogenated ( f - h ) bi honeycomb monolayer family @xcite , which serves as the background for the following analysis of the half - hydrogenated ( h - h ) bi monolayer . the third term is the zeeman term for the @xmath18 orbital of bi atoms of the dehydrogenated sites ( a sublattice ) . the fourth term is the soc between the @xmath18 and @xmath68 orbitals from a - site bi atoms . the fifth term is the intrinsic rashba soc for the @xmath18 orbital from the dehydrogenated sites , as a result of the broken mirror symmetry . the sixth term is the hopping of the @xmath18 orbital from the dehydrogenated site , which is very small and thus can be ignored due to the next nearest neighbor ( nnn ) hopping . the last is the on - site energy term for the @xmath69 orbitals . firstly , the spontaneous magnetization @xmath70 will lead to spin splitting with two eigenvalues -m and m , as shown in fig . 4(a ) in the main text , and their corresponding eigenstates @xmath71 where @xmath52 and @xmath53 are the polar and azimuthal angles of the spontaneous magnetization @xmath10 . secondly , as stated above , for the qsh state , the soc gap is huge ( > 1ev ) , and thus treated as the background in the following analysis . it s known that around the @xmath1 point , the dispersion is @xmath72 , and the basis is as shown in fig . [ fig : mechanism](a ) . the soc mixes the orbital and spin with total angular momentum conserved @xmath73 , which results in the level repulsion between @xmath74 and @xmath33 , thus pushs the @xmath75 upward and the @xmath33 downward , as shown in fig . [ fig : mechanism](b ) . it is reasonable to choose the basis @xmath76 as a low - energy subspace manifold . the corresponding hamiltonian reads @xmath77 with @xmath78 the on - site energy for the @xmath69 orbitals . through the down - folding procedure @xcite , the minimal two - band low - energy hamiltonian is obtained in the representation @xmath79 @xmath80 the fermi level is taken as @xmath81 during the above derivation . and @xmath2 for the h - h bi monolayer from fp calculation and the two - band low - energy effective hamiltonian with the magnetization along + @xmath0 axis . the dashed red curve is the fp result . the solid green curve represents the tb model s result . the fermi level is set to zero.,width=3 ] at the last stage , as shown in fig . [ fig : mechanism](c ) in the main text , the intrinsic rashba soc opens a band gap around valley @xmath1 , and results in the nontrivial state . after performing a fourier transformation , the rashba soc is written in the basis @xmath79 @xmath82 with @xmath83 $ ] . @xmath48 and @xmath49 are the lattice constant and the strength of the rashba soc , respectively . @xmath54 is the angle between the vector @xmath55 and the @xmath56 axis . consequently , the total minimal two - band model around @xmath1 point reads @xmath84 following a similar three - step procedure for the minimal two - band model around @xmath2 point , as shown in fig . [ fig : mechanism](a - c ) in the main text , the total minimal two - band model in the representation @xmath79 around valley @xmath2 is found to be @xmath85 with @xmath86 by fitting the band structures between fp and the above low - energy two - band model around the two valleys @xmath1 and @xmath2 , the above parameters are determined with @xmath58 , @xmath59 , @xmath60 , and @xmath61 , as shown in fig . [ fig : tbvsfp ] . we investigate the adiabatic evolution of the gap of the vp - qah from the quasi - planar honeycomb geometry to the low - buckled geometry with keeping the bi - bi bond length constant , as shown in fig . [ fig : gapbuckled ] in the main text . it is surprising that the slightly buckled geometry remarkably magnifies the size of the gap ( even reach 0.19 ev ) , which make the giant - gap h - h bi monolayer an ideal platform to realize the exotic vp - qah phases and fabricate new quantum devices operating at room temperature . the projected band structures and density of states for the four typical points ( @xmath87 ) during the gap evolution as well as the @xmath88 case are plotted in fig . [ fig : angle ] . chern number @xmath90 is an integer of berry curvature @xmath91 over the whole brillouin zone and can be expressed explicitly as @xcite @xmath92 the above summation is over all occupied bands below the bulk gap . @xmath93 note this summation is over all bands except inself . @xmath94 . velocity operator @xmath95 . the valley chern number @xmath96 and @xmath97 are obtained by integrating the berry curvature around two valleys @xmath1 and @xmath2 respectively . j. t. robinson , j. s. burgess , c. e. junkermeier , s. c. badescu , t. l. reinecke , f. k. perkins , m. k. zalalutd- niov , j. w. baldwin , j. c. culbertson , p. e. sheehan , _ et al . _ , nano lett . * 10 * , 3001 ( 2010 ) .

based on first - principles calculations , we find novel valley - polarized quantum anomalous hall ( vp - qah ) phases with a large gap-0.19 ev at an appropriate buckled angle and tunable topological phase transitions driven by the spontaneous magnetization within a half - hydrogenated bi honeycomb monolayer . depending on the magnetization orientation , four different phases can emerge , i.e. , two vp - qah phases , ferromagnetic insulating and metallic states . when the magnetization is reversed from the + @xmath0 to -@xmath0 directions , accompanying with a sign change in the chern number ( from -1 to + 1 ) , the chiral edge state is moved from valley @xmath1 to @xmath2 . our findings provide a platform for designing dissipationless electronics and valleytronics in a more robust manner through the tuning of the magnetization orientation .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Emergency Relief Tax Check-Off for Our Armed Forces Act of 2007''. SEC. 2. ABOVE-THE-LINE DEDUCTION FOR CERTAIN CONTRIBUTIONS TO THE ARMED FORCES RELIEF TRUST. Section 62(a) of the Internal Revenue Code of 1986 (defining adjusted gross income) is amended by inserting after paragraph (21) the following new paragraph: ``(22) Certain contributions to armed forces relief trust.--In the case of an individual, the deduction allowed by section 170 to the extent it does not exceed the lesser of-- ``(A) the amount contributed by the taxpayer pursuant to the designation procedure under section 6097, or ``(B) $1,000 ($2,000 in the case of a joint return).''. SEC. 3. DESIGNATION OF OVERPAYMENTS AND CONTRIBUTIONS FOR THE ARMED FORCES RELIEF TRUST. (a) In General.--Subchapter A of chapter 61 of the Internal Revenue Code of 1986 is amended by adding at the end the following new part: ``PART IX--DESIGNATION OF OVERPAYMENTS AND CONTRIBUTIONS FOR THE ARMED FORCES RELIEF TRUST ``Sec. 6097. Designation. ``SEC. 6097. DESIGNATION. ``(a) In General.--In the case of an individual, with respect to each taxpayer's return for the taxable year of the tax imposed by chapter 1, such taxpayer may designate that-- ``(1) a specified portion (but not less than $1) of any overpayment of tax for such taxable year, and ``(2) any cash contribution which the taxpayer includes with such return, shall be contributed to the Armed Forces Relief Trust. ``(b) Manner and Time of Designation.--A designation under subsection (a) may be made with respect to any taxable year only at the time of filing the return of the tax imposed by chapter 1 for such taxable year. Such designation shall be made in such manner as the Secretary prescribes by regulations except that such designation shall be made either on the first page of the return or on the page bearing the taxpayer's signature. ``(c) Overpayments Treated as Refunded.--For purposes of this title, any portion of an overpayment of tax designated under subsection (a) shall be treated as being refunded to the taxpayer as of the last date prescribed for filing the return of tax imposed by chapter 1 (determined without regard to extensions) or, if later, the date the return is filed. ``(d) Explanation.--The Secretary shall include in the general instructions for filing returns by individuals of the tax imposed by chapter 1-- ``(1) a description of the deduction under section 62(a)(22) and the designation procedure under this section, ``(2) an explanation that charitable contributions to the Armed Forces Relief Trust that are not described in section 62(a)(22) are still allowable as a deduction to taxpayers who itemize deductions, and ``(3) a notice that the use of funds contributed to the Armed Forces Relief Trust under this section shall be determined by the Advisory Board established under subsection (e). ``(e) Advisory Board.-- ``(1) Appointment.-- ``(A) In general.--There is established an advisory board for the Armed Forces Relief Trust. The members of such board shall be appointed as follows: ``(i) One individual appointed by the Chairman of the Committee on Finance of the Senate. ``(ii) One individual appointed by the Chairman of the Committee on Armed Services of the Senate. ``(iii) One individual appointed by the Chairman of the Committee on Veterans' Affairs of the Senate. ``(iv) One individual appointed by the Chairman of the Committee on Appropriations of the Senate. ``(v) One individual appointed by the Chairman of the Joint Committee on Taxation. ``(vi) One individual appointed by the Chairman of the Committee on Armed Services of the House of Representatives. ``(vii) One individual appointed by the Chairman of the Committee on Veterans' Affairs of the House of Representatives. ``(viii) One individual appointed by the Chairman of the Committee on Appropriations of the House of Representatives. ``(ix) One individual appointed by the President from each of the following: the Army Emergency Relief Society, the Navy Marine Corps Relief Society, the Air Force Aid Society, and the Coast Guard Mutual Assistance Relief Society. ``(x) Two individuals appointed by the President from 2 veterans service organizations. ``(B) Term.--The term of each member of the advisory board shall be 3 years, except that any member whose term of office has expired shall continue to serve until such member's successor is appointed. No member shall serve more than 2 3-year terms. ``(C) Appointment of successors.--The appointment of any successor member shall be made in the same manner as the original appointment. If a member dies or resigns before the expiration of the member's term, a successor shall be appointed for the unexpired portion of the term in the same manner as the original appointment. ``(D) Prohibition.--No member of the advisory board may be an employee of the Federal Government. ``(2) Chairman; vice chairman.-- ``(A) Designation.--The President shall designate a chairman for the advisory board. The advisory board shall not later than its second meeting, by majority vote, designate a vice chairman, who shall perform the duties of the chairman in the absence of the chairman. ``(B) Duties of chairman.--The chairman shall call the meetings of the advisory board, propose meeting agendas, chair the meetings, and establish, with the approval of a majority of the members, the rules and procedures for such meetings. ``(3) Operations of board.--The advisory board shall meet semi-annually, for the purpose of providing ongoing advice to the Armed Forces Relief Trust regarding the distribution of contributed funds, policies governing said distribution, and the administrative costs and operations of the Armed Forces Relief Trust. A majority of the members shall constitute a quorum. Advisory board members shall serve without compensation. While performing duties as a member of the advisory board, each member shall be reimbursed under Federal Government travel regulations for travel expenses. Such reimbursements and any other reasonable expenses of the advisory board shall be provided by the budget of the Executive Office of the President. ``(4) Control over designated funds.--Amounts contributed to the Armed Forces Relief Trust pursuant to this section may be used by such Trust only as provided by the advisory board. ``(5) Audit.--The General Accountability Office shall audit the distribution and management of funds of the Armed Forces Relief Trust on an annual basis to ensure compliance with statutory and administrative directives. The Comptroller General of the United States shall report to the advisory board and Congress on the results of such audit. ``(6) Reports.--Within 60 days after its semi-annual meeting, the advisory board shall submit a written report to the President of its action, and of its views and recommendations. Any report other than the semi-annual report, shall, if approved by a majority of the members of the advisory board, be submitted to the President within 60 days after such approval.''. (b) Clerical Amendment.--The table of parts for subchapter A of chapter 61 of such Code is amended by adding at the end the following new item: ``Part IX. Designation of Overpayments and Contributions for the Armed Forces Relief Trust.''. SEC. 4. EFFECTIVE DATE. The amendments made by this Act shall apply to taxable years beginning after December 31, 2006.

Emergency Relief Tax Check-Off for Our Armed Forces Act of 2007 - Amends the Internal Revenue Code to allow a tax deduction (available to taxpayers who do not itemize their tax deductions) for charitable contributions of up to $1,000 ($2,000 in the case of a joint return) to the Armed Forces Relief Trust. Allows taxpayers to designate on their tax returns a portion of any overpayment of tax as a contribution to the Trust or to make a cash contribution to the Trust with their tax returns. Establishes an advisory board to advise the Trust on its operation and on the distribution of contributed funds.

in this supplementary material , we describe the numerical method used in our article , provide absolute values of experimental observables and discuss the numerical errors . we employ matrix product states ( mps ) in 1d and projected entangled pair states ( peps ) in 2d to compute ground states and time evolution @xcite . for a chain of @xmath22 quantum systems , each having physical dimension @xmath38 , a mps has the form @xmath42^{s_{1 } } a[2]^{s_{2 } } \ldots a[n]^{s_{n } } ) |s_{1 } s_{2 } \ldots s_{n}\rangle \qquad , \end{aligned}\ ] ] where the @xmath43 run from @xmath20 to @xmath38 and the @xmath44^{s_{i}}$ ] , for a fixed @xmath43 , are matrices of dimension . the number of variational parameters in the ansatz is determined by the bond dimension , @xmath40 , which also bounds the entanglement of the mps . the mps family constitutes a very good approximation to ground states of gapped local hamiltonians in one dimension @xcite , and it has become a very successful tool for the study of quantum many - body systems . peps constitute the natural generalization of the mps ansatz to larger dimensions @xcite , and they are also known to be good approximations for ground and thermal states of gapped local hamiltonians @xcite . the basic algorithms for the study of many - body systems using these families of states are the variational search for the ground state and the simulation of time evolution . a detailed description of these algorithms , which are similar for 1d and 2d systems , can be found in the review paper @xcite ( see also references therein ) . the computational cost of mps algorithms scales as , which allows the simulation of large chains and bond dimensions . peps algorithms scale as , so that 2d simulations are much more demanding , and only smaller values of the virtual bond dimension @xmath40 can be considered . in the variational search for ground states , the numerical error comes from limiting the bond dimension to a certain maximum value . comparing the results with those obtained after running the search with a larger @xmath40 gives an estimation of the magnitude of this truncation error . typically , the algorithm is run repeatedly with increasing bond dimension until convergence is achieved within the desired numerical precision . the simulation of time evolution of mps ( or peps ) is based on a suzuki - trotter decomposition of the evolution operator @xcite . this introduces another source of numerical error , in addition to the truncation of the bond dimension . the magnitude of this trotter error can be controlled by decreasing the size of the time step , @xmath41 , or using a higher order decomposition of the exponential . in particular , we use a second order trotter decomposition in the case of one - dimensional simulations , while a first order decomposition is used in 2d . for each time step , the evolution operator for @xmath41 is applied and an optimal mps or peps approximation to the evolved state is found as described in @xcite . the magnitude of the trotter error is controlled by comparing results for various values of @xmath41 , and the truncation error , as in the ground state search , is estimated from the comparison of results for different @xmath40 . the relative quantities shown in the main text result from normalizing the computed expectation values at the end of the evolution to the corresponding values in the true afm ground state . for completeness , we show in this section the actual absolute values obtained for each observable , as well as the reference afm values , and discuss the convergence of the numerical results . as explained in the article , we model our system by a bipartite hamiltonian , that , in 1d , reads : @xmath45 where the subscripts e and o denote even and odd sites and double occupancy of sites is forbidden , as implicitly assumed for the model . the couplings on even links are constant , @xmath46 and @xmath47 , while the time - dependent odd couplings are increased from @xmath48 to their final values , @xmath29 and @xmath10 , during a total ramping time @xmath5 , according to and . the two - dimensional system consists of several such chains , coupled in the transverse direction by @xmath49 , @xmath50 . we use the algorithms described above to compute numerically the true afm ground state for various lattices , as shown in tab . [ tab:1supp ] ( for chains of lengths @xmath51 ) . the numerical convergence is checked by comparing the values obtained using bond dimensions @xmath52 and @xmath53 . as can be seen from the values in the table , the maximum relative error is of the order @xmath54 for the magnetization . note that the energy is correct up to @xmath55 . we use these values as the reference for adiabaticity of the total chain of length @xmath22 . .[tab:1supp ] squared staggered magnetization @xmath13 , mean singlet fraction per double well @xmath56 , and mean spin energy per site @xmath14 , for the afm of total length @xmath22 obtained from ground state computation with mps of bond dimension and . [ cols="^,^,^,^,^,^,^",options="header " , ]

we analyze the possibility to prepare a heisenberg antiferromagnet with cold fermions in optical lattices , starting from a band insulator and adiabatically changing the lattice potential . the numerical simulation of the dynamics in 1d allows us to identify the conditions for success , and to study the influence that the presence of holes in the initial state may have on the protocol . we also extend our results to two - dimensional systems . ultracold atoms trapped in optical lattices offer a unique possibility to experimentally explore strongly correlated states of quantum matter . currently , one of the main experimental challenges in this field is the preparation of a heisenberg antiferromagnet ( afm ) , which represents the necessary next experimental step towards a true quantum simulator of the fermionic hubbard model @xcite . although the creation of a fermionic mott insulator ( mi ) has recently been reported @xcite , the realization of antiferromagnetic order requires temperature and entropy significantly lower than presently achieved @xcite , despite many existing proposals for direct cooling within the lattice @xcite . an alternative to the direct generation is to use an adiabatic protocol @xcite . in such a scheme , it is desirable to tune interactions initially to give a ground state with very low entropy . then , they are changed slowly , until the heisenberg hamiltonian is realized at the end . if the process is adiabatic , the entropy will stay low and the final state will be the desired afm . the following questions immediately arise : what are the conditions to achieve adiabaticity ? what occurs if these conditions are too restrictive and can not be met ? and , how will the protocol be affected by a finite temperature and the presence of a harmonic trap ? in this letter , we propose a specific adiabatic scheme and analyze these issues . our adiabatic protocol is the first to attain an afm with ultracold fermions within feasible timescales , even in the presence of experimental imperfections . additionally , we show that it is possible to realize antiferromagnetic order on a part of the sample in a shorter time than required for the whole system . finally , we simulate the dynamics of holes to demonstrate their destructive effect on the afm and devise a strategy to control them . the initial ground state of our protocol is a band insulator ( bi ) , which is transformed first to an array of decoupled singlets and finally to the afm , by adiabatically changing the depth of two superimposed optical lattices . a bi is easier to prepare with low entropy than a mi for two reasons . on the one hand , its energy gap is given by the band gap , which is much larger than the interaction energy ( mi gap ) and favors a redistribution of the entropy towards the surrounding metallic shell @xcite . on the other hand , the preparation can be done using weakly or noninteracting atoms , thereby avoiding the long timescales associated with mass and entropy transport at higher interactions @xcite . for the one - dimensional case , we simulate the fermionic model with matrix product states ( mps ) @xcite . we first identify the adiabatic conditions that allow the preparation of the antiferromagnetic state in an ideal case with no defects . second , we study how these conditions are relaxed if one imposes that antiferromagnetic order is only obtained on a subset of fermions around the center of the sample . we observe that , when restricted to a middle sublattice , adiabaticity is determined by an effective gap related to this sublattice and not by the gap of the total system . third , we include the presence of holes in the initial state , expected to occur in real experiments due to the finite temperature . the large initial energy of the holes can in principle destroy the afm as they delocalize inside the sample . we find that , if the holes are initially located at the outer part of the sample , as expected in an experiment , a tradeoff can be reached between the degree of adiabaticity of the process and the distance the holes travel inside the chain , so that the antiferromagnetic order is still produced in the center . moreover , we show that a harmonic trap can prevent the destructive effect of holes by confining them to the outside of the sample . finally , via projected entangled pair states ( peps ) @xcite , we complement our analysis with a simulation of the two - dimensional model of hardcore bosons with antiferromagnetic interaction . this setting is easier to investigate numerically than the corresponding 2d fermionic system and provides evidence that the physics studied in the one - dimensional case can be extrapolated to understand the conditions of an equivalent scheme in 2d . in the following , unless stated otherwise , we will focus on the one - dimensional case and consider a two component fermi gas in an optical lattice . the physical setting consists of two adiabatic stages , depicted in fig . [ fig:1 ] . the first transition has already been realized experimentally @xcite and can be straightforwardly described , so that we can focus on the second one and take fig . [ fig:1](b ) as the initial state for our theoretical study . in this situation , the system is governed by a one - band model . this model emerges in the limit of strong interactions from the hubbard model , which describes ultracold atoms in optical lattices @xcite . we consider a bipartite hamiltonian with different couplings for even and odd links , , where @xmath0 the superexchange interaction @xmath1 and the tunneling parameter @xmath2 are related through the on - site interaction @xmath3 as . we fix the couplings on the even links , and @xmath4 , and choose a linear ramping of the superexchange interaction on the odd links , over total ramping time @xmath5 so that and , for @xcite . in the following , we set . a harmonic trap is included by adding a term to eq . ( 1 ) . the proposed adiabatic protocol . first , a bi in a lattice with depth @xmath6 ( a ) is transformed to a product of singlets ( b ) by slowly switching on a second lattice with depth @xmath7 and half the original wave length . then , by lowering the barrier @xmath8 , the system turns into an afm ( c).,scaledwidth=45.0% ] the ramping time from fig . [ fig:1](b ) to [ fig:1](c ) needs to be long enough such that the final state is close to the true afm . the required time to ensure a certain degree of adiabaticity can be seen to scale as @xcite , where @xmath9 is the minimum gap between the ground and the first excited state during the evolution . a closer look at the relevant energy levels reveals that in this adiabatic transition the gap decreases monotonically from @xmath10 to the heisenberg gap , which vanishes in the thermodynamic limit , and there is no phase transition occurring in between @xcite . the adiabaticity of the evolution and the final antiferromagnetic order can be probed by two experimentally accessible observables . the first one , the squared staggered magnetization , , is the antiferromagnetic order parameter and can be determined by noise correlations @xcite . the second one is the double well singlet fraction , . since the initial state , fig . [ fig:1](b ) , has a pure singlet in each double well , measuring at the end indicates a change in the state . the generation and detection of singlet and triplet dimers in double well lattices has been recently reported @xcite . whereas the squared staggered magnetization is experimentally detected over the whole sample and captures information on long - range correlations , the singlet fraction can be determined _ in situ _ and hence allows us to probe parts of the sample . for the heisenberg antiferromagnetic chain in the thermodynamic limit , these observables take on the values @xmath11 and @xmath12 @xcite , while in 2d and @xcite . notice that for the finite 1d systems considered in this work , @xmath13 does not vanish , but has a sizable value , comparable to the 2d thermodynamic limit @xcite . [ [ absence - of - holes . ] ] absence of holes . + + + + + + + + + + + + + + + + + using the numerical simulation of the chain dynamics with mps , we investigate the state at the end of the protocol for varying ramping time . to characterize the antiferromagnetic order independently of the system size , we define the relative quantities , , and , where the denominator is the expectation value of the observable in the true afm for a given lattice @xcite . for the last quantity , @xmath14 is the expectation value of the spin term in the total hamiltonian of eq . ( 1 ) . absence of holes . ( a ) , ( b ) @xmath15 , @xmath16 , and @xmath17 as functions of the ramping time @xmath5 , for chain length ( solid blue lines ) , ( dashed red lines ) , ( dash - dotted green lines ) , and ( dash double - dotted brown lines ) . the inset of ( a ) shows the squared size @xmath18 of the longest chain reaching a fixed at ramping time @xmath5 , and reveals the scaling . ( c ) , ( d ) same quantities as above , evaluated on sublattices of length ( solid blue lines ) , ( dashed red lines ) , and ( dash - dotted green lines ) for . now , the inset of ( c ) shows the squared size @xmath19 of the largest sublattice reaching at ramping time @xmath5 , and reveals the scaling . all results were obtained with mps of bond dimension and trotter step @xcite.,title="fig:",scaledwidth=48.0% ] absence of holes . ( a ) , ( b ) @xmath15 , @xmath16 , and @xmath17 as functions of the ramping time @xmath5 , for chain length ( solid blue lines ) , ( dashed red lines ) , ( dash - dotted green lines ) , and ( dash double - dotted brown lines ) . the inset of ( a ) shows the squared size @xmath18 of the longest chain reaching a fixed at ramping time @xmath5 , and reveals the scaling . ( c ) , ( d ) same quantities as above , evaluated on sublattices of length ( solid blue lines ) , ( dashed red lines ) , and ( dash - dotted green lines ) for . now , the inset of ( c ) shows the squared size @xmath19 of the largest sublattice reaching at ramping time @xmath5 , and reveals the scaling . all results were obtained with mps of bond dimension and trotter step @xcite.,title="fig:",scaledwidth=48.0% ] figure [ fig:2 ] shows our results for an ideal case with no holes in the initial state , with all relative quantities converging to @xmath20 , as expected , in the limit of large @xmath5 [ figs . [ fig:2](a),(b ) ] . the ramping time necessary to reach a certain relative magnetization @xmath21 grows with the system size . if we study , given @xmath5 , which is the largest system for which a fixed value @xmath15 can be achieved [ fig . [ fig:2](a ) inset ] , we find , which is consistent with the adiabaticity condition for a gap closing like @xcite . for very long chains , the required @xmath5 might not be experimentally feasible . remarkably , this does not exclude the preparation of antiferromagnetic order on large systems . we may evaluate the magnetization over a sublattice in the center of the sample . if , given @xmath5 and @xmath22 , we ask for the largest sublattice size @xmath23 for which the magnetization reaches a fixed value [ fig . [ fig:2](c ) ] , we find a scaling , as governed by an effective local gap , and not by the gap of the total system . in contrast to @xmath15 , the observables @xmath16 and @xmath17 do not depend on @xmath23 [ fig . [ fig:2](d ) ] . this can be understood from the fact that @xmath16 and @xmath17 are determined by a two - site observable averaged over a sublattice of length @xmath23 , whereas @xmath15 is a true @xmath23-site observable , and thus effectively probes the adiabaticity on the sublattice . these observations can be addressed analytically by means of spin wave theory @xcite . the experimental consequence is that with a large sample , high values of @xmath21 can be obtained in short ramping times @xmath5 on small parts of the system , @xmath24 . [ [ effect - of - holes . ] ] effect of holes . + + + + + + + + + + + + + + + + in a real experiment , the finite temperature causes the sample to be in a thermal mixture . as a consequence , localized holes will be present in the initial state , fig . [ fig:1](b ) . since the double wells are decoupled , the wave function of a hole will be an equal superposition of being in the left and in the right side of a single double well . our simulation reveals that holes have a highly destructive effect on magnetic order . as seen in fig . [ fig:3](a ) , a few holes initially located on the boundary of the sample are enough to cause a dramatic reduction of the final staggered magnetization . effect of holes and harmonic trap . ( a ) @xmath15 as a function of the ramping time @xmath5 , evaluated on a sublattice of length for , without holes ( thin solid line ) , and with initially 2 holes at each boundary ( thick solid line ) , and . the inset shows the largest sublattice size @xmath23 reaching at ramping time @xmath5 , for the two cases of the main plot , and the size of the hole - free region ( dashed red line ) . ( b ) @xmath15 evaluated on a middle sublattice of length for , with no holes ( thin solid line ) , and with initially 10 holes at each boundary and a harmonic trap of strength ( dash - dotted green line ) , @xmath25 ( dashed red line ) , and @xmath26 ( solid blue line ) , and . for @xmath27 ( not shown ) the exact behavior of the ideal case is recovered . again , the inset shows the largest sublattice size @xmath23 reaching at ramping time @xmath5 , for the cases of the main plot . all results were obtained with mps of bond dimension and trotter step @xcite.,scaledwidth=48.0% ] we observe that the dynamics of holes can be qualitatively well understood using a simplified picture , in which the spreading of an initially localized hole , propagating in an antiferromagnetic background , is modeled by a free particle . this picture is accurate in the limit , when the spin term in eq . ( 1 ) is negligible . we checked that it is also valid in the whole experimentally reasonable parameter regime by comparing the behavior of single holes to that of free particles with the same initial wave function @xcite : for the relevant range of times and tunneling values , , the hole spreads like a free particle with a maximal velocity @xmath28 . in the case of small , a hole with higher initial energy causes a higher spin excitation , while for a large , the hole excites the spin background by in the beginning , independent of its initial kinetic energy . this can be understood by assuming a simple classical nel background , where the delocalization of a hole , initially positioned at a boundary , breaks up exactly one antiferromagnetic bond . this assumption should become a good approximation for the hole dynamics in the regime , where the timescale of the delocalization is much faster than the timescale of the reacting spin background . in all cases , the squared staggered magnetization is reduced substantially during propagation of the hole until it reaches a minimum after the hole has travelled once over the whole sample . we found that the magnetization reduction depends only weakly on the initial kinetic energy , and on @xmath29 , but it depends strongly on the number of holes in the sample . the simplified free particle picture allows us to interpret the results from fig . [ fig:3](a ) . in particular , the strong magnetization drop around indicates the arrival of holes at the middle sublattice . we can roughly predict this arrival time from the spreading of a free particle wave function , which , after time @xmath5 , will have covered sites , taking the ramping of the lattice into account . we observe that the magnetization for a given sublattice @xmath23 behaves like in fig . [ fig:2](c ) only for short ramping times , while the region is hole - free , until the holes reach the sublattice [ fig . [ fig:3](a ) , inset ] . [ [ harmonic - trap . ] ] harmonic trap . + + + + + + + + + + + + + + the simplified picture described above points out that the negative effect of holes can be controlled by the presence of a trap . an external potential changes sign for a hole and effectively turns into an inverse trap , capable of confining the holes to the outer parts of the chain . the trap strength should be chosen as large as possible without exceeding the on - site interaction @xmath3 , what would destroy the mi fig . [ fig:1](c ) . the results of the dynamics within the harmonic trap are shown in fig . [ fig:3](b ) . from energy considerations , a hole delocalizes at most by @xmath30 @xcite . as the trap strength is increased , the holes get more localized on the outside . as a consequence , the magnetization of the total sample increases , and the behavior of the hole - free case is recovered . [ [ two - dimensional - case . ] ] two - dimensional case . + + + + + + + + + + + + + + + + + + + + + for the 2d case , the adiabatic setting consists of an array of initially decoupled chains like fig . [ fig:1](b ) , connected by a transverse lattice with the time - dependent couplings @xmath31 and @xmath32 . different to the 1d case , this system exhibits a phase transition in the thermodynamic limit at @xcite . although the numerical simulation of the 2d setting is much more demanding than the one for chains , we can relatively easily obtain results for hardcore bosons on lattices of moderate size . in the absence of holes , the bosonic and fermionic models are equivalent , and our simulations serve to test our protocol on a 2d system . similarities between both models under inclusion of holes are a subject of current research @xcite , but our simulations can still provide a qualitative indication of the controlling effect of the trap . it is worth noticing that the afm can also be realized with ultracold bosons @xcite . in the ideal case of no holes , we observe [ fig . [ fig:4](a ) ] that , whereas the energy converges quickly , the magnetization does not , and thus we can not claim convergence to the true afm within the numerically accessible ramping times studied here . remarkably enough , we find that for a @xmath33 lattice , a significant magnetization value @xmath21 is obtained in times of the same order of magnitude as for a chain of length @xmath34 , suggesting that the generation of antiferromagnetic order on much larger 2d lattices will be experimentally possible within reasonable timescales . upon hole injection , a similarly dramatic magnetization reduction is observed [ fig . [ fig:4](b ) ] which can be controlled by the presence of a harmonic trap , as in the 1d case . performance in 2d . ( a ) @xmath15 and @xmath17 as functions of the ramping time @xmath5 , for systems of size ( solid blue line ) , ( dashed red line ) , ( dash - dotted green line ) , and ( dash double - dotted brown line ) . ( b ) @xmath15 for , with initially 4 holes at the boundary and no harmonic trap ( dash - dotted green line ) , and with a trap of strength ( dashed red line ) , and @xmath35 ( solid blue line ) , and . the results were obtained with peps of bond dimension ( a ) and ( b ) and trotter step @xcite.,scaledwidth=48.0% ] [ [ discussion . ] ] discussion . + + + + + + + + + + + we have proposed and analyzed an adiabatic protocol , suitable to prepare an antiferromagnetically ordered state in an optical lattice , even from an initial state containing defects . the timescales for the finite systems studied in this work lie well within the range of current experiments . furthermore , we have observed that antiferromagnetic order can be produced in a sublattice in times governed only by its size . this scheme offers several advantages over other proposals . first , starting from a bi simplifies the preparation of a sufficiently low entropy initial state . additionally , the initial ground state in fig . [ fig:1](b ) already features the final @xmath36 symmetry of the afm , so that the number of excited states to which the evolution couples is minimum , as compared with an alternative proposal @xcite with only @xmath37 initial symmetry . moreover , since hole doping is experimentally feasible , the same procedure can possibly be used to prepare the ground state with varying hole densities . this would open the door to the experimental exploration of open questions in condensed matter theory , ultimately the existence of @xmath38-wave superconductivity in the model . [ [ acknowledgements . ] ] acknowledgements . + + + + + + + + + + + + + + + + + we are grateful to immanuel bloch for inspiring discussions . this work was partially funded by the european projects quevadis and aqute . 99 t. esslinger , annu . . condens . matter phys . * 1 * , 129 ( 2010 ) . r. jrdens _ et al . _ , , 204 ( 2008 ) . u. schneider _ et al . _ , science * 322 * , 1520 ( 2008 ) . f. werner _ et al . _ , , 056401 ( 2005 ) . r. jrdens _ et al . _ , , 180401 ( 2010 ) . d. c. mckay and b. demarco , rep . prog . phys . * 74 * , 054401 ( 2011 ) . t .- l . ho , arxiv:0808.2677 . a. s. srensen _ et al . _ , , 061603(r ) ( 2010 ) . u. schneider _ et al . _ , _ supporting online material _ , science * 322 * , 1520 ( 2008 ) . u. schneider _ et al . _ , arxiv:1005.3545v1 . g. vidal , , 040502 ( 2004 ) ( we use the method introduced in : f. verstraete , j. j. garca - ripoll and j. i. cirac , , 207204 ( 2004 ) ) . f. verstraete and j. i. cirac , arxiv : cond - mat/0407066v1 . v. murg , f. verstraete and j. i. cirac , , 033605 ( 2007 ) . j. sebby - strabley _ et al . _ , , 033605 ( 2006 ) . s. trotzky _ et al . _ , science * 319 * , 295 ( 2008 ) . s. trotzky _ et al . _ , , 265303 ( 2010 ) . d. jaksch _ et al . _ , , 3108 ( 1998 ) . other ramping schemes for different values of @xmath39 give qualitatively similar results . c. zener , proc . r. soc . lond . a * 137 * , 696 ( 1932 ) . m. matsumoto _ et al . _ , , 014407 ( 2001 ) . g. m. bruun _ et al . _ , , 033622 ( 2009 ) . l. hulthn , ark . mat . astron . fys . * 26a * , 1 ( 1938 ) . a. w. sandvik and h. g. evertz , , 024407 ( 2010 ) . see supplemental material for details to our numerical method and errors , and absolute values of experimental observables . mps and peps are characterized by a bond dimension @xmath40 that determines their number of variational parameters , and convergence of numerical results to the exact solution is checked by increasing @xmath40 . the time evolution is done with a second ( 1d ) and first ( 2d ) order trotter decomposition of the evolution operator , and hereby convergence is checked by decreasing the trotter step @xmath41 @xcite . i. affleck _ et al . _ , j. phys . a : math . gen . * 22 * , 511 ( 1989 ) . m. lubasch _ et al . _ , ( to be published ) . m. boninsegni and n. v. prokofev , , 092502 ( 2008 ) . the hardcore bosonic system has a ferromagnetic interaction , but the antiferromagnet can be obtained as the highest excited state @xcite . j. j. garca - ripoll , m. a. martin - delgado and j. i. cirac , , 250405 ( 2004 ) .

the in - vivo radio - resistance of human tumor cells varies greatly . some tumor types have high degrees of radio - resistance both in - vitro and in clinical experience . these tumors include glioblastoma multiforme @xcite , poorly differentiated / anaplastic thyroid cancer @xcite , unresectable salivary tumors @xcite , certain head and neck sarcomas @xcite , and head and neck squamous cell carcinomas that recur after prior radiotherapy @xcite . the lack of durable radiation response within these tumor types poses a significant clinical challenge . patients with these tumors have some of the worst disease - free and overall survival statistics among all cancer patients . double - strand breaks generated by particle tracks with high linear energy transfer ( let ) are thought to be more complex and more difficult to repair @xcite . the treatment of salivary tumors , thyroid malignancies and glioblastoma with neutrons and carbon ions has demonstrated increased local control when compared with historical controls . for protons , the let and relative biological effectiveness ( rbe ) vary along particle trajectories , increasing towards track ends . although an absolute prediction of rbe values is very difficult , the relationship between rbe and let can be approximated as linear . proton treatment plans that exploit this rise in let to deliver increased biological dose ( bd ) to the target can potentially result in improved outcomes for radio - resistant tumors . to estimate bd distributions , one requires the dose - averaged let ( let@xmath0 ) . the most reliable way to calculate let@xmath0 is through monte carlo ( mc ) simulations , since contributions from secondary particles produced in non - elastic proton - nucleus interactions can be significant . previous authors have employed a variety of methods to elevate the target bd @xcite . bd escalation methods that involve the use of mc techniques are usually of the forward - planning type . furthermore , they are not clinically viable because cpu - based mc calculations are overly time - consuming . to the best of our knowledge , mc - calculated let@xmath0 distributions have not yet been directly incorporated in inverse planning for proton therapy . compared to other bd escalation methods , mc - based inverse biological planning is not only expected to be more accurate , but also to produce plans with more conformal and homogeneous bd , and with better normal tissue sparing . the goal of this work is to demonstrate clinically - applicable , mc - based inverse biological planning in pencil - beam scanning proton therapy . the target bd is escalated in comparison with conventional intensity modulated proton therapy ( impt ) planning , while keeping the same organ - at - risk ( oar ) constraints and restricting physical dose ( pd ) hotspots to within 25% or so of the prescription dose . two pieces of software that made such plans calculable in less than 30 minutes are : ( a ) a gpu - based proton transport mc @xcite , and ( b ) a gpu - based impt optimizer that uses pre - calculated , spot - wise let@xmath0 and pd maps from the mc @xcite . the applicability and limitations of the method is illustrated with four cases . the focus is on head - and - neck tumors , although other sites can benefit as well . recently , our group has developed a very fast and accurate proton transport mc for the gpu , with net computational times of @xmath120s for @xmath2 proton histories @xcite . this gpu - based mc includes a bertini cascade simulation @xcite for handling non - elastic interactions on an event - by - event basis , and is thus capable of performing accurate let@xmath0 computations . the mc model for computing the pd was extensively verified with topas version beta-6 @xcite and geant4.9.6 . the let@xmath0 computations were also compared with topas predictions . as an example , figure 1 shows the pd and let@xmath0 calculations from topas and our in - house mc for a head - and - neck patient . the 3d - gamma @xcite pass rate at 2%/2 mm was above 98% for the dose calculation . and physical dose calculations are shown in the top and bottom left panels , respectively . the corresponding computations from the in - house gpu - based mc are shown on the right . ] in addition , our group has built a fast gpu - accelerated impt optimizer @xcite , which uses the previously - described mc as the dose calculation engine . on a 24-gpu system , this optimizer can generate impt plans within a clinically viable time frame ( i.e. within 30 minutes ) . because they are mc - based , these plans are not adversely affected by inaccuracies due to tissue heterogeneities . the impt optimizer was slightly modified for the purposes of this work , by allowing the input of let@xmath0 maps , implementing voxel - wise bd estimates ( see equation 1 below ) , and modifying the cost function . to simplify the bd calculation during the optimization process , a simple linear relationship between let@xmath0 and bd was assumed : @xmath3 where @xmath4=0.05 @xmath5m / kev and @xmath6=0.95 . pd and let@xmath0 are in units of gy and kev/@xmath5 m , respectively . these coefficients were chosen so that equation 1 roughly corresponds to a linear - quadratic model with @xmath7 gy . with these values of a and b , equation 1 yields a dependence of rbe on let@xmath0 that is close to previously published models from carabe et al @xcite , wedenberg et al @xcite and mcnamara et al @xcite , which were derived from fits to in - vitro cell survival data . a dose per fraction of 2 gy was assumed when comparing equation 1 to these models . the post - optimization bd was evaluated by using the published models instead of equation 1 . the term in brackets is the deviation from the conventional @xmath8 . suggestive evidence for a linear relation between rbe and let can be found in references @xcite . the same linear relation was naively assumed to be valid for all cell kinds . as discussed below , the choice of @xmath4 and @xmath6 values ( and hence @xmath9 ) does not affect the ability of the optimizer to converge to a plan with increase target let@xmath0 . the assumed value of @xmath7 gy is our rough guess for highly radio - resistant tumors . for each patient in this study , the following three plans were created : 1 . a photon imrt plan 2 . a conventional two or three - field impt plan 3 . a five - field biologically optimized plan , using the in - house treatment planning system ( tps ) described above . the imrt and impt planning were done using a commercially - available tps ( eclipse , varian medical systems ) . the number of fields used in the conventional impt plans is reflective of our current clinical practice . to create the biologically optimized plan , an optimization target volume ( otv ) @xcite , which is akin to a planning target volume ( ptv ) , was derived from the physician - delineated clinical target volume ( ctv ) , and expanded by 0.5 cm to create a scanning target volume ( stv ) . the mc was then used to place spots inside the stv , with a hexagonal spot spacing of 0.5 cm , and the pd and let@xmath0 maps for each spot was calculated using @xmath10 proton histories . to minimize gpu memory use , voxels receiving less than 0.5% of the maximum dose were ignored @xcite . constraints were placed so as to maintain the otv pd to within @xmath125% of the prescription dose , while maximizing the otv bd . to achieve this , a lower limit was placed on the otv bd ( 115% of prescription dose ) and the relative weights of the pd constraint and bd objective were adaptively changed during each optimization step . the biologically - optimized , impt and imrt plans had the same oar pd constraints . the plan that best satisfies the above requirements is the ` biologically optimal ' plan . it should be stressed that constraints were not set on the bd for oars , since absolute bd values are currently not reliably calculable . even if they were , relating the high - let proton bd to past photon - based experience is not trivial . in this work , the proton pd constraints for oars in plans 2 and 3 were derived from photon dose constraints , assuming an rbe of 1.1 . the impt plan was recalculated using our in - house mc to obtain its let@xmath0 and bd distributions . the percentage gains in bd and let@xmath0 in plan 3 relative to plan 2 were quantified by : @xmath11 where @xmath12 , @xmath13 , @xmath14 , @xmath15 are the mean target bd and let@xmath0 in plans 2 and 3 . similarly , the increase in mean pd in plan 3 relative to plan 2 is : @xmath16 ideally , it is desirable to have large @xmath17 and @xmath18 for a small @xmath19 , i.e. keep the target pd as close to the prescription dose as possible . the quantities @xmath20 are used to assess the gain in bd and let@xmath0 relative to the increase in pd . although the magnitude of @xmath17 depends on the values of @xmath4 and @xmath6 in equation 1 , the optimization process does not . in other words , the choice of @xmath4 and @xmath6 does not affect the ability of the in - house tps to converge to a biologically optimal plan . for each patient , after optimization the bd distributions were generated using the rbe let@xmath0 relations from references @xcite and equation 1 . for each rbe model , the pd and bd dose - volume histograms ( dvhs ) from plan 3 were compared with plan 2 to assess @xmath17 , @xmath19 , @xmath21 and oar doses . to remove dependence on the coefficients @xmath4 and @xmath6 , @xmath21 was calculated using the average @xmath17 obtained from the carabe , wedenberg and mcnamara models . before calculating these metrics , all plans were normalized so that 98% of the target gets the prescription dose . comparisons were also made with plan 1 to gauge oar pd sparing relative to standard imrt treatment . values of @xmath18 and @xmath22 were also calculated for each patient . in contrast to @xmath17 and @xmath21 , these are completely model - independent . this method can not be successfully applied to all patients . intuitively , the magnitude of @xmath17 depends on the number of beams , their directions and target volume . beam directions should be preferentially spread out isotropically around the target to facilitate let@xmath0 elevation . however , this somewhat defeats the purpose of proton therapy , and normal tissue irradiation should be avoided where possible . furthermore , the contribution of any beam can be substantially reduced if an oar is in its path . bd escalation in large - volume targets is expected to be more difficult to achieve , since low let@xmath0 track sections inevitably contribute to the dose . in this study , four cases are discussed to illustrate the above points : a. small thyroid tumor , otv size : 94 @xmath23 b. small thyroid tumor with oar in the path of posterior beams , otv size : 108 @xmath23 c. large thyroid tumor , otv size : 654 @xmath23 d. small brain stem tumor , otv size : 9 @xmath23 the field directions and target geometries in each case are shown in figure 2 below . the prescription doses for cases a - d were 66 , 60 , 66 and 54 gy , in 33 , 50 , 30 and 30 fractions , respectively . cases b and c were included to demonstrate situations where our technique would not be applicable . in case b the left brachial plexus ( shown as the yellow contour ) is in the path of the posterior beams . case d demonstrates the applicability of the technique to a site outside the neck region . the initial pd and let@xmath0 map calculations , as well as the bd optimization , were carried out on a remote cluster @xcite using 10 to 50 nvidia k20x cards , depending on the target volume . a multi - gpu system is mandatory due to the sheer scale of the initial map computations . in the optimization stage , the workload was also divided among a large number of gpus . fast inter - node communication was therefore essential for efficient data transfer . further details of the multi - gpu implementation are given elsewhere @xcite . figure 2 shows the bd distributions from the mc re - calculations of the conventional eclipse impt plans ( left ) and our biologically optimized plans ( right ) , for patients a to d. the bd distributions in figure 2 were generated using the mcnamara model with @xmath7 gy ( please see appendix for the let@xmath0 colorwash distribution ) . the values of @xmath19 , @xmath17 from each publised rbe model @xcite and their averages at @xmath7 and 6 gy , @xmath21 , @xmath24 and @xmath22 for all cases are given in table 1 . patients a and d had nearly 60% increase in the mean target let@xmath0 and demonstrate the largest values of @xmath22 . the values of @xmath17 and @xmath25 are model - dependent . for patients a and d with @xmath7 gy , raising the target pd by 5.1 and 8.6% resulted in 11.3 and 17.3% increase in target bd ( i.e. relative gains of 2.21 and 2.02 , respectively ) . patients b and c had less favorable results , the gain in bd being marginal relative to the increase in pd . the gain in mean let@xmath0 relative to the pd increase was also much lower than for a and d. oar dvhs for patients a ( larynx and esophagus ) and d ( optic chiasm and pituitary gland ) from the biologically optimized , standard impt and imrt plans are shown in figure 3 . the target pd dvhs are shown in the appendix . .post bio - optimization metrics ( defined in equations 24 ) for cases a d . [ cols="^,^,^,^,^",options="header " , ] bd optimization by mc - based inverse planning has been demonstrated for two patients with small tumor targets ( a and d ) . for a modest rise in mean target dose , roughly twice as much increase in bd was obtained . @xmath21 and @xmath22 are a rough guide to the extent of the bd escalation ` quality ' . a high value of @xmath21 means that not much additional pd is required to significantly boost the target bd , which implies that the target dose can stay relatively close to prescription . for plans with high @xmath21 and @xmath22 , the bd gain is a consequence of the successful and deliberate placement of high - let track ends inside the targets . compared to conventional impt planning , more beams were required to elevate let@xmath0 in the target . as observed in figure 2 , the beams were not spread uniformly around the target in order to spare normal tissue . however , a higher degree of bd escalation could have been achieved by irradiating the opposite areas . a five - beam arrangement was used in this work because splitting the beams ( but keeping the same anatomical avoidance regions ) does not result in significantly larger @xmath21 and @xmath22 values . for a small - target patient , the bd gain of a 10-field plan was found to be comparable to that of a 5-field plan . the limitations of the methods are illustrated by cases b and c. as shown in case c , achieving bd escalation in large - volume targets is far more challenging because of the unavoidable contribution of low - let track sections to pd . case b has comparable volume to a , but the presence of an oar ( the left brachial plexus ) in the path of the posterior beams considerably diminished their contribution . as a result , the remaining field directions ended up being rather similar to those in the impt plan , and no significant bd boost was achieved . figure 3 shows that dose sparing to critical structures in the biologically optimized plans is improved compared to both eclipse imrt and impt plans . in contrast to eclipse , the in - house optimization algorithm continuously drove down the dose to a given oar even when user - defined constraints on it were met . to achieve this , the user - defined upper constraints and their weightings were automatically adjusted during each iteration step @xcite . it might be thought that the bd gain relative to standard impt planning was mostly due to the additional fields , and that a 5-field impt plan would demonstrate a similar level of bd gain . in fact , bd escalation can not be deliberately achieved if the optimizer is not explicitly instructed to do so . to illustrate this , a 5-field standard impt plan was created in eclipse for patient d , using the same beam angles , constraints and objectives ( except the bd objective , which can not be applied ) as the biologically optimized plan . figure 4 shows the let@xmath0 colorwash distributions for the 5-field impt and biologically optimized plans in an axial cut . the central plot shows the let@xmath0 profile across the target . although the target pd objectives and oar constraints were met by both plans , the let@xmath0 distributions are very different from each other . the two peaks in the red curve indicate that eclipse placed high - let proton track ends near the target edges . conversely , the biologically optimized plan was constructed such that protons stopped preferentially within the target , resulting in bd escalation . relative to the 3 field conventional impt plan , the values of @xmath19 , @xmath17 and @xmath21 ( @xmath7 gy ) obtained for the 5-field eclipse impt plan were 1.8% , 2.1% and 1.17 , showing no evidence for bd escalation . colorwash distributions for a standard 5-field impt plan ( left ) and our biologically - optimized plan ( right ) for patient d. the let@xmath0 for voxels receiving less than 1% of the maximum dose is not shown . the central plot shows the let@xmath0 profile across the target . the same beam angles , objectives and constraints were used in both plans ( see text ) . ] it should be pointed out that although our let@xmath0 predictions are in very good agreement in topas , recent work @xcite has shown that the default let@xmath26 scoring method in early topas versions ( including beta-6 , which we used in this work ) is biased . to resolve this , the let@xmath0 scoring method adopted in our mc will be modified to use tabulated unrestricted stopping power tables , based on recommendations from references @xcite . in the near future , we also plan to update our optimizer to use a linear - quadratic rbe model @xcite instead of equation 1 . the use of a linear rbe model in this feasibility study was purely out of simplicity , and this update is not expected to impact our ability to achieve bd escalation . as mentioned previously , a multi - gpu system is necessary to perform the calculations within a clinically acceptable timeframe . compared to a k20x , a titan x card can process a given dose calculation in around half the time . from table 2 , assuming the processing time to scale with the number of gpus , a system consisting of 24 nvidia titan x cards can complete the calculations for case a in under 30 minutes . a feasibility trial on proton bd optimization is planned to start at our institution in 2016 . this trial is geared towards patients with : ( a ) anaplastic thyroid cancers , ( b ) salivary gland tumors , ( c ) recurrent squamous cell carcinomas of the head and neck , and ( d ) recurrent glioblastomas . a total of 24 patients will be enrolled , with 6 from each tumor category type . the tumor target size will be critical in selecting patients . the treatment planning calculations will be carried out on a small local cluster of 24 gpu cards , using the method described above . candidates will be planned using both standard impt and biological planning , and the treatment modality will be chosen at the physician s discretion . the requirements for treatment using the biologically optimal plan include large @xmath17 , @xmath18 , @xmath21 and @xmath22 values . by taking advantage of gpu acceleration , the bd in small tumors was successfully escalated via mc - based inverse planning optimization . in the examples given , compared to standard impt planning , a modest increase in the target pd significantly raised the mean let@xmath0 and can result in twice as much increase in the bd . the estimated bd increase depends on the let@xmath0 to bd conversion model . the applicability of the technique was discussed . to summarize , its main advantages are : * accurate mc - based dose and let@xmath0 calculation * inverse planning optimization * clinically applicable the main limitations are : * irradiation to normal tissue due to additional fields * not applicable to all cases , especially large target volumes * expected to be less robust than standard impt the ability to produce such plans within a clinically acceptable timeframe opens exciting new prospects for proton therapy . this work was partially funded by varian medical systems , inc . distributions from the mc recalculations of the eclipse impt plans for aptients a d . the let@xmath0 distributions for the biologically optimized plans are shown on the right , in the same slices as figure 2 of the paper . targets are delineated in red . for patients a and d , the mean target let@xmath0 is increased by nearly 60%.,width=491 ] 100 shu hk , kim mm , chen p , et al . the intrinsic radioresistance of gliobastoma - 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based intranuclear cascade and evaporation simulation . _ computer physics communications _ 2014;185:2029 - 2033 . perl j , shin j , schuemann j , et al . topas : an innovative proton monte carlo platform for research and clinical applications . _ medical physics _ 2012;39:6818 - 6837 . low da , harms wb , mutic s , et al . a technique for the quantitative evaluation of dose distributions . _ medical physics _ 1998;25:656 - 661 . carabe a , moteabbed m , depauw n , et al . range uncertainty in proton therapy due to variable biological effectiveness . physics in medicine and biology 2012;57:1159 - 1172 . wedenberg m , lind bk , hardemark b. a model for the relative biological effectiveness of protons : the tissue specific parameter alpha / beta of photons is a predictor for the sensitivity to let changes . _ acta oncologica _ 2013;52:580 - 588 . mcnamara al , schuemann j , paganetti h. a phenomenological relative biological effectiveness ( rbe ) model for proton therapy based on all published in vitro cell survival data . _ physics in medicine and biology _ 2015;60:8399 - 8416 . paganetti h , niemierko a , ancukiewicz m , et al . relative biological effectiveness ( rbe ) values for proton beam therapy . _ international journal of radiation oncology , biology , physics _ 2002;53:407 - 421 . american society for radiation oncology ( astro ) model policies : + http://www.astro.org/uploadedfiles/main_site/practice_management/reimbursement/astro%20pbt%20model%20policy%20final.pdf ; 2014 . blue waters , national center for supercomputing applications , university of illinois at urbana - champaign . cortes - giraldo ma , carabe a. a critical study of different monte carlo scoring methods of dose average linear - energy - transfer maps calculated in voxelized geometries irradiated with clinical proton beams . _ physics in medicine and biology _ 2015;60:2645 - 2669 . granville da , sawakuchi go . comparison of linear energy transfer scoring techniques in monte carlo simulations of proton beams . _ physics in medicine and biology _ 2015;60:n283 - 291 . guan f , peeler c , bronk l , et al . analysis of track- and dose - 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* purpose : * to demonstrate the feasibility of fast monte carlo ( mc ) based inverse biological planning for the treatment of head and neck tumors in spot - scanning proton therapy . * methods : * recently , a fast and accurate graphics processor unit ( gpu)-based mc simulation of proton transport was developed and used as the dose calculation engine in a gpu - accelerated impt optimizer . besides dose , the mc can simultaneously score the dose - averaged linear energy transfer ( let@xmath0 ) , which makes biological dose ( bd ) optimization possible . to convert from let@xmath0 to bd , a simple linear relation was assumed . using this novel optimizer , inverse biological planning was applied to four patients , including two small and one large thyroid tumor targets , and one glioma case . to create these plans , constraints were placed to maintain the physical dose ( pd ) within 1.25 times the prescription while maximizing target bd . for comparison , conventional imrt and impt plans were also created using eclipse ( varian medical systems ) in each case . the same critical structure pd constraints were used for the imrt , impt and biologically optimized plans . the bd distributions for the impt plans were obtained through mc re - calculations . * results : * compared to standard impt , the biologically optimal plans for patients with small tumor targets displayed a bd escalation that was around twice the pd increase . dose sparing to critical structures was improved compared to both imrt and impt . no significant bd increase could be achieved for the large thyroid case , and when the presence of critical structures mitigated the contribution of additional fields . the calculation of the biological optimized plans can be completed in a clinically viable time ( below 30 minutes ) on a small 24-gpu system . * conclusion : * by exploiting gpu acceleration , mc - based , biologically optimized plans were created for small - target tumor patients . this optimizer will be used in an upcoming feasibility trial on let@xmath0 painting for radio - resistant tumors .

The tapestry has had a purpose-built home since 1983, having once been kept at Bayeux Cathedral Alamy Napoleon Bonaparte flaunted it to whip up enthusiasm for invading England. Heinrich Himmler tried to grab it for Nazi Germany and Britain failed to borrow it to celebrate the Coronation in 1953. Now the Bayeux Tapestry, the great graphic depiction of the Norman Conquest, is to cross the Channel at last — although it may really be a homecoming. Some experts have long claimed that the distinctive Anglo-Saxon art of the 230ft-long work is proof that it was sewn in England after William of Normandy rolled up King Harold’s army at the Battle of Hastings on October 14, 1066. The chronicle of William’s campaign is told from the Norman side, with bloody scenes of slaughtered English troops and Harold’s death with an arrow in the… ||||| Image copyright Getty Images Image caption The Bayeux Tapestry is 70m (230ft) long The Bayeux Tapestry is set to be displayed in the UK after France agreed it could leave its shores for the first time in 950 years, the BBC understands. French President Emmanuel Macron is expected to announce the loan during his visit to the UK on Thursday. He has said the tapestry - which depicts the Norman Conquest of England - would not be transferred before 2020. The Times said the loan was subject to the outcome of tests to make sure the 11th Century artwork was safe to move. The tapestry tells the story of the future William I's conquest of England, culminating in the Battle of Hastings and the defeat of Harold in 1066. It is on permanent display at a museum in the town of Bayeux, in Normandy, and has very rarely been moved. However, President Macron is expected to announce the proposed loan at a meeting with Prime Minister Theresa May in the UK this week. The Times said the agreement was made after "months of talks between culture department officials in London and Paris" but it has not yet been decided where in the UK the tapestry will be displayed. What are the origins of the tapestry? Historians have long debated the origins of the tapestry, which is 70m (230ft) long and 50cm high. The earliest written reference to it is an inventory from Bayeux Cathedral in 1476, but little is known about how or why it was created. According to Reading Museum, which houses a replica of the tapestry, it was "probably commissioned" in the 1070s by the half-brother of William the Conqueror - the Bishop Odo of Bayeux. Some say it was created by teams of nuns across England - not France - possibly in Canterbury, Kent. In 2012, a PhD researcher at the University of Manchester said the artwork's needlework was "consistent throughout", suggesting one group of specialist embroiderers worked on it, in the same place at the same time. What does it depict? The tapestry shows the events leading up to the Norman takeover of England. It starts with Edward the Confessor, who became king in 1042, on the throne and tells the story of his death and the questions over who was the rightful heir. In 1066, on the day of Edward's funeral, his brother-in-law Harold was crowned king. News of his appointment reached France and William of Normandy, who claimed he should be king as Edward had promised him the throne of England. Image caption Harold is crowned king after the death of Edward the Confessor On 14 October 1066, William I and King Harold II came to loggerheads at the Battle of Hastings - one of the most famous battles in English history. It is likely both sides had between 5,000 and 7,000 men each when they met in battle at a hilltop near Hastings. Thousands of soldiers were killed in a day of a fighting, which ended in King Harold II's death. It was a turning point in history as it ended the Anglo-Saxons's long reign of more than 600 years. You might also like: Where has it been exhibited? Image caption The tapestry shows a soldier being killed by an arrow in his eye, which could be King Harold Napoleon put the tapestry on display in Paris in 1804, while he was planning an invasion of England. It was then exhibited in Paris for the second time in 1944, during World War II, before it was returned to Bayeux. Mr Macron's offer comes after previous attempts to bring the tapestry to Britain failed. One request is thought to have been made ahead of the Queen's Coronation in 1953, while another was made for the 900th anniversary of the Battle of Hastings, in 1966. Some have suggested the tapestry could be relocated to the British Museum if it gets the go ahead to come to the UK. Dr Michael Lewis of the museum told the Victoria Derbyshire programme 1066 was a date "we all know" from being at school so it would be "amazing" if children could go and see the tapestry. "For the wider public, people will be amazed about how long it is, and it definitely has a real impact when you see this work of art," he added. Can it be moved? Tests will decide if the tapestry can be moved safely and get to the UK in one piece. BBC History magazine's Dr David Musgrove says its size, age and obvious fragility makes moving it a concern. But he told the BBC Radio 4's Today programme moving it would also present an opportunity to conduct some interesting historical research on its dyes and fabrics. What are the myths and legends of the tapestry? The story that Harold was killed by an arrow in the eye is thought to have come from the tapestry. However, earlier sources dispute this and claim he was hacked to death by four Norman knights. Dr Levi Roach, a medieval historian at the University of Exeter, said the tapestry was confiscated for military use, for covering weapons, during the French Revolution, before a lawyer saved it. Should we give them something in return? Tom Tugenhadt, chair of the foreign affairs select committee, said the UK should "definitely" consider it. "This is an opportunity for us to cement the relationship," he told BBC Radio 4's Today. "One of the interesting items we might perhaps think about lending... is the Rosetta stone, which was discovered in Egypt." According to the British Museum, it is likely that the stone was found by Napoleon Bonaparte's soldiers while on a mission to threaten Britain's hold on India. ||||| President to allow Battle of Hastings embroidery to leave France for first time in 950 years The Bayeux tapestry will be loaned to Britain after Emmanuel Macron agreed to let it leave France for the first time in 950 years. The president is expected to announce at an Anglo-French summit on Thursday that the artefact depicting the the Norman buildup to, and success in, the Battle of Hastings in 1066 will be loaned to the UK, probably in 2022.. Quick guide The Bayeux tapestry Show Hide The Bayeux tapestry is a graphic depiction of the Norman buildup to, and success in, the Battle of Hastings in 1066. In a series of scenes told in 70m of coloured embroidery and Latin inscriptions, it shows how William the Conquerer crossed the Channel to seize the English crown from King Harold. Commissioned by William’s half-brother Odo, it is an early example of history being written, or in this case embroidered, by the victors. It shows vivid and often gory battle scenes between two sides clearly identifiable by their haircuts: the English with shoulder-length hair and moustaches fighting the clean-shaven Normans with short back and sides. Highlights include an appearance in the sky of Halley’s comet, seen as a bad omen for Harold, William’s dragon-headed ships crossing the sea and the death of Harold after being shot through the eye with an arrow. Photograph: Alinari/REX/Shutterstock/Rex Features Theresa May will use the decision, which has involved lengthy talks between each country’s respective culture departments, to highlight the strength in UK-French relations after Brexit. An Elysée official said the loan was agreed in principle but would not happen for several years because work needed to be done on the tapestry to ensure it was safe to move it. “It’s very symbolic for France and maybe even more for the UK,” he said. The date of the loan would probably be 2022 when, it is understood, the Bayeux Museum closes for refurbishment. Why the Bayeux Tapestry’s loan to Britain is a homecoming | John Lichfield Read more One leading contender to show the tapestry would be the British Museum. Its director, Hartwig Fischer, said it would be “honoured and delighted” to display the tapestry. “This would be a major loan, probably the most significant ever from France to the UK. It is a gesture of extraordinary generosity and proof of the deep ties that link our countries. The Bayeux tapestry is of huge importance, as it recounts a crucial moment in British and French history, 1066.” He said the museum was the “UK’s most visited and internationally renowned institution” and added: “Here it would be seen by the widest UK and international audience in the context of a museum of world cultures.” Adding to the museum’s case is the size of its temporary Sainsbury exhibition gallery, which opened in 2014 and has staged major shows on subjects including the Vikings and the Scythians. The gallery is 70 metres long, making it able to host the 68-metre tapestry.. It is understood the museum has been in talks about a possible loan of the tapestry for several years, but there will be other contenders to host it. The bookmaker Ladbrokes is offering odds on where it might go, with the British Museum evens favourite, followed by Westminster Cathedral at 3/1, Canterbury Cathedral at 5/1 and Hastings at 8/1. If the tapestry does come to the UK, it raises the question of what reciprocal loan could be made to France, with the Rosetta Stone, originally in French hands until Britain defeated the French in Egypt in 1801, a likely contender. The tapestry is thought to have been made shortly after the Battle of Hastings in the 11th century. Some historians argue it was made in Kent, a debate that is set to reignite following the announcement. The first written record of it is in 1476 when it was recorded in the Bayeux Cathedral treasury as “a very long and narrow hanging on which are embroidered figures and inscriptions comprising a representation of the conquest of England”. The Bayeux Tapestry – historic, yes, but is it any good? Read more There have been previous unsuccessful attempts to negotiate a loan of the embroidery to the UK: once for the Queen’s coronation in 1953, and in 1966 for the 900-year anniversary of the Battle of Hastings. The embroidery has rarely been moved even within France. In 1803, Napoleon Bonaparte put it on display in Paris and in 1945 it was briefly displayed in the Louvre after being seized from the Nazis. The announcement is likely to lighten the mood when May hosts Macron at Sandhurst military academy on Thursday. The leaders are expected to discuss the migration crisis at Calais and agree closer cooperation on fighting al-Qaida-linked militants “at source” in north Africa. The prime minister is expected to announce that Britain will send military helicopters to join a French campaign against Islamist extremists in the region.

– As the story goes, before Queen Elizabeth's 1953 coronation, Britain asked France if it might borrow the storied Bayeux Tapestry. The answer was no. Heinrich Himmler was also unsuccessful in transferring it to Nazi Germany. The 220-foot-long tapestry, which is on permanent display in Bayeux, France, has not left that country in some 950 years. That looks set to change. Multiple outlets are reporting that upon his arrival in the UK Thursday, French President Emmanuel Macron will announce that the tapestry will be loaned to England, though not for a few years and only if tests show the 11th-century tapestry—which details the Norman Conquest of England, complete with King Harold dying with an arrow in his eye—can be safely moved. There is some speculation that the tapestry was actually created in Kent, England, reports the Guardian, and the Times of London writes the decision to loan it "would be a huge gesture towards les Anglais"—and a fraught one, as bright light, extreme temperatures, humidity, and moths could ruin it. The BBC reports a British museum believes it was commissioned in the 1070s by the half-brother of William the Conqueror; the historical trail doesn't start until 1476, when it appears on an inventory of Bayeux Cathedral. One interesting line of speculation: whether the UK will loan France something equally impressive. One member of parliament suggests temporarily parting with the Rosetta Stone, which was likely uncovered by the French—specifically by soldiers of Napoleon in Egypt. Read more on Harold, England's last Anglo-Saxon king, here.

the non - local correlations of a quantum mechanical system are encoded in the behavior of the entanglement properties of its wave functions . a pure quantum state of a bipartite system @xmath0 defines a mixed state in the observed region @xmath1 obtained from tracing out the degrees of freedom in the unobserved region @xmath2 . the non - local correlations connecting regions @xmath1 and @xmath2 are encoded in the behavior of the von neumann entanglement entropy , @xmath3 , where @xmath4 is the reduced density matrix of region @xmath1 . the entanglement entropy of a local quantum field theory , relativistic or not is known to exhibit an `` area law '' scaling of the form @xmath5 in spatial dimensions @xmath6 where @xmath7 is a non - universal coefficient@xcite . there has been growing interest in the scaling behavior of the entanglement entropy at quantum critical points and in topological phases . the entanglement entropy of quantum critical systems in @xmath6 should contain universal subleading terms , whose structure for a general quantum critical system is not yet known . the scaling behavior of the entanglement entropy has only been studied in detail in quantum critical systems in @xmath8 space dimension . such systems are described by a @xmath9-dimensional conformal field theory ( cft ) . in a @xmath10-dimensional cft , the entanglement entropy of a subsystem @xmath1 of linear size @xmath11 of an otherwise infinite system ( _ i.e. _ of linear size @xmath12 ) obeys a logarithmic scaling law , @xcite @xmath13 , where @xmath14 is the _ central charge _ of the cft , and @xmath15 is the short distance cutoff . there has been a number of studies on topics related to this 1d logarithmic scaling form . for instance , a possible connection between this result and gravitational physics was suggested@xcite . a similar logarithmic scaling behavior was found at infinite disorder fixed points of 1d random spin chains@xcite . the quantum entanglement of quantum impurity systems has also been studied . @xcite in this paper , we consider the universal scaling form of the entanglement entropy at 2d conformal quantum critical points ( qcp ) two - dimensional quantum critical systems with scale - invariant many body wave functions . at a 2d conformal qcp , equal - time correlators of local operators coincide with the correlation functions of an appropriate 2d _ classical _ system at criticality ( which is described by an euclidean 2d cft)@xcite . the entanglement entropy of 2d conformal qcps was first considered in ref . [ ] , where a scaling form was found : @xmath16 , where @xmath14 is the central charge of the 2d euclidean cft associated with the norm squared of the wave function and @xmath17 is the change of the euler characteristic @xmath18 , @xmath19 . notice for a region @xmath20 with a smooth boundary , @xmath21 and hence the logarithmic term vanishes . hence , if region @xmath1 has a smooth boundary , there is no universal logarithmic term . in this case , we will show that instead there is a _ , @xmath22 , _ universal term _ @xmath23 in the entanglement entropy at these quantum critical points , _ i.e. _ @xmath24 through explicit calculations and using general arguments based on cft , we will show that @xmath23 has a topological meaning in the sense that it is determined by the contributions of the winding modes of the underlying cft . in a topological phase in 2d , the entanglement entropy scales as@xcite @xmath25 where @xmath26 is a non - universal coefficient and @xmath27 , the _ topological entanglement entropy _ , is a topological invariant , the logarithm of the so - called total quantum dimension @xmath28 of the underlying topological field theory describing the topological phase.@xcite topological phases have non - trivial ground state degeneracies on surfaces of non - trivial topology . the topological entanglement entropy @xmath27 also depends on the global topology of the manifold , and on surfaces with non - trivial topology , on the degenerate ground state on that surface.@xcite although superficially similar , the finite universal contributions to the entanglement entropy in topological phases and conformal quantum critical points , @xmath27 and @xmath23 , have a different origin and structure . in the case of a topological phase , @xmath27 is in general determined by the modular @xmath29-matrix of the topological field theory of the topological phase.@xcite this modular @xmath29-matrix governs the transformation properties of the ( degenerate ) ground states of the topological phase on a torus under modular transformations , @xmath30 , where @xmath31 is the modular parameter of the torus.@xcite however , we show below that for a general conformal quantum critical point , whose ground state wave function is given by the gibbs weights of a euclidean rational unitary cft , the universal term @xmath23 is determined by the modular @xmath29-matrix associated with the norm squared of the wave function . thus , the modular @xmath29-matrix of the topological phase and that of the wave functions of 2d conformal quantum critical points have a conceptually different origin . in particular , in all the cases we checked here , @xmath23 and @xmath27 contribute with opposite signs to their respective entanglement entropies , as implied by the conventions we used in eq . and eq .. we will show that , when the logarithmic terms in the entanglement entropy cancel , the finite terms @xmath23 are universal and are determined not only by the central charge but also by the restrictions on the states imposed by the compactification conditions . furthermore , the form of the result for the entanglement entropy of eq . implies a connection with boundary cft , as developed by cardy.@xcite thus , in addition of it being determined by the central charge @xmath14 , it must also depend on the operator content of the cft . for the same reason , the structure of eq . also suggests a direct connection between this problem and the affleck - ludwig boundary entropy of 1d quantum cfts . @xcite the paper is organized as follows . in section [ sec : qdm ] we apply this approach first to the simpler case of the quantum lifshitz model ( and the related quantum dimer models , qdms ) on planar , cylindrical and toroidal geometries . these results apply to the qcps of ( generalized ) quantum dimer model on bipartite lattices @xcite and in quantum eight - vertex models@xcite . through explicit calculations for various geometries , we show that that , when the logarithmic terms in the entanglement entropy cancel , and that the subleading finite terms @xmath23 are universal , determined not only by the central charge but also by the restrictions imposed by the compactification conditions . in section [ sec : generalizedqcps ] we generalize this result to all 2d conformal qcps whose scale - invariant wave functions have norms that are the partition functions of 2d euclidean rational cfts ( rcft ) , cfts with a finite number of primary fields@xcite . more specifically , we show that the finite term in the entanglement entropy of the 2d wave function is determined by the change of the affleck - ludwig boundary entropy of the 1d cft a quantity determined by the modular @xmath29-matrix of the associated cft and by the coefficients in the fusion rules . we also discuss specific examples of this class including 2d quantum loop models @xcite which , with the naive inner product , are known to be quantum critical . @xcite we also briefly discess the quantum net models.@xcite in section [ sec : conclusions ] we conclude with a summary and a discussion on open questions . in particular , we comment on the implications of our results to the nature of related topological phases . the quantum lifshitz model@xcite ( qlm ) in two space dimensions is defined by the following hamiltonian with an arbitrary paramter @xmath32 : @xmath33 , \label{eq : qlm}\ ] ] where @xmath34 is a scalar field @xmath35 is its canonical momentum conjugate to @xmath34 . the qlm hamiltonian eq . defines a class of qcp s with dynamic critical exponent @xmath36 , and a continuous parameter @xmath32 . this remarkable property of the model is evident in the exactly known wave function for the ground state @xmath37 which is a superposition of all field configurations @xmath38 with the configuration dependent weight@xcite : @xmath39 = \langle[\phi]|gs\rangle=\frac{1}{\sqrt{z } } e^{\displaystyle{-s[\phi]/2 } } , \label{eq : psi0qlm}\ ] ] with @xmath40=\int d^2x \ ; \frac{k}{4\pi } \left({\vec \nabla } \phi(x)\right)^2 \label{eq : sofphi}\ ] ] and the norm squared of the state @xmath41}}. \label{eq : norm}\ ] ] notice @xmath42 is identical to the partition function for the gaussian model , which defines free boson euclidean cft@xcite , albeit with the `` stiffness '' @xmath32 . hence eq . defines an infinite class of 2d conformal qcp s all associated with free boson cfts . the qlm can be viewed low energy effective field theory capturing universal aspects of various microscopic lattice models with @xmath34 playing the role of coarse grained height field@xcite with the `` stiffness '' @xmath32 determined by the appropriate `` microscopic '' coupling constants@xcite . for such a mapping to work , the constraints of the lattice models should be build in through compactification of the boson field @xmath34 by demanding all physical operators to be invariant under the shift of @xmath43 or equivalently all physical operators to take the form of vertex operators @xmath44 for integer @xmath45 . in subsection [ subsec : micro ] we will discuss specific examples of this mapping corresponding to particular values of @xmath32 using the convention of fixing @xmath46 . the examples will include so - called rokhsar - kivelson point ( rk ) of the quantum dimer model@xcite and its generalizations @xcite and the _ quantum _ eight - vertex model@xcite special choices of the baxter weight@xcite . since @xmath32 can be varied in the qlm , this theory has an exactly _ marginal _ operator , resulting in continuously varying critical exponents ( scaling dimensions ) of the allowed ( vertex ) operators.@xcite to investigate the universal finite terms in the entanglement entropy at 2d conformal qcps , we will rely on the approach described in the work of fradkin and moore.@xcite they showed that @xmath47 , where @xmath4 is the ( normalized ) reduced density matrix of a region @xmath1 , with @xmath20 separated by the boundary @xmath48 , for the ground state @xmath49 on @xmath50 , is given by @xmath51 here @xmath52 is the partition function of @xmath45 copies of the equivalent 2d classical statistical mechanical system satisfying the constraint that their degrees of freedom are identified on the boundary @xmath48 , and @xmath53 is the partition function for @xmath45 decoupled systems . the partition functions on the r.h.s of eq . are @xmath54 with support on region @xmath1 and @xmath55 with support in region @xmath2 , both satisfying generalized dirichlet ( _ i.e. _ fixed ) boundary conditions on @xmath48 of @xmath1 and @xmath2 , and @xmath56 is the norm squared for the full system . the entanglement entropy @xmath29 is then obtained by an analytic continuation in @xmath45 , @xmath57 hence , the computation of the entanglement entropy is reduced to the computation of a ratio of partition functions in a 2d classical statistical mechanical problem , an euclidean cft in the case of a critical wave function , each satisfying specific boundary conditions . in order to construct @xmath47 , we need an expression for the matrix elements of the reduced density matrix @xmath58 . since the ground state wave function eqs . and is a local function of the field @xmath59 , a general matrix element of the reduced density matrix is a trace of the density matrix of the pure state @xmath60 $ ] over the degrees of freedom of the `` unobserved '' region @xmath2 , denoted by @xmath61 . hence the matrix elements of @xmath4 take the form @xmath62 \,\ , e^{\displaystyle{-\left(\frac{1}{2 } s^{a}(\phi^{a } ) + \frac{1}{2 } s^{a}({\phi^\prime}^a ) + s^b(\phi^b)\right ) } } , \nonumber \\ & & \end{aligned}\ ] ] where the degrees of freedom satisfy the _ boundary condition _ at the common boundary @xmath48 : @xmath63 proceeding with the computation of @xmath64 , it is immediate to see that the matrix product requires the condition @xmath65 for @xmath66 , and @xmath67 from the trace condition . hence , @xmath68 takes the form @xmath69 _ subject to the boundary condition @xmath70 _ of eq .. notice that the numerator , @xmath52 is the partition function on @xmath45 systems whose degrees of freedom are identified in @xmath48 but are otherwise independent . also notice the absence of the factors of @xmath71 in the exponentials of eq .. the other important consideration is that the compactification condition requires that two fields that differ by @xmath72 be equivalent . hence , the boundary condition of eq . is defined _ modulo @xmath72_. ( equivalently , the proper form of the degrees of freedom is @xmath73 . ) this means that one can alternatively define @xmath52 as a partition function for @xmath45 systems which are decoupled _ in the bulk _ but have a boundary coupling of the form ( in the limit @xmath74 , which enforces the boundary condition ) @xmath75 here the fields @xmath76 extend over the entire region @xmath50 . thus , this problem maps onto a boundary cft for a system with @xmath45 `` replicas '' coupled only through the boundary condition on the closed contour @xmath48 , the boundary between the @xmath1 and @xmath2 regions . for the special case of the free scalar field , one can simplify this further by taking linear combinations of the replica fields . then the condition that the scalar fields @xmath77 agree with each other on @xmath48 can be satisfied by forming @xmath78 relative coordinates @xmath79 ( @xmath80 ) that vanish ( _ mod _ @xmath72 ) on @xmath48 , and one `` center of mass coordinate '' field @xmath81 that is unaffected by the boundary @xmath48 ( reflecting the fact that nothing physical takes place at @xmath48 ) . hence , the computation of @xmath47 reduces to the product of two partition functions : 1 . the partition function for the `` center of mass '' field @xmath34 ; since @xmath34 does not see the boundary @xmath48 , this is just the partition function @xmath82 for a single field in the entire system . 2 . the partition function for the @xmath78 fields @xmath83 which are independent from each other and vanish ( _ mod _ @xmath72 on @xmath48 . we denote this by @xmath84 . however , the fields @xmath83 on the @xmath1 and @xmath2 regions are effectively decoupled from each other . hence , this partition function further factorizes to @xmath85 , where @xmath86 and @xmath87 are the partition functions for a single field @xmath34 on @xmath1 and @xmath2 respectively , satisfying in each case dirichlet ( fixed ) boundary conditions ( _ mod _ @xmath72 ) at their common boundary @xmath48 . thus , we can write the trace @xmath47 as @xmath88 here the denominator factor , @xmath89 comes from the normalization factors , and represents the partition function over the entire system . the entanglement entropy is then@xcite @xmath90 which , as indicated in the r.h.s of eq . reduces to the computation of the free energies @xmath91 , @xmath92 and @xmath93 , for the equivalent 2d euclidean cft on regions @xmath1 and @xmath2 , each satisfying dirichlet ( fixed ) boundary conditions on the common boundary @xmath48 , and on the full system , @xmath50 , respectively . the behavior of the free energy of a cft as a function of the system size @xmath11 has been studied in detail . the divergent terms , as @xmath94 , have the form@xcite @xmath95 provided the boundary @xmath48 is smooth ( and differentiable ) . here , @xmath96 and @xmath97 are two non - universal quantities , and @xmath15 is the short - distance cutoff ; @xmath14 and @xmath18 are , respectively , the central charge of the cft and the euler characteristic of the manifold . it follows from this result that the entanglement entropy for region @xmath1 takes the form@xcite @xmath98 provided the boundary @xmath48 is smooth . in all the geometries we discuss , the change in the euler characteristic vanishes , @xmath99 , and there is no logarithmic term . however we will show below that , if the logarithmic terms cancel , there exist a universal finite @xmath100 term , as well as other universal dependences on the geometry ( such as aspect ratios ) . we will now extract these universal finite terms . here we calculate @xmath23 at qcps of the qlm universality class defined by eq . for three different geometries : ( i ) a cylindrical geometry , ( ii ) a toroidal geometry , and ( iii ) a disk geometry . for the cylinder and disk we assume the dirichlet boundary conditions at the open ends . we use the known results on the free boson partition function for different topologies and boundary conditions@xcite , which are necessary for the calculation of entanglement entropy . it is useful to note that the action eq . for general value of the `` stiffness '' k turns into the standard form : @xmath101= \frac{1}{8\pi } \int d^2x \ ; \left(\partial_\mu \varphi \right)^2 , \label{eq : rescaling}\ ] ] upon a rescaling of the field @xmath102 . if @xmath34 is compactified with radius @xmath46 , the rescaled field @xmath103 has an effective compactification radius @xmath104 . we find @xmath23 to depend linearly on @xmath105 in all cases we consider . let us begin by considering first a system on a long cylinder of linear size @xmath106 and circumference @xmath11 with @xmath107 . region @xmath1 to be observed , is a cylinder of length @xmath108 and circumference @xmath11 . the complement region , @xmath2 , is a cylinder of length @xmath109 ( see fig.[fig : cylinder ] ) , also with circumference @xmath11 . we assume that the qlm wave function eq . and hence the associated 2d partition function eq . obey the dirichlet boundary conditions at both ends of the cylinder , @xmath50 . from eq . , the entanglement entropy @xmath110 is given by @xmath111 here @xmath112 is the partition function of eq . for a boson with compactification radius @xmath113 on cylinder of length @xmath106 and circumference @xmath11 with dirichlet boundary conditions on both ends , which is well known:@xcite @xmath114 where @xmath115 is the effective compactification radius ( as before ) , and @xmath116 is a non - universal regularization - dependent prefactor , responsible for the area and perimeter dependent terms in the free energy shown in eq .. ( there are no logarithmic terms for a cylinder or a torus as their euler characteristic @xmath18 vanishes . ) in eq . @xmath117 is the modular parameter , encoding the geometry of the cylinder , and @xmath118 . the elliptic theta - function @xmath119 and the dedekind eta - function @xmath120 are given by @xmath121 the important feature of eq . is the factor @xmath122 , the contribution of the winding modes of the compactified boson on the cylinder with dirichlet boundary conditions . putting it all together , it is straightforward to find an expression for the entanglement entropy using eq .. in general , the entanglement entropy depends on the geometry ( _ e.g. _ the aspect ratios @xmath123 ) of the cylinders , encoded in ratios of theta and eta functions . however , in the limit @xmath124 , in which the length of the cylinders are long compared to their circumference , the entanglement entropy given by eq . and . takes a simple form @xmath125 where @xmath7 is a non - universal constant that depending on the regularization - dependent pre - factor @xmath116 of eq .. hence , there is a @xmath126 universal contribution to the entanglement entropy @xmath127 for the cylinderical geometry . the explicit dependence of @xmath23 on the effective effective compactification radius @xmath128 shows that it is determined by the winding modes of the compactified boson and thus it is a universal quantity determined by the topology of the surface . in particular we find that the universal piece of the entanglement entropy , @xmath23 , for a compactified boson is a continuous function of the radius @xmath113 , a consequence of the existence of an exactly marginal operator at this qcp . we find the similar relations for all topologies we considered . we will come back to this point in section [ subsec : micro ] , in the context of several microscopic models of interest . we now consider the case in which the full system @xmath0 is a torus for which the real part of the modulus @xmath129 , as shown in fig.[fig : torus ] . the two subsystems , @xmath1 and @xmath2 are now two cylinders , of length @xmath108 and @xmath109 respectively ( @xmath130 ) , both with the same circumference @xmath11 . we will thus need the partition function on a torus and on two cylinders ( with both ends of the cylinders obeying dirichlet boundary conditions . ) the trace @xmath47 now becomes @xmath131 the partition functions for the two cylinders , @xmath1 and @xmath2 has the form of eq . . the partition function for the torus is@xcite @xmath132 where @xmath133 is the partition function on a cylinder of length @xmath134 and circumference @xmath11 , with neumann boundary conditions at both ends : @xmath135 where @xmath117 and @xmath136 . in the limit @xmath137 and @xmath138 , the entanglement entropy for the toroidal geometry is @xmath139 hence , for the toroidal geometry , the universal term is @xmath140 . in eq . @xmath7 is , once again , a non - universal factor which depends on both the short distance regularization and boundary conditions ( in fact , it is not equal to the constant we also called `` @xmath7 '' in the entanglement entropy for the case of the cylinder , eq .. ) as was the case for the cylindrical geometry , in the case of the torus @xmath23 is also determined by the contribution of the zero modes of the compactified boson to the partition functions . thus , here too , @xmath23 depends on the effective boson radius @xmath128 . however , the different values of @xmath23 in eq . and eq . is due to the fact that on the torus all three partition functions have contributions from the zero modes . finally , we compute the entanglement entropy for the disk geometry , shown in fig.[fig : disk ] . the line of argument used above applies here as well . this is the case discussed in ref . [ ] , where it was found that the logarithmic term in the entanglement entropy cancels exactly if the boundary @xmath48 is smooth . here we compute the ( subleading ) finite universal piece . to compute the entanglement entropy we need to compute three partition functions , on the two disks @xmath1 and @xmath50 , and on the annulus @xmath2 , all with dirichlet boundary conditions . these partition functions were computed in the literature long ago for an uncompactified boson.@xcite they can be obtained from the partition functions on cylinders , with dirichlet - dirichlet ( for the annulus ) and dirichlet - neumann ( for the disks ) boundary conditions by a conformal mapping @xmath141 , from the @xmath142 complex plane to the cylinder ( labeled by @xmath143 ) . the partition function for the annulus ( region @xmath2 ) of inner circumference @xmath11 and outer circumference @xmath106 ( with dirichlet boundary conditions ) is @xmath144 except for the factor of @xmath145 , which is due to the zero modes of the compactified boson , this result agrees with those of ref . [ ] . in eq . we have used @xmath146 ( with the modular parameter @xmath147 ) . similarly , the partition functions on the two disks , regions @xmath1 and @xmath0 , are conformally mapped to two infinitely long cylinders ( as the uv cutoff @xmath148 ) with neumann - dirichlet boundary conditions . these partition functions are @xmath149 where @xmath150 for regions @xmath1 and @xmath50 , respectively , and @xmath31 is their corresponding modular parameter ; @xmath151 is the elliptic theta - function @xmath152 the resulting entanglement entropy for the planar ( disk ) geometry is found to be @xmath153 + \ln r. \label{eq : sdisk}\ ] ] hence , for the case of the disk there is also a universal finite piece in the entanglement entropy , @xmath154 . as in the cases discussed above ( the cylinder and the torus ) , here too @xmath23 has a topological origin as it is due to the winding modes of the compactified boson . however , unlike the case of the of the cylinder and toroidal geometries , in the case of the disk there is also a dependence on the aspect ratio @xmath123 ( the double logarithmic term ) , as already noted in ref . ( note that we included the factor of @xmath155 in the double logarithm since it arises from the conformal mapping . ) the results on the entanglement entropy of the preceding subsections apply to several `` microscopic '' systems of interest . the simplest of them is the quantum dimer model on bipartite lattices at the rk point ( associated with the rk wave function of the qdm ) . as noted in ref . [ ] , the rk point of the qdm maps onto the quantum lifshitz model for a particular value of the radius @xmath46 and stiffness @xmath156 ( in the notation used here . ) this corresponds to a 2d euclidean boson cft at the free fermion radius . of course , this is not an accident , since in this case the lattice partition functions can also be computed exactly by pfaffian methods , @xcite and hence it is a free dirac fermion system . generalized quantum dimer models have been discussed recently.@xcite in these models the wave functions correspond to dimer models with weights that depend on the number of dimer pairs on the plaquettes . for a considerable range of values of these weights the system remains critical and can also be mapped onto a quantum lifshitz model , albeit with a different stiffness connected with the presence of an exactly marginal operator . thus , in these models the stiffness varies continuously as a function of the microscopic weights . this dependence , discussed in detail in ref . [ ] , is of course non - universal , as it depends on the microscopic structure of the system . nevertheless , the critical exponents have a universal dependence on the stiffness . the same applies to the universal piece of the entanglement entropy @xmath23 , which can be read - off from the results presented in this section . similarly , the _ quantum _ eight - vertex model wave function@xcite also maps onto a free fermion problem for a special choice of weights.@xcite for general values of @xmath32 the fermions are interacting ( see the discussion below ) but the effects only enter through an exactly marginal operator . the mapping of the quantum 2d eight - vertex model to the quantum lifshitz model was shown in detail in ref . [ ] where the relation between the stiffness @xmath32 of the compactified boson and the baxter weights is given explicitly . @xmath32 and the weight @xmath14 in the baxter wave function ( along the six vertex line ) are related by @xmath157 for a boson with compactification radius @xmath46 or , equivalent , an effective radius @xmath128 . the results of the preceding subsections on the entanglement entropy for the quantum lifshitz model apply to the lattice models almost without change . once the mapping of the stiffness to the microscopic parameters ( as in the case of the quantum eight vertex model ) is known , the universal piece , @xmath23 , can be read - off immediately . the only caveat here is that in lattice models it is impossible to have closed simply connected regions with smooth boundaries . the resulting paths of the effective coarse grained quantum lifshitz model will always have singularities , such as corners , which contribute with a logarithmic dependence to the entanglement entropy ( as discussed in ref . [ ] ) rendering the finite terms generally non - universal . the cylinder and torus geometries are exceptional in this sense , and allow for a direct check of these ideas in microscopic models , either through an exact solution or by means of numerical computations . we end this discussion by giving the results for the universal entanglement entropies @xmath23 for the lifshitz universality class at the free fermion ( or dimer ) and kosterlitz - thouless transition of the dimer and baxter ( six vertex ) wave functions for all three geometries . ( see the summary of table [ table : entropies ] . ) at the `` free dimer '' point ( the free fermion point of the dimer models ) the stiffness @xmath156 ( corresponding to @xmath158 in the baxter wave function ) , and the universal term of the entanglement entropy for a disk geometry is @xmath159 . for the cylinder , also at the free dimer point , we also found @xmath160 , while for the torus we obtained @xmath161 . ( below we will discuss the relation of these results with the _ topological _ entanglement entropy of the nearby @xmath162 topological phase . ) away from the free dimer ( or fermion ) points , the stiffness @xmath32 changes and so does the entanglement entropy . thus , at the kosterlitz - thouless transition point of both the dimer and six vertex wave functions ( where the baxter weight is @xmath163 ) , the stiffness is @xmath164 . ( at this point the associated @xmath165 cft has an @xmath166 kac - moody current algebra , and the effective compactification radius here is @xmath167 . ) the ( finite ) entanglement entropies now are @xmath168 , @xmath169 , and @xmath170 . 2 ( rk point ) & 2 & 2 2 & 2 + ( kt point ) & & 0 & + the only caveat in applying the calculation of @xmath23 in the qlm to microscopic models is that is impossible to have closed simply connected regions with smooth boundaries on a lattice . hence the resulting paths of the effective coarse grained qlm will always have singularities ( such as corners ) which contribute a finite logarithmic dependence to the entanglement entropy . @xcite the cylinder and torus geometries are exceptional in this sense , and allow for a direct check of these ideas in microscopic models , either through an exact solution or by means of numerical computations . we now generalize the application of eq . to the computation of the entanglement entropy to more general case of conformal qcps , specifically those associated whose wave functions have an associated 2d euclidean rcft ( a cft with a finite number of primary fields . ) the ground state wave function for a conformal quantum critical point can be expressed as gibbs weight associated with a 2d euclidean cft : @xmath39=\frac{1}{\sqrt{z } } e^{\displaystyle{-s[\phi]/2}}\ ] ] as in the case of the qlm discussed in the previous section . hence there is a one - to - one mapping between the norm square of the wave function and the partition function of a local 2d euclidean cft , and also between the equal - time correlators of the operators of the 2d conformal qcp map onto and the correlators of primary fields of the 2d euclidean cft . furthermore , we will also assume that the associated euclidean cft is _ unitary _ ( the @xmath29-matrix to be defined below is unitary ) and that it is a _ rcft_. the restriction to unitary rcft allows us to exploit well developed technology for this large class of cfts@xcite , especially that of operator product expansion ( ope ) and of _ modular s - martirx _ , in calculation of @xmath23 . the behavior of rcfts with specified boundary conditions ( especially their partition functions ) , is the subject of boundary conformal field theory , and was discussed extensively by cardy@xcite . we will follow the approach and results of cardy in this section . we also need to specify the boundary conditions at the ends of the cylinder , _ i.e. _ the _ boundary states _ of the boundary cft.@xcite let us denote these conformal boundary conditions by @xmath171 . the associated ( conformally invariant ) boundary states @xmath172 and @xmath173 can be constructed for each cft . on the other hand , at the common boundary @xmath48 between the regions @xmath1 and @xmath2 , all @xmath78 fields must obey fixed ( ` dirichlet ' ) boundary conditions . as shown by cardy,@xcite this boundary condition is quite generally given by the boundary state @xmath174 in the conformal block of the identity @xmath175 . for simplicity , we will consider here only the geometries of a cylinder ( with specific boundary conditions at each end ) and a torus . . we will need to compute the free energies of region @xmath1 , @xmath2 and @xmath50 with fixed boundary conditions . the partition function for a rcft on a cylinder of length @xmath106 and circumference @xmath11 , with boundary conditions @xmath15 and @xmath176 on the left and right ends respectively , @xmath177 , can be expressed in terms of the characters @xmath178 of the rcft : @xmath179 where the integers @xmath180 are the fusion constants , the coefficients in the ope of the rcft , @xmath181 the virasoro characters @xmath182 are given by the trace over the descendants @xmath183 of the highest weight state , which are obtained by acting on it with the virasoro generators @xmath184 ( @xmath185 ) : @xmath186 where @xmath14 is the central charge of the cft , @xmath187 is the @xmath188 virasoro generator . here the modular parameter is @xmath189 . under a modular transformation @xmath190 , which exchanges the euclidean `` space '' and `` time '' dimensions of the cylinder ( _ i.e. _ it flips the cylinder from the `` horizontal '' to the `` vertical '' position ) , the characters transform as @xmath191 where @xmath192 is the _ modular @xmath29-matrix _ of the rcft . the modular @xmath29-matrix and the fusion coefficients are related by the verlinde formula @xcite @xmath193 the limit of interest here is , once again , @xmath107 . under a modular transformation , the partition function of eq . becomes @xmath194 in the limit @xmath195 , @xmath177 is dominated by the the descendants of the identity @xmath196 ( up to exponentially small corrections ) . hence , in this limit , @xmath197 and @xmath198 becomes @xmath199 dropping uv singular ( non - universal ) terms . the quantity @xmath200 in eq . is the _ boundary entropy _ of a boundary rcft introduced by affleck and ludwig@xcite , where the `` ground state degeneracy '' @xmath201 is given by @xmath202 using eq . , these standard results imply that the entanglement entropy of the 2d rational conformal qcp for a cylindrical geometry(see fig.[fig : cylinder ] ) . for boundary conditions @xmath15 and @xmath176 at the two ends associated with regions @xmath1 and @xmath2 , the entanglement entropy is @xmath203 where we explicitly used the fact that the state at the common boundary @xmath48 should be fixed to be the _ fixed _ bc with boundary state @xmath174 . the result eq . provides an explicit way to compute @xmath23 for the entire class of many - body wave functions at qcps associated with rcft in terms of the data of the rcft : @xmath204 this is the main result of this section . it shows that @xmath23 is in general determined by the ope coefficients @xmath205 ( which encode the boundary conditions on the partition functions ) and by the modular @xmath29-matrix , @xmath206 , of the rcft associated with the _ norm squared of the many - body wave function _ at the given qcp . it is important to note that it is also possible to define a unitary @xmath29-matrix that governs the transformation properties of the _ wave function _ itself under a modular transformation . this modular @xmath29-matrix plays a central role in 2d topological phases and in topological field theories.@xcite however , only for topological theories these are two @xmath29-matrices are the same and in general they are different or not even defined at all . we will come back to this issue in the discussion section . a particularly simple result is obtained for the case of a cylinder with fixed boundary conditions on both ends . in this case , @xmath207 , @xmath208 and @xmath82 are cylinders with fixed boundary conditions , and hence the boundary states for all three cases are in the conformal block of the identity @xmath175 . since in this case the only non - vanishing ope coefficient is @xmath209 , the universal term of the entanglement entropy , @xmath23 , depends only on the element @xmath210 of the modular @xmath29-matrix of the rcft : @xmath211 for the case in which the full region@xmath50 is a torus , we can use an analogue of eq . by writing the partition function @xmath82 in the denominator of eq . as a modular invariant . in the limit of interest @xmath107 , the denominator @xmath201 of eq . is replaced by a sum of terms with similar structure corresponding to a sum over boundary conditions ( and twists ) needed to represent the torus ( see , for instance , ref . [ ] ) . similarly , eq . can also be applied to the disk geometry upon a conformal mapping as it was done for the case of the compactified boson in section [ subsec : disk ] . we will now discuss some examples of interest . in applying the results eq . to specific systems , one should keep in mind that that choice of the inner product of the 2d quantum theory can play a subtle role . as it was pointed out recently by fendley@xcite , a scale invariant wave function does not necessarily imply scale invariance of the correlators . their actual behavior depends also on the choice of inner product . here we have assumed that the states labeled by the set of field configurations @xmath38 form an orthogonal basis . hence , the norm of the wave function is a sum over states with the local weights squared . however what matters is that the _ matrix elements _ ( and in particular the norm of the states ) be scale - invariant . a number of interesting counterexamples are known.@xcite the qlm is a special case where such `` naive '' inner product maintains scale invariance . this is due to the existence of exactly marginal operators in the qlm . below we discuss four cases where the ground state wave function with the `` naive '' inner product describes qcps : ( i ) a qcp associated with the 2d ising cft , ( ii ) the qcps associated with compactified boson cft , ( iii ) qcps in quantum loop models@xcite , and ( iv ) quantum net models@xcite . ( see footnote ref . [ ] . ) as an example of a system described by an rcft we consider a 2d quantum spin system whose ground state wave function has for amplitudes the gibbs weights of the 2d classical ising model . this system is quantum critical if the square of the weights ( which also have the form of a gibbs weight for the 3d ising model ) are at the critical point of the 2d ising model , the onsager value . the critical point of the 2d ising model is the simplest rcft . it has central charge @xmath212 , and three ( bulk ) primary fields : 1 ) the identity ( @xmath196 , with conformal weight @xmath213 ) , 2 ) the energy density ( @xmath214 , with conformal weight @xmath215 ) , and 3 ) the spin field ( @xmath97 , with conformal weight @xmath216 ) , which obey the operator algebra ( ope ) @xmath217 the critical ising model has three possible boundary states:@xcite 1 ) the _ spin up _ state @xmath218 , 2 ) the _ spin down _ state @xmath219 , and 3 ) the _ free _ state @xmath220 . ( either the up or the down state can be regarded as the fixed boundary state . ) these three boundary states , @xmath218 , @xmath219 , and @xmath220 are in the conformal blocks of the identity @xmath175 ( denoted by @xmath221 ) , the energy density @xmath214 ( denoted by @xmath222 , and the spin field @xmath97 ( denoted by @xmath223 ) , respectively . the boundary states are given by@xcite @xmath224{2}}\ket{\sigma}\nonumber\\ \ket{-}&\equiv&\ket{\tilde { \frac{1}{2}}}=\frac{1}{\sqrt{2 } } \ket{0}+\frac{1}{\sqrt{2}}\ket{\varepsilon}- \frac{1}{\sqrt[4]{2}}\ket{\sigma}\nonumber\\ \ket{f}&\equiv&\ket{\tilde{\frac{1}{16}}}= \ket{0}-\ket{\varepsilon}.\nonumber\\ & & \label{eq : boundary - states - ising}\end{aligned}\ ] ] the modular @xmath29-matrix is @xmath225 where the columns are labeled by the highest weights @xmath226 , @xmath71 , and @xmath216 , in that order . the entanglement entropy for this wave function can now be computed , using the result of eq .. we will take region @xmath50 to be a long cylinder of length @xmath106 and circumference @xmath11 , and regions @xmath1 and @xmath2 to be two cylinders of lengths @xmath108 and @xmath109 respectively , with the same circumference @xmath11 , and with @xmath130 . let us take the boundary conditions at both ends of @xmath50 to be free . by a conformal mapping , this maps onto the disk . back on the cylinder , the free boundary condition is described by the boundary state @xmath220 , which is in the conformal block of the primary field @xmath97 . on the other hand , at the boundary @xmath48 between regions @xmath1 and @xmath2 , we have the fixed boundary condition , the up state @xmath218 we readily find @xmath227 the universal term of the entanglement entropy , @xmath23 now is @xmath228 on the other hand , we could consider instead the case of fixed boundary conditions at both ends of the cylinder @xmath50 . this corresponds to the boundary state @xmath221 . since the boundary condition on @xmath48 is always fixed , @xmath23 is now @xmath229 in the case where @xmath50 is torus of large circumference @xmath106 and small circumference @xmath11 ( hence with modular parameter @xmath230 ) , the regions @xmath1 and @xmath2 are cylinders each of length @xmath108 and @xmath109 and circumference @xmath11 , with fixed boundary conditions at both ends . the partition function for the torus , @xmath231 , is@xcite @xmath232 using the modular invariance of @xmath42 on the torus ( @xmath30 ) , one finds that in the limit @xmath233 , @xmath234 . hence , in the case of the torus , @xmath23 is @xmath235 we can also use this approach to compute the entanglement entropy for the compactified boson wave function ( the quantum lifshitz state ) discussed in the previous section . however , unlike the explicit computation of the boson determinant presented in the previous section , a computation that can be done for any compactification radius @xmath113 , the boundary cft approach we are using in this section only applies for a rational cft . this restricts the compactification radius to be such that @xmath236 is a rational number . ( the general case can be regarded as a limit . ) it is now straightforward to compute the entanglement entropy using eq .. for this case we find @xmath237 , consistent with the results of the preceding section . quantum loop models are two - dimensional quantum systems whose hilbert space is spanned by states labelled by loop configurations ( or coverings ) of a two - dimensional lattice . we will denote by @xmath238 the set of these configurations . conventionally , this set of states are taken to be a basis of the loop hilbert space , and hence they are assumed to be linearly independent , complete and orthonormal , ( with respect to the naively defined inner product . ) quantum loop models were originally proposed as candidates for time - reversal invariant topological phases . @xcite wave functions in the hilbert space of ( multi ) loop configurations have the form @xmath239 } d^{n[\mathcal{l } ] } \ket{\mathcal{l}}. \label{eq : loop - zd}\ ] ] here @xmath240 $ ] is the number of loops in state ( configuration ) @xmath241 , @xmath242 $ ] is the length of loop in the configuration , @xmath243 is the `` loop fugacity '' , and @xmath244 is the weight ( fugacity ) of a unit length of loop . the candidate wave functions of a quantum loop model in a putative topological phase depends on the loop configuration but not on the length of the loops . the simplest such state is the `` @xmath243-isotopy '' ( multi ) loop wave function @xcite @xmath245 } \ket{\mathcal{l } } \label{eq : loop - d}\ ] ] obtained from @xmath246 by setting the fugacity of the unit length of loop @xmath247 . this is a generalization of kitaev s `` toric code '' wave function@xcite ( @xmath248 ) , _ i.e. _ a @xmath162 gauge theory deep in its deconfined phase in @xmath249 dimensions . another limit of interest is the `` fully packed '' state @xmath250}d^{n[\mathcal{l } ] } \ket{\mathcal{l } } \label{eq : loop - infty - d}\ ] ] obtained by setting @xmath251 , which forces the constraint that the loops cover the maximal allowable set of links on the lattice . with the naively defined inner product , the norm squared of the @xmath243-isotopy state @xmath252 , eq . , is @xmath253 } , \label{eq : zd}\ ] ] which is the same as the partition function of a 2d classical loop model on the same lattice , with a weight @xmath254 per loop . likewise , the norm squared of the fully packed loop state @xmath255 is the partition function @xmath256 of the classical fully packed loop model , with fugacity @xmath254 , on the same lattice . the partition functions of classical loop models on a 2d lattice have been studied extensively , particularly on the honeycomb lattice ( for a detailed review see refs . [ ] . ) in the fully packed limit , the partition function @xmath256 is critical for @xmath257 . the universality classes of the fully packed loop models ( on the honeycomb lattice ) are rational _ unitary _ cfts only for @xmath248 ( the @xmath166 rcft ) and @xmath258 ( the @xmath259 rcft ) . for finite @xmath244 , the partition function for the dense loop gas @xmath260 is also critical for @xmath257 . the universality classes are again rational unitary cfts only for @xmath248 and @xmath258 . the fixed point for the case @xmath248 is equivalent to the statistics of the proliferated domain walls of the classical 2d ising model at infinite temperature.@xcite for @xmath258 the dense and dilute loop gases have the same critical theory , the kosterlitz - thouless critical point , and hence also the @xmath166 rcft . we can now use the result in eqs . and to compute the universal term of the entanglement entropy for the loop wave functions with @xmath261 , on a cylinder with fixed boundary conditions ( for the loops ) . the modular @xmath29-matrices are known,@xcite and the needed @xmath210 matrix elements are @xmath262 , for @xmath166 and @xmath259 , respectively . the universal term @xmath23 of the entanglement entropy for each case is @xmath263 for the fully packed state at @xmath248 ( and also for the loop gas at @xmath258 ) , the fully packed loop state at @xmath258 , and the dense loop gas at @xmath248 ( corresponding to the kitaev state ) , respectively . here we have used a recent result on the behavior of of the dense loop model by cardy@xcite who showed ( among many other things ) that for @xmath248 the partition function of the dense loop model on the cylinder @xmath264 . we will see in the discussion section that this _ negative _ value , @xmath265 , coincides with the direct computation of the _ topological _ entanglement entropy in the kitaev wave function.@xcite finally , we will briefly discuss the more interesting , but less understood problem of the wave functions for _ quantum net models_@xcite . these states were proposed as candidates for a time - reversal invariant non - abelian topological phase . the hilbert space of quantum net models is spanned by the coverings of a lattice by configurations of nets , _ i.e. _ branching loops ( with trivalent vertices ) . an interesting example is the chromatic polynomial state.@xcite in this state , the nets are regarded as a configuration of domain walls of a @xmath266-state potts model . the weight of a given state @xmath267 is the chromatic polynomial @xmath268 $ ] of the configuration . the chromatic polynomial counts the number of ways of coloring regions of the lattice separated by domain walls of a @xmath266-state 2d potts model . they were first introduced in the computation of the low temperature expansion for the 2d potts models ( see , for instance , ref . [ ] . ) for non - integer @xmath266 , the chromatic polynomial can be computed by an iterative procedure.@xcite the 2d potts model is known to have a critical point for @xmath269 . following ref . [ ] , we consider the norm of the chromatic polynomial state with @xmath269 . in order to compute the norm , we have to square the weight , resulting in a partition function involving the sum of the _ square _ of the chromatic polynomial . it is then natural to ask for a value of @xmath266 such that @xmath270 \propto \chi_{q_{{\rm eff}}}[\mathcal{l}]$ ] , for some @xmath271 . then the nets will be critical provided @xmath272 . it turns out@xcite that , up to a suitably chosen fugacity for trivalent vertices@xcite , this property holds only for @xmath273 , the _ golden ratio _ , with @xmath274 . thus , for this state the nets are critical . this case is interesting for several reasons . one is that strong arguments@xcite suggest that it is possible to define for this wave function an excitation ( a defect ) which is denoted by @xmath31 , a fibonacci anyon ( not to be confused with the modular parameter ! ) with the fusion rule , @xmath275 . fibonacci anyons are of prime interest in the topological approach to quantum computation.@xcite however , for this approach to work it is necessary that this state should describe a topological state , which requires that its local excitations ( not the nets ) be gapped . fendley@xcite has recently given strong arguments that imply that this state , with the naive inner product we use here , is not topological but a quantum critical state . another feature that makes this state interesting is that the correlations encoded in the norm of the state for @xmath273 are described by a rcft , the minimal model of the friedan - qiu - shenker@xcite series of unitary rcfts at level @xmath276 , with central charge @xmath277 . this minimal model has a large number of primaries ( 36 ) and has not been studied in detail . nevertheless , its modular @xmath29-matrix is known ( as it is for the entire series@xcite ) . although to the best of our knowledge the boundary cft of this minimal model has not been investigated , we conjecture that the boundary state corresponding to the fixed boundary condition is the analog of the state @xmath278 in the 2d critical ising model ( the @xmath279 member of the same series . ) , _ i.e. _ the state in the conformal block of the identity.@xcite thus , if we consider this state on a cylinder with fixed boundary conditions , the entanglement entropy for observing only half of the system , has a universal term @xmath23 of the form given in eq . , and hence is given in terms of the @xmath210 element of the modular @xmath29-matrix of this rcft:@xcite @xmath280 we have shown that at 2d conformal qcps ( with dynamical exponent @xmath36 ) , the entanglement entropy for a region with a smooth boundary quite generally has universal finite contributions which we denoted by @xmath23 : @xmath281 we studied the universal nature of @xmath23 with two complementary approaches for large classes of 2d conformal qcps : first for the qlm universality class , we calculated @xmath23 explicitly in terms of the partition functions ( that of compactified boson ) associated with the norm squared of the wave function . later we used known results from boundary cft to show that @xmath23 is determined by the detailed structure of the associated rcft encoded in the modular @xmath29-matrix and the ope fusion coefficients for the primary fields . we also applied this general results to compute @xmath23 in several systems of interest : the quantum lifshitz model , the generalized quantum dimer and quantum eight - vertex models , and quantum loop and net models . however , we showed ( c.f . that for a general conformal quantum critical point , whose ground state wave function is given by the gibbs weights of a euclidean rational unitary cft , the universal term @xmath23 is determined by the modular @xmath29-matrix associated with the norm squared of the wave function . thus , the modular @xmath29-matrix of the topological phase and that of the wave functions of 2d conformal quantum critical points have a conceptually different origin . we note that while our result for the entanglement entropy has the _ same form _ as the entanglement entropy for a _ topological phase _ , @xcite the finite universal terms @xmath23 and @xmath27 have a different origin and structure . in the case of a topological phase , @xmath27 is in general determined by the modular @xmath29-matrix of the topological field theory of the topological phase , and it is given in terms of topological invariants of the effective topological field theory that describes this phase.@xcite this modular @xmath29-matrix governs the transformation properties of the ground state within the degenerate ground state hilbert space of the topological phase under modular transformations on a torus : @xmath30 , where @xmath31 is the modular parameter of the torus@xcite . on the other hand , for 2d conformal qcps whose ground state wave function is given by the gibbs weights of a euclidean rational unitary cft , the universal term @xmath23 is determined by the modular @xmath29-matrix associated with the norm squared of the wave function and the @xmath29-matrix connects between different boundary conditions . hence the roles of the modular @xmath29-matrix in the computation of the universal @xmath126 terms to the entanglement entropy have conceptually different origin . moreover , @xmath23 and @xmath282 enter with opposite signs in their contributions to their respective entanglement entropies . in fact , in all the cases we looked at we found that @xmath283 , except for the kitaev state which is topological , and we recovered the known result . ( it is unclear to us how general this difference actually is and , more importantly , if it has a deeper meaning . ) in any case , the fact that the entanglement entropy has the universal form of eq . has led to the widespread assumption that this scaling is a signature of a topological phase . however we have shown here that this is not necessarily the case as this scaling is also obeyed at conformal quantum critical points in 2d . it is also interesting to note the striking similarity of the structure of eq . ( with its dependence on the @xmath29-matrix and the fusion rules ) with the results of fendley , fisher and nayak@xcite for the change in the entanglement entropy of a 2d topological fluid , a fractional quantum hall state , by the action of a point contact . recently , refs . [ ] found finite universal terms in the entanglement entropy for @xmath10 dimensional cfts with a similar structure to what we found here in 2d conformal qcps . calculations of quantum fidelity in 1d also find a similar structure.@xcite recent work by li and haldane@xcite also raises the interesting possibility of computing the entanglement spectrum for a theory with a wave function described by a known cft , but this is beyond the scope of this paper . finally , given the close connection between the universal piece of the entanglement entropy @xmath23 and the affleck - ludwig entropy of the associated 2d classical partition functions it is interesting to inquire if @xmath23 may flow under some perturbation . clearly this can not happen under the action of a _ boundary perturbation _ ( as in the affleck - ludwig case ) as that would require one to make a physical change of the wave function on the boundary @xmath48 , rather than a measurement . however , it is interesting to consider instead how the entanglement entropy ( and in particular the finite term @xmath23 ) would evolve as one perturbed the ( bulk ) system either by a finite non - zero temperature into the quantum critical regime , or by a relevant operator that drives the system into a nearby topologically ordered phase that can be accessed by local perturbations @xcite and to investigate possible connections with rcft.@xcite we thank john cardy , paul fendley , greg moore , and joel moore for their comments and suggestions . bh and mm thank the les houches summer school for its hospitality . the work of ef and bh was supported by the national science foundation grant no . dmr 0758462 and dmr 0442537 at the university of illinois . mm was supported by the stanford institute for theoretical physics , the nsf under grant phy-0244728 , the doe under contract de - ac03 - 76sf00515 , and the arcs foundation . eak was supported by the stanford institute for theoretical physics during a part of this work .

we study the scaling behavior of the entanglement entropy of two dimensional conformal quantum critical systems , _ i.e. _ systems with scale invariant wave functions . they include two - dimensional generalized quantum dimer models on bipartite lattices and quantum loop models , as well as the quantum lifshitz model and related gauge theories . we show that , under quite general conditions , the entanglement entropy of a large and simply connected sub - system of an infinite system with a smooth boundary has a universal finite contribution , as well as scale - invariant terms for special geometries . the universal finite contribution to the entanglement entropy is computable in terms of the properties of the conformal structure of the wave function of these quantum critical systems . the calculation of the universal term reduces to a problem in boundary conformal field theory .

this habit can occur during the day and night and it can be conscious or non conscious . the prevalence of bruxism has a wide range because of difficult diagnosis of this parafunctional habit and different methodologies . the etiology of bruxism is multifactorial and the studies concerning this matter could n't gain exact results . however , the discussed causes of bruxism include : local and mechanical factors , systemic factors , neurologic factors , psychological factors and genetics factors . the most common clinical sign of bruxism is abnormal wear of teeth which is caused by periodic clenching or condensation of teeth . other side effects of bruxism are tooth hypermobility , recession and inflammation of the gums , pain and hypertrophy of maseteric muscles , degenerative changes of temporomandibular joint and headache[3 , 5 ] . alert parents ask dentists and physicians about tooth grinding of their children as well as the side effects of it and also how to stop this habit . the aim of this investigation was to determine the prevalence of the bruxism and its etiologic factors to make some helping recommendations to the parents . the awareness of parents about bruxism and its side effects make them keen to contribute in recall sessions ; on the other hand , dentists and physicians will be able to recognize etiologic factors to eliminate them . this cross - sectional descriptive study was done on 600 4 - 12 year old children , who were referred to four dental schools of tehran in 2007 - 2008 . after acquiring the parents informed consent , the questionnaire included two sections : the first part contained the information about the age , sequence of birth , medical history and also parents age , education , and job . the second part was questions related to the time of bruxism during the day or night , manifestation of distressing events in the family ( such as parental divorce , birth of new baby , start going to school or death of child 's loved one ) , family history of bruxism , temporomandibular joint disorder , parasomnias , oral habits ( nail biting , pacifier sucking and lip or thumb sucking ) and psychological disorders . temporomandibular joint disorders were considered as jaw clicking , pain or tenderness in muscles and limitation in mouth opening . items related to psychological disorders include irritability , seclusion , sadness , neophobia , crying easily , gazing at one point , hyperactivity , obsession , depression , acrophobia or lygophobia and finally parasomnias items include drooling , sleep talking , sleep walking , mouth breathing and snoring . after collecting information with the questionnaire filled out by parents , the analysis of data to determine the prevalence of bruxism and the percentage of contributing factors in children with or without bruxism was done , and the results of these 2 groups were compared . , fisher test , mann - whitney and t - test were used to analyze the data . our sample was comprised of 600 children , 314 boys ( 52.3% ) and 284 girls ( 47.7% ) , with the mean age of 7.42.4 years . based on parent 's report , 157 ( 26.2% ) children showed bruxism as a parafunctional habit . there was no significant relation between the gender , the sequence of birth , father 's age , and parent 's education and father 's job with the prevalence of bruxism ( table 1 ) . distributaion of frequency of the gender , the sequence of birth and parent 's education and their correlation with bruxism the prevalence of bruxism was 28.7% in full time mothers , 18.9% in employed and 9.1% in self - employed mothers . the analysis of data showed significant difference between the job condition of mothers and the prevalence of bruxism ; the prevalence of bruxism in children with full time mothers was higher ( p=0.03 ) . also 7.8% of children had fathers with bruxism history , 6.8% mothers with bruxism history and 1.3% of children had both parents bruxism history . the analysis of data showed a significant correlation between the family history of bruxism and the prevalence of it ( p<0.001 ) , which the prevalence of bruxism was 20.8% in children without family history of bruxism , 51.1% in children with fathers history of bruxism , 51.2% in children with mothers history of bruxism and 87.5% in children with both parents history of bruxism ( table 2 ) . distribution of frequency of family history of bruxism , distresing events and their correlation with bruxism according to parent 's report , 7.6% of children had a history of distressing events in their life , whereas 87% of children with bruxism had a history of distressing events in their life , and 13% of children with bruxism did n't report any history of distressing events in their life . parasomnias were stated by parents in 53.2% of children , drooling being the most ( 25.8% ) , and snoring the least ( 4.5% ) . bruxism was seen in 35.1% of children with parasomnias and merely in 16% of subjects without any sleep disorders . there was a significant difference between these 2 groups , and there was a correlation between drooling , sleep walking and bruxism ( p<0.001 ) . frequency of parasomnias and their correlation with bruxism temporomandibular disorder oral habits were reported in 18.8% of children . thirty - four ( 30.1% ) of children with oral habits demonstrated bruxism , while this was observed in 25.3% of other children ; however this was statically not significant ( p=0.3 ) . in the study of tmd , the frequency of joint click was 1.2% , facial muscles pain 0.7% , limitation of opening the mouth 2% , and pain during opening the mouth 0.7% . the prevalence of bruxism in children with tmd was 63.6% and in children without tmd 24.7% ; the difference was significant ( p<0.001 ) . based on our study there was no significant relationship between the history of asthma and allergy or systemic disease with bruxism ( table 3 ) . in our study psychological disorders , i.e. irritability ( 47.2% ) , crying easily ( 38.7% ) and hyperactivity ( 19.8% ) were the most frequent ones . there was a significant relationship between depression , acrophobia and lygophobia with the prevalence of bruxism ( table 4 ) . in the present study conducted on 600 children with an average age of 7.42.4 years , the prevalence of bruxism was 26.2% . cheifetz declared the prevalence of bruxism in children under 17 years old 38% based on parent 's reports while liu et al stated that bruxism occurred in 6.5% of 2 - 12 year - old chinese children . also chen and coworkers reported the prevalence of bruxism in 3 - 6 year- old chinese children 36.4% . reding reported the prevalence of bruxism in 3 - 17 year - old american children 15.1% . these differences in the prevalence of bruxism are because of difficult diagnosis of bruxism , various methods in collecting data and also diverse samples from different racial origins . in the present study the beginning age of bruxism was 4.92 years . but cheifetz et al reported the beginning age of bruxism to be 3.6 years and also showed that there was a male predilection in acquiring bruxism but they gave no explanation for this . in our study there was no significant correlation between age , parent 's education and father 's job with the prevalence of bruxism in children and these results were the same as laberge and cheifetz studies[12 , 7 ] . but in this study the difference in the prevalence of bruxism in full time mothers and working mothers was significant which may be to more attention of full time mothers , because they spend more time with their children . one of the etiologic factors assessed in the present study was the occurrence of distressing events in the child 's life and its relationship with the prevalence of bruxism , which was not mentioned in any other study till now . one of these events was divorce of parents , separation of one of the parents for any reason , death of the loved one of the child , birth of a new child , the beginning of kinder care or school , watching terrifying movies , etc . bruxism occurred 2.6 times more in children who had a family history of bruxism ( father - mother ) , compared to children who did not have such a history . the results of our study regarding this matter are in agreement with cheiftez et al . these researchers stated if either parent had a history of bruxism the chance of demonstrating bruxism by their children will be 1.8 times more . 25.8% of children had drooling and 3.2% of children had sleepwalking which showed a direct relationship with bruxism . weidman et al also showed a significant relation between bruxism and parasomnias and declared that children who had drooling or talking during sleep had more chance to get bruxism . this is in agreement with cheifetz et al study , although in their research , drooling was 33% and sleep talking 16% . they expressed that in children who had drooling and sleep talking the bruxism was observed 1.7 and 1.6 times respectively more than in other children . kato et al also confirmed this relationship and explained that bruxism causes to provisionally increase drooling to lubricate the esophagus and oral cavity , thus it is logical to expel the excess of saliva , consequently drooling is more reported in these children . in our study the most common ( 12.5% ) oral habit was nail biting , which was reported 33.37% in bosnyak study , 48% in egermark study , 51% in farsi study and 55% in weideman study . all of these investigations showed a far more prevalence compared to our results but in their studies nail biting had the most frequency . in contrast to our study cheifetz et al declared that the children with bruxism revealed less oral habits but widmalm reported that the bruxism is seen along with other oral habits such as thumb sucking and only in 3.4% of subjects existed without oral habit . in the present study 3.7% of children had tmd . this result was similar to those of widmalm , restrepo and winocur but cheifetz found no significant relationship between tmd and bruxism . in our study there was no relation between asthma and allergy with bruxism , which was similar to cheifetz et al . in contrast to our result weideman et al declared that the children with bruxism were even healthier than other children . marks also showed that there was an association between bruxism , headache and allergy . in the study of psychologic disorders of children , hyperactivity , depression , acrophobia and lygophobia revealed a significant relation with bruxism . cheifetz and agargun also confirm the relation between bruxism and psychologic disorders , also the relation between hyperactivity and bruxism . furthermore , our result regarding depression was similar tothat o manfredini . in this descriptive study we were encountered with limitations such as the credibility and reliability of the parent 's answers to the questionnaire . based on parent 's report , the prevalence of bruxism in 4 - 12 old children was 26.2% and the average age for beginning of bruxism was 4.92 years . in the study of etiologic factors there was a significant relation between bruxism and mother 's job , family history , distressing event in life , parasomnias specially drooling and sleep walking , tmd , hyperactivity , depression , acrophobia and lygophobia .

objectivebruxism is defined as the habitual nonfunctional forceful contact between occlusal tooth surfaces . the aim of this study was to determine the prevalence of bruxism and correlated factors in children referred to dental schools of tehran , based on parent 's report.methodsthis cross - sectional descriptive study was conducted on 600 4 - 12 year - old children with a mean age of 7.42.4 years , who were referred to four dental schools in tehran . after collecting information with questionnaire filled out by parents , 2 , fisher test , mann - whitney and t - test were used to analyze the data.findingsthe prevalence of bruxism was 26.2% . bruxism begun in average at the age of 4.92 years . also it occurred 2.6 times more in children who had a family history of bruxism ( father - mother ) , compared to children who did n't have such a history . 87% of children with bruxism had a history of distressing events in their life , and 13% of children with bruxism did not report any history of distressing events in their life . in this study most common oral habit was nail biting . in study of parasomnias , drooling was the most , and snoring the least reported sleep disorder . bruxism in children with drooling was twice more than in other children . the prevalence of bruxism in children with temporomandibular disorder was 63.6% and in children without tmd was 24.7%.conclusionbased on parent 's report , 26.2% of children showed bruxism and there was a significant relation between bruxism and mother 's job , family history , distressing event in life , parasomnias , especially drooling and sleep walking , tmd , hyperactivity , depression , acrophobia and lygophobia .

road traffic injury ( rti ) as a major public health problem is the ninth leading cause of death globally . it is even more alarming that it is mostly the young population and poor and vulnerable road users who are the main victims . over 1.2 million people die each year from road injuries and between 20 and 50 million suffer non - fatal injuries , which themselves are an important cause of disability . the south - east asia and western pacific regions accounted two - thirds of deaths due to rtis in the world . in addition , cases of rtis are increasing in most of the regions of the world . research into rtis indicates that there are distinct differences in the pattern of economic growth between high - income countries ( hic ) and low - middle - income countries ( lmic ) . rtis affect all age groups , but it is mostly young people who are affected . the global losses related to rtis are estimated to be 518 billion united states dollars ( usd ) and cost governments between 1% and 3% of their gross domestic product ( gdp ) - more than the total amount of these countries receive in development assistance per year . the increase in rtis world - wide also has a considerable impact on the economies of many countries , particularly in low income countries ( lic ) and middle income countries ( mic ) that are frequently struggling with other development needs . lic and mic , despite having only 48% of the world 's registered vehicles have higher road traffic fatality rates of more than 90% . rtis can place a heavy burden on the family and friends of the injured person , many of whom also experience adverse social , physical and psychological short - term or long - term effects . risk factors for rtis were widely explored literatures . general risk factors of rtis include the increasing number of motor vehicles , social deprivation , demographic factors , insufficient transport planning , land use and road networks . individual risk factors contributing to rti could be young males , excess speed , alcohol consumption , medicinal or recreational drugs , fatigue , road - user 's poor eyesight . circumstance factors were classified as travelling in darkness , vehicle factors , defective road design and inadequate visibility due to environmental factors . the factors , which with special influence upon the severity of rtis include the lack of vehicle crash protection , lack of roadside protection , non - use of protective devices in vehicles ( for example , seat - belts and air bags ) , non - use of helmets , inappropriate speed and alcohol intake . rtis put a huge strain on health - care services in terms of financial resources , hospital bed occupancy and the demand placed on health professionals . people of lower social - economic status were reported to have the highest risk for rtis . individual local level studies in several countries have tried to highlight the economic burden of rti . however , the global economic burden of rti at the country level is not well explored . the important macro factors like death due to rti and health system factors , like health expenditure , may have relationships with disability - adjusted life year ( daly ) . no study has tried to explore the relationship between economic loss of rti and health system factors . the aim of the current study is to estimate the potential economic burden of rtis at the global level . we have tried to estimate the economic loss of rtis and related issues according to countries income levels . the top 25 countries with greatest daly and economic loss due to dalys of rti are presented . we have also tried to explore the relationship between economic loss of rti and health system variables . country level data of mortality , rtis , socio - economic and health - care system variables are used from the world bank and the world health organization ( who ) websites . there were fourteen variables of three different types consisting of ( i ) dependent and independent variables as ( ii ) macroeconomic and ( iii ) health system variables [ table 1 ] . the independent variables are divided into two groups : macroeconomic factors and health system factors . dependent variables and independent variables in three aspects the unit for total expenditures on health is purchasing power parity ( ppp ) , which can adjust differences in price levels among countries . this meant that total expenditures on health measured by ppp were comparable within different countries . we delimited income groups based on the definition of the world bank into four categories according to the 2009 gross national product ( gnp ) per capita : lic $ 765 or less , lmic $ 766 - 3035 , upper middle income countries ( umic ) $ 3036 - 9385 and hic $ 9386 or higher ( world bank , country income levels ) . data is missing for three countries : nauru , niue and the former yugoslav republic of macedonia . it is the sum of years of life lost ( yll ) due to premature mortality in the population and the years lost due ( yld ) to disability for incident cases of the disease or injury ( daly = yll + yld ) . daly focuses more on the time lost due to premature death and the time spent as disabled by disease or injury and therefore it is an appropriate measurement method for rtis . daly data were obtained from the who global burden of disease estimates for 2004 for each of the who member states . gdp is the monetary value of all goods and services produced within a country in a financial year , without deductions for depreciation of fabricated assets or for the depletion and degradation of natural resources . gdp is the sum of all consumer spending ( c ) , governmental spending ( g ) , businesses spending on capital ( i ) and national net exports ( nx ) , i.e. , gdp = c + g + i + nx . gdp per capita is the country 's gdp divided by the mid - year population . gdp per capita and economic loss in this study are expressed in usd , 2005 . therefore , economic loss due to rti has been calculated as the multiplication of daly and gdp per capita . in the present study , arithmetic means with standard deviations were used to compare the differences within four income groups . correlations between economic loss associated with rti and all independent variables were used to test the bivariate relations . based on the result of the correlations , rti deaths , total expenditure on health and nurse density were used to build up the linear regression model . the aim of the linear regression analysis was to analyze the relationship between the economic losses associated with rtis and the selected health system factors . country level data of mortality , rtis , socio - economic and health - care system variables are used from the world bank and the world health organization ( who ) websites . there were fourteen variables of three different types consisting of ( i ) dependent and independent variables as ( ii ) macroeconomic and ( iii ) health system variables [ table 1 ] . the independent variables are divided into two groups : macroeconomic factors and health system factors . dependent variables and independent variables in three aspects the unit for total expenditures on health is purchasing power parity ( ppp ) , which can adjust differences in price levels among countries . this meant that total expenditures on health measured by ppp were comparable within different countries . we delimited income groups based on the definition of the world bank into four categories according to the 2009 gross national product ( gnp ) per capita : lic $ 765 or less , lmic $ 766 - 3035 , upper middle income countries ( umic ) $ 3036 - 9385 and hic $ 9386 or higher ( world bank , country income levels ) . data is missing for three countries : nauru , niue and the former yugoslav republic of macedonia . it is the sum of years of life lost ( yll ) due to premature mortality in the population and the years lost due ( yld ) to disability for incident cases of the disease or injury ( daly = yll + yld ) . daly focuses more on the time lost due to premature death and the time spent as disabled by disease or injury and therefore it is an appropriate measurement method for rtis . daly data were obtained from the who global burden of disease estimates for 2004 for each of the who member states . gdp is the monetary value of all goods and services produced within a country in a financial year , without deductions for depreciation of fabricated assets or for the depletion and degradation of natural resources . gdp is the sum of all consumer spending ( c ) , governmental spending ( g ) , businesses spending on capital ( i ) and national net exports ( nx ) , i.e. , gdp = c + g + i + nx . gdp per capita is the country 's gdp divided by the mid - year population . gdp per capita and economic loss in this study are expressed in usd , 2005 . therefore , economic loss due to rti has been calculated as the multiplication of daly and gdp per capita . arithmetic means with standard deviations were used to compare the differences within four income groups . correlations between economic loss associated with rti and all independent variables were used to test the bivariate relations . based on the result of the correlations , rti deaths , total expenditure on health and nurse density were used to build up the linear regression model . the aim of the linear regression analysis was to analyze the relationship between the economic losses associated with rtis and the selected health system factors . in the year 2004 , 1,224,750 people died from rtis , with a dalys loss of 40,738,000 years . the republic of moldova has the lowest percentage ( 0.015% ) and nepal has the highest percentage ( 6.30% ) of gdp loss due to rti according to the health system factors , the mean of physician density , nurse density and hospital beds are 16 , 36 and 32/10,000 populations , respectively . both dalys and death reflect the decreasing trend from umic to hic and increasing trend from lic to lmic . the economic loss due to dalys of rti was almost 33 times greater in hic compared with lic . mean of variables based on different income groups the top 25 countries with the greatest number of dalys loss due to rtis and their economic loss according to world - wide rank and percentage of economic loss of gdp are presented in table 3 . china has the highest amount of daly loss , accounting for 8,192,000 ( usd ) while the united states of america shows the greatest financial loss at 53 billion dollars . top 25 countries with greatest number of dalys lost to road traffic injuries and estimated economic value of dalys table 4 illustrates the results of the correlations between estimated economic values of dalys loss caused by rtis and other variables . rti death , gdp , number of cars , vehicles per thousand , passenger car per thousand , expenditure on health and nurse density were show significant positive correlations with economic loss , which means as the amounts of the variables increased , economic loss due to rtis also increase ( p < 0.05 ) . death and gdp express the significant relationship with economic loss in four income groups . in the cases of the other variables , the associations varied . correlations between estimated economic values of dalys loss to rtis and other variables * the results of the regressions between estimated economic values of dalys loss due to rtis and health system factors are shown in table 5 . the model employed for all the countries representing 39.4% of the cases is significant ( f < 0.001 ) , which relates significantly with death , health expenditure and nurse density ( p < 0.01 ) . . in lic , death and expenditure on health have significant coefficient with economic loss of rtis ( p < 0.01 ) . in lower and umic only death furthermore , death and expenditure on health are correlated significantly in hic ( p < 0.01 ) . both dalys and death reflect the decreasing trend from umic to hic and increasing trend from lic to lmic . the economic loss due to dalys of rti was almost 33 times greater in hic compared with lic . the top 25 countries with the greatest number of dalys loss due to rtis and their economic loss according to world - wide rank and percentage of economic loss of gdp are presented in table 3 . china has the highest amount of daly loss , accounting for 8,192,000 ( usd ) while the united states of america shows the greatest financial loss at 53 billion dollars . top 25 countries with greatest number of dalys lost to road traffic injuries and estimated economic value of dalys table 4 illustrates the results of the correlations between estimated economic values of dalys loss caused by rtis and other variables . rti death , gdp , number of cars , vehicles per thousand , passenger car per thousand , expenditure on health and nurse density were show significant positive correlations with economic loss , which means as the amounts of the variables increased , economic loss due to rtis also increase ( p < 0.05 ) . death and gdp express the significant relationship with economic loss in four income groups . in the cases of the other variables , the associations varied . the results of the regressions between estimated economic values of dalys loss due to rtis and health system factors are shown in table 5 . the model employed for all the countries representing 39.4% of the cases is significant ( f < 0.001 ) , which relates significantly with death , health expenditure and nurse density ( p < 0.01 ) . all the models based on different income groups are significant ( f < 0.01 ) . in lic , death and expenditure on health have significant coefficient with economic loss of rtis ( p < 0.01 ) . in lower and umic only death is significantly associated ( p < 0.001 ) . furthermore , death and expenditure on health are correlated significantly in hic ( p < 0.01 ) . from an overall perspective , the results of the current study show that rti is a serious public health issue with a great number of deaths and a large loss of dalys , especially in lic and mic . because of rtis , countries are losing up to 6% of their gdp . geographically , most of the rtis occurred in south - east asia , which has the highest number of deaths and daly losses . found that 96% of deaths among children in rtis occur in lmic , which would explain the greater disability adjusted life years ( dalys ) in these countries . another reason for lmic having greatest death and daly could be the large population in these countries , for example , in china and india . according to the prevention report of rti from who , it was predicted that south asia would have the largest growth in road traffic mortality during 2000 and 2020 , perhaps because of the high numbers of two - wheeled and three - wheeled vehicles . there are some reasons why we develop a standard measurement to estimate the economic loss of rtis through dalys loss . the top five countries with the greatest dalys of rtis accounted for 5% of the total daly loss . these countries were china , india , indonesia , the russian federation and the usa . on the other hand , if we compare the cost of rtis at the country level - there are great variations between countries . the top five countries , in relation to economic loss of rti , constitute more than half ( 51.56% ) of the total economic loss of rti in the world . secondly , there are both underestimations and overestimations of the cost of rtis within countries . the reporters from the who suggested that the costs in lic and mic may be significantly underestimated . although the who data represent the best available at present , they have various limitations . if we compare individual country - based studies the results may be significantly different . for example , blincoe et al . estimated the human capital cost of rtis in usa to be usd 230 billion while the current study estimated the cost as being usd 53.252 billion . the amount is over four times higher than the estimated cost calculated in the current study . both direct and indirect costs per year of the rtis in europe were likely exceed 207 billion usd through the comprehensive data and measurement techniques . thirdly , available studies have estimated the economic loss of rtis in different ways using different methods of costing . in industrialized countries , the overall cost of rtis were estimated with reference to : cost of injuries and fatalities sustained in the accidents , the cost of damage to property and administrative costs ( for instance , legal expenditure and insurance ) as well as the value of transportation problems caused by crashes . considering the vast infrastructural , economic and demographic differences , the countries have significant differences in their manner of systems for reporting deaths and economic factors . that is a major reason for the plethora of materials of rtis and related issues in hic instead of lic and mic ; though , the burdens of rti deaths are opposite . blincoe 's study also found that almost 75% of the rtis costs were paid for by society ( through , for example , insurance premiums , taxes and travel delays ) . this mean , some economic losses related to rtis are covered by governments for the relevant public policies . fourthly , this study has attempted to induce further discussion about the need for in - depth economic analyses of the global burden of rtis . an american study advocated that daly is the available common metrics to qualify the public health burden . therefore by using a standard method throughout the world , the current study has estimated the economic loss due to rtis , which may give a standard platform for comparison purposes and which could help inform future policy issues . most importantly , the current study has focused on the issue of rtis world - wide in the financial context . china and india have the highest dalys and also ( almost ) highest economic loss due to rtis . as we have observed that the top 25 countries of rti dalys and rti economic loss are mostly different . therefore , economic losses due to rtis were the biggest economic burden in the hic . in the study by jacobs et al . , the percentages of gnp in relation to economic loss for rtis increases from low to hic , similar to current findings , which calculated the cost via gdp . furthermore , in the present study , we analyzed the correlation between economic loss of rtis and related factors . globally , as the number of cars , vehicles and passenger car per 1000 population , total health expenditure and nurse density increase , the economic losses increase . the relationship between economic loss due to rtis and health system factors has demonstrated statistically significant associations at the global level . from the linear regression result , when we control the other factors , increasing nurse density would contribute to the reduction of economic losses due to rtis . thus , policy makers could build up rti prevention and intervention programs , focusing on increasing the number and skills of nurses . this study shows that lic and mic have limited resources in health - care since they have less health expenditure , physician density , nurse density and fewer hospital beds . a review focusing on lic and mic pointed out that in surgical wards 48% of beds were occupied by rti patients , who accounted for the most use of operating theatres and intensive care units in some countries . many studies propose that medical care and technology improvement can contribute to the reduction of road traffic fatalities in industrialized countries . according to spanish research , primary health - care would be an optimal arena in which to promote rti prevention and intervention . all the studies show the need for comprehensive construction of and investment in healthcare systems in lic and mic . this is the first study that calculates the economic loss due to rtis at a global level using a standard method and also compares them by income groups . the monetary aspect of rtis could be used by governments when deciding public health policies . moreover , the study tries to determine the relationship between economic losses due to rtis and health system factors , which could also be useful in the development of injury prevention strategies . this provides further strength for the argument that prevention works also from the economic point of view . however , there are some limitations in this study . also , extreme data inside each income group have made the standard deviation bigger than the mean . the high level of dispersion of the country level data may prevent the significant association as reflected in the standard deviations . however if we drop the extreme data , which means we do not consider that country , so we include the extreme data in this study . because of the underreported death or injury of road traffic , there may be some underestimated governmental data relying on police reports , especially in the lic . bhalla suggested that instead of police reports , the country - specific patchwork of alternate data sources including death registers , hospital records , funeral records , injury surveillance studies and health surveys would be more completed estimated and representative . the current study reveals the challenges arise in estimating the economic loss of rtis at the country level due to variation of death rate , population size , per capita income and national income . country level studies using national statistics generally use information from near about years as it is difficult to receive information for the same year . to get statistics for the maximum number of countries the current study has used daly from 2004 , gdp from 2005 and other macroeconomic and health system variable from 2008 . however , considering the macroeconomic nature and health system variables we can assume that there were no overall significant changes in the country statistics . therefore , the current study has tried to provide an overall relationship and results for the world , instead of individual country . it is worthwhile to note here that the economic loss of rtis due to disability , yld may differ from that for yll due to premature mortality . unlike those lost their lives due to rtis , persons who are disabled as a result of rtis may affect the national economies significantly . therefore , the estimation of economic loss of rtis in the current study might over - or under - estimate the actual economic loss of rtis . however in the absence of other common measures of burden of disease and injuries at the global level , daly is the most appropriate measure , which provides the best available measure of economic loss of rtis . recently , the international responses to rti prevention of world health organization comprise seat belt and helmet promotion , speed management , drinking refraining and so on . there are many measures could change the road traffic death rate over time , such as , highway safety policies and intervention , road user type distribution and demographics . who structured a report about strategies for rtis prevention to guide the rti intervention programs . most hic have stronger road traffic policies and higher use of strategies expressed to be effective at reducing rtis , including seat belt use , traffic law enforcement ( e.g. , motorcycle helmet laws , blood alcohol content laws ) and traffic calming intervention . unfortunately , to the lic and mic , the reduction for traffic injury were not reported an improvement , which increase the necessary to explore the economic cost and relevant factors of rtis to structure appropriate interventions in these countries . because of the high burden of rtis in south east asia , the specific risk factors research and prevention is exigent required in this area . recently , the international responses to rti prevention of world health organization comprise seat belt and helmet promotion , speed management , drinking refraining and so on . there are many measures could change the road traffic death rate over time , such as , highway safety policies and intervention , road user type distribution and demographics . who structured a report about strategies for rtis prevention to guide the rti intervention programs . most hic have stronger road traffic policies and higher use of strategies expressed to be effective at reducing rtis , including seat belt use , traffic law enforcement ( e.g. , motorcycle helmet laws , blood alcohol content laws ) and traffic calming intervention . unfortunately , to the lic and mic , the reduction for traffic injury were not reported an improvement , which increase the necessary to explore the economic cost and relevant factors of rtis to structure appropriate interventions in these countries . because of the high burden of rtis in south east asia , the specific risk factors research and prevention is exigent required in this area . rtis cause enormous death and daly loss in lmic and tremendous economic loss in hic . south east asia with the greatest number of death and daly loss the regression model suggests that increasing nurse density could decrease the economic loss of rtis . so the rtis prevention in the health - care system can put more effort on increasing the number and skills of nurse . the study illustrates the necessary to have further and depth research of the economic burden due to rtis world - wide and more investigations about the relationship of the health system factors and rtis burdens . and

background : to estimate the economic loss due to road traffic injuries ( rtis ) of the world health organization ( who ) member countries and to explore the relationship between the economic loss and relevant health system factors.methods:data from the world bank and the who were applied to set up the databases . disability - adjusted life year ( daly ) and gross domestic product per capita were used to estimate the economic loss relating to rtis . regression analysis was used . data were analyzed by ibm spss statistics , versions 20.0.results:in 2005 , the total economic loss of rtis was estimated to be 167,752.4 million united states dollars . high income countries ( hic ) showed the greatest economic losses . the majority ( 96% ) of the top 25 countries with the greatest daly losses are low and middle income countries while 48% of the top 25 countries with the highest economic losses are hic . the linear regression model indicates an inverse relationship between nurse density in the health system and economic loss due to rti.conclusions:rtis cause enormous death and dalys loss in low - middle income countries and enormous economic loss in hic . more road traffic prevention programs should be promoted in these areas to reduce both incidence and economic burden of rtis .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Federal Travel Transparency Act''. SEC. 2. DISCLOSURE OF INFORMATION REGARDING TRAVEL BY CERTAIN SENIOR OFFICIALS. (a) In General.--Section 5707 of title 5, United States Code, is amended by adding at the end the following: ``(d) Additional Disclosure of Information Regarding Travel by Certain Senior Officials.-- ``(1) Definitions.--In this subsection-- ``(A) the term `Administrator' means the Administrator of General Services; ``(B) the term `covered individual' means-- ``(i) the head of an Executive agency; or ``(ii) an individual serving in a position at level I or II of the Executive Schedule under section 5312 or 5313, respectively; ``(C) the term `machine-readable form' means a format in which information or data can be easily processed by a computer without human intervention while ensuring no semantic meaning is lost; ``(D) the term `open format' means a technical format based on an underlying open standard that is-- ``(i) not encumbered by restrictions that would impede use or reuse; and ``(ii) based on an underlying open standard that is maintained by a standards organization; and ``(E) the term `travel information website' means the website used by the Administrator to make available information under paragraph (2)(B)(i). ``(2) Public availability of travel information for covered individuals.-- ``(A) Reporting.--Not later than 30 business days after the end of each calendar quarter, each Executive agency employing 1 or more covered individuals who performed official travel during the calendar quarter shall submit to the Administrator data in machine- readable form and open format regarding the travel by each such covered individual during the calendar quarter on a commercial aircraft, privately-owned aircraft, or Government-owned or Government-leased aircraft, which shall include-- ``(i) the duration of the travel; ``(ii) the destination or destinations of the travel; ``(iii) the individuals in the travel party; ``(iv) the justification for the travel; ``(v) the authorizing official who approved the travel; and ``(vi) the total cost to the Government for-- ``(I) the travel as a whole; ``(II) transportation during the travel; and ``(III) lodging accommodations during the travel. ``(B) Public availability.-- ``(i) In general.--The Administrator shall make available online to the public, at no cost to access, the information provided by Executive agencies to the Administrator under subparagraph (A). ``(ii) National security information.-- ``(I) In general.--An Executive agency may exclude national security sensitive travel information from the travel information submitted to the Administrator if the Executive agency determines public online disclosure of the national security sensitive travel information would result in harm to national security interests. ``(II) Justification.--Each Executive agency shall establish and preserve an accurate record documenting each instance in which the Executive agency excluded national security sensitive travel information from submission, as authorized in subclause (I), which shall include information explaining how public online disclosure of the national security sensitive travel information would have resulted in harm to national security interests. ``(C) Use of existing resources.--To the maximum extent practicable, the Administrator shall use a website in existence on the date of enactment of this subsection to carry out this subsection. ``(3) Requirements.--Not later than 30 business days after the date on which the Administrator receives information from an Executive agency regarding travel by a covered individual under paragraph (2)(A), the Administrator shall make the information available on the travel information website. ``(4) Classified trips.-- ``(A) In general.--Nothing in this subsection shall preclude an Executive agency from excluding from the information submitted to the Administrator information regarding classified travel. ``(B) Maintaining of information.--An Executive agency shall maintain information relating to classified travel by a covered employee until the end of the 2-year period beginning on the date on which the classified travel concludes. ``(5) Auditing.--The Inspector General of each Executive agency may, as determined appropriate by the Inspector General-- ``(A) conduct and publish an audit of the accuracy and completeness of information the Executive agency provides to the Administrator under paragraph (2)(A); ``(B) conduct an audit of determinations by the Executive agency to exclude information under paragraph (2)(B)(ii) to ensure each such decision was appropriate and justified in regard to protecting national security interests from harm that would have resulted from public online disclosure; and ``(C) provide each committee of Congress with jurisdiction over the activities of or appropriations for the Executive agency with written notification if the Inspector General determines that the Executive agency is improperly withholding, or failed to justify the withholding of, information from the Administrator under paragraph (2)(B)(ii).''. (b) Relation to Other Reporting Requirements.--Nothing in the amendment made by subsection (a) shall be construed to modify or supercede the reporting requirements under the Federal Travel Regulation (including the requirements relating to the Senior Federal Travel report, or any successor thereto) or under any other provision of law.

Federal Travel Transparency Act This bill requires a federal executive agency to report additional information to the General Services Administration (GSA) regarding travel by the agency head or certain high-level officials compensated on the Executive Schedule. The GSA must make the information publicly available on a travel information website.

in this paper we begin the systematic study of legendrian graphs in @xmath6 with the standard contact structure . these are embedded graphs that are everywhere tangent to the contact planes . legendrian graphs have appeared naturally in several important contexts in the study of contact manifolds . they are used in giroux s proof of existence of open book decompositions compatible with a given contact structure , see @xcite . legendrian graphs also appear in the proof of eliashberg s and fraser s result which says that in a tight contact structure the unknot is determined up to legendrian isotopy by the invariants @xmath7 and @xmath8 , see @xcite . yet no study of legendrian graphs , until now , has been undertaken . we remedy this by establishing the foundations for what we expect will be a very rich field . a _ spatial graph _ is an embedding of a graph into @xmath9 an _ abstract graph _ is a set of vertices together with a set of edges between them , without any specified embedding . we will throughout this paper refer to an abstract graph as simply a graph . in section [ graphs ] , we show there is no obstruction to having a legendrian realization of any spatial graph . we extend the classical invariants thurston - bennequin number , @xmath7 , and rotation number , @xmath8 , from legendrian knots to legendrian graphs . in @xcite , mohnke proved that the borromean rings and the whithead link can not be represented by legendrian links of _ trivial unknots _ , that is unknots with @xmath1 and @xmath2 . the trivial unknot is the one unknot among all unknots that attains the maximal thurston - bennequin number of its topological class . as an application of our invariants , we ask which graphs admit legendrian embeddings with all cycles trivial unknots . in section [ maxtb ] , we give a full characterization of these graphs , in the form of the following : a graph @xmath10 admits a legendrian embedding in @xmath0 with all its cycles trivial unknots if and only if @xmath10 does not contain @xmath3 as a minor . the proof of this theorem relies partly on the fact that the trivial unknot has an odd thurston - bennequin number , that is @xmath1 . we prove the reverse implication in more generality , for @xmath11 which represents the set of topological knot classes with odd maximal thurston - bennequin number . let @xmath10 be a graph that contains @xmath3 as a minor . there does not exist a legendrian realization of @xmath10 such that all its cycles are knots in @xmath12 realizing their maximal thurston - bennequin number . it is known that certain legendrian knots and links are determined by the invariants @xmath7 and @xmath8 : the unknot ( see @xcite ) , the torus knots and the figure eight knot ( see @xcite ) , the links consisting of an unknot and a cable of that unknot ( see @xcite ) . in section [ classification ] , we ask what types of spatial graphs are classified up to legendrian isotopy by the pair @xmath4 . we show that the pair @xmath4 does not classify graphs which contain both cycles and either cut vertices or cut edges , independent of the chosen topological class . this means that even uncomplicated graphs carry more information than the set of knots represented by their cycles . in order to have a classification by the pair @xmath4 , we must first narrow to a specific topological class . we investigate _ topological planar graphs _ , that is an embedded graph that is ambient isotopic to a plannar embedding . not to be confused with _ planar graphs _ , which refers to an abstract graph that has a planar embedding . in the case of the handcuff graph , for topological planar graphs , we prove there are exactly four legendrian realizations for each pair @xmath4 . for the lollipop graph , for topological planar graphs , we prove there are exactly two legendrian realizations for each pair @xmath4 . the authors would like to thank tim cochran for his support and interest in the project . they would also like to thank john etnyre for helpful conversations . a _ spatial graph _ is an embedding @xmath13 of a graph @xmath10 into @xmath6 ( or @xmath14 ) , also called a _ spatial embedding _ or _ graph embedding_. we remind the reader that an abstract graph , one without an embedding well be referred to as simply a graph . we will be considering spatial graphs in @xmath6 throughout this paper . two spatial graphs @xmath15 and @xmath16 are _ ambient isotopic _ if there exits an isotopy @xmath17 such that @xmath18 and @xmath19 similar to knots , there is a set of reidemeister moves for spatial graphs , described by kauffman in @xcite . here we remind the reader of some basic graph theoretic terminology . we are considering the most general of graphs , so there can be _ multi - edges _ ( edges that go between the same pair of vertices ) , and _ loops _ ( edges that connect a vertex to itself ) . the _ valence _ of a vertex is the number of endpoints of edges at the given vertex . two vertices are _ adjacent _ if there is an edge between them . the complete graph on @xmath20 vertices , denoted @xmath21 , is the graph with @xmath20 vertices were every vertex is adjacent to every other vertex , with exactly one edge between each pair of vertices . two edges are _ adjacent _ if they share a vertex . a graph @xmath22 is a _ minor _ of @xmath10 if @xmath22 can be obtained from a subgraph of @xmath10 by a finite number of edge contractions . since we are considering topological questions about legendrian graphs throughout this paper , it is important to be aware of intrinsic properties of graphs . a property is called _ intrinsic _ if every embedding of @xmath10 in @xmath6 ( or @xmath14 ) has the property . a graph @xmath10 is _ minor minimal _ with respect to a property if @xmath10 has the property but no minor of @xmath10 has the property . such properties are characterized by their full set of minor minimal graphs . a spatial graph is said to _ contain a knot ( or link ) _ if the knot ( or link ) appears as a subgraph of @xmath10 . a graph , @xmath10 , is _ intrinsically knotted _ if every embedding of @xmath10 into @xmath6 ( or @xmath14 ) contains a nontrivial knot . a link @xmath23 is _ split _ if there is an embedding of a @xmath24sphere @xmath25 in @xmath26 such that each component of @xmath27 contains at least one component of @xmath23 . a graph , @xmath10 , is _ intrinsically linked _ if every embedding of @xmath10 into @xmath6 ( or @xmath14 ) contains a nonsplit link . the combined work of conway and gordon @xcite , sachs @xcite , and robertson , seymour , and thomas @xcite fully characterized intrinsically linked graphs . they showed that the petersen family is the complete set of minor minimal intrinsically linked graphs . that is no minor of the petersen family is intrinsically linked and any intrinsically linked graph contains a graph in the petersen family as a minor . unlike the intrinsically linked graphs , the set of intrinsically knotted graphs has not been characterized . however , there are many graphs that are known to be minor minimal intrinsically knotted . as consequence of how intrinsically linked graphs were characterized , it is known that all intrinsically knotted graphs are intrinsically linked , see @xcite . as we examine legendrian graphs and their properties , it is important to be aware of what topological properties ( without restricting to legendrian embeddings ) are known to be intrinsic to the graph . these issues will be present when considering theorem [ thmg ] and corollary [ unknot ] . let m be an oriented 3-manifold and @xmath28 a 2-plane field on @xmath29 . then @xmath28 is a _ contact structure _ on @xmath29 if @xmath30 for some @xmath31form @xmath32 on @xmath29 satisfying @xmath33 on @xmath34 , the @xmath31form @xmath35 defines a contact structure called the standard contact structure , @xmath36 . there is a diffeomeorphism of @xmath34 taking the standard contact structure , @xmath36 , to the symmetric contact structure , @xmath37 given in cylindrical coordinates by @xmath38 . in this paper , we switch between @xmath36 and @xmath39 when convenient . darboux s theorem says that any contact structure on a manifold @xmath29 is locally diffeomorphic to @xmath36 . a curve @xmath40 is called _ legendrian _ if for all @xmath41 and @xmath42 the contact plane at @xmath43 , @xmath44 . in @xmath0 , legendrian curves , in particular knots and links , are studied via projections , and a common projection is the front projection ( on @xmath45plane ) . the legendrian condition implies that @xmath46 ( i.e. the @xmath47coordinate can be recovered as the slope in the @xmath45plane ) , and so front projections of legendrian knots do not have vertical tangencies . figure [ unknot_trefoil ] shows two front projections of legendrian unknots and that of a legendrian right - handed trefoil . since the positive @xmath48-axis points inside the page , at each crossing the overstrand is always the one with smaller slope . ( 385 , 72 ) ( 0,0 ) apart from the topological knot class , there are two classical invariants of legendrian knots , the thurston - bennequin number , @xmath7 , and the rotation number , @xmath8 . the thurston - bennequin number measures the amount of twisting of the contact planes along the knot and does not depend on the chosen orientation of @xmath49 . to compute the thurston - bennequin number of a legendrian knot @xmath49 consider a non - zero vector field @xmath50 transverse to @xmath28 , take @xmath51 the push - off of @xmath49 in the direction of @xmath50 , and define @xmath52 if @xmath49 is null - homologous , @xmath53 measures the twisting of the contact framing on @xmath49 with respect to the seifert framing . for a legendrian knot @xmath49 , @xmath53 can be computed from its front projection @xmath54 as @xmath55 the rotation number , @xmath56 , is only defined for oriented null - homologous knots , so assume @xmath49 is oriented and @xmath57 , where @xmath58 is an embedded oriented surface . the contact planes when restricted to @xmath59 form a trivial @xmath24dimensional bundle , and the trivialization of @xmath60 induces a trivialization on @xmath61 . let @xmath50 be a non - zero vector field tangent to @xmath49 pointing in the direction of the orientation on @xmath49 . the winding number of @xmath50 about the origin with respect to this trivialization is the rotation number of @xmath49 , @xmath56 . in @xmath6 , the vector fields @xmath62 and @xmath63 define a positively oriented trivialization for @xmath36 . therefore , @xmath56 can be computed by counting with sign ( + for counterclockwise and @xmath64 for clockwise ) how many times the positive tangent vector to @xmath49 crosses @xmath65 as we travel once around @xmath49 . the tangent vector aligns with with one of the vectors @xmath65 or @xmath66 at the points corresponding to cusps in the front projection , @xmath54 , and one can check that @xmath67 given a legendrian knot @xmath49 , legendrian knots in the same topological class as @xmath49 can be obtained by _ stabilizations_. a strand of @xmath49 in the front projection of @xmath49 is replaced by one of the zig - zags as in figure [ stabilizations ] . the stabilization is said to be positive if down cusps are introduced and negative if up cusps are introduced . the legendrian isotopy type of @xmath49 changes through stabilization and so do the thurston - bennequin number and rotation number : @xmath68 and @xmath69 . ( 300 , 115 ) ( 0,0 ) ( 53,67)@xmath49 ( 135,85)@xmath70 ( 135,28)@xmath71 it is known , @xcite , that if @xmath49 is a null - homologous legendrian knot in @xmath0 and @xmath59 is a seifert surface for @xmath49 then @xmath72 in particular , if @xmath49 is the unknot then @xmath73 and if @xmath74 is the right hand trefoil knot then @xmath75 . both inequalities are sharp and are realized for the first and third knots in figure [ unknot_trefoil ] . a _ legendrian graph _ in a contact 3-manifold @xmath76 is a graph embedded in such a way that all its edges are legendrian curves that are non - tangent to each other at the vertices . when the graph @xmath10 must be specified this will also be referred to as a _ legendrian embedding of @xmath10 _ or a _ legendrian realization of @xmath10_. it should be noted for legendrian graphs , if all edges around a vertex are oriented outward , then no two tangent vectors at the vertex coincide in the contact plane . however , two tangent vectors may have the same direction but different orientations resulting in a smooth arc through the vertex . it is a result of this structure that the order of the edges around a vertices is not changed under legendrian isotopy . given any embedded graph @xmath10 in @xmath34 there exists a legendrian realization of @xmath10 in @xmath0 . [ leggraph ] denote the vertices of @xmath10 by @xmath77 , and fix these points . every point @xmath78 has an @xmath79neighborhood @xmath80 contactomorphic to a neighborhood of the origin in @xmath81 . via this diffeomorphism , the contact plane @xmath82 is identified with the plane @xmath83 at the origin . near each vertex @xmath78 , we modify @xmath10 through ambient isotopy , such that the edges incident with @xmath78 are segments which lie in the contact plane @xmath82 and are identified with @xmath84-constant segments in the plane @xmath83 . the edges of @xmath10 are thus legendrian near each vertex . consider @xmath85 an edge between two vertices @xmath78 and @xmath86 and let @xmath85 be identified with the @xmath87ray near @xmath78 and with the @xmath88ray near @xmath86 . denote by @xmath89 and @xmath90 the two points which are identified with @xmath91 and @xmath92 . denote by @xmath93 the legendrian segment between @xmath78 and @xmath94 identified with the segment @xmath95 , and by @xmath96 the legendrian segment between @xmath86 and @xmath97 identified with the segment @xmath98 . denote by @xmath99 the arc of @xmath85 between @xmath94 and @xmath97 . we can @xmath100approximate @xmath99 by a legendrian arc @xmath101 , in such a way that the union of arcs @xmath102 is a @xmath103 curve . we do this by choosing a @xmath100close approximation of the front projection of @xmath99 by a regular curve @xmath104 with no vertical tangencies , isolated cusps , and such that at each point @xmath105 the slope of @xmath104 is close to the @xmath48-coordinate of the point on @xmath99 projecting to @xmath43 . we can do this while keeping the endpoints @xmath94 and @xmath97 fixed and in such a way that the legendrian lift of @xmath99 , @xmath101 , coincides with @xmath85 near @xmath94 and @xmath97 . for more details see @xcite , section 3.3.1 . the curve @xmath102 is a legendrian curve which is @xmath100close to @xmath85 . by making @xmath104 have only transverse intersections , no self - intersection in the approximating curve are introduced , thus @xmath102 is an embedded arc . additionally , we can avoid introducing any non - trivial knotting . we approximate all other edges in the same way , and we obtain a legendrian @xmath100 approximation of @xmath10 ( i.e. a legendrian graph topologically ambient isotopic to @xmath10 ) . legendrian graphs can also be studied via front projections and two generic front projections of a legendrian graph are related by reidemeister moves i , ii and iii together with three moves given by the mutual position of vertices and edges , see @xcite . see figure [ moves ] . ( 360 , 188 ) ( 0,0 ) ( 84 , 153)i ( 82,99)ii ( 80,33)iii ( 256 , 150)iv ( 328 , 151)iv ( 295,93)v ( 291,30)vi through legendrian isotopy , the order of the edges around a vertex does not change . since two edges which share a vertex can never have the same ( oriented ) tangent vector throughout a legendrian isotopy , when seen in the contact plane at the vertex , the order of the edges around the vertex is the same up to a cyclic permutation . we extend the classical invariants @xmath7 and @xmath8 to legendrian graphs . a cycle in a legendrian graph is a _ piecewise smooth legendrian knot _ , that is , a simple closed curve that is everywhere tangent to the contact planes , but has finitely many points , at the vertices , where it may not be smooth . we first define the invariants , @xmath7 and @xmath8 , for piecewise smooth legendrian knots and then we extend the definition to legendrian graphs . given any piecewise smooth legendrian knot @xmath49 , there is a natural way to construct a smooth knot from @xmath49 . we define the _ standard smoothing _ of a cycle @xmath49 of a legendrian graph to be the @xmath103curve obtained by replacing @xmath49 in an @xmath79neighborhood of each vertex by the lift of a minimal front projection of a smooth curve , which coincides with @xmath49 outside of the @xmath79neighborhood . the projection is minimal , in the sense that no extra stabilizations or knotting are introduced with this approximation . see figure [ smoothing ] . we denote the standard smoothing of a piecewise smooth legendrian knot @xmath49 by @xmath106 . + [ isosmoothing ] if @xmath107 and @xmath108 are piecewise smooth legendrian knots which are isotopic as legendrian graphs , then their standard smoothings are isotopic legendrian knots . since @xmath107 and @xmath108 are isotopic as legendrian graphs , their front projects , @xmath109 and @xmath110 , are related by a finite sequence of the standard reidemeister moves i , ii , iii , as well as , the moves iv , v , vi , and legendrian planar isotopy . thus to show that the standard smoothings of @xmath107 and @xmath108 are isotopic , we need only show that the standard smoothings of valence two subgraphs of the reidemeister moves iv , v , and vi are moves that result in isotopic legendrian knots . for reidemeister move iv there are two different possibilities of valence two subgraphs up to reflection and planar isotopy to be considered , see figure [ moveivi](a ) . after smoothing the move either shows no changed , or a minor planar isotopy . for reidemeister move v there are two different possibilities of valence two subgraphs up to reflection and planar isotopy to be considered , see figure [ moveivi](b ) . after smoothing the move either shows a minor planar isotopy , or a difference of a reidemeister ii move . for reidemeister move vi there are three different possibilities of valence two subgraphs up to reflection and planar isotopy to be considered , see figure [ moveivi](c ) . after smoothing the move either shows no change , a minor planar isotopy , or a difference of a reidemeister i move . in all cases the standard smoothing can be moved to the other standard smoothing by a single reidemeister move or planar isotopy . ( 360 , 100 ) ( 0,0)curve near a vertex . the blue edges which are part of the cycle @xmath49 are replaced by the red @xmath103arc near the vertex . , title="fig : " ] ( 410 , 216 ) ( 10,0 ) ( -10,15)(c ) ( -10,100)(b ) ( -10,175)(a ) ( 57,181)iv ( 119,181)iv ( 267,181)iv ( 337,181)iv ( 111 , 101)v ( 300 , 102)v ( 56,22)vi ( 198,22)vi ( 345,22)vi of course , for any piecewise smooth legendrian knot there are isotopic legendrian knots , which can be obtained by a small isotopy near each vertex moving the edges so that they have parallel tangents at the vertex . in light of this , proposition [ isosmoothing ] shows that the isotopy class of a piecewise smooth legendrian knot contains legendrian embeddings from exactly one isotopy class of a legendrian knot , the knot obtained by its standard smoothing . so given a piecewise smooth legendrian knot @xmath49 , and its standard smoothing @xmath111 one could take the definition of the classical invariants to be : @xmath112 and @xmath113 . however , since we will be using the said definitions to define invariants for legendrian graphs , we would like to defined them in such a way that smoothings are not needed . it should be noted that any other definition of @xmath7 and @xmath8 that coincides with the invariants for smooth legendrian knots will be equivalent to the above definition , as a result of proposition [ isosmoothing ] . let @xmath49 represent a piecewise smooth legendrian knot and @xmath50 a vector field along @xmath49 which is transverse to the contact planes . take the push - off of @xmath49 , @xmath51 in the direction of @xmath50 and let @xmath114 . this definition coincides with that for smooth knots . there is no obstruction given by the direction change at the vertices . for a legendrian graph @xmath10 , we fix an order on the cycles of @xmath10 and we define _ the thurston - bennequin number of @xmath10 _ , denoted by @xmath115 , to be the ordered list of the thurston - bennequin numbers of the cycles of @xmath10 . if @xmath10 has no cycles , we define @xmath115 to be the empty list . we define the rotation number of a null - homologous piecewise smooth legendrian knot @xmath116 as follows : consider @xmath59 with @xmath117 and endow @xmath49 with the orientation induced by that on @xmath59 . consider the trivialization of @xmath36 given by the two vectors @xmath62 and @xmath63 . denote by @xmath118 , @xmath119 , ... , @xmath120 , @xmath121 the vertices on @xmath49 , in cyclic order as given by the orientation , denote by @xmath122 , @xmath123 , the smooth edge of @xmath49 between @xmath94 and @xmath124 , and denote by @xmath78 , @xmath123 , the unit vector field tangent to @xmath122 pointing in the direction of the orientation on @xmath49 . we follow the @xmath125 in the trivialization given by @xmath126 and @xmath127 and count the number of times @xmath126 is passed , with sign . at each vertex @xmath94 , @xmath128 if @xmath129 and @xmath78 do not coincide we complete the rotation counterclockwise if @xmath130 is a positively oriented basis for @xmath131 and clockwise if @xmath130 is a negatively oriented basis for @xmath131 . this is equivalent to completing by a rotation from @xmath129 towards @xmath78 in the direction of the shortest angle between the two . note that , since one edge is oriented towards the vertex and one edge is oriented away from the vertex , @xmath129 and @xmath78 can not be opposite to each other . denote by @xmath132 the number of times @xmath133 is passed in the counterclockwise direction and by @xmath134 the number of times @xmath133 is passed in the clockwise direction as @xmath49 is traced once . we define @xmath56 by @xmath135 let @xmath136 denote the legendrian isotopy class of @xmath49 . the above discussion gives a recipe of how to compute the rotation number for a particular embedding of a piecewise smooth legendrian knot . however , when @xmath49 changes through legendrian isotopy , the tangent vector at @xmath49 changes continuously and the edges can not pass over one another at the vertices . thus we get a continuous map @xmath137 . the rotation number is therefore a legendrian isotopy invariant for piecewise smooth legendrian knots . if @xmath49 is a smooth legendrian knot then we recover the rotation number for @xmath49 . for a legendrian graph @xmath10 , we fix an order on the cycles of @xmath10 with orientation and we define _ the rotation number of @xmath10 _ , denoted by @xmath138 , to be the ordered list of the rotation numbers of the cycles of @xmath10 . if @xmath10 has no cycles , we define @xmath138 to be the empty list . in @xcite , mohnke proved that the borromean rings and the whithead link can not be represented by legendrian links of trivial unknots . a _ trivial unknot _ is one with @xmath1 and @xmath2 ( like the first unknot shown in figure [ unknot_trefoil ] ) . the trivial unknot attains the maximal possible thurston - bennequin number for an unknot . the obstruction comes from upper bounds on @xmath7 given by the minimal degree of one of the variables in the kauffman polynomial . in this section we determine which graphs can be legendrian realized in such a way that all cycles are trivial unknots . we will see that there are many graphs ( even planar graphs ) with no such legendrian realization . we give a full characterization of these graphs . we also present a more general result about which graphs can be realized with all their cycles having maximal @xmath7 for a class of knots . the following two lemmas will be useful . ( 144 , 50 ) ( 0,0).,title="fig : " ] ( 15,42)@xmath139 ( 20,6)@xmath140 ( 107,3)@xmath141 ( 111,38)@xmath142 the front projections of any two legendrian realizations of a graph in @xmath0 are related by a finite sequence of legendrian isotopies and changes involving 1 . one edge ( i.e. stabilizations , crossings of the edge with itself ) 2 . two adjacent edges ( i.e. change in the number of crossings between the two edges ) 3 . two nonadjacent edges ( i.e change in the number of crossings between the two edges ) [ two_fronts ] if the two legendrian realizations are legendrian isotopic then the two front projections differ by legendrian isotopy only . if not , the two front projections may differ in number of edge stabilizations or number of crossings . the stabilizations occur on a single edge while the crossings may occur on a single edge , between two adjacent edges or between two nonadjacent edges . for any legendrian embedding @xmath23 of @xmath3 in @xmath143 @xmath144 where @xmath145 is the set of cycles in @xmath23 . [ mod2 ] denote by @xmath139 , @xmath140 , @xmath141 and @xmath142 the vertices of an abstract @xmath3 . there are seven cycles in @xmath3 : four 3-cycles ( @xmath146 and three 4-cycles @xmath147 + @xmath148 each edge appears in four different cycles and each pair of edges appears in two different cycles . consider the embedding @xmath49 of @xmath3 shown in figure [ k4 ] . for this embedding , there are six cycles with @xmath1 and one cycle ( @xmath149 ) with @xmath150 , thus @xmath151 take an arbitrary legendrian embedding of @xmath3 , call it @xmath23 . by lemma [ two_fronts ] , the front projection for this embedding differs from @xmath49 by a finite sequence of legendrian isotopy and changes of the form described above in one edge , two adjacent edges , or two non - adjacent edges . first , since @xmath7 is an invariant , @xmath152 does not change under isotopy . 1 . if a change in a single edge is made , the @xmath7 for all four cycles containing this edge is modified by the same quantity . 2 . if a change in two adjacent edges is made , the @xmath7 for both cycles containing this pair of edges is modified by the same quantity . if a change in two non - adjacent edges is made , the @xmath7 for both cycles containing this pair of edges is modified by the same quantity . thus , the parity of the sum of the @xmath7 s over all cycles remains unchanged throughout the process and @xmath153 we define @xmath12 to be the set of topological knot classes with odd maximal thurston - bennequin number . we have the following theorem : let @xmath10 be a graph that contains @xmath3 as a minor . then there does not exist a legendrian realization of @xmath10 such that all of its cycles are knots in @xmath12 realizing their maximal thurston - bennequin number . [ thmg ] it suffices to prove the theorem for @xmath154 , since any graph that contains @xmath3 as a minor contains a subdivision of @xmath3 ( see definition [ sub ] ) . assume all seven cycles of @xmath3 can be realized with maximal odd thurston - bennequin number , @xmath155 . then , @xmath156 , contradicting the conclusion of lemma [ mod2 ] . since the unknot has odd maximal @xmath1 we obtain the following corollary . recall that the trivial unknot is the unknot with maximal thurston - bennequin number . let @xmath10 be a graph that contains @xmath3 as a minor . then there does not exist a legendrian realization of @xmath10 such that all of its cycles are trivial unknots . [ unknot ] when we consider a graph @xmath10 that contains @xmath3 as a minor and an arbitrary legendrian embedding @xmath157 corollary [ unknot ] guaranties , either @xmath15 contains a nontrivial knot , or that all of the cycles of @xmath15 are unknots , but they do not all have maximal @xmath7 . for any intrinsically knotted graph ( see section [ spatialgrph ] ) corollary [ unknot ] is not surprising , since every embedding of an intrinsically knotted graph contains a nontrivial knot . while there are many graphs that contain @xmath3 as a minor and are not intrinsically knotted , all of the intrinsically knotted graphs contain @xmath3 as a minor . this can be seen , by noting that @xmath3 is a minor of all graphs in the petersen family . then since all intrinsically knotted graphs are also intrinsically linked , we see @xmath3 is a minor of all of the intrinsically knotted graphs . the same should be considered for theorem [ thmg ] . given an arbitrary legendrian embedding @xmath157 of a graph @xmath10 that contains @xmath3 as minor , theorem [ thmg ] implies that either @xmath15 does not only contain knots from @xmath11 or @xmath15 contains only knots from @xmath11 and they do not all attain their maximal @xmath7 . so theorem [ thmg ] gives more information about intrinsically knotted graphs . one example of an intrinsically knotted graph is @xmath158 , ( see @xcite ) . there are embeddings of @xmath158 with unknots as all but one cycle which is a trefoil . both the unknot and the right handed trefoil have odd maximal thurston - bennequin number , so then theorem [ thmg ] implies for such a legendrian embedding not all of the cycles will attain their maximal @xmath7 . there are many other knots whose maximal thurston - bennequin number is odd . a few examples are the right handed trefoil ( figure [ unknot_trefoil ] ) , the figure eight knot , the @xmath159 knot and its mirror image , the @xmath160 knot and its mirror image . there is a more general version of theorem [ thmg ] that is an immediate consequence of the proof , though it is cumbersome to state . let @xmath10 be a graph that contains @xmath3 as a minor . let @xmath152 be the subdivision of @xmath3 that @xmath10 contains . then there does not exist a legendrian realization of @xmath10 such that @xmath152 contains precisely an odd number of cycles that are knots in @xmath11 where all the knots in @xmath152 realize their maximal thurston - bennequin number . if we focus on embeddings with only unknots as in corollary [ unknot ] the converse also holds . before proving this we introduce some needed definitions and observations . 1 . 2 . a _ path _ between two vertices @xmath139 and @xmath140 of a graph @xmath10 is a finite sequence of at least two edges starting at @xmath139 and ending at @xmath140 , with no repetition of vertices . a vertex of the graph @xmath10 is said to be _ a cut vertex _ if by deleting the vertex ( and all incident edges ) the resulting graph has more connected components than @xmath10 . an edge of @xmath10 is said to be a _ cut edge _ if by deleting the edge the resulting graph has more connected components than @xmath10 . 5 . a _ subdivision _ of the graph @xmath10 is a graph obtained by replacing a finite number of edges of @xmath10 with paths ( one can think of this as adding a finite number of vertices along edges of @xmath10 ) . [ sub ] let @xmath10 be a graph which does not contain @xmath3 as a minor . let @xmath139 , @xmath140 , @xmath141 , @xmath142 be four vertices in a cycle of @xmath10 , appearing in this order . for any such formation , there are not two edges or paths , other than the ones already contained in the cycle , connecting @xmath139 and @xmath141 and connecting @xmath140 and @xmath142 . otherwise @xmath139 , @xmath140 , @xmath141 , and @xmath142 represent the vertices of a ( subdivision of ) @xmath3 . see figure [ nok4_remarks](a ) . [ alternates ] let @xmath10 be a graph which does not contain @xmath3 as a minor . let @xmath139 , @xmath140 , @xmath141 , be three vertices in a cycle of @xmath10 . for any such formation , there is not an additional vertex @xmath50 with distinct edges or paths , connecting @xmath50 to the other vertices @xmath139 , @xmath140 , and @xmath141 . otherwise @xmath139 , @xmath140 , @xmath141 , and @xmath50 represent the vertices of a ( subdivision of ) @xmath3 . see figure [ nok4_remarks](b ) . [ triangle ] ( 200 , 70 ) ( 0,0 ) as described in remarks [ alternates ] and [ triangle].,title="fig : " ] ( 28,-12)(a ) ( 169,-12)(b ) ( 63,63)@xmath161 ( 0,63)@xmath162 ( -2,9)@xmath163 ( 65,9)@xmath164 ( 178,38)@xmath165 ( 172,77)@xmath161 ( 129,16)@xmath162 ( 208,16)@xmath163 let @xmath10 be a graph , if @xmath10 does not contain @xmath3 as a minor then it can be legendrian realized in @xmath0 in such a way that all its cycles are trivial unknots . [ thmgrec ] we need only prove the theorem for @xmath10 connected , with no cut edges and no cut vertices . in all other cases such components ( connected components with no cut edges nor cut vertices ) of @xmath10 can be realized in the same way and cut edges can be realized in any fashion ( as they do not appear in any cycle ) . in what follows , all edges of @xmath10 are realized as non - stabilized arcs . let @xmath166 be one of the cycles of @xmath10 and @xmath167 the number of vertices of @xmath166 . realize @xmath166 in such a way that its front projection consists of @xmath168 horizontal edges and one edge on top of these . label the vertices on @xmath166 with @xmath139 , @xmath140 , ... , @xmath169 , in this order , from left to right . realize all the other edges between vertices of @xmath166 on top of the horizontal edges of @xmath166 , in a nested fashion as shown in figure [ nok4_one](a ) . by remark [ alternates ] , we can realize these edges without any crossings . otherwise , the four endpoints of two crossing edges represent the vertices of a @xmath3 . next , for each pair of vertices @xmath170 , @xmath171 , of @xmath166 for which there exists at least one path between @xmath78 and @xmath86 not containing any edges of @xmath166 , realize one of these paths under the horizontal line of @xmath166 . call this path @xmath172 . for each @xmath173 , if there is another path between @xmath78 and @xmath86 not containing edges of @xmath166 or edges of @xmath172 , ... , @xmath174 , realize this path under @xmath174 . see figure [ nok4_one](b ) . denote by @xmath175 this is a finite set . by construction , all paths in @xmath176 are nested , without any crossings , they have the vertices @xmath78 and @xmath86 in common and are disjoint otherwise . by remark [ alternates ] , we can realize all the paths appearing thus far without any crossings . additionally , for any vertices @xmath78 , @xmath86 , @xmath177 and @xmath178 of @xmath166 , with @xmath179 , no element of @xmath180 has any vertices ( distinct from @xmath78 , @xmath86 , @xmath177 and @xmath178 ) or edges in common with any element of @xmath181 . we prove the observation by contradiction . there are four different cases of @xmath179 , that is : ( 1 ) @xmath182 and @xmath183 ( 2 ) @xmath184 and @xmath185 ( 3 ) @xmath186 , and ( 4 ) @xmath187 and @xmath188 are all distinct . suppose a path @xmath189 in @xmath180 and a path @xmath190 in @xmath181 have at least one vertex other than @xmath78 , @xmath86 , @xmath177 and @xmath178 in common . let @xmath191 be the non - empty set of vertices that the paths @xmath189 and @xmath190 have in common distinct from @xmath78 , @xmath86 , @xmath177 and @xmath178 . let @xmath192 be the left most vertex on @xmath189 with @xmath193 , and let @xmath194 be the right most vertex on @xmath189 with @xmath195 . ( we need only show that a contiguous overlap can not occur , for if there are paths with multiple overlaps there are paths with a single overlap . ) for the subcases ( 1 ) , ( 3 ) , and ( 4 ) , let @xmath196 be the vertex in this set closest to @xmath178 on the path @xmath190 . then the part of the path @xmath190 from @xmath197 to @xmath178 is distinct from the path @xmath189 . so this path between @xmath197 and @xmath178 together with the two parts of @xmath189 going from @xmath78 to @xmath197 and from @xmath197 to @xmath86 are all distinct paths joining @xmath197 to the cycle @xmath166 . thus by remark [ triangle ] we have a contradiction . similarly , for the case ( 3 ) let @xmath196 be the vertex in this set closest to @xmath78 on the path @xmath189 . then the part of the path @xmath189 from @xmath197 to @xmath78 together with the two parts of @xmath190 going from @xmath177 to @xmath197 and from @xmath197 to @xmath178 are all distinct paths joining @xmath197 to the cycle @xmath166 . thus by remark [ triangle ] we have a contradiction . further , we treat each of the elements in @xmath180 , @xmath198 , @xmath199 , as if it were the path of horizontal edges in @xmath166 . we realize the edges with vertices on each such path above the path and the paths with endpoints on each such path below the path . we continue to realize each new edge on top of the path its vertices end lie on and each new path below the path its vertices lie on . ( 450 , 85 ) ( 0,0 ) with all cycles unknots of maximal @xmath7 . the cycle @xmath166 is blue.,title="fig : " ] ( 85,0)(a ) ( 305,0)(b ) ( 60,85 ) ( 288,87 ) ( 0,32)@xmath161 ( 28,32)@xmath162 ( 263,49)@xmath200 ( 310,49)@xmath201 ( 160,32)@xmath202 ( 180,32)@xmath203 claim : 1 . this is a legendrian embedding of @xmath10 ( all edges and vertices of @xmath10 are realized ) . all cycles in this embedding have maximal @xmath1 . proof of ( 1 ) : the above construction is a prescription for a front projection thus as long as all vertices and edges of @xmath10 are realized we have a legendrian embedding . the two cases of assuming a vertex was not realized and assuming an edge was not realized will be treated concurrently . if there exists an edge of @xmath10 which has not been realized , then there is an edge or a path in @xmath10 between two realized vertices that has not been realized . if there exists a vertex of @xmath10 which has not been realized , then since @xmath10 was assumed without cut edges and connected , there is a path in @xmath10 between two realized vertices that has not been realized . we show that the existence of such an edge or path leads to a contradiction . let @xmath50 and @xmath204 represent two realized vertices of @xmath10 such that there is a non - realized edge or path ( containing exclusively edges that have not been realized ) between @xmath50 and @xmath204 . the vertices @xmath50 and @xmath204 can not both be in @xmath166 , since all paths and edges between these vertices have been realized . for the same reason , @xmath50 and @xmath204 can not both be vertices on the same element of a @xmath180 , or on the same path realized at a later stage . from the vertex @xmath204 we will form a cycle , @xmath205 . the cycle @xmath205 is made by taking the path to the right of @xmath204 formed by choosing the edge that is to the right and upper most at each vertex ( this path will connect @xmath204 with @xmath169 ) , the path to the left of @xmath204 made by taking the edge that is to the left and upper most at each vertex ( this path will connect @xmath204 with @xmath139 ) , together with the edge connecting @xmath139 and @xmath169 . the vertex @xmath50 is not on the cycle @xmath205 , or we would have realized a path between these vertices . now let @xmath206 be the path formed by starting at @xmath50 choosing the edge that is to the right and upper most at each vertex until the vertex is a vertex of @xmath205 , call this vertex @xmath207 , and let @xmath208 be the path formed by starting at @xmath50 choosing the edge that is to the left and upper most at each vertex until the vertex is a vertex of @xmath205 , call this vertex @xmath48 . the vertices @xmath204 , @xmath207 and @xmath48 are all on the cycle @xmath205 , the ( edges or ) paths @xmath206 , @xmath208 , and the unrealized edge or path from @xmath50 to @xmath204 are all distinct , thus by remark [ triangle ] , this can not occur . therefore there is no such unrealized edge or path . proof of ( 2 ) : since the construction does not contain any crossings , we need only show that no cycle exhibits a stabilization . assume there is a cycle in the embedding which represents a stabilized unknot . since all edges were realized as non - stabilized arcs in the first place , at each cusp of this unknot there is a vertex of @xmath10 . since a stabilization occurs , there are at least two left cusps and two right cusps . we denote the vertices at the left cusps by @xmath192 and @xmath209 and the vertices at the right cusps by @xmath194 and @xmath210 , with the four vertices appearing in order @xmath192 , @xmath194 , @xmath209 , @xmath210 in the cycle . without loss of generality we may assume that either @xmath194 , @xmath209 , and @xmath210 are at consecutive right - left - right cusps and @xmath192 is on the left of @xmath209 ( figure [ nok4_three ] , ( a ) ) or @xmath192 , @xmath210 , and @xmath209 are consecutive left - right - left cusps and @xmath194 is on the right of @xmath210 ( figure [ nok4_three ] , ( b ) ) . we show that a @xmath3 necessarily exists . ( 380 , 108 ) ( 0,0 ) ( -8,52)@xmath192 ( 144,78)@xmath194 ( 66,52)@xmath209 ( 146,22)@xmath210 ( 174,78)@xmath192 ( 326,51)@xmath194 ( 172,22)@xmath209 ( 251,52)@xmath210 ( 78,-10)(a ) ( 248,-10)(b ) we prove the case pictured in figure [ nok4_three](a ) . the other case is similar . we consider a path @xmath211 which starts at @xmath194 and always follows along an edge to the right at each vertex . we also consider a path @xmath212 which starts at @xmath210 and always follows along an edge to the right at each vertex . denote the first vertex where @xmath211 and @xmath212 intersect by @xmath213 . the vertex @xmath213 may be @xmath194 , @xmath210 , @xmath169 , or a point in between . the path which follows @xmath211 from @xmath194 to @xmath213 and then @xmath212 from @xmath213 to @xmath210 is a path between @xmath194 and @xmath210 , which is disjoint from both @xmath192 and @xmath209 , since both @xmath192 and @xmath209 lie on the left of both @xmath194 and @xmath210 . this is a third path between @xmath194 and @xmath210 , in addition to the two included in the stabilized cycle . now , consider a path @xmath214 which starts at @xmath209 and always follows along an edge to the left at each vertex . the path @xmath214 will eventually reach @xmath139 , and will intersect the stabilized cycle in a vertex @xmath215 situated on the arc of the cycle which goes between @xmath194 and @xmath210 and does not contain @xmath209 . the vertices @xmath215 , @xmath194 , @xmath209 , @xmath210 are the vertices of a ( subdivision of ) @xmath3 . recall , a graph @xmath10 is _ minor minimal _ with respect to a property if @xmath10 has the property , but no minor of @xmath10 has the property . corollary [ unknot ] together with theorem [ thmgrec ] show that @xmath3 is minor minimal with respect to the property of not having a legendrian embedding with all cycles trivial unknots . not only that , but theorem [ thmgrec ] shows that @xmath3 is the only graph in this minor minimal set , thus characterizing this property . it is known that certain types of legendrian knots and links are determined by the classical invariants @xmath7 and @xmath8 in @xmath143 . in @xcite , eliashberg and fraser showed that the legendrian unknot is determined by @xmath7 and @xmath8 . in @xcite , etnyre and honda showed the same holds for torus knots and the figure eight knot , and in @xcite , ding and geiges showed that links consisting of an unknot and a cable of that unknot , are classified by their oriented link type and the classical invariants in @xmath143 . in this section we investigate what types of spatial graphs are classified up to legendrian isotopy by the pair @xmath4 . it is useful to recall that within each legendrian isotopy class , at each vertex , the edges appear in a fixed cyclic order . for now we consider graphs that have cut edges or cut vertices . [ cute ] let @xmath10 be a graph containing a vertex of valence at least three which is incident to at least one cut edge . for different legendrian realizations of @xmath10 , the order of edges at this vertex can differ , while the classical invariants for all cycles are the same . this is because the cut edge @xmath85 does not appear in any cycle . see figure [ tbrot](a ) . that is , a legendrian embedding of @xmath10 is not determined by the pair @xmath4 . [ cutv ] let @xmath10 be a graph containing a cut vertex of valence at least four . for different legendrian realizations of @xmath10 , the order of edges at this vertex can differ , while the classical invariants for all cycles are the same . for an example see figure [ tbrot](b ) . note that there are no cycles containing edges from both @xmath49 and @xmath22 . in particular , the modified edge is not in such a cycle , thus @xmath7 and @xmath8 are the same for the two embeddings . that is , a legendrian embedding of @xmath10 is not determined by the pair @xmath4 . suppose that @xmath10 has at least one cut edge or vertex and is determined by the pair ( @xmath7 , @xmath8 ) . suppose @xmath10 has a cut vertex @xmath50 , then by remark [ cutv ] the vertex @xmath50 must have valence 3 or less . if @xmath50 is a cut vertex with valence 3 then it must be adjacent to a cut edge , but by remark [ cute ] this would imply that @xmath10 is not determined by the pair ( @xmath7 , @xmath8 ) . so @xmath50 must have valence 2 or less . however , to be a cut vertex it must have at least valence two . for a valence 2 cut vertex both incident edges are cut edges , so by remark [ cute ] both of the vertices defining these edges must have valence 2 or less . therefore the only such graph with a cut vertex is a path graph . so @xmath10 has no cycles . suppose @xmath10 has a cut edge @xmath85 with no cut vertices . by remark [ cute ] the valences of the two vertices must be 2 or less . since the two vertices can not be cut vertices they are of valence one . thus the graph @xmath10 is a single edge . thus there does not exist a graph containing at least one cycle and at least one cut edge or one cut vertex that is determined by the pair ( @xmath7 , @xmath8 ) . next , we focus on legendrian embeddings of the lollipop graph and the handcuff graph . see figure [ lollipop ] . both these graphs have one cut edge . for any topological class of these graphs the legendrian class can not be determined by the pair @xmath4 , by proposition [ cutedge ] . a _ planar spatial graph _ is a spatial graph which is ambient isotopic to an embedding in the plane . a _ legendrian planar graph _ ( or a _ planar legendrian realization _ ) is a legendrian realization of a planar spatial graph . we show that if we restrict to planar spatial graphs , a pair @xmath4 determines exactly two legendrian isotopy classes of the lollipop graph and a pair @xmath4 determines exactly four legendrian isotopy classes of the handcuff graph . we do this by constructing a legendrian isotopy between an arbitrary embedding and a _ standard form _ embedding . we define a standard form embedding below . 1 . 2 . we say a legendrian unknot is in _ standard form _ if it is the lift of a front projection as in figure [ standard_unknotef](a ) or ( b ) . the front projection in figure [ standard_unknotef](a ) represents two distinct legendrian classes , depending on the chosen orientation . for the front projection shown in figure [ standard_unknotef](b ) both orientation give the same legendrian class , we fix the orientation to be the one which makes the left cusp a down cusp . we say a planar legendrian realization of the lollipop graph is _ in standard form _ if it is the lift of a front front projection consisting of one front projection of an unknot @xmath216 in standard form as in figure [ standard_unknotef ] and a nonstabilized arc at the lower right cusp of the unknot . the arc can sit in one of two ways with respect to the other edge segments coming together at the vertex . we say the planar legendrian realization of the lollipop graph is in _ standard form a _ or _ b _ if the cut edge sits as in figure [ standard_vertex_lollipop](a ) or ( b ) , respectively . we say a planar legendrian realization of the handcuff graph is _ in standard form _ if it is the lift of a front projection consisting of two non - crossing front projections of unknots @xmath217 and @xmath218 each in standard form as in figure [ standard_unknotef ] , one on the left and one on the right , and a nonstabilized arc between the lower right cusp of the unknot on the left and the leftmost cusp of the unknot on the right . the arc can sit in one of two ways with respect to the other edge segments coming together at each vertex . we say the planar legendrian realization of the handcuff graph is in _ standard form aa , ab , ba _ or _ bb _ if the cut edge sits as in figure [ standard_vertex](a ) , ( b ) , ( c ) or ( d ) , respectively . ( 320 , 90 ) ( 0,0 ) , ( b ) standard form @xmath226 , ( c ) standard form @xmath227 , ( d ) standard form @xmath228.,title="fig : " ] ( 80,58)(a ) ( 232,58)(b ) ( 80,-5)(c ) ( 232 , -5)(d ) ( 28 , 18)@xmath217 ( 130 , 18)@xmath218 ( 184,18)@xmath217 ( 286 , 18)@xmath218 ( 28 , 82)@xmath217 ( 130 , 82)@xmath218 ( 184,82)@xmath217 ( 286 , 82)@xmath218 in @xcite , eliashberg and fraser showed that a legendrian unknot @xmath49 is legendrian isotopic to a unique unknot in standard form . the number of cusps and crossings of the unknot in standard form ( see figure [ standard_unknotef ] ) are uniquely determined by @xmath53 and @xmath56 as follows : let @xmath10 be a legendrian graph consisting of a legendrian knot and a cut edge connected to it . through legendrian isotopy , the cut edge can be moved to be connected at any point of the knot . [ slide0 ] we work with a front projection of the graph @xmath10 . away from the cusps the cut edge can be moved by planar isotopy . a cut edge can be passed through a right cusp as in figure [ slide ] ( below or above , depending on how it sits with respect to the cusp ) . passing from the lower strand to the upper strand of a right cusp can be obtained by vertical reflection of the two illustrated cases . diagrams for passing through a left cusp can obtained by horizontal reflection of the diagrams for the right cusp . we construct a legendrian isotopy between @xmath23 and one of the two standard forms . denote by @xmath139 the valence three vertex of @xmath23 , by @xmath140 the valence one vertex of @xmath23 , denote by @xmath216 the loop edge of @xmath23 , and denote by @xmath85 the cut edge of @xmath23 . we work with a front projection of @xmath23 . _ step 1 _ ( remove the crossings of the cut edge with itself and with @xmath216 ) . starting from @xmath140 towards @xmath139 , retract the edge @xmath85 in a @xmath238neighborhood of @xmath139 , and remove all its self crossings in the front projection , as well as the crossings between @xmath85 and @xmath216 . _ step 2 _ ( put @xmath216 in standard form ) . change @xmath23 by legendrian isotopy in a neighborhood of @xmath139 such that the unknot @xmath216 is everywhere smooth . by @xcite , there exists a unique unknot in standard form which is legendrian isotopic to @xmath216 . take @xmath216 to standard form through legendrian isotopy , while keeping @xmath140 and its neighborhood containing @xmath85 away from the isotopy . we can do this by sliding the cut edge when necessary , as in lemma [ slide0 ] . _ step 3 _ ( slide the cut edge to the lower right cusp of @xmath216 ) . using lemma [ slide0 ] , slide the cut edge so that it connects to the rest of the graph at the lower right cusp of @xmath216 . starting from @xmath140 towards @xmath139 , retract the edge @xmath85 in a @xmath238neighborhood of @xmath139 , and remove all self crossings in the front projection , as well as the all crossings between @xmath85 and @xmath216 . now the graph is in one of the two standard forms . since a standard form of the unknot is uniquely determined by @xmath7 and @xmath8 , each of the standard forms of the lollipop graph are also determined by @xmath7 and @xmath8 . thus we have two legendrian isotopy classes for the lollipop graph for each pair @xmath4 . we construct a legendrian isotopy between @xmath23 and one of the four standard forms . denote by @xmath139 and @xmath140 the two vertices of @xmath23 , denote by @xmath217 and @xmath218 the two loop edges of @xmath23 , and denote by @xmath85 the cut edge of @xmath23 . we work with a front projection of @xmath23 . _ step 1 _ ( make @xmath217 and @xmath218 disjoint in the front projection ) . since the graph @xmath23 is topologically equivalent to the embedding in figure [ lollipop](b ) , the two unknots @xmath217 and @xmath218 bound disks @xmath239 and @xmath240 which are disjoint from each other and disjoint from the rest of the graph . shrink the disks @xmath239 and @xmath240 in @xmath238neighborhoods of @xmath139 and @xmath140 , with @xmath241 small enough for there to exist no crossings between @xmath217 and @xmath218 in the front projection . ( 390 , 280 ) ( 0,0 ) undoes the stabilization in the cut edge for the case when the cut edge connects _ outside _ the cusp at @xmath140 . , title="fig : " ] ( 110 , 256)iv ( 244 , 256)iv ( 370 , 254)vi ( 100 , 181)ii ( 235 , 182)ii ( 120 , 107)ii s ( 373 , 182)ii ( 249 , 108)ii ( 117 , 33)i ( 40 , 260)@xmath223 ( 180 , 187)@xmath224 ( 313 , 187)@xmath224 ( 57 , 115)@xmath242 ( 171 , 128)@xmath224 ( 58 , 43)@xmath223 ( 117 , 33)i _ step 2 _ ( remove crossings of the cut edge with itself and with @xmath217 and @xmath218 ) . there exists an embedded @xmath24sphere @xmath243 such that @xmath217 is contained in the @xmath244ball @xmath245 bounded by @xmath243 and @xmath243 intersects the cut edge at one point , @xmath192 . shrink @xmath245 in a small neighborhood of @xmath192 . starting from @xmath192 retract the cut edge while carrying along the neighborhood of @xmath192 and undo its knotting outside of @xmath245 as well as all crossings with @xmath218 . next , there exists an embedded @xmath24sphere @xmath246 disjoint from the sphere @xmath243 such that @xmath218 lies in the @xmath244ball @xmath247 bounded by @xmath246 and @xmath246 intersects the cut edge at one point , @xmath194 . shrink @xmath247 in a small neighborhood of @xmath194 . this move may introduce a crossing between @xmath85 and @xmath218 in the front projection . starting from @xmath194 retract the cut edge while carrying along the neighborhood of @xmath194 and undo its knotting outside of @xmath247 as well as all crossings between the cut edge and @xmath217 in the front projection . _ step 3 _ ( put @xmath217 and @xmath218 in standard form , slide one end of the cut edge to the lower right cusp of @xmath217 , and slide the other end to the left cusp of @xmath218 ) . take @xmath217 into a small neighborhood of @xmath139 . modify @xmath218 through a legendrian isotopy which takes it to the unknot in standard form having the assigned @xmath7 and @xmath8 . by sliding the cut edge repeatedly ( as in lemma [ slide0 ] ) , we can keep @xmath139 and @xmath217 away for this isotopy . once @xmath218 is in standard form , using lemma [ slide0 ] slide the cut edge so that it connects to @xmath218 at the left cusp of @xmath218 . the cut edge can sit in two ways with respect to the other two edge segments at this cusp . leaving @xmath218 in standard form and leaving @xmath85 connected to @xmath218 at the left cusp , move @xmath217 and @xmath85 through legendrian isotopy so that the front projection of @xmath217 lies outside and to the right of the bounded region in the plane determined by the front projection of @xmath218 . modify @xmath217 through a legendrian isotopy which takes it to the unknot in standard form having the assigned @xmath7 and @xmath8 . by sliding the cut edge repeatedly ( as in lemma [ slide0 ] ) without contracting it , we leave @xmath218 unchanged . once @xmath217 is in standard form , using lemma [ slide0 ] slide the cut edge without contracting it so that it connects to @xmath217 at the lower right cusp of @xmath217 . ( 380 , 240 ) ( 0,0 ) undoes the stabilization in the cut edge for the case when the cut edge connects _ inside _ the cusp at @xmath140.,title="fig : " ] ( 107 , 224)iv ( 237 , 224)vi ( 357 , 224)vi ( 107 , 155)ii ( 243 , 156)iv ( 359 , 155)iv ( 108 , 91)ii ( 241 , 91)ii ( 363 , 93)ii s ( 234 , 27)i , vi , iv ( 28 , 230)@xmath223 ( 190,162 ) @xmath224 ( 305 , 99)@xmath242 ( 22 , 47)@xmath223 _ step 4 _ ( undo stabilizations of the cut edge and reach one of the standard forms ) . the cut edge can connect in two ways at @xmath140 relative to the other two edge segments , _ outside _ the cusp , or _ inside _ the cusp . 1 . if the cut edge connects outside the cusp , then the stabilizations of the cut edge can be removed by flipping @xmath218 horizontally , as in figure [ flip1 ] . the other type of stabilization is solved by reflecting the diagrams . after undoing the additional stabilizations , the graph is in one of the standard forms @xmath219 or @xmath227 , depending on how the cut edge sits at @xmath139 relative to the other two edge segments . if the cut edge connects inside the cusp , then the stabilizations of the cut edge can be removed by flipping @xmath218 horizontally , as in figure [ flip2 ] . the other type of stabilization is solved by reflecting the diagrams . after undoing the additional stabilizations , the graph is in one of the standard forms @xmath226 or @xmath228 , depending on how the cut edge sits at @xmath139 relative to the other two edge segments .

we investigate legendrian graphs in @xmath0 . we extend the classical invariants , thurston - bennequin number and rotation number to legendrian graphs . we prove that a graph can be legendrian realized with all its cycles legendrian unknots with @xmath1 and @xmath2 if and only if it does not contain @xmath3 as a minor . we show that the pair @xmath4 does not characterize a legendrian graph up to legendrian isotopy if the graph contains a cut edge or a cut vertex . for the lollipop graph the pair @xmath5 determines two legendrian classes and for the handcuff graph it determines four legendrian classes .

the nambu jona - lasinio model has been extensively studied for several decades [ 1 - 3 ] . in recent years there has been strong interest in the study of quark matter at high densities , using the njl model and related models . in particular , one finds color superconductivity under certain conditions and it has been suggested that some compact stars might be made of superconducting quark matter [ 4 - 10 ] . it is our belief that in such studies one should use a model which reproduces , as well as possible , know features of qcd . in this work we wish to generalize the su(3)-flavor version of the njl model to be consistent with the type of momentum - dependent quark masses found in lattice simulations of qcd [ 11 ] . for example , in figs . 1 and 2 we show some of the results obtained in ref . [ 11 ] . it may be seen from these figures that , in euclidean space , the quark mass goes over to the current mass for euclidean momentum @xmath2 2 gev . on the other hand , the njl model , in the standard analysis [ 1 ] , gives rise to a constant value for the constituent quark mass . as we will see , the form of the nonlocality used here is different from that used in refs . [ 6 , 12 - 16 ] . for example , in reference [ 12 ] the @xmath3 vertex is modified by a form factor which depends on the relative momentum of the quark and antiquark , while , in another scheme , a form factor is associated with each quark line appearing in a diagram . in the latter procedure no further regularization is needed . however , for the problem considered in this work , the nonlocal models that appear in the literature are of limited applicability , since , in the limit of zero current quark mass , the quark self - energy is proportional to the form factors used to define the nonlocality [ 12 ] . in contrast , in the current work , we calculate the form of the quark self - energy after introducing a regulator and a nonlocal quark interaction . we stress that the procedure used here differs from any that appears in the literature . the organization of our work is as follows . in section ii we review the standard analysis for the condensates and gap equation " of the su(3)-flavor njl model [ 1 ] . we then go on to review a procedure for including the contribution to the quark self - energy due to the addition of a confining interaction for the case of the su(2)-flavor model . in section iii we introduce a nonlocal interaction in the su(3)-flavor njl model while maintaining the separable nature of the interaction . we also describe the approximation used for the t hooft interaction in the nonlocal model . in section iv and v we present some of the results of our numerical calculations . in section vi we discuss the density dependence of the quark condensate and the momentum dependent quark mass . finally , section vii contains some additional discussion and conclusions . using an extrapolation of the current quark mass to zero . ( the small dip at @xmath4 gev is not statistically significant [ 11 ] . ] in order to best introduce the nonlocal model , we will first review the calculation of the quark self - energy in the local su(3)-flavor njl model and then proceed to add a confinement interaction , as was done in an earlier study of the quark self - energy [ 17 ] . we consider the generalization to a model with nonlocal short - range and t hooft interactions in the next section . the lagrangian of the model is @xmath5\nonumber\\ & & + \frac{g_d}{2}\{\det[\bar q(1+\gamma_5)q]+\det[\bar q(1-\gamma_5)q]\}\,.\end{aligned}\ ] ] here @xmath6 is the matrix of quark current masses , @xmath7 and the @xmath8 are the gell - mann matrices . further , @xmath9 , with being the unit matrix in the flavor space . the quark propagator is written as @xmath10 with @xmath11 we may define @xmath12 and @xmath13 with similar definitions for @xmath14 and @xmath15 . in the absence of a confinement model , we have @xmath16 and @xmath17 , where @xmath18 and and @xmath19 are constants . ( here , we have take @xmath20 . ) in this case we have [ 2 ] @xmath21 @xmath22 @xmath23 these equations are depicted in fig . 3a , where the last term represents the t hooft interaction . the up quark vacuum condensate is given by @xmath24 here , @xmath25 is a function needed to regulate the integral . in this work we will use the pauli - villars procedure and evaluate the integral in euclidean space , as was done in ref . [ 17 ] . in the general case we may write @xmath26 where @xmath27 and @xmath28 were defined in eqs . ( 2.4 ) and ( 2.5 ) . in the appendix of ref . [ 17 ] we considered lorentz - vector confinement , with @xmath29 and @xmath30 ^ 2 } -\frac{4\mu^2}{[(k_e - k_e^{\,\prime})^2+\mu^2]^3}\right\}\,,\ ] ] where @xmath31 denotes the euclidean - space momentum transfer . here , @xmath32 is a small parameter introduced to soften the momentum - space singularities . note that the form @xmath33 ^ 2 } -\frac{4\mu^2}{[(\vec k-\vec k^{\,\prime})^2+\mu^2]^3}\right\}\,,\ ] ] represents the fourier transform of @xmath34 , so that for small @xmath35 approximates a linear potential over the relevant range of _ r_. in fig . 3b we show the equation for the self - energy when the confining field is included . in ref . [ 17 ] we obtained the following coupled equations in the case of the su(2)-flavor model @xmath36a(\kpsq)}{k^{\,\prime \,2}[1-b(k^{\,\prime \,2})]^2-a^2(k^{\,\prime \,2})+i\epsilon}\,,\ ] ] @xmath37v^c(k - k^{\,\prime})}{k^{\,\prime \,2}[1-b(k^{\,\prime \,2})]^2-a^2(k^{\,\prime \,2})+i\epsilon}\,.\ ] ] these equations were solved after passing to euclidean space and including a pauli - villars regulator of the form @xmath38[k_e^{\,2}+a^2(k_e^{\,2})+2\lambda^2]}\ ] ] in euclidean space . note that the form @xmath39[k_e^{\,2}\left(1-b(k_e^{\,2 } ) \right)^2+a^2(k_e^{\,2})+2\lambda^2]}\ ] ] may also be used . ( 2.15 ) and ( 2.16 ) @xmath40 appears with a sign opposite to that given in ref . [ 17 ] , since , in that work , we used a negative value of @xmath41 . for the present work we use a positive value of @xmath41 to be consistent with all of our other publications . ) in this section we describe the procedures we use to create a nonlocal version of our generalized njl model . we consider the second term of eq . ( 2.1 ) and make the replacement @xmath42\\\nonumber & & \longrightarrow\frac{g_s}{2}\sum_{i=0}^8\{[\bar q(x)\lambda^if(x)q(x)\cdot \bar q(y)\lambda^if(y)q(y)\\[0.4cm]\nonumber & & \hspace{0.9cm}+[\bar q(x)i\gamma_5\lambda^if(x)q(x)\cdot\bar q(y)i\gamma_5\lambda^if(y)q(y)]\}\,.\end{aligned}\ ] ] this replacement corresponds to the use of a separable interaction @xmath43 . a related modification may be made for the t hooft interaction . it is useful , however , to describe these modifications as they affect momentum - space calculations . with reference to fig . 4 , we replace @xmath44 by @xmath45 in the evaluation of the second term of fig . 2 we need @xmath46 and choose to write @xmath47 g_s\exp[-(k - k^{\,\prime})^{\,2n}/2\beta]\\\nonumber & = & \:g_s\exp[-(k - k^{\,\prime})^{\,2n}/\beta]\,.\end{aligned}\ ] ] in this work we take @xmath48 and @xmath49 gev@xmath50 . in fig . 5 we exhibit the function @xmath51 $ ] . it is clear that many other functions may be chosen . we now rewrite eqs . ( 2.15 ) and ( 2.16 ) for the up , down and strange quarks . for example , for the su(3)-flavor case @xmath52a_u(k^{\,\prime\,2 } ) } { k^{\,\prime\,2}[1-b_u(k^{\,\prime\,2})]^2-a_u^2(k^{\,\prime\,2})+i\epsilon}\ , , \\[0.35 cm ] k^2b_u(k^2)&=&i\myint{\kp } \frac{2(k\cdot\kp)[1-b_u(\kpsq)]v^c(k-\kp ) } { k^{\,\prime\,2}[1-b_u(k^{\,\prime\,2})]^2-a_u^2(k^{\,\prime\,2})+i\epsilon}\,,\end{aligned}\ ] ] with similar equations for @xmath53 etc . again , these equations are solved after passing to euclidean space and introducing regulator functions : @xmath54 . in euclidean space we write c_u()= , etc . note that without the t hooft interaction the equations for the up , down and strange quarks are uncoupled . , by the nonlocal ( separable ) term , @xmath55 . the distinction between our separable model and that of ref . [ 12 ] , for example , is that in ref . [ 12 ] the alternative replacement @xmath56 was used . ] $ ] is shown for @xmath48 and @xmath49 . ] our treatment of the t hooft interaction is based upon a generalization of the last term in eqs . ( 2.6)-(2.8 ) . with reference to the third term on the right in fig . 6 , we introduce a correlation between the quark of momentum _ k _ and the quark of momentum @xmath57 . we also include a correlation between the quark of momentum _ k _ and that of momentum @xmath58 . ( therefore , our procedure does not introduce a correlation between the two quarks in the separate condensates . at this stage of the development of our model that seems to be a reasonable approximation and avoids having to define a three - quark correlation function , @xmath59 ) for example , we generalize the term @xmath60 to obtain the contribution to @xmath61:a_u^t(k)= -g_d + in minkowski space . this expression is then evaluated in euclidean space and added to the right - hand side of eq . ( 3.3 ) . in a similar fashion , we calculate @xmath62 and @xmath63 . there is a good deal of flexibility in choosing the regulators @xmath64 , @xmath65 , and @xmath66 . also , various forms could be chosen for the correlation functions , @xmath67 . previously , in our minkowski - space studies of the @xmath1 mesons we used @xmath68 gev@xmath69 and @xmath70 [ 18 ] . however , in that work we used a gaussian regulator in minkowski space so that a direct comparison with the present study can not be made . on the other hand , we do not expect to find radically different parameters , if the constituent masses in the two calculations are similar . for example , in our earlier work , in which @xmath18 and @xmath19 were parameters , we used @xmath71 , which can be compared to the value of @xmath72 calculated here . we have also used either @xmath73 [ 19 - 23 ] or @xmath74 [ 18 ] , values which may be compared to @xmath75 . to proceed , we take @xmath76 , @xmath77 , @xmath78 , @xmath79 , @xmath80 , @xmath81 and @xmath82 . we then consider values of @xmath83 , @xmath84 , @xmath85 and @xmath86 . the results of our calculations are given in table i. recall that the function @xmath87 does not appear in our expression for the condensates . the calculation of the condensates includes the pauli - villars regulators , @xmath64 , @xmath65 and @xmath66 , however . [ see eqs . ( 2.9)-(2.11 ) . ] in our calculation of the properties of the @xmath1 mesons [ 18 ] we had @xmath88 , since we used @xmath89 values in the range @xmath90@xmath91 in that work . in order to specify a value of @xmath89 for this work , we note that a calculation based upon chiral perturbation theory yields @xmath92 [ 24 ] . inspection of table i suggests that the values of @xmath89 , other than @xmath83 , given in table i are acceptable . for @xmath93 we have @xmath94 and @xmath95 , which are reasonably close to the phenomenological parameters @xmath96 and @xmath97 used in our earlier work [ 19 - 23 ] . it is worth noting that , in standard application of the su(3)-flavor njl model , one finds @xmath98 [ 1 ] , so that the results shown in table i are encouraging , given that the value for @xmath99 obtained using chiral perturbation theory is about 1.7 [ 24 ] , as noted above . .calculated values for the condensates and for @xmath100 are given for the up and strange quarks for four values of @xmath89 . the parameters @xmath79 gev , @xmath80 gev , @xmath782 , @xmath498 , @xmath81 gev , @xmath76 gev , @xmath77 were used . the values of @xmath41 and @xmath32 were fixed in earlier work [ 18 - 23 ] . values of @xmath101 have been suggested [ 28 ] , so we see that our calculated values are at , or near , the lower limit for that quantity . [ cols="<,<,<,<,<",options="header " , ] in fig . 7 we show @xmath102 , where _ k _ is the magnitude of the euclidean momentum . the dashed line exhibits the result without the confining interaction ( @xmath103 ) . it is interesting to see that inclusion of confinement improves the shape of the curve when we compare our results to the lattice results shown in figs . 1 and 2 . we note that @xmath102 goes over to @xmath79 for large _ k_. in fig . 8 we show @xmath104 . ( recall that @xmath105^{-1}$ ] . ) we remark that @xmath106 when @xmath103 . in figs . 9 and 10 we show @xmath107 and @xmath108 , respectively . as expected , we find that @xmath107 goes over to @xmath80 when _ k _ is large . are shown for the parameters @xmath79 gev , @xmath80 gev , @xmath78 , @xmath81 gev , @xmath76 gev , @xmath49 , @xmath109 , and @xmath93 . the dashed line shows the result without confinement ( @xmath103 ) . ] are shown . ( see caption to fig . ] are shown . ( see caption to fig . 7 . ) ] are shown . ( see caption to fig . 7 . ) as stated earlier , the behavior of the njl model for finite values of the baryon density is an extensively explored topic [ 1 , 25 , 26 ] , with particular recent emphasis on color superconductivity [ 4 - 10 ] . in this section we explore the behavior of our model at finite baryon density . ( it should be noted that the nature of the phase transition describing chiral symmetry restoration at finite density is quite model dependent . for example , the inclusion of current quark masses can change a strong first - order transition to a smooth second - order transition [ 26 ] . ) a comprehensive study of the thermodynamics of the three - flavor njl model has been reported in ref . [ 27 ] . there it is found that the up , down and strange quark masses are essentially constant up to the density where a first - order phase transition appears . at that point , the up and down quark masses drop from a value of about 380 mev to about 30 mev . that behavior differs from the behavior expected at low density . for example , we have the well - known relation between the value of the condensate and the baryon density of nuclear matter = 1- , where @xmath110 is the pion - nucleon sigma term . this relation is valid to first - order in the density . it may be derived , in the case of nuclear matter , by writing |qq_= |qq_0+n||qq|n_b and making use of the definition of the pion - nucleon sigma term , @xmath110 , and the gell - mann oakes renner relation . if we put @xmath111 gev , we have @xmath112 , where @xmath113 is in units . for nuclear matter @xmath114(0.109 gev)@xmath115 , so we see that the condensate is reduced by about 35% , if we evaluate eq . ( 6.1 ) at nuclear matter density . we can check whether the density dependence given by eq . ( 6.1 ) is reproduced in our model , since it should not matter whether the scalar density of the background matter is generated by quarks in nucleons or by the presence of free quarks . in the former case , we may write , for the baryon density , _ b=4^k_f where the factor of 4 is arises from the product of the spin and isospin factors . in the case of quarks , we have _ b=4n_c ( ) ^k_f where , in this case , the factor of 4 again arises from the spin and isospin factor . ( both up and down quarks are present in equal numbers . ) the color factor , @xmath116 , is cancelled by the baryon number of 1/3 of each quark . we need to modify the equations for the quark self - energy to take into account the presence of the fermi seas of up and down quarks whose fermi momentum is @xmath117 . we take one fermi sea to be composed of on - mass - shell up quarks with constituent mass @xmath72 . the following term is then added to the equation for @xmath61 . a_u^()(k)=-(2g_s)n_c2^k_f f^2(k- ) where @xmath118^\frac{1}{2}$ ] . the second factor of 2 in eq . ( 6.5 ) reflects the spin degeneracy . we note that @xmath72 is density - dependent and could be written as @xmath119 in keeping with the labelling of fig . 11 , where @xmath120 is used . also , if @xmath121 , @xmath122 would then represent @xmath123 , where @xmath124 is the scalar density associated with the up - quark fermi sea . in fig . 11 we show @xmath125 calculated for four values of @xmath126 and in fig . 12 we show _ m_(0 ) as a function of @xmath127 . since the quarks in the fermi sea are taken to be on - mass - shell , we would , in principle , require @xmath120 in minkowski space . however , since @xmath117 = 0.268 gev for the case of nuclear matter , only a very modest extrapolation of the curves shown in fig . 11 is needed for the densities considered in this work . in fig . 13 we show the value of the up quark condensate as a function of @xmath127 . ( note that @xmath128 represents the density of nuclear matter . ) it is seen that , for small values of the density , the density dependence of the condensate reproduces what is expected from eq . ( 6.1 ) . ( if we extrapolate the curve using a linear approximation , the condensate is reduced by about 30% at nuclear matter density . ) are shown for @xmath129 [ dotted line ] , @xmath130 [ dashed line ] , and @xmath131 [ dash - dot line ] . ] are shown as a function of @xmath127 . note that @xmath132 . note that @xmath132 we have remarked earlier in this work that the large values of the condensate ratio @xmath99 seen in table i play a role in obtaining a good fit to the mixing angles of the @xmath1(947 ) and @xmath133(958 ) mesons [ 18 ] . to understand this remark we note that the effective singlet - octet coupling constants for pseudoscalar states are [ 3 ] g_00^p&=&g_s-(++ ) , + g_88^p&=&g_s-(-2 - 2 ) , and g_08^p=-(2 - - ) , where @xmath134 , @xmath135 and @xmath136 . we take @xmath137 , so that g_08^p=-(-).if @xmath138 , the result for @xmath139 is six times larger than when @xmath140 . in addition to the effects of @xmath139 , singlet - octet mixing is induced by the quantity [ 18 ] e_08(k)=[e_u(k)-e_s(k)],where @xmath141^\frac{1}{2}$ ] , etc . it is found that , since @xmath139 and @xmath142 tend to cancel in our formalism , the significant singlet - octet mixing generated by @xmath142 is reduced by the values of @xmath139 obtained for the larger value of the ratio @xmath143 , with the result that we reproduce the values of the mixing angles found in other studies that make use of experimental data to obtain values for the mixing angles [ 18 ] . in our earlier work , which was carried out in minkowski space , the values of @xmath144 and @xmath19 were taken as parameters . inspection of our figures which exhibit values of @xmath102 and @xmath107 suggests that an extrapolation into minkowski space may be made if @xmath145 is not too large . the fact that @xmath72 and @xmath75 are close to our phenomenological parameters for @xmath93 is encouraging and suggests that some support for our choice of quark mass parameters may be found in our euclidean - space analysis . the full consequences of separating the specification of the nonlocality of the quark interaction from the choice of the regulator of the theory should be explored more fully . although that feature of our model introduces greater flexibility , that comes with the disadvantage of having to introduce other parameters in the model . we have made only limited variation of the form of the nonlocality and the regulator . for further applications it may be of interest to explore a more comprehensive parameter variation . it is also necessary to extend the calculations reported in figs . 1113 to larger values of the density than those considered here . that step will require more complex methods for solving our nonlinear equations for the self - energy than the simple iteration scheme we have used thus far . our work may be compared to that of alkofer , watson and weigel [ 29 ] who have solved the schwinger - dyson equation using a gluon propagator whose low - momentum behavior is enhanced by a gaussian function . ( that modification requires the introduction of two phenomenological parameters [ 30 ] . ) the behavior found for @xmath146 and @xmath147 in euclidean space is similar to that obtained in this work . . 1 of ref . those authors also solve the bethe - salpeter equation to obtain the properties of various @xmath148 mesons with generally satisfactory results . it is of interest to note that the minkowski space solution for @xmath146 and @xmath147 is such that the quark can go on - mass - shell . that feature may be related to our work [ 18 - 23 ] in which we use on - mass - shell quarks with masses @xmath149 gev and @xmath73 gev ( or 0.585 gev [ 18 ] ) when solving the bethe - salpeter equation in our study of @xmath150 mesons . 99 s. p. klevansky , rev . @xmath152 , 649 ( 1992 ) . u. vogl and w. weise , prog . @xmath153 , 195 ( 1991 ) . t. hatsuda and t. kunihiro , phys . @xmath154 , 221 ( 1994 ) . for reviews , see k. rajagopal and f. wilcek , in b. l. ioffe festscrift , at the frontier of particle physics / handbook of qcd , m.shifman ed . ( world scientific , singapore , 2001 ) ; + m. alford , hep - ph/0102047 . m. alford , j. berges and k. rajagopal , nucl . phys . b @xmath155 , 219 ( 1999 ) ; + j. kundu and k. rajagopal , hep - ph/0112206 ( 2002 ) . c. gocke , d. blaschke , a. khalatyan and h. grigoria , hep - ph/0104183-v2 ( 2002 ) . i. a. shovkovy , hep - ph/0110352 ( 2002 ) . m. alford , r. rajagopal and f. wilcek , phys . b @xmath156 , 247 ( 1998 ) . d. t. son , phys . rev . d @xmath157 , 094019 ( 1999 ) . t. sh@xmath158fer , e. v. shuryak and m. velkovsky , phys . @xmath159 , 53 ( 1998 ) . j. skullerud , d. b. leinweber , and a. g. williams , phys . rev . d @xmath152 , 074508 ( 2001 ) . h. ito , w. w. buck and f. gross , phys . c @xmath160 , 2483 ( 1991 ) ; c @xmath161 , 1918 ( 1992 ) . s. schmidt , d. blaschke , y. l. kalinovsky , phys . c @xmath162 , 435 ( 1994 ) . r. s. plant and m. c. birse , nucl . a @xmath163 , 607 ( 1998 ) . r. d. bowler and m. c. birse , nucl . a @xmath164 , 655 ( 1995 ) . r. s. plant and m. c. birse , hep - ph/0007340 and references therein . l. s. celenza , xiang - dong li , and c. m. shakin , phys . c @xmath165 , 1492 ( 1997 ) . + in this reference a negative value of @xmath41 was used . therefore , the sign on the right - hand sides of eqs . ( 2.4 ) and ( 2.5 ) , appearing in this reference , should be corrected to be positive . c. m. shakin and huangsheng wang , role of the t hooft interaction in the calculation of the mixing angles of the @xmath1(547 ) and @xmath166(958 ) mesons , brooklyn college + report no . bccnt : 01/082/307 ( 2001 ) . to be published in physical rev . c [ dh8173 ] . c. m. shakin and huangsheng wang , phys . d @xmath167 , 014019 ( 2000 ) . l. s. celenza , huangsheng wang , and c. m. shakin , phys . c @xmath167 , 025209 ( 2001 ) . c. m. shakin and huangsheng wang , phys . d @xmath167 , 074017 ( 2001 ) . c. m. shakin and huangsheng wang , phys . d @xmath167 , 114007 ( 2001 ) . c. m. shakin and huangsheng wang , phys . d @xmath152 , 094020 ( 2001 ) . g. amoros , j. bijnens , and p. talavera , nucl . b @xmath168 , 87 ( 2001 ) . m. asakawa and k. yazaki , nucl . a @xmath169 , 668 ( 1989 ) . v. bernard , ulf - g . meissner , and i. zahed , phys . d @xmath170 , 819 ( 1987 ) . f. gastineau , r. nebauer , and j. aichelin , hep - ph/0101289 ( 2001 ) . m. shifman , a. vainstein and v. zakarov , nucl . b @xmath171 , 385 ( 1979 ) ; 448 ( 1979 ) ; + l. reinders , h. rubinstein and y. yazaki , phys . rep . @xmath172 , 2 ( 1985 ) . r. alkofer , p. watson and h. weigel , hep - ph/0202053 ( 2002 ) . p. maris and p. c. tandy , phys . c @xmath173 , 055214 ( 1999 ) .

the nambu jona - lasinio ( njl ) model has been extensively studied by many researchers . in previous work we have generalized the njl model to include a covariant model of confinement . in the present work we consider further modification of the model so as to reproduce the type of euclidean - space momentum - dependent quark mass values obtained in lattice simulations of qcd . this may be done by introducing a nonlocal interaction , while preserving the chiral symmetry of the lagrangian . in other work on nonlocal models , by other researchers , the momentum dependence of the quark self - energy is directly related to the regularization scheme . in contrast , in our work , the regularization is independent of the nonlocality we introduce . it is of interest to note that the value of the condensate ratio , @xmath0 , is about 1.7 when evaluated using chiral perturbation theory and is only about 1.1 in standard applications of the njl model . we find that our nonlocal model can reproduce the larger value of the condensate ratio when reasonable values are used for the strength of the t hooft interaction . ( in an earlier study of the @xmath1(547 ) and @xmath1(958 ) mesons , we found that use of the larger value of the condensate ratio led to a very good fit to the mixing angles and decay constants of these mesons . ) we also study the density dependence of both the quark condensate and the momentum - dependent quark mass values . without the addition of new parameters , we reproduce the density dependence of the condensate given by a well - known model - independent expression valid for small baryon density . the generalization of our model to include a model of confinement required the introduction of an additional parameter . the further generalization to obtain a nonlocal model also requires additional parameters . however , we believe our results are of sufficient interest so as to compensate for the introduction of the additional parameters in our formalism .

in lattice qcd calculation , evaluating the fermion determinant is computationally expensive and as a consequence @xmath2 is often not evaluated and is simply set equal to a constant . this is called the _ quenched approximation _ and amounts to neglecting internal fermion loops . the goal of this work is to study the systematic error introduced by quenching and to compensate for quenching errors by constructing an expansion in quark - loop count and using it to improve monte carlo estimators of wilson loops measured on quenched gauge field configurations . we examine a source of statistical error and a method for its partial alleviation . with the full qcd action @xmath3 = s^{wilson}_{fermion}[u ] + s_{gauge}[u,\psi,\bar\psi ] \ ; , \label{eq : qcd_lattice_action}\ ] ] the expectation value of some operator , @xmath4 is given by @xmath5[d\psi][d\bar\psi ] { \cal o}e^{-s[u,\psi,\bar\psi ] } \nonumber \\ & = & \frac{1}{z } \int[du ] { \cal o}det{\bf m}[u]e^{-s_{gauge}[u ] } \ ; , \label{eq : o_expectation}\end{aligned}\ ] ] where @xmath6 det{\bf m}[u]e^{-s_{gauge}[u ] } \;. \label{eq : z_qcd}\end{aligned}\ ] ] by rewriting @xmath7 $ ] as @xmath8 & = & n_f \log{\det{{\bf m}[u ] } } \nonumber\\ & = & n_f \mbox{tr}\log{\bf m}[u ] \nonumber\\ & = & \delta s[u ] \ ; , \label{eq : delta_s_log}\end{aligned}\ ] ] and dividing through by @xmath9 , ( [ eq : o_expectation ] ) becomes @xmath10 { \cal o}e^{-s_{\rm gauge}[u ] } e^{(\delta s[u]-\left\langle \delta s\right\rangle ) } } { \int[du ] e^{-s_{\rm gauge}[u ] } e^{(\delta s[u]-\left\langle \delta s\right\rangle ) } } \;. \label{eq : o_reweighted}\end{aligned}\ ] ] expanding the exponential in the fluctuations in @xmath11 leads to @xmath12 here , the subscript on @xmath13 signifies the quenched expectation value of @xmath4 . in order to make use of ( [ eq : o_reweighted_first_order ] ) one needs to be able to find @xmath11 . we use the pad z@xmath0 method to find @xmath14 as per @xcite . the pad approximant for @xmath14 can be written as @xmath15 @xmath16 can be estimated using noise z@xmath0 vectors , @xmath17 . @xmath18 where @xmath19 are the solutions of @xmath20 where @xmath21 and @xmath22 . the variance of these estimators can be greatly reduced by subtracting suitably chosen traceless matrices @xmath23 where the @xmath24 are chosen to minimise the variance of the estimator . the @xmath25 used are @xmath26 where @xmath27 . the odd powers of @xmath28 are traceless , but the even powers greater than two are not . @xmath29 and @xmath30 are calculated from @xmath31 and @xmath32 link loops respectively . for this work we expand to order @xmath33 , using @xmath34 noise vectors and @xmath35 traceless subtraction matrices . the variational procedure to set @xmath24 was found not to be necessary and so we set them equal to unity . to solve ( [ eq : original_ax_equals_b ] ) we used the mr@xmath36 algorithm from @xcite and the odd even preconditioner in from @xcite . we apply the preceding numerical techniques to finding improved estimates of wilson loops . measurements were made on two sets of @xmath37 gauge field configurations ; a set of @xmath38 quenched qcd configurations and a set of @xmath39 full qcd configurations , generated using the milc collaboration software . both have @xmath40 , and the full qcd configurations have @xmath41 and @xmath42 . fig . [ fig : nodeltabetawilson ] shows the results for various wilson loops with corrections done to first order as per ( [ eq : o_reweighted_first_order ] ) in all of figs . [ fig : nodeltabetawilson ] [ fig : yesdeltabetawilsonrelativelimitedsum ] the loop number on the x axis labels @xmath43 from left to right in the following order : @xmath44 , @xmath45 , @xmath46 , @xmath47 , @xmath48 , @xmath49 , @xmath50 , @xmath51 , @xmath52 , @xmath53 , @xmath54 , @xmath55 . in figs . [ fig : nodeltabetawilson ] , [ fig : nodeltabetawilsonrelative ] and [ fig : yesdeltabetawilsonrelative ] , points have been offset slightly for clarity . a method for controlling the statistical error in ( [ eq : o_reweighted_first_order ] ) is suggested by looking at the form of the correlator between the diagonal elements of @xmath56 and the operator , @xmath4 , being measured . given that @xmath4 and @xmath11 can be written @xmath57 then the first order correction to @xmath4 can be written as @xmath58 if we write @xmath59 , where @xmath60 , then @xmath61 fig . [ fig : nodeltabetawilsonlogcorr3 ] shows @xmath62 and @xmath63 as a function of @xmath64 for the case @xmath65 . the former shows that the two operators are correlated , as would be expected . the latter shows that most of the signal for @xmath66 is at small @xmath67 and but most of the noise is at large @xmath67 , and that for large lattices this has the potential to swamp the signal . one way to address the problem is to cut the integral off at some @xmath68 . @xmath69 this has been done using @xmath70 , and the results are shown in fig . [ fig : nodeltabetawilsonrelative ] . the cut off scheme reduces the size of the statistical error but also looses some signal . the monte carlo estimator for @xmath71 is @xmath72 an efficient way to do this is with fourier convolution . given a windowing function @xmath73 , where @xmath74 then ( [ eq : o_reweighted_first_order_limited_sum_estimator ] ) becomes @xmath75_x \nonumber \label{eq : o_reweighted_first_order_limited_sum_estimator_fourier}\end{aligned}\ ] ] where @xmath76 and @xmath77 are defined in the usual way and implemented as fast fourier transforms . using this method to compute @xmath78 also makes it easy to choose a more elaborate windowing function should this be desired . following @xcite and identifying @xmath79 we again look at corrections to wilson loops . these are measured on a set of @xmath80 @xmath37 full qcd configurations with @xmath81 , @xmath41 and @xmath42 and also the set of quenched qcd configurations used earlier . the results are shown in fig . [ fig : yesdeltabetawilsonrelative ] and are in accordance with @xcite . a notable difference between the two is the computational savings afforded by the choice of algorithm for @xmath14 . use of unbiased subtractors means that only @xmath82 noise vectors are needed . in addition to this we do not have to fix the configurations to landau gauge . the previously mentioned method of cutting the integral off to reduce the statistical error turns out not to work for @xmath11 defined in ( [ eq : lw_delta_s ] ) . the contributions from @xmath14 and @xmath83 are nearly equal but are opposite in sign and so the total correction is small as is shown in fig . [ fig : yesdeltabetawilsonrelativenolimitedsum ] introducing a cutoff reduces the contributions from @xmath14 and @xmath83 by different amounts which produces a large variation in the total correction . this is shown in fig . [ fig : yesdeltabetawilsonrelativelimitedsum ] . we have also looked at corrections to two point functions but the noise is such that this method can not be used _ as is _ to provide improved mass measurements . a method of improving estimates of observables measured on quenched qcd configurations was tested on some sets of small ( @xmath37 ) configurations . expanding to first order in @xmath84 gave moderate improvement to estimators for wilson loops . analysis of the source of the statistical error hinted at problems that the method would have on larger lattices and with two point functions , and also suggested a technique for its partial alleviation . the technique does have the potential to address these problems but at the price of reducing the size of the correction . it was shown in @xcite that combining the above method with an appropriate shift in the gauge coupling can provide more accurate corrections to wilson loop values . we obtained the same results using a more economical method of calculating @xmath14 . we would like to thank keh - fei liu , john sloan and don weingarten for useful discussions and in particular keh - fei liu for his support of john markham during his visit to the university of kentucky . c. thron , s.j . dong , k.f . liu and h.p . ying , phys . rev . * d57 * ( 1998 ) 1642 ( hep - lat/9707001 ) . u. glassner , s. gusken , t. lippert , g. ritzenhofer , k. schilling and a. frommer , hep - lat/9605008 . a. frommer , b. nockel , s. gusken , t. lippert and k. schilling , int . c6 * ( 1995 ) 627 ( hep - lat/9504020 ) .

we use the pad z@xmath0 stochastic estimator for calculating @xmath1 to compute quark loop corrections to quenched qcd . we examine the main source of error in this technique and look at a way of controlling it .

in order to understand shocks in supernova remnants ( snr ) we need to separate three issues : intrinsic properties of the explosions themselves , the character of the snr environment , and observational constraints . in order to obtain fundamental facts about the explosion such as the age and energy released we must understand the structure of the circumstellar medium . in order to interpret observations we must understand observational limits imposed by the nature of single dish and interferometric observations . low frequency interferometric observations can help disentangle these three overlapping issues and will have the opportunity to contribute to three multifrequency issues : finding x - ray synchrotron emission , measuring spectral curvature predicted by particle theory , and clearing up uncertainties in observed spectral index variations . in order to understand supernovae ( sn ) and snr , we must separate snr from their environs . since snr are found preferentially near star forming regions , in the galactic plane , they are , not by chance , often in complex regions of the sky ( for a convincing example consult the galactic plane surveys by effelsberg : reich , reich , & fuerst , 1990 , 1997 ) . even something as simple as measuring the total flux from a snr requires imaging to avoid confusing the emission from nearby sources . while interferometers can over resolve the remnant , losing total flux information , fluxes obtained from single dish measurements often confuse the snr with nearby objects . an individual electron of energy e radiates its peak synchrotron emission at frequency @xmath0 . since frequency is proportional to the energy squared , we need the leverage of much wider frequency `` baselines '' to study subtle changes in the electron spectrum . comparing observations from 6 to 20 cm is only a range of 1.7 in energy , whereas 74 mhz to 4.6 ghz buys a factor in energy of 8 . low frequencies also avoid a scale problem . for the vla , many galactic snr are large enough they are over - resolved at wavelengths longer than 6 cm . total flux is more reliably measured at at lower frequencies . while low - frequency interferometric observations can be affected by absorption , even a lower limit to the flux would help firm up the predictions . x - ray emission in snr is generally considered to be thermal ; however , certain snr look suspiciously similar in the x - ray and radio ( such as g41.1 - 0.2 ; see dyer & reynolds 1999 ) . morphological similarity does not prove the x - rays are synchrotron but at the very least it suggests that x - rays are being excited at the same location as the relativistic electrons that produce radio synchrotron emission . in fact , x - ray observations of some snr like sn1006 ( koyama et al 1993 ) and ( slane et al . 2000 ) show the spectra are dominated by synchrotron emission . a more serious threat to our understanding of shocks is the possibility that other snr could have a smaller synchrotron component confusing the thermal emission this would stymie thermal fits and prevent accurate measurements of shock temperatures and elemental abundances . models have been developed by reynolds ( 1993 , 1996 ) to describe this emission . two simple models , _ srcut _ and _ sresc _ , are available in xspec 11.0 . these models rely on the radio flux and spectral index as reported by green ( 1998 ) . the models differ subtly the precise shape of the x - ray synchrotron spectrum can be used to determine properties of the snr , including the age of the shock , magnetic fields and electron energies and synchrotron losses . the models depend on accurate extrapolations of the radio synchrotron spectrum over eight orders of magnitude of frequency . the current state of this knowledge is very poor , as can be seen from examining collections of flux measurements ( truskin 1999 , see g041.1 - 0.2 for example ) . reported fluxes can vary by a factor of 1/3 to 2 , sometimes even between measurements made by the same instrument . most single dish instruments do not have the resolution to separate snr from nearby sources and absolute fluxes are not well calibrated from one instrument to another . the uncertainties reported in the literature are often absent or optimistic underestimates . low frequency interferometric observations can contribute reliable measurements with ( most importantly ) accurate uncertainties , allowing us to separate thermal and non - thermal x - rays . non - linear first - order fermi shock acceleration has been shown to be the leading model describing particle acceleration in snr shocks . since protons determine the shock structure , in the past particle codes studying shocks have ignored electrons . however it is commonly held that higher energy electrons have longer scattering lengths across the shock . if this is true , electrons interact differently with the shock . highly energetic electrons see a shock with a higher compression ratio than low energy electrons , and therefore gain more energy than their low energy counterparts . tests with particle codes including electrons by ellison & reynolds ( 1991 , 1992 ) showed the synchrotron spectrum , while very close , is not exactly a powerlaw it deviates very slightly concave upwards or flattening to higher energies . this subtle curvature had already been found observationally in single dish measurement of well studied remnants such as tycho and kepler . this is one of the few methods by which limits can be set on the magnetic field * independent * of the electron energy , putting us closer to to the goal of finding intrinsic properties of the snr . in some cases a single accurate measurements at low frequency can discriminate between models with different magnetic fields . it is worth noting that the spectral index variations theorists look for , to obtain insight on shock mechanisms , should be very small . snr look very similar from one frequency to the next . in addition , if parts of the remnant varied widely it would be unlikely that the spatial average would come as close as it does to a power law over three orders of magnitude in frequency . studies of spectral index variations across the face of the remnant bring out the worst in interferometric measurements . there are two serious problems underlying spectral index fluctuations reported in the literature . first , even with scaled arrays , interferometric observations at different frequencies have slightly different uv coverage . this difference is compounded by processing with non - linear deconvolution methods . second , if we are to believe the small effects we are looking for , we must be able quantify the noise accurately and the noise on extended sources , processed through clean or mem , is not well understood . a 3@xmath1 effect is meaningful only if @xmath1 is well known . we have found that re - observing a snr with the vla with slightly better uv coverage found spectral index variations on the same scale as previous observations : however these variations were in different locations with different signs ( dyer & reynolds 1999 ) . this was true even when linear regression algorithms were used , designed to take into account an offset due to lack of short - spacing information . however some snr do show statically significant variations ( & green 19 ? ? ) . the situation can be improved by adding single dish data , deriving indices from observations at three or four frequencies rather than two ( including lower frequencies ) , and by testing algorithms designed to avoid the zero spacing problem and finally by better understanding of the statistical noise across diffuse cleaned emission . the last two issues could be addressed by a small but critical project the techniques used to find spectral index variations ( regression methods , t - t plots and spectral tomography ) in snr could be used to look for spectral index variations where we know there should be none in thermal h ii regions such as the orion nebula . a thermal nebula should have a flat spectrum ( @xmath2 ) with no spectral index variations beyond statistical fluctuations , therefore the variations found would tell us something about the noise in our spectral index maps of snr . a thermal nebula also provides extended emission where the unknown effects of clean on source noise could be checked . green d.a . 1998,`a catalogue of galactic supernova remnants ( 1998 september version ) ' , mullard radio astronomy observatory , cambridge , united kingdom ( available on the world - wide - web at `` http://www.mrao.cam.ac.uk/surveys/snrs/ '' )

low frequency observations at 330 and 74 mhz can provide new insights into supernova remnants ( snr ) . we can test theoretical predictions for spectral index variations . nonlinear models of shock acceleration predict that the spectra from young snr should be slightly concave rather than power laws flattening toward higher energies . however , few snr are bright and compact enough to be studied at millimeter wavelengths , restricting studies to the small range from 6 to 20 cm ( a factor of 1.7 in electron energies ) . observations at 330 mhz increase the electron energy baseline to a factor of 4 , while providing sensitivity to larger spatial scales that are resolved out by centimeter - wavelength interferometers . such observations can also separate thermal from nonthermal emission and detect excess free - free absorption associated with cool gas in remnants . wide field images also provide an efficient census of both thermal and nonthermal sources over a large region .

the progressive loss of auditory function with advancing years , age - related hearing loss ( arhl ) , is the most common sensory ailment exhibited by the elderly population . recent estimates suggest that 438 million individuals worldwide experience moderate or severe forms of hearing loss , a large proportion of which is adult onset ( stevens et al . , 2011 ) . the etiology of arhl is complex ; the heritability is estimated to be between 35% and 55% ( christensen et al . , 2001 ; 2009 ) , and it is exacerbated by environmental factors , particularly noise ( van eyken et al . , 2007a ) . histological studies in both humans ( nelson and hinojosa , 2006 ) and animals ( fetoni et al . , 2011 ) show that when the cochlea is examined , the predominant pathological feature is loss of the sensory hair cells , with defects in the stria vascularis and spiral ganglion neurons also evident . associations that have been replicated include grhl2 ( van laer et al . , 2008 ) , kcnq4 ( van eyken et al . , 2006 ) , and nat2 * 6a ( unal et al . , 2005 ; van eyken et al . , 2007b ) in candidate gene studies , and 2 different metabotropic glutamate receptors , grm7 ( friedman et al . , 2009 ; van laer et al . , 2010 ) and grm8 ( girotto et al . , 2011a ) have been identified in genome wide association studies ( gwas ) . the gwas so far reported for adult hearing status exhibit the phenomenon of missing heritability also observed in other common , complex diseases ( manolio et al . , 2009 ) . given that more than 100 genes are known to be involved in congenital deafness then it is likely that a similar number are involved in susceptibility to arhl . the future challenge in delineating the etiology of arhl is to discriminate the valid associations that fall below the genome - wide significance threshold , using replication studies and functional genomics . 2005 ) and more severe ( pearson et al . , 1995 ) , with earlier onset ( davis et al . , 1995 ) , in men than in women . historically , this has been attributed to greater occupational noise exposure in men compared to women , but it is clear that sex differences in hearing loss exist in cohorts without a significant history of noise exposure ( girotto et al . it has therefore been suggested that estrogen may act as an auditory protectant , and there is now considerable evidence linking estrogen signaling , the estrogen receptors ( er ) , and estrogen - related receptors ( esrr ) with auditory protection ( hultcrantz et al . hence , mice carrying a targeted deletion of er display an age - related hearing loss at 12 months , concurrent with a basal to apical degeneration of the organ of corti in the cochlea ( simonoska et al . , 2009 ) . additional studies with mice deficient for both er and cyp19a1 , which encodes the aromatase enzyme responsible for the aromatization of androgens into estrogens , show that these mice exhibit an impaired response of the auditory system to acoustic trauma ( meltser et al . , furthermore , mutations in the estrogen - related receptor , esrrb , underlie autosomal recessive , non - syndromic hearing loss in humans ( dfnb35 ) ( collin et al . , 2008 ) , and esrrb knockout ( ko ) mice are deaf by 3 months of age ( chen and nathans , 2007 ) . a decline in hearing sensitivity has been linked to menopause in both humans ( hederstierna et al . in addition , women with turner 's syndrome who are estrogen deficient undergo an early sensorineural hearing loss characteristic of arhl ( beckman et al . , 2004 ) . estrogen - related receptor ( esrrg ; nr3b3 ; err3 ) is an additional member of the esrr family , which , together with esrrb and a third isoform esrra , form the nr3b subgroup of the well - characterized , nuclear receptor superfamily . all 3 paralogues are orphan nuclear receptors and share a high structural homology with the classical ers ( tremblay and giguere , 2007 ) . esrrg mrna has been shown to be present in the mouse embryonic inner ear in the cochlear and vestibular ganglion ( hermans - borgmeyer et al . , , we investigate the relationship between esrrg and adult hearing status in 3 independent cohorts , 2 population - based hearing cohorts and a case - control association study in a london - based arhl cohort . in addition , we report for the first time that esrrg knock - out mice are hearing impaired , and we characterize the expression of esrrg in the adult mouse inner ear . in regard to human participants , all studies had appropriate ethical consent , and consent forms for clinical and genetic studies were signed by each participant in the study . ethical approval for the london arhl cohort was granted from the royal free local research ethics committee ( ref 6202 ) . for the isolated populations cohort , approval was granted by the relevant local ethical committee . details of the ethical permission and consent for the 1958 british birth cohort ( b58c ) can be found at http://www.b58cgene.sgul.ac.uk/consent.php . in regard to animal use and care , sprague - dawley rats and c57bl/6j mice used in this study generation and care of the animals and experimental procedures were in accordance with institutional guidelines and national laws for protection of experimental animals , and were approved by the local animal ethics committee ( hamburg 69/01 ) . the b58c and the collection of hearing data have been described previously ( http://www.b58cgene.sgul.ac.uk/ ; ecob et al . , 2008 ; in brief , participants were drawn up from 17,638 individuals born in england , scotland , and wales in 1 week of march 1958 . of the original cohort , 9377 members were revisited by a research nurse for a biomedical follow - up in 20022004 . hearing measure consisted of pure tone audiometry at 1 khz and 4 khz at age 4445 years and were adjusted for sex , nuisance variables ( noise at test , nurse performing test , audiometer used in test ) , conductive loss , and hearing loss in childhood . dna was collected from 3900 of these individuals and genotyped for 555,164 single nucleotide polymorphisms ( snps ) on the illumina infinium human hap550 array ( data deposited by dr panos deloukas , wellcome trust , sanger institute , cambridge , uk ) . these genetic data have been used extensively as part of the wellcome trust case control consortium ( wtccc ) , ( https://www.wtccc.org.uk/ ) ( barrett et al . , 2009 ; wtccc , 2007 ) . no associations from the analysis of b58c genetic data and hearing thresholds at age 44 - 45 reached genome - wide significance ( a version of this analysis can be accessed at : http://www.b58cgene.sgul.ac.uk/ ) . a total of 260 patients with sensorineural hearing loss ( snhl ) consistent with an age - related decline were recruited from the adult hearing aid clinic at the royal national throat nose and ear hospital , london ; this formed our initial patient group ( arhl_1 ) . air conduction and bone conduction thresholds at 0.25 , 0.5 , 1 , 2 , 4 , and 8 khz and 0.5 , 1 , 2 , and 4 khz , respectively were measured with masking according to bsa recommended procedures ( http://www.thebsa.org.uk/docs/recpro/pta.pdf ) . at interview , a questionnaire was completed that recorded relevant medical history , family history of hearing loss , and history of noise exposure . this questionnaire was then amended based on answers to stage 1 questions to become self - directional , and patient recruitment was extended to the royal free hospital , london . an additional 323 patients were recruited across both hospitals , forming our replication group ( arhl_2 ) and bringing the total number of patients to 583 ( arhl_com ) . noise exposure was graded using the occupations listed by lynch and kil , 2005 and tak and calvert , 2008 as a guide : grade 0 = no noise exposure documented ; grade 1 = low to medium noise exposure ; and grade 2 = medium - to - high noise exposure . patients were not excluded from the study if there was an asymmetric hearing loss as long as the better hearing ear was consistent with the criteria for late - onset snhl . ( full details of the exclusion criteria are available upon request ) . with regard to controls , the control sample group comprised ecacc human random control ( hrc ) dna panels . in association analysis , isolated populations were recruited from italy and silk road countries ( for an overall number of 1651 subjects ) belong to the international consortium g - ear , described previously ( girotto et al . , 2011a ) . in brief , several quantitative measures of hearing function were undertaken : air conduction thresholds were determined at 0.25 khz , 0.5 khz , 1 khz , 2 khz , 4 khz , and 8 khz and pure tone averages ( ptas ) of air conduction thresholds were determined for : ptalow ( 0.25 , 0.5 and 1 khz ) , ptamedium ( 0.5 , 1 and 2 khz ) and ptahigh ( 4 and 8 khz ) . genomic dna was extracted from blood , using a standard phenol - chloroform extraction procedure , or from saliva , using oragene dna extraction kits ( dnagenotek , kanata , ontario , canada ) . the esrrg rs2818964 snp genotyping was performed using abi taqman snp genotyping assay ( c_222941_10 ) on a sds7500 real time pcr system ( life technologies , paisley , uk ) . genotyping rates for rs2818964 were : 99.7% , and 99.4% in arhl_com and control populations , respectively . genotype frequencies for rs2818964 did not deviate from hardy weinburg equilibrium ( hwe ) in arhl_1 ( p = 0.4000 ) , arhl_2 ( p = 0.7651 ) , arhl_com ( p = 0.4310 ) , or the control population ( p = 0.7199 ) . genotyping for the b58c and international consortium , g - ear has been described previously ( http://www.b58cgene.sgul.ac.uk/ ; barrett et al . , 2009 ; wtccc , 2007 ; girotto et al . cochlea , kidney , and spleen tissues were dissected from p2-p30 female rats and transferred to rnalater ( qiagen , manchester , uk ) , and total rna was extracted using a rneasy kit ( qiagen , manchester , uk ) . samples were treated with rq1 rnase - free dnase ( promega , southampton , uk ) , and 1 g rna was reverse transcribed in a 20-l reaction with omniscript reverse transcriptase ( qiagen , manchester , uk ) and random primers ( promega , southampton , uk ) . esrrg forward ( 5-agagttggtggttatcattggatg-3 ) and reverse ( 5-agaaggctcatctgatccgc-3 ) primers and gapdh forward ( 5-aacgggaagcccatcacc-3 ) and reverse ( 5-cagccttggcagcaccag-3 ) primers were used to amplify an 81 bp esrrg and 442 bp gapdh cdna fragment , respectively using 2 l cdna and 0.5 u gotaq dna polymerase ( promega , southampton , uk ) in a total volume of 20 l . esrrg : an initial denaturation step at 95 c for 2 minutes , followed by 40 cycles at 95 c for 15 seconds ; 60 c for 60 seconds ; and 72 c for 30 seconds . gapdh : an initial denaturation step at 95 c for 2 minutes followed by 25 cycles at 94 c for 30 seconds ; 60 c for 30 seconds ; and 72 c for 30 seconds . the rabbit polyclonal anti - esrrg antibody has been described previously and was a gift from dr ronald evans , salk institute for biological studies , san diego , ca , usa ( dufour et al . , 2007 ) and used at 1:200 , whereas goat anti - rabbit alexafluor488 secondary antibody was used at 1:1000 dilution ( life technologies , paisley , uk ) . auditory bullae were dissected from female mice , fixed in 4% paraformaldehyde for 1 hour at room temperature , washed in phosphate - buffered saline solution ( pbs ) and decalcified in 4.13% ethylenediaminetetraacetic acid ( edta ) , ph7.4 , in pbs for 72 hours at 4 c . bullae were mounted in 4% low melting point agarose ( sigma - aldrich , gillingham , uk ) and sectioned at 300 m using a 1000 plus vibratome ( intracel , royston , uk ) . vibratome slices were permeabilized and blocked in 0.5% triton - x 100 with 10% goat serum for 2 hours at room temperature and incubated with primary antibodies at 4 c overnight . after pbs washes , slices were incubated with secondary antibodies for 2 hours at room temperature in the dark . hair cell stereocilia were stained with phalloidin - atto 647n to f - actin ( sigma - aldrich , gillingham , uk ) , which was added to the secondary antibody incubations at 1:200 ; nuclei were visualized with 1 mol / l dapi . imaging was performed with a laser scanning confocal microscope ( lsm meta 510 ; zeiss , oberkochen , germany ) using 10 ( 0.3 na ) , 20 ( 0.75 na ) , and 63 ( 1.2 na ) objectives . a bacterial artificial chromosome ( bac ) clone containing the esrrg gene was identified from mouse strain 129/svj bac library pools ( genome systems , st . a 1665-bp pcr fragment ending with a synthetic nrui site in the second coding exon was amplified from the bac clone and used as the 5 homology region . it was placed in front of a lacz marker gene of ptlzn such that the start methionines of esrrg and that of the -galactosidase ( -gal ) reporter coincide . in addition , the parental vector harbors a pgk - neomycin - bpa ( neo ) cassette oriented in the opposite direction . a 4356-bp bamhi fragment starting further downstream at a bamhi site in the same exon and ending in the neighboring intron was used as 3 homology region . both the combination of 5 homology region with the lacz neomycin cassette and the 3 homology region were inserted in pko with a flanking diphtheria toxin subunit cassette ( dta ) as a negative selection marker . the construct was linearized with noti and purified by a standard phenol - chloroform extraction . the noti - linearized esrrg targeting construct was introduced by electroporation into r1 es cells ( 129 x1 129 s1 ) ( nagy et al . , 1993 ) , a kind gift from prof . toronto , on , canada ) , which were then selected with 200 g g418 per milliliter of medium . ecori - digested genomic dna prepared from resistant es cell clones was probed with a 509-bp fragment derived from genomic sequences located 3 of the targeting vector . the radiolabeled probe recognized a 20-kb fragment of the wild - type allele and an 11-kb fragment of the targeted allele . appropriate integration at the 5 end of the targeting construct was verified by rehybridization of the blot with a 912-bp fragment located 5 of the targeting vector . this probe hybridized to a 14.5-kb fragment in the targeted allele , as opposed to the 20-kb fragment in the wild - type allele . cells from 3 correctly targeted lines were injected into c57bl/6j blastocysts to generate chimeras , and chimeric males mated to c57bl6/j females transmitted the targeted allele to their offspring . dna was isolated with a genomic dna kit ( applichem , darmstadt , germany ) from tail tips . no mrna transcripts or protein for the esrrg gene were detected in the esrrg ko mice ( data not shown ) . studies were performed with littermates of the f2 and f3 generation of esrrg ko mice . to evaluate hearing thresholds abr to clicks were recorded in anesthetized animals ( xylazin hydrochloride 16 mg / kg body weight , and s - ketamin hydrochloride 60 mg / kg body weight ) in a sound - proof chamber . alternating acoustic stimuli were delivered monaurally at a rate of 21/s using a beyer dt-48 earphone and monitored with a probe microphone ( mk301 , microtech gefell , gefell , germany ) integrated into the earpiece . bioelectric potentials were recorded by subcutaneous silver electrodes at both mastoids and responses averaged ( 400 - 2000 ) . stimulus intensities were varied starting at 117 peak equivalent db spl [ pe db spl ] in increments of 20 db except near threshold where 5 db steps were used . the hearing threshold was defined as the lowest intensity to generate a reproducible abr waveform . for b58c , hearing thresholds at 1 khz and 4 khz were log transformed and adjusted for sex , nuisance variables , and conductive hearing loss in childhood ; they were analyzed by performing a 1-df per allele significance test for association between mean hearing threshold and number of minor alleles ( 0 , 1 , or 2 ) , and a 2-df significance test for association between mean hearing threshold and genotype . this analysis has been described previously ( http://www.b58cgene.sgul.ac.uk/ ; ecob et al . , 2008 ; strachan et al . , 2007 ) . results were ranked according to p value and the 500 snps with lowest p value analyzed as a candidate gene set ( see supplementary information s2 , available online ) . for the london arhl cohort , deviation from hwe and differences in genotype and allele frequencies were evaluated by test with a significance threshold of p unless otherwise stated , medcalc ( version 11.2 ) was used to calculate the odds ratios ( or ) and 95% confidence intervals ( ci ) . patient diagnosis was declared the dependent variable ( 1 = affected , 0 = unaffected ) , and sex and snp genotype the independent variables . sex was set as a categorical variable ( 1 = female , 0 = male ) . for the recessive and dominant genetic models , genotypes were set as a categorical variable : recessive ( gg = 1 , ga+aa = 0 ) ; dominant ( ga+gg = 1 , aa = 0 ) . for the additive genetic model , = aa , 1 = ga and 2 = gg ) . for the co - dominant model , genotypes were coded as for the additive model , but treated as independent categorical variables and the aa genotype set as the reference . all statistical tests were conducted using spss : statistics ( version 17.0 ) unless otherwise stated . for the candidate gene association analysis in the london arhl cohort , we used a p value of 0.05 as a test of significance , based on the primary analysis being that of a single snp in a single candidate gene . subsequent stratification analysis for effects of sex , family history , and noise exposure is a secondary analysis of the effect of the same snp and a bonferroni correction for multiple testing was therefore considered overly conservative . isolated populations cohort : association analysis was adjusted for age by regressing it out and the residuals were then normalized using rank normal transformation . association analysis was conducted using a mixed model linear regression , where the kinship matrix was the random effect and the snp the fixed effect as implemented in genabel ( aulchenko et al . , 2007 ) . hearing thresholds at age 44 to 45 years collected as part of the b58c ( ecob et al . , 2008 ) were compared to genetic data obtained on the same individuals as part of the wellcome trust case control consortium ( barrett et al . , 2009 ; wtccc , 2007 ) ( these data are available at http://www.b58cgene.sgul.ac.uk/phenosearch.php?pheno=6 ) . to investigate the role of estrogen in adult hearing , the 500 snps most strongly associated with hearing thresholds in the b58c gwas data were screened for presence of estrogen signaling genes . the rs2818964 snp located in the last intron of the long isoform of the esrrg gene ( transcript enst00000361525 ) was the only snp within an estrogen candidate gene locus identified in the top 500 snps . rs2818964 was associated with hearing status at 4 khz , allelic effect p = 0.0008 ( table 1 ) . because of the different roles of estrogen in males and females , the data were also dichotomized according to sex ; evidence of association was found to be stronger in males than in females for both allelic ( p = 0.0157 males ; p = 0.0212 females ) and genotype ( p = 0.0092 males ; p = 0.0624 females ) effects . detection of stronger associations with hearing loss in males can be a surrogate for the effect of greater noise exposure . however , stratification of data according to number of years of noise exposure ( > 5 years or < 5 years ) identified an association only in subjects reporting less than 5 years of noise exposure ( allelic effect p = 0.0004 ) . in each of these associations , the trend direction was consistent with the major allele , a , being associated with poorer hearing . no association was identified between hearing thresholds at 1 khz and snp rs2818964 . to determine whether the esrrg rs2818964 snp may be associated with risk of arhl , we performed a case - control association study in a london arhl cohort ( table 2 ) . the minor allele , g , of snp rs2818964 was more common in our initial patient group , arhl_1 , compared to controls , but only in women ( p = 0.0385 ) ( table 2 ) . this sex - specific association was consistent in our replication group , arhl_2 , and in the combined cohort , arhl_com , for both allele ( p = 0.0139 and p = 0.0058 , respectively ) and genotype effects ( p = 0.0384 and p = 0.0238 , respectively ) . backward logistic regression analysis with rs2818964 genotypes re - coded based on dominant , co - dominant , recessive , and additive inheritance models showed that the additive model alone was significant and identified a sex genotype interaction ( p = 0.0073 , or = 1.40 , 95% ci = 1.101.80 ) . in contrast to the trend direction observed in the b58c , these data suggested at least 1 copy of the minor allele , g , of snp rs2818964 is associated with risk of arhl in women . secondary analysis to examine the effect of noise exposure and family history of arhl on this association identified the strongest evidence of association in non noise - exposed women who report a family history of arhl ( allelic effect p = 0.0023 , org / a = 1.61 , 95% ci = 1.842.20 ; see supplementary information s3 , available online ) . in contrast , no evidence of an association was identified in males for any of the subgroups examined . the esrrg snp rs2818964 was genotyped in cohorts collected as part of the g - ear international consortium ( girotto et al . , 2011a ) incorporating cohorts from several distinct european isolated populations including carlantino , friuli venezia giulia genetic park , and different countries located along the silk road ( georgia , azerbaijan , uzbekistan , kazakhstan , and tajikistan ) . the relationship between the esrrg rs2818964 snp and quantitative measures of hearing were analyzed for each population and for the combined cohort . given the evidence of a sex - specific association in the london arhl cohort and the role of estrogen , males and females were examined separately ( table 3 ) . analysis of each population showed evidence of a significant association only in women from the carlantino population for thresholds averaged across pure tone average ( pta ) at low and medium frequencies and at each of the individual low and medium pure tone thresholds ( 0.125 , 0.25 , and 0.5 khz , 1 khz , and 2 khz ) , with the strongest association occurring at 2 khz ( p = 0.0065 ) . no evidence for association with hearing thresholds was found for women in the friuli venezia giulia genetic park and silk road populations or for males in any of the 3 populations . when data from the 3 cohorts were combined , evidence of an association was found with pta at medium frequencies ( allelic effect p = 0.0385 ) and at 1 khz ( p = 0.0157 ) in women only . for each of these associations , the minor allele , g , was associated with poorer hearing , which is consistent with the trend direction observed in the london arhl cohort but in contrast to the b58c cohort . to explore the role of esrrg in the cochlea , we generated a novel esrrg ko mouse model by targeting the second exon of the mouse esrrg gene with a lacz - neomycin fusion cassette by homologous recombination in mouse embryonic stem cells . consistent with the published data for the 2 previously reported esrrg ko mouse models ( s strain , salk institute , alaynick et al . , 2007 ; g strain , glaxosmithkline / deltagen , alaynick et al . , 2010 ) only a fraction of our mice homozygous for the esrrg deletion survived into adulthood ; most died in the early postnatal period before the onset of hearing . auditory evoked brain stem responses ( abrs ) hearing thresholds in esrrg heterozygotes were not statistically different from those in wild - type animals , and therefore both groups were pooled for controls . hearing thresholds in esrrg ko mice were significantly elevated at 5 weeks and 12 weeks of age ( fig . 1b ) . in the oldest group , at 18 weeks , this difference was still present , but only very few ko animals survived to 18 weeks of age ( n = 3 ) and this finding remained below statistical significance . when age groups were examined for sex effects , a statistically significant higher threshold in female compared to male esrrg ko mice was found at 12 weeks of age ( p < 0.05 , mann whitney rank sum test , fig . recorded potentials in wild - type and heterozygous mice displayed no obvious differences , whereas potentials in esrrg ko mice were of lower amplitude and altered in waveform ( fig . 2a and b ) and a distinct cluster of supporting cells adjacent to the third row of outer hair cells ( fig . 2a , b , and d ) which is consistent with the location of hensen 's cells . intense esrrg immunoreactivity was also detected in the elongated cell bodies of the inner and outer pillar cells ( fig . 2a c ) that were identified by phalloidin staining of f - actin in the apical and basal region . esrrg staining was not detected in outer hair cells , but appeared to localize in the supporting cell bodies of deiters ' cells and their phalangeal processes intervening the outer hair cells ( fig . abundant esrrg mrna was detected in p2 rat cochlea as well as positive control tissue p30 rat kidney and spleen ( fig . despite some recent progress in the genetic analysis of adult hearing , very little is known about the genetic risk factors for arhl , and virtually nothing about their role in the pathogenesis of this common sensory loss . in this study , based on the hypothesis that estrogen plays a role in protecting pre - menopausal women from arhl , we investigated whether variants in estrogen signaling genes may be risk factors for adult - onset hearing loss . the rs2818964 snp in the esrrg gene was associated with hearing status in a london arhl cohort , the minor allele being associated with poorer hearing but only in women . this association was replicated in the carlantino and the combined cohort of isolated populations from italy and silk road countries , both in the direction of the allelic effect and in the female - specific association . although this association had also been detected in the discovery cohort b58c , the effect was in the opposite direction with the major allele associated with poorer hearing and here the evidence of association was stronger in males than in females . replications should be cautious , as they may be spurious ; alternatively they can be indicators of real effects due to genetic architecture or differences in cohort characteristics ( lin et al . , 2007 ) . audiometric data are not trivial to collect , and therefore large , well - characterized cohorts are limited . here , we have sought to replicate an association in 3 of the largest cohorts , in a total of 6134 individuals . however , the cohorts have different characteristics that are not ideal for genetic replication . the b58c is a cross - sectional study of the uk population conducted at age 4445 years , younger than the subjects recruited for the london arhl case - control study . the average age in the london cohort is 71 years , and 96% of the women are more than 50 years of age and predominantly post - menopausal . the isolated populations cohort is population - based , 1892 years of age , and incorporating women more than 50 years of age , especially in carlantino . data from the london arhl and carlantino cohorts indicate a sex - specific predisposition to a low - to - mid frequency hearing loss in women is conferred by variation in the esrrg gene inherited as an additive trait . it is possible that the menopausal state of the women is a key determinant of the association with hearing status and esrrg genotype ; with the minor allele of the rs2818964 snp being a risk factor for arhl after estrogen declines in women after menopause and therefore not detected in the younger women in the b58c . this snp has previously been linked to risk of osteoporosis in women , an effect that also shows an interaction with the menopause status of women ( elfassihi et al . , 2010 ) . evidence of replication in our genetic cohorts are suggestive of a role for esrrg in maintenance of hearing ; but , given the difference in trend direction observed in the b58c , we sought functional evidence to establish the role of esrrg in hearing . to explore the function of esrrg in the auditory system , we generated a novel esrrg ko mouse model , and abrs to click stimuli were measured . our data showed that absence of the esrrg gene in mice leads to a mild hearing impairment at 5 weeks of age ; this hearing loss , although present , had not progressed by 12 and 18 weeks of age . strikingly , auditory thresholds were significantly worse in female mice compared to males at 12 weeks of age , resembling the sex difference observed with the rs2818964 snp in the london arhl and carlantino cohorts . relatively little previous studies with esrrg null mice show that these mice die in the first few weeks after birth because of abnormal heart function ( alaynick et al . , 2007 ) . gene expression profiling and chromatin immunoprecipitation ( chip)-on - chip analysis shows that esrrg regulates a network of genes that control oxidative metabolic function in embryonic and adult heart ( alaynick et al . , 2007 ; dufour et al . , 2007 ) , as well as genes involved in cellular ion homeostasis in tissues subject to high metabolic demand ( alaynick et al . , a number of these genes are involved in potassium transport , some of which are implicated in inner ear homeostasis ( wangemann , 2002 ) . in this study , we have shown for the first time that esrrg is expressed in the adult mouse inner ear . similar to the expression pattern of esrrb in the inner ear ( meltser et al . , 2008 ) , we find that expression of esrrg is widespread but predominantly confined to discrete supporting cell populations of the organ of corti , reissner 's membrane , and the inner hair cells . further work is required to establish the role of esrrg in the inner ear ; however , the known role of esrrgs in regulation of genes involved in ion homeostasis in other tissues with high metabolic demand is one that is also critical for cochlear function . one such gene involved in potassium ion transport that is reported to be down - regulated in a essrg ko mouse model is kcne1 ( alaynick et al . , interestingly , mice with targeted deletion of the kcne1 gene exhibit a profound hearing loss ( warth and barhanin , 2002 ) . in humans , mutations in kcne1 account for approximatelly 10% of cases of jervell and lange - nielsen syndrome , a syndromic form of deafness that presents with cardiac defects ( bitner - glindzicz and tranebjaerg , 2000 ) . therefore , 1 putative mechanism by which esrrg might underlie arhl is through down - regulation of the kcne1 gene , leading to impaired potassium ion homeostasis . in summary , our genetic association study , characterization of the expression of esrrg in the inner ear , and impaired hearing in our esrrg ko mouse model support an important role for esrrg in hearing , particularly for maintenance of hearing in women after menopause . it also provides further evidence of gwas as a discovery tool in complex disease to provide a candidate gene set for further investigation by the use of replication and functional genomics .

since estrogen is thought to protect pre - menopausal women from age - related hearing loss , we investigated whether variation in estrogen - signalling genes is linked to hearing status in the 1958 british birth cohort . this analysis implicated the estrogen - related receptor gamma ( esrrg ) gene in determining adult hearing function and was investigated further in a total of 6134 individuals in 3 independent cohorts : ( i ) the 1958 british birth cohort ; ( ii ) a london arhl case - control cohort ; and ( iii ) a cohort from isolated populations of italy and silk road countries . evidence of an association between the minor allele of single nucleotide polymorphism ( snp ) rs2818964 and hearing status was found in females , but not in males in 2 of these cohorts : p = 0.0058 ( london arhl ) and p = 0.0065 ( carlantino , italy ) . furthermore , assessment of hearing in esrrg knock - out mice revealed a mild 25-db hearing loss at 5 weeks of age . at 12 weeks , average hearing thresholds in female mice(-/- ) were 15 db worse than in males(-/- ) . together these data indicate esrrg plays a role in maintenance of hearing in both humans and mice .

over - the - counter ( otc ) derivatives represent a sizable fraction of financial transactions worldwide , encompassing a wide variety of contracts and asset classes . figure [ notionals_fig ] depicts the development in the otc derivatives markets for different asset classes since 1998 . although the increase in notionals has stopped since the peak of the financial crisis the overall growth is impressive . the contraction in some otc derivatives asset classes since the beginning of the crisis is clearly seen from table [ notionals.table ] , which shows gross notional values in different asset classes as of june 2007 and june 2010 . [ c]lrr asset class & 2007 & 2010 + commodity & 8,255 & 3,273 + equity linked & 9,518 & 6,868 + foreign exchange & 57,604 & 62,933 + interest rate & 381,357 & 478,093 + credit derivatives & 51,095 & 31,416 + other & 78 & 72 + total & 507,907 & 582,655 + [ notionals.table ] most bilateral otc contracts involve exchange of collateral between counterparties , to mitigate counterparty risk . however , there is evidence that collateral requirements in bilateral credit support annexes ( csas ) lead to non - negligible residual counterparty exposures . this is particularly the case in credit derivatives contracts where jump - to - default risk is typically not covered by bilateral collateral requirements @xcite . in fact , the collapse of aig in september 2008 was triggered by cds collateral requirements it could not meet . @xcite and @xcite both show that even in the extreme case of continuously collateralized cds contracts , counterparty risk is present , e.g. jump - to - default risk . @xcite find evidence of counterparty risk in the interdealer cds markets . @xcite finds that most large banks active in the otc derivatives market are under - collateralized . one of the solutions proposed for mitigating counterparty risk is the central clearing of otc derivatives . the dodd - frank wall street reform and consumer protection act of 2010 has mandated central clearing for standardized over - the - counter ( otc ) derivatives . many classes of otc derivatives are already being partially cleared through central counterparties ( ccps ) , e.g. lch clearnet for interest rate swaps ( irss ) , ice clear and cme for credit default swaps ( cds ) , fixed income clearing corp ( ficc ) for fixed - income otc derivatives and many others . the volume of otc derivatives cleared through central counterparties will most likely increase with the implementation of the dodd - frank act and increased capital requirements in basel 3 for non - cleared otc transactions . with a ccp , a bilateral otc derivative trade between two counterparties is replaced by two symmetric trades between the ccp and each counterparty . trading otc derivatives through a ccp has some desirable effects : in a bilateral market default of one entity can spread throughout the system leading to a chain of contagious defaults @xcite . a ccp can break this chain of contagion . it has been argued that clearing trades through a ccp leads to a gain in multilateral netting among market participants in the asset class being cleared , higher transparency , risk sharing among members of the clearinghouse , no duplicative monitoring , mitigation of counterparty risk as counterparties are insulated from each other s default , a reduction in commitment frictions @xcite . moreover , by centralizing information , supervision and transparency for regulators are facilitated while retaining trade anonymity , and from a moral hazard perspective it is less problematic to bail out a ccp compared to bailing out individual banks . while a ccp leads to higher multilateral netting it comes at the cost of reduced bilateral netting : if only a subset of otc contracts is cleared , netting _ across _ asset classes due to hedging is not accounted for , e.g. if a fixed income position is hedged with an otc interest rate derivative , separate clearing of the derivative leads to larger collateral requirements . [ c]lrrrr dealer & forwards & options & swaps & credit + jp morgan chase & 8,422 & 10,633 & 51,221 & 7,495 + bank of america & 9,132 & 6,908 & 50,702 & 5,649 + goldman sachs & 1,631 & 6,754 & 30,958 & 6,601 + morgan stanley & 1,127 & 3,530 & 26,112 & 6,307 + citigroup & 4,743 & 5,868 & 15,199 & 2,950 + wells fargo & 1,217 & 543 & 2,748 & 286 + hsbc & 595 & 185 & 1,565 & 913 + taunus & 667 & 20 & 162 & 144 + bank of new york & 371 & 304 & 404 & 1 + state street & 571 & 45 & 24 & 0 + total & 28,476 & 34,792 & 179,094 & 30,348 + [ indivnotionals2009.table ] [ c]lrrrr dealer & forwards & options & swaps & credit + jp morgan chase & 11,807 & 8,899 & 49,332 & 5,472 + bank of america & 10,287 & 5,848 & 43,482 & 4,367 + citigroup & 6,895 & 7,071 & 28,639 & 2,546 + goldman sachs & 3,805 & 8,568 & 27,392 & 4,233 + morgan stanley & 5,459 & 3,855 & 27,162 & 4,648 + wells fargo & 1,081 & 463 & 1,806 & 93 + hsbc & 758 & 127 & 1,901 & 700 + bank of new york & 420 & 367 & 555 & 1 + taunus & 848 & 21 & 199 & 33 + state street & 599 & 76 & 79 & 0 + total & 41,959 & 35,295 & 180,547 & 22,093 + [ indivnotionals2010.table ] tables [ indivnotionals2009.table ] and [ indivnotionals2010.table ] show the otc derivatives notionals in four different asset classes of the 10 largest us derivatives dealers . inspection of the tables reveals a decrease in the notional of the credit derivatives class between 2009 and 2010 . this is primarily a consequence of increased trade compression and the increased use of central clearing in the cds market @xcite : the first cds clearing facility , operated by ice clear , started its operations in 2009 and currently clears a sizable fraction of interdealer trades in index and single name corporate cdss . comparing table [ indivnotionals2010.table ] with table [ indivnotionals2009.table ] suggests that the central clearing of cdss initiated in 2009 and the resulting compression of bilateral trades led to an overall decrease of the magnitude of dealer exposures . to understand why central clearing of otc trades can lead to such a decrease in the sum of bilateral exposures , consider a stylized market of four participants with bilateral exposures like shown in the left part of figure [ bilateral_fig ] . in this market the sum of bilateral exposures amounts to 350 , taking into account bilateral netting . introducing a ccp enables _ multilateral netting _ of the exposures ( figure [ bilateral_fig ] , right ) which reduces the total net exposure to 180 . the above example highlights the benefits of multilateral netting through a ccp . but there are also situations where central clearing of a single asset class may actually increase overall net exposures . if only a subset of otc contracts is cleared , netting _ across _ asset classes due to hedging is not accounted for . for instance , if a fixed income position is hedged with an otc interest rate derivative , separate clearing of the derivative leads to larger exposure , which in return leads to larger collateral requirements . a relevant question is thus to compare the impact of these two competing effects : * the reduction of net exposures due to multilateral netting across counterparties through central clearing , and * the increase in net bilateral exposures through the loss of netting across asset classes . in an influential paper widely disseminated to regulators , @xcite argue that if only a subset of otc contracts is cleared in a clearinghouse , then there may be a loss of netting _ across _ asset classes which exceeds the gain in multilateral netting across market participants . this conclusion has been interpreted by some to mean that ccps increase net exposure. [ [ contribution ] ] contribution + + + + + + + + + + + + in the present work , we reconsider the impact of central clearing of over - the - counter ( otc ) transactions on counterparty exposures in a market with otc transactions across several asset classes with heterogeneous characteristics . we find that the impact , on total expected interdealer exposure , of introducing a central counterparty for a single class of otc derivatives is highly sensitive to assumptions on heterogeneity of asset classes in terms of ` riskyness ' of the asset class as well as correlation of exposures across asset classes . in particular , while a model with independent , homogeneous exposures suggests that central clearing is efficient only if one has an unrealistically high number of participants , these conclusions are not robust to departures from the assumptions of independent and homogeneity . in fact , we find that the opposite conclusion is reached if differences in riskyness across asset classes are realistically taken into account . empirically plausible specifications of these parameters lead to the conclusion that the gain from multilateral netting in a ccp overweighs the loss of netting across asset classes in bilateral netting agreements . when a ccp exists for interest rate derivatives , adding a ccp for credit derivatives is shown to decrease overall exposures . this result distinguishes our study from @xcite where the marginal effect of clearing credit derivatives is very limited when interest rate swaps are already being cleared . these findings are shown to be robust to the choice of distribution for otc credit derivatives exposures . [ [ outline ] ] outline + + + + + + + the remainder of the paper is structured as follows . section [ model_section ] introduced a stylized model of an otc market with @xmath0 different asset classes and examines how the separate or joint clearing of one or more asset classes in a ccp affects bilateral exposures . section [ sec : heterogeneity ] emphasizes the key role played by assumptions on heterogeneity of various parameters heterogeneity of riskyness across asset classes , heterogeneity of exposure sizes across dealers and proposed a flexible parameterization to account for this heterogeneity . section [ analysis_sec ] uses this framework to study how the introduction of ccps affects otc derivatives exposures , using three different risk measures . finally , section [ conclusion_sec ] concludes . to compare the impact on exposures of multilateral netting across counterparties , as opposed to cross - asset netting in otc markets with bilateral transactions , we consider a market where @xmath1 participants trade over - the - counter derivatives in @xmath0 different asset classes , labeled @xmath2 . collateral requirements , whether bilateral or in ccps , are typically based on an estimation of exposures over a horizon which we denote by @xmath3 ; the net value of the total positions at some future time point that @xmath4 owns of derivatives belonging to asset class @xmath5 with @xmath6 as the counterparty . the exposure of @xmath4 to @xmath6 in asset class @xmath5 is then defined as @xmath7 we want to compare total exposures across three configurations : 1 . the total exposure @xmath8 of company @xmath4 under bilateral netting ( no central clearing ) : @xmath9 2 . the exposure @xmath10 assuming asset class @xmath0 is cleared through a central counterparty @xmath11 where @xmath12 denotes the fraction of asset class @xmath5 that is being cleared . hence in this case we have that , @xmath13 for @xmath14 . the exposure @xmath15 when two asset classes @xmath16 and @xmath0 are separately cleared through a central counterparty @xmath17 where @xmath13 for @xmath18 . in equation all netting is done bilaterally across all @xmath0 asset classes and the total net exposure of dealer @xmath4 is the sum of the net exposure with each counterparty @xmath6 . when a ccp is introduced in the market , as in equations and , the total net exposure is the sum of the bilateral net exposures to all counterparties and the exposures to the ccps . hence , the introduction of clearinghouses transfers exposure reductions from bilateral netting to multilateral netting . whether the introduction of a clearinghouse increases or decreases net exposures depends on the particular market , e.g. the notional sizes of the asset classes , riskyness of the asset classes , correlation between the asset classes , the number of asset classes , the number of banks etc . in terms of dealer risk management our analysis underestimates the risk reduction from central clearing since we put the same risk weights on bilateral dealer exposures and exposures to a ccp . in most cases the riskyness of a ccp will be lower than that of a dealer - and hence have a smaller risk weight . the reader is referred to @xcite for a model to quantify the ccp risk a dealer faces when participating in a ccp . in the sequel we consider different distributional choices for the exposures , and we compare expected net exposures , value at risk ( var ) , expected shortfall and the mean of the maximum of realized exposures across dealers across various clearing scenarios . the stylized model above requires assumptions on the joint distribution of exposures . let us first consider the baseline case where @xmath19 are normally distributed for all @xmath20 and allowed to be correlated across asset classes . as in @xcite , we assume that the standard deviation of @xmath3 is proportional to the credit exposure @xmath21 [ c]lr asset class & exposure + commodity & 457 + equity linked & 706 + foreign exchange & 2,524 + interest rate & 17,533 + cds & 1,666 + other & 1,788 + total & 24,673 + [ exposures.table ] table [ exposures.table ] shows the gross credit exposures @xmath22 in six different asset classes as of june 2010 . otc interest rate derivatives clearly account for the major portion of this value . consider first a market where only one single asset class is being cleared . in @xcite it is shown that if @xmath23 for all @xmath24 and if the exposures are uncorrelated , the number of entities required to participate in the central clearinghouse has to be equal to or greater than 461 in order to see a reduction in expected exposures : this is an unrealistically high number , so it would imply in practice that existing clearing schemes do not result in reduction of exposures . but , altering the assumption on risk per dollar notional to e.g. @xmath25 in the same model , the picture is changed dramatically and the threshold number drops to 54 . if furthermore we assume the correlation between the asset class exposures is , e.g. , @xmath26 , then the number of clearing members needed to achieve compression of exposures is down to ... 17 ! table [ participants.table ] reports the required number of participants for different scenarios . figure [ clearingmembers_fig ] depicts the minimal number of members required to participate in the clearinghouse in order to see expected exposure reductions as a function of correlation and riskyness of the cleared asset class . the figure clearly reveals that the base case considered in @xcite . @xmath27 and @xmath28 , is a singularity : a slight deviation from these parameters alters the conclusions of the model dramatically . [ c]lr assumptions & @xmath1 + duffie & zhu s example : & + @xmath29 & 461 + @xmath30 & + @xmath31 & 54 + @xmath32 & + @xmath31 & 17 + @xmath33 & + @xmath31 & 11 + [ participants.table ] required to participate in the ccp in order to see a reduction in the expected exposures as a function of riskyness of the asset class being cleared @xmath34 and the correlation between asset classes @xmath35.,scaledwidth=90.0% ] these observations illustrate that , even in a simple setting with ( gaussian ) identically distributed exposures , the tradeoff between netting across asset classes versus multilateral netting across market participants is highly sensitive to assumptions on the correlation of exposures and the heterogeneity of riskyness across asset classes . conclusions based on a model with homogeneous risk across asset classes are not robust to departures from this homogeneity assumption . we now introduce a model which allows to parametrize this heterogeneity of exposure sizes across dealers and asset classes and differentiates various asset classes in terms of their risk characteristics , as measured by the risk ( or collateral requirement ) per dollar notional . instead of credit exposures we now use notional values to determine the distribution of the @xmath3s and assume that they are proportional to the notional values via @xmath36 where @xmath37 is a random variable with zero mean and unit variance , and @xmath38 is the total notional size of dealer @xmath4 in asset class @xmath5 . in this way the exposure of @xmath4 to @xmath6 in class @xmath5 is a weighted fraction of company @xmath4 s total notional in derivatives class @xmath5 , where the weight equals @xmath6 s notional size in asset class @xmath5 relative to the total notional size of the dealers in asset class @xmath5 . we first study the case where @xmath37 is a standard normally distributed variable . in the gaussian case we can get closed formulas for the expected net exposures @xmath39 = & \frac{1}{\sqrt{2\pi}}\sum_{j\neq i } \sqrt{\sum_{k=1}^k \sum_{m=1}^k \rho_{km } \beta_k z_i^k \frac{z_j^k}{\sum_{h\neq i } z_h^k } \beta_m z_i^m \frac{z_j^m}{\sum_{h\neq i } z_h^m}}\\ \mathbf{e}\left[e_i^1\right ] = & \frac{1 } { \sqrt{2\pi } } \sum_{j\neq i } \sqrt{\sum_{k=1}^{k } \sum_{m=1}^{k } \left ( 1 - w_{k } \right)\left ( 1 - w_{m } \right ) \rho_{km } \beta_k \frac { z_i^kz_j^k}{\sum_{h\neq i } z_h^k } \beta_m \frac { z_i^mz_j^m}{\sum_{h\neq i } z_h^m}}\nonumber\\ & + \frac{1 } { \sqrt{2\pi } } \beta_k w_k z_i^k \frac{\sqrt { \sum_{j\neq i } \left(z_j^k \right)^2}}{\sum_{h\neq i } z_h^k } \\ \mathbf{e}\left[e_i^2\right ] = & \frac{1 } { \sqrt{2\pi } } \sum_{j\neq i } \sqrt{\sum_{k=1}^{k } \sum_{m=1}^{k } \left ( 1 - w_{k } \right)\left ( 1 - w_{m } \right ) \rho_{km } \beta_k \frac{z_i^k z_j^k}{\sum_{h\neq i } z_h^k } \beta_m \frac{z_i^m z_j^m}{\sum_{h\neq i } z_h^m}}\nonumber\\ & + \frac{1 } { \sqrt{2\pi } } \beta_{k-1 } w_{k-1 } z_i^{k-1 } \frac{\sqrt{\sum_{j\neq i } \left(z_j^{k-1 } \right)^2}}{\sum_{h\neq i } z_h^{k-1 } } \nonumber\\ & + \frac{1 } { \sqrt{2\pi } } \beta_k w_k z_i^k \frac{\sqrt{\sum_{j\neq i } \left(z_j^k \right)^2}}{\sum_{h\neq i } z_h^k } \end{aligned}\ ] ] where @xmath40 for @xmath41 . we compute the value at risk and expected shortfalls at the 99% level by simulation as these quantities are not available in closed form . we also assume that the value of the cds positions are given by @xmath43 where @xmath44 is a normalized @xmath42-distribution with unit variance and 3 degrees of freedom @xcite . the other asset classes are kept normally distributed as in equation . correlation between the classes with different distributional assumptions is introduced via a normal copula with correlation parameter @xmath35 . in the case of the @xmath42-distribution the risk measures are not known in analytical closed form so we will use simulation in order to compute them . another important feature which affects the analysis is the difference of asset classes in terms of riskyness . for example , an interest rate swap and a cds with same notional and maturity typically will not lead to the the same collateral requirements , since their risk is not considered to be identical . a simple metric for this is the exposure per dollar notional for a given asset class . to obtain an estimate of this parameter for various asset classes , a simple approach is to examine the standard deviation of the historical daily profit / loss , in terms of percentage of contract notional . for the cds asset class , we estimate @xmath45 as the mean of the standard deviation of the daily profit - loss of 5-year credit default swaps on the names constituting the cdx na ig hvol series 12 in the period july 1st , 2007 to july 1st , 2009 . in the estimation the notionals of the cdss are assumed equal to 1 and the recovery rate equal to 0.4 . for the same period , we compute the @xmath46 for the interest rate class as the standard deviation of the historical daily profit - loss from holding a 5-year interest rate swap with notional of 1 and we use this estimate for all asset classes other than the cds class . the estimated values are @xmath47 i.e. the risk per dollar notional is around three times higher for the cds asset class . using the setting described in the previous section , we now compare the magnitude of inter - dealer exposures under different market clearing scenarios : 1 . no central clearinghouse . 2 . one central clearinghouse for irss . 3 . one central clearinghouse for cdss . 4 . two central clearinghouses : one for irss and one for cdss . 5 . one central clearinghouse for both irss and cdss . given that , in each of these scenarios , the total interdealer exposure is a random variable , we need a criterion for evaluating the magnitude of exposures . @xcite focus on the _ expected exposures _ ; to check for robustness of results with respect to this choice we have computed various risk measures for the total interdealer exposure in each scenario : * expected exposure * @xmath48 quantile of the total exposure * @xmath48 tail conditional expectation these risk measures are reported below in terms of the ratio to their value under the base scenario where no clearinghouse exists . currently some markets for otc derivatives are already being cleared . following a meeting on january 27th , 2010 at the federal reserve new york , 14 major dealers say in a letter of march 1st , 2010 that they will aim to centrally clear @xmath49 of new and historical credit derivatives trades . in interest rate derivatives , dealers are working to clear @xmath50 of new eligible trades . we will use these clearing fractions in equations - when evaluating the above scenarios . in the case where one single ccp clears both irss and cdss the classes can be considered to belong to the same class and we use equation we use the notional values reported in table [ indivnotionals2009.table ] and assume that there exist 10 identical european dealers , hence the total number of participants is 20 . this is not a high number , at the time of writing the number of participants in swapclear at lch clearnet is 38 . for the case of the gaussian cds exposures we use the analytical formulas to compute the expected exposures and @xmath51 simulated scenarios to compute the other two risk measures . when @xmath42-distributed exposures are involved we approximate the three measures using @xmath51 simulations and correlate the exposures across asset classes via a gaussian copula . tables [ riskmeasures2009rhozero.table ] and [ riskmeasures2009rho01.table ] report the results for the cases where the exposures are decorrelated and correlated with @xmath52 , respectively . from table [ riskmeasures2009rhozero.table ] , comparing the case of no central clearing in the market to the case where the otc interest rate swaps are cleared ( columns 1 , 5 and 9 ) , we see that the overall exposures are reduced significantly for almost all dealers and in all risk measures . the notional positions of the dealers who have no reduction are very small compared to the total notionals of the 10 biggest dealers . the rows with totals report the total expected exposure of all 20 dealers relative to the total expected exposures in the scenario 0 with no ccp . we only compute the total " for the expected exposures as the other two risk measures are not additive . while it is debatable whether the introduction of a clearinghouse for cdss will reduce exposures when there is no existing clearinghouse in the market ( columns 2 , 6 and 10 ) , the results are more definitive when the interest rate class is already being cleared ( columns 3 , 7 and 11 ) . for both distributional choices of the cds class , adding a ccp for the cds class decreases the three different risk measures . depending on the assumptions made , the total expected exposures are decreased with additional 6 - 11% compared to the case when only interest rate swaps are cleared . in absolute values this corresponds to reductions in the order of usd 41 - 76 billions in total expected net exposure . in the case where a single ccp clears both irss and cdss the net exposure reductions are higher since multilateral netting is possible across both types of derivatives classes . we also note that the difference in exposure reductions between scenarios 1 ) and 3 ) are bigger than the difference between scenarios 3 ) and 4 ) , and especially for the risk measures var and expected shortfall . hence , the decision to clear the cds asset class is the most important , whether it is done by the same ccp that clears irss or not . as expected , the results reported in table [ riskmeasures2009rho01.table ] confirm that in the presence of positive asset class correlation , introduction of central clearinghouses increases the benefit from clearing compared to the zero correlation case . all the fractions are slightly smaller with a correlation parameter of @xmath52 . when the asset classes are positively correlated the exposure reductions due to bilateral netting across classes are reduced . interestingly , we note that using @xmath42-distributed cds exposures instead of gaussian exposures does not change the conclusions . for the different scenarios , table [ maxexposures.table ] reports the average of the maximum realized net exposure across dealers , which can be interpreted as a worst case measure of dealer exposure . yet again we observe that scenarios 1),3 ) , and 4 ) result in significant exposure reductions . [ c]lrrrrrscenario & bilateral & irs & cds & two & joint + & & ccp & ccp & ccps & ccp + gaussian cds , @xmath27 & 136,460 & 114,340 & 138,830 & 108,110 & 103,190 + gaussian cds , @xmath52 & 145,040 & 120,440 & 144,850 & 113,130 & 109,160 + t - distributed cds , @xmath27 & 136,020 & 111,630 & 138,480 & 107,770 & 103,070 + t - distributed cds , @xmath52 & 144,140 & 117,500 & 144,370 & 112,650 & 108,820 + [ maxexposures.table ] for the different clearinghouse scenarios , figure [ histograms_fig ] depicts the histograms of the reduction in exposures across counterparties @xmath53 where @xmath54 corresponds to the clearing scenario , in a market with 20 participants and independent gaussian exposures . positive values correspond to cases where central clearing reduces the exposure . hence , scenarios 1),3 ) , and 4 ) are generally giving rise to positive reductions in exposures . in particular it is observed how the cds clearing scenarios 3 ) and 4 ) significantly reduce the tail of the distribution of differences compared to scenario 1 ) where only irs are cleared . using a stylized model of otc exposures with multiple asset classes , we have compared the effects of bilateral netting across classes with those of multilateral netting across counterparties as allowed in a ccp . we find that the impact , on total expected exposure , of introducing a central clearing facility for a given class of otc derivatives is highly sensitive to assumptions of heterogeneity across asset classes in terms of riskyness , as measured by the exposure per dollar notional , as well as correlation of exposures across asset classes . the base example ( iid , homogeneous gaussian exposures ) previously considered by @xcite suggested that ccps are inefficient in reducing exposures unless one has an unrealistically high number of participants , but the opposite conclusion is reached if plausible model parameters are used to take into account differences in riskyness across asset classes . a second finding is that , when a ccp already exists for interest rate swaps , clearing of credit derivatives decreases exposures whether it is done by a new ccp or by the same ccp clearing irss . this result distinguishes our study from @xcite where the marginal effect of clearing credit derivatives is very limited when interest rate swaps are already cleared . the findings are robust to distributional assumptions on ( cds ) exposures . we find , as in @xcite , that the exposure reduction is highest if one ccp clears all asset classes . however , this scenario would lead to a high concentration of systemic risk in the clearinghouse and also expose it to a high level of operational risk , since simultaneous clearing of different asset classes requires a more sophisticated risk management technique . a serious examination of the benefits and drawbacks of having multiple ccps can not be done solely based on expected exposures and requires a model where systemic risk can be quantified as part of the tradeoff .

we study the impact of central clearing of over - the - counter ( otc ) transactions on counterparty exposures in a market with otc transactions across several asset classes with heterogeneous characteristics . the impact of introducing a central counterparty ( ccp ) on expected interdealer exposure is determined by the tradeoff between multilateral netting across dealers on one hand and bilateral netting across asset classes on the other hand . we find this tradeoff to be sensitive to assumptions on heterogeneity of asset classes in terms of ` riskyness ' of the asset class as well as correlation of exposures across asset classes . in particular , while an analysis assuming independent , homogeneous exposures suggests that central clearing is efficient only if one has an unrealistically high number of participants , the opposite conclusion is reached if differences in riskyness and correlation across asset classes are realistically taken into account . we argue that empirically plausible specifications of model parameters lead to the conclusion that central clearing does reduce interdealer exposures : the gain from multilateral netting in a ccp overweighs the loss of netting across asset classes in bilateral netting agreements . when a ccp exists for interest rate derivatives , adding a ccp for credit derivatives is shown to decrease overall exposures . these findings are shown to be robust to the statistical assumptions of the model as well as the choice of risk measure used to quantify exposures .

low back pain ( lbp ) is one of the most common problems in adolescents and adults1 , 2 . many studies indicate that nonspecific low back pain in these individuals is caused by occupational factors . many factors affecting low back pain such as anthropometric data in individuals twenties , physiological structure , genetic factors , age , gender , smoking , the duration of working with a computer , lumbar support usage , school furniture , sitting position , physical activity , and socio - economic situations have been investigated3 , 4 ) . although lbp is a physical and physiological disorder , it is commonly manifested as an occupational factor . moreover , it may be seen in school and university students who have not yet entered their working life , and may induce permanent symptoms6 . the prevalence of lbp increases with an increase in classes7 . however , the recent extraordinary increase in the data has made it difficult to process , evaluate and convert it into information . thus , the aim of this study was to investigate the factors affecting nonspecific low back pain of university students , using the chaid analysis method , which can examine much data at the same time . a total of 514 ( 311 females and 203 males ) university students with nonspecific low back pain , aged between 17 and 29 ( mean : 20.51.8 ) were included this study . the exclusion criteria were having any kind of musculoskeletal , orthopedic , rheumatic , somatic or psychiatric disorder . subjects were selected from the faculty of medicine , faculty of engineering , faculty of science - literature , and faculty of education by a convenience sampling method . a special questionnaire was created to investigate the pre - determined factors affecting nonspecific low back pain . these factors included gender , weight , height , bmi , working periods sitting straight ( television , computer , seminar , etc . ) , working periods bending at a table ( reading , writing , etc . ) , using lumbar support while sitting , the mean duration of pain within the last one year , type of pain , time of the pain , faculty , class , physical activity habits and smoking . these data and demographic data were recorded under the supervision of a physiotherapist . a visual analogue scale ( vas ) was used to determine the severity of the pain . on the vas scale , was indicated by the zero point , no pain , and unbearable pain by the point of 100 on a vertical line of 100 mm . the types of pain were chosen as combustive , stinging , obtuse and pulsative pains . in order to evaluate the durations of working hours bending at a table and staying upright , those who had quit smoking were included under the smoker category , and to determine the activity levels of the subjects , all subjects were asked to define themselves to be active or passive according to the criteria of our survey . categorical data were indicated as percentages . in order to determine how the variables explain nonspecific low back pain , the chaid ( automatic interaction detection ) method of decision trees was used . the chaid analysis is a method that determines the relations between the variables in the formed matches , and expresses the results in the shape of a tree and its branches . this analysis divides the data set of categorical variables into detailed homogeneous sub - groups that explain the dependent variable in the best way . when checking if the grouping of the variables is proper or not , it uses the bonferroni recovered p value9 . for this study , nonspecific low back pain was determined as the dependent variable , and the independent variables that could explain the reason of the pain were examined . a total of 514 students with nonspecific low back pain were evaluated : 229 ( 44.6% ) of them were from the faculty of medicine , 87 ( 16.9% ) of them were from the faculty of engineering , 104 ( 20.2% ) of them were from the faculty of education , and 94 ( 18.3% ) of them were from the faculty of science - literature . their bmis , departments , classes , physical activity , smoking status , usage of lumbar support , pain duration , working durations , and gender are shown as n and percentages in table 1table 1 . 14.8185.8489.4facultyhealth70 34.515951.122944.6engineering6833.5196.18716.9educational4723.25718.310420.2art188.97624.49418.3classfirst year5225.66219.911422.2second year673310634.117333.7third year3919.26821.910720.8fourth year4522.27524.112023.3physical activityinactive11355.7214 68.832763.6active9044.397 31.218736.4smokingex - smoker or smoker86 57.68273.616832.7non - smoker11742.422926.434667.3lumbar supportnot used106 52.2166 46.625148.8used29747.8145 53.426351.2duration of paina few days3215.8299.36111.9one week10250.217556.327753.9more than a week2612.83210.35811.3one month3517.26019.39518.5more than one month83.9154.8234.5working periods sitting straight ( last week)none73.420.691.8110 hours2311.33611.65911.51120 hours209.9268.446 8.92130 hours2813.84113.269 13.43140 hours2813.85718.38516.54150 hours2311.444 14.1671.350 over7436.510533.817934.8working periods bending at a table ( last week ) none2110.3154.8367110 hours49 24.17022.511923.21120 hours3919.25116.49017.52130 hours2713.36119.68817.13140 hours3014.83410.96412.54150 hours104.9278.7377.250 over2713.353178015.6bmi : body mass index . dependent variable were identified by the analysis , which determined that working duration , bending at table , physical activity , gender , weight , height , bmi and educational department did not affect the pain . the strongest associated variable was duration of pain complaints within the last one year the pain severity of students with pain lasting longer than one month was determined as the highest mean value , 5.951.69 cm . the pain severity of students with pain lasting for a few days within the last one year was found to have the lowest mean value , 3.681.84 cm . a short duration of pain in the last one year indicated low pain severity , and long duration indicated high pain severity . in the students indicating a pain duration of one week or longer within the last one year , it was determined that working duration and sitting upright affected the severity of the pain ( p=0.001 ) . the severity of the pain was determined as 4.771.56 cm for the students whose working periods sitting straight were over 30 hours within the last week , and as 4.161.43 cm for = students whose working periods sitting upright were less than 30 hours . these values indicate that the duration of working while sitting straight was a factor affecting both the duration and the severity of the pain . the class variable affected the severity of the pain of the students working sitting upright for less than 30 hours in the last one week ( p=0.000 ) . in the first and second class students , 3.751.24 cm pain severity was determined , whereas in the third and fourth class students , 4.731.50 cm pain severity was determined . lumbar support usage affected the pain of students who worked more than 30 hours sitting upright ( p=0.011 ) . the students who worked for long periods sitting upright not using lumbar support had a 5.101.53 cm pain severity , whereas students who used a lumbar support had a 4.461.53 cm pain severity . the mean pain severity of the students whose pain lasted for one month within the last one year was 5.251.42 cm . the pain severity of students under 19 years was 4.511.37 cm , whereas it was 5.571.32 cm those over 19 years . the pain severity was 5.771.28 cm in the smokers , whereas it was 4.661.15 cm in non - smokers . we determined that pain duration within the last one year , working duration sitting upright , educational class , lumbar support usage , age and smoking habit affects the nonspecific low back pain severity of university students . the most important independent variables that may explain the pain were investigated using the decision tree technique . for example alkherayf and agbi reported a relationship between daily smoking amount and chronic lbp of young adults in 200910 . wang et al . reported a relationship between smoking and musculo - skeletal pain in 201111 . however , in general it is known that bone mineral density is reduced by smoking , and osteoporosis may develop following this reduction , enabling micro - fractures to form in the vertebrae . some researchers have suggested that this may cause degenerative changes in the vertebral column . another suggestion is that coughing , that causes an increase in the intradiscal and intra - abdominal pressure , is increased by smoking . this pressure increase may cause disc herniation in some cases12 . in our study , smoking appeared as a factor that increases nonspecific low back pain in university students . however , the reasons for this effect on nonspecific low back pain in this study are unclear , since the subjects were young adults showing no degeneration . further studies need to conducted investigating the relationship of breathing problems with nonspecific low back pain . the duration of sitting straight was another variable explaining nonspecific low back pain , and not using a lumbar support was determined as a factor increasing the pain . previous studies have shown that ergonomic problems cause pain while working . in the study of kanchanomia et al . of 524 university students , it was reported that physical risk factors and absence of a lumbar support while sitting straight had important roles in low back pain13 . furthermore , low back pain was reported to be affected by age and gender . wang et al . conducted a study in 2011 of 1,508 automobile workers , and reported that their musculo - skeletal problems were affected by bad ergonomics and excess weight11 . there are other studies in the literature that show a relation between obesity and low back pain14 , 15 . similar to these studies , this study , too , showed a correlation between lack of a lumbar support , smoking and age factors . however , in contrast to the literature , weight was not a factor influencing low back pain . since this was a study that included young adults , subjects with normal weights were the majority . however , in elderly subjects it may be a variable that affects low back pain . in the literature , there are studies which were conducted of university students from different departments which investigated low back pain according to department . this study also investigated students from different departments , as well as students of different classes . however , the prevalence of low back pain was 53.4% in medicine students , whereas it was 60.7% in sports students16 . in the study of falavigna , a clear relationship was found between physiotherapy bachelor s level education and lbp17 . they stated that the long periods of studying hours had an important effect on the onset of lbp . in another study of dentistry students , it was determined that the onset of lumbar , cervical and shoulder pain was seen when the students started their clinical practice training18 . it was previously reported that students of medical departments are at higher risk of low back pain than students of other departments . although there are conflicting results in the literature , the present study did not find a difference between the students of physiotherapy and nursing and other departments , with regard to low back pain , and showed that the educational department was not a variable explaining low back pain . however , the class variable was a factor influencing low back pain , and it increased with the increase in classes . the reason may be students undervaluing ergonomics . because it was determined that the upper classes commonly had practical lessons , whereas the lower classes commonly had theoretical lessons . many previous studies were conducted in order to determine the reason for lbp in students . however , lbp is not dependent on only one reason , it is a multi - factorial disease . thus , the analysis method should evaluate all the possible factors that may affect the pain . this study evaluated many factors that possibly affect low back pain at the same time . the chaid method used in this study however , chaid makes it possible to compare many variables at the same time . thus , such methods , which have more explanatory power , should be used more frequently , as they strengthen the validity of study results . university students with low back pain have been grouped as a single category , but they include cases with different pathologies and symptoms . studies should be conducted following the formation of categories for different pathologies , symptoms and medical histories . many factors that may cause low back pain were investigated in this study . however , psychological factors , other physiological factors such as posture , muscle strength or flexibility should also be investigated . thus , subject characteristics should be included in the analysis in order to shed light in future studies . age , smoking situations , classes , pain durations , sitting upright in front of monitors and disuse lumbar support are variables that affect nonspecific low back pain in students . in order to reduce or prevent nonspecific low back pain , students should be educated in their first classes and their smoking habits should be changed .

[ purpose ] this study was conducted on university students with nonspecific low back pain in order to determine the independent variables that affect their pain . [ methods ] a total of 514 students were included in this study . pain was evaluated using a visual analogue scale ( vas ) . a special form was prepared in order to evaluate the following independent variables : gender , weight , height , body mass index ( bmi ) , working periods sitting straight ( television , computer , seminar , etc . ) , working periods bending at a table ( reading , writing , etc . ) , using lumbar support while sitting , the mean duration of pain within the last one year , type of pain , time of the pain , faculty , class , physical activity habits and smoking . the collected data were evaluated using the chaid ( chi - squared automatic interaction detection ) analysis method . [ results ] the working hours bending at a table , physical activity , height , weight , bmi and educational departments were found not to affect the severity of the pain . the pain severity was affected by the duration of pain complaints within the last one year , the duration of working staying upright , smoking , classes , usage of lumbar support and age variables . [ conclusions ] the results of this study show that nonspecific low back pain of university students is affected by many factors such as smoking , class , age , using a computer and lumbar support .

systems with magnetic moments usually order as one approaches zero temperature . however , magnetic systems that form triangle- or tetrahedron - based lattices are often able to avoid ordering until unusually low temperatures , and have been found to have interesting properties both theoretically and experimentally@xcite . such lattices are generally referred to as geometrically frustrated as , for example , antiferromagnetic interactions between spins render the systems unable to find a unique ground state from magnetic considerations alone . it has been argued@xcite that the degree of frustration of a lattice can be quantified in terms of the connectivity of its triangular units . this leads to a hierarchy of lattices increasing in frustration from the ordered edge - shared hexagonal lattice , through the corner - shared triangle kagom , garnet and @xmath3-mn lattices , to the corner - shared tetrahedral lattice ( common to the pyrochlore , cubic laves and normal spinel structures ) . as we will show , the three dimensional corner - shared equilateral triangle structure of fig . [ figure1 ] is a fascinating new addition to this hierarchy . to avoid the cumbersome use of the terminology `` three dimensional corner - shared triangle '' ( which also applies to the distorted windmill @xmath3-mn structure ) , we will henceforth name this lattice the trillium lattice@xcite . the trillium lattice is a sublattice of the co ( b21 ) , nh@xmath4 ( d1 ) , nissb ( f0@xmath0 , ullmanite ) and fesi ( b20 ) structures . for example , the mn atoms of mnsi ( b20 structure ) form the trillium lattice . ( color online ) the trillium lattice . each site belongs to 3 equilateral corner - sharing triangles . @xmath5 denote the four atoms of the cubic unit cell . normal vectors to each triangle point along local ( 111 ) axes . ( 1,1,1 ) is a c@xmath4 rotation axis of the crystal ; the front right lower triangle is related to the front left top triangle by translation . in blue ( at left ) we identify the layer number that each point of the equilateral triangles shown belongs to . the separation between layers 4 and 5 is 4@xmath6 ; between 3 and 4 : ( 1 - 4@xmath7)@xmath8 and alternates . after triangles , the next smallest nearest neighbor connection has 5 sides as shown by the dashed line . ] recently pfleiderer et al @xcite reported the observation of a `` partially ordered '' magnetic state in single crystals of mnsi near and above the critical pressure of this itinerant helimagnet . in this neutron scattering measurement , the well - defined magnetic bragg peak ( @xmath90.0214 @xmath10 ) with wavevector along ( 111 ) was seen to shift to point predominantly along ( 110 ) ( with @xmath90.0304@xmath10 ) upon the application of pressure . the magnetic scattering pattern was seen to feature a sphere at fixed wavevector magnitude , with anisotropic intensities which weakly peaked along ( 110 ) . this sphere was found to onset at temperatures consistent with a continuation of the slope of @xmath11 ( where helimagnetism sets in ) . coincident with the appearance of this unusual magnetic signature an anomalous non - fermi liquid resistivity @xmath12 has been observed and found to persist up to twice the critical pressure@xcite . the lack of a rapid recovery of @xmath13 in such an apparently clean system ( @xmath14 ) poses an important challenge to our understanding of hertz - millis - moriya spin - fluctuation theory near a ferromagnetic or helimagnetic@xcite quantum critical point . magnetic susceptibility measurements have been found to exhibit high temperature curie - weiss tails@xcite with curie - weiss constants tuning continuously from weakly positive temperatures@xcite , consistent with the onset of helimagnetic order at ambient pressures , to weakly negative offsets above the critical pressure . this may be indicative of a crossover from ferro- to antiferromagnetically dominated fluctuations , although debate exists in the literature on this point@xcite . therefore , we ask whether any link might possibly be made between an enhancement of the antiferromagnetic couplings and the observed quasi - degenerate nature of the spin - spin correlations in this material at high pressures . to begin to address this question , we need to understand the role of antiferromagnetic interactions on this lattice . here we advance a microscopic description of the physics on the magnetic lattice of mnsi . it is important to notice that the mn bonds of this lattice form a trillium lattice@xcite ( see fig . [ figure1 ] ) whose degree of geometric frustration lies on the border between previously studied frustrated systems and those known to order despite frustration inherent to their lattices . we first classify the degree of magnetic frustration of the classical heisenberg antiferromagnet on this lattice , and then use mean field theory and a mapping to a classical rigid rotor model , to explore the corresponding low energy physics . in our model , we have chosen only to include the localized spin degrees of freedom . for the majority of magnetic systems forming on this lattice this is clearly an oversimplification , and a more complete model for the monosilicides might be the kondo lattice model . within this model magnetic correlations which arise between neighboring localized spins are mediated by conduction electrons . the basic magnetic physics of such an rkky interaction@xcite is thought to be captured by the extended heisenberg model . this paper represents the first step toward such a treatment which will be presented in the near future@xcite and is expected to yield a rich phase diagram and potentially account for the small positive curie - weiss offset seen in mnsi near its critical pressure . mapping the antiferromagnetic heisenberg model to a classical rotor model , we find an ordered ground state with wavevector ( @xmath15,0,0 ) featuring @xmath16 rotated spins on each triangle . monte carlo calculations have been carried out@xcite and support this conclusion . however , the commonly used mean field approximation does not find an ordered ground state . rather , mean field theory finds a macroscopically degenerate ground state with degenerate wavevectors forming a sphere - like surface in momentum - space , reminiscent of the partially ordered state of mnsi . although the detailed anisotropy of the structure factor is not reproduced , to our knowledge this is the first model to find such a partially ordered ground state . the disagreement between monte carlo and mean field approximations is surprising in light of the excellent qualitative agreement between these methods on the kagom and pyrochlore lattices , and the reason for this disagreement is discussed . the strength of magnetic order within the rotor model and its relationship to the mean field results is presented , laying the groundwork for future finite temperature studies where monte carlo and mean field results find qualitative agreement to reasonably low temperatures@xcite . the outline of this paper follows . in section ii an overview of recent excitement in the study of geometrically frustrated materials allows us introduce the trillium lattice in its proper context . in section iii we employ the standard @xcite mean field approximation which implicitly relaxes the constraint on the spin ( @xmath17 ) at each site and calculate the neutron structure factor . in section iv we numerically impose a hard spin constraint ( @xmath18 ) at each site . we use a classical rotor model to characterize the low - lying excitations and ground state . section v contains a discussion of the main results of this work . .[table ii ] the nearest neighbor sites in relation to the unit cell depicted in fig . [ figure1 ] . the subscript denotes translation by one unit cell in the direction noted . [ cols="<,<,<",options="header " , ] since real spins live in three - dimensional space , specifying one angle in principle only tells us information about the relative orientation of two components of the spin . we see from fig . [ figure7 ] ( a ) that , with a soft spin constraint , the mean field ground state with ( 111 ) order had 120@xmath19 rotated spins on triangles in the plane with normal vector ( 111 ) and no spin at the @xmath20 sites . all other triangles featured two opposite spins . it is instructive to add spin components normal to this plane to recover equal spins at each site . that is , to obtain a spin structure with unit magnitude spins at each site , we perform a vector summation of the mean field spin structure of fig . [ figure7 ] ( a ) and spin components orthogonal to this plane . clearly one must add a full spin to the @xmath20 site , while contributions to the @xmath21 sites must be added such that the spin components at each site square to one . on the @xmath21 sites , we assign an amplitude @xmath22 to spins of the mean field structure and an amplitude @xmath23 to the spin component perpendicular to the plane . we refer to this perpendicular component of the spins as a @xmath24 component because , despite structure within the 4-site cubic unit cell , it is unchanged from one unit cell to another . ( inset ) an illustration of the spin components of the noncoplanar spin structure at @xmath25 on the four unique triangles of the trillium lattice . analytic results have been derived by the addition of a perpendicular @xmath26=@xmath27 spin component ( see main text ) to the mean field results of fig . [ figure7 ] ( a ) , to enforce the hard spin constraint . in the main figure we present a comparison of the rotor model results ( points ) with analytic results of eq . [ equation29 ] obtained by minimization of @xmath28 as explained in the text . the @xmath29 link matrix written above each point shows the number of spin sites of each one dimensional lattice under consideration . the corresponding wavevector along ( 111 ) can be extracted as @xmath30 , where @xmath31 is an integer . ] this is shown pictorially in the inset to fig . [ figure16 ] on the four different magnetic triangles of the trillium lattice . then we can write the total energy per unit spin as a function of the angle @xmath28 as , @xmath32 and to find a true minimum of this function , we simply solve for the derivative,@xmath33 which yields @xmath34 . substitution of @xmath28 in eq . [ equation27 ] yields an energy of @xmath35 . this is the same as the lowest energy solution found by the rotor model along ( 111 ) , and is the true minimal energy state with this wavevector direction . within the mean field approximation , the lowest energy solution of eq . [ equation4 ] can be shown to be @xmath36 . the spin structure remains as presented in section iii d , with the exception of the relative angle change of the spin from one unit cell to the next ; for generic values of @xmath37 the triangles which include the @xmath20 site no longer feature parallel spins . as we have analytic expressions for our eigenvalues , it is interesting to write the general expression in the ( 111 ) direction following the same steps , @xmath38 which is plotted in fig . [ figure16 ] and agrees very well with the rotor model . note that in principle this must be done also within the mean field solution of reimers paper@xcite , in such a way as to satisfy the hard spin constraint on the pyrochlore lattice . that is , an analogous mean field solution is found along @xmath39 at @xmath40 in the pyrochlore case , but the high degeneracy of the lattice allows the addition of a @xmath24 ( ie . the same in each unit cell ) components to satisfy the hard spin constraint . relative to mean field calculations , monte carlo calculations ( which satisfy a hard spin constraint ) on the pyrochlore lattice would be expected to differ by a small factor . that this has not previously been appreciated is likely due to the high degeneracy of the pyrochlore lattice it is not nearly as important an effect there as it is here . motivated by recent neutron scattering and spin susceptibility measurements of mnsi , we have considered the role of antiferromagnetic interactions and their possible relevance to a partially ordered state in this system . to address this issue , we have studied a heisenberg model on the trillium lattice , a new three dimensional corner - shared triangle lattice formed by the mn atoms of mnsi . the trillium lattice is also a sublattice of other systems including the co ( b21 ) , nh@xmath4 ( d1 ) , nissb ( f0@xmath0 , ullmanite ) and fesi ( b20 ) structures . the heisenberg model is an oversimplified model for an itinerant system such as mnsi . however , this model has been used to reproduce the measured spin correlations in other itinerant systems including ( y@xmath41sc@xmath42)mn@xmath43 , liv@xmath43o@xmath44 and @xmath3-mn , where it has been considered the first step in an understanding of the magnetic correlations present . we found that a certain degree of geometric frustration does exist on the trillium lattice with a nave estimation of the number of degrees of freedom available to the ground state less than the kagom and pyrochlore lattices , but on a par with the @xmath3-mn lattice and greater than the hexagonal lattice . we have treated the classical antiferromagnetic heisenberg model on the trillium lattice within the mean field approximation and by mapping the model to a lattice of rigid rotors . within mean field theory on the trillium lattice , this model was found to have a degenerate ground state with wavevectors found to lie around a sphere - like surface given by eq . [ equation6 ] . at small but finite temperatures , the neutron scattering structure factor would then be expected to feature weight predominantly confined to lie on this surface . along this sphere - like surface , a disperse weight modulation would arise solely from geometrical factors and be roughly independent of temperature as found of the `` bow - ties '' of the corner - shared tetrahedral lattice . measurements normal to these sphere - like shells would show resolution limited sharp peaks as the temperature decreased as shown in fig . [ figure6 ] . these features bear a strong qualitative resemblance to neutron scattering measurements near the critical pressure of the itinerant helimagnet , mnsi , although notable differences are present . chief among these are the radius of the observed sphere - like shape , which is smaller by a factor of 10 , and the detailed nature of the pattern seen . more precisely , the measurements@xcite appear to have been made with respect to the lattice bragg peaks at ( @xmath15,@xmath15,0 ) . about this point there is no reason to expect an inversion symmetry of the structure factor and the c@xmath4 symmetry of the lattice which is responsible for the vanishing of weight along ( 111 ) shown in fig . [ figure5 ] would not be present . by mapping the classical antiferromagnetic heisenberg model to a rigid rotor description with a spin of unit magnitude at each site of the trillium lattice , we have found an ordered ground state at wavevector@xcite ( @xmath45 ) featuring 120@xmath19 rotated spins on each triangle . the rotor model is a real space construction which imposes periodic boundary conditions on finite size clusters of three dimensional vectors representing the spin at each site of the lattice . for several small cluster sizes ( see table [ table iv ] ) , we have found the minimal energy state to be consistent with order along ( 100 ) as analytically described in table [ table v ] , indicating that low - lying longitudinal fluctuations from the ground state are quite soft . we have designed an extension of the rotor model in such a way as to allow only one particular wavevector direction at a time . that is , rather than studying an @xmath46 lattice , where @xmath47 are integers counting the number of cubic unit cells in each direction , we have used symmetry to map the lattice to a one dimensional lattice of unit cells . for example , to investigate spiral order along ( 111 ) , unit cells at @xmath48 are all identical and can be replaced in the mapping by a single unit cell . despite the strength of ( 100 ) order , this allows us access to low - lying energetic saddle - points . in table [ table iii ] we have shown that the wavevector associated to these saddle - points continues to lie close to solutions of eq . [ equation6 ] . an analytic derivation of the wavevector and spin structure at the saddle - point along ( 111 ) has been developed in section iii d which illustrates the relationship between mean field and rotor model results . the discrepancy between the results obtained via the mean field approximation and those obtained by the mapping to the rotor model arises from the use of soft and hard spin constraints in the respective approximations . the soft spin constraint allows the magnitude of the spin to vary within the unit cell as illustrated by the `` spin '' structures of section iii d. for itinerant magnetic systems , it is not unusual for the magnetization density to vary spatially within an effective magnetic model . the hard spin constraint of the rotor model sets the magnitude of the spin at each site to be 1 . it is interesting to note that problems associated with the soft spin constraint of the mean field approximation arise in earlier treatments of frustrated lattices , yet do not seem to have been commented on . this is due , in part , to the extensive ground state degeneracy of these systems . for example , on the corner - shared tetrahedral lattice ( a sublattice of the pyrochlore structure ) , the mean field approximation yields@xcite a doubly degenerate flat band with a three band degeneracy at @xmath24 . even though the coplanar mean field ground state spin structure along ( 111 ) does not satisfy a unit spin magnitude ( @xmath18 ) at one of the four sites on each tetrahedron , it is possible to add spin components ( with @xmath24 ) to every site to recover this constraint . in this way , one finds a spin structure which belongs to the ground state and has components of its spins which rotate along ( 111 ) . calculations of the neutron scattering structure factor@xcite within the mean field approximation make the implicit assumption that the entire spin rotates . that along certain wavevector directions only a component of the spin is rotating must imply that the detailed nature of the relative neutron scattering weight is not fully captured within the mean field approximation , despite the remarkable qualitative agreement seen with monte carlo results . discrepancies between the soft and hard spin constraints are simply more clearly evident on the trillium lattice , as satisfying the hard spin constraint lifts the degeneracy of the ground state . the advantage of the mean field approximation is that it allows one to access all wavevectors and easily generalizes to finite temperatures . indeed , at temperatures @xmath49 one sees , from the rotor model ( see table [ table iii ] ) , that all wavevector orientations should become accessible to the system . one might hope at such temperatures to recapture many of the qualitative features of the mean field description . a finite temperature comparison between the mean field approximation and monte carlo results will be presented in the near future@xcite . future work@xcite will treat the extended heisenberg model which is expected to exhibit a rich phase diagram , possibly relevant to currently available magnetic monosilicides . it is worthwhile to mention the possibility of frustrated ferromagnetically coupled spin systems forming on this lattice . indeed , on the pyrochlore lattice there are arguably more candidates for spin - ice physics than for degenerate antiferromagnetic ground states . as we will show in future work@xcite , if ising spins are restricted to lie along the local ( 111 ) axes of the crystal ( this is the direction of the closest non - magnetic atoms in some of the ullmanites and may arise due to crystal / ligand field splittings ) , then antiferromagnetically coupled spins will be expected to order while ferromagnetically coupled spins will be extensively degenerate possessing a generalized version of the two - spins out , two spins in rule of the corner - shared tetrahedral lattice . j.h . would like to thank krishnendu sengupta , sergei isakov and benedikt binz for many useful discussions . we are grateful to b. canals and c. lacroix for pointing us towards ref . [ @xcite ] and [ @xcite ] , d. van der marel for providing us with a copy of his results prior to their publication , and d. khomskii for noticing that the next smallest loop after triangles is 5 sided . this work was supported by an nserc pdf , an nserc crc , an alfred p. sloan fellowship , nserc and the ciar . 00 c. urano , m. nohara , s. kondo , f. sakai , h. takagi , t. shiraki and t. okubo , phys . rev . lett * 85 * 1052 ( 2000 ) . m. hermele , m.p.a . fisher and l. balents , phys . rev . b * 69 * 064404 ( 2004 ) . i. mirebeau , i. n. goncharenko , p. cadavez - perez , s. t. bramwell , m. j. p. gingras and j. s. gardner , nature * 420 * , 54 ( 2002 ) . k. takada , n. sakurai , e. takayama - muromachi , f. izumi , r. a. dilanian and t. sasaki , nature * 422 * , 53 ( 2003 ) . r. coldea , d. a. tennant , a. m. tsvelik and z. tylczynski , phys . lett . * 86 * 1335 ( 2001 ) . r. moessner and j. t. chalker , phys . b * 58 * 12049 ( 1998 ) . about any site of the lattice , three equilateral triangles join in a corner - shared manner reminiscent of the trillium . both the foliage and flowers of the trillium feature three parts which join at the stem . this naming allows us to distinguish this unstudied lattice from the distorted windmill structure named in ref . @xcite and studied in ref . @xcite . c. pfleiderer , d. reznik , l. pintschovius , h. v. lhneysen , m. garst and a. rosch , nature , * 427 * , 227 ( 2004 ) . c. pfleiderer , s. r. julian and g. g. lonzarich , nature * 414 * , 427 ( 2001 ) ; n. doiron - leyraud , i. r. walker , l. taillefer , m. j. steiner , s. r. julian and g. g. lonzarich , nature * 425 * 595 ( 2003 ) ; p. pedrazzini , d. jaccard , g. lapertot , j. flouquet , y. inada , h. kohara and y. onuki , physica b * 378 - 380 * 165 ( 2006 ) . d. belitz , t. r. kirkpatrick and a. rosch , phys . rev . b * 74 * , 024409 ( 2006 ) . although the ordered magnetic moment is found to be quite small@xcite ( @xmath50 ) , above t@xmath51 , the curie - weiss slopes are consistent with a much larger curie - weiss moment ( @xmath52)@xcite which seems consistent with spin-1 local moments at each site at higher temperatures . in attempting to explain why his x - ray absorption results seemed to indicate s=@xmath53 spins at each mn site , despite the 0.4 @xmath54 moment observed in the ordered metallic state , d. van der marel first noticed the unusual sublattice structure of mnsi , talk at trieste workshop on strongly corrrelated electron systems , july 2004 . since this time , the x - ray absorption spectra has been improved by the same group to find mn takes a mixed valent spin configuration , f. carbone , m. zangrando , a. brinkman , a. nicolaou , f. bondino , e. magnano , a. a. nugroho , f. parmigiani , th . jarlborg and d. van der marel , phys . b * 73 * , 085114 ( 2006 ) . c. thessieu , k. ishida , y. kitaoka , k. asayama and g. lapertot , j. mag . and mag . mat . * 177 - 181 * 609 ( 1998 ) . d. van der marel , a. damascelli , k. schulte and a.a . menovsky , physica b , * 244 * 138 ( 1998 ) . c. pfleiderer , g. j. mcmullan , s. r. julian and g. g. lonzarich , phys . b * 55 * , 8330 ( 1997 ) . c. thessieu , c. pfleiderer , a. n. stepanov and j. flouquet , j. phys . : * 9 * 6677 ( 1997 ) . m. a. ruderman and c. kittel , phys . rev . * 96 * , 99 ( 1954 ) ; 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j. hopkinson and p. coleman , phys . lett . * 89 * 267201 ( 2002 ) . note that the four sites of the corner - shared tetrahedral lattice are `` equivalent '' after a rotation of their symmetry axes . in exactly the same manner , the four sites of the trillium lattice are `` equivalent '' . this state is equivalent to ( -@xmath63 ) , ( 0,@xmath64 ) , ( 0,0,@xmath65 ) , where the latter four states arise due to the @xmath66 symmetry of the lattice and the signs reflect the chirality of the spin structure . h. nakamura , k. yoshimoto , m. shiga , m. nishi and k. kakurai , j. phys . cond * 9 * 4701 ( 1997 ) .

we study the classical heisenberg model on a recently identified three dimensional corner - shared equilateral triangular lattice , a magnetic sublattice to a large class of systems with the symmetry group p2@xmath03 . since the degree of geometric frustration of the nearest neighbor antiferromagnetic model on this lattice lies on the border between the pyrochlore ( not ordered ) and hexagonal ( ordered ) lattices , it is non - trivial to predict its ground state . using a classical rotor model , we find an ordered ground state with wavevector @xmath1 featuring 120@xmath2 rotated spins on each triangle . however , a mean field approximation on this lattice fails to find an ordered ground state , finding instead a non - trivially degenerate ground state . as the mean field approach is known to agree with monte carlo on the pyrochlore lattice , the reasons for this discrepancy are discussed . we also discuss the possible relevance of our results to mnsi .

millisecond pulsars ( msps ) are fast - spinning neutron stars with rotation periods ( @xmath2 ) from a few to tens of milliseconds . they are believed to be old pulsars spun up through accretion process from a companion star . msps generally show small spin - down rates ( ) that imply low surface magnetic fields ( @xmath3 ) of the order of @xmath4 g , much lower than those of young pulsars . nonetheless , msps exhibit broadband emission as young pulsars do , and are detected across the electromagnetic spectrum from radio to x - ray to gamma - ray bands . recently there has been significant progress in the high - energy studies of msps . the large area telescope ( lat ) onboard the _ fermi gamma - ray space telescope _ has detected over 60 msps in gamma - rays since 2008 ( see the lat second pulsar catalog ; * ? ? ? * ) . in addition , the _ chandra x - ray observatory _ and the _ xmm - newton _ mission have provided sensitive measurements of the x - ray properties of over a dozen msps ( see * ? ? ? * and references therein ) . these have significantly expanded the sample and allowed detailed studies of the population . in this study we focus on the x - ray and gamma - ray emission properties of , which is a representative of an emerging class of msps that shows aligned pulse profiles in different energy bands @xcite . this could possibly indicate a different emission mechanism than that of typical pulsars . psr b1937 + 21 ( also known as psr j1939 + 2134 ) is the first msp discovered @xcite and it remains the second fastest - spinning pulsar known , with @xmath5ms and @xmath6 . ( corrections of due to proper motion and differential galactic rotation are negligible ) . these timing parameters suggest @xmath7 g and spin - down power @xmath8ergs@xmath9 , where @xmath10g@xmath11 is neutron star moment of inertia . this is the second largest among msps , only after psr b1821@xmath1224 . at high energies , psr b1937 + 21 was first detected in x - rays with _ asca _ the emission has a non - thermal spectrum and exhibits strong pulsations . the pulse profile shows a narrow peak structure with a pulsed fraction ( pf ) of 44% . the study also suggests a hint of a second peak in the profile . subsequent observations with _ rxte _ and _ bepposax _ confirmed the second peak @xcite , and it was claimed that the relative strength of the two peaks and the pf could vary with energy , from pf@xmath13% in 1.310kev to pf@xmath14% in 410kev @xcite . @xcite reported on a _ chandra _ observation of the source and found an x - ray photon index @xmath15 . using 1.5yr of _ fermi _ survey data , @xcite detected gamma - ray pulsations from psr b1937 + 21 . the pulse profile well aligns with the radio profile , indicating that both emission could originate from the same region in the outer magnetosphere . spectral analysis using the _ fermi _ data suggests that the phase - averaged pulsar spectrum could be fitted with an exponentially cutoff power - law model @xcite . however , note that the spectral parameters of this source are not listed in the lat second pulsar catalog that uses three years of data , due to low detection significance with a test - statistic ( ts ) value of 10 only @xcite . lcccccc _ chandra _ & 2005 jun 28 & 5516 & acis - s & faint & 3.2 & 49.5 + _ xmm _ & 2010 mar 29 & 0605370101 & mos1 & full frame & 2.6 & 40.4 + & & & mos2 & full frame & 2.6 & 47.5 + & & & pn & timing & @xmath16 & 40.4 we present a new study of the high - energy emission of psr b1937 + 21 using archival x - ray data made with _ chandra _ and _ xmm _ and 5.5yr of _ fermi _ survey data . the observations and data reduction are described in section [ s2 ] and the analysis and results are presented in section [ s3 ] . in section [ s4 ] , we compare the results with other msps and discuss possible physical emission mechanisms . our findings are summarized in section [ s5 ] . we reprocessed the archival _ chandra _ and _ xmm _ data . the former , which have been used in the previous study @xcite , were taken on 2005 jun 28 using the acis - s detector in the imaging mode and have a time resolution of 3.2s . the _ xmm _ observation was taken on 2010 march 29 with the mos1 and mos2 cameras in the full frame mode that has a frame time of 2.6s and the pn camera in the timing mode that has a high time resolution of 0.03ms . we performed the _ chandra _ and _ xmm _ data reduction using ciao 4.5 and sas 12.0 , respectively . in the _ xmm _ analysis , only ` pattern ` @xmath17 events from mos and ` pattern ` @xmath18 events from pn were used to ensure good data quality . after removing periods of high background , we obtained net exposures of 49.5ks , 40.4ks , 47.5ks , and 40.4ks from _ chandra _ , mos1 , mos2 , and pn , respectively . the observation parameters are listed in table [ table : obs ] . for the gamma - ray analysis , we selected _ fermi _ lat pass 7 reprocessed data ( p7rep ; * ? ? ? * ) taken between 2008 august 4 and 2014 january 17 . class 2 events in the p7rep_source_v15 instrument response function ( irfs ) were used throughout this paper , and the data reduction was carried out with the _ fermi _ science tools v9r32p5 . we restricted the analysis on data with zenith angles less than 100 , with spacecraft rocking angle less than 52 , and in the 0.1100gev energy range . psr b1937 + 21 is clearly detected in both the _ chandra _ and the _ xmm _ observations , and the radial profiles of the images are consistent with a point source , same as what @xcite found . using a 3 radius aperture centered on the pulsar , we found @xmath19 background - subtracted _ chandra _ counts from the in the 0.57kev energy range . similarly , we extracted @xmath20 and @xmath21 net counts from mos1 and mos2 , respectively , using a 20-radius aperture . the pn data have higher background since they were taken in the timing mode . we obtained @xmath22 source counts from a 33-wide rectangular region in 0.57kev . we performed timing analysis with only the pn data , as they have a high time resolution . the photon arrival times were first corrected to the solar system barycenter , then folded using the tempo2 photons plug - in with the ephemeris from radio timing @xcite . the resulting x - ray profile in the 0.57kev energy range is shown in figure [ fig : profile ] . we have tried other energy bands between 0.5 and 10kev , and found no energy dependence . the profile exhibits very sharp main pulse and interpulse components @xmath23180 apart . in addition , there is a hint of a third peak in between , albeit it is not statistically significant . a direct comparison with the background level obtained from a nearby region indicates that the emission is nearly 100% pulsed . we also plotted the 1.4ghz radio profile in the figure for comparison . the x - ray pulse and interpulse slightly lag the radio ones . to quantitatively measure the peak position and width , we followed @xcite to fit the pulse profile using an unbinned maximum likelihood method . we employed a simple model with two asymmetric lorentzians . the functional form is given by @xmath24 where @xmath25 @xmath26 are the amplitudes , @xmath27 are the peak positions , and @xmath28 are the width parameters such that the full widths at half - maximum ( fwhms ) of the two peaks are given by @xmath29 and @xmath30 . we found that the main pulse and interpulse peak at phase @xmath31 and @xmath32 , respectively . the best - fit results with statistical uncertainties at the 1@xmath33 level are listed in table [ table : results ] and the model profile is plotted in figure [ fig : profile ] . the uncertainties are estimated using monte carlo simulations . we generated 1000 random realizations of the best - fit model and fitted each one to obtain distributions of the best - fit parameters . the confidence intervals are determined from the most compact regions that contain 68% of the sample . note that we did not account for any systematic uncertainties , such as the absolute timing accuracy of the instrument . finally , we searched for bursts that may correspond to the giant pulses and any flux variabilities at longer timescale , but found negative result . lccc position , @xmath34 & @xmath35 & @xmath36 + width parameter , @xmath37 & @xmath38 & @xmath39 + width parameter , @xmath40 & @xmath41 & @xmath42 + fwhm@xmath43 & @xmath44 & @xmath45 + radio lag , @xmath46 & @xmath47 & @xmath48 + position , @xmath49 & @xmath50 & @xmath51 + width parameter , @xmath52 & @xmath53 & @xmath54 + width parameter , @xmath55 & @xmath56 & @xmath57 + fwhm@xmath58 & @xmath59 & @xmath60 + radio lag , @xmath61 & @xmath62 & @xmath63 + column density , @xmath64 ( @xmath65@xmath66 ) & @xmath67 & + photon index , @xmath68 & @xmath0 & @xmath1 + statistic & @xmath69 & ts - value=112 + unabsorbed energy flux ( @xmath70 & @xmath71 & @xmath72 + erg@xmath66s@xmath9 ) & & + luminosity ( @xmath73ergs@xmath9 ) & 0.7 & 49 + efficiency , @xmath74 & @xmath75 & 0.044 we extracted the pulsar spectrum from the regions stated above . backgrounds were obtained from nearby regions on the same chip . as the pulsar is 100% pulsed , we extracted the pn spectrum from the on - pulse phase intervals only , between phase 00.15 and 0.520.65 , in order to boost the signal - to - noise ratio . note that there is a faint source cxo j193939.3 + 213506 located 13 northeast of the pulsar , which is not resolved by _ xmm_. however , there should be negligible contamination to the pulsar spectrum , since its _ chandra _ count rate in 0.57kev is only 2% of that of the pulsar . this is also supported by the @xmath23100% pf of the pn counts . the spectral fitting was performed in the sherpa environment . we grouped the acis and mos spectra to at least 20 counts per bin , and the pn spectrum to at least 30 counts per bin . all four spectra ( acis , mos1 , mos2 , and pn ) were fitted jointly in the 0.57kev energy range . we employed a simple absorbed power - law model with abundances and the absorption cross sections given by @xcite . this provides a good fit with a reduced @xmath76 value of 0.86 over 122 degrees of freedom . the best - fit parameters are listed in table [ table : results ] and the model is shown in figure [ fig : spec ] . the fit gives a column density of @xmath77@xmath66 and a photon index of @xmath78 ( all uncertainties are at the @xmath79 confidence level ) . the absorbed and unabsorbed fluxes in 0.57kev are @xmath80erg@xmath66s@xmath9 and @xmath81erg@xmath66s@xmath9 , respectively . for the source distance of 5kpc @xcite , this converts to x - ray luminosity of @xmath82ergs@xmath9 , implying an efficiency of @xmath83 . to check the cross - calibration , we fit the _ chandra _ and _ xmm _ data separately and obtained @xmath84@xmath66with @xmath85 from the former and @xmath86@xmath66with @xmath87 from the latter . these values are fully consistent . we have also tried a blackbody model , but the fit is slightly worse ( @xmath88 ) and the temperature seems too high ( @xmath89kev ) to be physical . moreover , adding a blackbody component to the power - law model shows no significant improvement to the fit . nonetheless , we can still post a limit on the thermal emission by adjusting the blackbody parameters until the @xmath76 value exceeded a certain level . we obtained a temperature limit of @xmath90kev at the 99% confidence level , for any thermal emission from the polar cap region with a radius @xmath91 km , where @xmath92 km is the neutron star radius . using a 1 radius region of interest ( roi ) centered on the pulsar position , @xmath93 events in the 0.1100gev energy range were extracted from the _ fermi _ observation . we applied a barycentric correction to the photon arrival times and folded them using the tempo2 fermi plug - in , with the same radio ephemeris as for the x - ray analysis . pulsations are clearly detected and the @xmath94-test @xcite gives a statistic of 78 , which corresponds to 7.6@xmath33 detection . the pulse profile is shown in figure [ fig : profile ] . we have also tried the 1100gev energy range and the profile looks very similar , albeit with a lower @xmath94-statistic of 19 only . the gamma - ray profile in the figure shows sharp main pulse and interpulse that resemble the x - ray ones , but the gamma - ray pulses better align with the radio peaks . we fitted the gamma - ray profile with the same algorithm as described in the x - ray analysis above and the best - fit parameters and statistical uncertainties are listed in table [ table : results ] . finally , we checked the long term gamma - ray flux evolution of the source , and found no significant variability . we performed a binned likelihood analysis using a @xmath95 square roi . our model includes all sources in the second fermi - lat source catalog ( 2fgl ; * ? ? ? * ) within 20 from the pulsar , the galactic diffuse emission ( gll_iem_v05.fits ) , and the extragalactic isotropic emission ( iso_source_v05.txt ) . the source spectral models are all adopted from 2fgl . for sources located more than 8 from the pulsar , their spectral parameters are held fixed during the fit . we have tried a power - law model and a power - law with exponential cutoff model ( plec ) for the pulsar spectrum . the latter has a functional form of @xmath96 where @xmath97 is the photon flux and @xmath98 is the cutoff energy . we found that both models give low ts values that correspond to a detection significance below 3@xmath33 level . lccccccccc b1821@xmath1224 & 3.1&22&23&7.3&5.1&@xmath99&14&@xmath100&1 + b1937 + 21 & 1.6&11 & 4.1 & 10 & 5.0 & @xmath0&6.8&@xmath101 & this work + b1820@xmath1230a&5.4&8.3&43&2.5 & 7.9 & & & & + j1701@xmath123006f&2.3&7.3&7.2 & 5.5&6.9 & & & & + j1701@xmath123006e&3.2&3.6&10 & 2.7&6.9 & & & & + j0218 + 4232 & 2.3&2.4&4.3 & 3.1 & 2.7 & @xmath102 & 3.3&@xmath103&2 , 3 + b1957 + 20&1.6&1.1&1.4 & 3.0 & 2.5 & @xmath104 & @xmath105 & & 4 + j1750@xmath123703d & 5.1&1.4&16 & 1.1 & 12 & @xmath106 & & & 5 + b0021@xmath1272f&2.6&1.4&4.1&2.1&4.0&&0.055 & & 6 + j1740@xmath125340a&3.7&1.4&7.9&1.5 & 3.4&@xmath107 & 0.22 & & 7 + j1701@xmath123006d&3.4&1.2&6.6&1.5 & 6.9 & & & & to boost the signal , we restricted the analysis on the on - pulse data only , in phase 0.50.65 and 0.951.1 . these intervals are indicated in figure [ fig : profile ] . we obtained a much higher ts value of 112 , i.e. , above 10@xmath33 significance , using the power - law model . the fit gives a photon index of @xmath108 . the best - fit parameters and the phase - averaged energy flux are listed in table [ table : results ] . we have also tried the plec model and found a sightly better fit ( ts = 116 ) with @xmath109 and @xmath110gev . however , the likelihood ratio test gives @xmath111 . we therefore follow the convention in @xcite to conclude that the improvement is not significantly preferred . the best - fit power - law and plec models are plotted in figure [ fig : fermi ] . the _ chandra _ and _ xmm _ observations offer better angular resolution and sensitivity than previous x - ray studies with _ asca _ , _ rxte _ , and _ bepposax _ , providing substantial improvements on the spectral and timing measurements . while @xmath112 we obtained is consistent with the reported values , we found a lower @xmath113 of @xmath114@xmath66compared to @xmath115@xmath66 given by @xcite , @xcite , and @xcite . our result is closer to the total galactic hi column density of @xmath116@xmath66 in the direction measured with radio observations @xcite . we however note that it is not unusual for sources near the galactic plane to have an x - ray absorption column density larger than the total hi column density , because x - rays are mostly absorbed by molecular clouds instead of neutral hydrogen atoms ( see * ? ? ? * ) . the small @xmath64 value results in slight smaller unabsorbed flux of @xmath117erg@xmath66s@xmath9 in 210kev , as compared to @xmath118erg@xmath66s@xmath9 in @xcite and @xcite . for the timing analysis , the _ xmm _ pn observation allows us to isolate the pulsar flux from the background emission , revealing for the first time the near 100% pf of the x - ray emission . this is much higher than @xmath2360% found with _ asca _ @xcite . our results show no evidence of energy - dependent pulse profile in the soft x - ray band , thus , rejecting the claim of a lower ( @xmath119% ) pf below 4kev @xcite . the x - ray peak positions we obtained are mostly consistent with the published values . while a direct comparison with the _ rxte _ results may seem to indicate slight offsets ( @xmath120 , @xmath121 ) , we note that these are smaller than the 40@xmath122s absolute timing accuracy of _ xmm _ @xcite , which corresponds to 0.03 in phase units . psr b1937 + 21 is one of the few pulsars with radio giant pulses detected . @xcite noticed phase alignment between the radio giant and x - ray pulses , suggesting a possible correlation . although there is no contemporaneous radio observation accompanied with the _ xmm _ timing data , a large number of giant pulses are expected during the 11hr long x - ray exposure , given their observed rate of a few hundreds to a few thousands per hour ( e.g. , * ? ? ? * ; * ? ? ? we found no clustering of x - ray photon arrival times , same as what @xcite concluded . similar negative results have been reported for other pulsars that show giant pulses ( e.g. , * ? ? ? * ; * ? ? ? thanks to more _ fermi _ data and the improved irf ( see * ? ? ? * ) , our gamma - ray timing results are fully consistent with , but better constrained than , those from @xcite . for the spectral analysis , we found a slightly harder photon index @xmath108 compared to @xmath123 @xcite . on the other hand , our plec fit gives a softer @xmath124 ( @xmath125 versus @xmath126 ) , although the two are formally compatible given the large uncertainties of the latter . we also obtained a higher cutoff energy at @xmath110gev as compared to @xmath127gev . however , we note that @xmath98 is not very well determined in both cases . the non - thermal spectrum and large pf of the x - ray emission of psr b1937 + 21 indicate a magnetospheric origin . these characteristics seem common among high - msps ( see * ? ? ? we list in table [ table : highedot ] all known msps with @xmath129ergs@xmath9 . three of them , psrs b1821@xmath1224 , b1937 + 21 , and j0218 + 4232 , have confirmed x - ray pulsations . they all exhibit hard power - law spectrum in x - rays with @xmath130 , large pf of 64%100% , general alignment between the x - ray and radio pulses @xcite , and giant radio pulses @xcite . it has been suggested that these properties could be attributed to a strong magnetic fields at the light cylinder . its strength , @xmath128 , is related to the surface dipole field @xmath131 by @xmath132 , where @xmath133 is the light cylinder radius . all msps listed in the table have strong @xmath128 above @xmath134 g . in particular , psr b1937 + 21 has the highest @xmath128 of @xmath135 g , even higher than that of the crab pulsar . lcccccc b1937 + 21&1.6&110&4.1&9.9&pl & ii + b1821@xmath1224&3.1&220&23&7.3&pl&ii + j0218 + 4232&2.3&24&4.3&3.2&pl&ii + j1747@xmath124036&1.7&12&1.5 & 3.1&&i / ii + b1957 + 20&1.6&7.6&1.2&2.5&&ii + b1820@xmath1230a&5.4&83&43 & 2.5&&ii + j1902@xmath125105&1.7&6.7&1.3 & 2.2&&ii + j1810 + 1744&1.7&4.0&0.9&1.8 & & ii + j1125@xmath125825&3.1&8.1&4.4 & 1.4&&i + j1446@xmath124701&2.2&3.7&1.5&1.3 & & i + j2215 + 5135&2.6&5.2&2.5&1.3 & & i + j2241@xmath125236&2.2&3.3&1.4&1.2 & & i + j1658@xmath125324&2.4&3.0&1.7&1.1 & & i + j0034@xmath120534&1.9&1.7&0.75&1.0&&ii + j1124@xmath123653&2.4&1.6&1.2&0.78 & & iii + j0614@xmath123329&3.2&2.2&2.4&0.71 & & iii + j2043 + 1711&2.4&1.3&1.0&0.70&&i + j0102 + 4839&3.0&1.8&1.9&0.67 & & iii + j2214 + 3000&3.1&1.9&2.2&0.66 & & ii / iii + j1858@xmath122216&2.4&1.1&1.0&0.66 & & iii + j0023 + 0923&3.1&1.5&1.8&0.60 & & i + j2017 + 0603&2.9&1.3&1.6&0.59 & & i + j1741 + 1351&3.8&2.2&3.3&0.58&&iii + j0101@xmath126422&2.6&1.0&1.1&0.58&&i + j0613@xmath120200&3.1&1.2&1.7&0.53&&i + j1514@xmath124946&3.6&1.6&2.6&0.52 & & i + j0751 + 1807&3.5&0.72&1.7&0.36&&1 + j0340 + 4130&3.3&0.65&1.4&0.36 & & ii / iii + j2047 + 1053&4.3&1.1&3.0&0.35 & & iii + j1600@xmath123053&3.6&0.73&1.8&0.35&&i + j1614@xmath122230&3.2&0.38&1.0&0.29&&i + j1231@xmath121411&3.7&0.51&1.6&0.29&&i + j2051@xmath120827&4.5&0.54&2.4&0.24&&i + j1744@xmath121134&4.1&0.41&1.7&0.23&&iii + j1713 + 0747&4.6&0.34&2.0&0.19&&i + j2124@xmath123358&4.9&0.37&2.4&0.18&bb&iii + j0030 + 0451&4.9&0.35&2.3&0.18&bb+pl&i + j2302 + 4442&5.2&0.38&2.7&0.18 & & i / ii + j0437@xmath124715&5.8&0.29&2.9&0.14&bb+pl&i + j0610@xmath122100&3.9&0.08&0.69&0.11&&iii + j1024@xmath120719&5.2&0.05&0.92&0.06&&i in table [ table : fermimsp ] we list all gamma - ray msps detected with _ fermi_lat in decreasing order of @xmath128 . we classified them according to their phase alignment between the gamma - ray and radio pulses , using a scheme similar to @xcite : sources with gamma - ray peak lagging , aligned with , and preceding the radio peak are divided into classes i , ii , and iii , respectively . class ii pulsars are required to have a radio peak aligned with the gamma - ray peak to better than 1/10 of the spin period , and the two peaks should have a similar profile . there are a small number of pulsars , e.g. , psr j2214 + 3000 , that can not be unambiguously classified . these cases are noted in the table . finally , we also list in the table the x - ray spectral type of the msps , although only a few of them are detected since msps are generally faint . it is obvious that most high-@xmath128 msps belong to class ii and they exhibit non - thermal x - ray emission with hard spectra . @xcite first noted that a group of msps show aligned radio , x - ray , and gamma - ray pulse profiles , suggesting the same location for the emission . the authors proposed that the radio emission could be generated in caustics in the outer magnetosphere , same as the gamma - ray emission . as table [ table : fermimsp ] indicates , the phase alignment is typical among the highest-@xmath128 msps . we discuss below possible emission mechanisms in different energy bands , with a focus on their connection with @xmath128 . we qualitatively compare our toy model with the spectral energy distributions ( seds ) of three msps psrs b1937 + 21 , b1821@xmath1224 , and j0218 + 4232 , which have been detected in both x - rays and gamma - rays . we briefly summarize the gamma - ray emission mechanism in the context of the outer gap model @xcite , in which electrons and positrons are accelerated up to a lorentz factor of @xmath136 near the light cylinder . for a more detailed calculation of the gamma - ray emission process , we refer to @xcite and @xcite . in the outer gap , electrons and positrons are accelerated by the electric field along the magnetic field lines and emit gev gamma - rays via the curvature radiation process . the magnitude of the electric field is given by @xmath137 where @xmath138 is the curvature radius and @xmath139 is the ratio between the gap thickness and the light cylinder radius , typically @xmath140 for msps @xcite . the lorentz factor of the accelerated particles can be estimated by the balance between the electric force and the back reaction force of the curvature radiation , @xmath141 the energy of the curvature photons is of the order of gev , @xmath142 and the gamma - ray luminosity from the outer gap is typically @xmath143 in the standard pulsar theory , non - thermal x - ray emission is attributed to synchrotron radiation from secondary pairs in the outer magnetosphere , which are generated via the pair - creation process between gamma - rays and the background x - rays ( e.g. , * ? ? ? the secondary pairs have an initial lorentz factor of @xmath144 , then quickly lose their energy via synchrotron radiation and eventually leave the light cylinder with @xmath145 , where @xmath146 is the pitch angle . during this process , synchrotron cooling gives non - thermal x - rays with @xmath147 between @xmath148kev to @xmath149kev . this is the general case for young pulsars ; they have @xmath112 observed in the range of 1.52 ( e.g. , * ? ? ? * ; * ? ? ? * ) . for high-@xmath128 msps , while non - thermal x - rays can be produced near the light cylinder , the very hard photon indices ( @xmath150 ) are difficult to explain . a hard spectrum is expected below @xmath151 , but this is outside the observation bands . @xcite proposed that the primary particles in msps could maintain large momenta and undergo cyclotron resonant absorption of radio emission to produce synchrotron x - rays with a very hard spectrum . however , this process is not efficient between particles with @xmath152 and radio waves of 0.11ghz , unless the @xmath153-field is of the order of @xmath154@xmath4 g . such a condition can only occur near the neutron star surface . one possible scenario to explain the non - thermal x - rays from the outer magnetosphere is inverse - compton ( ic ) scattering between the primary particles and radio waves . as we discussed , the radio , x - ray , and gamma - ray emission regions of high-@xmath128 msps are likely co - located . therefore , the radio waves emitted in the outer magnetosphere may possibly irradiate the outer gap region and be up - scattered by the ultra - relativistic particles . we can estimate the energy density of the radio waves in the magnetosphere from the flux density . assuming a radio spectral index of @xmath155 , the typical energy density of @xmath23100mhz radio waves is @xmath156@xmath157erg@xmath158 in high-@xmath128 msps . the radiation power of ic scattering from a single particle is then @xmath159 , where @xmath160 is the thomson cross section . as a comparison , the power of the curvature radiation is @xmath161 . hence , @xmath162 this suggests that the expected energy flux from the ic process is only slightly smaller than that of the gev emission and it could be observable in high-@xmath128 msps . to model the ic spectrum , we consider the scattering between outgoing particles in the outer gap and outwardly propagating radio waves . we assume that the radio emission region lies just above the outer gap and approximate the magnetic field lines by concentric circles . the collision angle between the primary particles and radio waves can be crudely estimated by @xmath163 . for each particle , the ic power per unit energy per unit solid angle is given by @xmath164 where @xmath165 is the differential klein - nishina cross section , @xmath166 , @xmath167 , @xmath168 is the angle between the particle motion and the scattered photon direction , and @xmath169 is the radio spectrum . the ic spectrum depends sensitively on the radio spectrum . although the latter is not very clear at low radio frequency @xmath170ghz , it is believed that a spectral turnover should exist below 100mhz for msps ( see * ? ? ? * ) , which is lower than that of young pulsars ( @xmath171ghz ; e.g. , * ? ? ? for a turnover at 10100mhz , the corresponding break in the ic spectrum would be at @xmath172mev . this is well above the _ chandra _ and _ xmm _ energy bands , suggesting that the ic emission could contributed to the observed x - rays . to compare with observations , we assume a broken power - law spectrum in radio with a turnover at 10mhz , i.e. @xmath173 the spectral index @xmath174 is inferred from the observed flux densities at 400mhz and 1.4ghz listed in the atnf pulsar catalog @xcite . the index below 10mhz , @xmath175 , is taken to be 0.5 , which provides a good match to the x - ray spectra ( see below ) . the normalization @xmath176 is related to the observed flux density at 400mhz ( @xmath177 ) and the source distance @xmath178 by @xmath179 as the exact geometry of the radio emission region is unknown , we allowed @xmath176 to vary by a factor of a few to fit the observed seds . we also considered synchrotron x - rays contributed by the secondary pairs . the particles accelerated towards the star would eventually reach the stellar surface and heat up the polar cap region . @xcite estimated a surface temperature of @xmath180mk and a luminosity of @xmath181ergs@xmath9for the thermal emission of psr b1937 + 21 . these values are below our detection limit of 1.5mk . the thermal x - rays may collide with the gev gamma - rays to create new pairs , which emit non - thermal x - rays via the synchrotron process . the optical depth of the pair - creation process is @xmath182 , where @xmath183 is the boltzmann constant and @xmath184 . the energy distribution of the secondary pairs follows @xmath185 where @xmath186 is the lorentz factor of the secondary pairs , @xmath187 , @xmath188 is the curvature radiation power per unit energy , and @xmath189 is the rate of energy loss from synchrotron radiation . with @xmath190 , equation ( [ sdist ] ) describes a power - law with index @xmath191 . the synchrotron spectrum from secondary pairs is @xmath192 where @xmath193 , @xmath194 , and @xmath195 . in figure [ fig : sed ] we compare our simple model with the observed seds of psrs b1937 + 21 , b1821@xmath1224 , and j0218 + 4232 . it shows that our model provides reasonable fits to the data . the peak flux of the ic and curvature radiation are similar and the ic emission dominates over the synchrotron radiation in the x - ray band above a few kev . since the ic spectrum is sensitive to the radio spectral index , low - frequency radio measurements below 100mhz in future can offer essential inputs to refine the modeling . for the assumed spectral turnover at 10mhz , the ic emission peaks at @xmath23100kev , which could be detectable with hard x - ray telescopes such as _ nustar _ or _ astro - h_. the radio emission process in pulsars is not clearly understood , nonetheless , it has been suggested that plasma instability could play an important role in the generation of the coherent radio emission ( e.g. , * ? ? ? the characteristic timescale for the instabilities ( e.g. , two - stream instability ) to develop is related to the inverse of the plasma frequency @xmath196 . the electron and positron number density , @xmath197 , is proportional to the goldreich - julian charge density ( @xmath198 ) such that @xmath199 . therefore , high-@xmath128 msps tend to have a higher plasma frequency , and hence a shorter instability timescale , in the outer magnetosphere . above the outer gap accelerator , the outgoing and incoming gamma - rays produce electron - positron pairs moving towards the light cylinder and the star , respectively . these flows could develop two - stream instability in the outer magnetosphere . since there are more pairs created near the inner boundary than near the outer boundary of the outer gap @xcite , the outflow is stronger than the inflow at the light cylinder . the lorentz factor of the two flows are of the order of @xmath200 , for which the synchrotron cooling timescale is comparable to light - crossing time of the magnetosphere . the instability development timescale can be estimated by @xmath201 where @xmath202 and @xmath203 are the number densities of the outgoing and incoming flows , respectively , and @xmath204 is the plasma frequency of the outgoing flow @xcite . with a typical multiplicity of the order of @xmath205 , we may assume @xmath206 and @xmath207 in the outer magnetosphere . hence , the timescale becomes @xmath208 which is much shorter than the light - crossing time of @xmath209s . as a result , the instability could develop before the outgoing particles escape the magnetosphere . we speculate that the two - stream instability may generate non - homogeneous and separated plasma clouds , and the scattering or emission process of the plasma cloud eventually produce the observed radio emission in phase with the gamma - ray pulses . finally , we note that some high-@xmath128 msps , e.g. , psrs b1821@xmath1224 and j1810 + 1744 , show complex radio profiles with additional components that offset from the gamma - ray peaks . these could be contributed by emission from the polar cap region as in the conventional theory of pulsar radio emission . we have analyzed x - ray and gamma - ray observations of psr b1937 + 21 taken with _ chandra _ , _ xmm _ and _ fermi _ lat . we obtained much improved spectral and timing measurements than previous studies . our results show that the pulsar x - ray emission is @xmath23100% pulsed and has a purely non - thermal spectrum that can be described by a hard power - law of photon index @xmath210 . the x - ray pulse profile consists of two sharp peaks @xmath23180 apart . they generally align with the radio peaks and the phase offsets are less than 7% of the spin period . in gamma - rays , the 5.5yr of _ fermi _ survey data provide a good quality pulse profile in 0.1100gev with a significance of over 7@xmath33 . we performed a binned likelihood analysis on the pulsed emission and found that a simple power - law model with @xmath108 gives a ts value of 112 , corresponding to over 10@xmath33 significance . adding an exponential cutoff to the power - law model slightly improves the fit , but the change is not statistically significant . a comparison of psr b1937 + 21 with other msps indicates that sources with a strong magnetic field at the light cylinder tend to show a hard , non - thermal x - ray spectrum and good alignment of pulse profiles in different energy bands . the latter suggests that the radio , x - ray , and gamma - ray emission could originate from the same region in the outer magnetosphere . we speculate that radio emission could be generated in the outer gap region when @xmath128 is large , since this could give rise to short instability time scales . we investigate a simple model in which the non - thermal x - rays are contributed by ic scattering between radio waves and primary particles in the outer magnetosphere and by synchrotron radiation from secondary particles . we showed that this toy model is capable to qualitatively reproduce the observed seds of the highest-@xmath128msps . future observations at low radio frequencies and in hard x - rays can help refine the modeling . we thank the referee for careful reading and useful suggestions and thank vicky kaspi and anne archibald for useful discussions . jt , gckl , and ksc are supported by a grf grant of hong kong government under hku7009/11p .

we report on x - ray and gamma - ray observations of the millisecond pulsar ( msp ) b1937 + 21 taken with the _ chandra x - ray observatory _ , _ xmm - newton _ , and the _ fermi _ large area telescope . the pulsar x - ray emission shows a purely non - thermal spectrum with a hard photon index of @xmath0 , and is nearly 100% pulsed . we found no evidence of varying pulse profile with energy as previously claimed . we also analyzed 5.5yr of _ fermi_survey data and obtained much improved constraints on the pulsar s timing and spectral properties in gamma - rays . the pulsed spectrum is adequately fitted by a simple power - law with a photon index of @xmath1 . both the gamma - ray and x - ray pulse profiles show similar two - peak structure and generally align with the radio peaks . we found that the aligned profiles and the hard spectrum in x - rays seem to be common properties among msps with high magnetic fields at the light cylinder . we discuss a possible physical scenario that could give rise to these features .

six percent of the world population is affected by diabetes mellitus ( dm ) which is a chronic metabolic disorder . the who defines diabetes mellitus as a metabolic disorder of multiple aetiology characterized by chronic hyperglycemia with disturbances of carbohydrate , fat and protein metabolism resulting from defects in the insulin secretion , insulin action , or both . a survey on indian population shows that 4% of the adults suffered from diabetes mellitus in the year 2000 and it is expected to rise to 6% by the year 2025 . in developing country like india , the majority of diabetics are in the age group of 45 - 64 years in contrast to developed countries it is highly prevalent in more than 65 years of age . the management of type 1 diabetes mellitus depends mainly on insulin , whereas the oral antidiabetic drugs ( oads ) are the first line treatment for type 2 diabetes mellitus . complications due to hyperglycemia in diabetes mellitus can be prevented by using rational use of oral antidiabetic drugs ( oads ) and insulin . rational use of the drugs is a complex issue with a goal that is difficult to achieve , defined as follows : that patients receive medications appropriate to their clinical needs , in doses that meet their own individual requirements for an adequate period of time , and at the lowest cost to them and their community . rational use of the drugs in populations can be effectively studied with drug utilization reviews . the world health organization ( who ) defines drug utilization as the marketing , distribution , prescription and use of the drugs in a society considering its consequences , either medical , social , and economic . drug utilization studies is an invaluable investigational resource to study pharmacoepidemiology , pharmacovigilance , pharmacoeconomics and pharmacogenetics . the world health organization ( who ) has formulated a set of core prescribing indicators for improvement in the rational drug use in the outpatient practice . so the cost of antidiabetic drug is the major deciding factor for the patients compliance . selection of oral antidiabetic drugs as first - line drug or combined therapy should be based on both the pharmacological properties of the compounds like efficacy , safety profile and also on the clinical characteristics of the patient like stage of disease , body weight , bmi etc . , there exists a wide range of variation in the prices of drugs marketed in india and other countries of the world . percentage cost variation is an effective tool to find out the difference between the various brands prescribed by prescriber in the same setting . in 2005 , indian council of medical research has given guidelines for treatment of diabetes in which the selection of drugs are mainly based on body mass index ( bmi ) . judicious use of anti - diabetic drugs by adhering to these guidelines will decrease the complications and cost of the drug therapy . there are many studies carried out on drug utilization in diabetic patients but a limited number of studies had focus on analyses of cost and adherence to treatment guidelines . so , we planned to carry out this study drug utilization studies in diabetic patient with focus on cost analyses and adherence to standard treatment guideline . to study prescription pattern , calculate cost of antidiabetic agents and to evaluate the adherence to treatment guidelines in diabetic patients attending the medicine outpatient department in a tertiary care teaching hospital . to study prescription pattern , calculate cost of antidiabetic agents and to evaluate the adherence to treatment guidelines in diabetic patients attending the medicine outpatient department in a tertiary care teaching hospital . a prospective , cross - sectional study was carried out over the duration of 5 months from october 2012 to february 2013 . all the diabetic patients attending the medicine outdoor department were enrolled in the study after explaining the aim of the study . written informed consent prior approval of institutional ethics committee , hospital superintendent and from the head of the medicine department was obtained . patients receiving any of the anti - diabetic drugs were included in the study irrespective of their gender and those patients who were pregnant and having insufficient data or records were excluded from the study . for those prescriptions whose generic name of the drugs and price were not mentioned in the prescription , they were obtained from cims ( current index of medical specialty ) and indian drug review ( idr ) [ 2012 issues ] . we collected the patient 's pharmacy bills and analyzed the retail cost of a particular drug being manufactured by different companies , in the same strength , number and dosage form was compared . the difference in the maximum and minimum price of the same drug manufactured by different pharmaceutical companies was calculated . the drugs being manufactured by only one company or being manufactured by different companies however , in different strengths were excluded . for calculation of adherence to standard diabetes guidelines we used indian council of medical research guidelines , 2005 . the data was calculated using mystat software 12.0 and statistical package for social sciences software 21.0 ( spss ) . we used unpaired t - test and fischer 's exact test to evaluate the difference between two groups . the data was calculated using mystat software 12.0 and statistical package for social sciences software 21.0 ( spss ) . we used unpaired t - test and fischer 's exact test to evaluate the difference between two groups . a total of 250 prescriptions were collected in the study during the period of 5 months . highest numbers of the patients were found in the age group of 51 - 60 ( 36% ) years . out of the 250 the age difference between two gender groups ( p 0.05 ) was statistically significant as shown in table 1 . demographic variables ( n=250 ) number of drugs prescribed was 1,391 ( range 2 - 11 ) . number of drugs prescribed ranged from 2 - 14 drugs , with a mean of 5.56 2.52 drugs . a total of 539 antidiabetic drugs were used as shown in table 2 and figure 1 ( range 1 - 6 ) . most commonly used drug combination was of glimepiride and metformin in 119 ( 76.28% ) patients . most commonly used drugs other than antidiabetic were aspirin 146 ( 18.9% ) and atorvastatin 119 ( 15.41% ) . drug use pattern of anti - diabetic drugs ( n=250 ) number of anti - diabetic drug prescribed per patient in our study , therapy cost for a diabetic patient ranged from 15 to 2501 inr per month and most of the patients fall in the cost range of 100 - 400 inr i.e. in 68.4% of the patients . percentage cost variation is shown in table 3 which ranges from 1.47 to 181.81 for glimepiride + metformin + pioglitazone and glimepiride alone , respectively . who drug prescribing indicators are shown in table 4 and adherence to icmr guidelines on diabetes is shown in table 5 . percentage cost variation of anti - diabetic agents who core prescribing indicators adherence of treatment to indian council of medical research guidelines , 2005 this study was carried out with aim to analyze the drug utilization pattern in diabetic patients in medicine outpatient department in a tertiary care teaching hospital . drug utilization research study will help for improvement in drug usage , more focused generic brand prescribing pattern . selecting proper cost effective brand will help in quality of the drug usage , cost reduction , proper dose selection and better health outcome . although lifestyle modifications play an important role in diabetes management , drugs become unavoidable in many patients . this study was focusing on the prescription pattern in diabetic patients attending the outpatient departments in a hospital . demography details shows male patients were 126 ( 50.4% ) and females patients were 124 ( 49.60% ) . in our study , however in earlier study male predominance was seen in the study population which is not in agreement with the results of our study majority of 90 ( 36% ) of the patients were found in 51 - 60 years of age group and among 43 ( 17.2% ) newly diagnosed patients with type - ii dm , 30% were of the age group of 41 - 50 years indicating that the risk of type - ii dm increases after the age of 40 years , this result was similar to study of roy v et al ( 1998 ) . middle age preponderance was seen in our study which was similar to an earlier study of das p et al . , ( 2011 ) average age of male was 59 years and female was 56 years . it was reported in near to study of wu et al . average bmi observed in our study was 27.16 2.85 in male patients and 26.40 3.65 in female patients during course of antidiabetic therapy , which implies that the patients were overweight ( bmi 25 kg / m2 ) and were on the borderline of becoming obese ( bmi 30 kg / m2 ) , which in itself is a well - recognized significant risk factor for diabetes mellitus . in our study , average fbs and ppbs notified was 113.19 27.80 and 209.5 46.92 mg / dl respectively in female and 115.85 31.46 and 0.89 35.78 mg / dl respectively in male . it was higher than that reported in the study done by dave dj et al . similar result was obtained by the study conducted by rataboli p et al . , ( 2007 ) stated that among all diabetic complications , cardiovascular complications ( hypertension ) pose a major threat . , we also found out that the genetic basis i.e. , majority of the patients had either of their parents suffering from diabetes mellitus this finding was further substantiated by study of kannan et al . , ( most of our patients had a history of diabetes around 5 - 15 years which an earlier study also reported . in our study , most commonly used drug group used was biguanides and sulfonylureas and not insulin as it was opd based as compared to other studies . the most common drug prescribed was metformin as compared to previous studies done a decade back . this suggests the gradual takeover of metformin as a first - line agent for type-2 dm in a decade . among sulfonylureas , selection of glimepiride and glipizide has been recommended by texas diabetes council because these agents have lower incidence of hypoglycemia . johnson ja et al . ( 2006 ) stated that a study from spain reported that 25.3% of the patients were prescribed insulin . this difference is due to difference in presentation in different study populations . in this study most commonly used drug combination was of glimepiride and metformin which was a common finding seen with earlier study of v. sivasankari et al . , and das p et al . , ( 2011 ) which also suggest combination of biguanides and sulfonylureas was most frequently used combination and most effective one . this combination is most desirable and having a rational basis of use i.e. both of this drugs act through different mechanism one is insulin sensitizer and other insulin secretogogue . most commonly used drug other than anti - diabetic drugs was aspirin , atorvastatin and clopidogrel which suggest association of cardiovascular disease especially hypertension and higher blood cholesterol level in diabetes mellitus patients . whereas certain other drugs like pregabalin and mecobalamin were prescribed for patients having signs and symptoms of diabetic neuropathy . mean drugs prescribed per patient was 5.56 2.52 whereas study by das p et al out of all drugs 619 ( 44.50% ) antidiabetic drugs were prescribed which was a similar finding of an previous study conducted by upadhyay d et al . ( 2007 ) where anti - diabetics accounted for 314 ( 45.84% ) of the total drugs . average number of antidiabetic drugs per prescription was 1.45 which was similar to an early indian studies . our study and another study of upadhyay d et al . , ( 2007 ) reported that 95.62% of the drugs were prescribed in oral dosage form and only insulin was prescribed by parenteral route . data was analyzed for who drug utilization indicators , we have seen a trend of using brand name for prescribing and a very less amount of drugs was prescribed by generic names . more and more amount of drugs should be prescribed by generic names as it increases uniformity and decreases cost of drug therapy . in earlier study essential drugs were prescribed to a large extent but in our study nearly half numbers of drugs were prescribed from essential drug list which suggest a trend of using newer drugs in prescribing and also suggest the influence of pharmaceutical companies in prescribing . a very less amount of drugs was given in injections as compared to earlier study . this finding can be explained as we collected only outpatient prescriptions and insulin was the most frequently prescribed drug by injection route which is a cornerstone of type 1 dm and also this also suggest better knowledge of the doctors about the risks and high cost of these injections . only few antibiotics ( 0.79% ) were prescribed out of all drugs it was an expected finding as patient in outpatient department arrives only for refilling of prescription and present mostly without infection . the percentage of generics and drug use from essential drug list are higher when compared to those from a study reported in delhi by kumar r et al ( 2013 ) . cost of therapy per month was higher as compared to study by kannan et al . cost of drug therapy was a cause for non - adherence . in this study cost of the drugs per prescription the cost of prescription can be reduced by choosing most economic drugs without changing its quality . cost of prescription is important in chronic diseases like diabetes . in our study therapy cost for a diabetic patient ranged from 15 to 2501 inr and most of the patients fall in the cost range of 100 - 400 inr per month . mean cost of therapy for a diabetic patient was 354.60 305.72 inr , in our study it was found higher as expected as no anti - diabetic drug was given free of cost in our institute as compared to other government hospitals . we found out the percentage cost of variation an estimation of variability in cost for different brands prescribed to the patients . glimepiride , metformin and pioglitazone combination had the least percentage cost variation i.e. 1.47 whereas glimepiride had highest percentage cost variation i.e. 181.81 , this finding suggest availability of more brands in glimepiride as compared to other drugs and total cost of treatment can be reduced drastically by using the cheapest brand of glimepiride and prescriber should avoid writing the costliest brand of glimepiride in order to curtail the total cost of drug therapy . ( 2013 ) stated that glimepiride ( 1 mg ) shows maximum price variation of 655.38% . icmr guidelines have suggestion that in patient less than 18.5 body mass index metformin should not be used , in patients in between 18.6 to 24.9 bmi guidelines suggest that metformin should be used as second line oad only in the resistance cases after using other oad and metformin should be combined when used . whereas in patients above 25 bmi first - line drug used should be metformin . in our study majority ( 15.6% ) of the non - adherence was due to prescribing of other drugs in place of metformin in the patients having bmi more than 25 . prescribing drugs other than metformin in inappropriate as literature showed that using in obese patient metformin should be preferred . sulfonylurea and biguanide combination drugs were used . in these glimepiride and metformin combination drugs were prescribed and used commonly . oral dosage form was the most commonly used to increase the patient compliance in type 2 dm . the cost of prescription can be reduced by choosing the most economic drugs ( generic ) without changing its quality . prescribers followed the icmr guidelines to a large extent . the pattern of prescription for diabetic patients should be more rational as per our study and compliant with current evidence and clinical guidelines .

introduction : diabetes mellitus is on alarming rise in india . drug utilization studies help to identify the adherence to standard treatment guidelines and to evaluate the rational drug usage.objective:to study prescription pattern , calculate the cost of antidiabetic drugs and to evaluate the adherence to treatment guidelines in diabetic patients attending the medicine outpatient department in a tertiary care teaching hospital.materials and methods : a prospective observational study was carried out for a period of 5 months . the diabetic patients who visited the medicine outdoor department were included . demographic data and complete prescription details were recorded in the structured case record form . cost of the drug therapy was calculated from the patient 's bills . indian council for medical research guidelines-2005 for diabetes management was used to evaluate the adherence.results:a total of 250 patients were enrolled in the study with mean age 57.91 9.37 . out of 250 patients 126 ( 50.4% ) were male and rest were female . a total of 1,391 drugs were prescribed , with mean of 5.56 2.52 drugs and out of which 539 drugs were antidiabetics with mean of 2.18 0.96 . in monotherapy , metformin was frequently 218 ( 40.45% ) prescribed . glimepiride and metformin was the most frequently prescribed in 119 ( 76.28% ) out of 156 antidiabetic drug combinations . most commonly used drugs other than antidiabetics were aspirin 146 ( 18.9% ) and atorvastatin 119 ( 15.41% ) . mean cost of therapy for a month for a diabetic patient was 354.60 305.72 inr . majority 209 ( 83.6% ) of prescriptions was in accordance to guidelines.conclusion:metformin was the most frequently prescribed drug in the diabetes patient . metformin and glimeperide being the most frequent combination used . majority of the prescriptions followed standard guidelines .

ANDERSON, Calif. - The Anderson Police Department will start using nunchucks as a way to forcibly restrain suspects. Though nunchucks are not new to law enforcement, they are making a come back in Shasta County. They originated in Japan and have been used in martial arts for years. APD said they want to start using them because they are a multipurpose weapon. Nunchucks are illegal for citizens to own in California; however, police can be certified to use them within the state. The ones used by officers are made of plastic and are connected with a nylon rope. Sgt. Casey Day was recently certified to use nunchucks for the Anderson Police Department. He explained the different ways they can be used to help law enforcement. He said they can be used to hit, strike, jab and take someone down. They can also be used as a restraint to lock someone's hand, elbow or ankle. "These were kind of designed with a different goal in mind to be more of a control weapon, but like I said, it's not like we can't use these as an impact weapon," Day explained. "They work really good as an impact weapon, but we try to emphasis a control tool over impact." Day stated he's replacing his baton with the nunchucks because they work well and are more universal. He explained that if they are used with force, officers will focus on aiming at the criminal's hands, knees or wrists. They can also be used to block a punch or hit. Day added that he hasn't had to use them yet. Currently, the department is working to train all their officers to use nunchucks. ||||| Looking for another nonlethal way to take down suspects, the Anderson Police Department decided to go the way of the dragon. The police force in the Northern California town of about 10,000 people plans to equip its 20 officers with nunchakus, also known as nunchucks. Basically, they’re what martial arts legend Bruce Lee used – besides his fists of fury and feet -- to take down all those bad guys in his movies. The police department was looking for a versatile tool that would limit injuries to officers and the people they detained – but that would still be an effective means of subduing an unruly suspect. Anderson’s top brass decided nunchakus were the way to go, said Sgt. Casey Day. “It gives us the ability to control a suspect instead of striking them,” he said. Of course, if you’ve watched enough Lee movies you’ll notice that he didn’t use nunchakus to pacify his enemies. He beat them up with them. But Anderson police insist they can detain someone with them in a relatively peaceful way. Graphic: comparing batons and nunchucks On the website of the nunchakus’ manufacturer, Orcutt Police Defensive Systems Inc., the restraint technique is demonstrated. It shows a male officer using the nunchakus to grip the ankle of a man who is kicking his foot toward the officer’s face. The photo also depicts a female officer using them to hold a man’s wrist. The weapon, or tool, is often made of two wooden sticks or bars tethered together by a metal chain. (Developed by retired Colorado police Sgt. Kevin Orcutt in the 1980s, the Anderson Police Department's nunchakus are made of a hard plastic connected by a nylon cord designed to wrap around wrists and ankles). Wielded by martial arts experts, nunchakus can be used in complicated motions to fight off attackers. In the movies, including some of Lee’s, the occasional bad guy who gets the bright idea of trying to use it himself usually whacks himself in the face. Day was recently certified to train the department’s officers on the proper use of the nunchakus. He wants officers to have another option besides the baton, a traditional impact weapon. Officers won’t be required to use nunchakus, he said. But if officers decide to use them, they must pass a 16-hour training program. Day, a 15-year police veteran, said he has given up his baton for nunchakus. “I see the value and the safety they bring to me,” he said, adding that nunchakus provide a distance between an officer and a suspect. Sure, he was skeptical at first, Day said. But once he used the nunchakus, he was sold. The pincher-style nunchakus became popular in the police community in the 1980s, said Greg Meyer, a use-of-force expert and former Los Angeles Police Department training captain. Anaheim, San Diego and the LAPD are just some of the agencies that have used them– at least for a while. Some law enforcement agencies stopped using nunchakus when officers improperly used them -- in some cases resulting in broken wrists, he said. In 1991, the LAPD agreed to stop using nunchakus at protests– a decision sparked by a federal lawsuit filed by anti-abortion activists. The department opted to settle the lawsuit following the March 3 beating of Rodney G. King, which happened that same year. At the time, Deputy City Atty. Jack Brown, who was representing the LAPD, said the department was concerned about the public perception over using nunchakus to subdue people. Day hasn’t used his nunchakus, but is confident he will use them properly. “I don’t go around looking for trouble,” he said. Neither did Bruce Lee. Twitter: @VeronicaRochaLA ALSO Black LAPD officer sues city, says white officer wrongly followed and stopped him FBI to investigate South Carolina deputy who threw student across classroom floor In face of criticism, S.F. supervisor reaffirms city's sanctuary policies

– If you run into a police officer in Anderson, California, don't be surprised if he's sporting some nunchucks instead of a baton. The Northern California police department is outfitting its 20 officers with the weapon popularized by Bruce Lee because it wanted another nonlethal way to bring a suspect under control while minimizing officer and suspect injuries. The Los Angeles Times has illustrations showing how nunchucks can be used in place of a baton to restrain a suspect by winding around an ankle or wrist. "It gives us the ability to control a suspect instead of striking them," says Sgt. Casey Day, who's already been trained on the weapon and plans to use it instead of a baton. He notes that nunchucks also allow for distance between an officer and a suspect, but that they can be used as an "impact weapon" as well if need be. "These were kind of designed with a different goal in mind to be more of a control weapon, but like I said, it's not like we can't use these as an impact weapon," Day tells KRCR. "They work really good as an impact weapon, but we try to [emphasize] a control tool over impact." The Anderson PD nunchucks were developed by a retired Colorado police sergeant and are made of hard plastic. A nylon cord connects the two pieces and is used to restrain a suspect via the wrist or ankle—and while Day is confident Anderson officers will use the martial arts weapons properly, the Times notes that some departments have used them improperly in the past, sometimes leading to broken wrists. Officers won't be required to carry nunchucks, but anyone wishing to do so will have to undergo 16 hours of training. Nunchucks are illegal for regular citizens to own in California.

SECTION 1. MUSIC LICENSE FEES. Section 110(5) of title 17, United States Code, is amended to read as follows: ``(5) communication within a commercial establishment of a transmission embodying a performance or display of a work by the reception of a broadcast, cable, satellite, or other transmission, if communicated-- ``(A) in an area within the establishment where a transmission is intended to be received by the general public that is smaller than 5,000 square feet; ``(B) within an establishment whose gross annual income does not exceed 20 percent of the gross annual income of a small business under the applicable Standard Industrial Code as defined by the Small Business Administration; ``(C) by means of 10 or fewer loudspeakers, not including speakers in audiovisual devices; or ``(D) by means of speakers in audiovisual devices only, if no direct charge is made to see or hear the transmission, the reception of the transmission is authorized, and the transmission or retransmission is not further transmitted to the public beyond the premises of the retail establishment;''. SEC. 2. ARBITRATION BETWEEN GENERAL MUSIC USERS AND PERFORMING RIGHTS SOCIETIES; AVAILABILITY OF REPERTOIRE. (a) Arbitration.-- (1) In general.--Chapter 1 of title 17, United States Code, is amended by adding after section 120 the following new section: ``Sec. 121. Arbitration between general music users and performing rights societies; availability of repertoire ``(a) Arbitration.-- ``(1) In general.--Any controversy or dispute arising out of or related to the appropriate fee to be paid for the user's past or future performance of nondramatic musical works in the repertoire of the performing rights society shall be settled by arbitration administered by the American Arbitration Association under its Commercial Arbitration Rules, and judgment on the award may be rendered by the arbitrators may be entered in any court having jurisdiction thereof. ``(2) Findings.--The arbitrator's findings shall be confidential and shall not provide any precedent for the determination of rates, except as to the parties involved. ``(3) Duration of determination.--In any arbitration proceeding initiated under this subsection, the arbitrator's determination of a fair and reasonable license fee for the performance of nondramatic musical works in the repertoire of the performing rights society shall apply for a period of not less than 3 years nor more than 5 years after the date of the arbitrator's determination. ``(b) Access to Licensing Information and Repertoire.-- ``(1) In general.--Performing rights societies shall make available, free of charge, to all interested persons, online computer access to copyright and licensing information for each nondramatic musical work in its repertoire which is published or performed, without regard to whether the work is identified in the society's survey of music use. Such information shall, for each such nondramatic musical work, identify the work by the title of the work; the name of the writer; the name, address, and telephone number of the publisher; when the work will enter the public domain, if determinable; and the names of any artists known by the society to have recorded the work, to the extent such artist information is tracked by the society for any purpose other than this section. Such online computer access shall permit the efficient review of multiple musical works consistent with reasonably available technology. ``(2) Directory.--Each performing rights society shall make available at its reproduction cost, not including the cost of maintaining the database or any other overhead, not less frequently than semiannually, a printed directory or CD ROM directory of each title in its repertoire, at the choice of the music user, as of the date which is not more than 30 days before the date on which the directory is published, containing the information under paragraph (1).''. (2) Technical and conforming amendment.--The table of sections for chapter 1 of title 17, United States Code, is amended by adding after the item relating to section 120 the following: ``121. Arbitration between general music users and performing rights societies; availability of repertoire.''. (b) Restrictions on Infringement Actions.--Section 504 of title 17, United States Code, is amended by adding at the end thereof the following new subsection: ``(d) Restrictions.--No fee for a license may be charged and no action may be instituted, maintained, or supported by the society for the public performance of a nondramatic musical work in a society's repertoire, that is not identified and documented as required under section 121, without regard to whether the nondramatic musical work has been published or performed, if a good faith effort to search the repertoire of the performing rights society as provided under section 121 has been made.''. SEC. 3. RADIO PER PROGRAMMING PERIOD LICENSE. Section 504 of title 17, United States Code, as amended by section 2 of this Act, is further amended by adding at the end thereof the following new subsection: ``(f) Radio Per Programming Period License.-- ``(1) In general.--Each performing rights society shall offer, to any radio broadcaster that so requests, a per programming period license to perform nondramatic musical works in the repertoire of the performing rights society. Such license shall be offered on reasonable terms and conditions that provide an economically and administratively viable alternative to the blanket license offered by the society to radio broadcasters for all such broadcasters. ``(2) Price of per programming period license.-- ``(A) The total price of a per programming period license described under paragraph (1)-- ``(i) shall include separate components for incidental and feature performances, with the incidental performance component to be independent of the quantity of such performances by the broadcaster and not to exceed the relative value the performing rights society assigns to such performances in its distribution of royalties; and ``(ii) shall vary between the incidental performance component, for a broadcaster that makes only incidental performances of music in the society's repertoire, and the fee that would be payable under the blanket license offered to radio broadcasters, in direct proportion to the percentage of the broadcaster's revenue attributable to programming periods containing feature performances of nondramatic musical works in the society's repertoire compared to the industry average percentage of revenue attributable to programming periods containing feature performances of such musical works. ``(B) A nondramatic musical work shall not be considered in calculating any per programming period license fee under this subsection, if the performance of such work-- ``(i) has been licensed directly, at the source, or other than by the society; or ``(ii) constitutes fair use or is otherwise exempt from liability under this title. ``(3) Administration of license.--Commencing on January 1, 1998, the performance of nondramatic musical works by a broadcaster under any per programming period license shall be determined on the basis of statistically reliable sampling or monitoring by the performing rights society, and the society may not require the broadcaster to report such performances to the society. The society shall provide the broadcaster with a report detailing the results of such sampling or monitoring, identifying each programming period containing the performance of nondramatic musical works in the society's repertoire and the nondramatic musical works in the society's repertoire performed during each such period. ``(4) Implementation.--Any radio broadcaster entitled to a per programming period license under this subsection may bring an action to require compliance with this subsection in an appropriate United States district court, including any district court established by court order or statute as a court that resolves disputes, with respect to license rates, that may arise between performing rights societies and persons who perform musical works in the society's repertoire. ``(5) Definitions.--As used in this subsection-- ``(A) the term `blanket license' means a license provided by a performing rights society that authorizes the unlimited performance of musical works in the society's repertoire, for a fee that does not vary with the quantity of performances of musical works in the society's repertoire, or any other license with comparable economic effect; ``(B) the term `incidental' as applied to performances shall include commercial jingles not exceeding 60 seconds in duration, bridges, themes or signatures, arrangements of works in the public domain, and background music, including music used in conjunction with sporting events; and ``(C) the term `programming period' means any 15 minute period of radio broadcasting commencing on the hour, or at 15, 30, or 45 minutes past the hour.''. SEC. 4. RELIGIOUS SERVICE EXEMPTION. Section 110(3) of title 17, United States Code, is amended by inserting after ``religious assembly'' the following: ``the transmission of such services, whether live or recorded, or the recording of copies or phonorecords of a transmission program embodying such services in their entirety, if there is no commercial advertisement or commercial sponsor within the program.''. SEC. 5. CONFORMING AMENDMENTS RELATING TO DEFINITIONS. (a) Performing Rights Society.--Section 101 of title 17, United States Code, is amended by inserting after the undesignated paragraph relating to the definition of ``perform'' the following: ``A `performing rights society' is an association, corporation, or other entity that licenses the public performance of nondramatic musical works on behalf of copyright owners of such works, such as the American Society of Composers, Authors, and Publishers, Broadcast Music, Inc., and SESAC, Inc. The repertoire of a performing rights society consists of those works for which the society provides licenses on behalf of the owners of copyright in the works.''. (b) General Music User.--Section 101 of title 17, United States Code, is amended by inserting after the undesignated paragraph relating to the definition of ``fixed'' the following: ``A `general music user' is any person who performs musical works publicly but is not engaged in the transmission of musical works to the general public or to subscribers through broadcast, cable, satellite, or other transmission. For purposes of this paragraph, transmissions within a single commercial establishment or within establishments under common ownership or control are not transmissions to the general public.''. (c) Loudspeaker.--Section 101 of title 17, United States Code, is amended by inserting after the undesignated paragraph relating to the definition of ``Literary works'' the following: ``A `loudspeaker' is any device or self contained collection of devices that converts electronic signals to audible sound.''.

Exempts from copyright infringement the communication within a commercial establishment of the transmission of a performance or display of a work by the reception of a broadcast, cable, satellite, or other transmission, if no direct charge is made to see or hear the transmission, its reception is authorized, and such transmission is not retransmitted to the public beyond such premises, and if communicated: (1) in an area where a transmission is intended to be received by the general public that is smaller than 5,000 square feet; (2) within an establishment whose gross annual income does not exceed 20 percent of the gross annual income of a small business as defined by the Small Business Administration; (3) by means of ten or fewer loudspeakers; or (4) by means of speakers in audiovisual devices only. (Sec. 2) Requires any controversy or dispute arising out of the appropriate fee to be paid for the user's past or future performance of nondramatic musical works in the repertoire of a performing rights society (PRS) to be settled by arbitration administered by the American Arbitration Association. Outlines provisions: (1) requiring the confidentiality of arbitration findings; (2) limiting the length of time that the finding of an appropriate fee shall apply; (3) requiring a PRS to make available to all interested persons access to copyright and licensing information for each nondramatic musical work in its repertoire; and (4) requiring a PRS to make available a printed directory of each title in its repertoire. Provides restrictions for PRSs not in compliance with such requirements. (Sec. 3) Requires each PRS to offer to any radio broadcaster that so requests a per programming period license (license) to perform nondramatic musical works in the repertoire of the PRS. Outlines provisions: (1) determining the price of each such license; (2) providing for the determination of the performance of nondramatic musical works by a broadcaster under any such license; and (3) enforcing a broadcaster's right to apply for and receive such a license. (Sec. 4) Exempts from copyright infringement the transmission of religious services, or the recording of a program embodying such services in their entirety, if there is no commercial advertisement or commercial sponsor within such program. (Sec. 5) Defines "performing rights society," "general music user," and "loudspeaker" for purposes of the copyright laws.

until recently , the assessment of the endometrial - myometrial junctional zone ( emj ) was mainly used on magnetic resonance images ( mri ) for the diagnosis of adenomyosis ( hricak et al.,1983 ) . . however , on ultrasound the emj is not always easy to display and there are currently no strict guidelines on how to analyse the emj . only few studies on 3d imaging of the emj have been published ( alcazar et al . , 2009 ; exacoustos et al . , 2011 ; naftalin et al . , 2012 ) . a proper visualization of the emj is deemed to be important in the diagnosis of adenomyosis ( bromley et al . , 2000 ; dueholm , 2006 ) , myometrial invasion in endometrial cancer , the extension of submucous fibroids and the exact character of congenital uterine anomalies ( naftalin et al . , 2009 ) . a standardized sonographic evaluation of the emj is therefore important in order to study its relevance in such endometrial and myometrial diseases . volume contrast imaging ( vci ) is a technology based on a volume acquisition technique that leads to contrast enhancement and speckle suppression in the two - dimensional ultrasound image . the use of vci improves the contrast in ultrasound images ( henrich and stupin , 2011 ; jantarasaengaram et al . , 2014 ) and may offer a better assessment of size , margins and aspect of emj . the aim of this study was to evaluate which 3d reconstruction technique allows for optimal visualization of the emj on 3d stored images . 3d volumes from 183 consecutive patients who presented at the leuven university hospital bleeding clinic were selected in decreasing chronological order from 2009 - 2010 database . the protocol was approved by the local ethics committee of the university hospitals leuven and patients had given informed consent . the 3d volumes were collected using a voluson e8 ( ge healthcare ultrasound , milwaukee , wi , usa ) with a 6 - 12 mhz transvaginal probe . out of the 183 cases , 65 cases with incomplete data were excluded . of the remaining 118 3d volumes , the first author scored the image quality of the emj , for each reconstructed image without the use of vci , as good ( the emj is clearly visible and can be evaluated on the fundal , right lateral and left lateral borders ) , moderate ( one border is not clearly visible ) , poor ( two borders are not clearly visible ) or insufficient ( none of the borders are clearly visible ) . after exclusion of 38 cases because of insufficient image quality , 80 patients ( study group ) were selected for further analysis . for each 3d volume , the uterus was examined in the sagittal plane to identify the cervical canal and the uterine cavity , and after complete rotation of 360 , the first author reconstructed the best image on 2d midcoronal plane without vci , with vci set at 4 mm and with vci set at 2 mm . the coronal view was obtained by placing the dot into the endometrial stripe on the sagittal and transverse views ( plane a and b of the multiplanar view ) . the multiplanar view was then adjusted until a satisfactory coronal image was obtained of both the endometrial cavity and the external uterine contour . the gradient light and sepia settings were used to optimize the view of the emj , which was visualized as a hypoechoic area surrounding the endometrial cavity . for each 3d volume , 3 images in the coronal plane were reconstructed ( 2d coronal plane without vci , with vci 4 mm and vci 2 mm ) , resulting in 240 images . together with a questionnaire pertaining to these images , they were integrated into the web - based electronic data capture software clinical data miner ( cdm ) ( install et al . , 2014 ) five gynaecologists with experience in gynaecological ultrasound used cdm to evaluate the questionnaire for all images , which were shown in random order to each examiner . the questionnaire comprised two questions . in the first question , examiners reported image quality as good , moderate , poor , or insufficient , encoded as 4 , 3 , 2 , and 1 , respectively . significance of differences in reported quality for the different technologies were assessed using paired t - tests . in the second question , examiners assessed the emj of these images using ieta terminology ( leone et al . , 2010 ) , as regular , irregular , interrupted , or not defined , with one examiner ( cvp ) re - evaluating the same set of images after 12 days . these evaluations were used to calculate both inter- and intra - rater agreement , by means of fleiss kappa coefficient ( fleiss et al . , 1971 ) . compared to the coronal view without vci , the use of both 4 mm and 2 mm vci improved subjective image quality reported by participants ( p < 0.001 ) . the fleiss kappa coefficient for evaluating the inter - rater agreement of the emj description using coronal view without vci , with vci at 4 mm and vci at 2 mm were 0.36 0.05 , 0.34 0.05 and 0.42 0.05 , respectively . the corresponding figures for the intra - rater agreement for emj were 0.58 0.08 , 0.36 0.08 and 0.68 0.07 , respectively . the use of vci 2 mm improved inter - rater and intra - rater agreement of emj description ( p < 0.001 ) , while vci 4 mm did not . this study demonstrates that the visualization of the emj in the coronal plane using vci 2 mm outperforms vci 4 mm and 2d coronal plane without vci . if 3d - rendering is used , the best images of the emj will be obtained using a thin region of interest ( roi ) box ( fig . exacoustos et al . , 2011 ) proposed the use of vci 2 and 4 mm in the evaluation of the emj . additionally , we have shown that the image quality of vci 2 mm is superior to that of vci 4 mm . naftalin et al . , 2012 ) studied the inter- and intra - rater agreement in three - dimensional ultrasound assessment of the emj . they scored the quality of visualization of the emj by coronal view obtained using render mode as optimal , satisfactory or unsatisfactory . their results showed good inter- and intra - rater variability with kappa values of 0.77 and 0.83 respectively . in our study the results using vci 2 mm were 0.42 and 0.68 , respectively . these differences may be explained by the fact naftalin et al moreover our study addressed the issue of the clinical relevance by evaluating the inter- and intra - rater agreement in reporting the emj according to the ieta terminology ( leone et al . , 2010 ) . the use of a standardized technique facilitates the dialogue between different observers and allows to evaluate the diagnostic relevance of ultrasound images of the emj , e.g. in the evaluation of adenomyosis , endometrial cancer , fibroids and congenital uterine anomalies .

objectives : the aim of this study was to find the best 3d reconstruction technique to visualize the endometrial - myometrial junction ( emj).methods : retrospective observational study on 240 stored 3d volumes of 80 patients . the first author reconstructed the 2d midcoronal image without volume contrast imaging ( vci ) , with vci set at 4 mm and with vci set at 2 mm . three images per patient ( 240 images ) were saved and integrated in the web - based electronic data capture software clinical data miner ( cdm ) ( http://cdm.esat.kuleuven.be ) . five experienced gynaecologists analysed the images shown in random order . they scored the image quality ( good , moderate , poor , insufficient ) and described the emj of these images using ieta terminology ( regular , irregular , interrupted , not defined ) . one of the examiners ( cvp ) also re - evaluated the same set of images after 12 days to assess intra - observer variability.results : the use of vci significantly improved the recorded subjective image quality . the fleiss kappa coefficient for evaluating the inter - observer variability of the emj description using coronal view without vci , with vci at 4 mm and vci at 2 mm were 0.36 0.05 , 0.34 0.05 and 0.42 0.05 , respectively . the corresponding figures for the intra - observer variability were 0.58 0.08 , 0.36 0.08 and 0.68 0.07 , respectively.discussion : in this study on 3d reconstructed coronal images of the uterine cavity , the 2 mm vci slices gave the best quality images of the emj .

hyperuricemia has been reported to be an independent risk factor for hypertension,1,2 cardiovascular diseases,3 and kidney diseases.4 approximately 25% of patients with hypertension have hyperuricemia,1 while approximately 30% of patients with hyperuricemia or gout have hypertension.2 in diabetic patients , hypertension and decreased renal function with hyperuricemia are major problems.5 therefore , the effects of antihypertensive drugs on serum uric acid level ( sua ) , especially angiotensin ii receptor blockers ( arbs ) , have been closely scrutinized in recent years . we have examined the influence on sua by arbs and shown that one of the arbs , irbesartan , inhibits uric acid ( ua ) transport via the renal ua transporters , urate transporter 1 ( urat1 ) and glucose transporter 9 ( glut9).6 urat1 is involved in lumen - to - cytosol reabsorption of ua at the apical membrane of proximal tubules,7 whereas glut9 functions as a ua efflux transporter from tubular cells at the basolateral membrane.8 mutations of urat1 or glut9 are associated with renal hypouricemia,911 indicating that these two transporters play a dominant role in renal ua reabsorption and regulation of sua . we previously reported that irbesartan ( 100500 m ) inhibited the uptake of ua via both urat1 and glut9 in vitro.6 losartan has been shown to increase urinary ua excretion and to decrease sua.12 losartan is associated with a lower risk of incident gout among patients with hypertension.13 since losartan is not effective for hypouricemic patients harboring urat1 mutation , it has been demonstrated that the uricosuric action of losartan is via the inhibition of urat1.14 the urat1 inhibitory effects of irbesartan exceeded those of losartan in vitro , and the results suggest that irbesartan has the effect of decreasing sua through increasing urinary ua excretion.6 except for losartan and irbesartan , arbs have been reported to increase the risk of gout13 and to increase the sua.15 if irbesartan decreases sua , its multiple effects would also make it useful for the treatment of hypertension combined with hyperuricemia . a large study was performed in hypertensive patients with hyperuricemia to examine the effects of irbesartan on sua for 2 months.16 although the sua decrease was observed in irbesartan - treated subjects ( from 7.06 mg / dl baseline to 6.85 mg / dl ) , it was not significant and was less than in those treated with losartan ( from 7.09 mg / dl to 6.03 mg / dl).16 in contrast , irbesartan was reported to decrease sua significantly in hypertensive patients with advanced chronic renal disease.17 since inconsistent results have been reported regarding its effects on sua , it is necessary to determine whether irbesartan has an sua decreasing effect . in the present study , we investigated the effects of irbesartan on sua in hypertensive diabetic patients treated with 50150 mg irbesartan . the study was approved by the ethics committee of tokyo university of pharmacy and life sciences and carried out in accordance with recommendations from the declaration of helsinki . this was a retrospective study performed at a diabetic clinic in chigasaki ( japan ) . the subjects were 134 stable diabetic outpatients treated with irbesartan for 612 months in 20112012 . we excluded 27 patients treated with drugs that influenced sua such as allopurinol , diuretics , or fenofibrate . 72 patients had been previously treated with other arbs and the medicine was switched to irbesartan ( designated the arbs irb switch group ) . other patients were started on irbesartan as the first arb ( designated the irb group ) . diabetic nephropathy was staged according to an analysis of the urinary albumin excretion ( uae ) and egfr as defined by the japanese society of nephrology from the japanese historical cohort study:18 stage i , uae < 30 mg / g creatinine ; stage ii , 30 uae < 300 mg / g creatinine ; stage iii , uae 300 mg / g creatinine or continuous proteinuria ( 0.5 g / g creatinine ) ; stage iv , egfr < 30 ml / min/1.73 m. seven patients had the complication of myocardial disease and four of them were treated with a calcium channel blocker in combination with irbesartan . three other patients had stopped treatment with anticoagulant , calcium channel blocker or nitrate before irbesartan was started . the follow - up period was 12 months for 101 patients and 6 months for the other six patients . systolic blood pressure ( sbp ) and diastolic blood pressure ( dbp ) were recorded before irbesartan treatment ( pre ) , at the beginning of the study ( 0 month ) , and 1 , 3 , 6 , and 12 months after irbesartan was started . serum creatinine ( scr ) and sua were measured at the same time point as sbp and dbp . estimated glomerular filtration rate ( egfr ) was calculated from scr , sex , and patients age . the calculation formula defined by the japanese society of nephrology is : baseline values were calculated as the average of values between pre - treatment examinations and month zero . student s t - test was adopted to compare continuous variables and a value of p<0.05 was considered significant . sua decline after 6 or 12 months irbesartan treatment was employed as the dependent variable . we introduced significant ( p<0.05 ) independent variables from the univariate analysis into multiple logistic regression analysis . the sex , history of alcohol intake , and diabetic disease duration were included in the multiple logistic regression analysis as independent variables . the receiver operating characteristic ( roc ) curves were used to estimate the sua cut - off point and this was determined to be where the sum of sensitivity and specificity was maximized . the bonferroni multi - comparison test method19 was used when correcting for redundancy as required and p - values < 0.05 were again considered to be statistically significant . to compare the time - series data , we introduced a mixed - linear model adjusted for the cutoff of sua baseline ( < 5.9 mg / dl or 5.9 mg / dl ) and the treatment before irbesartan ( the irb group or the arbs irb switch group ) as fixed effects . analyses were performed with subjects as random effects . data were analyzed using spss statistical software package for windows ( v21.0 ; spss inc . , chicago , il , usa ) . the study was approved by the ethics committee of tokyo university of pharmacy and life sciences and carried out in accordance with recommendations from the declaration of helsinki . this was a retrospective study performed at a diabetic clinic in chigasaki ( japan ) . the subjects were 134 stable diabetic outpatients treated with irbesartan for 612 months in 20112012 . we excluded 27 patients treated with drugs that influenced sua such as allopurinol , diuretics , or fenofibrate . 72 patients had been previously treated with other arbs and the medicine was switched to irbesartan ( designated the arbs irb switch group ) . other patients were started on irbesartan as the first arb ( designated the irb group ) . diabetic nephropathy was staged according to an analysis of the urinary albumin excretion ( uae ) and egfr as defined by the japanese society of nephrology from the japanese historical cohort study:18 stage i , uae < 30 mg / g creatinine ; stage ii , 30 uae < 300 mg / g creatinine ; stage iii , uae 300 mg / g creatinine or continuous proteinuria ( 0.5 g / g creatinine ) ; stage iv , egfr < 30 ml / min/1.73 m. seven patients had the complication of myocardial disease and four of them were treated with a calcium channel blocker in combination with irbesartan . three other patients had stopped treatment with anticoagulant , calcium channel blocker or nitrate before irbesartan was started . the follow - up period was 12 months for 101 patients and 6 months for the other six patients . systolic blood pressure ( sbp ) and diastolic blood pressure ( dbp ) were recorded before irbesartan treatment ( pre ) , at the beginning of the study ( 0 month ) , and 1 , 3 , 6 , and 12 months after irbesartan was started . serum creatinine ( scr ) and sua were measured at the same time point as sbp and dbp . estimated glomerular filtration rate ( egfr ) was calculated from scr , sex , and patients age . the calculation formula defined by the japanese society of nephrology is : baseline values were calculated as the average of values between pre - treatment examinations and month zero . the data are presented as means sd . student s t - test was adopted to compare continuous variables and a value of p<0.05 was considered significant . sua decline after 6 or 12 months irbesartan treatment was employed as the dependent variable . we introduced significant ( p<0.05 ) independent variables from the univariate analysis into multiple logistic regression analysis . the sex , history of alcohol intake , and diabetic disease duration were included in the multiple logistic regression analysis as independent variables . the receiver operating characteristic ( roc ) curves were used to estimate the sua cut - off point and this was determined to be where the sum of sensitivity and specificity was maximized . the bonferroni multi - comparison test method19 was used when correcting for redundancy as required and p - values < 0.05 were again considered to be statistically significant . to compare the time - series data , we introduced a mixed - linear model adjusted for the cutoff of sua baseline ( < 5.9 mg / dl or 5.9 mg / dl ) and the treatment before irbesartan ( the irb group or the arbs irb switch group ) as fixed effects . data were analyzed using spss statistical software package for windows ( v21.0 ; spss inc . , chicago , il , usa ) . here , the sua - depressing effect of irbesartan was investigated retrospectively in 107 hypertensive outpatients with diabetes . patients in the arbs irb switch group had significantly lower baselines of sbp and dbp than those of the irb group because of their antihypertensive treatment . the arb treatment is reported to decrease blood glucose level and total cholesterol.20,21 in agreement with those reports , the arbs irb switch group showed significantly lower glucose baseline and low density lipoprotein - cholesterol baseline than the irb group ( table 1 ) . there were no significant differences between baseline values of scr and egfr in the irb and arbs irb switch groups . the arbs irb switch group had statistically significantly higher sua baseline than the irb group . the possibility of sua increase by the pre - treatment of arbs was examined in 53 cases from 72 patients of the arbs irb switch group . the sua at 612 months did not change significantly from the arb - nave baseline values . the number of patients who had elevated sua from the start of arb use was almost the same as that of patients with decreased sua ( table s1 ) . from those results , the baseline values of bp , scr , egfr , and sua of the patients diagnosed with diabetic nephropathy are shown in table s2 . the hba1c values at 612 months did not change significantly from the baseline values ( data not shown ) and it was suggested that diabetes progression did not occur in the patients over the monitoring period . results for the change in blood pressure ( bp ) are shown in figure 1a . the bp baseline values were compared with bp levels at 112 months . in all patients , bp was well - controlled in the follow - up period ( figure 1a ) . sbp levels were decreased significantly at 1 , 6 , 12 months from baseline and dbp levels were decreased significantly at 1 , 3 , 6 , and 12 months ( figure 1a ) . there was no significant difference in bp between the irb group and the arbs irb switch group during the study ( data not shown ) . the egfr did not change significantly from the baseline since irbesartan treatment started ( figure 1b ) . the sua of the subjects at the end of the study period was compared with the baseline values and the number of the patients with sua decline was more than half of the patients ( table s3 ) . thus , we performed univariate logistic regression analysis to identify the factors that influenced sua changes after 612 months ( table s4 ) . sua decline after 612 months was introduced as the dependent variable and some clinical factors were examined with positive effects for sua changes . the sua baseline tended to be higher in men than women ( table 1 ) ; however , sex was not found to be a significant relative factor for sua changes ( table s4 ) . the dose of irbesartan , the bp or scr baseline values , and existence of diabetic nephropathy ( stage ii and iii ) were not found to be correlated to sua . cardiovascular diseases such as myocardial disease , cerebrovascular disease , and arteriosclerosis showed no significant effect on the sua changes . irb switch , a history of alcohol intake , and higher sua baseline caused significant sua decline . subsequently , we introduced the three significant variables from the univariate analysis into the multiple logistic regression analysis ( table s4 ) . the arbs irb switch and sua baseline were determined to be significant relative factors in the final model . the arbs irb switch group had significantly higher sua baseline than the irb group ( table 1 ) , and this could be the reason why the arbs irb switch was a positive factor for sua decline . the result of the multiple logistic regression analysis suggested that the higher sua baseline led to sua decline after irbesartan treatment . we performed an roc analysis to determine the cutoff sua baseline for evaluating dependence of its effect on sua decreases ( figure s1 ) . the roc analysis showed that patients with 5.9 mg / dl sua at baseline had a positive benefit in terms of sua decline . based on the results of the roc analysis , the subjects were classified into those with an sua baseline < 5.9 mg / dl and those 5.9 mg / dl . there was no significant difference in the sua between the arbs irb and irb groups except at baseline ( data not shown ) . the irbesartan efficacy on sua decrease was validated with a mixed - linear model using the 5.9 mg / dl cutoff . the group with an sua baseline < 5.9 mg / dl showed no significant sua changes during the study period with the mixed - linear model . subjects in the sua baseline 5.9 mg / dl group had significantly higher sua than the other group over the monitoring period ( p<0.001 ) and their sua decreased gradually in a time - dependent manner , with a significant decrease observed at 12 months ( from the sua baseline value 6.60.16 mg / dl to 6.20.16 mg / dl , p=0.010 by the bonferroni method ) . the present study revealed that irbesartan showed a significant effect on sua decline on patients with higher sua baseline and that the effect of irbesartan was seen markedly in patients with sua 5.9 mg / dl . this result demonstrates that irbesartan treatment could achieve a decrease of sua in hyperuricemic patients . this multiple effect of irbesartan enables efficient treatment for diabetic patients with hypertension and hyperuricemia . notes : decrease of sua over 12 months was set to a positive influence and specificity and sensitivity of sua baseline value were plotted . the cutoff point of sua when the sum of specificity and sensitivity is maximized was 5.9 mg / dl ( specificity , 0.860 ; sensitivity , 0.414 ) . abbreviations : ci , confidence interval ; roc , receiver operating characteristic ; sua , serum uric acid . sua changes of the arbs irb switch group by the pre - treatment of arbs note : baseline means the average of values between arbs - nave examinations and the onset of arbs . abbreviations : arb , angiotensin ii receptor blockers ; irb , irbesartan ; sua , serum uric acid . the baseline values of the subjects classified with the stages of diabetic nephropathy note : the values are represented as meanstandard deviation . abbreviations : dbp , diastolic blood pressure ; egfr , estimated glomerular filtration rate ; sbp , systolic blood pressure ; scr , serum creatinine ; sua , serum uric acid . sua changes from baseline after 612 months of irbesartan treatment abbreviation : sua , serum uric acid . logistic regression analysis of the factors associated with sua decline notes : sua decline after 612 months was introduced as dependent variable and was coded 1 . abbreviations : arb , angiotensin ii receptor blockers ; ci , confidence interval ; dbp , diastolic blood pressure ; hba1c , glycated hemoglobin ; irb , irbesartan ; or , odds ratio ; nd , not determined ; sbp , systolic blood pressure ; scr , serum creatinine ; sua , serum uric acid .

backgroundhyperuricemia has been proposed to be a risk factor for cardiovascular disease and chronic kidney disease . since diabetes is often complicated by hypertension and hyperuricemia , efficient therapeutic strategy against these two complications is very important in diabetic treatment . it has been reported that the antihypertensive drug , irbesartan , inhibits the renal uric acid reabsorptive transporters , urat1 and glut9 ; this result suggests that irbesartan decreases serum uric acid level ( sua).subjects and methodsa retrospective study of 107 patients with hypertension and diabetes was performed to analyze the effects of irbesartan on blood pressure , estimated glomerular filtration rate ( egfr ) , and sua . the follow - up period was 612 months . seventy percent of the patients were diagnosed with diabetic nephropathy stage ii iv . we excluded patients treated with drugs that influenced sua . the multiple logistic regression analysis was introduced to identify the relative factors for sua decline . the time - dependent sua changes were examined in a mixed - linear model.resultsirbesartan reduced blood pressure significantly after 1 , 6 , and 12 months treatment . no subject showed significant change in egfr from baseline level throughout the period . the multiple logistic regression analysis revealed that sua baseline significantly influenced sua decline after 612 months . in patients whose sua baseline was 5.9 mg / dl , the sua was significantly decreased from 6.60.16 mg / dl to 6.20.16 mg / dl ( p=0.010 ) , after 12 months irbesartan treatment . in the sua baseline < 5.9 mg / dl group , the sua did not show significant change over the monitoring period.conclusionour results demonstrate that irbesartan reduces the risk of hyperuricemia . no decline in renal function was observed after the initiation of irbesartan treatment . the present report determines the criteria of sua baseline for introducing an antihyperuricemic effect using irbesartan . its antihypertensive effect coupled with sua decline would be effective for the treatment of hypertension complicated by hyperuricemia .

Eating ice actually burns calories because it requires energy for the body to melt the cube. One curious doctor suggests this can be used as a legitimate weight-loss tool. Kevin Saff/Flickr When he became determined to lose weight, Dr. Brian Weiner decided to change his eating and exercise regimes. "One of the first changes I made," explains Weiner, a gastroenterologist in New Jersey and assistant professor at Robert Wood Johnson Medical School, "was to give up my beloved ice cream." Aiming for something lighter, Weiner replaced it with Italian ices. The cups at his supermarket listed their calorie content as 100—calculated by multiplying 25 grams of carbohydrate by four calories per gram. "One evening, in a burst of insight," Weiner writes, "I realized that this calculation was incorrect. The manufacturer of the ices did not calculate the energy required to melt the ice, and did not deduct this from the calorie calculation." By Weiner's math, he was actually only consuming 72 calories, or "icals," his term for the net caloric content of ice-containing foods after considering the calories that the body burns to produce the thermal energy that melts the ice. Weiner reviewed the medical literature. "I found that no one has clearly identified this oversight," he writes. "I could not locate references to considerations of the implications of the energy content of ice as food." Everything in your life would be different because you would be eating a liter of ice every day. After discussing the issue in detail with his son, an engineering student at Rutgers who vetted his father's calculations, Weiner submitted his story as a letter to editors of the widely-read medical journal Annals of Internal Medicine. They published it. In the article, Weiner said the idea could be of real importance to people trying to lose weight. It's meant as a supplement to overall diet and lifestyle that go into maintaing a healthy physical form. "While eating ice, you are serving two purposes," Weiner explains, "you are burning calories and not eating positive-calorie foods." Now Weiner has also written an e-book, The Ice Diet. It's free—part of his stated wish "not to get lumped in with the counter-productive fad diet (snake oil) promoters." As a practicing gastroenterologist, Weiner says he regularly avoids micromanaging food selection. He manages obesity as an illness and diets as part of a holistic approach to good eating. "I would usually cringe when patients brought up the weight loss diet of the day, usually some poorly documented and improbable strategy. I never thought I would be actively promoting and discussing weight loss diets." But now he is, so, what's to know about using Weiner's ice diet? Samuel John/Flickr When you eat a significant amount of ice, your body burns energy to melt it. Eating ice should, by the logic of this diet, also provide some level of satiety, if only so far as it physically fills space in the stomach and mouth. By Weiner's calculations, ingesting one liter of ice would burn about 160 calories, which is the energy equivalent of running one mile. So you get to eat and burn calories. Ever since the death of upward mobility, that has been The American Dream. What's more, it's probably safe. "Ingesting ice at this level should not have any obvious adverse consequence in otherwise healthy persons," Weiner, who trained at Johns Hopkins, writes. "For the vast majority of adults and children, there does not appear to be any contraindication to the use of the Ice Diet right now." One piece of evidence for the safety of ingesting substantial amounts of ice, Weiner notes, comes from the case study of the 32-ounce 7/11 Slurpee, from which he concludes, "The ingestion of one liter of ice per day appears to be generally safe." At some point beyond that liter, too much ice can be a problem. In the case of one obese person who attempted to eat seven quarts of ice per day, Weiner says, "Not surprisingly, this person suffered an uncomfortable feeling of coldness." In his professional opinion, that much ice per day would, for most people, be a "toxic dose." He recommends avoiding eating much more than the Slurpee-tested one liter of ice daily, "to avoid hypothermia or unusual cooling of the body. ... Some organs do not work optimally when the body temperature drops too much." ||||| The premise of the ice diet is that it takes energy to melt ice, so you can lose weight by eating it. According to the science, you'd have to eat an impractical amount of ice to see any benefit. Tom Grill, Getty Images By Andrew Zimmerman Jones Updated September 10, 2016 . Question: Does the ice diet work? I've heard about something called the ice diet. Does it work? It seems like an easy way to burn off calories. Answer: The Ice Diet is a proposed diet in which people say that eating ice causes your body to spend energy to heat the ice. Similarly, some diets suggest the drinking of a lot of ice water to help burn calories. While it's true you need to drink water to metabolize fat and it's also true energy is required in order to change the state of matter of ice into water, eating ice simply doesn't burn enough calories to matter. Here's the science of why this diet doesn't work. The Ice Diet Premise The calorie is a measurement of heat energy which is defined as the amount of heat needed to raise the temperature of a gram of water one degree. In the case of solid ice, it also takes 80 calories to turn a gram of ice into liquid water. Therefore, eating one gram of ice (0 degrees Celsius) will burn calories to heat it to body temperature (about 37 degrees Celsius), plus 80 calories for the actual melting process. continue reading below our video 4 Tips for Improving Test Performance Each gram of ice causes the expenditure of approximately 117 calories. Eating an ounce of ice therefore causes the burning of approximately 3,317 calories. Considering that losing a pound of weight requires the burning of 3,500 Calories, this sounds like a pretty good deal, doesn't it? Why the Ice Diet Doesn't Work The problem is that when talking about food, we're talking about Calories (capital C - also called a kilogram calorie) instead of calories (lowercase c - also called a gram calorie), resulting in: 1,000 calories = 1 Calorie Performing the above calculations for kilogram Calories, we find that a single kilogram of ice consumed takes 117 calories. To reach the 3,500 Calories required to lose a pound of weight, it would be necessary to consume about 30 kilograms of ice. This equates to consuming about 66 pounds of ice to lose a single pound of weight. Therefore, if you did everything else exactly the same, but consumed a pound of ice a day, you would lose a pound of weight every two months. Not exactly the most efficient diet plan. There are some other issues to consider, which are more biological. For example, some of the thermal energy involved may not actually be a result of biochemical metabolic processes. In other words, melting ice into water may not really result in calories burned from the metabolic storehouse of energy. Ice Diet - The Bottom Line Yes, it's important to drink water if you're trying to lose weight. Yes, if you eat ice you'll burn slightly more calories than if you drank the equivalent amount of water. However, it's not enough calories to aid your weight loss efforts, you could harm your teeth eating ice, and you'll still need to drink water. Now, if you really want to use temperature to lose weight, just lower the temperature of the room or take cold showers. Then, your body has to expend energy to maintain your core temperature and you'll actually burn calories! Ice diet? Not scientifically sound. Edited by Anne Marie Helmenstine, Ph.D. ||||| Listen Now [5 min 17 sec] SAUL LOEB/AFP/Getty Images US President Barack Obama eats a shave ice alongside his daughter Sasha at Island Snow in Kailua, Hawaii, January 3, 2011. Dr. Weiner says that covering the ice in sugar can negate any positive effects of the diet. According to Dr. Brian C Weiner, a gastroenterologist and Assistant Professor at the Robert Wood Johnson Medical School in New Jersey, "...It turns out that when you eat ice and melt it, that takes energy. Ultimately what this leads to is that ice is a negative calorie food." The idea of using ice as a dietary aid came when the Weiner wanted to lose some weight. He had given up ice cream, but was still eating 100 calorie Italian ice cups. As it turns out, he eventually realized, it takes energy to heat up the ice when it goes into a persons body. So, in terms of overall calories, an ice cup should only account for about 76 calories, when all is said and done. So far he's lost more than 50 pounds on the diet. He's been eating shaved ice with flavorings, but it's important to know that he's also eating healthily otherwise and exercising regularly. While it's a pretty straight forward diet, Weiner notes that it's important to not eat too much. He recommends sticking to one liter max. Oh and that chewing ice cubes is a bad idea, because it can ruin enamel on teeth. Shaved ice and popsicles work best. ||||| The Ice Diet Many excess pounds ago, when I was determined to lose weight, I resolved to change my eating habits and exercise regime. One of the first changes I made was to give up my beloved ice cream. As an accommodation, I substituted Italian ices. I would typically enjoy the ices sold at the supermarket, sold in 6 ounce cups. These cups characteristically list their calorie content as 100 calories. That number is calculated by knowing the number of grams of carbohydrate in the container, multiplied by the known calories per gram. One evening, earlier this year, in a burst of insight, I realized that this was incorrect. The manufacturer of the ices did not calculate the energy required to melt the ice, and did not deduct this from the calorie calculation. After spending some time reviewing the Internet, the medical and clinical dietary literature, I found that no one has clearly identified this oversight. I could not locate references to considerations of the implications of the energy content of ice as food. I discussed this in detail with my son, Alex, an engineering student at Rutgers. He reviewed and agreed with my rough calculations. I wrote up this observation, and the editors of the Annals of Internal Medicine were kind enough to publish this in a letter to the editor, in their August 17, 2010 edition [Weiner BC, Weiner AC. Ann Intern Med. The Ice Diet. 2010;153[4]:279]. The Annals is published by the American College of Physicians. I believe that this observation may have significant importance to persons trying to lose weight. At this point, I also want to make two disclaimers. As a clinical gastroenterologist, I speak to patients all day long about what they eat. For most patients, their problem was not in the details of food selection, but in the management of their illness. Most of my work, therefore, was in the management of illness. It is ironic that I am now making detailed food recommendations. As a second disclaimer, I have long prided myself on being a scientifically trained physician. I would usually cringe when patients brought up the weight loss diet of the day, usually some poorly documented and improbable strategy. I never thought I would be actively promoting and discussing weight loss diets. I earnestly hope not to get lumped in with the counter-productive fad diet [snake oil] promoters. Up until August 17, 2010, if you wanted to lose weight, you needed to: 1. comply with a calorie deficient diet; 2. increase your level of exercise; or, 3. both. With regard to calorie deficient diets, there are many proposed strategies of modulating the diet, several active drugs and several surgical procedures. Some weight loss drugs act to increase the basal metabolic rate and increase the burning of calories. These drugs are controversial, because of concerns about side effects and addiction. Rimonibant, a cannabanoid receptor antagonist, had been used in Europe as an appetite suppressant that resulted in significant weight loss. My practice, Marlboro Gastroenterology, was selected as a site for US studies of this drug, in the treatment of NASH [non-alcoholic steatohepatitis], thought to be a potentially serious side effect of obesity. This drug was recently removed from the overseas market because of concern about psychiatric side effects. As a consequence, this ground-breaking US study was cancelled. The Ice Diet is a proposed new weight loss treatment choice with a unique mechanism. It exploits the error in the calculation of calorie content of frozen foods. The Ice Diet works by increasing the basal metabolic rate. When ingesting clinically significant amounts of ice, the body must burn energy to warm the ice to body temperature. The ingestion of ice would also provide some level of satiety. The ingestion of 1 liter of ice [equals 1.06 quart] would burn about 160 calories, the amount of energy used in running one mile. This approach has the paradoxical potential to cause weight loss while actually consuming food [realizing the Don Quixote quest equivalent of the bariatric world]. Ingesting ice at this level should not have any obvious adverse consequence in otherwise healthy persons. By the way, in the case of the six ounce cup of ices, noted to have 100 calories on the label, you are actually only consuming 72 calories or icals [“Icals” are my term for the corrected caloric content of an ice containing food product, adjusted for the energy required to melt the ice]. Brian C. Weiner, M.D., M.S., F.A.C.P., A.G.A.F Clinical Assistant Professor, Medicine

– Not only does ice offer a calorie-free way to snack—it actually burns calories as your body melts it, says an expert. Gastroenterologist Dr. Brian Weiner steers patients away from fad diets, but his findings on ice have inspired him to write a free e-book of his own: The Ice Diet. "While eating ice, you are serving two purposes," Weiner tells the Atlantic. "You are burning calories and not eating positive-calorie foods." (He calls ice a "negative-calorie food," KPCC notes). By Weiner's calculations, it appears to be "generally safe" for adults to eat a liter of ice a day. That one liter burns 160 calories, he argues—the number you'd burn by running a mile. A physics writer, however, calculates that you'd need to eat 66 pounds of ice to lose a pound of weight. "Not exactly the most efficient diet plan," writes Andrew Zimmerman Jones at About.com. Weiner, meanwhile, offers a number of safety guidelines: Don't, for instance, eat more than a liter a day. That could be toxic. And be careful eating ice when it's cold out. "I never thought I would be actively promoting and discussing weight loss diets," Weiner writes. "I earnestly hope not to get lumped in with the counter-productive fad diet (snake oil) promoters." (Another interesting recent diet idea? The ice cream cleanse.)

recent el nio events have stimulated interest in the development of modeling techniques to forecast extremes of climate and related health events . previous studies have documented associations between specific climate variables ( particularly temperature and rainfall ) and outbreaks of arboviral disease . in some countries , such diseases are sensitive to el nio . here we describe a climate - based model for the prediction of ross river virus epidemics in australia . from a literature search and data on case notifications , we determined in which years there were epidemics of ross river virus in southern australia between 1928 and 1998 . predictor variables were monthly southern oscillation index values for the year of an epidemic or lagged by 1 year . we found that in southeastern states , epidemic years were well predicted by monthly southern oscillation index values in january and september in the previous year . the model forecasts that there is a high probability of epidemic ross river virus in the southern states of australia in 1999 . we conclude that epidemics of arboviral disease can , at least in principle , be predicted on the basis of climate relationships.imagesfigure 1

the development of efficient methods for generating clean and sustainable energy is critically important to limit harmful greenhouse - gas emissions from burning of fossil fuels and to meet the rapid increase in global energy demand . therefore , considerable research has been conducted , spanning several decades , to find alternative , clean , and more efficient energy resources and conversion pathways to replace finite resources such as fossil fuels . artificial photosynthesis ( water splitting ) is an attractive approach to meet current targets to efficiently and inexpensively convert solar energy to a storable and transportable form of energy . splitting of water by direct sunlight into molecular oxygen and hydrogen in a photoelectrochemical ( pec ) cell is one such promising method to produce a chemical fuel ( hydrogen ) that can be utilized in a fuel cell or by direct combustion . of the two half - reactions , water oxidation is widely considered to be more challenging , given the fact that generation of one molecule of o2 requires four holes , generated on a timescale five orders of magnitude slower than the reduction reaction . therefore , the search for stable , efficient water - oxidation photocatalysts is widely regarded to be significant for large - scale water photolysis . since the discovery of tio2 as a stable photoanode for photoelectrochemical water cleavage by honda and fujishima in 1972 , considerable efforts have been made to seek an efficient and stable photoanode for water oxidation . studies have focused on semiconductor metal oxides such as tio2 , zno , wo3 , bivo4 , , fe2o3 , and ag3po4.[3a ] however overcoming their poor stabilities and/or poor utilization of solar energy still remains a significant challenge . furthermore , the efficiency of these semiconductor photocatalysts is seriously limited by factors including , but not limited to , low charge - carrier mobility , poor conductivity , low rates of surface reactions , and high charge - carrier recombination . studies have shown that photogenerated electrons and holes recombine rapidly , on the scale of nano - microseconds for colloidal tio2,[3b,10 ] and on the order of picoseconds for -fe2o3 . despite this , carrier recombination could be alleviated by applying a small external bias to the light - absorbing photoanode to provide sufficient overpotential to transfer electrons to the counter electrode in a pec . zinc oxide ( zno ) , with a bandgap energy of 3.2 ev , has been reported to be a suitable model semiconductor for solar water oxidation due to its low onset potential and high electron mobility . the latter is several orders of magnitude higher than that of tio2 , and thus its electrical resistance is lower and its electron - transfer efficiency higher . however , the drawbacks of utilizing zno include low hole mobility and slow kinetics at the zno / electrolyte interface , which result in fast electron hole recombination and thus limit the overall applied bias photon - to - current efficiency ( abpe ) . additionally , the extremely poor photostability of zno in aqueous solution limits the performance of zno - based photoanodes significantly , and has restricted their widespread employment in commercial devices . to date , numerous strategies have been developed to overcome its poor activity , including 1 ) fabricating a multisemiconductor system ( e.g. , si / zno core / shell nanowires ) to reduce hole electron recombination , 2 ) constructing 1d nanostructured zno - based electrodes with various morphologies ( e.g. , nanotubes , nanorods / nanowires ) for increased surface area and improved charge transport and light trapping , and 3 ) loading of oxygen - evolution catalysts ( oecs ) such as cobalt phosphate ( co - pi ) to improve the electron hole separation and o2 evolution kinetics . to address the issue of poor stability , it has been demonstrated that a thin layer of sno2 can act as a partial passivating layer for zno nanowires . however , in all cases the abpe ( ) and incident photon - to - current conversion efficiency ( ipce ) are still moderate , for example , nitrogen - doped zno ( =0.35 % , ipce=35 % at 350 nm ) and si / zno core / shell nanowires ( =0.38 % ) . the poor stability of the photoanode still remains a significant challenge . in our material - design strategy , employing a 1d nanostructured morphology for zno offers the potential advantage of improved charge transport over a flat surface , while simultaneously suppressing light scattering due to the light - trapping effect.[12a , 21 ] furthermore , the optimization of their length and diameter will maximize light absorption and provide a short charge - carrier diffusion length , and the use of cheap , earth - abundant oecs on the surface of zno nanowires could improve the photoanodic performance by their acting as hole - trapping sites for water oxidation and in situ charge separation . we also expect that employing high surface area zno nanowires would result in significantly increased cocatalyst deposition on the zno surface compared to flat zno films . therefore , to directly address the aforementioned challenges in the employment of zno photoanodes , we herein report the morphological optimization of well - aligned 1d zno nanowire arrays . the loading of water - oxidation catalysts [ co - pi and nickel borate ( ni - b ) ] on zno for efficient photoelectrochemical water splitting was investigated . finally , the highest ipce recorded for zno - based photoelectrodes and unprecedented stability were achieved . the effect of deposition time and the concentration of precursor were investigated for growth of bare zno nanowire arrays . xrd ( figure 1 a ) revealed that the as - prepared zno film has a wurtzite structure , with the strongest zno ( 002 ) peak indicating strong preferred orientation in the c - axis direction , as expected . a ) xrd pattern of zno nanowire array grown on fto glass substrate at 90 c for 4 h. asterisks indicate peaks of sno2 ( fto substrate ) . b ) uv / vis transmittance spectra of zno films fabricated at 90 c for 4 h as a function of precursor concentration . the uv / vis transmittance spectra and sem images of bare zno films prepared with different reaction times are shown in figures s1 and s2 ( supporting information ) . all films exhibited good transparency in the visible range ( 380500 nm ) ; for example , the sample grown for 1 h displayed close to 90 % transmittance in this wavelength range . the bandgap energy of zno nanowires was estimated to be about 3.3 ev from the uv / vis absorption spectra ( supporting information figure s1 , inset ) , and as expected , did not vary with reaction time . the sem images obtained for bare zno nanowires synthesized with varying deposition time ( supporting information figure s2 ) clearly show that all nanowires had an average diameter of about 50 nm independent of deposition time , whereas their lengths increased with time , similar to previous reports.[22b ] however , only a slight increase in length was observed when the reaction time increased to 5 h , which indicated that the dissolution / precipitation equilibrium was attained . figure s3 ( supporting information ) shows the i v curves for zno films prepared with 0.025 m precursor at 90 c as a function of growth time in 0.2 m na2so4 with phosphate buffer ( ph 7 ) electrolyte under 100 mw cm illumination . the dark current was negligible over the entire potential range from 0.2 to 1.6 v ( vs. rhe ) . longer nanowires maximize the light absorption and provide more reaction sites , and thus higher photocurrent . zno nanowires prepared at 4 and 5 h , which had similar lengths of about 1300 nm , both resulted in similarly high photocurrents . next , we investigated the effect of precursor concentration while keeping the reaction time fixed ( 4 h ) . table 1 summarizes the effect of precursor concentration on the length and diameter of the nanowires . both the average length and diameter increased as a function of precursor concentration , the length from 1300 nm ( 0.025 m ) to 1800 nm ( 0.075 m ) and the diameter from about 50 to about 110 nm ( figure 2 ) . however , sem images of zno nanowires grown with a zinc nitrate concentration of 0.1 m show a significant morphology change to a mixture of nanowires and nanoflakes that results in a condensed structure ( 1500 nm length ) . the uv / vis transmittance spectra of zno films as a function of precursor concentration are shown in figure 1 b. as a reference , the transmittance spectrum of an uncoated fluorine - doped tin oxide ( fto ) glass substrate was recorded ( figure 1 b inset ) . as expected , all zno films showed closed to zero transmittance in the uv range and exhibited no variation in bandgap ( 3.3 ev ) . the i v curves of zno nanowires prepared at 90 c for 4 h with various precursor concentrations ( figure 3 ) indicate the dramatic effect of nanowire length and diameter on the photocurrent . since zno - based semiconductors have a high electron mobility ( ca . 400 cm v s at 300 k ) but low hole mobility ( 115 cm v s at 300 k ) , efficient charge - carrier separation and activity are highly dependent on the hole diffusion length . although longer and wider nanowires can absorb more photons , as indicated by the uv / vis absorption spectra , and likely provide a larger surface area , a larger diameter also leads to a longer hole diffusion length , which would increase charge recombination and then lower reactivity . therefore , the best - performing zno nanowire arrays should have optimized length and diameter to balance these key factors related to the photoreaction . effect of precursor concentration c on the length l and diameter d of the zno nanowires sem images of zno nanowire arrays grown by hydrolysis / condensation reaction at 90 c for 4 h as a function of precursor concentration . a ) 0.025 , b ) 0.05 , c ) 0.075 m , and d ) 0.1 m. insets : top - view sem images . i v curves measured in a 0.2 m na2so4 solution with phosphate buffer ( ph 7 ) for zno films synthesized at 90 c for 4 h with varying precursor concentration . our optimization procedure resulted in a zno nanowire array with a length of 1400 nm and diameter of 70 nm prepared with 0.05 m precursor concentration at 90 c for 4 h , which gave a photocurrent density of 0.62 ma cm at 1 v ( vs. rhe ) and highest photocurrent density of 1.2 ma cm at 1.6 v ( vs. rhe ) due to its optimized surface area , light absorption , and hole diffusion length , which is much higher than the photocurrent density of bare zno nanowires reported recently ( 0.4 ma cm at 1.0 v vs. rhe ) . to improve the kinetics for water oxidation and electron hole separation , the oecs co - pi and ni - b were deposited on the optimized zno nanowire arrays by a simple photoassisted electrodeposition procedure.[27 , 28 ] figure 4 shows typical sem images of co - pi / zno and ni - b / zno films before pec tests , as well as that of a bare zno film ( figure 4 e , prepared with 0.05 m precursor concentration at 90 c for 4 h ) for comparison . deposition of co - pi or ni - b on the zno surface resulted in uniform coverage along the entire length of the nanowires . in addition , compared with bare zno nanowires , the average length of the co - pi / zno and ni - b / zno nanowires is maintained , but their average diameter increased slightly from 70 nm for bare zno to 120 nm and 100 nm for co - pi / zno and ni - b / zno nanowires , respectively , which is attributed to addition of the catalyst layer and formation of catalyst / zno core / shell - type arrays . the uv / vis transmittance spectra of optimized bare zno and cocatalyst - modified zno films are shown in figure 5 . all zno - based films exhibited good transparency in the visible range but almost zero transmittance in the uv range . the bandgap energy eg of as - prepared zno films was estimated from the absorption spectra . the eg value was calculated to be about 3.3 ev for both bare and cocatalyst - modified zno films ; thus , addition of cocatalysts did not alter the bandgap or light absorption of zno significantly . uv / vis transmittance spectra of bare zno , co - pi / zno , and ni - b / zno . high - resolution x - ray photoelectron spectroscopy ( xps ) was used to ascertain the presence and exact valence states of the elements of the cocatalyst - loaded zno nanowire arrays . in all cases zn 2p peaks were seen at 1022 and 1045 ev due to zn ( supporting information figure s4 ) . for co - pi - loaded zno , the presence of the co 2p peaks at 781.1 and 796.3 ev are in good agreement with those previously reported for co - pi oecs loaded on the surface of semiconductors ( figure 6 a ) . furthermore , the p 2p peak was observed at 133.4 ev , but in addition another p peak was observed at 140.1 ev ( marked with a star ) , which is characteristic of p absorption on defect states in zno but is not part of the oec ( figure 6 b ) . however , due to peak overlap , it is possible that this could be due to contributions from the zn 3s peak and the sn 4s peak ( from the fto substrate ) , both commonly found in the same region , as we also observed a similar peak in the xps spectrum of bare zno ( supporting information figure s4b ) . for ni - b - loaded zno , two clear ni 2p peaks were observed at 855.2 and 872.8 ev , which likely correspond to ni or ni ( figure 6 c ) ; however , as the binding energies of these two states suffer from a high degree of overlap , it is difficult to distinguish the exact nature of ni with confidence . the two corresponding ni 2p satellite peaks ( marked with stars ) were also found , at 860.7 and 878.6 ev , respectively . for boron , the expected singlet peak was found at 191.1 ev ( figure 6 d ) , indicative of a b environment and in agreement with recently reported xps spectra of ni - b catalysts . xp spectra of a ) co 2p , b ) p 2p , c ) ni 2p , and d ) b 1s . figure 7 a shows the i v curves of optimized zno ( length 1400 nm , diameter 70 nm ) , co - pi / zno , and ni - b / zno photoelectrodes in sodium sulfate or potassium borate electrolyte . in comparison with bare zno , which has an onset potential of 0.5 v ( vs. rhe ) , the photocurrent onset is cathodically shifted by about 0.1 v ( vs. rhe ) for co - pi - modified zno , which is attributed to the co - pi catalyst mitigating hole electron recombination by acting as a hole - trapping site to increase charge - separation efficiency . surprisingly , the onset potential for ni - b / zno is shifted cathodically by as much as 0.2 v compared to bare zno to about 0.3 v ( vs. rhe ) . a low onset potential is crucial for widening the operating window and therefore achieving a high abpe . similar to the co - pi cocatalyst , ni - b also appears to act as a hole - trapping site that can facilitate hole transfer on the semiconductor surface and thus decrease electron the overall photocurrent density is also increased by loading of co - pi and ni - b onto zno , which results in photocurrent densities of 0.72 and 1.22 ma cm at 1.0 v ( vs. rhe ) for co - pi / zno and ni - b / zno , respectively . more interestingly , a saturated photocurrent density of about 1.1 ma/ cm was achieved at 0.9 v ( vs. rhe ) for ni - b / zno instead of 1.6 v ( vs. rhe ) for both bare zno and co - pi / zno nanowires . a ) i v curves of bare zno , co - pi zno , and ni - b / zno films . b ) ipce spectra of bare zno , co - pi / zno , and ni - b / zno films . recent studies have reported that the deposition of co - pi oec onto n - type semiconductors such as fe2o3,[27 , 32 ] bivo4 , wo3 , n - type silicon ( n - si ) , and zno can enhance the pec performance under neutral conditions , because the co - pi complex functions as a hole - trapping site for in situ charge separation , and thus reduces surface recombination and improves the kinetics for water oxidation . for example , zhong et al . reported a simple photoassisted electrodeposition strategy to deposit co - pi oec on -fe2o3 ( hematite ) photoanodes in an aqueous , neutral phosphate medium containing co ions . in this process , photogenerated holes from hematite are used to oxidize co to co , which results in deposition of co - pi on the surface of the semiconductor . ni - b has a similar catalytic mechanism for water oxidation to co - pi . hole pairs generated by the light - absorbing semiconductor are separated by an internal electric field , and conduction - band ( cb ) electrons move towards to the back contact ( fto substrate ) , through the external circuit to the pt counter electrode under external bias ( for hydrogen evolution ) . photogenerated holes migrate to the ni - b surface and oxidize ni from 2 + to 3 + , and then o2 evolution occurs by withdrawal of electrons from water , accompanied by a change in ni oxidation state back to 2 + . on the other hand , it has recently been reported that the active site in the ni - b catalyst has an intermediate oxidation state of 3.6 , which indicates that the ni center is in a formal oxidation state of 4 + . to compare the light - conversion efficiency of bare zno and cocatalyst - modified zno , ipce spectra were measured for all samples ( figure 7 b ) . the ipce of optimized bare zno nanowires ( 1400 nm length ) is , as expected , near - zero in the visible region ( 400440 nm ) but increases rapidly to about 52 % at 370 nm , which is consistent with its uv / vis spectrum and high photocurrent , as well as being much higher than that reported for zno nanowire arrays in the literature ( 40 % ) .[6 , 26 , 37 ] both co - pi and ni - b deposits on zno result in a sharp increase in ipce ; co - pi / zno has a dramatically increased ipce of about 72 % at 370 nm , and ni - b / zno an even higher ipce of about 90 % at 370 nm , which represents an increase of nearly 75 % compared to the bare zno film . this observation provides further explanation for the somewhat early attainment of the saturated photocurrent density ( 1.1 ma cm at ca . 0.9 v vs. rhe ) observed in figure 7 a. in general , an efficient water - splitting process is highly dependent on three factors : efficient light absorption by the photocatalyst , efficient charge - carrier separation , and efficient surface reaction ( charge utilization ) . the saturated photocurrent is observed for ni - b / zno at an early stage due to efficient hole trapping and subsequent faster surface reaction compared to both co - pi / zno and bare zno . zno has an intrinsically high electron mobility but very low hole mobility , which leads to fast recombination ; therefore , bare zno requires a higher electrical bias to obtain a saturated photocurrent . the early saturated photocurrent observed for ni - b / zno but not co - pi / zno strongly indicates that ni - b is a much more efficient surface cocatalyst and hole acceptor than co - pi . the high ipce of ni - b / zno can be attributed to increased light trapping by zno nanowires , efficient separation of photogenerated electrons and holes through loading with an improved surface oec , fast rectifying electron transport through 1d zno nanowires to the counter electrode , and efficient surface catalysis . furthermore the abpe of ni - b / zno was measured to be 0.4 % , which is considerably higher than recently reported values for nitrogen - doped zno nanowires ( 0.15 % ) , si / zno core / shell nanowires ( 0.38 % ) , and even some visible - light - driven semiconductor - based photoanodes , such as wo3/c3n4/coox , however , it is lower than that of the recently reported benchmark co - pi / w : bivo4 photoelectrode.[39a ] thus , a new visible - light - driven junction based on 1-d zno , such as c3n4 is underway for more efficient utilization of solar energy.[39b ] an important consideration in the employment of photoanodes for water cleavage on a commercial scale is their stability under prolonged illumination in aqueous solution , which is a problem for zno - based photoanodes . therefore , the stabilities of zno , co - pi / zno , and ni - b / zno were investigated at a potential of 1.0 v ( vs. rhe ) for 1 h ( figure 8 a ) . for bare zno nanowires , very poor stability was observed with continuous decay of photocurrent ; only 34 % residual photocurrent remained at the end of the experiment . a slight improvement in stability was observed for co - pi / zno , as co - pi itself appears to have some short - term stability in solution , followed by a relatively stable stage ( 65 % photocurrent remaining at the end of the experiment ) . this is most likely due to facile exchange of cobalt and phosphorus ions directly between the film and solution . most significantly , ni - b / zno exhibited unprecedented retention of photocurrent over 1 h , which , to the best of our knowledge , is the first such observation for zno photoelectrodes . similarly , a recent report also mentioned that a nickel film deposited by electron beam evaporation on an otherwise low - stability n - si photoanode results in an unprecedented improvement in stability during pec measurements in aqueous solution and a major shift in onset potential on immersion in potassium borate electrolyte . time curves of bare zno , co - pi / zno , and ni - b / zno photoelectrodes measured at 1.0 v ( vs. rhe ) for 1 h. b)d ) typical side - on sem images of ni - b / zno , co - pi / zno and bare zno nanowire arrays , respectively , after 1 h of pec measurements . to confirm the improved stability of our ni - b / zno junction , the morphologies of these zno - based photoelectrodes were examined by sem after prolonged pec testing ( figure 8 b d ) . in agreement with the stability test , no photocorrosion was observed for ni - b / zno , but the images of the bare zno and co - pi / zno electrodes revealed significant transformation of the structures into dense , compact films with very few distinct features and , significantly , they no longer resembled nanowire arrays . the side - on views of these samples before and after pec testing clearly show the effect of photocorrosion on their morphologies . only ni - b / zno retains the vertically aligned nanowire morphology ( figure 4 and figure 8 b furthermore , xrd analysis of the zno and co - pi / zno photoelectrodes after water - oxidation experiments ( figure s5 , supporting information ) revealed the emergence of a zn3(po4)2 phase ( jcpds card no . 33 - 1474 ) due to reaction with phosphate ions and is consistent with zno photocorrosion . similarly , high - resolution xps analysis of these samples ( supporting information figure s6 ) revealed that the o 1s peak of bare zno shifted to 531.3 ev with only a small contribution from zno at 529.7 ev , whereas extreme broadening of both the zn 2p and p 2p peaks was observed for co - pi / zno after pec measurements , commensurate with the formation of zn3(po4)2 species . at the same sample , the signal for co 2p is barely observed above the background ; this indicates desorption of cobalt from the oec . in contrast , the xp spectra of ni - b / zno after pec measurements revealed no obvious changes in positions and intensities of zn , ni , and b peaks , which is also in agreement with the recently reported enhanced stability of ni - protected n - si photoelectrodes . overall , this study demonstrates the application of ni - b not only as an efficient surface water - oxidation catalyst , but also as an effective passivation layer for semiconductor electrodes . we have reported a mild and efficient approach to significantly improve the photoelectrochemical performance of 1d zno nanowire arrays through optimization of their length and diameter followed by surface modification with cheap , earth - abundant cocatalysts . optimized bare zno nanowires ( 1400 nm length , 70 nm diameter ) exhibit a photocurrent density of 0.62 ma cm at 1.0 v and 1.2 ma cm at 1.6 v ( vs. rhe ) under 1 sun illumination . loading of co - pi cocatalyst onto the surface of these optimized zno nanowires by photoassisted electrodeposition resulted in a higher steady - state photocurrent ( 0.75 ma cm at 1.0 v vs. rhe ) and improved ipce ( 72 % at 370 nm ) for co - pi / zno compared to bare zno . furthermore , ni - b / zno exhibited twofold higher steady - state photocurrent density ( 1.22 ma cm at 1.0 v vs. rhe ) compared to unmodified zno , which resulted in an ipce of about 90 % at 370 nm . more importantly , a significant cathodic shift in onset potential ( by 0.2 v ) and potential for saturated photocurrent ( by nearly 0.7 v ) were observed after modification with ni - b . the stability of zno was improved significantly on introduction of these surface oxidation catalysts , and ni - b / zno exhibited an unprecedented zero loss of photocurrent over a 1 h test period , which demonstrates the dual functionality of ni - b as a benign water - oxidation catalyst and robust surface - protection layer that can inhibit photocorrosion . the overall enhancement in current is due to efficient hole trapping by the surface cocatalyst and its catalytic effect . besides , fast electron transfer along highly charge mobile , well aligned zno wires to the counter electrode also plays an important role . this simple strategy that dramatically improved the efficiency of zno may be applicable to other photoanodes , for example , bivo4 , -fe2o3 , as well as to those that exhibit poor stability that limits their practical use in water - splitting devices . a potential heterojunction architecture would likely involve the coupling of a visible - light - driven photocatalyst to a zno nanowire charge acceptor to achieve efficient photocatalytic water cleavage . zno nanowire arrays were fabricated on fto glass substrates from zno seeds by a hydrothermal ( hydrolysis / condensation ) method described by greene et al . firstly , zno seed crystals were deposited onto fto glass ( tec 15 , pilkington nsg ) by spray pyrolysis ( nozzle size 2 cm , at a distance of 15 cm ) from a solution containing 0.005 m zinc acetate dihydrate ( 98 % , aldrich ) in ethanol followed by an annealing process in air at 350 c for 20 min . this procedure was repeated twice to obtain a uniform coverage of zno seed crystals with density and size similar to those already reported.[22a ] secondly , a precursor solution with 0.025 m zn(no)36 h2o ( 98 % , sigma ) and hexamethylenetetramine ( hmt , 99.5 % , sigma ) was heated in an open water bath at 90 c . in our optimized procedure , zno films were synthesized by varying the growth time from 0.5 to 5 h , and then by varying the concentration of the precursor solution from 0.025 to 0.01 m in intervals of 0.025 m. the concentration ratio of zn(no)36 h2o and hmt was kept constant at 1:1 while varying the concentration of precursor . both co - pi and ni - b catalysts were deposited onto optimized zno films by photoassisted electrodeposition.[2728 ] a three - electrode system with as - prepared zno films as working electrode , ag / agcl as reference electrode , and a pt mesh as counter electrode were used for the photoassisted electrodeposition process . co - pi / zno and ni - b / zno junctions were synthesized by applying a constant potential of 0.4 v ( vs. ag / agcl ) in a solution of 0.5 mm cobalt nitrate containing 0.1 m potassium phosphate buffer at ph 7 and a solution of 0.1 m potassium borate at ph 9.2 containing 1 mm ni(no3)2 , respectively , for 600 s under am 1.5 g light ( 100 mw cm ) illumination . x - ray diffraction ( xrd ) was carried out on a bruker d8 advance x - ray diffractometer ( 40 kv , 30 ma ) with cuk radiation ( =1.54 ) equipped with a psd lynxeye silicon - strip detector . the bandgap energy was estimated by using equation ( 1 ) where is the absorption coefficient , h the photon energy ( h is planck s constant , is the frequency ) , n a constant with a value of 2 for direct - bandgap semiconductors , a a proportionality constant related to the material , and eg the bandgap energy . high - resolution xps was performed by using a thermo scientific k - alpha photoelectron spectrometer with monochromatic alk radiation ; peak positions were calibrated to carbon ( 284.5 ev ) and plotted with the casaxps software . the pec measurements were conducted in a three - electrode cell equipped with a quartz window and potentiostat ( ivium technology ) . a pt mesh and ag / agcl were used as a counter electrode and reference electrode , respectively . the scan speed was 20 mv s between 0.4 and 1.0 v ( vs. ag / agcl ) all measurements were carried out with a ag / agcl ( 3 m kcl ) reference electrode , but results reported in this study are presented against the reversible hydrogen electrode ( rhe ) for ease of comparison with the h2 and o2 redox levels and with other literature reports that used electrolytes with different ph . thus electrode potentials were converted to the rhe scale by using equation ( 2 ) . the electrolyte was a 0.2 m aqueous solution of na2so4 with 0.1 m phosphate buffer ( ph 7 ) or 0.1 m potassium borate solution ( ph 9.2 ) . all electrolytes were purged with argon for 10 min to remove dissolved o2 before pec measurement . a 150 w xenon lamp ( newport , usa ) equipped with an am 1.5 g filter was used to irradiate the zno electrodes from the front side and was calibrated to 1 sun illumination ( 100 mw cm ) by using a photodiode . for ipce measurements , monochromatic light was generated by using a monochromator and the resultant photocurrent was recorded for wavelengths between 350 nm and 440 nm . the light intensity was measured with a silicon photodiode and a newport optical meter ( model 1918-r ) . ipce was calculated by using equation ( 3 ) the abpe was estimated by using equation ( 4)[43 , 44 ] zno nanowire arrays were fabricated on fto glass substrates from zno seeds by a hydrothermal ( hydrolysis / condensation ) method described by greene et al . firstly , zno seed crystals were deposited onto fto glass ( tec 15 , pilkington nsg ) by spray pyrolysis ( nozzle size 2 cm , at a distance of 15 cm ) from a solution containing 0.005 m zinc acetate dihydrate ( 98 % , aldrich ) in ethanol followed by an annealing process in air at 350 c for 20 min . this procedure was repeated twice to obtain a uniform coverage of zno seed crystals with density and size similar to those already reported.[22a ] secondly , a precursor solution with 0.025 m zn(no)36 h2o ( 98 % , sigma ) and hexamethylenetetramine ( hmt , 99.5 % , sigma ) was heated in an open water bath at 90 c . in our optimized procedure , zno films were synthesized by varying the growth time from 0.5 to 5 h , and then by varying the concentration of the precursor solution from 0.025 to 0.01 m in intervals of 0.025 m. the concentration ratio of zn(no)36 h2o and hmt was kept constant at 1:1 while varying the concentration of precursor . both co - pi and ni - b catalysts were deposited onto optimized zno films by photoassisted electrodeposition.[2728 ] a three - electrode system with as - prepared zno films as working electrode , ag / agcl as reference electrode , and a pt mesh as counter electrode were used for the photoassisted electrodeposition process . co - pi / zno and ni - b / zno junctions were synthesized by applying a constant potential of 0.4 v ( vs. ag / agcl ) in a solution of 0.5 mm cobalt nitrate containing 0.1 m potassium phosphate buffer at ph 7 and a solution of 0.1 m potassium borate at ph 9.2 containing 1 mm ni(no3)2 , respectively , for 600 s under am 1.5 g light ( 100 mw cm ) illumination . x - ray diffraction ( xrd ) was carried out on a bruker d8 advance x - ray diffractometer ( 40 kv , 30 ma ) with cuk radiation ( =1.54 ) equipped with a psd lynxeye silicon - strip detector . the bandgap energy was estimated by using equation ( 1 ) where is the absorption coefficient , h the photon energy ( h is planck s constant , is the frequency ) , n a constant with a value of 2 for direct - bandgap semiconductors , a a proportionality constant related to the material , and eg the bandgap energy . high - resolution xps was performed by using a thermo scientific k - alpha photoelectron spectrometer with monochromatic alk radiation ; peak positions were calibrated to carbon ( 284.5 ev ) and plotted with the casaxps software . the pec measurements were conducted in a three - electrode cell equipped with a quartz window and potentiostat ( ivium technology ) . a pt mesh and ag / agcl were used as a counter electrode and reference electrode , respectively . the scan speed was 20 mv s between 0.4 and 1.0 v ( vs. ag / agcl ) all measurements were carried out with a ag / agcl ( 3 m kcl ) reference electrode , but results reported in this study are presented against the reversible hydrogen electrode ( rhe ) for ease of comparison with the h2 and o2 redox levels and with other literature reports that used electrolytes with different ph . thus electrode potentials were converted to the rhe scale by using equation ( 2 ) . the electrolyte was a 0.2 m aqueous solution of na2so4 with 0.1 m phosphate buffer ( ph 7 ) or 0.1 m potassium borate solution ( ph 9.2 ) . all electrolytes were purged with argon for 10 min to remove dissolved o2 before pec measurement . a 150 w xenon lamp ( newport , usa ) equipped with an am 1.5 g filter was used to irradiate the zno electrodes from the front side and was calibrated to 1 sun illumination ( 100 mw cm ) by using a photodiode . for ipce measurements , monochromatic light was generated by using a monochromator and the resultant photocurrent was recorded for wavelengths between 350 nm and 440 nm . the light intensity was measured with a silicon photodiode and a newport optical meter ( model 1918-r ) . ipce was calculated by using equation ( 3 ) the abpe was estimated by using equation ( 4)[43 , 44 ] as a service to our authors and readers , this journal provides supporting information supplied by the authors . such materials are peer reviewed and may be re - organized for online delivery , but are not copy - edited or typeset . technical support issues arising from supporting information ( other than missing files ) should be addressed to the authors

zno has long been considered as a model uv - driven photoanode for photoelectrochemical water splitting , but its performance has been limited by fast charge - carrier recombination , extremely poor stability in aqueous solution , and slow kinetics of water oxidation . these issues were addressed by applying a strategy of optimization and passivation of hydrothermally grown 1d zno nanowire arrays . the length and diameter of bare zno nanowires were optimized by varying the growth time and precursor concentration to achieve optimal photoelectrochemical performance . the addition of earth - abundant cobalt phosphate ( co - pi ) and nickel borate ( ni - b ) oxygen evolution catalysts onto zno nanowires resulted in substantial cathodic shifts in onset potential to as low as about 0.3 v versus the reversible hydrogen electrode ( rhe ) for ni - b / zno , for which a maximum photocurrent density of 1.1 ma cm2 at 0.9 v ( vs. rhe ) with applied bias photon - to - current efficiency of 0.4 % and an unprecedented near - unity incident photon - to - current efficiency at 370 nm . in addition the potential required for saturated photocurrent was dramatically reduced from 1.6 to 0.9 v versus rhe . furthermore , the stability of these zno nanowires was significantly enhanced by using ni - b compared to co - pi due to its superior chemical robustness , and it thus has additional functionality as a stable protecting layer on the zno surface . these remarkable enhancements in both photocatalytic activity and stability directly address the current severe limitations in the use of zno - based photoelectrodes for water - splitting applications , and can be applied to other photoanodes for efficient solar - driven fuel synthesis .

the phenomenon of optical bistability already has more than thirty years of history , going back to the theoretical prediction of mccall @xcite in 1974 , followed by experimental demonstration of the effect by gibbs , mccall , and venkatesan @xcite in 1976 ( see also refs . , and for an overview ) . since then a vast amount of literature has been devoted to explore the topic ( an extended bibliography can be found in our recent paper , ref . ) ; controlling the flow of light by light itself is of great importance for optical technologies , especially on the micro- and nano - scale . more recently , new materials such as photonic crystals , @xcite surface - plasmon polaritonic crystals , @xcite and materials with a negative index of refraction , @xcite have revealed bistable behavior . in our previous work , @xcite we studied theoretically the bistable optical response of a thin film of linear molecular j - aggregates . to describe the optical response of a single aggregate , we exploited a frenkel exciton model with an uncorrelated on - site energy disorder , taking into account only the optically dominant transitions from the ground state to the one - exciton manifold , while neglecting the one - to - two exciton transitions . within this picture , an aggregate can be viewed as a meso - ensemble of two - level localization segments , @xcite which allows for a description of the optical dynamics by means of a @xmath0-density matrix . employing a joint probability distribution of the transition energy and the transition dipole moment of frenkel excitons , allowed us to account for the correlated fluctuations of these two quantities , obtained from diagonalizing the frenkel hamiltonian with disorder . by solving the coupled maxwell - bloch equations , we calculated the phase diagram of possible stationary states of the film ( stable , bistable ) and the input - dependent switching time . from the analysis of the spectral distribution of the exciton population at the switching point , we realized that the field inside the film is sufficient to produce one - to - two exciton transitions , confirming a similar statement raised in ref . . the goal of the present paper is to extend the one - exciton model @xcite by including two - exciton states and transitions between the one- and two - exciton manifolds , respectively . furthermore , two excitons spatially located within the same localization domain usually quickly annihilate , transferring their energy to an appropriate resonant monomer vibronic level . @xcite hence , the generalized model requires the consideration of exciton - exciton annihilation . @xcite we will assume that exciton - exciton annihilation prevents the three - exciton states from playing a significant role in the response of the film . the relevant transitions of the model are depicted in fig . [ fig : four level model ] . to make the two - exciton model tractable , we will select the optically dominant transitions between the ground state and the one - exciton manifold ( as we did in ref . ) , and also between the one- and two - exciton manifolds . treating the different localization segments independently , in combination with the state selection , allows one to considerably reduce the set of relevant states , namely to four states of a segment : the ground state , the optically dominant one- and two - exciton states , and a high - lying molecular electronic or vibronic state , through which the excitons annihilate . this model has been implemented for the first time in ref . , using the simplifying assumption that the transition energies and transition dipole moments are correlated perfectly . unlike ref . , we will account for the correct joint statistics of both quantities , similarly to our previous work . @xcite the optical dynamics of a single localization segment is described within the framework of a @xmath1-density matrix . we derive a steady - state equation for the output field intensity as a function of the input intensity . the field inside the film is calculated taking into account the field produced by the aggregate dipoles . we find that , counterintuitively , tuning away from the resonance may , depending on the dephasing rate , promote bistable behavior . in addition , we show that fast exciton - exciton annihilation combined with slow relaxation from the high - lying vibronic level enhances the tendency towards bistablity . the phase diagram of bistability is computed and compared with the one - exciton model . we address also the realizability of the bistable behavior in actual materials . the outline of this paper is as follows . in the next section we present our model of a single aggregate , consisting of a frenkel hamiltonian with uncorrelated on - site energy ( diagonal ) disorder ( sec . [ sec : single agregate ] ) . next , we describe the selection of the optically dominant transitions in sec . [ sec : selection procedure ] and introduce our model for the exciton - exciton annihilation of two - exciton states in sec . [ sec : ex - ex annihilation ] . in sec . [ sec : density matrix - field equations ] , we formulate our approach , based on the density matrix equations in the @xmath2 space of states , as well as the maxwell equation for a thin film of oriented linear j - aggregates . section [ sec : steady - state analysis ] deals with the results of our numerical analysis of the bistable optical response of the film in a multidimensional parameter space . we identify conditions that are most favorable for bistable behavior of the film . in sec . [ sec : estimates ] , we estimate the driving parameters and the input light flux required for experimental realization of bistability for films of pseudoisocyanine j - aggregates . section [ summary ] summarizes the paper . the geometry of the model system and the assumptions we adopt hereafter are essentially the same as in our previous paper . @xcite in short , we aim to study the transmittivity of an assembly of linear j - aggregates arranged in a thin film ( with the film thickness @xmath3 small compared to the emission wavelength @xmath4 inside the film ) and aligned in one direction , parallel to the film plane . the aggregates in the film are assumed to be decoupled from each other ; their coupling to the environment is treated through phenomenological relaxation rates ( see ref . for a detailed discussion ) . we model a single aggregate as a linear chain of @xmath5 three - level monomers . the two lower states are assumed to form multi - exciton bands , as a result of strong dipole - dipole excitation transfer interactions between the monomers . to simplify the treatment of the multi - exciton states , we restrict ourselves to nearest - neighbor interactions . the transition dipole moments between the two lower molecular states are considered to align in one direction for all monomers . then the ( frenkel ) exciton part of the aggregate hamiltonian reads @xmath6 where @xmath7 denotes the creation ( annihilation ) pauli operator of an excitation at site @xmath8 . the monomer excitation energies @xmath9 between the two lower states are modeled as uncorrelated gaussian variables with mean @xmath10 and standard deviation @xmath11 . the parameter @xmath12 represents the magnitude of the nearest - neighbor transfer integral . we assume that it does not fluctuate . after applying the jordan - wigner transformation , the multi - exciton eigenstates are found as slater determinants of one - exciton states @xmath13 with different @xmath14 . @xcite the multi - exciton eigenenergies are given by @xmath15 , with @xmath16 being the one - exciton eigenenenrgies and @xmath17 depending on whether the @xmath14th state is occupied or not . particularly , we will be interested in the one- and two - exciton states : [ one- and two - exciton states ] @xmath18 @xmath19 where @xmath20 and @xmath21 , and @xmath22 is the ground state of the aggregate ( with all monomers in the ground state ) . we also will need the transition dipole moments from the ground state @xmath22 to a one - exciton state @xmath23 and from a one - exciton state @xmath23 to a two - exciton state @xmath24 . in units of the single - molecule transition dipole moment , they obtain the dimensionless form [ eq : oscillator strengths ] @xmath25 @xmath26 where it was assumed that the aggregate is small compared to an optical wavelength . at low temperatures , exciton states reduce their extension from the physical size of the aggregate to much smaller segments as a result of the disorder - induced anderson localization @xcite . we will denote the typical size of these segments as @xmath27 , often referred to as the number of coherently bound molecules or localization length in terms of the localization theory . for j - aggregates , the optically dominant localized states reside in the neighborhood of the bottom of the exciton band . some of them resemble @xmath28-like atomic states : they consist of mainly one peak with no node within the localization segment ( see fig . [ fig : reduced wavefunctions]_a _ ) . we will denote the subset of such states as @xmath29 . to find all the @xmath28-like states from the complete set of wave functions @xmath13 , we used the rule proposed in ref . , @xmath30 with @xmath31 . the inequality selects those states that contain approximately 75% of the density in the main peak . we found numerically that for a wide range of the disorder strength @xmath11 ( @xmath32 ) , the thus selected states accumulate on average 73% of the total oscillator strength ( equal to @xmath5 ) . recall that for a disorder - free aggregate , the optically dominant ( lowest ) exciton state contains 81% of the total oscillator strength of the one - exciton transitions ( see , e.g. , refs . and ) . furthermore , we have shown that the @xmath28-like states , used as a basis to calculate the linear absorption spectrum , well reproduce its peak position and the shape of its red part , failing slightly in describing the blue wing , where higher - energy exciton states contribute as well . @xcite from this , we conclude that our procedure to select the optically dominant ( @xmath28-like ) one - exciton states works well . similar to the @xmath28-like states , one may also distinguish states that resemble atomic @xmath33 states . they have a well defined node within localization segments and occur in pairs with @xmath28-like states . each pair forms an @xmath34 doublet localized on the same chain segment . the levels within a doublet undergo quantum level repulsion , with their spacing nicely following the one that exists between @xmath35 and @xmath36 exciton states in a homogeneous chain of size @xmath27 . @xcite from the theory of multi - exciton transitions in homogeneous aggregates , @xcite we know that the slater determinant of the @xmath35 and @xmath36 states forms the two - exciton state that predominantly contributes to the two - exciton optical response . this gives us a solid ground to believe that the @xmath28-like one - exciton states and the two - exciton states composed of @xmath37 doublets dominate the one - to - two exciton transitions in disordered aggregates ( see below ) . usually , well defined @xmath37 doublets occur below the bare exciton band edge at the energy @xmath38 . these doublets are responsible for a hidden level structure of the lifshits tail . @xcite for the @xmath28-like states located close to or above the bare band edge , it is already impossible to assign a @xmath33-like partner localized on the same segment : higher - energy states have more than one node and spread over segments of size larger than @xmath27 ( see fig . [ fig : reduced wavefunctions ] ) . to obtain all the states that give a major contribution to the one - to - two exciton transitions , the following procedure has been used . first , we selected all the @xmath28-like states , as described above . after that , we considered all the two - exciton states @xmath39 given by eq . ( [ two - exciton states ] ) and calculated the corresponding transition dipole moments @xmath40 . from the whole set of @xmath40 , we took the largest ones denoted by @xmath41 , were the substrict @xmath28 in @xmath42 indicates its relation with the state @xmath43 . this procedure catches all true @xmath44 doublets and assigns a partner to solitary @xmath28-like states , which do not necessarily look like real @xmath33 states . in fig . [ fig : reduced wavefunctions]_b _ , we depicted the final set of the doublets selected from the states in fig . [ fig : reduced wavefunctions]_a _ according to the above procedure , which contribute mostly to the one- and two - exciton transitions . the average ratio of the oscillator strength of the thus selected transitions @xmath45 and @xmath46 turned out to be approximately 1.4 . for a homogeneous chain , this ratio equals 1.57 ( then @xmath47 and @xmath48 ) . the similarity of these numbers gives support to our selection procedure . even stronger support is obtained from computing the pump - probe spectrum , using our state selection , and comparing the result to that of the exact calculations . @xcite the comparison revealed that the model spectrum only deviates from the exact one in the blue wing of the induced absorption peak , similarly to the linear absorption spectra . as was already mentioned in the introduction , two excitons created within the same localization segment efficiently annihilate ( the intra - segment annihilation in terms of refs . and ) . thus , the authors of ref . studied experimentally the exciton dynamics in j - aggregates of pseudoisocyanine bromide ( pic - br ) at low temperature and found a 200 fs component in the two - exciton state decay . they attributed this to the annihilation of two - excitons located within the same chain segment of typical size of @xmath49 . we adopt this mechanism for @xmath50 states described in the preceding section . note that 200 fs is much shorter than all other population decay times . other processes , such as radiative decay , occur at times of tens - to - hundreds of picoseconds . two excitons located on different localization segments can also annihilate ( the inter - segment annihilation in terms of refs . ) . this process , however , is much slower as compared to the intra - segment channel ; @xcite we neglect it . the thermally activated diffusion of excitons accelerates the annihilation of excitons created far away from each other . we consider this diffusion - limited exciton annihilation as irrelevant to our problem , because for bistability to occur we need the majority of @xmath28-like states to be saturated ( also see sec . [ sec : estimates ] ) . it is usually assumed that the annihilation occurs via transferring the two - exciton energy to a resonant molecular vibronic level ( see , e.g. , ref . ) , which undergoes a fast vibration - assisted relaxation to the ground vibronic state . the population collected in this state relaxes further to the one - exciton state @xmath51 of the segment or to the ground state @xmath52 of the aggregate ( cf . fig [ fig : four level model ] ) . in this way , one or two excitations , respectively , are taken from the system . in summary , a four - level model , including the ground , one- and two - exciton states , and a molecular vibronic level through which the excitons annihilate , should be employed to describe the optical response of the film in the two - exciton approximation . within the four - level model introduced in the preceding sections , we describe the optical dynamics of a segment in terms of a @xmath53 density matrix @xmath54 , where the indexes @xmath55 and @xmath56 run from 0 to 3 , where @xmath57 and @xmath58 . we neglect the off - diagonal matrix elements @xmath59 , and @xmath60 , assuming a fast vibronic relaxation within the molecular level 3 . within the rotating wave approximation , the set of equations for the populations @xmath61 and for the amplitudes of the relevant off - diagonal density matrix elements @xmath62 reads @xcite [ eq : density matrix truncated ] @xmath63 + \gamma _ { 10}\rho_{11 } + \gamma _ { 30}\rho_{33 } \ , \ ] ] @xmath64 @xmath65 @xmath66 @xmath67 @xmath68 @xmath69 here , @xmath70 and @xmath71 are the radiative relaxation rates of the one - exciton state @xmath72 and the two - exciton state @xmath73 , respectively , with @xmath74 denoting the monomer radiative rate , and @xmath75 and @xmath76 being the corresponding dimensionless transition dipole moments . furthermore , @xmath77 is the annihilation constant of the two - exciton state @xmath73 and @xmath78 is the population relaxation rate of the vibronic state @xmath79 . the constants @xmath80 and @xmath81 stand for the dephasing rates of the corresponding transitions . they include a contribution from the population decay as well as a pure dephasing part @xmath82 , which , for the sake of simplicity , we assume equal for all off - diagonal density matrix elements and not fluctuating . by @xmath83 and @xmath84 we denote the detuning between the exciton transition frequencies @xmath85 and @xmath86 , and the frequency @xmath87 of the incoming field . it is worth to notice that eqs . ( [ eq : density matrix truncated ] ) automatically conserve the sum of level populations : @xmath88 . the quantity @xmath89 in eqs . ( [ eq : density matrix truncated ] ) is the amplitude @xmath90 of the field inside the film in frequency units , where @xmath91 is the transition dipole moment of a monomer and @xmath92 is the planck constant . it obeys the following equation @xcite @xmath93 where @xmath94 is the amplitude @xmath95 of the incoming field in frequency units , @xmath96 is the average number of @xmath28-like states in an aggregate , and @xmath97 is the superradiant constant , an important parameter of the model . @xcite in this expression , @xmath98 is the number density of monomers in the film , @xmath99 is the field wave number , and @xmath3 is the film thickness . the angular brackets in eq . ( [ eq : field equation ] ) denote the average over disorder realizations . the set of equations ( [ eq : density matrix truncated ] ) forms the basis of our analysis of the effects of one - to - two exciton transitions , exciton - exciton annihilation from the two - exciton state , and relaxation of the annihilation level back to the one - exciton and ground states on the optical bistable response from an ultrathin film of j - aggregates . in the remainder of this paper , we will be interested in the dependence of the transmitted field intensity @xmath100 on the input field intensity @xmath101 , following from eqs . ( [ eq : density matrix truncated ] ) and ( [ eq : field equation ] ) . to study the stationary states of the system , we first consider the steady - state regime of the film s optical response and set the time derivatives in eqs . ( [ eq : density matrix truncated ] ) to zero . furthermore , we will mostly focus on the limit of fast exciton - exciton annihilation , assuming the annihilation constant @xmath77 to be largest of all relaxation constants and also much larger than the magnitude of the field inside the film , @xmath102 . the reason for the latter assumption is based on the fact that below the switching threshold , the field magnitude @xmath103 , @xcite where @xmath74 and @xmath104 are the radiative decay rate of a monomer and the half width at half maximum ( hwhm ) of the linear absorption spectrum , respectively . as @xmath105 , the magnitude of the field is also much smaller than @xmath104 . above the switching threshold , @xmath102 becomes comparable to @xmath104 . @xcite the typical hwhm of j - aggregates of pic at low temperatures is on the order of a few tens of @xmath106 , which in time units corresponds to one picosecond . on the other hand , the time scale of exciton - exciton annihilation is 200 femtoseconds ( see sec . [ sec : ex - ex annihilation ] ) . this justifies our assumption @xmath107 and allows us to neglect @xmath108 in steady - state eqs . ( [ eq : density matrix truncated ] ) , because @xmath109 . within this approximation , we are able to derive a closed steady - state equation for the @xmath110-vs-@xmath111 dependence , which reads @xmath112 ^ 2 \nonumber\\ \nonumber\\ + \left [ \gamma_r \frac{n_s}{n } \bigg\langle \mu_{10}^2 \frac{\delta_{10}}{\gamma_{10}^2 + \delta_{10}^2 } \left(\rho_{00 } - \rho_{11 } \right ) + \mu_{21}^2 \frac{\delta_{21 } + w/2}{\left(\gamma_{21 } + w/2\right)^2 + \delta_{21}^2 } \left(\rho_{11 } - \rho_{22}\right ) \bigg \rangle \right]^2 \bigg\ } |\omega|^2 \ .\end{aligned}\ ] ] the steady - state populations are given by @xcite @xmath113 @xmath114 where @xmath115 @xmath116 the terms proportional to @xmath117 in eq . ( [ eq : steady state output field ] ) describe the effects of the two - exciton state , exciton - exciton annihilation , and relaxation from the vibronic level back to the one - exciton and ground states . equation ( [ eq : steady state output field ] ) reduces to the one - exciton model considered in our previous paper @xcite by setting @xmath118 . similarly to the one exciton model , eq . ( [ eq : steady state output field ] ) contains a small factor @xmath119 , absent in the earlier paper , ref . . this smallness , however , is compensated by the @xmath96-scaling of the average in eq . ( [ eq : steady state output field ] ) : it is proportional to @xmath120 . @xcite thus , the actual numerical factor in eq . ( [ eq : steady state output field ] ) is approximately 2 . we stress that , unlike previous work , @xcite eq . ( [ eq : steady state output field ] ) properly accounts for the joint statistics of all transition energies and transition dipole moments . it is worth to notice that the second term in the first square brackets in eq . ( [ eq : steady state output field ] ) represents the imaginary part of the nonlinear susceptibility , while the one in the second square brackets is its real part . hence , we will will refer to these terms as to absorptive and dispersive , respectively , following the convention adapted in the standard theory of bistability of two - level systems in a cavity . @xcite we numerically solved eq . ( [ eq : steady state output field ] ) , looking for a range of parameters ( @xmath121 ) where the output - input dependence becomes s - shaped , the precursor for bistability to occur . in all simulations , we used linear chains of @xmath122 sites and the radiative constant of a monomer @xmath123 ( typical for monomers of polymethine dyes ) . the exciton - exciton annihilation rate was set to @xmath124 , corresponding to an annihilation time of 200 fs . @xcite the average single molecule transition energy @xmath10 was chosen as origin of the energy scale . 10000 localization segments were considered in disorder averaging . figure [ fig : steady state gammar ] shows the output intensity @xmath125 versus the input intensity @xmath126 , varying the superradiant constant @xmath127 from small to large values to find the threshold for @xmath127 at which bistablity sets in . the relaxation constants @xmath128 and @xmath129 from the state @xmath79 were taken to be equal to the radiative rate of a monomer , @xmath74 , which is the smallest one in the problem under study . the incoming field was tuned to the absorption maximum @xmath130 , which naively speaking is expected to give the lowest threshold for bibtability ( see a discussion of the detuning effects in sec . [ sec : effect of detuning ] ) . the other parameters of the simulations are specified in the figure caption . as follows from fig . [ fig : steady state gammar ] , for the given set of parameters the bistability threshold is @xmath131 . from the physical point of view , the most favorable conditions for bistability occur in the case of slow relaxation from the vibronic state @xmath79 , which is populated via a fast energy transfer from the two - exciton state @xmath132 ( fast exciton - exciton annihilation ) . indeed , under these conditions , all population can be rapidly transferred to the state @xmath79 , and , accordingly , the system can be made transparent easier as compared to the case of the one - exciton model . clearly , faster relaxation from the state @xmath133 to the ground state @xmath22 will deteriorate the condition for the occurrence of bistability , while slower relaxation improves the situation . figure [ fig : steady state 2 ] demonstrates this . as we mentioned in sec . [ sec : bistability equation ] , a naive viewpoint is that tuning of the incoming field to the absorption maximum is expected to give the lowest threshold for bistability . in this section , we show that in general this expectation is incorrect . in fig . [ fig : steady state ] we plotted the results of our simulations of the film s optical response as a function of the detuning off - resonance , @xmath134 , obtained for two values of the dephasing constant @xmath82 . the disorder strength was set to @xmath135 , resulting in an inhomogeneous hwhm @xmath136 . from these data , one can distinguish two regimes . first , for a relatively large @xmath137 [ panels ( a ) and ( b ) ] the film s response behaves according to the naive reasoning : the output - input characteristic looses its s - shaped form upon a deviation of the incoming field frequency from the absorption maximum . in contrast , as is observed in figs . [ fig : steady state](c ) and ( d ) , for @xmath138 , when the absorption width is dominated by inhomogeneous broadening @xmath104 , tuning away from the resonance favors bistability . we note that similar behavior has been found for assemblies of inhomogeneously broadened two - level emitters placed in a cavity , @xcite where it was suggested that this counterintuitive frequency dependence results from the interplay of absorptive and dispersive contributions to the nonlinear susceptibility . we believe that our model exhibits the same spectral behavior because only the ground state to one - exciton transitions lead to spectral sensitivity . the one - to - two exciton transitions and the relaxation from the molecular vibronic level do not : the former because of the fast exciton annihilation , which washes out all spectral details , and the latter because it occurs from a relaxed state . thus , all spectral features of the two - exciton model of the film s bistability are driven by the ground state to one - exciton transitions . in other words , the one - exciton ( two - level ) model considered in our previous paper @xcite is relevant for explaining the observed spectral behavior . in this case , the bistability equation ( [ eq : steady state output field ] ) is reduced to @xmath139 ^ 2 \nonumber\\ \nonumber\\ + \left [ \gamma_r \frac{n_s}{n } \bigg\langle \mu_{10}^2 \frac{\delta_{10}}{\gamma_{10}^2 + \delta_{10}^2 + |\omega|^2 \gamma_{10}/\gamma_0 } \bigg \rangle \right]^2 \bigg\ } |\omega|^2 \ .\end{aligned}\ ] ] in our further analysis we show that , indeed , the interplay of the absorptive and dispersive terms in eq . ( [ eq : steady state output field two - level model ] ) is responsible for the counterintuitive spectral behavior . first , let us assume that we are far outside the resonance , i.e. , @xmath140 is large compared to the absorption hwhm , whether the homogeneous ( @xmath141 ) or the inhomogeneous one ( @xmath104 ) . then , the dispersive term drives the bistability , because its magnitude decreases as @xmath142 upon increasing @xmath134 , while the absorptive one drops faster , proportionally to @xmath143 . the critical superradiant constant for the dispersive bistability has been reported to be @xmath144 $ ] ( see , e.g. , ref . ) which is reduced to @xmath145 in the limit of @xmath146 . on the other hand , we found within the one - exciton model @xcite that close to the resonance ( @xmath147 ) , where the contribution of the absorptive term is dominant , @xmath148 scales superlinearly with the hwhm , namely as @xmath149 with @xmath150 . similar scaling ( @xmath151 ) has been obtained in ref . for a collection of inhomogeneously broadened two - level systems placed in a cavity . the superlinear dependence of @xmath148 for the absorptive type of bistability is a key ingredient in understanding the counterintuitive @xmath134 behavior of the film s optical response . indeed , let @xmath152 and @xmath153 , i.e. , we are at the ( dispersive ) bistability threshold . now , let us go back to the resonance , where bistability is of absorptive nature . choose for the sake of simplicity @xmath151 as the critical value . if @xmath154 , we are still above the ( absorptive ) bistability threshold , while in the opposite case bistable behavior is not possible . for @xmath155 , the line width is almost of homogeneous nature , and tuning away from the resonance deteriorates the conditions for the occurrence of bistability . @xcite in our simulations , this holds for the case of @xmath156 and @xmath157 [ see panels ( a ) and ( b ) in fig . [ fig : steady state ] ] . to conclude this section , we note that the detuning effect found in our simulations is asymmetric with respect to the sign of @xmath134 : the behavior of @xmath158 versus @xmath159 is different for the incoming frequency tuned to the red or to the blue from the absorption maximum . we believe that this arises from the asymmetry of the absorption spectrum . in fig . [ fig : phase diagram sigma ] we plotted the results of a comparative study of phase diagrams of the film s response calculated within the one- and two - exciton model under the resonance condition , @xmath130 . presented is the critical superradiant constant @xmath148 versus the quantity @xmath160 , where @xmath161 is the homogeneous width of the one - exciton transition . the last term denotes the averaged rate of population relaxation from the one - exciton state to the ground state , see eq . ( [ eq : rho11 ] ) . roughly , @xmath162 can be interpreted as the hwhm of the absorption spectrum accounting for both inhomogeneous and homogeneous broadening ( through @xmath104 and @xmath163 , respectively ) . the upper ( lower ) solid curve in both panels was obtained for the dephasing constant @xmath164 ( @xmath165 ) and varying the disorder strength @xmath11 . for a given @xmath82 , the film is bistable ( stable ) above ( below ) the corresponding curve . to compare these results with those calculated under the assumption that the detuning is the only stochastic parameter , @xcite we also plotted the @xmath166 vs @xmath162 dependence taking all the transition dipole moments and relaxation constants equal to their averaged values ( dotted curves ) . one of the principal conclusions which can be drawn from the data in fig . [ fig : phase diagram sigma ] is that a more efficient dephasing helps the occurrence of bistability : all curves calculated for @xmath164 lie above those obtained for @xmath167 . the physics of this behavior is simple : as the threshold for the absorptive bistability is @xmath168 ( see sec . [ sec : effect of detuning ] ) , a smaller @xmath163 gives rise to a higher threshold value for @xmath127 . thus , adjusting the dephasing constant @xmath163 , we can manipulate the film s optical response . this conclusion has been drawn already in ref . within the simplified one - exciton model . another observation is that the magnitude of the critical superradiant constant @xmath148 is considerably lower in the two - exciton model than in the one - exciton approach . this was to be expected from the physical reasoning which we presented above : a fast exciton - exciton annihilation combined with a slow relaxation from the high - lying molecular vibronic level favors bistability . without showing detailed data , we note that also the critical switching intensity , i.e. , the intensity calculated at the bistability threshold , is smaller in the two - exciton model compared to the one - exciton model . in both models , it also decreases upon increasing the dephasing rate . finally , from comparison between the solid and dotted curves in fig . [ fig : phase diagram sigma ] , it appears that , surprisingly , bistability is favored by the fact that also transition dipole moments and relaxation constants are stochastic variables and not only the detuning , as was assumed in the simplified model of ref . . at first glance this seems counterintuitive . however , inspection of changes in the absorption spectrum allows to shed light of on this result . we found that upon neglecting the fluctuations , the absorption spectrum , first , acquires a shift which introduces an additional detuning off - resonance . second , the shape of the absorption spectrum gets more asymmetric . as the film s response is sensitive to both the detuning and asymmetry , the combined effect of these changes produces the observed big difference between the two sets of calculations . in principle , this discrepancy may be reduced by adjusting the detuning ; it is impossible , however , to correct for asymmetry . most importantly , this comparison shows that to adequately calculate the film s optical response , fluctuations of all variables should be taken into account . in this section we will analyze low - temperature experimental data of @xmath12-aggregates of pseudo - isocyanine ( pic ) to shed light on the feasibility of measuring optical bistability in a thin film of pic . we will focus , in particular , on aggregates of pic - br studied experimentally in detail in refs . and . at low temperatures , the absorption spectrum of pic - br is dominated by a very narrow absorption band ( hwhm = 17 @xmath106 ) peaked at @xmath169 = 573 nm and red shifted relative to the main monomer feature ( @xmath169 = 523 nm ) . for these aggregates , vibration - induced intra - band relaxation is strongly suppressed ( no visible stokes shift of the fluorescence spectrum with respect to the @xmath12-band is observed ) . this favors a long exciton lifetime , which is highly desirable from the viewpoint of saturation , and thus for optical bistability . the lifetime of the exciton states forming the @xmath12-band in pic - br is conventionally assumed to be of radiative nature . for temperatures below about 40 k , it has been measured to be 70 ps . @xcite within the one - exciton model studied in our previous paper , @xcite we found that the number density of monomers , required for the driving parameter @xmath170 to exceed the bistability threshold , has to obey @xmath171 @xmath172 . such densities can be achieved in thin films prepared by the spin - coating method . @xcite within the extended four - level model considered in the present paper , the critical ratio of @xmath170 may be even lower . thus , we believe that from the viewpoint of monomer density , j - aggregates of pic are promising candidates . another important requirement for candidates , potentially suitable for bistable devices , is their photostability . j - aggregates are known to bleach if they are exposed for a long time to powerful irradiation . therefore , it is useful to estimate the electromagnetic energy flux through the film . for the field slightly below the higher switching threshold , the dimensionless intensity inside the film obeys @xmath173 ( see , e.g. , fig.[fig : steady state gammar ] ) . using the expression for the monomer spontaneous emission rate @xmath174 , we obtain @xmath175 . the electromagnetic energy flux through the film is determined by the poynting vector , whose magnitude is given by @xmath176 . being expressed in the number of photons @xmath177 , passing per @xmath178 and per second through the film , this value corresponds to @xmath179 photons/(@xmath180s ) . as is seen from fig . [ fig : steady state gammar ] , above the switching threshold the intensity inside the film rises by an order of magnitude . hence , above threshold the electromagnetic energy flux reaches a value on the order of @xmath181 photons/(@xmath180s ) . furthermore , the typical time @xmath182 for the outgoing intensity @xmath158 to reach its stationary value is on the order of the population relaxation time , which is 70 ps , except for values of @xmath158 slightly above ( below ) the higher ( lower ) switching threshold , where the relaxation slows down . @xcite this means that typically , a nanosecond pulse is enough to achieve the steady - state regime . bearing in mind the above estimates for @xmath183 , we obtain the corresponding flux for a nanosecond pulse @xmath184 photons/(@xmath178 ns ) . on the other hand , for a thin film of thickness @xmath185 and number density of monomers @xmath186 @xmath172 , the surface density is @xmath187 @xmath188 . combining these numbers , we conclude that only one photon per @xmath189 monomers produces the effect , which is well below the bleaching threshold . we theoretically studied the optical response of an ultrathin film of oriented j - aggregates with the goal to examine the effect of two - exciton states and exciton - exciton annihilation on the occurrence of bistable behavior . the standard frenkel exciton model was used to describe a single aggregate : an open linear chain of monomers coupled by delocalizing dipole - dipole excitation transfer interactions , in combination with uncorrelated on - site disorder , which tends to localize the exciton states . we considered a single aggregate as a meso - ensemble of exciton localization segments , ascribing to each segment a four - level system consisting of the ground state ( all monomers in the ground state ) , an @xmath28-like one - exciton state , a two - exciton state constructed as the antisymmetric combination of this @xmath28-like state and an associated @xmath33-like one - exciton state , and a vibronic state of the monomer through which the two - exciton states annihilate . to select the @xmath28- and @xmath33-like states , a new procedure was employed which correctly accounts for the fluctuations and correlations of the transition energies and transition dipole moments , improving on earlier works . @xcite the optical dynamics of the localization segment was described within the @xmath2-density matrix formalism , coupled to the total electromagnetic field . in the latter , in addition to the incoming field , we accounted for a part produced by the aggregate dipoles . we derived a novel steady - state equation for the transmitted signal and demonstrated that three - valued solutions to this equation exist in a certain domain of the multi - parameter space . analyzing this equation , we found that several conditions promote the occurrence of bistable behavior . in particular , a fast exciton - exciton annihilation , in combination with a slow relaxation from the monomer vibronic state , favors bistablity . in contrast , fast relaxation from the vibronic level to the ground state acts against the effect . additionally , a faster dephasing also works in favor of the occurrence of bistability . the interplay of detuning away from the resonance and dephasing was found to be counterintuitive . when homogeneous broadening of the exciton states ( associated with the incoherent exciton - phonon scattering ) is comparable with the inhomogeneous broadening ( resulting from the localized nature of the exciton states ) , the detuning destroys bistability . oppositely , at a slower dephasing , the bistability effect is favored by tuning away from the resonance . we relate this anomalous behavior to an interplay of the absorptive and dispersive parts of the nonlinear susceptibility , which jointly contribute to the overall effect . we found that in general , including the one - to - two - exciton transitions promotes bistability . all critical parameters , such as the critical superradiant constant , driving the bistability , and the critical switching intensity are lower than in the one - exciton model . @xcite in addition , bistable behavior is easier to reach if the ratio of the inhomogeneous and homogeneous width is reduced . we also found that the stochastic nature of the transition dipole moments ( the aspect in which our model goes beyond ref . ) strongly influences the film s optical response . estimates of parameters of our model for aggregates of polymethine dyes at low temperatures indicates that a film with a monomer number density on the order of @xmath190 @xmath106 and a thickness of @xmath191 , achievable with the spin coating method , @xcite is sufficient to realize the effect . under these conditions , one photon per 20 monomers produces the switching of the film s transmittivity . to conclude , we point out that a microcavity filled with molecular aggregates @xcite in the strong coupling regime of excitons to cavity modes is another promising arrangement to realize an all - optical switch . the recent observation of optical bistability in planar _ inorganic _ microcavities @xcite and the prediction of the effect for hybrid _ organic - inorganic _ microcavities @xcite in the strong coupling regime suggest that _ organic _ microcavities can exhibit a similar behavior . this work is part of the research program of the stichting voor fundamenteel onderzoek der materie ( fom ) , which is financially supported by the nederlandse organisatie voor wetenschappelijk onderzoek ( nwo ) . support was also received from nanoned , a national nanotechnology programme coordinated by the dutch ministry of economic affairs . m. soljaci , m ibanescu , c. luo , s. g. jonson , s. fan , y. fink , and j. d. joannopoulos , proceedings of spie , _ photonic crystal materials and devices _ , ali adibi , alex sherer , and shawn yu lin , editors , vol . 5000 , p. 200 ( 2003 ) . d. g. lidzey , d. d. c. bradley , m. s. skolnick , t. virgili , s. walker , and d. m. whiteker , nature * 395 * , 53 ( 1998 ) ; d. g. lidzey , d. d. c. bradley , t. virgili , a. armitage , m. s. skolnick , and s. walker , phys . lett . * 82 * , 3316 ( 1999 ) .

we generalize our recent work on the optical bistability of thin films of molecular aggregates [ j. chem . phys . * 127 * , 164705 ( 2007 ) ] by accounting for the optical transitions from the one - exciton manifold to the two - exciton manifold as well as the exciton - exciton annihilation of the two - exciton states via a high - lying molecular vibronic term . we also include the relaxation from the vibronic level back to both the one - exciton manifold and the ground state . by selecting the dominant optical transitions between the ground state , the one - exciton manifold , and the two - exciton manifold , we reduce the problem to four levels , enabling us to describe the nonlinear optical response of the film . the one- and two - exciton states are obtained by diagonalizing a frenkel hamiltonian with an uncorrelated on - site ( diagonal ) disorder . the optical dynamics is described by means of the density matrix equations coupled to the electromagnetic field in the film . we show that the one - to - two exciton transitions followed by a fast exciton - exciton annihilation promote the occurrence of bistability and reduce the switching intensity . we provide estimates of pertinent parameters for actual materials and conclude that the effect can be realized . = cmr10 at 8pt

with increase of multi - drug resistant escherichia coli in community - acquired urinary tract infections ( ca - uti ) , other treatment option with a therapeutic efficacy and a low antibiotic selective pressure is necessary . in this study , we evaluated in vitro susceptibility of e. coli isolates from ca - uti to fosfomycin ( fm ) , nitrofurantoin ( ni ) , temocillin ( tmo ) as well as trimethoprim - sulfamethoxazole ( smx ) , ciprofloxacin ( cip ) and cefepime ( fep ) . the minimal inhibitory concentrations were determined by e - test or agar dilution method according to the clinical and laboratory standards institute guidelines , using 346 e. coli collected in 12 korean hospitals from march 2010 to february 2011 . fm , ni and tmo showed an excellent susceptibility profile ; fm 100% ( 346/346 ) , tmo 96.8% ( 335/346 ) , and ni 99.4% ( 344/346 ) . conversely , resistance rates of cip and smx were 22% ( 76/346 ) and 29.2% ( 101/349 ) , respectively . fep still retained an activity of 98.5% . in korea , ni and tmo in addition to fm are a good therapeutic option for uncomplicated ca - uti , especially for lower uti.graphical abstract

In a world of information, one small fraud by man can equal one giant headache for mankind. And this was way back in 1864. As the sun rose over Manhattan on May 18, 1864, thousands of New Yorkers picked up their morning paper to discover that their president was drafting another 400,000 men from their war-torn country to replenish the ranks of the Union Army. Most believed that the three-year-old Civil War had to be nearing its final chapter, but both the New York World and the New York Journal of Commerce carried the news from Abraham Lincoln that Gen. Ulysses S. Grant’s new offensive in Virginia was failing and the president was calling for additional troops as well as “a day of fasting, humiliation and prayer” across the nation. Another dark day in a very somber period, except for one thing: The story was utterly false. How could two of New York’s largest dailies get such a major announcement — from the president of the United States no less — completely wrong? A lie gets halfway around the world before the truth has a chance to get its pants on. — Winston Churchill It was a question that nobody wanted answered more than a furious Abraham Lincoln, who sent federal troops to shut down both papers and arrest their editors when he learned of the hoax. But by noon, when the State Department in Washington confirmed that the proclamation had been a forgery, the damage had already been done. The bogus announcement of a new round of conscription had caused shockwaves on Wall Street, sending share prices plunging and gold soaring 10 percent as nervous investors hunkered down for a prolonged war. As Winston Churchill would later say, “A lie gets halfway around the world before the truth has a chance to get its pants on.” An adage that was just as true in the 19th century as in an age of Twitter hacks and flash crashes. In this case, the globetrotting lie emanated from a forged dispatch from the Associated Press — precisely what would happen 149 years later when a spurious tweet that Barack Obama had been injured in two explosions at the White House wiped $136 billion from the S&P 500 index in a matter of minutes in 2013. But, as Lincoln’s troops occupied their offices in 1864, the besieged editors at the two New York papers were not pointing fingers at the AP’s Twitter feed but to one of the AP’s “flimsies” that had been delivered by courier in the early morning hours. Such overnight dispatches from the AP to New York’s seven dailies were the lifeblood of the morning news cycle. But this particular dispatch had been timed perfectly to arrive around 3.30 a.m. — right after the night editors at the papers had gone home but before the day staff arrived, leaving a single night foreman on duty to determine whether to include the dispatch’s contents in the morning edition of the paper. The night foremen at New York’s other five newspapers were suspicious enough about the story to ask the AP to verify it, but the World and the Journal of Commerce were sufficiently impressed by quality of the forgery, and its apparent source, to slap the story on their front page. Those responsible for the “Civil War gold hoax,” as investigators soon ascertained, were indeed quite familiar with the newspaper business. Three days later, authorities arrested Francis A. Mallison, a reporter for the Brooklyn Eagle, and Joseph Howard Jr., his boss and the paper’s city editor. Those responsible for perpetrating the “Civil War gold hoax”…were indeed quite familiar with the newspaper business. As is often the case with fraud, there can be a fine line between stupid and clever, and Howard, the 35-year-old mastermind behind the hoax, strayed onto the stupid side by making a conspicuously large investment in gold a mere day before the news headlines hit. But the disgraced journalist would serve fewer than three months in prison, his release coming just a month after Lincoln issued a very real conscription order for 500,000 more Union troops. It should be a comfort that we are no longer a single night foreman’s judgment away from a front-page fraud — but instead we have created a media landscape flush with lone foremen and forewomen, constantly making questionable calls on partial information, and rife with potential conduits for misinformation for the thousands of fraudsters, hackers and modern-day Howards. The lies will continue to make their way around the world. The question is: How quickly can the truth pull up its pants? ||||| PUEBLO, Colo. - A Colorado woman's Facebook post about her experience in a Walmart store has been shared more than 800,000 times since Friday but Walmart says while it's a sweet story, with a great message about kindness, it's simply not true. In the video, entitled "Pueblo Walmart changed my life" Paige Yore explains that she was in line behind a woman who was being rude to a teenage cashier at the store. "I'm in downtown Pueblo at this Walmart, waiting in line for like 20 minutes. And this young cashier, 16 maybe... he can't ring anything up. He can't remember the codes, he's taking deep breaths ..." "I thought to myself, 'I wonder what the hell happened to him this morning?'" Yore said. Then, the female customer in front of her started yelling at the cashier, Yore said. "'You suck at customer service! I don't know how you even got hired here!' Just being so rude to this young man," Yore explains. "Finally, I help her get her groceries all loaded up just to get her the hell out of there, and she runs her card and it gets declined," said Yore. "Then she really lays into this kid - that it's his fault, he can't work the computer ... she goes off on this kid." Yore said that's when she spoke up. "I was like, 'Ma'am, maybe you should just step aside, and let us cash out. This man's obviously having a bad day. Like, let it go, it's not his fault you don't have money, or whatever.'" Yore said the young man stopped in his tracks and started sobbing. Then he came around the counter and hugged her. Yore said she was a little "weirded out" but tried to comfort the crying cashier. "He finally gets it together, and I'm like 'It's OK, it's OK. Everybody has a rough day,'" Yore explained. "And he's like 'No, no, no... you don't understand. Ma'am, my mom just committed suicide this morning. And I have to work because I have to pay our rent. And I have to pay our bills. And I don't even have a mom anymore.'" Yore said at that point, she started crying, too. "I said 'You know, hang in there... it's going to be OK. It will be OK.'" "So this lady is standing there, totally humiliated... and this young man is just crying. I gave him all the money out of my purse. And he can't even get it together," Yore said, visibly moved. "That just showed me, no matter what, even if your customer service sucks, even if whatever happened, someone is rude to you, be YOUR customer service. Don't jump down their throat, because they are fighting a battle none of us know about." "Some days just suck. But we just have to be thankful to be alive. Treat people like you want to be treated," said Yore. "Don't lay into somebody like that because you never know what's going on in their life." -- Walmart debunks Yore's story -- While her message of kindness inspired hundreds of thousands of people to share her story, Walmart on Monday told Denver7 that the Yore was not telling the truth. "We have checked into this. It doesn't seem like it is actually true," said Walmart spokesman Aaron Mullins. Mullins said Walmart has received lots of calls asking about the young man, and the company looked into the incident extensively, including reviewing the surveillance video. He says surveillance video does show Yore shopping at the Pueblo store at 4080 West Northern Avenue on Friday, and going through a checkout line manned by a young cashier, but the truth stops there. "There was never a conversation about his mother. He never went around the bagging area and hugged her. He is in good health and his mother is in good health," Mullins said. The cashier said he could not think of anything he had said that would have led Yore to think he was in pain. "I don't know if there was a misunderstanding. The associate wasn't exactly sure what she was talking about. His mother is alive and well," Mullins said. While Mullins wouldn't speculate about why Yore made up the story, others on Facebook say she is seeking to grow her social media audience, and in her latest video posted on Sunday, Yore asks for more subscribers to her YouTube channel. "I have this crazy wild dream to change lives in this world, and to make this world a better place ... If you give power to positivity, power to God, power to prayer, power to your higher power, whatever it may be, it is going to go viral," Yore said. "I cannot thank you from the bottom of my heart enough for sharing my inspiring words on Friday because it is going to change my life. I'm taking one more step to getting to my big goal. One more step to changing lives - because of you guys." "Subscribe to my YouTube channels ... see my videos weekly and I hope to have another couple of experiences like I did Friday and be able to inspire some people," Yore concludes. Yore called her initial video "Pueblo Walmart changed my life." You can watch it here:

– Treat people with kindness, "because they are fighting a battle that none of us know about." That’s the message Paige Yore wants people to take to heart, but the story she told to drive her point home is shaping up to be a hoax. In a Facebook video with well over 20 million views as of Monday, Yore recounted an experience waiting in line at a Walmart in Pueblo, Colo. The young cashier, she says, was obviously having a rough day. To make matters worse, a customer he was ringing up was berating him. "You suck at customer service," Yore says she heard the woman say. When the woman’s payment card was declined, Yore claims things got even worse: "She really lays into this kid, like it's his fault." Yore says she told the woman to take it easy, and the cashier began to cry. He came around and hugged Yore, she says, "and I hug him back and he's sobbing." Soon the source of the cashier's anguish became clear, in Yore's telling: His mom had committed suicide that morning, he reportedly told Yore, and with rent and bills, he still had to work. "And I don't even have a mom anymore. And this lady is just yelling at me." Yore says she gave him all the cash in her wallet. "Don't lay into somebody like that," she says, "because you never know what's going on in their life." But Denver7 reports that Walmart dug into Yore's story and just can't corroborate a key part of it. Surveillance footage does show Yore shopping at the Pueblo Walmart on Friday and using a checkout lane staffed by a young employee. But there "was never a conversation about his mother. He never went around the bagging area and hugged her. He is in good health and his mother is in good health," says a Walmart rep. (This 1864 hoax panicked our nation.)

perinatal depression is considered the most underdiagnosed pregnancy complication in the united states with more than 400,000 infants born to mothers who are depressed each year.1 the pregnancy and postpartum phases of the perinatal period are considered periods of high risk.8 perinatal depression , defined here as minor or major episodes of depression occurring during pregnancy or the first postpartum year , affects an estimated 7% to 20% of women with rates as high as 35% to 40% among low - income and minority women.9,10 depressive symptoms occurring during pregnancy often persist after delivery , suggesting an important role of antenatal symptoms in predicting postpartum depression . approximately half of postpartum depression cases have onsets during pregnancy.11 recognizing insufficient evidence demonstrative of a clear difference between postpartum and pregnancy depressive episodes , the american psychiatric association recently proposed the term peripartum onset as a specifier for major depressive episodes that occur during pregnancy and/or in the postpartum period.12 understanding risk factors for perinatal depression is essential for healthcare providers to more easily identify women at risk for developing this condition . furthermore , antenatal period depression is the most significant risk factor for postpartum depression development.13 depression and anxiety are highly comorbid in nonpregnant samples , with nearly 60% of women diagnosed as depressed also meeting diagnostic criteria for an anxiety disorder.14 a recent systematic review , which examined the relation between maternal anxiety and depression in 11 studies , found anxiety to be one of the strongest associations with antenatal depressive symptoms.15 depression disproportionately affects low - income women . research suggests that poverty is a powerful predictor of depression irrespective of race / ethnicity.16 research has found that nearly 40% of mothers participating in head start , a program serving predominantly low - income preschool children and their families , may experience depression.17 other studies have concluded that race and ethnicity are risk factors for perinatal depression . this is particularly concerning , as research also demonstrates that ethnic minority patients are less likely to obtain care for depression than white patients and are less likely to receive clinically appropriate treatment when they do access care.18 stress is another established risk factor for perinatal depression . stress can be conceptualized in many ways , and the majority of studies that have examined the relation between stress and depression have conceptualized stress as stressful life events ( divorce , serious illness , death in the family ) or daily hassles ( work hassles , time pressures , financial strain).15 a significant body of research has examined life stress as a predictor of perinatal depression , with most studies finding positive associations . a sizeable body of research supports a significant relation between social support and perinatal depression . there is a moderate correlation between social support and perinatal depression across many studies when assessing social support available to perinatal women as support from any source.15 however , perinatal women who report the absence of a supportive partner have been found to be at greatest risk for perinatal depression across multiple studies.15 it is important to mention that many studies do not adequately control for important confounders of this relation ( income , education , socioeconomic status , relationship violence ) . extant research has found that between 3% and 9% of women experience ipv during pregnancy , though there are well - established risk factors associated with higher rates of abuse during pregnancy , including young age , low socioeconomic status , single marital status , and minority race / ethnicity.19 research conducted in low - income perinatal women found that up to 85% of women experiencing ipv during pregnancy also screened positive for depressive symptomatology on the edinburgh postnatal depression scale ( epds ) ; these women were at significantly increased risk for suicidal ideation.20 - 22 additional risk factors for perinatal depression include pregnancy complications.23 numerous studies have examined the relation between cesarean delivery and postpartum depression , with the majority of studies concluding mode of delivery is not a significant predictor ; however , research has demonstrated that women with a strong preference for vaginal delivery but who require a cesarean delivery are at increased risk for postpartum depression in the early postpartum period.24 - 26 further , neonatal factors may be associated with an increased risk for depressive symptoms , for example , infant colic and inconsolable crying are associated with maternal depressive symptoms.27 because perinatal depression can have serious consequences regarding maternal morbidity and mortality ( as well as adverse neonatal and early childhood outcomes ) , there is significant interest in improving its detection to increase appropriate treatment modalities.28 screening for depression has been widely supported as a component of routine obstetric care.29 in 2015 , the american congress of obstetricians and gynecologists ( acog ) released a committee opinion recommending that clinicians screen patients for depression and anxiety symptoms at least once during the perinatal period using a validated tool.30 acog 's guidelines also highlight the importance of coupling screening with appropriate follow - up and treatment as indicated.30 recognizing the negative effects of perinatal depression on early childhood outcomes and the critical role pediatric healthcare providers play in providing care , the american academy of pediatrics recommends that pediatric providers routinely screen mothers for depression during 1- , 2- , and 4-month well - child visits.1 the epds is the most commonly utilized instrument to screen for perinatal depression . this self - rated , 10-item instrument asks a woman to answer questions based on how she has felt in the previous 7 days ( i have felt sad or miserable ; i have been able to laugh and see the funny side of things ; things have been getting on top of me ) and choose one of four possible responses.31 the epds does not focus on some of the somatic symptoms ( changes in appetite , sleeping difficulties , energy level ) that are more common among perinatal women in the absence of a mental disorder . its psychometric properties are the most established of any depression screening tool and it has been validated in diverse perinatal populations.32 recognizing the importance of universal screening for perinatal depression , the national institute for health and clinical excellence recommends the use of two case - finding questions for depressive symptoms in perinatal women : during the past month , have you often been bothered by feeling down , depressed or hopeless ? ; and during the past month , have you often been bothered by little interest or pleasure in doing things ? if a positive response is given to either question , the recommended follow - up question states : is this something you feel you need or want help with ? these two case - finding questions have been validated in diverse primary care settings , including perinatal women , and are endorsed by united states and canadian bodies for depression screening in adults.33,34 screening for perinatal depression is viewed as acceptable by most perinatal women , and the majority of perinatal women are in favor of psychosocial screenings , such as depression and ipv.35 importantly , women are more likely to accept depression screening if they understand the purpose of the screening , interpretation of results , and treatment options available.35 these findings support providers of perinatal women using a patient - centered approach to screening . in addition to paper and pencil screening , healthcare providers should consider physiological disturbances , which may contribute to depressive symptoms . research has demonstrated an increased depression risk in perinatal women with concurrent anemia , thyroid dysfunction , and fatigue.36 screening for anemia , particularly among women with excessive blood loss during their deliveries , is an important consideration and easily remedied . in addition , iron deficiency anemia may alter thyroid hormone metabolism , so thyroid function should be assessed in cases of suspected anemia as well as in women with a history of thyroid disease or who exhibit symptoms of thyroid disease . in women with a history of thyroid disease or with symptoms suggestive of thyroid disease regardless of the instrument used to screen for depression , it is important for healthcare providers to be aware that a positive screening result is not diagnostic for depression . the epds was developed specifically to screen for symptoms of possible perinatal depression . screening techniques aim to identify women at risk for perinatal depression and in need of further diagnostic assessment . depressive symptoms in the perinatal period range from maternity blues ( commonly seen in the postpartum period ) to major depressive disorder and postpartum psychosis.1 approximately 50% to 80% of new mothers experience maternity blues within the first few days after delivery.1 symptoms may include crying , sadness , and mood swings ; however , these symptoms most often resolve within 1 to 2 weeks . major depressive disorder ( mdd ) is defined by one or more major depressive episodes ( mde ) along with the lifetime absence of mania and hypomania.12 an mde is constituted by a patient 's report of at least five of nine symptoms present during the same 2-week period . specific to mdd in the perinatal period , the diagnostic and statistical manual of mental disorders , fifth edition ( dsm-5 ) expanded the previous dsm - iv qualifier with postnatal onset to include with peripartum onset.12 in addition to mdd onsets occurring within 4 weeks after delivery , the dsm-5 now includes onsets over the course of the entire pregnancy . this change recognizes that a high prevalence of postpartum depressive episodes has an onset in pregnancy and persist ( often becoming more severe ) throughout the postpartum period.37 further , this revision dispels the previously held belief that the pregnancy timeframe was protective against the development of mdd and acknowledges the importance of healthcare providers in addressing mental health throughout the perinatal period . although generally accepted that pregnancy is not a protective period with respect to new onset or relapse of mdd , there continues to be a fair amount of controversy regarding how best to treat perinatal depression . regardless of the ongoing debate , medication use during pregnancy has become relatively common with a 2- to 4-fold increase in medications for mdd over the past decade.38 this increase is in spite of a fairly stable prevalence of psychiatric illness.39 recent research supports that nearly 13% of all pregnant women are taking an antidepressant during pregnancy with selective serotonin reuptake inhibitors ( ssris ) and selective serotonin norepinephrine reuptake inhibitors ( snris ) being the most frequently prescribed antidepressants.39,40 currently , the research literature on the safety of antidepressant use during pregnancy and breastfeeding has yielded mixed results , making clinical recommendations difficult . research examining the adverse reactions of ssri exposure during pregnancy on the developing fetus has found an increased risk of various congenital malformations ( congenital heart defects , craniosynostosis ) ; however , inconsistencies between study results remain . limitations in study interpretation include small sample sizes ( low statistical power ) , failure to adequately control for maternal depression effect , and failure to control for other important confounders ( smoking , folic acid intake , alcohol use).41 - 44 nonetheless , the healthcare provider must carefully discuss treatment options both pharmacologic and nonpharmacologic with each woman so an informed decision can be made . many healthcare providers initiate ssris if pharmacologic treatment is warranted , as they are generally well tolerated.38 of the ssri medications , fluoxetine and sertraline have more data regarding safety than the newer ssris ( escitalopram ) and snris.38,42 the risk of pharmacologic therapy is largely focused on the infant 's exposure to the antidepressant via breast milk in the postpartum period.45 the majority of research examining the safety of breastfeeding with antidepressant use has found low rates of adverse reactions in infants exposed to antidepressants , including ssris.45 as a general recommendation , breastfeeding mothers on drug therapy for perinatal depression should be instructed to take their medication immediately after breastfeeding . this helps minimize the amount of antidepressant present in the breast milk while maximizing its clearance prior to the next feeding.45 a growing number of nonpharmacologic interventions are aimed at mitigating the effects of perinatal depression , including individual cognitive behavioral therapy ( cbt ) , interpersonal psychotherapy ( ipt ) , and group therapy.46,47 ipt is a time - limited therapy with demonstrated benefit for treating mdd . ipt is designed to improve depressive symptoms by assisting patients in navigating changes in their personal relationships . ipt focuses on issues , such as role change , social support , relationships , and life stress.47 cbt has been used extensively in patients , including those with both depressive and anxiety disorders . cbt aims to reduce depressive symptoms by targeting and modifying negative patterns of thinking and behavior . cbt is typically provided by a clinical psychologist over a predetermined number of sessions ; however , in practice , the length of therapy can vary ( between 4 to 20 sessions).46 a recent meta - analysis provides strong support for incorporating these interventions into the treatment plan for perinatal depression , with all interventions examined demonstrating greater benefit on depressive symptoms as compared to control conditions.46 furthermore , results demonstrated ipt to be more beneficial than group psychotherapy with regards to change in depressive symptoms pre- and postintervention . interventions , including an interpersonal therapy component , had greater effects compared to interventions including a cbt component . further studies are needed that examine manual - based ipt and cbt , administered with high fidelity , to firmly establish one modality as more effective than the other . comparisons across these types of interventions have been difficult in part due to differences in intervention fidelity . this research is particularly vital given the rather low acceptability of pharmacologic therapy in this population coupled with a preference for nonpharmacologic interventions.48 similar to other screening ( behavioral , psychosocial ) initiatives in clinical practice , perceived barriers to implementation exist on the part of the healthcare provider , including a lack of time , inadequate training to diagnose or counsel , insufficient mental health referral sources , and lack of reimbursement.49 continuing to omit these critical screenings counters policies established to increase access to basic and quality care particularly for low - income communities . the new focus on comprehensive care and wellness is purported to be best delivered through the patient - centered medical home ( pcmh ) model , featured prominently in the affordable care act.50 the pcmh model is particularly salient for low - income and underserved women . a lack of health insurance and inadequate social support often render this population particularly vulnerable to fragmented care.51 however , the pcmh model can provide continuous , patient - centered care , assisting perinatal women with coordination of care through linkages with key community agencies.50 these linkages could be particularly helpful for women without adequate support as well as those women who had pregnancy complications that may be exacerbating depressive symptoms . social media provides an ideal platform to link mothers who may report difficulties breastfeeding or infants with colic , for example , with support groups or resources in their communities . additionally , national websites , such as postpartum support international ( www.postpartum.net ) , office on women 's health ( www.womenshealth.gov/mental-health/illnesses/postpartum-depression.html ) , and postpartum progress ( www.postpartumprogress.com ) offer an array of resources for antenatal , perinatal , and postpartum depression , including links to local resources . perinatal depression is an important public health issue with well - documented consequences for mothers , children , and families . healthcare providers caring for perinatal women and their children are uniquely situated to address perinatal depression given women are more likely to access healthcare during this time . providers caring for underserved women and families are well positioned to improve maternal and early childhood outcomes for families at greatest risk of healthcare disparities . efforts to expand access to care and facilitate the coordination of care in the perinatal period may serve to improve perinatal outcomes .

abstract : perinatal depression is a common condition with significant adverse maternal , fetal , neonatal , and early childhood outcomes . the perinatal period is an opportune time to screen , diagnose , and treat depression . improved recognition of perinatal depression , particularly among low - income women , can lead to improved perinatal health outcomes .

the 21-day experimental gingivitis model is an established noninvasive model in humans for investigating the induction and resolution of inflammation in response to increasing bacterial accumulation . from its inception in 1965 , this model of inflammation has been used to assess how drugs,(3 ) bioactive compounds in dentifrices and environmental toxins , such as tobacco smoke , affect the development of inflammation . the model is designed to enable the study of both the induction and resolution of inflammation , which can also be assessed over a relatively short period of time ( 35 days ) and in a controlled manner . the model involves periodontally and systemically healthy volunteers , who do not brush specified test teeth in one sextant of the dentition , but continue to brush the remaining control teeth over a 21 day period . accidental brushing of test teeth is prevented by the use of a vinyl shield ( mouth guard ) to cover them during cleaning . on day 21 , the accumulated plaque on all teeth is removed by a trained hygienist and study participants resume their normal oral hygiene practices . clinical assessment of plaque accumulation and gingival inflammation are made at baseline , day 7 , 14 , 21 on test and control teeth , following plaque accumulation on test teeth , and normal plaque removal from control teeth . assessments are repeated again on day 35 , following 14 days of resolution of inflammation at test sites , and maintenance of health at control sites . when performed by trained and calibrated experts , these measures show consistent increases in plaque - induced inflammation up to day 21 followed by a return to baseline , preinflammation levels at day 35 . however none of these assessments could potentially form the basis for a predictor of disease as they are all measures of existing inflammation or inducers of inflammation . a further and more objective assessment that can be made during the experimental gingivitis is that of the volume and composition of gingival crevicular fluid ( gcf ) and at individual sites around individual teeth . this fluid flows from the crevice between the tooth and the gum and comprises both a serum transdate(11 ) and tissue exudates . during inflammation , the volume and flow of this fluid increases,(1 ) and this alone can be used to demonstrate induction and/or presence of gingivitis and periodontitis . however , due to its very nature , as a mixed serum transudate and tissue exudate , gcf carries with it proteins from the crevice . thus its composition also provides a biological and pathological fingerprint of the various physiological and biochemical processes occurring within the gingival tissues . in 1980 , novaes et al.(15 ) demonstrated that the total protein present in gcf increased with increasing severity of periodontitis , although this was probably due to increases in gcf volume . by 1985 , lamster et al.(16 ) had measured differences in lactate dehydrogenase , beta - glucuronidase and arylsulfatase activity in gcf collected from experimental gingivitis sites and demonstrated increases in these biomarkers over the course of the 21 day study . since then , studies have targeted particular cytokines , antibacterial peptides and proteins(19 ) and many more individual proteins and peptides , revealing increases in pro - inflammatory species during disease . studies have also examined the effect of diseases , such as type i diabetes mellitus,(23 ) analysis of many anti - inflammatory or antimicrobial compounds , and environmental conditions , such as smoking,(8 ) on experimental gingivitis . surface enhanced laser desorption / ionization time - of - flight mass spectrometry ( seldi tof ms ) has been used to examine small proteins and peptides ( 2.530 kda ) from healthy volunteers and gingivitis patients.(24 ) that study employed a targeted approach to investigate neutrophil defensins . unfractionated gcf samples were also examined by matrix assisted laser desorption / ionization ( maldi)-tof ms , for neutrophil defensins.(25 ) similarly , pisano et al(26 ) used electrospray ionization(27 ) ( esi)ms to examine the acid - soluble protein content of gcf from healthy volunteers . they , too , identified the neutrophil defensins , along with cystatin a , statherin and serum albumin . only in the last year have tandem mass spectrometry ( ms / ms ) techniques been employed in the examination of gcf . ngo et al.(28 ) used both maldi - tof / tof and esims / ms to identify 66 proteins that had been separated by gel electrophoresis from a single patient , who had a history of periodontal disease but who was in the maintenance phase following treatment . proteins identified included a number of serum - derived proteins , such as albumin , complement and transferrin . other proteins that were present included : antimicrobial proteins calgranulin a and b ; amylase ; cytatin s ; and histone h4 . bostanci et al.(29 ) used a lcms label - free quantitative technique to identify 154 proteins from either healthy volunteers or patients with aggressive periodontitis . bostanci et al.(29 ) identified a wide range of proteins including those mentioned already and a large number of keratins , immunoglobulins , and other intracellular proteins . the majority of mass spectrometry - based proteomics is performed using the bottom - up(30 ) liquid chromatography tandem mass spectrometry ( lcms / ms ) approach . generally , proteins are digested with trypsin prior to online lc separation . as the peptides elute into the mass spectrometer , they are fragmented typically by collision induced dissociation(31 ) ( cid ) resulting in b and y ion series.(32 ) the ms / ms spectra are searched against protein databases by use of algorithms ( e.g. , mascot,(33 ) sequest,(34 ) omssa(35 ) ) which match the data to theoretical spectra from in - silico digests of proteins . two of the most popular are stable isotope labeled amino acids in cell culture(36 ) ( silac ) and isobaric tags for relative and absolute quantitation ( itraq).(37 ) in silac , cells are grown in media lacking essential amino acids . the media is supplemented with heavy or light amino acids . the labeled and unlabeled peptides elute together and the intensity of the peptide ions can be compared . a common approach for quantitation of biological fluids(38 ) and tissue samples(39 ) is postdigestion labeling with itraq(40 ) labels . itraq labels consist of a reporter ion with a m / z value of between 113 and 121 and a balance mass ( 191183 da ) such that all labeled peptides of the same sequence have the same nominal mass shift ( 304 da ) . test and control samples are treated with separate itraq labels postdigestion and combined prior to ms analysis . when the peptide ions are fragmented with cid , the reporter ions are cleaved from the peptide and detected in the mass spectrometer . the intensity of the reporter ions quantitation with itraq , allows for the analysis up to eight different treatment groups(41 ) simultaneously . one of the disadvantages of performing cid in ion traps is the instability of ions with m / z values approximately 1/3 that of the parent ion,(42 ) that is , fragment ions with m / z less than 1/3 of the precursor ions are not detected . itraq reporter ions have m / z 113121 and therefore ion trap cid of itraq labeled peptides often does not result in quantification . the recent introduction of pulsed - q dissociation(43 ) ( pqd ) has allowed for the analysis of itraq labeled samples in linear ion trap mass analysers . pqd excites ions with a high amplitude q value ; q is a resonance excitation pulse . when the ions are excited , they collide with neutral gas molecules in a similar manner to cid . the activation profile applied in pqd is different to that of cid meaning that low mass ions are stable and can be detected . to date , the proteomic profile of gcf during the active induction and subsequent resolution of inflammation under controlled conditions using the 21 day experimental gingivitis model has not been described . herein we describe the quantitative analysis of gcf , collected from volunteers undergoing experimental gingivitis , by lcms / ms using fourier transform ion cyclotron resonance(44 ) ( ft - icr ) ms and itraq isobaric mass tags , to establish a profile of changes in proteins in healthy young volunteers that may be used to compare to the inflammatory response in other subsets of the population , such as those predisposed to periodontitis . the experimental gingivitis model previously described by chapple et al.(9 ) was used , and the study was approved by the south birmingham local research ethical committee ( lrec 2004/074 ) . ten nonsmoking volunteers ( mean age 21 years ; range 1928 , 4 males and 6 females ) who had unremarkable medical histories , no periodontal problems ( past or present ) , were not undergoing orthodontic or prosthetic appliance therapy or taking medication that may have affected results were enrolled into the study , and informed consent was obtained . a split mouth design was employed with test sites being the maxillary left 4 , 5 , and 6 ( first and second premolars and first molar on the left - hand side of the upper jaw ) in right - handed individuals ( n = 9 ) and the equivalent teeth on the maxillary right side in left - handed individuals ( n = 1 ) . plaque accumulation was assessed using a modified quigley - hein index(45 ) ( pi ; scores 05 ) and the gingival index ( gi ) of le(46 ) ( scores 03 ) was used to measure gingival inflammation . bleeding was measured dichotomously as presence or absence following gentle probing and expressed as the percentage of sites that bled upon probing . all volunteers had no evidence of attachment loss ( destruction or loss of the connective tissues and bone holding the teeth within their sockets ) when admitted to the study . a soft vinyl splint was constructed to cover five teeth , with a 5 mm clearance at each free surface from the marginal tissues . the splint was inserted gently over test teeth before brushing , to ensure against any mechanical or chemical cleaning . the test and control teeth were given a thorough prophylaxis and oral hygiene was closely monitored for 2 weeks prior to the study commencing to ensure pristine gingival health at baseline ( see introduction and figure 1 ) . gcf samples were collected from both test and control sites on days 0 ( baseline ) , 7 , 14 , and 21 . on day 21 , following plaque accumulation at test sites and after gcf sampling and recording of clinical indices , volunteers were given a full mouth prophylaxis and recommenced brushing without using the splint , in order to resolve the experimentally induced inflammation at test sites . fourteen days later ( day 35 ) , the final set of gcf samples was collected and clinical indices recorded . control sites were treated identically until baseline , but normal plaque removal then continued until day 35 . gingival crevicular fluid was collected on periopaper strips ( oraflow , plainview , ny ) over a period of 30 s as previously described.(9 ) gcf volume was measured using a precalibrated periotron 8000 ( oraflow , plainview , ny),(47 ) from the 3 test teeth and the 3 control teeth . the three test strips were then placed into a cryotube ( appleton woods , birmingham , u.k . ) containing ammonium bicarbonate ( 100 mm , 200 l ) , sealed and immediately frozen in liquid nitrogen , prior to storage at 80 c . this procedure was repeated for the 3 control strips , thereby providing one pooled sample from test teeth and one pooled sample from control teeth for each volunteer . periopaper strips , showed a percentage recovery of 62 5% from spiked plasma ( 1 l ) ( data not shown ) as analyzed by the number of proteins identified . samples were defrosted on ice . from each sample within a time point and test or control site , 200 l of solution was removed and pooled to give rise to 10 1 ml samples : 5 from test sites and 5 from control sites , covering all time points . to each pooled sample dithiothreitol ( fisher scientific , u.k . ) ( 20 l , 50 mm ) was added and the samples incubated at 60 c for 40 min . the sample was returned to room temperature before iodoacetamide ( fisher scientific , u.k . ) ( 100 l , 22 mm ) was added and the samples incubated at room temperature for 25 min . to consume any remaining iodoacetamide , dithiothreitol ( 2.8 l , 50 mm ) the samples were digested overnight with trypsin gold ( 500 ng , promega , madison , wi ) at 37 c . the samples were vacuum centrifuged to dryness , resuspended in trifluoroacetic acid ( fisher scientific , u.k . ) ( tfa , 0.5% , 200 l ) and desalted using a michrom desalting macrotrap ( michrom , auburn , ca ) . the trap was wetted using acetonitrile : water ( 50:50 , 300 l ) and washed with tfa ( 0.1% , 200 l ) . the sample was loaded onto the trap and washed with tfa ( 0.1% , 200 l ) and eluted in acetonitrile / water ( 70:30 , 200 l ) . samples were resuspended in dissolution buffer ( 0.5 m triethylammonium bicarbonate , 30 l ) . the two day 0 samples were combined and half the sample was taken forward for labeling . the day 7 control was omitted such that 8 samples were labeled in total , as follows . the itraq 8-plex labels ( applied biosystems , foster city , ca ) were resuspended in isopropanol ( 50 l ) , added to the 8 samples as below , vortexed for 1 min and incubated at room temperature for 2 h. the labels were applied in the following order ( sampling time and condition , sample i d ) : day 0 , 113 ; day 7 test , 114 ; day 14 control , 115 ; day 14 test , 116 ; day 21 control , 117 ; day 21 test , 118 ; day 35 control , 119 ; and day 35 test , 121 . the pooled sample was desalted as above and resuspended in mobile phase a ( see below , 200 l ) . the sample was separated using strong cation exchange high performance liquid chromatography ( scx - hplc ) and fractions collected . the chromatography was performed on an ettan lc ( ge healthcare life science , u.k . ) with a frac-950 fraction collection system . the sample was separated on a polysulfethyl a column ( 100 mm 2.1 mm , 5 m particle size , 200 pore size . polylc , columbia , md ) with a javelin guard cartridge ( 10 mm 2.1 mm , 5 m particle size , 200 pore size . mobile phase a was potassium dihydrogen orthophosphate ( 10 mm , ph 3 ) dissolved in water : acetonitrile ( 80:20 ) . mobile phase b was potassium dihydrogen orthophosphate ( 10 mm ) , potassium chloride ( 500 mm , ph 3 ) dissolved in water / acetonitrile ( 80:20 ) . half of the sample was loaded onto the column and eighteen fractions were collected in eppendorf tubes ( 1.5 ml ) . fractions were combined to give a total of 8 fractions ( fractions 2 , 18 , and 19 were combined ; 3 , 16 , and 17 combined ; 4 and 15 combined ; 5 and 14 combined ; 6 and 13 combined ; 7 and 12 combined ; 8 and 11 combined ; 9 and 10 combined ) . online liquid chromatography was performed by use of a micro as autosampler and surveyor ms pump ( thermo fisher scientific , bremen , germany ) . peptides were loaded onto a 75 m ( internal diameter ) integrafrit ( new objective , woburn , ma ) c8 resolving column ( length 10 cm ) and separated over a 40 min gradient from 0% to 40% acetonitrile ( baker , holland ) . peptides were eluted directly ( 350 nl / min ) via a triversa nanospray source ( advion biosciences , ithaca , ny ) into a 7 t ltq ft mass spectrometer ( thermo fisher scientific ) , where they were subjected to data - dependent pqd . the mass spectrometer alternated between a full ft - ms scan ( m / z 4002000 ) and subsequent pqd ms / ms scans of the three most abundant ions above a threshold of 1500 . survey scans were acquired in the icr cell with a resolution of 100 000 at m / z 400 . pqd was performed with helium gas at a normalized collision energy of 45% , activation q 0.8 and activation time 200 ms . automated gain control was used to accumulate sufficient precursor ions ( target value 5 10 , maximum fill time 0.2 s ) . dynamic exclusion was used with a repeat count of 1 and exclusion duration of 180 s. data acquisition was controlled by xcalibur software v2.1.0 ( thermo fisher scientific inc . ) . the ms / ms spectra were searched against a concatentated forward and reverse ipi human database v3.66 supplemented with bacterial proteins ( 224 902 entries ) using the sequest algorithm in proteome discoverer sp 1.0 ( thermo fisher scientific ) . only the itraq labels were specified as variable modifications , with carboxyamidomethylation of cysteine as a static modification . the data were searched with a precursor mass error of 20 ppm and a fragment mass error of 0.5 da . the search results were filtered using xcorr vs charge state ( peptides reporting xcorr values < 2 for 2 + ions , < 2.25 for 3 + ions and < 2.5 for 4 + or greater ions are rejected ) resulting in a false discovery rate of less than 1% . the database used was compiled of human fasta proteins from the ipi database supplemented with bacterial families identified by socransky(48 ) as being associated with periodontal health or periodontal disease . these families were porphyromonas , bacterioides , treponema , fusobacterium , prevotella , campylobacter , eubacterium , streptococcus , capnocytophaga , eikenella , actinobaccillus , actinomyces , selenomonas and aggregaterbacter . these were filtered for proteins identified in at least three fractions by at least 2 peptides and quantified at all time points . the temporal quantitative profiles of these proteins were analyzed using polysnap3 software.(49 ) polysnap3 compares trends using a weighted mean of the pearson parametric and spearman nonparametric correlation coefficients employing every measured intensity data point common to all one - dimensional patterns . cluster numbers are estimated by : principal components analysis using transformed and nontransformed matrices ; multidimensional metric scaling ( mmds ) ; gamma statistic , calinski - harabasz statistic and c - statistic using either single linkage , group averages , ward method or complete linkage . clinical measurements revealed that the volunteers had complied with the study criteria as shown in figure 2 , where it can be seen that plaque accumulated significantly at the test sites but not the control sites , as assessed by the plaque index . after removal of all plaque from both test and control sites at day 21 microbial recolonization to baseline levels was observed at day 35 . clinical measurements also demonstrated that at test sites inflammation had been induced , as measured by the modified gingival index ( figure 3 ) and the bleeding index ( figure 4 ) . both these indices showed significant increases at test sites but not at control sites during plaque accumulation and returned to baseline levels , at day 35 , after removal of the inflammatory stimulus at day 21 and resumption of manual brushing ( figure 1 ) . similarly , gcf volume increased with plaque accumulation at test sites but not at control sites and returned to baseline levels after removal of the inflammatory stimulus ( figure 5 ) . data were analyzed by a kruskalwallis test with a dunn s post test . * * * represents p < 0.001 and * * represents p < 0.01 in comparison to day 0 ; $ represents p < 0.05 in comparison to control site at the same time point . * represents p < 0.01 in comparison to day 0 . bleeding on probing was measured dichotomously as presence or absence following gentle probing and expressed as percentage of sites that bled upon probing . data were analyzed by a kruskalwallis test with a dunn s post test . * * * represents p < 0.001 and * represents p < 0.05 in comparison to day 0 ; $ represents p < 0.05 in comparison to control site at the same time point . gcf was collected on periopaper tm strips over 30s and the volume was measured using a precalibrated periotron 8000tm . * * * represents p < 0.001 and * * represents p < 0.01 in comparison to day 0 ; $ represents p < 0.05 in comparison to control site at the same time point . using a meta - proteomics approach , the bacterial proteins showed little temporal variance across the course of the experimental gingivitis , from day 0 to day 35 . temporal changes in the abundance of human proteins across the course of the experiment at control sites were analyzed with polysnap3 software for patterns different from a stable unchanging profile . 170 proteins showed no change over the course of the experiment ( cluster 1 , not deviating from a ratio of 1 from day 0 ) at control sites , and 16 showed decreases from day 0 to day 35 ( clusters 25 ) , at control sites , that did not cluster with the other proteins ( maximum number of clusters : 5 , range 15 , median number of clusters 3 , figure 6 ) . the proteins in cluster 1 were then used to filter the data from the test sites , which were normalized to control sites . the normalized data for the 170 proteins were analyzed using polysnap3 to identify the proteins whose abundances showed the greatest change with development of experimental gingivitis . five clusters were determined ( clusters ae , maximum number of clusters : 6 , range 26 , median number of clusters 3 , figure 7 ) . clusters a and e , containing 3 proteins each , increased to a maximum value at day 14 and day 21 respectively before returning to baseline levels at day 35 . clusters c ( 1 protein ) and d ( 2 proteins ) , both decreased at day 14 and then either returned to baseline at days 21 and 35 ( cluster c ) or returned to baseline at day 21 and continued to increased to a maximum value at day 35 . cluster b , ( 161 proteins ) , appeared to remain constant at baseline levels and throughout the course of the experimental gingivitis . group 1 showed no changes from baseline , whereas groups 25 differed from baseline over the course of the experiment ( control clusters ) . below the flow diagram are graphs representing the mean ( sem ) changes of the proteins in each cluster , which are followed beneath by 3-dimensional metric multidimensional scaling ( mmds ) plots and dendrograms showing the relationships of individual proteins with others in the analysis group . colors of lines on graphs , spheres on 3d plots and bars on dengrograms coordinate to show the same clustering . proteins identified from group 1 were used for the next step of the analysis using normalized test data which were clustered using polysnap3 . five clusters ( clusters a - e ) were generated ( cluster round 1 summary ) , with 161 proteins identified in cluster b. the proteins in cluster b were then further analyzed by polysnap3 to generate 6 clusters ( clusters b16 ; cluster round 2 summary ) . this group was then further analyzed using polysnap3 to generate 6 clusters ( clusters b2i - vi , cluster round 3 summary ) . below the flow diagram are graphs representing the mean ( sem ) changes of the proteins in each cluster , which are followed beneath by 3-dimensional metric multidimensional scaling ( mmds ) plots and dendrograms showing the relationships of individual proteins with others in the analysis group . colors of lines on graphs , spheres on 3d plots and bars on dendrograms coordinate to show the same clustering . it should be noted that the highlighted , largest group on each dendrogram was the group taken forward into the subsequent round of clustering analysis . inspection of the dendrogram from this clustering analysis demonstrated that there were still many clusters within group b. thus further analysis of this group was performed . the second round of clustering revealed a further 6 clusters ( clusters b16 , maximum number of clusters : 6 , range 36 , median number of clusters 4 , figure 7 ) . clusters b4 ( 4 proteins ) and b5 ( 2 proteins ) demonstrated increases across the course of the experimental gingivitis peaking at days 14 and 21 respectively and remaining elevated at the peak level at day 35 . clusters b1 , b3 and b6 , containing 8 , 20 , and 4 proteins respectively , decreased during the course of the study . cluster b1 showed a small decrease at day 14 and then returned to baseline levels before decreasing greatly at day 35 . cluster b6 decreased at day 14 and remained at this level for the rest of the experimental gingivitis . cluster b2 ( 123 proteins ) did not fluctuate at this level of detail across the course of the experimental gingivitis and these proteins were again taken for further clustering analysis . that analysis gave rise to another 6 clusters ( clusters b2i - vi , maximum number of clusters : 6 , range 36 , median number of clusters 4 , figure 7 ) . at this point two observations were made : ( 1 ) the largest group ( b2i ) showed a slight increase at day 21 , i.e. , no longer showed little variation across the course of the experimental gingivitis and ( 2 ) the variation in the ratio to day 0 for all the clusters was now between 01 unit at its maximum . therefore , further rounds of clustering analysis were not pursued , even though there were still a large number of proteins in the largest cluster ( cluster b2i , n = 86 ) . inspection of the patterns generated from this third and final clustering showed that cluster b2ii ( 1 protein ) showed a peak at day 21 ; cluster b2iii ( 4 proteins ) peaked at day 14 and then decreased at days 21 and 35 ; cluster b2iv ( 13 proteins ) showed little change over 14 and 21 days but an increase at day 35 ; cluster b2v ( 1 protein ) showed a decrease at day 21 ; and cluster b2vi ( 18 proteins ) showed an increase at day 14 that was sustained to day 21 before returning to baseline at day 35 . fold changes for all proteins in cluster 1 can be found in the supplemental table 1 . gene ontology analysis for location revealed the majority of proteins identified to cover the entire range of nuclear , plasma membrane , cytoplasmic and extracellular compartments ( figure 8) . gene ontology analysis for function identified a wide range of possibilities with the greatest numbers of proteins for cellular transcription , dna binding , cytoskeletal functions , cell adhesion , defense against bacteria and cilia ( figure 8) . particular clusters did not preferentially fall into one of these categories and the proteins functions were diverse throughout the individual clusters . it should be noted that between 35 and 40% proteins did not have gene ontology terms that could be used . gene otology pie charts were generated using swiss - prot database with inforsense , embedded in proteome discoverer sp1.0 from thermo fisher scientific inc . across the course of experimentally induced gingivitis , we identified 16 bacterial and 186 human proteins by combining itraq and lcms / ms on an ft - icr mass spectrometer . this observation may be used as confirmation that the gcf samples were not significantly contaminated with plaque during sampling . furthermore , fusobacterium species ( fusobacterium outer membrane proteins ) were detected and although this family , particularly fusobacterium nucleatum which is part of the orange complex identified by socransky et al,(48 ) has being associated with increased periodontal pocket depth and worsening clinical parameters , it is also associated with nonperiodontitis sites.(48 ) other bacterial proteins identified were not immediately obvious candidates from oral pathogens . as gcf comprises both a serum transudate and tissue exudates , it is unsurprising to find both extracellular and intracellular components within samples . with respect to the extracellular components , serum proteins , such as albumin , igg3 and apolipoprotein b-100 ; as well as proteins displaying antibacterial properties , such as neutrophil defensin , cystatins b and s and annexins a1 and a3 , were found . the serum components ( albumin and igg3 ) clustered together ( cluster b3 ) and showed a decrease at day 14 at test sites . at this time point , the gcf volume from test sites was already significantly increased above control sites . on the other hand apolipoprotein b-100 falls into cluster b2vi , which follows the profile of the increase in gcf volume and bleeding index at test sites . apolipoprotein b-100 is the protein component of low density lipoprotein , which has a diameter of approximately 26 nm . this particle is unlikely to be able to pass across the permeable sulcular membrane and could potentially be used as a marker of increased microulceration of the sulcular epithelium . cystatins b and s and annexins a1 and a3 were found in cluster b2i , which was largely unchanged across the course of the experimental gingivitis . cystatin b and annexin a1 were found by bostanci et al.(29 ) only in healthy volunteers and not in developing inflammatory disease . that they seem not to change across the course of our experiment would support the idea that they are not associated with the development of moderate gingival inflammation . neutophil defensin was found in cluster b2iv that showed the greatest increases at day 35 for the test sites . bostanci et al.(29 ) also detected this protein at healthy sites , although the gcf volume at these sites is equivalent to day 7 in this experimental gingivitis study , perhaps highlighting a potential role of neutrophil defensin in population based health screening . intracellular proteins identified had functions such as cellular transcription , dna binding , cytoskeletal functions , cell adhesion , and cilia proteins . starting with cytoskeletal proteins , a large number of keratins were identified , which was expected from sampling adjacent to epithelial tissues . the oral epithelium has one of the highest turnover rates(50 ) and this will have contributed to the large number of keratins seen . the majority of keratins were clustered together in cluster b2i , which showed the least variation across the course of the experimental gingivitis , perhaps indicating that the differentiation or proliferation of the epithelium was not affected during the course of the induced inflammation , again consistent with a sulcular rather than a pocket lining epithelium that characterizes periodontitis . however , it is acknowledged that some keratin contamination could have occurred during sample handling . other cytoskeletal and associated proteins , such as titin and actin- and microtubule- associated proteins , also fell into cluster b2i . these proteins could be components of desquamated epithelial cells released during the turnover of the epithelium . to our knowledge , these cilia - associated proteins have not been identified in gcf before . however , a number of studies have used histology to investigate changes in the gingivae in periodontal disease . saglie et al.(53 ) used scanning electron microscopy to investigate the pocket epithelium from patients with advanced periodontal disease . at high resolution they observed individual epithelial cells , bacteria and erythrocytes ; however , large amounts of cilia were not seen , such as might be expected with lung epithelium . primary cilia , however , are present on nearly all cells , including internal stratified oral epithelium,(54 ) and play a chemo- or mechano - sensory role.(55 ) although they are not changed in this experimental gingivitis model , it will be interesting to determine how cilia proteins change with chronic periodontal diseases as it has been proposed that ciliopathies may impair wound healing.(55 ) among the cellular transcription and dna binding proteins that were identified were two histone proteins : histone h4 and histone h1.2 . they did not cluster together ; however , they were both in clusters ( b2iii and b2vi , respectively ) that showed an increase at test sites at day 14 . these proteins are associated with chromatin and may indicate the presence of neutrophil extracellular traps ( nets).(56 ) in addition to phagocytosis , neutrophils can discharge decondensed chromatin and associated proteins to trap and immobilize bacteria . these nets have been shown to be present in the gingival crevice of periodontitis patients.(57 ) neutrophils are the most important leukocytes in the periodontal tissues and have been implicated in periodontitis patients as being hyper - active and hyper - reactive . further evidence for neutrophils may be taken from the presence of plastin-2 ( or l - plastin ) , which was also identified by bostanci et al.(29 ) plastin-2 is an actin bundling protein that plays a role in signaling following fc receptor stimulation in adherent neutrophils . here we found plastin-2 clusters within cluster b3 , which demonstrated a decrease at day 14 at test sites , which might indicate a less adherent phenotype in neutrophils at this stage of the inflammatory response . bostanci et al.(29 ) reported this protein in aggressive periodontitis patients only , perhaps showing a further change in the behavior of neutrophils in diseased rather than healthy volunteers . in this study , we have used polysnap3 clustering software in a multilayered analytical approach . for ease of comprehension , an analogy may be used of examining the clusters of proteins in a manner similar to peeling away the layers of an onion or zooming in to different levels of detail in the clustering . the first layer isolated those proteins that did not maintain a broadly steady flat baseline in the control sites during the course of the experimental gingivitis . the greatest change was seen with nebulin ( cluster 5 ) ; however , other isoforms of this protein ( nebulin isoform 1 and 2 ) were clustered to cluster b2i which showed the least variation across the course of the experimental gingivitis . cluster analysis of the entire data set ( not shown ) always showed these particular proteins as lying outside the central core ( figure 6 control cluster 3d mmds plot ) , thus they may be viewed as outliers . following the exclusion of these proteins the normalized test data was clustered revealing the clusters that changed the most across the course of the experimental gingivitis and then subsequent clustering of the largest group showed the next level of changes , and so on in the third round of clustering . two groups ( clusters a and e ) in the first round of clustering and one ( cluster b2vi ) in the third round of clustering showed increases at days 14 , 21 , and 14 respectively , which were similar to increases in the clinical parameters . cluster a contained disparate proteins involved in neuronal axons , transcription and protein production ; cluster e contained proteins involved in signal transduction , actin - myosin based movement and synaptic transmission ; and cluster b2vi contained many proteins including actin - myosin based movement and synaptic transmission again . a common theme from these clusters might be the presence of neuronal and synapse associated proteins . sterling and matthews ( 2005)(60 ) suggest that ribbon synapses occur wherever synaptic exocytosis is evoked by graded depolarisation and where signalling requires a high rate of sustained release such as in the terminals of photoreceptors and auditory and vestibular hair cells . these synapses use glutamate as their primary neurotransmitter and this would fit with the identification of metabotropic glutamate receptors in cluster b2vi . histological investigations of gingival biopsies will be required to verify the presence of ribbon synapses within the gingivae as their presence has not been seen before . the role of their destruction during experimental gingivitis remains to be fully investigated , particularly with the knowledge that substance p , a neuropeptide , released from sensory neurones and an inducer of inflammation and pain , is increased in gingivitis and periodontitis,(61 ) and that in a recent transcriptomics investigation offenbacher et al ( 2009)(62 ) found that after changes to immune response pathways , neural process pathways where the second most abundant pathways activated during a similar experimental gingivitis model . lastly , cytokines have been investigated extensively in gcf as biomarkers of gingival inflammation . however , in this study we have not been able to detect any cytokines , consistent with bostanci et al.(29 ) this is probably due to the cytokines being at low , subattomol , concentrations . to conclude , here we have shown for the first time the quantitative analysis of temporal changes of proteins in gingival crevicular fluid , using a nonpresumptive approach . proteins identified included proteins already known to the dental community and verification of newly identified proteins in other mass spectral studies . we have also identified new proteins that highlight structural components of the gingivae that have not been seen before and that warrant further investigation .

the 21-day experimental gingivitis model , an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans , is designed to enable the study of both the induction and resolution of inflammation . here , we have analyzed gingival crevicular fluid , an oral fluid comprising a serum transudate and tissue exudates , by lcms / ms using fourier transform ion cyclotron resonance mass spectrometry and itraq isobaric mass tags , to establish meta - proteomic profiles of inflammation - induced changes in proteins in healthy young volunteers . across the course of experimentally induced gingivitis , we identified 16 bacterial and 186 human proteins . although abundances of the bacterial proteins identified did not vary temporally , fusobacterium outer membrane proteins were detected . fusobacterium species have previously been associated with periodontal health or disease . the human proteins identified spanned a wide range of compartments ( both extracellular and intracellular ) and functions , including serum proteins , proteins displaying antibacterial properties , and proteins with functions associated with cellular transcription , dna binding , the cytoskeleton , cell adhesion , and cilia . polysnap3 clustering software was used in a multilayered analytical approach . clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins .

virtual screening ( vs ) is a valuable hit discovery tool with tremendous potential to improve the efficiency and reduce the costs of modern high throughput screens ( hts ) . despite the increasing trend toward miniaturization and greater well plate density , reagents and other consumables drive up hts costs , particularly when large corporate or commercial databases are screened . rationally prioritizing compounds for experimental testing can reduce costs . for example , during a virtual high throughput screen , a computational model is developed and applied to rank compounds for testing . when paired with high quality compound libraries , this can result in novel , structurally diverse actives from which several lead series can be selected . structural diversity ultimately helps circumvent adme - tox and patent liabilities that can increase lead optimization costs . computational virtual screening models primarily fall into two classes , ligand - based and structure based , or docking methods . ligand - based methods predict the activity of novel compounds by assessing their similarity to known actives . docking methods , on the other hand , use predicted interactions between a small molecule and a target receptor to predict activity . numerous benchmarking studies have reported that ligand - based methods yield greater hit rates than structure - based methods . however , a reliance on chemical similarity may limit their ability to identify novel chemical matter . in contrast , the diversity of actives determined using docking methods is only constrained by the shape of the receptor - binding pocket . in principal , docking can enable the discovery of actives more novel and diverse than ligand - based methods . consistently , numerous successful examples of docking in early stage discovery can be found in the literature . despite these successes , docking has traditionally been to a single static representation of the target . a drug target is highly dynamic , and two notable models have been advanced that suggest a tight coupling between protein motion and small molecule binding . in 1958 , koshland proposed the induced fit model , which suggests that ligand binding induces a conformational change of the protein that enhances its affinity for the ligand . conformational selection is a more recent explanation of small molecule binding that incorporates energy landscape theory . it proposes that binding stabilizes one of many preexisting conformers of the unbound target . both models imply that the collection of low - energy receptor conformers defining the bound state depend upon ligand identity ; by extension , successful docking requires the receptor to be in , or at least near , the appropriate ligand - dependent bound state . ensemble docking , in which each ligand is docked to a set of receptor conformers , was introduced in an effort to address this requirement . there are a variety of means to generate structures for ensemble docking , including crystallography and nmr techniques . however , while experimental methods have shown promise , the materials , time , and expertise required to determine multiple , high quality structures is a significant bottleneck . in contrast , molecular dynamics ( md ) simulations offer a relatively inexpensive alternative to generate diverse , realistic conformational states . this is largely the result of the recent implementation of md codes on commodity graphical processor units ( gpus ) and the dramatic speedup of simulation benchmarks . regardless of whether structures are generated by experiment or simulation , for ensemble docking to be successful , a subset of conformations likely to offer the best vs performance must be identified . though several studies have provided hints , others have been unable to determine a meaningful relationship between observable receptor characteristics and virtual screening performance . even with insights from a growing body of careful studies , it remains difficult or impossible to know a priori which receptor conformations will result in an ensemble with virtual screening utility . the difficulties of selecting effective virtual screening conformations are compounded by the combinatorial nature of the ensemble selection process . when the number of receptor conformations is large , the problem results in a significant number of possibilities , and it can be difficult or impossible to know which of these ensembles will produce the best virtual screening performance . though systematic training and data - fusion methods exist that address similar issues in ligand - based vs , there is a relative paucity of knowledge - based structural selection methods . despite this , other knowledge - based ensemble selection methods have been described in the literature . for example , yoon and welsh proposed an ensemble docking method in which ensemble members are selected to maximize the correlation between the experimental and predicted binding affinities . the combinatorial problem was addressed by assigning each compound an ensemble score that consisted of a linear combination of score weights to each receptor conformation using a monte carlo scheme . using estrogen receptor , they demonstrated that the approach leads to more accurate classification than docking to the crystal structure alone . while yoon s and welsh s method can produce stronger correlation with experimental binding affinities and result in enhanced vs performance , experimental binding measurements are required . this precludes the use of single - point hts data and limits the method to compounds whose binding affinities have been measured or to those with dose response curves , from which binding affinities may be inferred . rather than optimizing the correlation with experimental binding affinities , selecting ensembles to maximize the value of a binary classification metric offers greater flexibility . since binary classification is categorical , once an appropriate activity threshold has been determined , any assay that delivers an activity measurement can be used . this opens the door to the use of single - point data , which is less expensive to determine and typically can be found in greater abundance than careful binding affinity measurements . for example , following a slightly different approach , xu and lill developed a knowledge - based ensemble selection technique that can be used with any type of affinity measurement . in it , receptor conformers are first ranked by their ability to separate the average docking scores of active and inactive compounds . then , by assuming that effective ensembles must be constructed from effective conformations , ensembles of successively larger size are formed by aggregating conformers from highest to lowest rank . for example , does the procedure ignore ensembles with significantly greater classification power ? while the underlying assumption went unexamined , the approach appeared promising . when classification ability was examined as a function of ensemble size , the performances of the trained ensembles were comparable or better than the those of ensembles selected by aggregating structurally diverse receptor conforms . a final approach , developed and widely applied by the cavasotto and abagyan groups , utilizes virtual screening performance on a small training set to select the most promising structure from an ensemble generated using either monte carlo side - chain sampling or normal - mode analysis . by including a ligand with the desired properties , for example , a high affinity binder or a receptor agonist / antagonist , the search may be biased toward structures that enrich ligands with similar properties . during model generation , the vs ability of each target conformer is evaluated , and conformational sampling continues until vs performance converges . following convergence , a single best performing structure can be derived and used for cross docking , selectivity studies , or vs. alternatively , multiple conformers may be extracted and combined into useful ensembles , and the methods we introduce here may prove useful in such an approach . in this work , we present three new training methods that select structure - based ensembles for vs use . all three methods construct ensembles by optimizing one of two binary classification metrics , which makes them flexible and enables their use with single - point data , competition assay data ( e.g. , ic50 values ) , or other binding data . to address the combinatorial problem , the population of ensembles is generated by complete enumeration , and two different heuristics are designed to generate population samples biased to exclude low performing ensembles . these approaches lead to different asymptotic scaling as the number of receptor conformations becomes large , and they allow us to examine the severity of the approximations underlying each heuristic relative to the enumerative solution . each method is evaluated on three different target proteins with active and decoy molecules taken from the dud - e : the androgen nuclear hormone receptor ( ar ) , the cyclin - dependent kinase 2 ( cdk2 ) , and the peroxisome proliferator - activated receptor ( ppar- ) . target conformations were selected from a range of sources , including rmsd and volumetric clustering of conventional md simulations , as well as multiple crystal structures . the knowledge - based training methods were tested on three protein targets : the androgen receptor , the cyclin - dependent kinase 2 ( cdk2 ) , and the peroxisome proliferator - activated receptor ( ppar- ) . conformations generated by volumetric clustering of conventional md trajectories along with the crystal structure pdbid 2am9 were used to train androgen receptor ensembles . similarly , conformations generated by rmsd clustering of md trajectories , along with the crystal structure pdbid 4gcj , were used to train ensembles of cdk2 . clustering and simulation details are provided in subsequent sections . for ppar- , ensemble training was performed using 12 crystal structure conformations with the following pdbids ( uniprot q03181 ) : 2awh , 2b50 , 2j14 , 2q5 g , 2xyj , 2znp , 3dy6 , 3et2 , 3gz9 , 3peq , 3sp9 , and 3tkm . structures were selected to ensure a resolution of 3.0 or lower and to ensure that each ligand was unique . additionally , all of the structures are antagonist bound , which is consistent with the antagonists that make up the actives of the training and test sets , as described below . active and decoy ligand sets from the directory of useful decoys - ehanced ( dud - e ) were used to perform virtual screening for each target . while a complete description of ligand set curation can be found in the original reference , we briefly describe the process here . compounds in chembl whose affinities ( ic50 , ec50 , ki , kd ) were less than or equal to 1 m were clustered by their bemis murcko ( bm ) frameworks . compounds with the highest affinity from each cluster were pooled and resulted in sets of actives with unique bm frameworks . for each active , 50 decoys were selected from the zinc database by matching the molecular weight , logp , number of rotatable bonds , hydrogen bond donor and acceptor counts , and net formal charge ( determined in a ph range from 6 to 8) of the active . to reduce the number of false negatives , only the 25% most dissimilar decoys , as judged by tanimoto scores using ecf4p fingerprints , were retained . evaluating the classification performance of a knowledge - based model on the training set will generally provide an overly optimistic estimate of the model s ability to correctly distinguish active and inactive molecules . to provide a more realistic estimate of the trained model s classification ability , dud - e compounds were randomly split in half , while maintaining the decoy - to - active ratio , forming training and test sets . the androgen receptor training and test sets were composed of 7150 compounds , 133 of which were active compounds . the cdk2 training and test sets were composed of 14,162 compounds , 237 of which were active compounds . the ppar- training and test sets were composed of 6245 compounds , 120 of which were active . simulations were initiated from a crystal structure of either the androgen receptor ( pdbid 2am9 ) or cdk2 ( pdbid 4gcj ) . the sulfate ion , glycerol , and the dithiotheritol molecule were deleted from 2am9 , while four molecules of ethanediol were deleted from 4gcj . in 2am9 , e893 are far from the receptor - binding pocket and have unresolved side - chain atoms . schrdinger s prime was used to add them . in 4cgj , atoms from the following residues had multiple occupancy values : d38 , s46 , d127 , k129 , r169 , l212 , m233 , k237 , k250 , s264 , and h268 . in each case , the position with the larger value was retained . protonation states for both 2am9 and 4gcj were predicted at ph 7.0 using the program propka3 , and hydrogen atom positions were assigned and optimized using schrdinger s protein preparation wizard . following protonation , water molecules with fewer than three hydrogen bonds to nonwater molecules were removed . the protonated crystal structures were built for md simulation using the xleap program that accompanies amber14 . the cholesterol and rc-3 - 89 ligand parameters were generated using the antechamber program in amber14 . ligand atomic partial charges were determined from the crystallographic conformations using the am1-bcc method , and all other force field terms were assigned according to the generalized amber force field ( gaff ) . each system was immersed in a box of pre - equilibrated tip4pew water that provided a minimum 10 water pad between the protein and the boundary of the periodic box in the x- , y- , and z - directions . each system was brought to electric neutrality by the addition of an appropriate number of chloride or sodium ions , modeled using the parameters developed by joung and cheatham . the androgen receptor system was comprised of 54,014 atoms , and the cdk2 system was composed of 50,644 atoms . the potential energy was described by the amber14 force field with the stony brook correction . a 20,000-step minimization was performed with 2 kcal mol heavy atom backbone restraint in two stages . during the first step , following minimization , a 200 ps npt simulation was carried out at 300 k and 1 atm . pressure was maintained with a monte carlo barostat with 100 steps between volume changes and a pressure relaxation time of 2 ps . following the npt simulation , a 5 ns nvt simulation was conducted , and restart files were written every 1 ns . these restart files were used to initiate five 20 ns nvt simulations , and frames were written every 2000 fs . all 50,000 frames were concatenated yielding a 100 ns trajectory . during npt and all nvt simulations , hydrogen heavy atom bonds were constrained using the shake algorithm , and a 2 fs time step was used . temperature was maintained in all simulations using a langevin thermostat with a collision frequency of 2 ps . the particle mesh ewald method was used to treat long - range electrostatics , and simulations were performed using pmemd.cuda on a geforce gtx titan card from nvidia . during nvt production runs , the simulation setup resulted in an average timing of 30.29 ns / day on the androgen receptor system and 31 ns / day on the cdk2 system . the 100 ns trajectories were each subsampled at an interval of 40 ps , or every 20th frame , resulting in a total of 2500 frames , which were then clustered . prior to clustering , external translation and rotation were removed from each trajectory by minimizing the rmsd distance of the c backbone atoms to the equivalent atoms of the first sampled frame of the trajectory . for the androgen receptor trajectory , the binding site shape of each sampled structure was determined using povme 2.0 . following binding site characterization , the tanimoto volume overlap between all pairs of structures was calculated , from which a normalized volume overlap matrix was generated . finally , hierarchical clustering was applied to the overlap matrix , 10 clusters were generated , and the structures corresponding to each of the cluster centroids were retained for docking . ligand - based autodetection of inclusion regions and hierarchical clustering are features that will be released in the forthcoming version of povme . for the cdk2 trajectory , rmsd clustering was performed using the algorithm described in daura et al . as implemented in version 5.0.3 of the gromacs g_cluster program . clustering was performed on the heavy atoms of all residues within 10 of the bound inhibitor rc-3 - 89 in the crystal structure pdbid 4gcj . a cutoff of 1.6 resulted in five clusters , and cluster centroids were retained for docking . the glide sp algorithm , from schrdinger , was used to perform docking to all target conformations . relative to the protein receptor , each pose has a unique position and orientation . following generation , all poses are independently subjected to a set of hierarchical filters that utilize precomputed grids to estimate ligand poses with the receptor are computed using a grid - based version of chemscore . poses that pass the initial filter are minimized in a grid - based approximation of the opls pose receptor interaction energy . following minimization , emodel , an empirical scoring function optimized to compare pose energetics , is used to identify the best pose for each ligand . the docking score is an empirical ligand binding affinity estimate , which incorporates epik state penalties that are based on the predicted populations of alternative ligand protonation and tautomerization states . prior to docking , two - dimensional representations of active and decoy molecules were downloaded from the dud - e in sdf format . ligprep program was used to add hydrogen atoms and generate three - dimensional ligand structures . alternative protonation and tautomer states were determined at ph 7 using the epik program , with default settings . alternative ring conformations were not generated since these are produced by glide during docking . input chiralities were retained , and all other options were set to their default values . tip4pew water and chloride ions were removed from the md trajectory . the resulting trajectory , which consisted of either the androgen receptor and the testosterone ligand or cdk2 and the inhibitor rc-3 - 89 were clustered as described above , resulting in 10 and 6 cluster centroids , respectively . schrdinger s protein preparation wizard was used to generate correct atom types for glide grid generation . protonation states from the md simulation were retained , and neither hydrogen bond network optimization nor structural minimizations were conducted . for each cluster centroid , the grid center was positioned on the center of geometry of the ligand ; all other options were set to their default values . docking was conducted locally on a dell precision t7500n workstation with a dual six - core intel x5680 processor , and each compound required roughly 15 s to dock . receiver operating characteristic , or roc , curves were used to evaluate the performance of each ensemble . roc curves provide two useful measures of binary classification performance : the area under the curve ( auc ) and the roc enrichment factor ( ef ) . a roc curve is determined by successively moving a threshold through compounds ranked by their docking scores . by assuming all compounds with scores better than the threshold are active , a true positive fraction ( tpf ) and false positive fraction ( fpf ) can be calculated at each threshold . for example , the tpf is the fraction of active compounds whose docking scores are equal to or better than the threshold , gt . tpf can be calculated as an average over an indicator function , , as described by eq 1.1 in eq 1 , na is the total number of active compounds . for a given active , the indicator function takes a value of 1 if the value of the docking score , gi , is better than or identical to the threshold and a value of 0 otherwise . similarly , the fpf is the fraction of inactive compounds whose docking scores are equal to or better than the threshold . it is also determined as an average of , but over the inactive compounds.2 in eq 2 , ni is the total number of inactive compounds , and all other terms are defined identically to eq 1 . once the tpf and fpf values have been calculated at each threshold , they are plotted along the y - axis and x - axis , respectively , resulting in a roc curve . the area under the roc curve ( auc ) is equivalent to the probability that a virtual screening protocol will rank a randomly selected active compound ahead of a randomly selected inactive compound . an auc value of 0.5 corresponds to random selection , or a method with no classification power , while a value of 1 indicates perfect separation of active and inactive compounds . additionally , the value of the auc is independent of the fraction of actives in the database , it has no free parameters , and an analytic estimate of its standard error is known . the auc value can be estimated using a left - handed riemann sum , which is equivalent to averaging the tpf values at each inactive compound of the ranked list.3 while the auc is a useful measure of global classification performance , the early enrichment , or the preferential ranking of active compounds early in the ranked list , is often used to judge the quality of a virtual screen . enrichment factors are frequently calculated as the ratio of the fraction of actives found in a given percent of the ranked database to the fraction of actives in the total database . unfortunately , the maximum value of this popular metric depends on the ratio of inactive to active compounds in the screened database . , we use the so - called roc enrichment , whose maximum value is independent of the ratio of decoy to active compounds . the roc enrichment factor ( ef ) is the ratio of the tpf , determined at some fpf of interest , to the fpf of interest.4random classification is indicated by an ef value of 1 , and perfect separation of actives and decoys is given by a maximum value of fpf . like the auc , the standard error of the roc enrichment factor may be calculated analytically , which facilitates statistical analysis . for any vs protocol , classification performance will vary as a result of having different compounds in the screened database . for example , assuming repeated screens are performed identically on different databases , the true mean should be found within identically constructed 95% confidence intervals ( ci95 ) in 95% of the measurements . ci95 values were constructed according eq 5.5the standard error , se , of the calculated classification metric ( auc or ef ) is given and is calculated differently for auc and roc - ef values . the exact form that each takes is provided in the supporting information . the value of l is selected such that l bounds 95% of student s t - distribution , where the number of degrees of freedom was determined by subtracting one from the sum of the number of active and inactive compounds . several different methods for combining multiple docking scores into a single docking score have been suggested . reported protocols include creating composite grids of all ensemble members , treating conformations as an independent variables during docking , and using different weighted averages , which include arithmetic and boltzmann weighted averages , as well as averages using weights determined by knowledge - based methods . one simple approach , and the one used in this work , takes the best scoring function value across all ensemble members . for example , a compound docked to an ensemble composed of n protein conformations will have n docking scores , { g1 , g2 , ... , gn } , and the ensemble score of the compound is defined as the smallest score of the set , i.e. , min{g1 , g2 , ... , gn}. if a compound has more than one protonation or tautomer state , the state with the lowest docking score is retained . given a collection of target conformations generated either by experiment or by simulation , it is difficult or impossible to know a priori which subset will result in the best vs performance . the problem becomes increasingly challenging as the number of target conformations grows , and this is the result of the combinatorial nature of the problem . to address this problem , we presented three knowledge - based ensemble selection methods : the exhaustive method , the slow heuristic method , and the fast heuristic method . for each method , the discussion includes schematic illustrations that describe the underlying selection algorithm and an examination of performance , scaling , and limitations ; results from the androgen receptor , cdk2 , and ppar- provide context . by enumeration of all possible combinations of conformers , the exhaustive method generates the complete ensemble population and only retains the highest performing individual ; that is , the exhaustive method is guaranteed to identify the best performing member of the population . three receptor conformers , colored red , green , and blue are shown , and the ensembles that can be constructed at each size are also shown . the population constitutes all of the ensembles at each size , and in the simple schematic , contains seven members . by performing a census of the population training method schematic : selecting the best performing ensemble from three target conformers . as indicated by the greater than symbols , the vs performance , measured by either the auc or ef , is greatest for the red conformer , followed by the green conformer , and the blue conformer is the poorest performer . each method is found in a column , and all combinatorial possibilities are shown . the vs performance of enumerations marked with an the slow heuristic assumes the next largest optimal ensemble is formed only from a combination of the current ensemble and one of the remaining conformers . the fast heuristic method ranks the vs performance of each target conformer and assembles ensembles by successively including conformers of decreasing performance . applying conformation enumeration to generate ensembles is not new , and the idea has appeared in the literature . for example , to retrospectively compare the vs performance of ensemble and single crystal structure vs protocols , korb et al . used a similar enumerative approach . however , in their work , enumeration was not tied to ensemble training , and we later proposed that enumeration could be used to identify ensembles with the greatest vs utility . as the exhaustive method does , guarantees that the best performing ensemble will be identified , but the process is computationally expensive . to reduce expense , we introduced the slow heuristic , which builds ensembles recursively . beginning with the best performing target conformer , each conformation not yet assigned to an ensemble is grouped with the best performing ensemble of the current size . this produces a sample of ensembles , each with one additional conformation and a characteristic vs performance , from which the best ensemble is selected . the process continues until all conformers have been included in an ensemble , and the ensemble that performs best overall is retained . following this heuristic produces a biased sample that neglects population members that do not contain the best performing ensembles of smaller sizes . to clarify how the slow heuristic results in biased samples column in figure 6 . of the three conformations , the red one performs best , the green next best , and the blue conformation performs worst . the one - membered ensemble is made up of the single best performing target conformer , or the red conformer , in this case . after identifying the one - membered ensemble , two two - membered ensembles are then generated . each contains the best one - membered ensemble : red - blue and red - green . since the blue - green ensemble does not contain the best performing one - membered ensemble , it is neglected . while it is not a given that the slow heuristic will result in samples biased to favor high performing ensembles , that did prove to be the case in the three targets considered in this work . this was illustrated in part by the overlap of the population and slow heuristic sample distributions in figure 1 and in part by the ability of the method to identify the best performing ensemble from the population . for example , in figure 1 , the slow heuristic sample favored ensembles that produced larger values of both classification metrics considered , and this was true across all three targets . additionally , the slow heuristic identified the best performing ensemble from the population in five out of the six cases considered ( tables 2 and 3 ) . these observations provide further support for the claim that the method produces biased samples favoring high performing ensembles , and they suggest that the method may be generally applicable across different target classes and roc - based objective functions . nevertheless , because the slow heuristic samples the population , it may miss ensembles in which synergism between poor performing conformations can lead to a higher performing ensemble . to help clarify this , consider the blue and green conformations in figure 6 . despite their poorer individual performances , if they pair to form a high performing two - membered ensemble , it will not be sampled by the slow heuristic . however , while missing potential synergism is possible , when the sample is biased toward high performing ensembles , the best performing sample member may perform comparably to the highest performing population member . for example , when the slow heuristic was used to train androgen receptor ensembles to maximize the auc , the sample did not contain the optimal ensemble from the population ; however , the performances of the best ensemble from the sample and the best ensemble from the population were within confidence intervals of one another ( table 2 ) . the slow heuristic appears to offer a reasonable compromise between computational efficiency and performance . to illustrate the computationally efficiency , in the supporting information , we show that the exhaustive method scales as o(2 ) , given n target conformations , while the slow heuristic scales as o(n ) . for example , if 23 receptor conformations are considered , the exhaustive method considers roughly 8.3 million ensembles , while the slow heuristic method only evaluates 264 ensembles . however , since each of the enumerated ensembles can be evaluated on a single processor , it is noteworthy to point out that the exhaustive method is embarrassingly parallel . by constructing ensembles of increasing size by successively merging conformations of decreasing performance , the fast heuristic ignores the pools of ensembles generated at each size by the slow heuristic and further reduces computational expense . thus , the fast heuristic produces a small , biased sample that neglects the poorest performing conformations at each ensemble size . to clarify how the fast heuristic produces biased samples , since the red conformation performs best , it is selected as the one - membered ensemble , and the poorer performing conformations are neglected . by merging the one - membered ensemble with the next best performing conformation , the two - membered red - green ensemble is produced . the green - blue ensemble is ignored , just as it is by the slow heuristic , but the red - blue ensemble is also ignored , which results in a smaller sample . relative to the exhaustive solution , which generates the entire ensemble population , the fast heuristic sample is significantly smaller . in general , given n target conformations , the ensemble population has a size 2 1 , and the fast heuristic only considers 2n 1 of these . in practice for example , with 11 androgen receptor conformations , the fast heuristic method ignores 2026 of the 2047 possible ensembles . the fast heuristic is nearly identical to the method of xu and lill , which was described in the introduction . however , rather than using the value of a roc classification metric , they ranked target conformations by the differences in average docking scores of decoy and active molecules to each conformer . while xu s and lill s results were promising , the effect of ignoring a significant fraction of the ensemble population was not assessed . to provide insight into the severity of the heuristic relative to the enumerative solution consistent with the small sample size , the fast heuristic was only able to identify the best performing population member in one of the six cases considered ( tables 2 and 3 ) . despite this , the ensembles identified performed similarly to the best performing ensemble of the population : fast heuristic performance values were within confidence intervals of the best performing members of the population for all three targets and both objective functions . despite the much smaller sample size , the fast heuristic may be a generally applicable approach that offers linear scaling without a dramatic sacrifice in classification ability . docking to structural ensembles is a promising means of identifying novel , structurally diverse active compounds . despite the potential of ensemble docking , it is difficult to know which structures will synergize and perform well during a virtual screen . this problem emerges from the combinatorial nature of ensemble selection . to address the selection problem each method scales differently in the limit of a large number of receptor conformations but can perform similarly , which was demonstrated by constructing ensembles of the androgen receptors , cdk2 , and ppar- and with either x - ray crystallographic structures or snapshots from all - atom molecular dynamics trajectories . as with all other knowledge - based methods , those presented here are fundamentally limited by the availability of high quality ligand sets . nevertheless , virtual screens are often carried out on targets for which active and inactive molecules are known . in these cases , the ensemble selection methods presented have broad applicability .

ensemble docking can be a successful virtual screening technique that addresses the innate conformational heterogeneity of macromolecular drug targets . yet , lacking a method to identify a subset of conformational states that effectively segregates active and inactive small molecules , ensemble docking may result in the recommendation of a large number of false positives . here , three knowledge - based methods that construct structural ensembles for virtual screening are presented . each method selects ensembles by optimizing an objective function calculated using the receiver operating characteristic ( roc ) curve : either the area under the roc curve ( auc ) or a roc enrichment factor ( ef ) . as the number of receptor conformations , n , becomes large , the methods differ in their asymptotic scaling . given a set of small molecules with known activities and a collection of target conformations , the most resource intense method is guaranteed to find the optimal ensemble but scales as o(2n ) . a recursive approximation to the optimal solution scales as o(n2 ) , and a more severe approximation leads to a faster method that scales linearly , o(n ) . the techniques are generally applicable to any system , and we demonstrate their effectiveness on the androgen nuclear hormone receptor ( ar ) , cyclin - dependent kinase 2 ( cdk2 ) , and the peroxisome proliferator - activated receptor ( ppar- ) drug targets . conformations that consisted of a crystal structure and molecular dynamics simulation cluster centroids were used to form ar and cdk2 ensembles . multiple available crystal structures were used to form ppar- ensembles . for each target , we show that the three methods perform similarly to one another on both the training and test sets .

Artist's depiction of Mars One astronauts and their colony on the Red Planet. A private Mars colonization effort has fallen far short of its expected number of astronaut applications but still aims to put boots on the Red Planet in 2023. With just a few days left in the application process, the nonprofit Mars One Foundation has received about 165,000 submissions from prospective Mars colonists — a far cry from the 1 million that officials had originally targeted in April before opening the process. The shortfall could affect Mars One's planning and progress, since the foundation is using application fees to fund its activities in these early days. But Mars One intends to pay most of its bills by staging a global media event around the colonization effort, and officials expressed confidence that interest in such a spectacle will still be high. [The Mars One Colony Project (Images)] "The 165,000 applicants that we have so far is still, a very, very large number, and the TV people that we talk to — we have two very serious discussions going on with consortia of investors that include media," Mars One co-founder and CEO Bas Lansdorp told SPACE.com last week. Lots of applications Mars One aims to land four people on the Red Planet in April 2023 at a cost of about $6 billion. Supply ships and four additional colonists will launch every two years thereafter to grow the Mars colony. At the moment, there is no plan to bring any of these explorers back to Earth. Twenty-four colonists will be selected by mid-2015 for the first six colony flights. After the initial 2023 flight, each colonist trip will cost $4 billion and the regular supply ship missions will be about $250 million each, foundation officials have said. Mars One opened its application process for potential colonists on April 22 of this year and set a deadline of Aug. 31. Applicants have to pay a fee, which ranges from $5 to $75 depending on which country they live in. The fee for United States citizens is $38. On April 10, Lansdorp told SPACE.com that Mars One expected to get 1 million applications. By mid-April, the foundation had 45,000 people registered for its mailing list and had received 10,000 emails from individuals. By early May, two weeks after applications opened, Mars One was claiming 78,000 applicants. At the time, Lansdorp said in a statement: "These numbers put us right on track for our goal of half a million applicants," lowering the applications bar he had set a few weeks earlier. By Aug. 22, Mars One had received about 165,000 applications, meaning the foundation could have a total of around 200,000 in hand by the Aug. 31 deadline. Lansdorp told SPACE.com on Aug. 23 that potential applicants should not be concerned about any perceived lack of qualifications: "We have the feeling that people feel that, 'If I’m not a pilot or I don’t have astronaut training already, how can I ever be qualified to go to Mars?' And actually, the opposite is true." Space.com Exclusive T-shirt. Available to Populate Mars. Buy Now Credit: Space.com Store The average application fee is about $25, Lansdorp said, so 200,000 submissions would bring in about $5 million. That would leave Mars One $20 million short of what it would have gotten from 1 million applications (and $7.5 million shy of the $12.5 million that 500,000 applications would have brought in). However, Lansdorp also told SPACE.com last week that the 165,000 included those that had not paid. He declined to say how much revenue applications had generated. Funding the mission Mars One may use proceeds from application fees to cover a variety of activities over the next two years, including the basic running costs of the organization and its website; selecting candidates from hundreds of thousands of applicants; managing its 2016 Mars robotic demonstration mission; building the mock Mars base that candidates will train in here on Earth; and paying for the initial development work for all the human spaceflight-related technologies the 2023 mission will need. Mars One may be able to share technology development costs with American millionaire and original space tourist Dennis Tito’s Inspiration Mars mission. Announced in February, Inspiration Mars aims to send a two-person crew on a Mars flyby in 2018. "I met Dennis Tito...and there are definitely areas where we can co-operate on the technology," Lansdorp said. "They will fly to Mars and back, and we will fly there...so there is definitely going to be technical cooperation." [Inspiration Mars: Private Mars Voyage in 2018 (Gallery)] Inspiration Mars and Mars One already share a supplier in Paragon Space Development Corp. Mars One announced in March that Paragon will study life support and spacesuit systems for the colonization effort. Lansdorp also said on Aug. 23 that Mars One will make an announcement soon about its 2016 robotic demonstration mission. The foundation is working on all the requirements documents with its potential suppliers so it can award contracts for this mission, which will send into Martian orbit a communication satellite capable of relaying images, videos and other data from the Red Planet's surface and test technologies needed for human spaceflight. However, some space engineering companies may not want to be paid in bitcoin. Lansdorp confirmed on Aug. 23 that Mars One is accepting the digital currency bitcoin. The foundation is offering bitcoin as an option to applicants because banking services such as Paypal are not available in every country, Lansdorp explained. "Literally in any country in the world, you can use bitcoin to pay," he said. "It is a little bit more complex than Paypal, but if you really want this [to go to Mars], you should be able to use bitcoin." Yes — Sign me up! No — I like life here on Earth just fine. Maybe — I need some time to think about it. Irrelevant — I don't think this mission will ever get off the ground. As well as generating revenue, the number of fee-paying applicants can convince broadcasters that there will be an audience for a Mars One television program, Lansdorp said. He points to the $4 billion generated by televising the three-week-long 2012 London Olympics as an example of how an ongoing worldwide media event can produce the enormous revenues Mars One needs. The foundation’s advisors and ambassadors include one of the co-creators of the Big Brother television show and a television producer in the United Kingdom with experience in various entertainment shows. "They are very, very impressed with the amount of feedback we are getting and...especially with our limited brand awareness, because if you ask people in the street in the U.K. or U.S., we have a brand awareness of 5-10 per cent," Lansdorp said of his potential media partners, "So with that in mind, they are extremely impressed with the people who are signing up and showing interest.” Lansdorp was insistent that there will be TV programs, “because we want the world to be involved in this adventure...We’re still under discussions with a number of parties on that so it could be an open thing, or it could be an exclusive thing where it's one broadcaster per country.” Mars One has several other revenue sources, including "silver sponsors" that advertise on the website, of which there are seven; its 22 contributors providing funds and in-kind services; Mars One-branded merchandise sales through the website; its Youtube channel hosting promotional videos; and crowdfunding. The foundation also has a 50/50 revenue-sharing agreement with Dutch audiovisual production company Tetteroo Media, which produced the pay-per-view independent documentary "One Way Astronaut." Lansdorp said he doesn't know how many people had paid the $2.95 to watch the documentary to date. In a phone call to Tetteroo Media on Monday (Aug. 26), the production company declined to say how many people had viewed the film. [Watch the film trailer for 'One Way Astronaut'] While Lansdorp declined to disclose how many hits Mars One's we bsite is getting, he told SPACE.com that the number is very attractive to potential sponsors. Meanwhile, crowdfunding is a work in progress, Lansdorp said. "That is one of things we’re preparing right now, and not just because of the funds, but also because this is mankind’s missions to Mars, and crowdfunding is one of the nicest ways to add people and really involve them in what you are doing, and that is very high on our things-to-do list," he said. More opportunities to apply Mars One will have more opportunities in the future to get application fees to help support its activities. The foundation plans to restart the application process after July 2015 to find 12 new people every year. Some of the 24 astronauts in the class of 2015 are expected to drop out, officials explained, and the colonization efffort needs to grow a steady supply of potential settlers. The Mars One website states that after this year’s Aug. 31 deadline, the next stage, round two, will require candidates to undergo an interview with a selection committee and have a physician confirm they are in good health. Those selected will join 20 to 40 others in their part of the world for regional selection rounds, which Mars One’s website states "could be broadcasted on TV and internet in countries around the world" and will involve "challenges that demonstrate their suitability to become one of the first humans on Mars." On Aug. 23, Lansdorp described the television aspect of this stage as "much more comparable to an election, a presidential election, where people decide who are our ambassadors to the red planet are,"than a reality show. The final fourth round, which will also be televised, will involve the Mars One selection committee creating international teams from the regional winners. Those groups will be expected to work together and demonstrate an ability to survive harsh conditions. The winners of that challenge will start training in 2015 as six teams of four for the 2023 Mars mission. Follow us @Spacedotcom, Facebook or Google+. Originally published on SPACE.com. ||||| Martian wannabes dust off those resumes: The application deadline for a one-way mission to Mars is almost here. While the prospect is off-putting to many, it's also the dream of a lifetime to some; more than 165,000 people have applied to join the manned Martian colony effort envisioned by the non-profit Mars One Foundation. But the foundation is only accepting applications until Aug. 31. ADVERTISEMENT ADVERTISEMENT After Aug. 31, Mars One officials will begin winnowing down the field of applicants — the only requirement to apply is to be over age 18 — to identify those most likely to thrive on the nine-month journey to the Red Planet, and in the settlement to be established upon arrival. [Mars One’s Red Planet Colony Project (Gallery)] "It's easily assumed that Mars One is only looking for pilots and engineers," Mars One chief medical officer Norbert Kraft said in a statement. "Don't disqualify yourself too easily. If you wish to be a Mars pioneer despite of the risks and challenges that come with this job, you are already more qualified than most people on this planet. It is most important that you are healthy and have the right mindset." Mission participants can hail from anywhere in the world, and the project has received applications from people representing more than 140 countries so far. The most applications — 37,852 — come from the United States, which represents about 23 percent of submissions, officials said, followed by China, Brazil, India, Russia, the United Kingdom, Mexico, Canada, Spain and the Philippines (10th on the list, with 3,516 applications). "The cultural diversity of Mars One applicants reflects the international nature of this project and ultimately makes it humanity's mission to Mars," Bas Lansdorp, CEO and co-founder of Mars One, said in a statement. Mars One plans to launch its first crew to the Red Planet in 2023. The team hopes to finance the huge cost of the operation in part through advertisement fees on a reality TV show following the astronaut selection process and the mission planning and training procedures. A new documentary, "One Way Astronaut," has already documented the early days of the application process for the ambitious Martian mission. The 19-week Round 1 application window opened in April, and initially Mars One officials said their goal was to gather half a million applications. Regional reviewers for Mars One plan to select 50-100 candidates in each of 300 geographic regions in the world to move on to the Round 2 stage of the application process. After two more selection rounds ending in 2015, between 28 and 40 Mars colonist candidates will be selected to be employed by Mars One. They will then begin training for the private Mars mission. Following seven years of training, a public vote will select the first group to be sent to Mars from among these finalists, foundation officials have said. You can apply for the Mars One mission here: http://www.mars-one.com/en/.

– Mars One, the heavily-hyped private expedition to Mars planned for 2023, hasn't quite found as many people willing to leave Earth forever as it had hoped. The project had expected 1 million people to jump at the chance to colonize the red planet; instead, just 165,000 applied, Space.com reports. That could be a problem, given that the nonprofit Mars One Foundation was planning on using the $38 application fees to help fund the project. Nevertheless, the company is forging ahead, and expects to cover the funding shortfall with a reality TV series following the astronaut selection and mission planning, Fox News reports. If you want to be one of the very first Martians, you have until the end of the month to apply—and you could be just who the project looking for. "It's easily assumed that Mars One is only looking for pilots and engineers," says Mars One's chief medical officer. "Don't disqualify yourself too easily. If you wish to be a Mars pioneer despite of the risks and challenges that come with this job, you are already more qualified than most people on this planet."

ovarian cancer represents the sixth most common malignancy as well as the seventh leading cause of cancer - related death in women worldwide [ 1 , 2 ] . in the usa , this neoplasm ranks second among gynecologic cancers , yet it is by far the most lethal one , accounting for more than 15,000 deaths annually . one of the major reasons underlying this dismal prognosis is the fact that nearly 75% of cases are diagnosed at an advanced stage ( i.e. , tumor already spread beyond the ovary ) [ 4 , 5 ] , despite great efforts to develop reliable screening and prevention strategies . to date , advanced ovarian cancer management has predominantly consisted of surgery followed by chemotherapy consisting of a combination of platinums and taxanes . more recently , neoadjuvant chemotherapy , a therapeutic alternative traditionally reserved for those patients considered poor candidates for upfront surgery , has emerged as a potential first - line option . even though up to 80% of these patients will respond to initial treatment , chemotherapy success rates after relapse range from 10% to 50% , depending on whether the tumor is platinum sensitive or resistant ( i.e. , a progression - free interval ( pfi ) following platinum - based first - line therapy of more or less than 6 months , resp . ) . thus , the 5-year overall survival ( os ) for late - stage disease is approximately 45% . since nonspecific therapies , namely , surgery , radiation , and conventional chemotherapy , have largely failed to achieve cure in the majority of patients affected by epithelial ovarian cancer , investigators have focused on developing novel treatment approaches . many of these new strategies are based upon an understanding of the critical molecules and pathways specifically involved in tumorigenesis and metastasis . this has led to the development of targeted oncologic therapies that might be ultimately more effective and less toxic . although significant overlap occurs , targeted therapies can be broadly divided into two categories : those focused on cellular mechanisms that are disregulated in carcinogenesis , those directed against the neoplasm 's microenvironment , a tumor component lately recognized as highly relevant in both cancer growth and dissemination . the present article addresses targeted therapies currently being employed or tested in epithelial ovarian cancer ( eoc ) . since their number has become as numerous as the myriad of critical pathways involved in ovarian neoplastic transformation , this review will focus on three of the most promising and/or well - studied targeted weapons in ovarian cancer therapeutics to date , namely , antiangiogenesis compounds , epidermal growth factor receptor ( egfr ) antagonists , poly ( adp ) ribose polymerase ( parp ) inhibitors . a comprehensive literature search was conducted using the following key terms : ovarian cancer , targeted therapies , antiangiogenesis , epidermal growth factor receptor ( egfr ) inhibitors , and poly ( adp ) ribose polymerase ( parp ) inhibitors . articles ' selection was limited to those written in english , without restriction to year of publication . the main analysis was focused on those studies providing clinical evidence , although preclinical data were included either when background information was required or when clinical assays were absent . highly valuable references cited by primarily collected studies as well as pivotal abstracts presented at prominent oncologic meetings , such as the society of gynecologic oncologists ( sgo ) , the american society of clinical oncology ( asco ) , the european society of gynaecological oncology ( esgo ) , and the international gynecologic cancer society ( igcs ) , were also assessed and their data incorporated whenever pertinent . angiogenesis ( i.e. , the formation of new blood vessels ) plays a critical role in cancer expansion and propagation . while many tumors start as avascular nodules , early data demonstrated that growth is impaired beyond 2 mm unless effective neovascularization is established . hence , this phenomenon appears to be a rate - limiting step in tumor progression . antiangiogenic therapies have been shown to inhibit new blood vessels development , induce endothelial cells apoptosis , and normalize vasculature . many components interact in this process , such as proangiogenic factors , metalloproteinases , and endothelial precursor cells . among angiogenesis - promoting molecules , the vascular endothelial growth factor ( vegf ) is the most sensitive and potent one , as well as the best characterized . it is overexpressed in many human tumors , including ovarian cancer . in ovarian malignancies , high levels of vegf have been associated with poor prognostic features , such as advanced stage , carcinomatosis , distant metastasis , as well as a decreased survival . thus , the vegf pathway has become one of the most attractive research areas in eoc therapeutics . preclinical data from animal models showed that vegf blockade was associated with inhibition of ascites formation and tumor growth . bevacizumab , a recombinant humanized monoclonal antibody directed against vegf - a , was the first of these agents to be evaluated in eoc . case reports and small series constituted the initial clinical evidence supporting its therapeutic value , mainly in recurrent , heavily pretreated patients [ 12 , 13 ] . based on these findings , two phase ii trials using single - agent bevacizumab in recurrent ovarian cancer , predominantly platinum - resistant disease , hypertension was the most common side effect documented , being usually well controlled with standard antihypertensive medication . however , two major complications emerged , gastrointestinal perforation and thromboembolic disease , both venous and arterial , ranging from 0% to 11% and 3% to 7% , respectively . indeed , one of the studies , cannistra et al . , carried out in heavily pretreated patients , was prematurely closed due to the high incidence of bowel perforation observed . this drug has been and continues to be tested in combination with chemotherapy , as a part of the first line treatment in newly diagnosed eoc and recurrent disease . table 1 both summarizes the most relevant past and ongoing trials conducted in this setting . other anti - vegf as well as non - vegf mediated antiangiogenic drugs are currently in clinical development . , to date antiangiogenesis appears as one of the most promising targeted strategies explored in eoc . given the encouraging initial results , bevacizumab has entered phase iii trial evaluation . meanwhile , it is considered a viable option in the recurrent setting . appropiate bevacizumab dose ( 7.5 versus 15 mg / kg ) and the ability to combine with other biologics require further study as well . adequate patient selection may potentially reduce the incidence of serious adverse events by excluding those at a highest risk for gastrointestinal perforation or a thromboembolic event . major risk factors for these two complications have been described ( table 3 ) , yet it should be noted that they still require further validation . the family of egf receptors ( egfrs ) is composed of 4 structurally similar receptors which exert a tyrosine kinase function : erbb1 ( commonly referred to as epidermal growth factor receptor ) , erbb2 ( her2/neu ) , erbb3 ( her3 ) , and erbb4 ( her4 ) . their activation triggers a cascade of events ultimately resulting in cell proliferation and survival . like vegf , egfrs ovarian cancer is not an exception , with up to 70% of cases exhibiting this aberrant phenotype , which has been linked to poor oncologic features and outcomes [ 5 , 7 , 29 ] . these observations have suggested that egfrs might represent a viable target for novel therapies in eoc . while blockade of these receptors can be achieved by several mechanisms , two of these have been most extensively explored : ( a ) small molecules capable of inhibiting the tyrosine kinase domain and ( b ) monoclonal antibodies directed against the extracellular region . preliminary preclinical data demonstrated antitumoral activity and a reversion of the chemoresistant phenotype secondary to egfr inhibition . nonetheless , and in contrast with the promising results obtained with anti - vegf therapies , to date clinical trials with egfr inhibitors alone have produced disappointing results . both are orally administrated and relatively well tolerated , which would represent a significant advantage in terms of patients ' quality of life . core findings from the most relevant trials conducted on these agents can be summarized as follows [ 3238 ] . an rr in recurrent ovarian cancer is of less than 10% along with stable disease in up to 44% of patients when used as single agents . these results were improved either when gefitinib was combined with standard chemotherapy or when erlotinib was combined with bevacizumab . the combination gefitinib - tamoxifen did not appear to add any clinical benefit . as a part of the first - line treatment in conjunction with a platinum and a taxane , either upfront or as consolidation therapy , tkis have yet to confirm a demonstrable survival advantage . the eortc has just finalized the recruitment of a phase iii trial exploring erlotinib as maintenance therapy in both high - risk early - stage and advanced diseases . in terms of side effects , the most frequently observed were diarrhea ( up to 30% , being the dose - limiting toxicity ) , nauseas and vomiting ( nearly 10% ) , and an acne - like cutaneous rash ( 5%15% ) , which interestingly correlated positively with tumor response . as noted above , the initial experience with these agents has not revealed a definitive role in the treatment of unselected eoc population , either in the first - line or the relapsed setting . however , a subgroup of patients showing an increased likelihood to respond to these compounds has been identified . in schilder 's trial , published in 2005 , clinical outcomes correlated with egfr status , with a significantly longer progression - free survival ( pfs ) as well as a trend in improved overall survival ( os ) among those who were egfr ( + ) . specifically , an enhanced response to gefitinib was linked to the presence of an infrequent mutation affecting the catalytic domain of this receptor . this relationship closely resembles what previously has been described in lung cancer [ 39 , 40 ] . thus , it has been suggested that prescreening patients for specific active egfr mutations could define the population most likely to benefit from this therapy . further investigation to validate this finding in eoc novel egfr inhibitors in development for eoc include lapatinib , canertinib , pki-166 , and ekb-569 . until better evidence supporting a relevant therapeutic value becomes available , the role of tkis in this neoplasm remains predominately confined to clinical trials . various humanized antibodies against the extracellular region of egfr have been thought to be potentially effective in eoc . nonetheless , similar to what has occurred with tkis , the theory has not been confirmed clinically . multiple initial studies confirmed that her-2/neu overexpression was associated with an adverse prognosis of patients with epithelial ovarian cancer [ 41 , 42 ] . trastuzumab , a selective her-2/neu inhibitor approved for the treatment of erbb 2 ( + ) metastatic breast cancer , was proposed to have antitumoral activity comensurate with that observed in breast cancer . further clinical evidence in a large gog trial , however , demonstrated a response rate of only 7% , with disease stabilization in other 39% of erbb 2(+ ) recurrent ovarian cancer patients . results obtained with other monoclonal antibodies , alone or in combination with standard chemotherapy , are outlined in table 4 . germline mutations affecting two genes , brca1 and brca2 , account for the vast majority of these cases . the lifetime risk of developing an epithelial ovarian carcinoma among women who carry these genetic defects has been estimated to be up to 60% . the proteins encoded by these tumor suppressor genes participate in multiple cellular processes , including transcription , cell cycle regulation , and repair of dna double - strand breaks . the enzyme poly ( adp ) ribose polymerase ( parp ) is a key component of this pathway . accordingly , its malfunction theoretically should not affect double - strand repair ; however , a persistent single - strand defect may ultimately result in dna replication interruption or a double - strand break . when this occurs in a cell that is already unable to repair dna damage , as the case for brca - defective cells , cell cycle arrest or death occurs . this observation , known as synthetic lethality , supports the contention that parp blockade would be therapeutically effective in hereditary eoc . this premise was initially confirmed in preclinical studies demonstrating a highly increased sensitivity to parp inhibition among brca - deficient cells , with a subsequent decreased cell survival , compared to those heterozygous or brca wild - type cells [ 53 , 54 ] . initial trials used these agents primarily as chemosensitizers , mainly in association with methylating compounds . however , with the demonstration of brca specific sensitivity , single - agent inhibitors were assessed . recently , final results of the first phase i trial evaluating olaparib , an orally administrated parp inhibitor , in brca - defective malignancies , including ovarian cancer , showed a low toxicity along with a response or disease stabilization rate of 63% . multiple parp inhibitors are currently being examined in phase ii trials . of interest , audeh et al . lately reported the interim analysis of a phase ii study employing olaparib in brca - deficient advanced ovarian cancer . overall 57% of patients demonstrated response to parp inhibition , using either recist or ca-125 criteria . potential use of parp inhibitors as chemoprophylactics in brca mutation carriers and for treating sporadic ovarian cancers has been proposed , as well . a potential barrier to parp inhibitors use has been the recently described emergence of resistance by reversal of the brca - deficient phenotype . women with epithelial ovarian cancer are living for longer periods of time than ever before . many cellular pathways have been implicated in ovarian carcinogenesis , and exploitation of these perturbations critical in forming or maintaining the malignant phenotype has yielded a number of promising compounds . however , to date only antiangiogenic agents have reached clinical relevance in eoc management . new therapeutic tools showing promising results , such as parp inhibitors that exploit the abnormality responsible for the initial neoplastic transformation , have demonstrated encouraging clinical potential . the mere presence of a particular molecule or pathway dysregulated in a particular tumor does not guarantee that its inactivation will have therapeutic benefit . response does not always translate into prolonged survival , symptom relief , or other valuable clinical endpoints . conversely , there may be significant improvements in time - to - event endpoints such as time - to - progression or pfs , and yet objective responses may be rare . thus different clinical parameters may be neccesary for efficacy assessment of targeted agents . given the multiplicity and redundancy of aberrant pathways involved in ovarian cancer , it is unlikely that inhibition of a single cascade will be highly effective . thus agents that act upon multiple levels or interconnected pathways simultaneously appear potentially more promising . the future of cancer therapeutics will likely include tailored , individualized treatments , designed on the basis of an even deeper understanding of the critical alterations in ovarian carcinogenesis . gene expression profiles have established that this neoplasia is far from being a uniform disease . thus , genotype - directed and pharmacogenomic therapies emerge as the next frontier for fruitful exploration and novel drug development .

epithelial ovarian cancer remains a major women 's health problem due to its high lethality . despite great efforts to develop effective prevention and early detection strategies , most patients are still diagnosed at advanced stages of disease . this pattern of late presentation has resulted in significant challenges in terms of designing effective therapies to achieve long - term cure . one potential promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis . this review examines three of the most provocative targeted therapies with current or future applicability in epithelial ovarian cancer .

wireless sensor networks ( wsn ) are known to have a broad range of applications such as environmental monitoring , battle - field surveillance and space exploration @xcite . a typical wireless sensor network is composed of numerous sensors with each sensor having limited on - board processing and communication capability . the sensors are usually randomly casted over a large field in space to sense the same physical event . in practice the sensing observations tend to be disturbed due to the noise from hardware device or environment . the noisy observations are collected by the fusion centers ( fc ) , where data fusion and further processing will be performed . the large amount of sensors are usually grouped into clusters , with each cluster formed by sensors located closely within a small neighborhood . within each cluster , a cluser - head(ch ) collects observations from other sensors free of error(this is reasonable since the cluster members lie in close vicinity ) and then transmit the collected data to fc . assume that hcs and fc are equipped with multiple antennas and linear transceivers , then a central question here is how to jointly design the transceivers to transmit the data reliably . this falls in the general problem of multi - input multi - output ( mimo ) transceiver(beamforming ) design problem , which has aroused a flurry of interest in recent years @xcite . we introduce the system model shown in fig . [ fig : sysmodel ] to capture the key characteristics of the afore - mentioned practical scenario . the event of interest @xmath0 is modeled as a complex scalar and sensed by a total of @xmath1 sensors ( cluster - members ) coming from @xmath2 clusters . these sensors communicate their imperfect sensing results to their respective cluster - heads . within each cluster @xmath3 , the observation distortion of the @xmath4 sensors are collectively modeled as an additive noise vector @xmath5 ( of size @xmath4 ) , which may have any distribution ( not necessarily gaussian ) . the cluster - head @xmath3 performs linear precoding @xmath6 to data before transmission with @xmath7 antennas . we assume that each cluster - head must conform to an individual transmission power constraint @xmath8 , in accordance to its specific power supply or battery life . it should be noted that , compared to a single overall power constraint for all the cluster - heads , the set of separate power constraints makes the model not only more practical , but also considerably harder . the mimo coherent - sum multiple access channel ( mac ) is considered for communications between cluster - heads and fusion center , which achieves a high bandwidth efficiency . the fading channel between the @xmath3-th cluster - head and the fusion center is denoted as @xmath9 . at the fusion center , the received signal is corrupted by additive noise @xmath10 ( of size @xmath11 ) . the fusion center performs linear postcoding @xmath12 to deduce an estimate @xmath13 . our goal is to jointly design the transceivers @xmath6 and @xmath14 to achieve a best estimate @xmath0 . the line of beamforming design in wsn research has actually received significant attention in recent years . a good variety of system setups have been investigated in the literature @xcite . compared to these existing literature , our system model is generally more generic and complicated . for example , @xcite considers the case where each cluster has only one sensor ( i.e. @xmath15 , @xmath16 ) and all cluster - heads and fusion center are equipped with one single antenna ( i.e. @xmath17 , @xmath16 and @xmath18 ) . under the total power constraint over all the cluster - heads , the transceiver design problem boils down to a power allocation problem . @xcite extends the scalar fading channel in @xcite to square nonsingular matrix channels , i.e. @xmath19 , @xmath20 . still all clusters share one total power constraint . note that the total power constraint over different clusters are usually nonrealistic since in practice different cluster - heads can be far away from each other without wired connections and are powered separately by build - in batteries . @xcite extends the research by employing separate power constraints for each cluster - head , but still restricts the channel matrices @xmath9 to be square and nonsingular . block coordinate descent(bcd ) algorithm is obtained in @xcite to solve the problem . several studies are particularly noteworthy @xcite . @xcite is the first to propose a very general wireless sensor network model , where separate power constraints are employed and each fading channel matrix @xmath9 can have arbitrary dimension(@xmath21 , @xmath22 or @xmath23 ) . @xcite studies solutions to several special but also rather meaningful cases including scalar channels , fading but noiseless channels and nonfading but noisy channels . @xcite focuses on the scalar target source with nonscalar fading and noisy channels and obtains an approximate bcd algorithm with fully closed form solution for each step . the work @xcite develop variant bcd algorithms to tackle the most general case proposed in @xcite , with convergence and closed form solutions being examined in @xcite . all the above works adopt mean square error(mse ) as performance metric . recently joint transceiver design problems aiming mutual information(mi ) maximization are studied in @xcite , where orthogonal and coherent - sumq mac are considered respectively . the primary interest of this paper is to solve the joint transceiver design problem for the system depicted in fig . [ fig : sysmodel ] . the previous studies in@xcite all used mse or mi as the design criterion , and many of them assume a single power constraint ( which renders an easier problem than separate power constraints ) . here we take the signal - to - noise ratio ( snr ) at the output of the fc postcoder @xmath14 as a figure of merit . the snr is an important performance indicator especially for discrete sources ( where mse becomes less meaningful ) . maximizing snr is equivalent to maximizing the symbol error rate ( ser ) in the discrete - source detection ; and in the special case of gaussian signaling , maximizing snr is also equivalent to maximizing the channel capacity . the joint optimization problem is first formulated . since it is non - convex , and since changing the design criterion ( e.g. snr instead of mse ) leads to a drastically different target function , the previous approaches and results can not be readily applied . instead , we develop three feasible methods , all of which stem from the celebrated block coordinated ascent ( bca ) principles , but each incorporates different techniques specifically tailored to the problem at hand , and renders computational strength in different scenarios . the rest of this paper is organized as follows . the problem is formulated is section [ sec : system model ] . the optimal linear receiver is obtained in section [ sec : opt_rec ] . two different realizations of 2-block coordinated ascent ( bca ) algorithm are discussed in section [ sec : opt_all_sensors ] , with their convergence being carefully examined . section [ sec : multiple_bca ] proposes a multiple - block coordinate ascent approach , which promises tremendous reduction in complexity for special system settings . extensive simulations are carried out to verify the effectiveness of the proposed algorithms in section [ sec : numerical results ] and section [ sec : conclusion ] concludes the whole paper . _ notations _ : we use bold lowercase letters to denote complex vectors and bold capital letters to denote complex matrices . @xmath24 , @xmath25 , and @xmath26 are used to denote zero vectors , zero matrices of dimension @xmath27 , and identity matrices of order @xmath28 respectively . @xmath29 , @xmath30 and @xmath31 are used to denote transpose , conjugate and conjugate transpose(hermitian transpose ) respectively of an arbitrary complex matrix @xmath32 . @xmath33 denotes the trace operation of a square matrix . @xmath34 denotes the modulus of a complex scalar , and @xmath35 denotes the @xmath36-norm of a complex vector . @xmath37 means vectorization operation of a matrix , which is performed by packing the columns of a matrix into a long one column . @xmath38 denotes the kronecker product . @xmath39 denotes the block diagonal matrix with its @xmath3-th diagonal block being the square complex matrix @xmath40 , @xmath41 . @xmath42 and @xmath43 denote the real and imaginary part of a complex value @xmath44 , respectively . we first discuss of the system model shown in fig.[fig : sysmodel ] and present a mathematical formulation of the optimization problem at hand . the system is composed of @xmath1 sensors with @xmath4 sensors belonging to the @xmath3th cluster , @xmath2 sensor - heads each equipped with @xmath7 transmitting antennas , and a fusion center equipped with @xmath11 receiving antennas . all sensors observe a common unknown source @xmath45 , and send their observation to their respective cluster - heads . without loss of generality , we assume @xmath0 has zero mean and unit variance , i.e. @xmath46 . the sensing noise and transmission noise ( to the @xmath3th cluster - head ) can be collectively modeled as an additive noise @xmath5 , such that the @xmath3th cluster - head observes : @xmath47 where @xmath48 is a vector of dimension @xmath49 with all the entries being @xmath50 , and @xmath5 denotes the additive noise vector with zero mean and covariance matrix @xmath51 , where @xmath52 . following the convention of wsn , we assume that @xmath5 s for the different clusters are mutually uncorrelated . the noisy observation @xmath53 is beamformed by a linear precoder @xmath54 at each cluster - head before being sent to the fusion center . let @xmath55 be the mimo channel state information ( csi ) from the @xmath3th cluster - head to the fusion center . suppose all the cluster - heads form a coherent - sum mac channel ; then the fusion center receives signal @xmath56 : @xmath57 where @xmath10 is the additive noise at the fusion center . without loss of generality , we assume @xmath10 has zero mean and white covariance matrix : @xmath58 . since the fusion center is usually far away from the sensing field , @xmath10 is assumed uncorrelated with @xmath5 s . in practice , it is highly likely that each cluster - head is provisioned with a different power supply and hence must observe a different transmission power constraint . the average transmission power for the @xmath3-th cluster - head is @xmath59 , which must be no greater than a power limit @xmath8 . the fusion center uses a linear postcoder @xmath14 to perform data fusion and obtain an estimate @xmath13 : @xmath60 the merit of the recovered signal @xmath13 can be evaluated from several different perspectives . when the source @xmath0 takes value from a continuous space , the most popular metric is the mean square error , defined as @xmath61 . mse - targeted optimization has also been extensively studied in the beamforming literature ( e.g. @xcite ) . instead of taking mse , here we target the average snr , another important metric widely used in the design of communication systems . when the source @xmath0 is taken from from a finite discrete alphabet set ( e.g. @xmath11-pam or @xmath11-qam ) , the detection accuracy is usually measured by the symbol error probability taking the form of @xmath62 , with @xmath63 and @xmath64 being some positive constants . when the source @xmath0 has gaussian distribution , the system throughput is usually measured by the mutual information between @xmath0 and its estimate @xmath13 , @xmath65 . hence , maximizing the snr automatically minimizes the ser ( for discrete source ) or maximizes the mutual information ( for gaussian source ) . from ( [ eq : received_theta ] ) , the signal obtained by the fusion center ( after linear postcoder @xmath14 ) is composed of a signal component and a noise component , and the average snr can be calculated and simplified to @xmath66\big[\sum_{j=1}^l\mathbf{h}_j\mathbf{f}_j\mathbf{1}_{k_j}\big]^h\mathbf{g}}{\sigma_0 ^ 2\|\mathbf{g}\|^2_2+\sum_{i=1}^{l}\mathbf{g}^h\mathbf{h}_i\mathbf{f}_i\mathbf{\sigma}_i\mathbf{f}_i^h\mathbf{h}_i^h\mathbf{g}},\label{eq : snr_func}\end{aligned}\ ] ] where the assumption of uncorrelated noise across the fusion center and different cluster - heads has been invoked . hence , the joint transceiver design problem maximizing snr for the clustered wireless sensor network can be formulated as [ eq : original_snr_prob ] @xmath67 the optimization problem ( @xmath68 ) is nonconvex , as can be easily examined by checking the special case of scalar transceivers . in what follows , we will exploit the general principle of block coordinate ascent method to solve ( @xmath68 ) in an iterative manner . in this section , we present the optimal linear receiver @xmath14 which leads to the maximal snr . the main result is as follows : [ thm : opt_g ] for any predefined @xmath69 , snr is maximized if and only if @xmath70 has the following form @xmath71 where @xmath72 is arbitrary nonzero complex scalar . the maximal snr is given as @xmath73 for simplicity we introduce the following notations @xmath74 with all sensors beamformers @xmath75 given , the snr maximization problem is the following optimization problem @xmath76 since @xmath77 , define @xmath78 . the above problem becomes @xmath79 from variational perspective , the maximal value of the above fractional is obtained if and only if @xmath80 is aligned with eigen - vector corresponding to the maximal eigenvalue of the matrix @xmath81 @xcite . notice that matrix @xmath81 is rank - one and has only one positive eigenvalue whose eigen - vector is @xmath82 , with @xmath72 being any nonzero complex value . thus the optimal solution of the above problem is @xmath83 , from which ( [ eq : opt_g ] ) and ( [ eq : opt_snr_g ] ) can be readily obtained . in practice the factor @xmath72 can be chosen as 1 for convenience . after obtaining the optimal linear receiver @xmath14 , we focus on optimizing precoders at the sensors side in this section . first by utilizing the identities @xmath84 and @xmath85{\mathsf{vec}}\big(\mathbf{b}\big)$ ] @xcite , the numerator of @xmath86 in ( [ eq : snr_func ] ) can be rewritten as follows @xmath87\bigg[\sum_{j=1}^l\mathbf{h}_j\mathbf{f}_j\mathbf{1}_{k_j}\bigg]^h\mathbf{g}\nonumber\\ \!\!\!\!\!\!&=\sum_{i , j=1}^{l}{\mathsf{tr}}\big\{\big(\mathbf{h}_j^h\mathbf{g}\mathbf{g}^h\mathbf{h}_i\big)\mathbf{f}_i\big(\mathbf{1}_{k_i}\cdot\mathbf{1}_{k_j}^t\big)\mathbf{f}_j^h\big\}\\ \!\!\!\!\!\!&\!=\!\sum_{i , j=1}^{l}\!\!{\mathsf{vec}}^h\big(\mathbf{f}_j\big)\bigg[\big(\mathbf{1}_{k_j}\!\!\cdot\!\!\mathbf{1}_{k_i}^t\big)\!\otimes\!\big(\mathbf{h}_j^h\mathbf{g}\mathbf{g}^h\mathbf{h}_i\big)\bigg]{\mathsf{vec}}\big(\mathbf{f}_i\big).\end{aligned}\ ] ] similarly the denominator of @xmath86 can be written as @xmath88{\mathsf{vec}}\big(\mathbf{f}_i\big)\!+\!\sigma_0 ^ 2\|\mathbf{g}\|^2_2,\end{aligned}\ ] ] and the @xmath3-th power constraint is expressed as @xmath89{\mathsf{vec}}\big(\mathbf{f}_i\big)\leq p_i.\nonumber\end{aligned}\ ] ] here we introduce the following notations [ eq : definition_fabcc ] @xmath90,\ i , j\!=\!1,\cdots , l;\label{eq : definition_fabcc_a}\\ \!\!\!\!\!\!\mathbf{b}_{i}&\triangleq\big[\mathbf{\sigma}_i^*\otimes\big(\mathbf{h}_i^h\mathbf{g}\mathbf{g}^h\mathbf{h}_i\big)\big],\ \ i=1,\cdots , l;\\ \!\!\!\!\!\!\mathbf{c}_i&\triangleq\big[\big(\big(\mathbf{1}_{k_i}\!\cdot\!\mathbf{1}_{k_i}^t\big)\!\!+\!\!\mathbf{\sigma}_{i}^*\big)\!\otimes\!\mathbf{i}_{n_i}\big],\ \ i=1,\cdots , l;\\ \!\!\!\!\!\!c_0&\triangleq \sigma_0 ^ 2\|\mathbf{g}\|^2_2.\end{aligned}\ ] ] and define the matrix @xmath91_{i , j=1}^{l}$ ] , ( i.e. the @xmath92-th elementary block of @xmath32 is @xmath93 ) , @xmath94 and @xmath95 and pack all @xmath96 s into one vector @xmath97^t$ ] . then the problem of optimizing beamformers @xmath75 with @xmath14 given is reformulated as follows [ eq : opt_prob_p1 ] @xmath98 in the following we discuss methods solving the problem ( @xmath99 ) . in this subsection we solve problem ( @xmath101 ) with help of recent progress in semidefinite relaxation techniques . first we rewrite the quadratic terms @xmath102 , @xmath103 and @xmath104 in ( @xmath99 ) into inner - product forms @xmath105 , @xmath106 and @xmath107 respectively by introducing an intermediate variable @xmath108 . omitting this rank - one constraint , a relaxation of ( @xmath99 ) is obtained as follows @xmath109 the fractional semidefinite programming ( sdp ) objective in ( @xmath110 ) is still nonconvex . to solve it , we utilize charnes - cooper s approach , which was originally proposed in @xcite and subsequently adopted in many fractional sdp optimization problems like @xcite@xcite . this turns ( @xmath110 ) into the following sdp problem : @xmath111 the equivalence between ( @xmath110 ) and ( @xmath112 ) is established by the following lemma . [ lem : p2_p3_equivalent ] the problem ( @xmath113 ) and ( @xmath114 ) have equal optimal values . if @xmath115 solves ( @xmath113 ) , then @xmath116 is an optimal solution to ( @xmath114 ) . conversely , if @xmath117 solves ( @xmath114 ) , then @xmath118 and @xmath119 solves ( @xmath113 ) . see appendix [ subsec : appendix_lem_p2_p3_equivalent ] . since ( @xmath112 ) is sdp problem , it can be solved by standard numerical solvers like cvx @xcite . remember that our goal is to solve problem ( @xmath99 ) . if the optimal solution @xmath120 to ( @xmath112 ) is rank - one , then the relaxation ( @xmath110 ) is tight to ( @xmath99 ) and the optimal solution of ( @xmath99 ) can be obtained by eigenvalue decomposition of @xmath121 . when the optimal solution @xmath120 has rank larger than one , constructing a solution to ( @xmath99 ) from @xmath122 still needs to be addressed . to introduce our first major conclusion we need the following lemma . [ lem : p3_solvability ] the problem ( @xmath114 ) and its dual are both solvable . see appendix [ subsec : appendix_lem_p3_solvability ] . for wireless sensor network with small number sensor clusters , we have the following conclusion . [ thm : l_less_3 ] if the wireless sensor network has no more than @xmath123 sensor clusters , i.e. @xmath124 , then the relaxation ( @xmath113 ) is tight with respect to ( @xmath100 ) . an optimal solution @xmath117 to ( @xmath114 ) with @xmath125 being rank - one can be constructed and solution to ( @xmath100 ) can be obtained by eigenvalue - decomposing @xmath119 . the proof is inspired by theorem 3.2 of @xcite . if @xmath120 has rank one , nothing needs to be proved . otherwise since the problem ( @xmath112 ) and its dual ( @xmath126 ) are both solvable by lemma [ lem : p3_solvability ] , theorem 3.2 of @xcite is valid to invoke . define @xmath127 and perform the following procedure : * * while * @xmath128 * do * + _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ * * perform a full rank decomposition @xmath129 , where @xmath130 ; * * find a nonzero pair @xmath131 , where @xmath132 is a @xmath133 hermitian matrix and @xmath134 is real scalar , such that the following linear equations are satisfied @xmath135 * * evaluate @xmath136 ; * * update @xmath137 , @xmath138 and @xmath127 ; _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ * * end while * in fact ( @xmath139 ) has two semidefinite variables @xmath140 and @xmath141(note that @xmath141 is actually a nonnegative real scalar ) and @xmath142 constraints . as long as the condition @xmath143 holds , nonzero solutions to ( [ eq : linear_eq1 ] ) and ( [ eq : linear_eq2 ] ) exist . thus after each repetition a new optimal solution is constructed with @xmath144 being reduced by at least 1 . finally we obtain @xmath145 . recall that @xmath118 by lemma [ lem : p2_p3_equivalent ] , so @xmath146 and we have @xmath147 . so @xmath148 and the theorem is proved . in the above , we have seen that ( @xmath99 ) can be tackled by solving a sdp problem and then a finite number of linear equations when @xmath124 . however the assumption that @xmath124 is still very stringent since in practice a sensor network can usually be composed of numerous clusters . a method to solve ( @xmath101 ) suitable for arbitrary @xmath2 is still desirable . in the sequel , we proceed to discuss randomization method inspired by the recent literature @xcite . before going into details , first we modify the problem ( @xmath112 ) a little bit . by changing the equality constraint ( [ eq : p3_constr1 ] ) into inequality , we have another sdp problem ( @xmath149 ) as follows @xmath150 we assert that ( @xmath139 ) and ( @xmath151 ) are equivalent and for any solution @xmath117 to ( @xmath149 ) , @xmath152 must be positive . in fact since ( @xmath149 ) is a relaxation of ( @xmath112 ) , @xmath153 . conversely , if @xmath122 is an optimal solution to ( @xmath149 ) , then the constraint ( [ eq : p4_constr1 ] ) must indeed be active . otherwise , @xmath120 and @xmath152 could be simultaneously inflated with a factor @xmath154 such that @xmath155 satisfies all constraints of ( @xmath149 ) with ( [ eq : p4_constr1 ] ) being active and gives an strictly larger objective , which contradicts the optimality of @xmath122 . so @xmath122 is feasible for ( @xmath112 ) and thus @xmath156 . consequently ( @xmath112 ) and ( @xmath149 ) have equal optimal value . this means solution to either problem also solves the other one . thus any solution @xmath122 to ( @xmath149 ) is also a solution to ( @xmath112 ) and by lemma [ lem : p2_p3_equivalent ] , @xmath118 . assuming that we have obtained an optimal solution @xmath122 to ( @xmath149 ) , we now generate a sufficiently large number of independent complex random variables following the gaussian distribution @xmath157 . the intuition behind randomization comes from the observation of the following stochastic optimization problem @xmath158 by utilizing the relation @xmath159 , the stochastic problem ( @xmath160 ) actually becomes the sdp problem ( @xmath149 ) . the random variable @xmath161 solves the problem ( @xmath149 ) in expectation . thus if we have a sufficiently large number of samples , the `` best '' sample should solve the problem . the `` best '' sample can be found as follows . first , note that random samples are not always feasible for ( @xmath149 ) . this issue can be addressed by the following rescaling procedure . for each sample @xmath162 , we define the scaling factor @xmath163 as @xmath164 and rescale the sample @xmath162 as @xmath165 it is easy to check that the obtained @xmath166 is guaranteed to be feasible for ( @xmath149 ) . thus by performing the above rescaling procedure we can obtain a large number of feasible samples to approximate the optimal solution @xmath120 . then we choose the one giving maximal objective value as solution to the problem ( @xmath99 ) . when the number of samples is sufficiently large , the obtained best objective value of ( @xmath151 ) by rescaled random samples can be extremely close to true optimal value of ( @xmath151 ) so the randomization solution can be regarded as tight to the original problem ( @xmath99 ) . in retrospect to the previous discussion , the motivation of transforming the problem ( @xmath112 ) into its equivalent ( @xmath149 ) now becomes clear . for implementation there is no chance that the randomly generated samples will satisfy the equality constraint ( [ eq : p3_constr1 ] ) . at the same time the positivity of @xmath152 guarantees that the rescaling in ( [ eq : rescaling_2 ] ) can be performed . up to here , we have actually come out an alternative maximization method to solve the snr optimization problem ( @xmath68 ) in ( [ eq : original_snr_prob ] ) . the algorithm starts from a random feasible point . in each iteration @xmath14 is optimized in a closed form by theorem [ thm : opt_g ] with @xmath167 being fixed and @xmath167 are optimized by solving ( @xmath112 ) followed by randomization - rescaling or solving linear equations with @xmath14 given . this algorithm is summarized in algorithm @xmath168 as follows . * initialization * : randomly generate nonzero feasible @xmath169 such that @xmath170 obtained by theorem [ thm : opt_g ] is also nonzero ; @xmath171 in the last subsection , we solve the problem ( @xmath101 ) with help of semidefinite relaxation by first solving its sdp relaxation and than construct the rank - one solution through solving linear equations or randomization method . in this subsection , we propose an alternative method which to solve ( @xmath99 ) in an iterative manner . first we have the following conclusion [ lem : a_rank1 ] matrix @xmath172 in ( @xmath100 ) is rank - one . specifically @xmath173 with the vector @xmath174 being given as @xmath175.\end{aligned}\ ] ] see appendix [ subsec : appendix_lem_a_rank1 ] . now looking at the fractional sdp objective of ( @xmath99 ) we have the following observation . for any given nonnegative real value @xmath176 , the snr is no smaller than @xmath176 is equivalent to the fact @xmath177 in other words , if @xmath178 , then there exits some @xmath179 such that the inequality ( [ eq : snr_larger_w ] ) and all power constraints @xmath180 for @xmath181 are simultaneously satisfied . if we define @xmath182 as follows @xmath183 then the fact that all power constraints are satisfied is equivalent to @xmath184 . thus the statement @xmath185 holds if and only if the following optimization problem ( @xmath186 ) [ eq : frac_power_min_prob ] @xmath187 has optimal value smaller than @xmath50 , i.e. @xmath188 . next we show that all constraints of problem ( @xmath186 ) can be written in a second order cone form . the constraint ( [ eq : frac_power_min_prob_constr1 ] ) , utilizing the result of lemma [ lem : a_rank1 ] , can be written as @xmath189 another key observation is that the optimal @xmath190 to ( @xmath186 ) is phase invariant@xmath191 is optimal solution to ( @xmath186 ) if and only if @xmath192 is optimal for any real value @xmath0 . so without loss of optimality we assume that @xmath193 with @xmath194 being a nonnegative real value . thus the constraint ( [ eq : socp_constr1 ] ) readily becomes the second order cone @xmath195\big\|_2\leq v$ ] . for the @xmath3-th power constraint in ( [ eq : frac_power_min_prob_constr2 ] ) , it can also be written in a second order cone form @xmath196 . thus the problem ( @xmath186 ) can be equivalently written in a standard second - order cone programming ( socp ) form : [ eq : p7gamma ] @xmath197 \left [ \begin{array}{c } \mathbf{f } \\ 1 \end{array } \right]\right\|_2\leq v , \\ & \mathsf{re}\{\mathbf{a}^h\mathbf{f}\}=v , \\ & \mathsf{im}\{\mathbf{a}^h\mathbf{f}\}=0 , \\ & \big\|\sqrt{p_i^{-1}}\mathbf{d}_i^{\frac{1}{2}}\mathbf{f}\big\|_2\leq u,\ i=1,\cdots , l.\end{aligned}\ ] ] thus if we know that the @xmath198 lives in some interval , then @xmath198 can be determined by a bisection search we set @xmath176 as middle point of the current search interval , if ( @xmath199 ) , then @xmath198 can achieve higher value and @xmath176 is a lower bound of @xmath198 . otherwise @xmath176 upper - bounds @xmath198 . now the remaining problem is to determine an interval containing @xmath198 , from which the bisection search can start with . since ( @xmath99 ) is maximization problem , any feasible solution gives a lower bound of @xmath198 . the following lemma provides an upper bound of @xmath198 . [ lem : opt_p1_upperbound ] optimal value of ( @xmath100 ) has an upper bound as follows @xmath200 see appendix [ subsec : appendix_lem_opt_p1_upperbound ] . thus we have obtained an alternative method to solve the original problem ( @xmath68 ) , which also falls in the 2-block bca framework . the steps are summarized in algorithm [ alg:2bca_socp ] . * initialization * : randomly generate nonzero feasible @xmath169 such that @xmath170 obtained by theorem [ thm : opt_g ] is also nonzero ; @xmath171 the two 2-block bca algorithms developed in the previous subsections have the following convergence property : [ thm:2bca_convergence ] the sequence of snr obtained by algorithm [ alg:2bca_sdr ] or [ alg:2bca_socp ] converges . moreover the solution sequence generated by algorithm [ alg:2bca_sdr ] or [ alg:2bca_socp ] has limit points and each limit point is a stationary point of problem ( @xmath201 ) . see appendix [ subsec : appendix_thm_2bca_convergence ] . the complexity of the proposed algorithms is complicated since the whole network has too many factors ( @xmath4 s and @xmath7 s ) that impact the problem size . to simplify the analysis , we consider homogeneous sensor networks , where each cluster has the same number of sensors and each cluster - head has the same the number of antennas , i.e. @xmath202 and @xmath203 for all @xmath204 . using the primal - dual interior point method @xcite , we can show that the complexity to solve ( @xmath149 ) is @xmath205 . the complexity to update @xmath14 by ( [ eq : opt_g ] ) comes primarily from the matrix inversion operation , which has a complexity @xmath206 . in general , a few thousand of random samples are sufficient to guarantee a satisfying tightness of the obtained rank - reduced solutions ( usually within @xmath207 from the true optimal value ) , and the required number of samples does not increase with the network size . thus , the complexity for each outer - layer iteration of the sdp - based 2bca algorithm is @xmath208 . from @xcite , the complexity for solving the socp problem ( @xmath209 ) is @xmath210 . recall that each round of bisection search solves ( @xmath209 ) once , so ( @xmath209 ) is solved multiple times within one outer - layer iteration . taking different channel conditions and levels of predefined precision into account , numerical results show that the number of times solving ( @xmath209 ) varies between the narrow range @xmath211 $ ] and thus can be considered as a constant . thus the complexity of outer - layer socp - based 2bca algorithm is @xmath212 . in the previous sections , the proposed algorithms are both 2-block coordinate ascent methods where all the beamformers sensors are jointly updated . one problem for these algorithms is that the complexity of solving the associated sdp or socp problem grows intensively with the increase of the size of the wireless sensor network . instead of jointly optimizing all beamformers , we can alternatively focus on just one sensor s beamformer each time . this actually results in a multiple - block bca approach , which , despite the many subproblems involves , often involves a lower complexity ( see complexity analysis and numerical results ) . specifically , for the case of @xmath213 ( 1 sensor in the @xmath3-th cluster ) , the solution to the @xmath3th block is quickly obtained in a closed form , requiring no numerical solvers . now we consider the problem of optimizing the @xmath3-th beamformer @xmath6 with @xmath14 and @xmath214 being fixed . by introducing the following notations [ eq : def_qcd ] @xmath215 this problem is formulated as follows @xmath216 first we introduce a one - shot method to solve ( @xmath217 ) , which performs semidefinite programming and rank - one matrix decomposition in tandem . this method is discussed in recent work @xcite and @xcite . by use of charnes - cooper s transformation and rank - one relaxation we turn ( @xmath217 ) into the following relaxed version @xmath218 with parameter matrices being defined as [ eq : def_q1234 ] @xmath219 , \mathbf{q}_2\triangleq\left [ \begin{array}{cc } \mathbf{b}_{i } & \mathbf{0 } \\ \mathbf{0}^t & d_i \\ \end{array } \right ] , \\ \mathbf{q}_3&\triangleq\left [ \begin{array}{cc } \mathbf{c}_{i } & \mathbf{0 } \\ \mathbf{0}^t & 0 \\ \end{array } \right ] , \mathbf{q}_4\triangleq\left [ \begin{array}{cc } \mathbf{o } & \mathbf{0 } \\ \mathbf{0}^t & 1 \\ \end{array } \right].\end{aligned}\ ] ] solving the sdp ( @xmath220 ) we obtain an solution @xmath221 . if the @xmath222 is rank one , i.e. @xmath223 with @xmath224^t$ ] , then @xmath225 is an solution to ( @xmath217 ) and the relaxation ( @xmath220 ) is actually tight with respect to ( @xmath217 ) . actually the rank - one solution @xmath222 always exits due to the recent matrix decomposition result in @xcite . in fact if @xmath222 has rank larger than one , by help of theorem 2.2 in , we can obtain a vector @xmath226 such that the equations @xmath227 , @xmath228 for @xmath229 . this means @xmath230 is rank - one optimal solution to ( @xmath220 ) and thus ( @xmath217 ) can be solved . besides the above one - shot method , here we propose an alternative iterative method to solve ( @xmath217 ) . as we will shortly see this iterative method can give birth to extremely efficient solution to ( @xmath217 ) in specific circumstance . for any given positive real value @xmath72 , the fact that the snr objective in ( @xmath217 ) is no smaller than @xmath72 equivalently reads @xmath231\mathbf{f}_i\!-\!2\mathsf{re}\big\{\mathbf{q}_i^h\mathbf{f}_i\big\}\!+\!(\alpha d_i\!-\!c_i)\leq0 . \end{aligned}\ ] ] this immediately implies that if the following problem with [ eq : opt_prob_p_i ] @xmath232\mathbf{f}_i\!\!-\!2\mathsf{re}\big\{\mathbf{q}_i^h\mathbf{f}_i\big\}\!\!+\!\!(\alpha d_i\!\!-\!\!c_i ) , \\ \!\!\mathsf{s.t.}&\ \mathbf{f}_i^h\mathbf{c}_i\mathbf{f}_i\leq p_i . \end{aligned}\ ] ] with @xmath72 given has a nonnegative optimal value then @xmath233 . otherwise @xmath72 can serve as an upper bound of @xmath234 . thus we can perform a bisection search to solve ( @xmath217 ) . now the problem reduces to how to solve the problem ( @xmath235 ) ? note that the quadratic matrix @xmath236 $ ] can be negative semidefinite or indefinite and thus ( @xmath235 ) is possibly nonconvex . the following theorem convinces us that ( @xmath237 ) can always be solved regardless of the convexity of its objective . [ thm : solvability_s_pros ] if the @xmath3-th sensor cluster has more than one sensor or the head is equipped with multiple antenna , i.e. @xmath238 or @xmath239 , the problem ( @xmath240 ) can be solved . see appendix [ subsec : appendix_thm_solvability_s_pros ] . although theorem [ thm : solvability_s_pros ] shows that the problem ( @xmath235 ) can be solved by sdr and thus the iterative method to solve ( @xmath217 ) works , it is generally less efficient than the one - shot method discussed above . since the former performs semidefinite programming and rank - one reductions multiple times while the latter for just once . however in the circumstance where @xmath15 , the following theorem indicates that ( @xmath235 ) has fully closed form solution and consequently the iterative method can become extremely efficient . [ thm : closedform_p_i_d1 ] when @xmath15 , denote @xmath241 and @xmath242 as scalars @xmath243 and @xmath244 respectively . the solution @xmath245 to ( @xmath240 ) is @xmath246 with @xmath247 and @xmath248 being defined as follows @xmath249 see appendix [ subsec : appendix_thm_closedform_p_i_d1 ] . note that the closed - form solution in theorem [ thm : closedform_p_i_d1 ] neither requires matrix decomposition or solving linear equations(matrix inversion ) nor depends on numerical solver . thus iteratively solving ( @xmath217 ) is easy for implementation and has very low computation cost . comparatively , the one - shot method for solving ( @xmath217 ) depends on numerical solvers ( like cvx ) which are iterative - based ( interior point method ) solvers with each iteration performing matrix decomposition and solving linear equations . to start the bisection search , the latest snr can serve as a lower bound for @xmath234 . from ( [ eq : bd_norm_f_i ] ) , we can derive an upper bound for @xmath234 : @xmath250 note that the above upper bound can be much tighter than the one given in ( [ eq : p1_upperbound ] ) since it utilizes the knowledge of @xmath214 . from the above discussion , we can utilize multi - block bca method to solve the original problem ( @xmath68 ) . in each update , we tackle either one individual precoder ( associated with one cluster ) or the poster ( associated with the fc ) . if the @xmath3-th cluster has @xmath251 sensors , then its precoder can be updated by the one - shot sdr - rank - reduction method ; otherwise , theorem [ thm : closedform_p_i_d1 ] provides a clean closed - form solution . the entire approach is summarized in algorithm [ alg : multiple_bca ] . * initialization * : randomly generate nonzero feasible @xmath169 such that @xmath170 obtained by ( [ eq : opt_g ] ) is nonzero although the multiple bca method generates monotonically increasing snr sequence , it is hard to prove that the limit points of its solution sequence guarantee to converge to stationary points of ( @xmath68 ) . numerical results in section [ sec : numerical results ] show that multiple bca algorithm usually has a very satisfying convergence behaviors . by primal - dual inter point method @xcite , the complexity of each outer - layer iteration of multiple bca for homogeneous wireless sensor network is @xmath252 . particularly for homogeneous network with @xmath253 , the complexity becomes @xmath254 with the help of theorem [ thm : closedform_p_i_d1 ] . in this section , numerical results are presented to testify the proposed algorithms performance . in our experiments , the observation noise at each sensor is colored , which has a covariance @xmath255 where the @xmath256 matrix @xmath257 has the toeplitz structure @xmath258.\end{aligned}\ ] ] the parameter @xmath259 is set to @xmath260 for all sensors in the following experiments . here we define the observation signal to noise ratio at the @xmath3-th sensor as @xmath261 and the channel signal to noise ratio as @xmath262 . in figure [ fig : avg_snr_sdr_vs_socp ] and [ fig : avg_snr_sdr_vs_l_bca ] the average snr obtained at the fc are plotted . it is assumed that the sensor network has 5 sensors and fc has 4 antennas . we set @xmath263 , @xmath264 and @xmath265 . for each fixed channel snr level , 50 random channel realizations are generated with each element of channel matrix follows circularly symmetric complex gaussian distribution with zero mean and covariance 2 . with channel snr and channel matrices given , the proposed algorithms are performed starting from one common random initial . the obtained average snr is plotted in figure [ fig : avg_snr_sdr_vs_socp ] and [ fig : avg_snr_sdr_vs_l_bca ] . the obtained average snr of sdr based and socp based 2bca algorithms are plotted in figure [ fig : avg_snr_sdr_vs_socp ] with respect to different outer iterations . the curve associated with random initials actually represents the performance of random feasible linear transmitters . from figure [ fig : avg_snr_sdr_vs_socp ] , optimized snr converges in 10 outer - iterations on average . these two algorithms have identical average convergence performance , this will also be verified by figure [ fig : initials_snr_sdr_vs_socp ] . the average snr performance obtained by multiple bca algorithm is presented in figure [ fig : avg_snr_sdr_vs_l_bca ] , where sdr based 2bca algorithm serves as a benchmark . multiple bca algorithm presents identical average snr performance with the other 2 block algorithms . in figure [ fig : initials_snr_sdr_vs_socp ] and [ fig : initials_snr_sdr_vs_l_bca ] , the impact of different initial points to the algorithms are examined . the system setup is identical with the experiment in figure [ fig : avg_snr_sdr_vs_socp ] and [ fig : avg_snr_sdr_vs_l_bca ] . we set the channel snr as 2db and fix the channel matrices with one specific random realization . the three proposed algorithms are started from 10 different random initials and each snr itinerary with respect to number of outer - layer iterations is plotted in figure [ fig : initials_snr_sdr_vs_socp ] and [ fig : initials_snr_sdr_vs_l_bca ] , where the itineraries of sdr based 2bca algorithm serve as benchmarks . from figure [ fig : initials_snr_sdr_vs_socp ] it can be seen that the two 2bca algorithms have almost identical snr itineraries . comparatively , multiple bca algorithm s itineraries are usually very different but finally it will converge to identical value . figures [ fig : initials_snr_sdr_vs_socp ] and [ fig : initials_snr_sdr_vs_l_bca ] reflect the fact that : the proposed three algorithms are initial - insensitive ; they finally converge to identical snr value ; and usually 30 iterations are sufficient for these proposed algorithms to converge . , width=364,height=288 ] , width=364,height=288 ] next we present numerical results for complexity . still we take homogeneous wireless sensor network as example . @xmath266 and @xmath11 denote the number of antennas for each sensor or sensor cluster and fc respectively and take modest values within several tens . comparatively the number of sensors or sensor clusters can be large , and one cluster can have numerous sensors . so we focus on the impact of @xmath2 and @xmath267 on the complexity . figure [ fig : complexity_k ] and [ fig : complexity_l ] represent the complexity for each outer - layer iteration for proposed algorithms with respect to @xmath267 and @xmath2 respectively . generally sdr based 2bca algorithm has higher complexity than the two others . the socp based algorithm has lowest complexity for large @xmath267 with small @xmath2 and multiple bca algorithm has the lowest complexity for large @xmath2 . in the following the average execution time of proposed algorithms using matlab with the standard toolbox cvx v2.1 on the same computer are presented in table [ tab : runtime_1 ] and [ tab : runtime_2 ] . the multiple bca algorithm requires much lower time for networks with large @xmath2 and socp based 2bca algorithm is more efficient for large @xmath267 and small @xmath2 . although the complexity of sdr - based 2bca algorithm increases drastically with the increase of @xmath267 , @xmath266 and @xmath2 in general , it can still be useful in specific scenarios . note that when the size of wireless sensor network is small , the execution time of sdr based 2bca algorithm mainly comes from random samples generation and rescaling . in the case where parallel computation is available , this procedure can requires very little time and thus competitive to the other two algorithms . [ cols="^,^,^,^,^,^,^",options="header " , ] [ tab : runtime_2 ] + note : `` '' means the problem is too large to be solved . + alg.1 : sdr-2bca alg . ; alg.2 : socp-2bca alg . ; alg.3 : multiple bca alg . this paper considers the joint transceiver design problem in cluster based wireless sensor network . to maximize the output snr at the fusion center , the difficult original problem is decomposed into two or more subproblems and solution to each subproblem is obtained . convergence and complexity are carefully examined . extensive numerical results show that the proposed algorithms provide equivalently good snr values while have different efficiency characteristics and suitable for various system settings . as an extension of current problem , robust design and decentralized algorithms are desirable and meaningful for future study . first we claim that @xmath118 . this can be proved by contradiction . if @xmath271 , then we readily obtain @xmath272 , for @xmath181 . this leads to @xmath273 . since it is assumed that @xmath52 , for @xmath274 , it holds that @xmath275 , for @xmath274 . thus @xmath276 and we obtain @xmath277 . however this violates the constraint ( [ eq : p3_constr1 ] ) , since its left hand side equals zero . thus @xmath118 . if @xmath122 solves ( @xmath112 ) , since @xmath118 , it is easy to check @xmath278 is feasible for ( @xmath110 ) and gives an objective value of @xmath279 . so @xmath280 . on the other hand , if @xmath268 solves ( @xmath110 ) , then @xmath281 is a feasible solution to ( @xmath112 ) and gives objective value of @xmath282 . so @xmath283 . the proof is complete . first we prove that ( @xmath112 ) is solvable . by ( [ eq : p3_constr1 ] ) we have @xmath284 , so @xmath141 is bounded . combining ( [ eq : p3_constr2 ] ) we readily obtain @xmath285 , @xmath274 , which implies @xmath286 . since @xmath287 , this means @xmath140 is bounded . so the feasible region of ( @xmath112 ) is bounded . obviously the feasible region of @xmath288 is also closed . so ( @xmath112 ) has compact feasible region . since the objective @xmath289 always takes finite values on the whole feasible region , by weierstrass theorem(proposition 3.2.1-(1 ) in @xcite ) , ( @xmath112 ) is solvable . the lagrangian function of problem ( @xmath112 ) is given as @xmath290\mathbf{y}\big\}\!+\!\big(-c_0\lambda\!+\!\sum_{i=1}^{l}p_i\mu_i\big)\nu\!+\!\lambda.\nonumber\end{aligned}\ ] ] by taking the supremum of lagrangian function with respect to @xmath291 and @xmath292 , the dual function is obtained as @xmath293 with the conditions @xmath294\preccurlyeq0 $ ] and @xmath295 satisfied . so the dual problem of ( @xmath112 ) can be given as next we prove that ( @xmath126 ) is solvable . to do this it is sufficient to show that there exists a real value @xmath176 such that the level set @xmath297 is nonempty and bounded , where @xmath298 means feasible region of ( @xmath126 ) . here we choose @xmath299 for @xmath181 , where @xmath300 and @xmath300 represent the maximal and minimal eigenvalue of a matrix respectively . set @xmath301 . by definition the constraints ( [ eq : d3_constr2 ] ) and ( [ eq : d3_constr3 ] ) are satisfied by @xmath302 . since @xmath303 and @xmath304 , @xmath305 thus constraint ( [ eq : d3_constr1 ] ) is also satisfied by @xmath302 . set @xmath306 . combination of @xmath307 and the constraint ( [ eq : d3_constr2 ] ) guarantees that @xmath308 and all @xmath309 s are bounded . so we conclude that the level set @xmath310 is nonempty and bounded . invoking weierstrass theorem(proposition 3.2.1-(2 ) in @xcite ) , ( @xmath126 ) is solvable . recalling the definition of @xmath93 in ( [ eq : definition_fabcc_a ] ) and utilizing the identity @xmath311 @xcite , we have @xmath312 then the @xmath313-th block column of @xmath32 is given as @xmath314 \!=\!\left[\ ! \big(\mathbf{1}_{k_1}\otimes\mathbf{h}_1^h\mathbf{g}\big)\big(\mathbf{1}^t_{k_j}\otimes\mathbf{g}^h\mathbf{h}_j\big)\\ \vdots\\ \big(\mathbf{1}_{k_l}\otimes\mathbf{h}_l^h\mathbf{g}\big)\big(\mathbf{1}^t_{k_j}\otimes\mathbf{g}^h\mathbf{h}_j\big ) \end{array } \!\right]\\ \!\!\!\!\!\!&\!=\!\left[\ ! \begin{array}{c } \big(\mathbf{1}_{k_1}\otimes\mathbf{h}_1^h\mathbf{g}\big)\\ \vdots\\ \big(\mathbf{1}_{k_l}\otimes\mathbf{h}_l^h\mathbf{g}\big ) \end{array } \!\right]\big(\mathbf{1}^t_{k_j}\otimes\mathbf{g}^h\mathbf{h}_j\big)\\ & \!=\!\mathbf{a}\big(\mathbf{1}^t_{k_j}\otimes\mathbf{g}^h\mathbf{h}_j\big).\end{aligned}\ ] ] the last equality utilizes the definition of @xmath315 in ( [ eq : def_a ] ) . then the matrix @xmath32 can be represented by packing all its column blocks as follows @xmath316\\ & = \big [ \mathbf{a}\big(\mathbf{1}_{k_1}^t\otimes\mathbf{g}^h\mathbf{h}_1\big),\cdots,\mathbf{a}\big(\mathbf{1}_{k_l}^t\otimes\mathbf{g}^h\mathbf{h}_l\big ) \big]\\ & = \mathbf{a}\big[\big(\mathbf{1}_{k_1}^t\otimes\mathbf{g}^h\mathbf{h}_1\big),\cdots,\big(\mathbf{1}_{k_l}^t\otimes\mathbf{g}^h\mathbf{h}_l\big)\big]\\ & = \mathbf{a}\mathbf{a}^h.\end{aligned}\ ] ] the proof is complete . by the @xmath3-th power constraint ( [ eq : opt_prob_p1_constr2 ] ) we have @xmath317 which implies @xmath318 by cauchy - schwarz inequality the numerator @xmath102 of snr is bounded as @xmath319 where the above first inequality uses lemma [ lem : a_rank1 ] . combining the fact that @xmath320 , the upper bound in the lemma is proved . since each update of @xmath75 or @xmath14 is obtained by solving a maximization problem , snr monotonically increases . at the time we note that snr is bounded . in fact since the snr is invariant to scaling of @xmath14 we can assume that @xmath321 . according to ( [ eq : f_i_bound ] ) in the proof of lemma [ lem : opt_p1_upperbound ] , @xmath6 is bounded for all @xmath181 . thus the numerator of snr is bounded above and the denominator of snr is bounded away from zero , so snr should be bounded . consequently the objective value sequence by algorithms [ alg:2bca_sdr ] or [ alg:2bca_socp ] converges since it is monotonically increasing and bounded . since @xmath75 are bounded , by bolzano - weierstrass theorem @xcite there exists a sequence @xmath322 such that @xmath323 converges . since @xmath324 is updated by ( [ eq : opt_g ] ) which is a continuous function of @xmath325 , thus the sequence @xmath326 also converges . the existence of limit points of the solution sequence is proved . the feasible region of ( @xmath68 ) is a cartesian product @xmath327 with @xmath328 and @xmath329 . corollary 2 in @xcite states that any limit point of solution sequence generated by 2-block coordinate ascent method is stationary . it should be noted that this conclusion is obtained under the assumption that the objective function is continuously differentialbe on feasible region and each block feasible region(each term in the cartesian product ) is nonempty , closed and convex set . unfortunately the problem ( @xmath68 ) does not satisfy this assumption since @xmath330 is nonconvex and not closed . in the following we will show that conclusion in @xcite still applies to our problem after appropriately adjusting its argument . first we assert that the solution sequence always has nonzero @xmath14 , i.e. @xmath331 for all @xmath332 . since algorithms [ alg:2bca_sdr ] or [ alg:2bca_socp ] starts from @xmath333 with @xmath334 , the assertion holds for @xmath335 and @xmath336 . assume that @xmath337 is the smallest integer such that @xmath338 , then according to ( [ eq : opt_g ] ) @xmath339 . notice @xmath340 . by ( [ eq : snr_func ] ) this readily implies @xmath341 , which contradicts the increasing monotonicity of snr . next we assert that any limit point @xmath342 of solution sequence has nonzero @xmath343 . by contradiction we assume that the subsequence @xmath326 converges to @xmath342 with @xmath344 . then by ( [ eq : opt_g ] ) @xmath345 . by rescaling each @xmath324 to @xmath346 such that @xmath347 for all @xmath348 , we actually construct another solution sequence which is also generated by 2-block coordinate ascent method , since scaling of @xmath14 does not change the snr value . now for this new solution sequence @xmath349 , since @xmath345 while @xmath350(consequently the denominator of snr ) is bounded away from zero , we have @xmath351 , which again contradicts the increasing monotonicity of snr sequence . in @xcite the closedness assumption of @xmath330 is implicitly invoked in its proposition 2 to ensure that any limit point of solution sequence is feasible . through the above proof we can see that this result holds true thus proposition 2 in @xcite applies to our problem . the convexity assumption of @xmath330 is explicitly utilized in @xcite in its proof of proposition 3 . here we identify the notations @xmath3 , @xmath352 , @xmath353 and @xmath354 used in the original proof of proposition 3 in @xcite as @xmath50 , @xmath14 , @xmath330 and @xmath355 respectively in our case . according to the proof in @xcite , we can find a descent direction @xmath356 with @xmath357 and @xmath358 ( ( [ eq : conv_proof_contrad_2 ] ) corresponds to the inequality @xmath359 in the original proof of proposition 3 in @xcite , which lies under equation ( 11 ) and is not labeled with number ) . then by armijo - type line search we can update @xmath360 with @xmath361 , where @xmath362 and @xmath363 $ ] . the convexity of @xmath330 in @xcite guarantees that @xmath364 . now we show that the fact @xmath364 still holds for our problem although our @xmath330 is nonconvex . by contradiction assume that @xmath365 , i.e. @xmath366 this is actually impossible . by substituting @xmath356 into ( [ eq : conv_proof_contrad_1 ] ) we have @xmath367 as a result of armijo - type line search algorithm(refer to ( 3 ) and proposition 1 in @xcite ) , @xmath368 . if @xmath369 , then @xmath370 , which contradicts the fact @xmath357 . if @xmath371 , then @xmath372 . this is also impossible since @xmath86 is invariant to scaling of @xmath14 and thus @xmath373 , which contradicts the fact ( [ eq : conv_proof_contrad_2 ] ) . thus the proposition 3 in @xcite also stands for our problem . since the problem ( @xmath235 ) is a quadratic problem with one quadratic constraint and is obviously strictly feasible , the result of appendix b.1 in @xcite is valid to invoke , which states that ( @xmath235 ) has the following relaxation @xmath374\!\mathbf{x}\!\big\}\!\!-\!\!2\mathsf{re}\big\{\!\mathbf{q}_i^h\mathbf{x}\big\}\!\!+\!\!(\alpha d_i\!\!-\!\!c_i\ ! ) , \\ \mathrm{s.t.}\ & { \mathsf{tr}}\big\{\mathbf{c}_i\mathbf{x}\big\}-p_i\leq0 , \\ & \left [ \begin{array}{cc } \mathbf{x } & \mathbf{x } \\ \mathbf{x}^h & 1 \end{array } \right]\succeq 0.\end{aligned}\ ] ] @xmath380 , \mathbf{p}_2\!\!\triangleq\!\ ! \left[\!\ ! \begin{array}{cc } \mathbf{c}_i & \mathbf{0 } \\ \mathbf{0}^t & 0 \end{array } \!\!\right ] , \mathbf{p}_3\!\!\triangleq\!\ ! \begin{array}{cc } \mathbf{o } & \mathbf{0 } \\ \mathbf{0}^t & 1 \end{array } \!\!\right].\nonumber\end{aligned}\ ] ] since @xmath275 , the feasible set of ( @xmath381 ) is bounded . obviously the objective of ( @xmath381 ) takes finite value over the feasible set , so ( @xmath381 ) is solvable by weierstrass s theorem(proposition 3.2.1-(1 ) in @xcite ) . assume that @xmath382 is one optimal solution . obviously @xmath382 is non - zero(otherwise constraint @xmath383 would fail ) . since @xmath382 has dimension @xmath384 , evoking theorem 2.2 of @xcite , we can obtain a vector @xmath385 such that @xmath386 for @xmath387 . denote @xmath388^t$ ] . notice that @xmath389 is nonzero(otherwise the constraint @xmath390 would fail ) . define @xmath391^t$ ] , it is easy to check that @xmath392 where @xmath393 denotes the objective function of ( @xmath235 ) and @xmath394 . the above two equations imply that @xmath395 is an optimal solution to ( @xmath235 ) since which gives optimal value @xmath396 and is feasible . the key observation is that the quadratic matrix @xmath401 in the objective function has rank one and thus an eigenvalue decomposition as follows @xmath402\mathbf{u}^h,\label{eq : rank_1_eigendcmps_1}\end{aligned}\ ] ] with @xmath403 $ ] being eigenvectors of @xmath401 . the first eigenvector @xmath404 corresponds to the unique nonzero eigenvalue and the other eigenvectors span the null space of @xmath401 . in other words , we have @xmath405 since @xmath406 is an orthonormal basis , @xmath96 can be represented as @xmath407 with vector @xmath408 being the coordinates in terms of basis @xmath409 . by ( [ eq : rank_1_eigendcmps_2 ] ) the objective of ( @xmath410 ) is independent of @xmath411 . to save power , we should set all @xmath411 as zero , which means @xmath412 . thus , the problem ( @xmath410 ) boils down to the following problem with respect to one complex scalar @xmath413 based on the sign of @xmath415 , the problem ( @xmath416 ) can be tackled in the following three cases : in this case , the objective function in @xmath417 degenerates to an affine function @xmath418 by the cauchy - schwarz inequality , the optimal @xmath419 and minimum objective is obtained as @xmath420 when @xmath421 by denoting @xmath422 the objective function is equivalently written as @xmath423 . to minimize @xmath424 , @xmath413 should be along the direction of @xmath425 . depending on whether the zero point of the absolute term in ( [ eq : opt_prob_p12i_2 ] ) satisfies the power constraint , two subcases are examined : ) if @xmath426 , the optimum is given as [ eq : opt_sol_p12i_case2_1 ] @xmath427 ) if @xmath428 , the optimum is given as @xmath429 still @xmath413 should be along the direction of @xmath430 , and takes full power . at this time the optimum is literally identical with ( [ eq : opt_sol_p12i_case2_2 ] ) in the above . y. liu , j. li , x. lu and c. yuen , `` optimal linear precoding and postcoding for mimo multi - sensor noisy observation problem , '' in _ ieee international conference on communications(icc ) _ , sydney , jun . a. s. behbahani , a. m. eltawil , h. jafarkhani , `` linear decentralized estimation of correlated data for power - constrained wireless sensor networks , '' _ ieee trans . signal process . 11 , pp . 6003 - 6016 , y. liu , x. lu and j. li and c. yuen , `` joint transceiver design for noisy - sensing decision - fusion networks through block coordinate descent optimization , '' available online : http://arxiv.org/abs/1409.7122 . j. fang , h. li , z. chen and y. gong , `` joint precoder design for distributed transmission of correlated sources in sensor networks , '' , _ ieee trans . wireless commun . , _ vol . 12 , no . 6 , pp . 2918 - 2929 , june 2013 . a. de maio , y. huang , d. p. palomar , s. zhang , and a. farina , `` fractional qcqp with applications in ml steering direction estimation for radar detection , '' _ ieee trans . signal process . 172 - 185 , jan . 2011 . c. jeong , i. kim , and d. i. kim , `` joint secure beamforming design at the source and the relay for an amplify - and - forward mimo untrusted relay system , '' _ ieee trans . signal process . 310 - 325 , jan . 2012

this paper investigates the transceiver design problem in a noisy - sensing noisy - transmission multi - input multi - output ( mimo ) wireless sensor network . consider a cluster - based network , where multiple sensors scattering across several clusters will first send their noisy observations to their respective cluster - heads ( ch ) , who will then forward the data to one common fusion center ( fc ) . the cluster - heads and the fusion center collectively form a coherent - sum multiple access channel ( mac ) that is affected by fading and additive noise . our goal is to jointly design the linear transceivers at the chs and the fc to maximize the signal - to - noise ratio ( snr ) of the recovered signal . we develop three iterative block coordinated ascent ( bca ) algorithms : 2-block bca based on semidefinite relaxation ( sdr ) and rank reduction via randomization or solving linear equations , 2-block bca based on iterative second - order cone programming ( socp ) , and multi - block bca that lends itself to efficient closed - form solutions in specific but important scenarios . we show that all of these methods optimize snr very well but each has different efficiency characteristics that are tailored for different network setups . convergence analysis is carried out and extensive numerical results are presented to confirm our findings .

the @xmath1 meson first observed by the cdf collaboration at fnal @xcite is expected to be copiously produced in the future experiments at hadron colliders @xcite with facilities oriented to the study of fine effects in the heavy quark interactions such as the parameters of cp - violation and charged weak current mixing . so , one could investigate the spectroscopy , production mechanism and decay features of @xmath1 @xcite with the incoming sample of several billion events . in such circumstances , in addition to the current success in the experimental study of decays with the cp - violation in the gold - plated mode of neutral @xmath3-meson by the babar and belle collaborations @xcite allowing one to extract the ckm - matrix angle @xmath4 in the unitarity triangle , a possible challenge is whether one could get an opportunity to extract some information about the ckm unitarity triangle from the @xmath1 physics in a model independent way or not . the theoretical principal answer is one can do it . indeed , there is an intriguing opportunity to extract the angle @xmath0 in the model - independent way using the strategy of reference triangles @xcite in the decays of doubly heavy hadrons . this ideology for the study of cp - violation in @xmath1 decays was originally offered by m.masetti @xcite , independently investigated by r.fleischer and d.wyler @xcite and extended to the case of doubly heavy baryons in @xcite . let us point out necessary conditions to extract the cp - violation effects in the model - independent way . 1 . interference . the measured quantities have to involve the amplitudes including both the cp - odd and cp - even phases exclusive channels . the hadronic final state has to be fixed in order to isolate a definite flavor contents and , hence , the definite matrix elements of ckm matrix , which can exclude the interference of two cp - odd phases with indefinite cp - even phases due to strong interactions at both levels of the quark structure and the interactions in the final state . 3 . oscillations . the definite involvement of the cp - even phase is ensured by the oscillations taking place in the systems of neutral @xmath3 or @xmath5 mesons , wherein the cp - breaking effects can be systematically implemented . 4 . tagging . once the oscillations are involved , the tagging of both the flavor and cp eigenstates is necessary for the complete procedure . the gold - plated modes in the decays of neutral @xmath3 mesons involve the oscillations of mesons themselves and , hence , they require the time - dependent measurements . in contrast , the decays of doubly heavy hadrons such as the @xmath1 meson and @xmath6 baryons with the neutral @xmath7 or @xmath8 meson in the final state do not require the time - dependent measurements . the triangle ideology is based on the direct determination of absolute values for the set of four decays , at least : the decays of hadron in the tagged @xmath7 meson , the tagged @xmath8 meson , the tagged cp - even state can be used , too . however , their registration requires the detection of cp - even state of @xmath9 , which can be complicated because of a detector construction , say , by a long base of @xmath9 decay beyond a tracking system . ] of @xmath7 , and the decay of the anti - hadron into the tagged cp - even state of @xmath7 . to illustrate , let us consider the decays of @xmath10 the corresponding diagrams with the decay of @xmath11-quark are shown in figs . [ fig:1 ] and [ fig:1a ] . we stress that two diagrams of the decay to @xmath7 have the additional negative sign caused by the pauli interference of two charmed quarks , which , however , completely compensated after the fierz transformation for the corresponding dirac matrices . ( 90,25 ) ( -10,0)=55 ( 33,0)=55 ( -2.3,6.5)@xmath12 ( 34.,6.5)@xmath13 ( 34.2,21)@xmath7 ( 47.2,6.55)@xmath12 ( 67.5,6.6)@xmath7 ( 67.5,18.1)@xmath13 ( 5.,11.5)@xmath14 ( 15.,2.)@xmath15 ( 26.,20.8)@xmath16 ( 27,15.)@xmath15 ( 29,11.5)@xmath17 ( 53.5,12)@xmath14 ( 63.5,11.5)@xmath16 ( 57.5,2)@xmath15 ( 63.2,20.2)@xmath17 ( 63,14.2)@xmath15 ( 90,25 ) ( -10,2)=55 ( 42,1)=55 ( -2.3,8.5)@xmath12 ( 34.,8.5)@xmath13 ( 34.2,23)@xmath8 ( 48.2,13.9)@xmath12 ( 87.5,4.2)@xmath13 ( 87.5,23.6)@xmath8 ( 5.,13.5)@xmath14 ( 15.,4.)@xmath15 ( 26.,22.8)@xmath15 ( 27,17.)@xmath16 ( 29,13.5)@xmath17 ( 56.5,16.7)@xmath14 ( 73.5,9.5)@xmath17 ( 56.5,12)@xmath15 ( 73.2,18.7)@xmath16 ( 83,16.8)@xmath15 ( 83,12.)@xmath15 the exclusive modes make the penguin terms to be excluded , since the penguins add an even number of charmed quarks , i.e. two or zero , while the final state contains two charmed quarks including one from the @xmath11 decay and one from the initial state . however , the diagram with the weak annihilation of two constituents , i.e. the charmed quark and beauty anti - quark in the @xmath18 meson , can contribute in the next order in @xmath19 as shown in fig . [ fig:1a ] for the given final state . nevertheless , we see that such the diagrams have the same weak - interaction structure as at the tree level . therefore , they do not break the consideration under interest . the magnitude of @xmath19-correction to the absolute values of corresponding decay widths is discussed in section [ sec:2 ] . thus , the cp - odd phases of decays under consideration are determined by the tree - level diagrams shown in figs . [ fig:1 ] and [ fig:1a ] . therefore , we can write down the amplitudes in the following form : @xmath20 where @xmath21 denote the cp - even factors depending on the dynamics of strong interactions . using the definition of angle @xmath0 @xmath22,\ ] ] for the cp - conjugated channels , which corresponds to fixing the representation of the ckm matrix , e.g. by the wolfenstein form @xcite . ] we find @xmath23 we see that the corresponding widths for the decays to the flavor tagged modes coincide with the cp - conjugated ones . however , the story can be continued by using the definition of cp - eigenstates for the oscillating @xmath2 system mesons are irrelevant here , and we can neglect them in the sound way . ] , @xmath24 so that we straightforwardly get @xmath25 \sqrt{2}{\cal a}(b^-_c\to d_s^- d_1 ) \stackrel{\mbox{\tiny def}}{= } \sqrt{2 } { \cal a}_{d_1}^{\mbox{\sc cp } } & = & e^{-2{\rm i}\gamma } { \cal a}_{d}+{\cal a}_{\bar d}. \label{eq:6}\end{aligned}\ ] ] the complex numbers entering ( [ eq:5 ] ) and ( [ eq:6 ] ) establish two triangles with the definite angle @xmath26 between the vertex positions as shown in fig . [ fig:3 ] . ( 80,50 ) ( 10,7)=75 ( 32,4)@xmath27 ( 68,22)@xmath28 ( 51.,14)@xmath29 ( 44.5,33)@xmath30 ( 7,23)@xmath31 thus , due to the unitarity , the measurement of four absolute values @xmath32 |{\cal a}_{d_1}| = |{\cal a}(b^+_c\to d_s^+ d_1)| , & \quad & |{\cal a}_{d_1}^{\mbox{\sc cp}}| = |{\cal a}(b^-_c\to d_s^- d_1)|,\end{aligned}\ ] ] can constructively reproduce the angle @xmath0 in the model - independent way . the above triangle - ideology can be implemented for the analogous decays to the excited states of charmed mesons in the final state . the residual theoretical challenge is to evaluate the characteristic widths or branching fractions . we address this problem and analyze the color structure of amplitudes . so , we find that the matrix elements under interest have the different magnitudes of color suppression , so that at the tree level we get @xmath33 and @xmath34 , while the ratio of relevant ckm - matrix elements , @xmath35 with respect to the small parameter of cabibbo angle , @xmath36 , which one can easily find in the wolfenstein parametrization @xmath37 v_{cd } & v_{cs } & v_{cb } \\[2 mm ] v_{td } & v_{ts } & v_{tb } \end{array}\right ) = \left(\begin{array}{ccc } 1-\frac{1}{2}\lambda^2 & \lambda & a \lambda^3 ( \rho-{\rm i}\eta ) \\[2 mm ] -\lambda & 1-\frac{1}{2}\lambda^2 & a \lambda^2 \\[2 mm ] a \lambda^3 ( 1-\rho-{\rm i}\eta ) & -a \lambda^2 & 1 \end{array}\right).\ ] ] nevertheless , the interference of two diagrams in the decays of @xmath18 to the @xmath7 meson is destructive , and the absolute values of the amplitudes @xmath28 and @xmath27 become close to each other . thus , we expect that the sides of the reference - triangles are of the same order of magnitude , which makes the method to be an attractive way to extract the angle @xmath0 . in section [ sec:2 ] we classify the diagrams for the decays of doubly heavy meson @xmath18 by the color and weak - interaction structures . section [ sec:3 ] is devoted to the numerical estimates in the framework of qcd sum rules . the results are summarized in conclusion . in the framework of @xmath38-expansion we have got the following scaling rules of color structures in the processes with the hadrons composed of the quark and anti - quark : 1 . the meson wavefunction @xmath39 2 . the coupling constant @xmath40 3 . the casimir operators @xmath41 4 . the fierz relation for the generators of su(@xmath42 ) group in the fundamental representation @xmath43 next , the non - leptonic weak lagrangian has a form typically given by the following term @xcite : @xmath44 where @xmath45 , and the wilson coefficients @xmath46 in the @xmath38-expansion . then , we can proceed with the analysis of decays under interest . two diagrams shown in fig . [ fig:1 ] scale with the different order in @xmath38 , so that @xmath47 more definitely we get the color factors @xmath48 where @xmath49,\\[1 mm ] a_2 & = & \frac{1}{2n_c}\,\left[c_+(n_c+1)-c_-(n_c-1)\right].\end{aligned}\ ] ] nevertheless , we have to calculate both diagrams in order to take into account their interference which is not suppressed by any kinematical factors except the color factor of @xmath38 . two diagrams shown in fig . [ fig:1a ] also scale with the different order in @xmath38 , so that @xmath50 more definitely we get the color factors @xmath51 where we have explicitly included the @xmath19 correction . however , we can easily find that due to the virtualities of quarks and gluons the kinematical suppression of second diagram in fig . [ fig:1a ] is given by the factor of @xmath52 where @xmath53 is the characteristic value of wavefunction , the gluon virtuality is determined by the expression @xmath54 with @xmath55 being the masses of the mesons in the initial and final states , respectively , and the virtuality of quark line connected to the virtual gluon is of the order of @xmath56 therefore , @xmath57 therefore , the above @xmath19-corrections can be neglected to the leading order in the @xmath58-expansion . finally , in this section we have analyzed the color and weak - interaction structures of decay amplitudes and isolate those of the largest magnitude , while the numerical estimates are presented in the next section . in this section we use the machinery of qcd sum rules @xcite in order to calculate the widths and branching ratios for the gold - plated modes under study . the calculations of exclusive non - leptonic modes usually involves the approximation of factorization @xcite , which , as expected , can be quite accurate for the @xmath1 , since the quark - gluon sea is suppressed in the heavy quarkonium . thus , the important parameters are the factors @xmath59 and @xmath60 in the non - leptonic weak lagrangian , which depend on the normalization point suitable for the @xmath1 decays . in this way , we , first , calculate the form factors in the semileptonic transitions @xcite and , second , evaluate the non - leptonic matrix elements in the factorization approach . we accept the following convention on the normalization of wave functions for the hadron states under study , i.e. for the pseudoscalar ( @xmath61 ) and vector ( @xmath62 ) states : @xmath63 & & \langle 0|{\cal j}_\mu|v\rangle = \epsilon_\mu\ , f_v\,m_v,\end{aligned}\ ] ] where @xmath64 denote the leptonic constants , so that they are positive , @xmath65 @xmath66 is a four - momentum of the hadron , @xmath67 is a polarization vector of @xmath62 , @xmath68 is its mass , and the current is composed of the valence quark fields constituting the hadron @xmath69 in this respect we can easily apply the ordinary feynman rules for the calculations of diagrams , so that the quark - meson vertices in the decay channel are chosen with the following spin structures : @xmath70 then , we get general expressions for the hadronic matrix elements of weak currents in the exclusive decays of @xmath71 and @xmath72 with the definitions of form factors given by the formulae @xmath73 where @xmath74 and @xmath75 . the form factors @xmath76 are dimensionless , while @xmath77 and @xmath78 has a dimension of inverse energy , @xmath79 is of the energy dimension . in the case of nonrelativistic description for both initial and final meson states we expect that @xmath80 f^a_0 > 0 , & f^a_+ < 0 , & f^a_- > 0 . \end{array}\ ] ] it is important to note that for the pseudoscalar state the hermitian conjugation in ( [ pseudo ] ) does not lead to the change of sign in the right hand side of equation because of the prescription accepted , since the conjugation of imaginary unit takes place with the change of sign for the momentum of meson ( the transition from the out - state to in - one ) . the same speculations show that the spin structure of matrix element in the quark - loop order does not involve a functional dependence of form factors on the transfer momentum squared except of @xmath79 , so that we expect that the simplest modelling in the form of the pole dependence can be essentially broken for @xmath79 , while the other form factors are fitted by the pole model in a reasonable way . following the standard procedure for the evaluation of form factors in the framework of qcd sum rules @xcite , in the @xmath1 decays we consider the three - point functions @xmath81 where @xmath82 and @xmath83 denote the interpolating currents for the final states mesons . the standard procedure for the evaluation of correlators and form factors is described in @xcite . the most important notes are the following @xcite : * for the heavy quarkonium @xmath84 , where the relative velocity of quark movement is small , an essential role is taken by the coulomb - like @xmath85-corrections . * we have found that the normalizations of leptonic constants for the heavy quarkonia are fixed by the appropriate choice of effective constant for the coulomb exchange @xmath86 , while the stability is very sensitive to the prescribed value of heavy quark mass . thus , these parameters of sum rules are extracted from the two - point qcd sum rules with a quite good accuracy . * in the framework of two - point sum rules for the heavy - light channel the fixed value of threshold energy @xmath87 determines the binding energy of heavy quark in the meson , @xmath88 gev , which yields the same value of mass for the beauty quark , @xmath89 gev , as it was determined from the analysis of two - point sum rules in the @xmath90 channel . however , taking into account the second order corrections in @xmath91 , we find that the mass of charmed quark is shifted to the value of @xmath92 gev in the heavy - light channel in comparison with the @xmath93 states . thus , in the transition of @xmath1 to the charmed meson we put the mass of spectator charmed quark equal to @xmath92 gev . * in the framework of the effective theory of heavy quarks with the expansion in the inverse masses of the heavy quarks @xcite , the spin symmetry relations between the form factors in the soft limit of zero recoil momentum can be derived @xcite . * we take the following ordinary ratios of leptonic constants for the vector and pseudoscalar states and for the heavy - strange mesons : @xmath94 which agree with both the lattice computations @xcite and the estimates in the framework of potential models taking into account relativistic corrections @xcite . * the leptonic constant of @xmath1 is taken from a scaling relation for the heavy quarkonia @xcite . [ cols="^,^,^,^,^,^,^",options="header " , ] in the above estimates we put the following values of parameters : * the leptonic constants : @xmath95 * the ckm elements : @xmath96 so that the numbers can be appropriately scaled at other values of input parameters . in the btev @xcite and lhcb @xcite experiments one expects the @xmath1 production at the level of several billion events . therefore , we predict @xmath97 decays of @xmath1 in the gold - plated modes under interest . the experimental challenge is the efficiency of detection . one usually get a 10%-efficiency for the observation of distinct secondary vertices outstanding from the primary vertex of beam interaction . next , we have to take into account the branching ratios of @xmath98 and @xmath7 mesons . this efficiency crucially depends on whether we can detect the neutral kaons and pions or not . so , for the @xmath98 meson the corresponding branching ratios grow from 4% ( no neutral @xmath99 and @xmath100 ) to 25% . the same interval for the neutral @xmath7 is from 11 to 31% . the detection of neutral kaon is necessary for the measurement of decay modes into the cp - odd state @xmath101 of the neutral @xmath7 meson , however , we can omit this cross - check channel from the analysis dealing with the cp - even state of @xmath102 . the corresponding intervals of branching ratios reachable by the experiment are from 0.5 to 1.3% for the cp - even state and from 1.5 to 3.8% for the cp - odd state of @xmath7 . the pessimistic estimate for the product of branching ratios is about @xmath103 , which results in @xmath104 reconstructed events . thus , an acceptance of experimental facility and an opportunity to detect neutral pions and kaons as well as reliable estimates of total cross section for the @xmath1 production in hadronic collisions are of importance in order to make expectations more accurate . in this work we have shown how the reference - triangle ideology can be used for the model - independent extraction of ckm - matrix angle @xmath0 from the set of branching ratios of doubly heavy meson @xmath1 exclusively decaying to the neutral @xmath5 mesons . tagging the flavor and cp - eigenstates of such the @xmath5 mesons allows one to avoid the uncertainties caused by the qcd dynamics of quarks . we have estimated the characteristic branching ratios in the framework of qcd sum rules , which yields the values of the order of @xmath105 \approx 5\cdot 10^{-6}.\ ] ] accepting the above value , and putting the efficiency of tagging procedure equal to 0.5% for the neutral charmed meson and 4% for the charmed strange meson in the final state as well as the vertex reconstruction efficiency equal to 10% , we can expect the observation of about 10 reconstructed events per year at the lhc collider in such the experiment like lhcb or in btev experiment at fnal . the author thanks prof . r.dzhelyadin for the possibility to visit cern in collaboration with the lhcb group , to which members i express a gratitude for a hospitality . i am grateful to profs . a.k.likhoded and m.a.ivanov for clarifications and a cooperation , to prof . v.f.obraztsov , yu.gouz , o.yushchenko and v.romanovsky for useful discussions and valuable remarks . * * f. abe et al . , cdf collaboration , phys . lett . * 81 * , 2432 ( 1998 ) , phys . rev . * d58 * , 112004 ( 1998 ) . s.s.gershtein et al . , sov . j. nucl . bf 48 , 327 ( 1988 ) , yad . fiz . * 48 * , 515 ( 1988 ) ; 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the model - independent method based on the triangle ideology is implemented to extract the ckm - matrix angle @xmath0 in the decays of doubly heavy long - lived meson @xmath1 . we analyze a color structure of diagrams and conditions to reconstruct two reference - triangles by tagging the flavor and cp eigenstates of @xmath2 mesons in the fixed exclusive channels . the characteristic branching ratios are evaluated in the framework of qcd sum rules .

Updated 10:30 p.m. Officials still don’t know what motivated a 34-year-old man, Aaron Alexis, to open fire Monday morning at the Washington Navy Yard, killing 12 people and wounding a number of others. Authorities initially said they were looking for two other suspects or persons of interest, but as the day wore on, D.C. police said they were certain Alexis acted alone. “We do now feel comfortable that we have the single and sole person responsible for the loss of life inside the base today,” said Police Chief Cathy Lanier. The victims range in age from 46-73, said DC Mayor Vincent Gray. Seven families have been notified of their deceased relatives, six are yet to be contacted. Eight people were injured in the attack—three of those were injured from gunshot wounds, including one law enforcement official. The other five have injuries ranging from extreme stress to various contusions; all eight are expected to make recoveries. “The response of the police, the taking down of the shooter so quickly, convinces me yet again that this is the safest city in the United States–not safe from attack, but safe,” Washington D.C. Rep. Eleanor Holmes Norton said at the press conference. Norton promised that “when I go on the floor tomorrow evening, I’ll remind the Congress that this shooting occurred in their neighborhood.” The attack began on a drizzly Monday morning just before 8:30 a.m. as some of the Navy Yard’s 3,000 workers filed into their offices for the start of the work week. Authorities believe Alexis arrived at the Navy Yard carrying only a shotgun, which investigators say he bought just last week at a gun dealer–Sharpshooters–in Lorton, Virginia, about 20 miles from Washington. They believe that he then picked up two other weapons as he began the shooting spree, taking one of them from a police officer he shot. When he was killed, authorities recovered three weapons–the shotgun, a handgun, and an AR-15-style assault rifle. “It was three gunshots straight in a row: pow, pow, pow,” said Patricia Ward, who heard the gunfire from the Naval Sea Systems Command Headquarters. “Three seconds later, it was pow, pow, pow, so it was like about a total of seven gunshots and we just started running.” Officials “don’t have any reason at this stage to suspect terrorism, but certainly it hasn’t been ruled out,” Mayor Gray said. Commander Tim Jirus said that he heard what sounded like the pop of a gun around 8:30 in the morning. As part of the Safety Section tasked with safely evacuating employees in the building, Jirus got people to safety. “There was an individual who came from the building behind us,” Jirus said. “He came up behind us and was talking to me basically saying, ‘hey, there’s a shooter in your building,’ and then I heard two more shots. One of them hit him, he went down in front of me and then I took off from there.” This video is playable across all supported devices. U.S. Navy Commander Tim Jirus explains how the man he was standing next to was shot during the D.C. Navy Yard shooting. At least one first responder, a male officer from the Metropolitan Police Department, was injured and taken to Washington Medical Center in critical condition. Two women, one who was shot in the shoulder and another one with wounds to the head and hand, were also treated at the Center. The woman who suffered a shoulder injury will be in surgery for a couple of hours, Dr. Janis Orlowski of the Center said during a press conference. “She’s in very, very good spirits. She was actually ordering the doctors and nurses around and we told her that we were in charge here,” Orlowski said. The third victim will not undergo surgery because the bullet “did not penetrate the skull, which means the bullet did not penetrate the bone,” Orlowski said. “I expect all three of them to make a full recovery.” The FBI, Lanier said, will now lead the investigation. Employees at the Naval Sea Systems Command Headquarters, where both civilians and military personnel design ships and submarines, have to pass through several layers of security before gaining entrance to the premises, Rick Mason, an employee at the facility told NBC’s Andrea Mitchell. The shooter was employed as a subcontractor for Hewlett Packard to work on the Navy’s intranet; that may have given him access to the base. “As I was walking up the stairs I heard what I thought was a locker door slamming; it didn’t sound like a shot to me,” a witness, Brian Chaney, told MSNBC’s Craig Melvin. The Senate sergeant-at-arms, Terry Gainer, said to NBC News that he recommended that Senate Leadership, including Majority Leader Harry Reid and Minority Leader Mitch McConnell, also shelter in place out of an “abundance of caution.” Capitol Hill is less than a mile away from the Navy Yard. President Obama registered the shock of having a secure military facility come under attack during scheduled remarks at a press conference marking the anniversary of the financial crisis. “They know the dangers of serving abroad but today they faced the unimaginable violence that they wouldn’t have expected to face here at home,” Obama said. The president tied the shooting to other instances of gun violence. “We are confronting yet another mass shooting,” Obama said. “And today it happened on a military installation in our nation’s capital.” Obama had pushed for stricter gun control legislation following the mass murders in an Aurora movie theater and at Sandy Hook Elementary School in Connecticut. But a bipartisan bill requiring universal background checks and restricting the size of gun magazines died on the floor. Monday night’s baseball game at Nationals Park was rescheduled to Tuesday at 1 p.m. EST. NBC News’ Pete Williams, Jim Miklaszewski, Courtney Kaube contributed reporting to this article. MSNBC’s Michele Richinick also contributed to this report. This video is playable across all supported devices. NBC’s Pete Williams shares details on the reported identity of the 34-year-old alleged gun man in the D.C. Navy Yard shooting. ||||| Aaron Alexis, 34, has been identified by officials as the gunman in Monday’s shooting at the Washington Navy Yard. In 2010, Alexis was arrested by Fort Worth police after a bullet was fired through the floor of his upstairs neighbor’s apartment. He told police that his gun accidentally discharged while he was cleaning it, and no charges were pursued. Aaron Alexis, 34, has been identified by officials as the gunman in Monday’s shooting at the Washington Navy Yard. In 2010, Alexis was arrested by Fort Worth police after a bullet was fired through the floor of his upstairs neighbor’s apartment. He told police that his gun accidentally discharged while he was cleaning it, and no charges were pursued. Fort Worth Police Department/via AFP/Getty Images Authorities say the former Navy reservist, who had been living in Fort Worth, was the dead gunman at the Washington Navy Yard. Authorities say the Navy veteran, who had been living in Fort Worth, was the dead gunman at the Washington Navy Yard. Authorities say the Navy veteran, who had been living in Fort Worth, was the dead gunman at the Washington Navy Yard. Aaron Alexis lived for a time in a bungalow in the woods near a Buddhist temple in Fort Worth, where he occasionally joined Thai immigrants in meditation. Aaron Alexis died Monday in a gun battle with police at the Washington Navy Yard after he allegedly killed at least 12 people. Along the way, the man named as the shooter in Monday’s mass killing at Building 197 was discharged from the Navy Reserve, arrested after firing a bullet through his upstairs neighbor’s floor and then asked to leave his Fort Worth apartment. One Navy official, speaking on the condition of anonymity, said that Alexis was discharged in January 2011 for “a pattern of misconduct” and that the 2010 gun incident in Texas played a role in his departure. But Alexis, 34, had no trouble landing a civilian job. He moved from Fort Worth to Washington about a month ago, friends said, and was hired as an hourly tech employee for The Experts, a Hewlett-Packard subcontractor that is updating computer systems at Navy and Marine Corps installations worldwide. He was scheduled to begin work at the Washington Navy Yard this month. Those who knew Alexis in recent years describe him as a “sweet and intelligent guy” (a regular customer at the Thai restaurant where he had been a waiter) and “a good boy” (his landlord), but also as “very aggressive,” someone who seemed as though he might one day kill himself (a lay worker at the Buddhist temple where Alexis worshiped). That angry streak flared often enough to create an arrest record in three states. In 2004, Alexis was arrested in Seattle after he fired three shots from a Glock pistol into the tires of a Honda Accord that two construction workers had parked in a driveway adjacent to Alexis’s house. Alexis’s father told detectives then that his son “had experienced anger management problems that the family believed was associated with PTSD,” or post-traumatic stress disorder, according to the police report. The father said Alexis had been “an active participant in rescue attempts of Sept. 11, 2001.” Alexis’s explanation for his behavior that day: The construction workers had “mocked” and “disrespected” him and then he had “a black-out fueled by anger.” He was arrested but not charged, Seattle police said. The paperwork apparently was lost. “That report never got to the Seattle city attorney’s office,” said Kimberly Mills, a spokeswoman for the city attorney. “Consequently, we never filed charges.” In 2008, Alexis was arrested on a disorderly conduct charge in DeKalb County, Ga. He spent two nights in jail, police said, but they had no other details. More recently, Alexis struck those who crossed his path as a man of sharp contrasts. He was learning the Thai language, visited Thailand for a month, was studying for an online degree in aeronautical engineering, and enjoyed conversing with diners, according to friends, customers and fellow worshipers. But some said he had an aggressive streak that made them keep their distance and avoid personal questions. “He’s a 13-year-old stuck in a 34-year-old body,” said Oui Suthamtewakul, owner of the Happy Bowl Thai restaurant in White Settlement, Tex., and a friend who lived with Alexis for most of the past three years. “He needs attention.” Alexis often worked as an unpaid waiter for Suthamtewakul and his wife, Kristi, but lived with them rent-free. The couple described Alexis as a helpful, chatty guy who liked to watch cooking shows on TV. “He always hit on girls,” Suthamtewakul said, adding that he had to scold his friend for being too forward with female customers. Suthamtewakul said Alexis “had a gun at all times” and fired a bullet through the wall of his room in the summer of 2012. “You’re gonna kill me,” the restaurateur told his friend. Alexis apologized and said it was an accident. Alexis drank alcohol frequently and in large quantities, Suthamtewakul said: “He can start drinking at 9:30 in the morning. He drinks often and for fun, but it was never a problem.” Asked what he will remember about his friend, Suthamtewakul said, “Him with a Heineken.” Alexis grew up in Brooklyn with his parents, Cathleen and Anthony Alexis, said his aunt Helen Weekes. “We haven’t seen him for years,” she said. He spent nearly four years in the Navy as a full-time reservist from May 2007 until January 2011, according to the Navy. A Navy official, speaking on the condition of anonymity, said that Alexis received a general discharge for “misconduct” and that the 2010 firearms incident in Texas played a role in his departure. Alexis achieved his final rank — aviation electrician’s mate 3rd class — in December 2009. He spent the bulk of his service time — 2008 to 2011 — assigned to the Fleet Logistics Support Squadron 46 at Naval Air Station Fort Worth, records show. He received the Global War on Terrorism Service Medal and the National Defense Service Medal, awards of minor distinction. Despite the circumstances surrounding his discharge, Alexis apparently was issued a government contractor access card that would have allowed him into the Navy Yard and other military installations, said Thomas Hoshko, chief executive of The Experts. His security clearance was updated in July. “There had to be a thorough investigation,” Hoshko said. “There is nothing that came up in all the searches.” Alexis had finished a contract in Japan for the company at the end of 2012, Hoshko said. “Nobody could have done anything to prevent this except Aaron Alexis,” he said. “Maybe he snapped. I don’t know.” In Fort Worth, Alexis lived for a time in a gated townhouse community called Orion at Oak Hill. In September 2010, police were called to Apartment 2023 after Alexis’s upstairs neighbor complained that a bullet had been fired through her apartment. Police determined that Alexis had fired a round that went up through her floor and into her ceiling. The woman told police that Alexis had complained several times that she was too loud. She said he had confronted her a few days earlier in the complex’s parking lot “about making too much noise,” according to a police report. The woman said that “she is terrified of Aaron and feels that this was done intentionally,” the police report said. Police tried three times to contact Alexis by knocking on his apartment door, but he didn’t respond. Only after they called in firefighters to force entry did he emerge. He told police that he had been cleaning his gun while cooking and that it accidentally discharged because his hands were greasy, according to the police report. “He told me that he began to take the gun apart when his hands slipped and pulled the trigger, discharging a round into the ceiling,” the officer wrote. Alexis was arrested for improperly discharging a firearm, but the county district attorney’s office said Monday that there was not enough evidence to pursue the case. Alexis’s mug shot from that arrest shows a clean-shaven man with soft eyes and an impassive expression. A couple of weeks later, the apartment complex began eviction proceedings against Alexis, according to county records. Soon after, Somsak Srisan, a Thai immigrant in Fort Worth, met Alexis at the Wat Busayadhammavanaram Meditation Center, where Alexis had occasionally practiced meditation starting in the summer of 2010. Alexis said he needed a place to stay, and Somsak offered him a two-bedroom white bungalow a short walk away — if he promised not to smoke or drink. Alexis rented the place for $600 a month and never missed a payment, said Somsak, 57. “He’s a good boy,” said Somsak, who spoke halting English. “Everybody would say, ‘He’s a good boy.’ ” Alexis occasionally meditated at the temple and helped there when needed, said Somsak, who was impressed that his tenant studied the Thai language and visited Thailand. On Monday, as word spread about the shootings, the temple filled with members eager to share recollections of Alexis. “They don’t believe it that he could kill 12 people like that,” Somsak said. “I think probably somebody tried to put him down. I don’t know. Did somebody try to discriminate against him?” Somsak asked Alexis only once why he had left his job at the naval base. It was a brief conversation. “I asked him, ‘Why you quit the job with the government?’ ” Somsak said. “He said, ‘Somebody doesn’t like me.’ ” Somsak left it there, he said, because “I don’t want to go too deep with him.” Alexis visited the center about twice a week and was known as a quiet, if tightly wound, participant, a temple staff member said. “He would help people if they came in carrying heavy things,” said J. Sirun, an assistant to the monks. “From the outside, he was a quiet person. But on the inside, I think he was very aggressive. He did not like to be close with anybody, like a soldier who has been at war.” Sirun said he avoided Alexis, who preferred to keep to himself. But Alexis was no loner; he had many Thai friends and spoke Thai “very well,” Sirun said. “He understood about 75 percent of the language.” Customers saw him studying Thai at a table there during his off hours. Alexis stopped showing up at the Buddhist center early in 2011, he said. “I didn’t think he could be this violent,” he said. “I would not have been surprised to hear he had committed suicide. But I didn’t think he could commit murder.” Relatives contacted by reporters were stunned to hear that Alexis was suspected in the shootings. “I’d be shocked if it was him, but I don’t know,” said Weekes, his aunt, her voice trailing off. Even as he worked for the defense contractor, Alexis was pursuing a bachelor’s degree in aeronautics as an online student at Embry-Riddle Aeronautical University. The university, in Daytona Beach, Fla., said he enrolled in July 2012 via the school’s Fort Worth campus. He remained a student in good standing, said Melanie Hanns, director of university communications. “He was enrolled for this semester,” she said. FBI Assistant Director Valerie Parlave asked the public to call 1-800-CALL-FBI with any details about Alexis. Marjorie Censer, David A. Fahrenthold, Jennifer Jenkins, Carol D. Leonnig, Annys Shin, Julie Tate and Craig Whitlock in Washington and special correspondent Leslie Minora in Fort Worth contributed to this report. ||||| Acquaintances of Navy Yard Gunman React: After Aaron Alexis was identified as the Washington Navy Yard gunman, family and former acquaintances reacted to the news. HOUSTON — Aaron Alexis, 34, the man killed by police officers and identified as the gunman in the deadly rampage at the Washington Navy Yard on Monday, served his country as a Navy reservist, had an abiding interest in Buddhism and Thai culture, and had problems with the law, records and interviews show. In 2004, according to a Seattle police report, Mr. Alexis walked out of his grandmother’s home one morning, pulled a .45-caliber pistol from his waistband and fired three rounds at a construction worker’s car, two at the rear tires and one into the air. A construction manager told the police he thought Mr. Alexis was frustrated with the parking situation outside the work site. But Mr. Alexis told the police that he had had an anger-fueled blackout and could not remember firing the weapon until about an hour after the episode. He said he was in New York during the Sept. 11 attacks, and described to a detective “how those events had disturbed him,” according to the detective’s report. His father told investigators that Mr. Alexis had problems associated with post-traumatic stress disorder, and had been an “active participant” in rescue attempts on Sept. 11. Mr. Alexis’s father could not be reached for comment Monday. Anthony Little, Mr. Alexis’s brother-in-law, told reporters Monday in Brooklyn that it had been five years since his wife, Naomi Alexis, had spoken to her brother. “No one saw it coming, no one knew anything, so all of this is just shocking,” he said. Law enforcement officials said the motive behind the navy yard shooting remained unclear. Mr. Alexis was born in Queens in 1979 and was representative of the borough’s diversity. He was African-American, grew up in a part of Queens that was home to South Asians, Hispanics and Orthodox Jews, and embraced all things Thai while living in Fort Worth. He worked as a waiter at a Thai restaurant, studied the language and regularly chanted and meditated at Buddhist temples. From 2007 to 2011, Mr. Alexis was a full-time reservist in the Navy, serving as an aviation electricians’ mate and achieving the rank of petty officer third class. For much of that time, from February 2008 to January 2011, when he left the service, he was assigned to the Fleet Logistics Support Squadron 46, in Fort Worth, Navy officials said. His specialty was fixing electrical systems on airplanes. Navy Secretary Ray Mabus said on CNN that Mr. Alexis was in “the ready reserve,” meaning he did not have day-to-day contact with the Navy, but, if called upon, “he would be one of the ones mobilized.” Mr. Alexis was awarded the National Defense Service Medal and the Global War on Terrorism Service Medal, two standard military honors, but there were indications that he struggled in the Navy. During his time in the service, he exhibited “a pattern of misbehavior,” Navy officials said, though they declined to elaborate. Upon leaving, he became a Navy contractor. At the time of the shooting, Mr. Alexis worked for a company affiliated with Hewlett-Packard that serviced the Navy’s Internet system, Hewlett-Packard said in a statement. He had been living for weeks in a long-term-stay hotel with colleagues to work on the Navy Yard project, according to a government official. In 2010, Mr. Alexis was arrested in Fort Worth for discharging a firearm. At the time, Mr. Alexis had been living in an apartment complex called Orion at Oak Hill. His upstairs neighbor called the police after she heard a pop, saw dust fly and noticed holes in her floor and ceiling. She told the police that Mr. Alexis had confronted her in the parking lot about making too much noise, and she felt threatened by him, according to the Fort Worth police report. Mr. Alexis later told an officer that he had been cleaning his gun while cooking, and that the gun had accidentally discharged. The officer asked him why he did not call the police or check on the resident above him, and he replied that he did not think the bullet went through because he could not see any light through the hole, according to the report. The officer noted that the gun was taken apart and covered in oil. James Rotter, the father of the woman in the apartment, said the shot came through close to where his daughter had been sitting. She moved out after the episode, and a lawyer advised the family not to press charges. “How could you prove he did it on purpose when he claimed he was cleaning his gun?” Mr. Rotter said. In recent years, Mr. Alexis dated a Thai woman and began showing up regularly at Wat Busayadhammavanara, a Buddhist Temple in White Settlement, Tex., a Fort Worth suburb. He had Thai friends, adored Thai food and said he always felt drawn to the culture, said Pat Pundisto, a member of the temple answering the phone there on Monday. He was a regular at Sunday services, intoning Buddhist chants and staying to meditate afterward. On celebrations like the Thai New Year in April, he helped out, serving guests dressed in ceremonial Thai garb the temple provided. At the temple, he met Nutpisit Suthamtewakul, who went on to open the Happy Bowl Thai restaurant in White Settlement in 2011, said the restaurant owner’s cousin, Naree Wilton, 51, in a phone interview. Mr. Alexis helped out at the restaurant in exchange for food and a room in Mr. Suthamtewakul’s house. There, he played computer games “at the nighttime and all day,” Ms. Wilton said, on one of three computers he kept in his room, driving up the house’s electricity bills. After he got a job fixing computers, the family asked him to help out with utility bills. He rarely paid and borrowed money often, Ms. Wilton said, complaining that his computer company was withholding pay. ||||| Story highlights It's unclear how Alexis got a shotgun past security A Washington police officer ended the 30-minute spree by killing Alexis, mayor says Alexis had issues in the Navy and with police, but still had security clearance Authorities don't know his motive, and friends say they're surprised by attack The one question we all desperately want answered may have gone to the grave with Aaron Alexis : Why? Why did he park at the Washington Navy Yard on Monday, walk into Building 197, perch himself on an overlook above the atrium and open fire? The bullets that rained down killed 12 people and wounded eight others. Why? But that's not the only missing puzzle piece. Investigators are painstakingly trying to piece together the motive, the means and the method. "No piece of information is too small," says Valerie Parlave of the FBI. "We are looking to learn everything we can about his recent movements, his contacts and associates." JUST WATCHED Who is Aaron Alexis? Replay More Videos ... MUST WATCH Who is Aaron Alexis? 02:36 JUST WATCHED Navy Yard shooting: A timeline Replay More Videos ... MUST WATCH Navy Yard shooting: A timeline 02:26 JUST WATCHED Man hid in room during shooting Replay More Videos ... MUST WATCH Man hid in room during shooting 03:40 JUST WATCHED Tragedy at the Washington Navy Yard Replay More Videos ... MUST WATCH Tragedy at the Washington Navy Yard 03:21 For now, here's what we know and what we don't know. THE MOTIVE What we know: Senate Majority Leader Harry Reid may have said it best Tuesday when he told colleagues that "there is no explanation for the violence." So far, investigators haven't offered any clue as to what motivated Alexis to kill. Friends say he had been frustrated over pay and benefits issues from a previous contracting job, and federal law enforcement sources said he may have contacted Veterans Affairs hospitals for possible treatment of psychological issues. But so far, investigators haven't said if either of those issues contributed to the attack. What we don't know: What he might have left behind in his Washington hotel room, either in writing or on any computers FBI agents may have found while searching the room. Terrorism hasn't been ruled out but seems unlikely, according to Washington Mayor Vincent Gray. THE SHOOTER What we know: Throughout the day, authorities said they were looking for a second man. But by nightfall, they said they were "confident" that Alexis was the lone gunman. "We have exhausted all means to eliminate that possible last suspect," said Metropolitan Police Chief Cathy Lanier. "So we do now feel comfortable that we have the single and sole person responsible for the loss of life inside of the base." On Tuesday, Parlave, the assistant director in charge of the FBI's Washington field office, underscored that, telling reporters it's believed that Alexis acted alone. What we don't know: While authorities have stated they don't think anyone else besides Alexis opened fire at the Navy Yard, that doesn't mean others didn't help him or know about the plot. Alexis arrived in Washington on or around August 25, staying in hotels in the capital ever since, said Parlave. Shawn Henry, a former executive assistant director of the FBI, said he believed authorities will be talking to people Alexis has known for years -- including those he went to school with and served in the Navy with -- as well as looking at things like bank and cell phone records. THE VICTIMS What we know: We now have all the names of 12 victims. They range in age from 46 to 73. Another eight people are recovering from wounds inflicted in the shooting, including three at MedStar Washington Hospital Center. JUST WATCHED Navy Yard shooting: Stories of survival Replay More Videos ... MUST WATCH Navy Yard shooting: Stories of survival 03:13 JUST WATCHED Navy Yard shooting and base security Replay More Videos ... MUST WATCH Navy Yard shooting and base security 04:25 JUST WATCHED America's battle over guns Replay More Videos ... MUST WATCH America's battle over guns 05:01 JUST WATCHED Rick Warren on shooting: 'I prayed' Replay More Videos ... MUST WATCH Rick Warren on shooting: 'I prayed' 01:00 Photos: Photos: Navy Yard shooter Photos: Photos: Navy Yard shooter Navy Yard gunman – The FBI identified Aaron Alexis, a 34-year-old military contractor from Texas, as the perpetrator of the shooting rampage at the Washington Navy Yard on Monday, September 16. Authorities said at least 12 people -- and Alexis -- were killed in the shooting. Hide Caption 1 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – Two days before the shooting, Alexis spent "a couple hours" shooting at Sharpshooters Small Arms Range in northern Virginia before buying the Remington 870 shotgun -- after being approved by the federal background check -- and a small amount of ammunition, the store's attorney, J. Michael Slocum, said. Hide Caption 2 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – Alexis appears to have had sporadic run-ins with the law, dating to at least 2004. Authorities are still searching for more information about him, and they're asking the public for help. Hide Caption 3 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – CNN obtained a series of images of Alexis from Kristi Suthamtewakul, the wife of his friend and former roommate Nutpisit Suthamtewakul, owner of the Happy Bowl Thai restaurant in Fort Worth, Texas, where Alexis used to work. Hide Caption 4 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – Nutpisit Suthamtewakul reeled at the news that Alexis was involved in the rampage at the Navy Yard. "I can't believe he did this," he said. "He never showed any sign of violence." Hide Caption 5 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – Alexis, who was from New York, served as a full-time Navy reservist between 2007 and 2011, according to military records. Hide Caption 6 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – His last known address was outside Fort Worth, Texas. Hide Caption 7 of 8 Photos: Photos: Navy Yard shooter Navy Yard gunman – Authorities have not released a possible motive for the shooting. Hide Caption 8 of 8 Washington Mayor Vincent Gray said many of the victims gunned down in the Navy Yard's Building 197 were eating breakfast when Alexis shot at them from above. What we don't know: We have yet to find out more about many of the victims, such as what they did at the Navy Yard, where they were at the time of the shooting, etc. THE EN D What we know: Washington Police Chief Cathy Lanier said Tuesday that Alexis had "multiple contacts" with officers from several agencies during the shooting spree. The ordeal ended when Washington police Officer Scott Williams fatally shot Alexis, 34, Mayor Vincent Gray told CNN. What we don't know: Exactly how Alexis died, beyond the fact it happened after 30 minutes of gunfire, according to Gray. HIS HISTORY What we know: He left New York after apparently helping rescue efforts at the site of the World Trade Center after the September 11, 2001, terror attacks, according according to a source with direct knowledge of the investigation. His father told Seattle police after a 2004 arrest that Alexis was suffering from post-traumatic stress disorder related to that experience. He had served in the Navy, but officials moved to discharge him in 2010 over a pattern of misconduct that included insubordination, unauthorized absences and other infractions, according to a U.S. defense official. It wasn't enough for a general discharge, so Navy officials decided to grant him an honorable discharge, the official said. As a contractor, he worked in information technology, had medium security clearance, high enough to work at multiple Navy offices over the summer. He had an ID badge to enter the Navy Yard. His employer says the shooter jumped through all the right hoops. "Alexis had a security clearance that was updated in July, approved by military security service personnel," said Thomas Hoshko, CEO at The Experts. "There is nothing that came up in all the searches." He appeared to become increasingly troubled in recent years, according to the source with direct knowledge of the investigation. He was hearing voices and having problems sleeping, the source said. He was growing increasingly troubled and in recent months had exhibited signs of mental problems, according to the source. Based on family accounts, it appears Alexis "basically snapped," the source said. On August 7, police in Newport, Rhode Island, investigating a harassment complaint at a Marriott hotel encountered Alexis. He told them that an individual "had sent three people to follow him and to talk, keep him awake and send vibrations into his body," according to a police report. These individuals, Alexis police, had followed him to three hotels in the area -- including talking to him through walls and the floor and using "some sort of machine" to send vibrations through the ceiling that prevented him from falling asleep. Police subsequently notified officials at a Navy base in Newport, the police report stated. Officials at Naval Station Newport referred CNN to the FBI on Tuesday when asked about the incident, and the FBI subsequently had no comment on the August police report. What we don't know: How he was able to get a security clearance with such a spotty background. Former Navy SEAL Cade Courtley says a poor or incomplete background check is to blame. "Most people, when they get into that, they are given an interim clearance, and that means that the background check hasn't been done but it's in the process of being done," Courtley said. "He may have started out with an interim clearance and a background check should have been done." The former SEAL says just running Alexis' fingerprints would have turned up his arrest record. In Seattle, he fired several shots into the tires of a car during an altercation over construction near where he lived in 2004. There was also a weapons incident in Texas in 2010. SECURITY AT THE YARD What we know: Alexis drove onto the grounds of Navy Yard on Monday morning with a shotgun, according to federal law enforcement sources with detailed knowledge of the investigation. He proceeded into Building 197 and opened fire. He had access to the Navy Yard because of his contracting work, and he used a valid pass to gain entry. City police were the first law enforcement personnel on site within eight minutes of when the first shots rang out, according to Gray, and they were joined soon by SWAT team members. Washington Police Chief Cathy Lanier said there's "no doubt in mind" that law enforcement officers response to the shooting "saved numerous lives." What we don't know: Even to drive or walk onto the base, a person would be required to present credentials, said Navy Capt. Mark Vandroff. Building 197 has armed security at the door. How did he get the guns past them? Did cost-cutting compromise Navy security? Rep. Mike Turner, an Ohio Republican and a member of the Armed Forces Committee, thinks so. He wants a congressional briefing from the Pentagon inspector general on a Navy security audit that he says was released after Monday's shooting. "It is my understanding that the IG report indicates the Navy may have implemented an unproven system in order to cut costs," Turner said. "I also learned that potentially numerous felons may have been able to gain restricted access to several military installations across the country due to insufficient background checks, increasing the risk to our military personnel and civilian employees." HIS WEAPONS What we know: Federal law enforcement sources say authorities have recovered three weapons from the scene of the mass shooting, including one -- a shotgun -- that investigators believe he brought in to the compound. The other two weapons -- handguns -- the sources say, may have been taken from guards. What we don't know: The sources, who have detailed knowledge of the investigation, cautioned that initial investigation information that an AR-15 rifle was used may have been incorrect. It is believed that Alexis had rented an AR-15, but returned it before Monday morning's shootings. On Sunday, Alexis purchased a Remington 870 shotgun and a small amount of ammunition at Sharpshooters Small Arms Range in northern Virginia, the store's attorney, J. Michael Slocum, said. Alexis spent "a couple hours" there, including at its practice range, the lawyer added. In according with federal law, Alexis name and other applicable information was provided to the National Instant Criminal Background Check System and he was approved to purchase the gun, according to Slocum. Alexis had the proper credentials to get into the Navy Yard, said Washington's mayor. But Gray added that it was unclear how he got the shotgun past security. Parlave, from the FBI, said Tuesday that Alexis may have gotten hold of the handguns after he got into the military facility. GUN DEBATE What we know: The incident will certainly rev up the often explosive debate over gun control. But initial reports show Alexis obtained his primary weapon legally. What we don't know: Will the shooting at Navy Yard change the political landscape? High-profile shootings over the last several years have done little to move the needle in Washington. President Barack Obama pushed for universal background checks and other directives after the the Newtown, Connecticut, shootings, to cut down on the access Americans would have to firearms, but they never gained traction. At the state level, it's been a similar story. The successful recall elections last week of two Colorado lawmakers who backed new gun restrictions sent a shiver through the gun control lobby.

– Aaron Alexis, who is now believed to have been the only shooter behind yesterday's Navy Yard massacre, suffered from serious mental issues, including paranoia and a sleep disorder, and had been hearing voices in his head, sources tell the AP. Alexis also suffered from PTSD, his father told investigators, according to the New York Times. He had been disturbed by the 9/11 attacks, his father explained; he was an "active participant" in rescue efforts in New York. Alexis had been getting treatment for these issues from the Veterans Administration, but the Navy hadn't declared him mentally unfit. Had it done so, he'd have lost his security clearance. Other details trickling out include: Alexis was kicked out of the Navy Reserve for a "pattern of misbehavior," one Navy official tells the Washington Post. He was given a "general discharge," which is seen as a reprimand. That misconduct included a 2010 incident in which he fired a gun into his floor. His downstairs neighbor told police she felt threatened, because Alexis had previously complained about the noise. Alexis said the gun went off accidentally. The incident got him evicted. Alexis was also arrested in 2008 on a disorderly conduct charge and spent two nights in jail. None of his arrests ever led to a conviction. Authorities say there's no evidence Alexis had any ideological motive, or any personal grudge against anyone at the Navy Yard. A friend does tell CNN that Alexis was upset about his pay in his contracting job, believing he hadn't been compensated properly for a months-long assignment in Japan. Alexis "had a gun at all times," according to Oui Suthamtewakul, the owner of the Thai restaurant where Alexis worked in exchange for free rent. Suthamtewakul considered Alexis a friend, and described him as "a 13-year-old stuck in a 34-year-old's body." He was a heavy drinker, and was forward with women. Suthamtewakul also reveals that Alexis shot a bullet through the wall of his room last summer. "You're gonna kill me," the landlord told him. Alexis apologized. For more on Alexis, click here.

Health Tennessee Will Now Criminally Charge Pregnant Women Who Use Drugs CREDIT: Shutterstock Tennessee Gov. Bill Haslam (R) has approved a measure that will allow Tennessee to bring criminal charges against pregnant women who use drugs for potentially harming their fetuses, even though there isn’t conclusive scientific evidence that being exposed to illicit drugs in the womb causes long-term harm to children. The governor’s approval of the legislation comes despite a massive outcry from reproductive rights and criminal justice groups across the country, who say that criminalizing pregnant women is the wrong policy approach. Threatening to bring charges against women who are struggling with substance abuse dissuades them from coming forward to seek the medical treatment they need. It’s also a policy that disproportionately harms low-income and non-white women. “Today, the Tennessee governor has made it a crime to carry a pregnancy to term if you struggle with addiction or substance abuse,” Alexa Kolbi-Molinas, a staff attorney with the ACLU Reproductive Freedom Project, said. “This deeply misguided law will force those women who need health care the most into the shadows. Pregnant women with addictions need better access to health care, not jail time.” In a statement accompanying his signature on the bill, Haslam claimed that he had “extensive conversations with experts including substance abuse, mental health, health and law enforcement officials” and will “be monitoring the impact of the law through regular updates with the court system and health professionals.” But most experts — including the American Medical Association, the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the American Public Health Association — oppose efforts to arrest pregnant women who use drugs. Medical professionals are concerned about women getting the prenatal care they need, since skipping out on those services actually leads to a greater risk of miscarriage, stillbirth, and infant death. Specialists in obstetric medicine and drug addiction called on Haslam to veto the measure. Although drug possession and drug sales can result in criminal charges, states typically do not arrest people simply for using drugs. Addiction is considered to be a medical issue, and under the Constitution’s definition of cruel and unusual punishment, states aren’t allowed to criminalize those types of disorders. But Tennessee is making an exception for pregnant people. “Do we arrest new fathers who come into the emergency room who test positive for drugs? This is not really about arresting pregnant women because they use drugs. This is arresting women because they became pregnant, making them vulnerable to charges of child endangerment for risking harm to a newborn,” Lynn Paltrow, the executive director of National Advocates for Pregnant Women (NAPW), one of the groups that’s been fighting against the criminalization of pregnant women for years, told ThinkProgress in an interview earlier this month. Two years ago, Tennessee barred the use of criminal charges against pregnant women for using drugs, opting to encourage drug-addicted women to enter treatment. Advocates are frustrated that the state is backtracking on that policy, which they supported. “Now we’re seeing the General Assembly take two big steps back,” Farah Diaz-Tello, a staff lawyer for NAPW, recently told the New York Times. “It’s going from a state with some of the best practices to one of the worst.” ||||| Buy Photo Dr. Stephen Patrick, right, and Michael Botticelli, deputy director of the White House Office of National Drug Control Policy, take a close look at a baby inside the NICU on Monday while touring the Monroe Carell Jr. Children’s Hospital at Vanderbilt University. (Photo: Jae S. Lee, The Tennessean)Buy Photo Tennessee women who use drugs while pregnant can be criminally charged for harm done to their infants beginning July 1. Gov. Bill Haslam signed the legislation Tuesday after "extensive conversations with experts including substance abuse, mental health, health and law enforcement officials," he wrote in a statement. "The intent of this bill is to give law enforcement and district attorneys a tool to address illicit drug use among pregnant women through treatment programs." The governor's decision comes after a week of mounting nationwide opposition from civil and reproductive rights groups. They argued that criminalization would drive vulnerable women away from drug addiction treatment. "I understand the concerns about this bill, and I will be monitoring the impact of the law through regular updates with the court system and health professionals," Haslam wrote. Simple Answer: What's best for babies born to drug-addicted mothers? The law brings back criminalization, which lawmakers had eliminated two years ago as the state moved toward programs that incentivize expecting mothers to get into treatment. Tennessee officials have wrestled with what to do about the growing numbers of infants born dependent on drugs and who often suffer from a condition known as neonatal abstinence syndrome. The legislation would allow mothers to avoid criminal charges if they get into one of the state's few treatment programs. Haslam said he wants doctors to encourage women to get into treatment before delivering their babies so they can avoid charges. The proposal also includes an unusual sunset provision, which means the criminal penalty will be in effect until 2016. At that time, lawmakers will have to revisit the issue. Opponents, including five national medical organizations and local doctors who treat pregnant women, worry that criminalization will scare women away from treatment and reverse last year's Safe Harbor Act, which protected the custody rights of mothers and gave them priority placement into the state's limited number of treatment programs. The director of the American Civil Liberties Union of Tennessee — joined by the national ACLU — said she was "extremely disappointed" by the governor's decision. "A pregnant woman struggling with drug or alcohol dependency will now be deterred from seeking the prenatal care she needs," said Hedy Weinberg. Abuse of prescription painkillers has fueled a tenfold increase in such births in the past decade, sending health officials scrambling. There were 921 drug-dependent births in 2013 and 253 so far this year. Reach Tony Gonzalez at 615-259-8089 or on Twitter @tgonzalez. MOMS AND DRUGS 921: The number of drug-dependent births in Tennessee in 2013 253: The number of drug-dependent births so far this year. The legislation would allow mothers to avoid criminal charges if they get into one of the state's few treatment programs. Read or Share this story: http://tnne.ws/1kqiiEn ||||| Public Health Tennessee Bill Could Send Addicted Moms To Jail itoggle caption Katie Collins/PA Photos/Landov Pregnant women addicted to illegal narcotics or prescription pain pills could soon be jailed in Tennessee under a bill awaiting the governor's signature. The strict proposal enjoys bipartisan support — despite objections from doctors. The medical term for what happens when a newborn has withdrawal symptoms a day or two after birth is "neonatal abstinence syndrome." At its worst, these babies suffer from seizures; it's not clear whether there might also be lasting effects. Tennessee last year forced every hospital to start reporting such cases, and the numbers have only been going up. As health officials have made drug-dependent babies a priority, the Legislature has taken a more punitive approach. "It's always somebody else's fault," says state Rep. Terri Lynn Weaver. "What's wrong with: 'You screwed up, you're wrong, you've got to pay the consequences.' What's wrong with that?" It's always somebody else's fault. ... What's wrong with: You screwed up, you're wrong, you've got to pay the consequences? Weaver initially wanted to make it possible to charge women with homicide if their drug-dependent newborn died, but ultimately she had to tone it down. The women would now have the option to seek treatment. "We can't make her get help herself," says Weaver, "but, by golly, we can give her an option and a choice." Weaver is a conservative Republican, but Democrats jumped on board too. State Rep. John DeBerry admits it seems unnatural to punish a pregnant woman for harming her unborn child. "We are always trying to save children who should be saved by their families, and I have said if there is a better way, bring it to me," he says. "I haven't seen it yet." In some other states, prosecutors have gone after addicts whose newborn dies, trying to charge them with murder. Farah Diaz-Tello of the National Advocates for Pregnant Women points to a case in Mississippi. "What Tennessee is doing is creating a law that would permit this kind of prosecution — not for murder," says Diaz-Tello, "but it would allow for reckless endangerment, which is a misdemeanor, all the way up to aggravated assault." And an assault charge could mean 15 years behind bars for the mother. Being a poorly controlled diabetic is terrible for pregnancy — probably equally as bad as drug addiction — and we don't legislate those choices. New mother Jackie Bains has returned to a Nashville women's clinic for a checkup. Her son is 7 weeks old and perfectly healthy. Bains says she was hooked on narcotic pain pills when she found out she was pregnant — but she got help. She says it was hard to tell people, but it would have been even harder if she thought she could be punished for her addiction. "I mean, some people are worried about going to jail and what it could do. But then you also have to worry about what it would do to the baby, too," she says. "I do think it will deter people from wanting to come in to seek help." It's a concern that worries many in the medical community — that the punitive approach, even with its treatment option, will drive away women or encourage more abortions. Jessica Young, an obstetrician at Vanderbilt University Medical Center who specializes in drug treatment during pregnancy, says lawmakers don't fully understand that addiction can be a sickness. "Being a poorly controlled diabetic is terrible for pregnancy — probably equally as bad as drug addiction — and we don't legislate those choices," says Young. "I just think this is an easy group to pick on because addiction has such a stigma." Tennessee Gov. Bill Haslam, a relatively moderate Republican, has been hearing from women's groups around the country asking him to veto the bill, but he says he's comfortable with the final language, given that a woman always has a way to avoid jail time, even after giving birth to a child going through drug withdrawal.

– Starting July 1, if you're pregnant and use drugs while living in Tennessee, you can be charged with a crime for causing harm to your unborn baby. Gov. Bill Haslam signed the controversial law yesterday, the Tennessean reports. Civil and reproductive rights groups had opposed it, saying it would scare women away from getting treatment for drug addiction, but Haslam said he talked to "experts including substance abuse, mental health, health, and law enforcement officials" before signing the legislation, and will closely monitor its impact. Critics also say the law disproportionately affects low-income and non-white women, ThinkProgress notes. Using drugs while pregnant was previously criminalized in the state, but decriminalized two years ago as lawmakers moved toward programs encouraging pregnant women to get treatment. But the law is back as the number of babies born dependent on drugs is on the rise. Pregnant drug users can avoid criminal charges if they enter a treatment program, and Haslam is asking doctors to encourage women to enter treatment programs before delivery to avoid being charged. If they don't enter treatment, women charged under the law could face as many as 15 years in jail, NPR reported last week.

Barack Obama has taken a swipe at his successor’s legal troubles, one day after the special counsel, Robert Mueller, ended a plea deal with Paul Manafort, Donald Trump’s former campaign chair. “Not only did I not get indicted, nobody in my administration got indicted,” the former president said at an event in Houston on Tuesday, “which by the way was the only administration in modern history that that can be said about. In fact, nobody came close to being indicted, partly because the people who joined us were there for the right reasons. We were there to serve.” Manafort breached a plea agreement he signed in September by “lying to the Federal Bureau of Investigation and the special counsel’s office on a variety of subject matters”, Mueller said in a court filing on Monday night. Mueller is investigating Russia’s interference in the 2016 presidential election, which US intelligence agencies concluded was aimed at boosting Trump’s bid for the White House, and any collusion between Russian operatives and Trump campaign team. Mueller’s inquiry has so far led to indictments against 32 individuals and three Russian entities on charges ranging from computer hacking to obstruction of justice. Obama also lamented the rise of insular nationalism in US politics, describing it as a threat to international stability and domestic prosperity. He did not mention his successor by name but Trump and his “America first” strategy cast a long shadow as the former Democratic president discussed the decline of bipartisanship in American politics and the undermining of democracy and decorum by populism and extremism. “People ask me what surprised me most about the presidency. It is the degree to which the United States underwrites the international order,” Obama said. “If there is a problem around the world, people do not call Moscow, they do not call Beijing. They call Washington. Even our adversaries expect us to solve problems and expect us to keep things running. “When you start getting dysfunction in Washington which [makes it] difficult for decisions to get made and policymaking to run in an orderly process, what is one of our greatest assets – which is an extraordinary civil service, career staff, let’s say at the state department – when that begins to get undermined, that doesn’t just weaken our influence, it provides opportunities for disorder to start ramping up all around the world and ultimately makes us less safe and less prosperous.” Obama also expressed regret over a hyper-partisan media landscape that he believes has made lawmakers and voters less willing to compromise and means Congress is stuck in a perpetual campaign mode. In previous decades, Obama said, “there was a common set of facts, a baseline around which both parties had to adapt and respond to. By the time I take office [in 2009] what you increasingly have is a media environment in which if you are a Fox News viewer you have an entirely different reality than if you are a New York Times reader. It means the bases of each party have become more ideological.” Leaders, Obama said, failed to anticipate how globalism and income inequality would breed the rise of populism and hostility towards immigrants even in countries with strong democratic traditions; trends exploited by Trump. “You suddenly had a winner-take-all economy; where back in 1960 maybe the CEO makes 10 times more than the guy on the assembly line, now suddenly it’s 200 times or 300 times,” he said. “We did not adapt quickly enough to the fact that people were being left behind and frustrations were going to flare up … In those environments you then start getting a different kind of politics, you start getting a politics that’s based on ‘that person’s not like me and it must be their fault’. And you start getting a politics based on a nationalism that’s not pride in country but hatred for somebody on the other side of the border.” After largely staying above the fray in the months after he left the White House, Obama has been more vocal in recent months, campaigning for Democratic candidates in the run-up to this month’s midterms and criticising Trump by name for the first time in a speech in September. Then, he accused the president of “capitalising on resentments that politicians have been fanning for years”, adding that “the politics of resentment and paranoia have unfortunately found a home in the Republican party”. The 44th president was in Houston for a gala marking the 25th anniversary of Rice University’s Baker Institute for Public Policy. The bipartisan thinktank is named for James Baker, who served in the White House under Ronald Reagan and George HW Bush. Baker shared the stage with Obama on Tuesday in a roughly 50-minute discussion moderated by the historian Jon Meacham. Earlier in the day, Obama met Bush at his home in Houston in what Bush’s spokesman, Jim McGrath, described as a “very pleasant and private visit … where they rekindled what was already a very warm friendship.” Relations between Trump and Obama are rather more frosty. In comments that invited a contrast with the chaotic incoming administration following the 2016 election and implicitly referenced Trump’s self-centred personality, Obama praised the outgoing George W Bush administration’s behaviour after the 2008 vote. “They had set up a transition process that was flawless and generous and thoughtful so that every member of 43’s staff had made themselves available to the person who was going to be taking their place,” he said. “Despite the political differences which were real and significant they recognised there was a value above those differences. And when I walked into the Oval Office there’s a reverence there for that office that is independent of you. And if you don’t feel that then you shouldn’t be there.” ||||| Obama at Baker Institute gala: 'Nobody in my administration got indicted' Former President Barack Obama speaks with Jon Meacham as he takes the stage during the 25th anniversary gala celebration for Rice University’s Baker Institute for Public Policy on Tuesday, Nov. 27, 2018, in Houston. less Former President Barack Obama speaks with Jon Meacham as he takes the stage during the 25th anniversary gala celebration for Rice University’s Baker Institute for Public Policy on Tuesday, Nov. 27, 2018, in ... more Photo: Brett Coomer, Staff Photographer Photo: Brett Coomer, Staff Photographer Image 1 of / 23 Caption Close Obama at Baker Institute gala: 'Nobody in my administration got indicted' 1 / 23 Back to Gallery Former president Barack Obama on Tuesday gave himself a pat on the back for his indictment-free tenure in office, yet during a nearly hour-long interview at Rice University avoided directly mentioning the legal machinations that have swept up the first two years of President Trump's administration. Obama's comments came near the end of an hour-long conversational interview with former Secretary of State James A. Baker III, the namesake of the nonpartisan Baker Institute for Public Policy think tank that is celebrating its 25th anniversary. Now Playing: "Not only did I not get indicted, nobody in my administration got indicted," Obama said to a crowd of more than a thousand at a gala honoring the institute. "By the way, it was the only administration in modern history that that can be said about. In fact, nobody came close to being indicted, probably because the people who joined us were there for the right reasons." The interview, moderated by presidential historian Jon Meacham — who at one point compared Trump to Voldemort, the fictional Harry Potter villain — carried an anti-Trump tone without many direct mentions of the president. Obama's "indictment" comment came after Baker himself joked that he was proud not to have been indicted, a response to Meacham's closing question about what Baker, 88, was most proud of from his time serving presidents. Numerous Trump aides or associates have been indicted or pleaded guilty for various charges, and on Monday special counsel Robert Mueller's office said former Trump campaign chairman Paul Manafort had violated a plea agreement by lying to the FBI. Baker, a Houston native, served under Ronald Reagan and both Bush presidents, including for four years as Reagan's chief of staff. He and Obama devoted most of the conversation to what might have caused the heightened partisanship that developed between Baker's initial years in Washington and Obama's presidency decades later. They largely agreed that a changing media landscape and partisan redistricting had caused the parties to diverge, with Obama at one point calling Texas a "champion of gerrymandering." The former president got behind the idea of independent redistricting commissions, saying under the current process, "the elected official chooses the voters rather than the other way around." On the topic of the media's impact on increased partisanship, Obama recalled the older, more consolidated news landscape that Baker experienced under the Reagan administration — when, with fewer publications, Obama said "there was a common set of facts, a baseline" to which both parties responded. "By the time I take office, what you increasingly have is a media environment in which if you are a Fox News viewer, you have an entirely different reality than if you are a New York Times reader," he said. Baker, who from the beginning insisted that the Baker Institute be nonpartisan, agreed, saying, "The responsible center in American politics has disappeared." Later, when the interview briefly turned to foreign policy matters, Baker indicated concern over the state of international institutions and the U.S.'s global standing since Trump became president. "American leadership in the world is absolutely imperative. No other country can do it," Baker said, later adding that America won the Cold War "because we had alliances." Obama's visit comes amid a fraught period for American foreign policy, including the death Tuesday of three American soldiers in a Taliban roadside bombing in Afghanistan and a highly partisan debate has ensued over an incident Sunday at a San Diego border crossing. The interview took a broader approach, however, and those current events went largely unmentioned. Meanwhile, Obama in recent months has grown politically active, stumping for Democrats in a handful of states in the final days of the midterm election campaign. In a post-election interview with David Axelrod, his former strategist, he also drew a parallel between his own presidential candidacy and the Senate bid of Democratic Rep. Beto O'Rourke, who fell about three points short in his challenge to Sen Ted Cruz, R-Texas. O'Rourke also went unmentioned Tuesday.

– Former President Obama got in a dig at the Trump administration at a Rice University gala on Tuesday without even mentioning the president's name. Obama's 50-minute interview with former Secretary of State James A. Baker III—the namesake of the nonpartisan Baker Institute for Public Policy, which was honored for its 25th anniversary—"carried an anti-Trump tone" despite almost no mention of the man, per the Houston Chronicle. Obama broached the subject toward the end of the conversation moderated by presidential historian Jon Meacham, however, after Baker said he was most proud not to have been indicted while serving under three presidents. "Not only did I not get indicted, nobody in my administration got indicted," Obama told the crowd of more than 1,000 invited guests, per the Chronicle and KPRC. "It was the only administration in modern history that that can be said about … probably because the people who joined us were there for the right reasons," Obama continued. Again without naming him, the 44th president also referenced Trump's ideology—"a nationalism that's not pride in country but hatred for somebody on the other side of the border," per the Guardian—though the conversation mostly centered on political partisanship and the media. "What you increasingly have is a media environment in which if you are a Fox News viewer, you have an entirely different reality than if you are a New York Times reader," Obama said. "It means the bases of each party have become more ideological." "The responsible center in American politics has disappeared," Baker agreed. (Obama was lately spotted bagging potatoes at a Chicago food bank.)

Life-size human statues and the remains of an ancient temple dating back some 2,500 years have been discovered in the Kurdistan region of northern Iraq. The region's hilly environment, shown here. Life-size human statues and column bases from a long-lost temple dedicated to a supreme god have been discovered in the Kurdistan region of northern Iraq. The discoveries date back over 2,500 years to the Iron Age, a time period when several groups — such as the Urartians, Assyrians and Scythians — vied for supremacy over what is now northern Iraq. "I didn't do excavation, just archaeological soundings —the villagers uncovered these materials accidentally," said Dlshad Marf Zamua, a doctoral student at Leiden University in the Netherlands, who began the fieldwork in 2005. The column bases were found in a single village while the other finds, including a bronze statuette of a wild goat, were found in a broad area south of where the borders of Iraq, Iran and Turkey intersect. [See Photos of the Life-Size Statues & Other Discoveries in Iraq] For part of the Iron Age, this area was under control of the city of Musasir, also called Ardini, Marf Zamua said. Ancient inscriptions have referred to Musasir as a "holy city founded in bedrock" and "the city of the raven." A lost ancient temple "One of the best results of my fieldwork is the uncovered column bases of the long-lost temple of the city of Musasir, which was dedicated to the god Haldi," Marf Zamuatold Live Science in an email. Haldi was the supreme god of the kingdom of Urartu. His temple was so important that after the Assyrians looted it in 714 B.C., the Urartu king Rusa I was said to have ripped his crown off his head before killing himself. A 19th-century drawing of an ancient relief that depicts the sacking of the temple of Haldi by the Assyrians. Credit: Drawing by Eugène Flandin, in public domain He "threw himself on the ground, tore his clothes, and his arms hung limp. He ripped off his headband, pulled out his hair, pounded his chest with both hands, and threw himself flat on his face …" reads one ancient account (translation by Marc Van De Mieroop). The location of the temple has long been a mystery, but with the discovery of the column bases, Marf Zamua thinks it can be narrowed down. [Photos: Ancient Temple Discovered in Turkey] Additionally, Marf Zamua analyzed an ancient carving of Musasir, discovered in the 19th century at Khorsabad. The carving, he found, shows hillside houses with three windows on the second floor and a doorway on the ground floor. Such a design can still be seen today in some villages, the bottom floor being used as a stable and storage area, he noted. Life-size statues This long-lost temple is just the tip of the archaeological iceberg. During his work in Kurdistan, Marf Zamua also found several life-size human statues that are up to 7.5 feet (2.3 meters) tall. Made of limestone, basalt or sandstone, some of these statues are now partly broken. They all show bearded males, some of whom "are holding a cup in their right hands, and they put their left hands on their bellies," said Marf Zamua. "One of them holds a hand ax. Another one put on a dagger." Originally erected above burials, the statues have a "sad moment" posture, Marf Zamua said. Similar statues can be found from central Asia to eastern Europe. "It is art and ritual of nomads/pastorals, especially when they [buried] their chieftains," Marf Zamua said. Mostof the newfound statues date to the seventh or sixth century B.C., after Musasir fell to the Assyrians, and during a time when the Scythians and Cimmerians were advancing through the Middle East. Modern-day dangers and ancient treasures Over the past few weeks, conflict in Iraq has been increasing as a group called the "Islamic State in Iraq and the Levant" (ISIS) has taken several cities and threatened to march on Baghdad. The Kurdistan area, including this archaeological site, is autonomous, and its militia has been able to prevent ISIS from entering it. Several life-sized human statues of bearded males, dating back to the seventh or sixth centuries B.C., have also been discovered in Kurdistan. Credit: Photo courtesy Dlshad Marf Zamua Marf Zamuasaid there are risks associated with living and working in the border area. Due to the conflicts of the past few decades, there are numerous unexploded land mines, one of which killed a young shepherd a month back, he said. Additionally the National Iraqi News Agency reports that Iranian artillery recently fired onto the Iraqi side of the border, and there have been past instances where planes from Turkey have launched attacks into Iraqi Kurdistan. Despite these risks, there are also terrific archaeological finds to be made. In addition to the statues and column bases, Marf Zamuafound a bronze statuette of a wild goat about 3.3 inches (8.4 centimeters) long and 3.2 inches (8.3 cm) tall. Researchers are now trying to decipher a cuneiform inscription on the statuette. Marf Zamua presented the discoveries recently in a presentation given at the International Congress on the Archaeology of the Ancient Near East, held at the University of Basel in Switzerland. In addition to his doctoral studies, Marf Zamua teaches at Salahaddin University in Erbil, which is the capital of Iraqi Kurdistan. Follow us @livescience, Facebook & Google+. Original article on Live Science. ||||| An archaeologist working in the Kurdistan region of northern Iraq has made several discoveries, including life-sized human statues and the remains of an ancient temple. The artifacts were found accidentally by villagers and were collected during fieldwork. The finds date back more than 2,500 years to the "Iron Age," a time when several groups, such as the Urartians, Assyrians and Scythians, vied for control of the area. This image shows the region's hilly environment. [ Read full story on the Iraq discoveries

– An archaeologist is closing in on the location of an ancient temple so venerated that when it was sacked in 714 BC, its king tore off his crown, "pulled out his hair, pounded his chest with both hands"—then killed himself, according to an early account. The long-lost temple in question was in the city of Musasir, and Dutch doctoral student Dlshad Marf Zamua thinks he's found its column bases in Kurdistan, in modern day Iraq, LiveScience reports. The temple was dedicated to Haldi, the supreme god of the Uratu kingdom, and its bases were found by villagers and date back 2,500 years to the Iron Age, when several groups competed for control of the region. The aforementioned drama king was the Urartu king Rusa I, after the Assyrians looted it. Discovery of the column bases isn’t the end of the story. Marf Zamua has found a bronze statuette of a wild goat with cuneiform inscriptions that need decoding, and several 7 1/2-foot-tall statues of bearded men that were once raised above burial sites. An ancient carving of Musasir also revealed architecture similar to that found in modern villages, Marf Zamua says. His discoveries in Kurdistan have been made under the growing cloud of ISIS. LiveScience has photos of the finds here, but it's not the only Iron Age story in the news today.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Commonsense Legislative Exceptional Events Reforms Act of 2014''. SEC. 2. CLEAN AIR ACT EXCEPTIONAL EVENTS. Section 319(b) of the Clean Air Act (42 U.S.C. 7619(b)) is amended-- (1) in paragraph (1)(B)-- (A) in clause (i)-- (i) by striking ``(i) stagnation of air masses or'' and inserting ``(i)(I) ordinarily occurring stagnation of air masses or (II)''; and (ii) by inserting ``or'' after the semicolon; (B) by striking clause (ii); and (C) by redesignating clause (iii) as clause (ii); and (2) in paragraph (3)-- (A) in subparagraph (B)(iv), by striking ``to petition the Administrator to'' and inserting ``to submit a petition (in this section referred to as an `exceptional event demonstration') to the Administrator to''; and (B) by adding at the end the following: ``(C) Criteria for determination of exceptional event demonstration.-- ``(i) In general.--The criteria for evidence, analyses, and documentation applicable to approval or disapproval of an exceptional event demonstration under the regulations under this section shall be stated with specificity in order to minimize the discretion of the Administrator in approving or disapproving that demonstration. ``(ii) State participation.--The Administrator shall develop the criteria in conjunction with input from the States. ``(iii) Contents.--The criteria shall reflect the varying levels of technical expertise and resources available in State and local agencies and the varying availability of meteorological and other monitoring data in rural areas, and may vary with respect to different regions. ``(iv) Considerations.--In developing the criteria, the Administrator shall consider the use of an expedited or streamlined approval process and conditions under which exceptional event demonstrations may be suitable for such a process. ``(D) Timing of determination of exceptional event demonstration.-- ``(i) Deadline for determination.-- ``(I) In general.--Not later than 90 days after submission of an exceptional event demonstration, the Administrator shall approve, disapprove, or request additional information from a State regarding the exceptional event demonstration. ``(II) Administration.--If the Administrator does not approve, disapprove, or request additional information relating to an exceptional event demonstration within the 90-day period described in subclause (I), the demonstration shall be considered to be approved on the day after the date on which that 90-day period ends. ``(ii) Deadline if additional information requested.-- ``(I) In general.--If the Administrator requests additional information from a State regarding an exceptional event demonstration under clause (i), not later than 90 days after the submission of that additional information, the Administrator shall approve or disapprove the demonstration. ``(II) Administration.--If the Administrator does not approve or disapprove a demonstration for which additional information is submitted within the 90-day period described in subclause (I), the demonstration shall be considered to be approved. ``(E) Burden of proof.--The regulations promulgated under this section shall provide that-- ``(i) a determination by the Administrator with respect to approval or disapproval of an exceptional event demonstration be based on a preponderance of the evidence; and ``(ii) in making a determination, the Administrator-- ``(I) shall accord substantial deference to the findings of the State exceptional event demonstration; and ``(II) may develop and use analyses and consider evidence not provided in the exceptional event demonstration, subject to the condition that the analyses are developed by the Environmental Protection Agency. ``(F) Appeals.-- ``(i) Disapproval.-- ``(I) In general.--Subject to subclause (II), disapproval by the Administrator of an exceptional event demonstration shall be considered final action subject to judicial review under section 307(b). ``(II) Limitation.--Notwithstanding subclause (I), disapproval by the Administrator of an exceptional event demonstration shall only be subject to appeal by the State that submitted the exceptional event demonstration. ``(ii) Approval.--Approval by the Administrator of an exceptional event demonstration shall not be subject to appeal or other judicial action.''. SEC. 3. REVISION OF REGULATIONS. After providing for a notice and comment period, but not later than 180 days after the date of enactment of this Act, the Administrator of the Environmental Protection Agency shall revise the regulations under section 319(b) of the Clean Air Act (42 U.S.C. 7619(b)) to carry out the amendments made by this Act.

Commonsense Legislative Exceptional Events Reforms Act of 2014 - Amends the Clean Air Act to revise the requirements for regulations that govern the review and handling of air quality monitoring data influenced by exceptional events. (The Environmental Protection Agency [EPA] may exclude monitored exceedances of the National Ambient Air Quality Standards from consideration when designating an area as nonattainment, redesignating an area as nonattainment, or reclassifying an existing nonattainment area to a higher classification if a state demonstrates that an exceptional event caused the exceedances.) Requires the criteria used to determine if an exceptional event was demonstrated to be specific in order to minimize the discretion of the EPA in approving or disapproving the demonstration. Requires the EPA to make a determination within 90 days after the submission of a petition by a state of an exceptional event demonstration. Considers the demonstration approved if the EPA does not make a determination by that deadline. Requires a determination to be based on a preponderance of the evidence and to accord substantial deference to the findings of the state exceptional event demonstration. Establishes an appeal process for reviewing a disapproval of a demonstration.

SECTION 1. SHORT TITLE. This Act may be cited as the ``American Timber Supply and Manufacturing Incentives Act''. SEC. 2. INVESTMENT INCENTIVE FOR DOMESTIC TIMBER PRODUCTION. (a) In General.--Part I of subchapter P of chapter 1 of the Internal Revenue Code of 1986 (relating to treatment of capital gains) is amended by adding at the end the following new section: ``SEC. 1202. INVESTMENT INCENTIVE FOR DOMESTIC TIMBER PRODUCTION. ``(a) In General.--At the election of any taxpayer who has qualified timber gain for any taxable year, there shall be allowed as a deduction from gross income an amount equal to the qualified percentage of such gain. ``(b) Qualified Timber Gain.--For purposes of this section-- ``(1) In general.--The term `qualified timber gain' means the lesser of-- ``(A) the net capital gain for the taxable year, or ``(B) the net capital gain for the taxable year determined by taking into account only gains and losses from qualified timber. ``(2) Qualified timber.--The term `qualified timber' means any timber with respect to which the taxpayer has provided assurances (which are satisfactory to the Secretary) that substantially all of the processing of the timber will occur within the United States. ``(c) Qualified Percentage.--For purposes of this section, the term `qualified percentage' means the percentage (not exceeding 30 percent) determined by multiplying-- ``(1) 2 percent, by ``(2) the number of years in the holding period of the taxpayer with respect to the timber. ``(d) Estates and Trusts.--In the case of an estate or trust, the deduction under subsection (a) shall be computed by excluding the portion (if any) of the gains for the taxable year from sales or exchanges of capital assets which, under sections 652 and 662 (relating to inclusions of amounts in gross income of beneficiaries of trusts), is includible by the income beneficiaries as gain derived from the sale or exchange of capital assets.'' (b) Coordination With Existing Limitations.-- (1) Subsection (h) of section 1 of such Code (relating to maximum capital gains rate) is amended by inserting after ``net capital gain'' each place it appears the following; ``(other than qualified timber gain with respect to which an election is made under section 1202)''. (2) Subsection (a) of section 1201 of such Code (relating to alternative tax for corporations) is amended by inserting after ``net capital gain'' each place it appears the following: ``(other than qualified timber gain with respect to which an election is made under section 1202)''. (c) Allowance of Deduction in Computing Adjusted Gross Income.-- Subsection (a) of section 62 of such Code (relating to definition of adjusted gross income) is amended by adding at the end the following new paragraph: ``(14) Investment incentive for domestic timber production.--The deduction allowed by section 1202.'' (d) Conforming Amendment.--The table of sections for part I of subchapter P of chapter 1 of such Code is amended by adding at the end the following new item: ``Sec. 1202. Investment incentive for domestic timber production.'' (e) Effective Date.--The amendments made by this section shall apply to sales or exchanges after the date of the enactment of this Act. SEC. 3. APPLICATION OF PASSIVE LOSS LIMITATIONS TO TIMBER ACTIVITIES. (a) Determination of Material Participation.--Subsection (h) of section 469 of the Internal Revenue Code of 1986 (defining material participation) is amended by adding at the end the following new paragraph: ``(6) Treatment of timber activities.-- ``(A) In general.--A taxpayer shall be treated as materially participating in any timber activity for a taxable year if-- ``(i) the taxpayer's participation in the activity for such year constitutes substantially all of the participation in the activity of all individuals for such year, other than individuals-- ``(I) who are not owners of interests in the activity, ``(II) who are retained and compensated directly by the taxpayer, and ``(III) whose activities are subject to the oversight supervision, and control of the taxpayer, or ``(ii) based on all of the facts and circumstances, the taxpayer participates in the activity on a regular, continuous, and substantial basis during such year, except that for purposes of this clause-- ``(I) the taxpayers shall not be required to participate in the activity for any minimum period of time during such year, and ``(II) the performance of services by individuals who are not owners of interests in the activity shall not be considered if the services are routinely provided by individuals specializing in such services and such services are subject to the oversight, supervision, and control of the taxpayer. ``(B) Partners and s corporation shareholders.-- Subject to paragraph (2), the determination of whether a partner or S corporation shareholder shall be treated as materially participating in any timber activity of the partnership or S corporation shall be based upon the combined participation of all of the partners or shareholders in the activity. ``(C) Timber activity.--For purposes of this paragraph, the term `timber activity' means the planting, cultivating, caring, cutting, or preparation (other than milling) for market, of trees.'' ``(b) Effective Date.--The amendment made by this section shall apply to taxable years beginning after the date of the enactment of this Act. SEC. 4. DENIAL OF CERTAIN EXPORT SUBSIDIES. (a) Foreign Sales Corporation.--Paragraph (2) of section 927(a) of the Internal Revenue Code of 1986 (relating to exclusion of certain property) is amended by striking ``or'' at the end of subparagraph (C), by striking the period at the end of subparagraph (D) and inserting ``, or'', and by adding at the end thereof the following: ``(E) any unprocessed timber. For purposes of subparagraph (E), the term `unprocessed timber' has the same meaning as that given to it in the Customs and Trade Act of 1990 (104 Stat. 629).'' (b) Domestic International Sale Corporations.--Paragraph (2) of section 993(c) of such Code (relating to exclusion of certain property) is amended by striking ``or'' at the end of subparagraph (C), by striking the period at the end of subparagraph (D) and inserting, ``, or'', and by adding after subparagraph (D) the following: ``(E) any unprocessed timber. For purposes of subparagraph (E), the term `unprocessed timber' has the same meaning as that given to it in the Customs and Trade Act of 1990 (104 Stat. 629).'' (c) Title-Passage Rule.--Subsection (b) of section 865 of such Code (relating to source rules for personal property sales) is amended by adding at the end thereof the following: ``Notwithstanding the preceding sentence, any income from the sale of any unprocessed timber which is a softwood and was cut from an area in the United States shall be sourced in the United States and the rules of sections 862(a)(6) and 863(b) shall not apply to any such income. For purposes of the preceding sentence, the term ``unprocessed timber'' has the same meaning as that given to it in the Customs and Trade Act of 1990 (104 Stat. 629).'' (d) Elimination of Deferral.--Subsection (d) of section 954 of such Code is amended by adding at the end thereof the following new paragraph: ``(4) Special rule for certain timber products.--For purposes of subsection (a)(2), the term `foreign base company sales income' includes any income (whether in the form of profits, commissions, fees, or otherwise) derived in connection with-- ``(A) the sale of any unprocessed timber referred to in section 865(b), or ``(B) the milling of any such timber outside the United States. Subpart G shall not apply to any amount treated as subpart F income by reason of this paragraph.'' (e) Effective Date.--The amendments made by this section shall apply to sales, exchanges, or other dispositions after the date of the enactment of this Act.

American Timber Supply and Manufacturing Incentives Act - Amends the Internal Revenue Code to provide taxpayers a deduction from gross income for qualified timber gain as an investment incentive. Allows such deduction in computing adjusted gross income. Provides for applying passive loss limitations to timber activities. Provides that export property eligible for certain tax incentives does not include any unprocessed softwood timber for purposes of: (1) taxation of foreign sales corporations (FSCs); and (2) taxation of domestic international sales corporations (DISCs). Requires any income from the sale of such unprocessed timber which was cut from an area in the United States to be sourced in the United States. Excludes such income from rules under which: (1) gains, profits, and income involving inventory property purchased in the United States but sold or exchanged elsewhere may be sourced foreign; and (2) income derived from the manufacture of products in the United States and their sale elsewhere may be treated as having a divided source. Repeals the deferral from income of the controlled foreign corporation from sales or milling (outside the United States) of unprocessed softwood timber to the extent that any controlled foreign corporation is owned by ten percent or more U.S. shareholders.

adolescence , considered as a transitional stage of physical and mental human development , occurs between childhood and adulthood . nutrition is one the most important health priorities of adolescence , but only a few interventional programs are concentrated on adolescents nutrition health in iran . based on related experiences , it can be observed that the adolescents health promotion needs more community partnership , training programs , capacity building , safe and supportive environment . regarding this , parents , especially mothers , have a unique position in influencing adolescents food selection at home . the effectiveness , utilization , and impact of the school - based health programs showed by different studies . considering the above , we conducted an interventional participatory study with the participation of adolescents parents and health trainers of target middle schools . this paper aimed to compare the effects of these different training methods on the adolescents nutrition health promotion . among the 95,250 female students of tehran 's middle schools , 1823 participants of age 11 - 15 years were selected by stratified quota random sampling method from 15 middle schools of five geographic regions of tehran . the second group received training by school health trainers and the third group received designed training through their parents . the main questionnaire of this multidimensional study included 93 closed questions in which 28 questions focused on nutrition . family suitable nutritional habits pattern means suitable consumption of nutrients , and suitable consumption of various kinds of nutrients was defined as daily consumption of dairy , fruits , and vegetables and at least two or three times a week consumption of meat and cereals . the validity of questionnaire was confirmed through the peer - reviewed literature by 10 experts . its reliability was confirmed by test retest ( reliability coefficient : 0.8 ) . on assessment following 2 years of intervention , it was 82% in the trained by parents group , 81% in the trained by health trainer group , and 80% in the control group . data analyses were done by the use of spss software version 16 ( chicago , il , usa ) . descriptive statistics alongside the chi - squared ( ) test and analysis of variance ( anova ) were used for the analysis . statistical significance level was set at p < 0.05 ( two tailed ) . participation in this study was voluntary , and self - administered questionnaires were filled anonymously on getting the consent of every participant after they were explained the objectives of the study . there was no significant difference in age , weight , height , body mass index ( bmi ) , and the wrist circumference in the three groups . based on bmi measurements , 64% of participants were thin , 28.6% normal , 6.3% overweight , and 1.1% were obese . 59.5% of the girls had a positive perception of their height , and in this regard , no significant difference was found between the study groups . overall , 14% of the students had imagined themselves as obese girls , and this imagination significantly was higher in the control group compared with the other two groups ( p = 0.0002 ) . 25.1% of the control group participants , 33.9% of those trained by school health trainers , and 41% of those trained by parents had positive perception about their physical form . the pattern of variables related to body image in the control group and the groups trained by school health trainers and parents , respectively , 34.8% , 31.9% , and 33.3% girls had special diet for losing weight . accordingly , having such diet in the trained groups , especially in the parents trained group , was less than in the control group . totally , 50% of the students who were on diet had normal bmi . only about 50% of subjects believed increasing need for calorie during puberty and 11.9% of them believed it decrease . with regard to participants nutritional habits , moreover , the habit of eating breakfast was significantly higher in the trained groups in comparison with their counterparts in the control group ( p = 0.000 ) . appropriate consumption of various kinds of nutrients , dairy , meat , cereals , fruits , vegetables in the group trained by parents was higher than in the other groups , while use of fatty foods was higher in the control group than in other groups ( p = 0.0005 ) . the study of suitable use pattern of nutrients among the groups showed significant statistical difference in the suitable consumption of dairy , meat , cereals , and vegetables between the group trained by parents and the other groups ( p = 0.000 ) . there was a positive correlation between parents educational level and their family suitable nutritional habits and also with awareness of the adolescents regarding requirement of different nutrients . following special diet for weight loss and skipping meals was significantly lower in the trained groups ( p = 0.002 ) . this study indicated that nutritional health training leads to more tendency to eating breakfast in trained groups ( p = 0.000 ) . 88.2% of the participants believed that there was no difference between family members meal , but 11% of the adolescents thought that the fathers in the families received more and better meal . data analysis showed the high level of parents education led to less gender discrimination in the family . adolescence is a window to a healthy life in future . in order to promote adolescents health , we mobilized parents and school health trainers as the key stakeholders to participate in this interventional program . in the present study , 50% of the participants , despite having normal bmi , were following the weight loss diets , although in the trained groups , weight loss diets consumption was significantly less than in the other groups . also , intake of adequate nutrients in the group trained by parents was higher than in the other groups , while use of fatty foods in the control group was higher than in others . lack of family support , inadequate training , and limitations in the availability of healthy food are some barriers of adolescents healthy nutritional behavior . in some countries , but in our experience , 88% of the participants believed that there was no gender discrimination . as shown in our study , parents play a key role in knowledge transfer to their female adolescents for promotion of attitude and practice . we also faced some limitations such as lack of cooperation of some invited participants and long - term follow - up problems . we suggest that family - based interventional programs provide the best situation for adolescents nutrition health promotion , but there is no doubt that further studies , especially qualitative research , for the analysis of adolescents view points are needed for implementation of these programs .

background : unhealthy nutritional behaviors are a threat to adolescents . in this regard , we compared different training methods through a participatory interventional study.materials and methods : through proportional random selection , 1823 female students were selected from 15 middle schools of tehran . following 2 years of intervention , nutritional habits of three different interventional groups were assessed.results:eating breakfast was significantly higher in the trained groups , and the use of weight loss diets was lower in them than in the control group . also , satisfactory consumption of various kinds of nutrients in the trained groups was more than in the control group.conclusion:participatory health training , especially through parents , leads to adolescence nutritional health promotion .

the chemical modification of proteins is an established tool for studying the structure , function , and regulation of this class of biopolymer . moreover , in recent years , a great deal of effort has been directed toward the modification of proteins for therapeutic applications . traditionally , protein conjugation chemistries have exploited the reactivity of surface - exposed nucleophilic amino acids , such as cysteine or lysine , however , these methods typically result in heterogeneous mixtures of products , which can complicate biological studies or efficacious medicinal applications . to address this concern , several strategies have been developed for the site - specific modification of proteins , ranging from total chemical synthesis ( usually via native chemical ligation , ncl ) to the genetic incorporation of unnatural amino acids or bio - orthogonal functional groups . in between these two extremes the most widely used protein semisynthesis technique is an extension of ncl termed expressed protein ligation ( epl ) in which a recombinant protein -thioester building block is ligated to a synthetic molecule equipped with a 1,2-aminothiol moiety ( most commonly an n - terminal cys - containing peptide ) through the formation of a native peptide bond ( scheme 1 ) . since its inception , epl has been applied to a wide variety of proteins , including enzymes , ion channels , transcription factors , transmembrane receptors , and antibodies ( for reviews see refs ( 15 and 16 ) ) . one of the basic requirements of epl is a thioester group at the c - terminus of a recombinant protein . this reactive handle is introduced by exploiting a process known as protein splicing ( scheme 1 ) , which is mediated by an autoprocessing domain called an intein . protein splicing typically takes place through the formation of one or more protein thioester intermediates , which ultimately resolve to form a native peptide bond between the sequences flanking the intein ( referred to as n- and c - exteins ) . by using appropriate intein mutants , it is possible to intercept these intermediates with exogenous thiols , resulting in an n - extein of choice being cleaved from the mutant intein as a reactive -thioester derivative suitable for chemical ligation . int and int represent n- and c - intein fragments , respectively . despite the many successes of epl , the approach often suffers from low overall efficiency due to complications associated with the generation of protein -thioesters . in particular , fusions to inteins are , to varying extents , susceptible to premature extein cleavage , both in vivo and during initial purification from cell lysates , which reduces the isolated yield of the intein fusion needed for the subsequent thiolysis step . importantly , the cleaved extein side - product is unreactive toward epl , and its separation from the desired -thioester or the ligation product is often difficult for large proteins , such as antibodies . to compound matters , the thiolysis reaction itself can be slow and inefficient , further strengthening the need to develop customized purification regimes , involving multiple chromatographic steps , to isolate the desired product from complex mixtures . collectively , these technical issues mean that a considerable investment in time and resources is usually required before a semisynthetic protein is obtained in useful quantities . ( a ) schematic of the procedure for the isolation of an -thioester derivative of a protein of interest ( poi ) using engineered split intein fragments ( int and int ) . epl can be performed in a one - pot fashion during thiolysis from the split intein or immediately after elution , without need of any further purification . ( b ) sequences of npu ( wt ) and the npuaa mutant used on the split intein column . catalytic residues mutated in npuaa are shown in bold , and the linker sequence added for immobilization onto the solid support is underlined . sequences are numbered according to the intein sequence alignment shown in figure s2 . to overcome the various drawbacks associated with the intein thiolysis process central to epl , we envisioned an alternative strategy based on naturally occurring split inteins . unlike inteins used in standard epl , which are contiguous polypeptides that catalyze protein splicing in cis , split inteins consist of two discrete polypeptides , herein termed int and int , which , upon association , catalyze protein splicing in trans ( protein trans - splicing , pts , scheme 1 ) . split inteins have two important properties that make them attractive for an improved epl strategy . first , cognate int and int pairs often bind tightly to one another ; dissociation constants in the low nanomolar range , reflecting extremely fast on - rates , have been reported for members of the naturally split dnae inteins from cyanobacteria . this ability of split inteins to self - associate has recently been exploited by lu et al . as part of a traceless protein purification system , in this case using an artificially split intein pair . the potential utility of split inteins in epl is further enhanced by the remarkable splicing efficiency of some members of the family . for instance , many of the split dnae inteins have half - lives for the splicing reaction of less than a minute , as compared to several hours in the case of the cis - splicing inteins commonly used in epl . moreover , recent mechanistic investigations indicate that these ultrafast dnae inteins have a highly activated n - terminal splice junction , making them superior reagents for protein -thioester generation . given the unique properties of split inteins , in particular , the ultrafast split dnae inteins , we conceived the integrated protein modification system shown in figure 1 in which the split intein association is employed both to purify the desired protein from complex biological mixtures and to trigger the generation of a desired protein -thioester for epl . in principle , this complementation system should address the major issues attendant to the standard epl protocol , including premature cleavage of the intein , which can not occur in the case of a split intein fragment absent its cognate partner . to implement our system , we designed a mutant of the ultrafast nostoc punctiforme ( npu ) split dnae intein suitable for efficient -thioester generation . specifically , we mutated the catalytic c - terminal residue in the int fragment ( asn137 ) and the first residue in the c - extein ( cys+1 ) to ala , to allow for efficient build up of the desired splicing intermediates upon exposure to an n - extein - npu fusion ( figure 1 ) . preliminary studies showed that mixing n - extein - npu fusions ( where n - extein corresponded to various model proteins ) with the mutant npu ( npuaa ) led to highly efficient n - extein -thioester formation in a thiol - dependent manner ( figures s3 and s4 ) . importantly , only very low levels of intein cleavage ( i.e. , unwanted hydrolysis ) were observed in the absence of thiols , thereby fulfilling a requirement of our integrated strategy . encouraged by these results , we adapted the system for the one - pot purification and generation of c - terminally modified proteins by taking full advantage of the strong and specific interaction between the split intein fragments . accordingly , the npuaa peptide was immobilized on a solid support through a unique cys residue engineered within its c - extein region ( figure s5 ) . the resulting npuaa column ( hereafter referred to as int column ) was then evaluated as an affinity - modification resin . three test proteins maltose binding protein ( mbp ) , ubiquitin ( ub ) , and protein histidine phosphatase type 1 ( phpt1 ) were genetically fused to npu and expressed in escherichia coli . in each case , cells were lysed , and the soluble fraction was loaded onto the int column to allow binding of the npu tagged protein to the immobilized npuaa . after a brief incubation ( 5 min at rt ) the column was extensively washed to remove contaminants , and thiolysis was triggered by addition of a buffer containing the thiol , mercaptoethansulfonate ( mes ) . in all three cases , the desired -thioester protein eluted from the int column with high recovery ( 7595% ) and high purity ( 95% as determined by rp - hplc and mass spectrometry ) ( figure 2 ) . total isolated yields of purified protein -thioesters varied from one protein to another and ranged from 2.5 mg ( per l of bacterial culture ) for ub - mes to 40 mg for mbp - mes . the calculated loading capacity of the int column used in these experiments was 36 mg of protein per ml of beads ( 0.12 mols / ml ) , but higher or lower loadings could easily be achieved by modifying the amount of npu - aa immobilized on the solid support . furthermore , we showed that the int column could be regenerated and reused at least 5 times with only minimal loss of capacity ( figures s11 and s12 ) . the utility of the -thioester derivatives of ub , mbp , and phpt1 obtained from the column was demonstrated by ligating each of them to an n - terminal cys - containing fluorescent peptide ( cgk(fl ) ) to give the corresponding semisynthetic products in excellent yield ( figure s10 ) . importantly , one - pot thiolysis / ligation reactions could be carried out , which allowed us to obtain a site - specifically modified protein directly from cell lysates without isolating the intermediate thioester ( figure 3 ) . ( a ) mbp , ( b ) phpt1 , and ( c ) ub mercaptoethansulfonate ( mes ) -thioesters were purified in one step from e. coli cell lysates using the int column . the purifications were monitored by coomassie stained sds - page analysis ( top ) ( inp : input , ft : column flow - through , w1 - 3 : washes , e1 - 4 : elutions , and bds : resin beads ) . rp - hplc ( detection at 214 nm ) and esi - tof ms analysis of the eluted fractions ( bottom left and right , respectively ) confirmed the identity of all protein -thioesters and indicated high purity . one - pot purification / ligation of ubiquitin to the h - cgk(fluorescein)-nh2 peptide ( cgk(fl ) ) . ub - npu from e. coli cell lysates was bound to the int column , as shown in figure 2 , and after removal of contaminants through extensive washes , intein cleavage and ligation were triggered by addition of 200 mm mes and 1 mm cgk(fl ) peptide . coomassie stained sds - page analysis and in gel fluorescence of the purification / ligation ( left ) . rp - hplc ( detection at 214 and 440 nm ) and esi - tof ms ( right ) of the eluted fractions confirm the desired ligated protein was obtained in one step directly from cell lysates with a ligation yield close to 95% ( quantified by rp - hplc ) . an attractive feature of epl is that it can allow for the preparation of site - specifically modified proteins in a virtually traceless manner . this is contingent on the ability to efficiently generate recombinant protein -thioesters when any of the 20 proteinogenic amino acids are present at the c - terminus of the protein . the activity of split inteins is known to be sensitive to the identity of the amino acids immediately flanking the splice junction . thus , we were eager to test the generality of our strategy and asked whether we could generate -thioesters of all 20 amino acids , using ubiquitin as the n - extein template . twenty ub - npu fusion proteins were individually expressed in e. coli and purified over the int column as before . thiol - induced cleavage yields from the solid support were determined by sds - page analysis of the eluted and resin beads fractions , and levels of competing side reactions ( mainly hydrolysis ) were measured by rp - hplc and esi - tof ms . the results clearly show that for most amino acids > 60% of the bound proteins were recovered after mes treatment . furthermore , 8095% of the eluted material was the desired -thioester product . the only exceptions were pro and glu , for which recovery were 49 and 50% , respectively ( figure 4 ) . the asn mutant displayed high levels of cleavage from the split intein , but almost no -thioester could be isolated due to side - chain cyclization to form a c - terminal succinimide . a second problematic residue was asp , for which we observed some premature cleavage during initial binding to the int resin . moreover , rp - hplc analysis of the eluted fractions upon thiolysis revealed two species with the molecular weight of the desired -thioester . these results were not wholly unexpected , as asp is known to cleave prematurely from contiguous inteins through side - chain cyclization , and its -thioesters have been reported to migrate to the side - chain carboxylate yielding mixtures of - and -isomers . these minor constraints aside , it is clear from these studies that our streamlined epl system is compatible when the majority of amino acids are present as the last residue in the protein of interest . the 20 mutants of the protein ub - x - npu were expressed in e. coli varying the identity of the c - terminal amino acid of ub ( x ) from the wt gly to all other proteinogenic amino acids . thiol - induced cleavage yields from the int column were calculated from the sds - page analysis of the eluted fractions and left over resin beads . ratios of -thioester vs side products were determined from rp - hplc and esi - tof ms analysis of the eluted fractions . the major competing reaction for all amino acids was hydrolysis with the exception of asn for which its succinimide form was isolated instead . * protein semisynthesis frequently requires the preparation of protein fragments , which are often poorly behaved and need to be purified in the presence of strong chaotropic agents . we first confirmed that the model protein ub - npu could bind the int column in the presence of 2 and 4 m urea and that the corresponding ub -thioester could be generated with similar yields as obtained under native conditions ( figure s14 ) . this is consistent with a previous study , which demonstrated npu dnae could splice in the presence of high concentration of denaturants . we then turned to a more challenging target , namely a fragment of histone h2b ( residues 1116 ) , a polypeptide that is prone to aggregation and difficult to generate as an -thioester derivative using standard epl procedures . we expressed human histone h2b(1116 ) fused to npu in e. coli , extracted it from inclusion bodies in 6 m urea , and diluted it to 2 m urea prior to loading on the int - intein column . the incubation was performed for 3 h at ph 6.0 to maximize binding while avoiding premature cleavage through hydrolysis . the ph was then raised to 7.2 , and thiolysis was carried out for 36 h at rt ( note that the presence of the denaturant slows down the thiolysis rate ) . using these conditions , hh2b(1116)-mes was obtained in excellent purity ( > 90% by rp - hplc ) and isolated yield ( 20 mg per l of culture ) . this represents a significant improvement over previous protocols which afford less protein ( 4 mg per l of culture ) and require the use of multiple chromatographic purification steps including rp - hplc . importantly , the hh2b(1116)-mes thioester obtained from the int column could be directly used in epl reactions without further purification . accordingly , we successfully ligated the protein to a hh2b(117125 ) peptide containing an acetylated lys at position 120 to yield semisynthetic hh2b - k120ac ( figure 5 ) . coomassie stained sds - page analysis of hh2b(1116 ) -thioester generation in the presence of 2 m urea ( sup : cell lysate supernatant , trit : 1% triton wash of the inclusion bodies , inp : solubilized inclusion bodies used as input for the int column ) . e1e3 were collected after 18 h of incubation with mes and e4e6 after an additional 18 h. e1e6 were pooled , concentrated to 150 m , and ligated to the peptide h - cvtk(ac)ytsak - oh at 1 mm for 3 h at rt . ( b ) rp - hplc ( left ) of the ligation reaction mixture and ms ( right ) of the ligated hh2b - k120ac product . finally , we tested our streamlined epl methodology for the modification of a monoclonal antibody . the site - specific modification of antibodies has become highly desirable in the area of biopharmaceuticals and diagnostics . currently , most commercially utilized methods to conjugate cargo to antibodies are relatively nonspecific and result in polydisperse mixtures that may vary from batch - to - batch . since this heterogeneity can adversely affect both efficacy and safety of the conjugate indeed , protein semisynthesis via standard epl and pts has recently been used to generate monoclonal antibody conjugates with full activity . given this , we were eager to see whether our streamlined epl process could be used in the facile generation of antibody conjugates . as a model immunoglobulin ( igg ) for our studies , we used an antibody against the dec205 receptor , a c - type lectin found predominantly on dendritic cells . accordingly , we designed a construct in which npu was fused to the c - terminus of the heavy chain of the antibody ( dec205-npu ) . initial expression tests of dec205-npu in 293 t cells resulted in very low levels of the antibody being secreted ( figure 6a ) . we have observed previously that the identity of the int can have an effect on expression levels of its fusions . consequently , we asked whether we could obtain higher levels of secreted dec205-int by varying the identity of the intein n - fragment . several new dec205-int constructs were generated in which int corresponded to the n - fragment of a series of ultrafast split dnae inteins , namely , ava , csp , cra , cwa , mcht , oli , and ter . we also tested an npu mutant ( c - s ) where the noncatalytic cysteines , cys28 and cys59 , were mutated to ser , to determine whether these residues influence secretion and maturation of the igg tetramer ( figure 6a ) . importantly , each of the int fragments in this set can cross - react with the c - fragment of npu without significant loss of splicing efficiency . thus , the int column already in hand is compatible with all of these dec205-int fusions . the contiguous mxe gyra intein was also fused to dec205 to test whether the use of n - intein fragments negatively affected expression levels compared to a full - length intein . an expression screen of this dec205-int library was performed in 293 t cells , revealing that the ava and csp fusions reproducibly exhibited higher expression levels than the other n - inteins , with the former being the best . indeed , the expression levels of the dec - ava construct were at least as good as the dec - gyra construct . based on this , the dec205-ava fusion was chosen and purified over the int column in an analogous manner to that of the soluble proteins described above ( figure 6b ) . elutions from the column contained the thiolyzed dec205 , which was subsequently ligated to the cgk(fl ) peptide ( figure 6c ) . size exclusion chromatography ( sec ) coupled to multiple angle light scattering ( mals ) analysis confirmed that the antibody retained its tetrameric folded state after thiolysis and ligation ( figure 6d ) . we also performed ms analysis of the deglycosylated and fully reduced antibody , which confirmed the formation of a stable , nonreducible amide bond between the dec205 heavy chain and the fluorescent peptide with a 75% yield ( figure 6e ) . importantly , we demonstrated that the semisynthetic dec - cgk(fl ) retains its ability to bind the dec205 receptor to the same extent as a control dec205 , previously shown to be fully functional in vivo(46 ) ( figure 7 ) . binding of dec - cgk(fl ) to the dec205 receptor could be monitored not only by flow cytometry using an antimouse igg secondary antibody ( figure 7 ) but also through the site - specifically incorporated fluorescein ( figure s20 ) . purification of a monoclonal antibody -thioester using a split intein and its site - specific modification . ( a ) test expression of dec205 genetically fused to the contiguous mxe gyra intein and different split dnae inteins through the c - terminus of its heavy chain ( hc ) . western blot of 293 t cell supernatants of several dec205-int fusions using an antibody against mouse igg . ( c ) elution fractions containing dec205-mes were concentrated to 20 m and ligated to the cgk(fl ) fluorescent peptide at 1 mm for 48 h at rt . ( d ) sec - mals analysis of the ligated antibody showing that it retains its tetrameric structure after thiolysis and ligation ( mw = 151 kda , mw calcd = 148 kda ) . ( e ) esi - tof ms analysis of degycosylated and fully reduced hc after ligation , showing 75% of the hc is labeled . ( a ) dose dependent binding of dec205-cgk(fl ) to cho cells expressing the mouse dec205 receptor monitored by flow cytometry using a pe - labeled -mouse igg . binding to control cho / neo cells , which do not express the receptor is shown in gray . ( b ) as in ( a ) but using a control -dec205 antibody . we have shown that split dnae inteins can be engineered for the efficient generation and isolation of protein -thioesters . furthermore , the strategy can be seamlessly integrated with epl , and one pot purification / ligations can be performed without isolation of the -thioester intermediates . we note , however , that the ligation step ( i.e. , ncl ) still requires the use of high concentrations ( high m or above ) of n - terminal cysteine peptide for efficient reactions . the strong and specific interaction between the two intein fragments facilitates the purification of protein -thioesters under a variety of conditions , including strong denaturants , and the isolation of these products directly from cell lysates proceeds significantly faster than via many mainstream epl strategies , which often take multiple days and several intermediate enrichment / purification steps . additionally , while split intein fusions are usually associated with low levels of expression , we show here that certain dnae int fragments express to the same levels as commonly used contiguous inteins when fused to a monoclonal ab . moreover , the absence of premature cleavage events allowed us to generate semisynthetic proteins , such as h2b - k120ac in far superior yields than those of previously established protocols . importantly , we have shown the utility of this methodology for the modification of complex biomolecules such as an igg . thus , streamlined epl via our split dnae intein column should provide an efficient route to site - specifically modified proteins for basic biochemical research as well as translational applications . npu - aa - cys - ome peptide ( 0.5 mols per ml of resin ) was dissolved in 2 column volumes ( cv ) of coupling buffer ( 50 mm trishcl at ph 8.5 , 250 l for 125 l resin ) and treated with 25 mm tcep from a 1 m stock for 15 min . the peptide solution was then added to 1 cv of agarose sulfolink resin ( from pierce , loading : 18.4 mol iodoacetyl groups / ml of resin ) in a small fritted column and incubated for 15 min on a nutator , followed by 30 min standing at rt . the column flow - through was collected , and the column was washed twice with 2 cv of coupling buffer . unreacted iodoacetyl groups on the resin were blocked by a treatment with 50 mm h - cys - ome in coupling buffer for 15 min on a nutator , followed by 30 min standing at rt . column was washed twice with 1 cv of coupling buffer , 2 cv of 1 m nacl , and finally 2 cv of water . int columns were stored in storage buffer ( 100 mm phosphate , 150 mm nacl , 1 mm edta , 0.05% nan3 , ph 7.2 ) , at 4 c for up to 2 weeks . e. coli bl21(de3 ) cells transformed with the desired poi - npu plasmid were grown in 1 l of lb containing 100 g / ml of ampicillin at 37 c until od600 = 0.6 . after harvesting the cells by centrifugation ( 10 500 rcf , 30 min ) , the cell pellets were transferred to 50 ml conical tubes with 20 ml of high - salt binding buffer ( 100 mm phosphate , 500 mm nacl , 1 mm edta , 1 mm tcep , ph 7.2 ) with complete protease inhibitor cocktail ( roche ) and stored at 80 c . resuspended cells were lysed by sonication , and the soluble fraction recovered by centrifugation ( 17 000 rcf , 10 min ) . onto 62.5 l of int column , 300 l of the soluble fraction were loaded and incubated at rt for 5 min . after incubation , the flow - through was collected , and the column was washed with 300 l of high - salt binding buffer , 300 l of wash buffer ( 100 mm phosphate , 300 mm nacl , 1 mm edta , 1 mm tcep , ph 7.2 ) , and 300 l of binding buffer ( 100 mm phosphate , 150 mm nacl , 1 mm edta , 1 mm tcep , ph 7.2 ) . the column was capped and incubated with 150 l of elution buffer ( 100 mm phosphate , 150 mm nacl , 200 mm mes , 10 mm tcep , 1 mm edta , ph 7.2 ) for 18 h. flow - through was collected , and the column was washed three times with 150 l elution buffer . onto 62.5 l of int column , 300 l cell lysate containing ub - npu was loaded and incubated as described before . the column was washed with 300 l high - salt binding buffer , 300 l wash buffer , and 300 l binding buffer . the column was capped and incubated with 75 l epl buffer ( 100 mm phosphate , 150 mm nacl , 200 mm mes , 50 mm mpaa , 1 mm edta , 10 mm tcep , ph 7.9 ) containing 1 mm cgk(fl ) peptide for 18 h. the flow - through was collected , and the column was washed three times with 75 l elution buffer . gels were first imaged using the green fluorescence channel on a ge imagequant las 4010 imager and then coomassie stained . t cells were transiently cotransfected with antimouse - dec205-lc and antimouse - dec205-hc - ava using lipofectamine 2000 ( invitrogen ) , according to the manufacturer s instructions . after 4 days incubation at 37 c with 5% co2 , cell supernatants were harvested and spun down at 2000 rcf for 20 min at 4 c , filtered through a 0.22 m filter , and supplemented with complete protease inhbitors . for a typical purification , 50 ml of dec205-ava transfected cell supernatants were concentrated to a final volume of 5 ml and exchanged into binding buffer . the resulting ab solution ( input ) was applied to an int column of 300 l beads ( loading : 1.8 mol npuc peptide / ml ) and incubated at rt for 30 min . column flow - through was collected , and column washed three times with 3 cv of wash buffer and once with 3 cv of binding buffer . the column was capped and incubated with 3 cv of ab elution buffer ( 100 mm phosphate , 150 mm nacl , 200 mm mes , 1 mm tcep , 1 mm edta , ph 7.2 ) for 20 h. the column flow - through was collected , and the column washed three times with 3 cv of ab elution buffer . ligation was initiated by addition of 1 mm cgk(fl ) peptide and 1 mm tcep and adjusting ph to 7.58.0 . the reaction was incubated in the dark at rt for 48 h and monitored by sds - page imaged using a fluorescence scanner and coomassie staining . once the reaction was completed , the ligated ab was diluted to 200500 l and dialyzed into 100 mm phosphate , 150 mm nacl , 1 mm edta , 1 mm tcep , ph 7.2 .

chemically modified proteins are invaluable tools for studying the molecular details of biological processes , and they also hold great potential as new therapeutic agents . several methods have been developed for the site - specific modification of proteins , one of the most widely used being expressed protein ligation ( epl ) in which a recombinant -thioester is ligated to an n - terminal cys - containing peptide . despite the widespread use of epl , the generation and isolation of the required recombinant protein -thioesters remain challenging . we describe here a new method for the preparation and purification of recombinant protein -thioesters using engineered versions of naturally split dnae inteins . this family of autoprocessing enzymes is closely related to the inteins currently used for protein -thioester generation , but they feature faster kinetics and are split into two inactive polypeptides that need to associate to become active . taking advantage of the strong affinity between the two split intein fragments , we devised a streamlined procedure for the purification and generation of protein -thioesters from cell lysates and applied this strategy for the semisynthesis of a variety of proteins including an acetylated histone and a site - specifically modified monoclonal antibody .

SECTION 1. SHORT TITLE; TABLE OF CONTENTS. (a) Short Title.--This Act may be cited as the ``Energy Emergency Consumer Protection Act of 2005''. (b) Table of Contents.--The table of contents for this Act is as follows: Sec. 1. Short title; table of contents. Sec. 2. Unfair or deceptive acts or practices in commerce related to gasoline and petroleum distillates. Sec. 3. Declaration of energy emergency. Sec. 4. Enforcement. Sec. 5. Enforcement by State attorneys general. Sec. 6. Penalties. Sec. 7. Effect on other laws. Sec. 8. Market transparency for crude oil, gasoline, and petroleum distillates. Sec. 9. Report on United States energy emergency preparedness. Sec. 10. Alternative fuels investment by major oil companies and automobile manufacturers. Sec. 11. Protective action to prevent future disruptions of supply. Sec. 12. Authorization of appropriations. SEC. 2. UNFAIR OR DECEPTIVE ACTS OR PRACTICES IN COMMERCE RELATED TO GASOLINE AND PETROLEUM DISTILLATES. (a) Sales to Consumers at Unconscionable Price.-- (1) In general.--During any energy emergency declared by the President under section 3, it is unlawful for any person to sell crude oil, gasoline, or petroleum distillates in, or for use in, the area to which that declaration applies at a price that-- (A) is unconscionably excessive; or (B) indicates the seller is taking unfair advantage of the circumstances to increase prices unreasonably. (2) Factors considered.--In determining whether a violation of paragraph (1) has occured, there shall be taken into account, among other factors, whether-- (A) the amount charged represents a gross disparity between the price of the crude oil, gasoline, or petroleum distillate sold and the price at which it was offered for sale in the usual course of the seller's business immediately prior to the energy emergency; or (B) the amount charged grossly exceeds the price at which the same or similar crude oil, gasoline, or petroleum distillate was readily obtainable by other purchasers in the area to which the declaration applies. (3) Mitigating factors.--In determining whether a violation of paragraph (1) has occurred, there also shall be taken into account, among other factors, the price that would reasonably equate supply and demand in a competitive and freely functioning market and whether the price at which the crude oil, gasoline, or petroleum distillate was sold reasonably reflects additional costs, not within the control of the seller, that were paid or incurred by the seller. (b) False Pricing Information.--It is unlawful for any person to report information related to the wholesale price of crude oil, gasoline, or petroleum distillates to the Federal Trade Commission if-- (1) that person knew, or reasonably should have known, the information to be false or misleading; (2) the information was required by law to be reported; and (3) the person intended the false or misleading data to affect data compiled by that department or agency for statistical or analytical purposes with respect to the market for crude oil, gasoline, or petroleum distillates. (c) Market Manipulation.--It is unlawful for any person, directly or indirectly, to use or employ, in connection with the purchase or sale of crude oil, gasoline, or petroleum distillates at wholesale, any manipulative or deceptive device or contrivance, in contravention of such rules and regulations as the Commission may prescribe as necessary or appropriate in the public interest or for the protection of United States citizens. SEC. 3. DECLARATION OF ENERGY EMERGENCY. (a) In General.--If the President finds that the health, safety, welfare, or economic well-being of the citizens of the United States is at risk because of a shortage or imminent shortage of adequate supplies of crude oil, gasoline, or petroleum distillates due to a disruption in the national distribution system for crude oil, gasoline, or petroleum distillates (including such a shortage related to a major disaster (as defined in section 102(2) of the Robert T. Stafford Disaster Relief and Emergency Assistance Act (42 U.S.C. 5122))), or significant pricing anomalies in national energy markets for crude oil, gasoline, or petroleum distillates, the President may declare that a Federal energy emergency exists. (b) Scope and Duration.--The declaration shall apply to the Nation, a geographical region, or 1 or more States, as determined by the President, but may not be in effect for a period of more than 45 days. (c) Extensions.--The President may-- (1) extend a declaration under subsection (a) for a period of not more than 45 days; and (2) extend such a declaration more than once. SEC. 4. ENFORCEMENT UNDER FEDERAL TRADE COMMISSION ACT. (a) Enforcement by Commission.--This Act shall be enforced by the Federal Trade Commission. In enforcing section 2(a) of this Act, the Commission shall give priority to enforcement actions concerning companies with total United States wholesale or retail sales of crude oil, gasoline, and petroleum distillates in excess of $500,000,000 per year but shall not exclude enforcement actions against companies with total United States wholesale sales of $500,000,000 or less per year. (b) Violation Is Unfair or Deceptive Act or Practice.--The violation of any provision of this Act shall be treated as an unfair or deceptive act or practice proscribed under a rule issued under section 18(a)(1)(B) of the Federal Trade Commission Act (15 U.S.C. 57a(a)(1)(B)). SEC. 5. ENFORCEMENT AT RETAIL LEVEL BY STATE ATTORNEYS GENERAL. (a) In General.--A State, as parens patriae, may bring a civil action on behalf of its residents in an appropriate district court of the United States to enforce the provisions of section 2(a) of this Act, or to impose the civil penalties authorized by section 6 for violations of section 2(a), whenever the attorney general of the State has reason to believe that the interests of the residents of the State have been or are being threatened or adversely affected by a person engaged in retail sales of gasoline or petroleum distillates to consumers for purposes other than resale that violates this Act or a regulation under this Act. (b) Notice.--The State shall serve written notice to the Commission of any civil action under subsection (a) prior to initiating such civil action. The notice shall include a copy of the complaint to be filed to initiate such civil action, except that if it is not feasible for the State to provide such prior notice, the State shall provide such notice immediately upon instituting such civil action. (c) Authority To Intervene.--Upon receiving the notice required by subsection (b), the Commission may intervene in such civil action and upon intervening-- (1) be heard on all matters arising in such civil action; and (2) file petitions for appeal of a decision in such civil action. (d) Construction.--For purposes of bringing any civil action under subsection (a), nothing in this section shall prevent the attorney general of a State from exercising the powers conferred on the attorney general by the laws of such State to conduct investigations or to administer oaths or affirmations or to compel the attendance of witnesses or the production of documentary and other evidence. (e) Venue; Service of Process.--In a civil action brought under subsection (a)-- (1) the venue shall be a judicial district in which-- (A) the defendant operates; (B) the defendant was authorized to do business; or (C) where the defendant in the civil action is found; (2) process may be served without regard to the territorial limits of the district or of the State in which the civil action is instituted; and (3) a person who participated with the defendant in an alleged violation that is being litigated in the civil action may be joined in the civil action without regard to the residence of the person. (f) Limitation on State Action While Federal Action Is Pending.--If the Commission has instituted a civil action or an administrative action for violation of this Act, no State attorney general, or official or agency of a State, may bring an action under this subsection during the pendency of that action against any defendant named in the complaint of the Commission or the other agency for any violation of this Act alleged in the complaint. (f) Enforcement of State Law.--Nothing contained in this section shall prohibit an authorized State official from proceeding in State court to enforce a civil or criminal statute of such State. SEC. 6. PENALTIES. (a) Civil Penalty.-- (1) In general.--In addition to any penalty applicable under the Federal Trade Commission Act-- (A) any person who violates section 2(b) or 2(c) of this Act is punishable by a civil penalty of not more than $1,000,000; and (B) any person who violates section 2(a) of this Act is punishable by a civil penalty of not more than $3,000,000. (2) Method of assessment.--The penalties provided by paragraph (1) shall be assessed in the same manner as civil penalties imposed under section 5 of the Federal Trade Commission Act (15 U.S.C. 45). (3) Multiple offenses; mitigating factors.--In assessing the penalty provided by subsection (a)-- (A) each day of a continuing violation shall be considered a separate violation; and (B) the Commission shall take into consideration the seriousness of the violation and the efforts of the person committing the violation to remedy the harm caused by the violation in a timely manner. (b) Criminal Penalty.--Violation of section 2(a) of this Act is punishable by a fine of not more than $1,000,000, imprisonment for not more than 5 years, or both. SEC. 7. EFFECT ON OTHER LAWS. (a) Other Authority of Commission.--Nothing in this Act shall be construed to limit or affect in any way the Commission's authority to bring enforcement actions or take any other measure under the Federal Trade Commission Act (15 U.S.C. 41 et seq.) or any other provision of law. (b) State Law.--Nothing in this Act preempts any State law. SEC. 8. MARKET TRANSPARENCY FOR CRUDE OIL, GASOLINE, AND PETROLEUM DISTILLATES. (a) In General.--The Federal Trade Commission shall facilitate price transparency in markets for the sale of crude oil and essential petroleum products at wholesale, having due regard for the public interest, the integrity of those markets, fair competition, and the protection of consumers. (b) Marketplace Transparency.-- (1) Dissemination of information.--In carrying out this section the Commission shall provide by rule for the dissemination, on a timely basis, of information about the availability and prices of wholesale crude oil, gasoline, and petroleum distillates to the Commission, States, wholesale buyers and sellers, and the public. (2) Protection of public from anticompetitive activity.--In determining the information to be made available under this section and time to make the information available, the Commission shall seek to ensure that consumers and competitive markets are protected from the adverse effects of potential collusion or other anticompetitive behaviors that can be facilitated by untimely public disclosure of transaction- specific information. (3) Protection of market mechanisms.--The Commission shall withhold from public disclosure under this section any information the Commission determines would, if disclosed, be detrimental to the operation of an effective market or jeopardize security. (c) Information Sources.-- (1) In general.--In carrying out subsection (b), the Commission may-- (A) obtain information from any market participant; and (B) rely on entities other than the Commission to receive and make public the information, subject to the disclosure rules in subsection (b)(3). (2) Published data.--In carrying out this section, the Commission shall consider the degree of price transparency provided by existing price publishers and providers of trade processing services, and shall rely on such publishers and services to the maximum extent possible. (3) Electronic information systems.--The Commission may establish an electronic information system if it determines that existing price publications are not adequately providing price discovery or market transparency. Nothing in this section, however, shall affect any electronic information filing requirements in effect under this Act as of the date of enactment of this section. (4) De minimus exception.--The Commission may not require entities who have a de minimus market presence to comply with the reporting requirements of this section. (d) Cooperation With Other Federal Agencies.-- (1) Memorandum of understanding.--Within 180 days after the date of enactment of this Act, the Commission shall conclude a memorandum of understanding with the Commodity Futures Trading Commission and other appropriate agencies (if applicable) relating to information sharing, which shall include provisions-- (A) ensuring that information requests to markets within the respective jurisdiction of each agency are properly coordinated to minimize duplicative information requests; and (B) regarding the treatment of proprietary trading information. (2) CFTC jurisdiction.--Nothing in this section may be construed to limit or affect the exclusive jurisdiction of the Commodity Futures Trading Commission under the Commodity Exchange Act (7 U.S.C. 1 et seq.). (e) Rulemaking.--Within 180 days after the date of enactment of this Act, the Commission shall initiate a rulemaking proceeding to establish such rules as the Commission determines to be necessary and appropriate to carry out this section. SEC. 9. REPORT ON UNITED STATES ENERGY EMERGENCY PREPAREDNESS. (a) Potential Impacts Report.--Within 30 days after the date of enactment of this Act, the Federal Trade Commission shall transmit to the Congress a report describing the potential impact on domestic prices of crude oil, residual fuel oil, and refined petroleum products that would result from the disruption for periods of 1 week, 1 year, and 5 years, respectively, of not less than-- (1) 30 percent of United States oil production; (2) 20 percent of United States refining capacity; and (3) 5 percent of global oil supplies. (b) Projections and Possible Remedies.--The President shall include in the report-- (1) projections of the impact any such disruptions would be likely to have on the United States economy; and (2) detailed and prioritized recommendations for remedies under each scenario covered by the report. SEC. 10. ALTERNATIVE FUELS INVESTMENT BY MAJOR OIL COMPANIES AND AUTOMOBILE MANUFACTURERS. The Comptroller General shall conduct an investigation within 1 year after the date of enactment of this Act and every 4 years thereafter of the extent to which companies with total United States wholesale or retail sales of crude oil, gasoline, and petroleum distillates in excess of $500,000,000 per year and automobile manufacturers have invested in alternative fuels production, infrastructure, and technology development to diversify the motor vehicle fuel and vehicle options available to consumers in the United States. At the conclusion of each such investigation, the Comptroller General shall transmit a report containing the findings and conclusions to the Congress. SEC. 11. PROTECTIVE ACTION TO PREVENT FUTURE DISRUPTIONS OF SUPPLY. The National Academy of Sciences shall review expenditures by, and activities undertaken by, companies with total United States wholesale or retail sales of crude oil, gasoline, and petroleum distillates in excess of $500,000,000 per year to protect the energy supply system from terrorist attacks, international supply disruptions, and natural disasters, and ensure a stable and reasonably priced supply of such products to consumers in the United States, that includes an assessment of the companies' preparations for the current forecasted period of more frequent and, due to global warming, more intense hurricane activity in the Gulf of Mexico and other vulnerable coastal areas. SEC. 12. AUTHORIZATION OF APPROPRIATIONS. There are authorized to be appropriated to the Federal Trade Commission such sums as may be necessary to carry out the provisions of this Act. D23/

Energy Emergency Consumer Protection Act of 2005 - States that during any presidentially-declared energy emergency it is unlawful to sell crude oil, gasoline, or petroleum distillates in, or for use in, the area involved at a price that: (1) is unconscionably excessive; or (2) indicates the seller is taking unfair advantage of the circumstances to increase prices unreasonably. Makes it unlawful to: (1) report to the Federal Trade Commission (FTC) false or misleading data and information regarding the wholesale price of crude oil, gasoline, or petroleum distillates; or (2) use or employ, in connection with the purchase or sale of crude oil, gasoline, or petroleum distillates at wholesale, any manipulative or deceptive device or contrivance, in contravention of FTC-prescribed rules and regulations. Authorizes the President to declare a federal energy emergency if the health, safety, welfare, or economic well-being of American citizens is at risk because there exists either: (1) an actual or imminent shortage of adequate supplies of crude oil, gasoline, or petroleum distillates due to a disruption in the national distribution system; or (2) significant pricing anomalies in national energy markets for such products. Empowers the FTC and state attorneys general to enforce this Act. Prescribes maximum civil and criminal penalties for violations of this Act. Instructs the FTC to: (1) facilitate price transparency in wholesale crude oil and petroleum product markets; and (2) conclude a memorandum of understanding with the Commodity Futures Trading Commission and other appropriate agencies relating to information sharing. Instructs the Comptroller General to investigate periodically the extent to which major oil companies and automobile manufacturers have invested in alternative fuels production, infrastructure, and technology development. Directs the National Academy of Sciences to review expenditures and activities by major U.S. companies to protect the energy supply system from terrorist attacks, international supply disruptions, and natural disasters, and ensure a stable and reasonably priced supply of such products to consumers.

SECTION 1. SHORT TITLE. This Act may be cited as the ``National Defense Energy Savings Act of 2004''. SEC. 2. ENERGY SAVINGS PERFORMANCE CONTRACTS. (a) Contracts Authorized.--The Secretary of Defense may enter into an energy savings performance contract under this section for the sole purpose of achieving energy savings and benefits ancillary to that purpose. The Secretary may incur obligations under the contract to finance energy conservation measures so long as guaranteed savings exceed the debt service requirements. (b) Terms and Conditions.-- (1) Contract period.--Notwithstanding any other provision of law, an energy savings performance contract may be for a period of up to 25 years beginning on the date on which the first payment is made by the Secretary pursuant to the contract. The contract need not include funding of cancellation charges (if any) before cancellation, if-- (A) the contract was awarded in a competitive manner, using procedures and methods established under this section; (B) the Secretary determines that funds are available and adequate for payment of the costs of the contract for the first fiscal year; (C) the contract is governed by part 17.1 of the Federal Acquisition Regulation; and (D) if the contract contains a clause setting forth a cancellation ceiling in excess $10,000,000, the Secretary provides notice to Congress of the proposed contract and the proposed cancellation ceiling at least 30 days before the award of the contract. (2) Costs and savings.--An energy savings performance contract shall require the contractor to incur the costs of implementing energy savings measures, including at least the cost (if any) incurred in making energy audits, acquiring and installing equipment, and training personnel, in exchange for a share of any energy savings directly resulting from implementation of such measures during the term of the contract. (3) Other terms and conditions.--An energy savings performance contract shall require an annual energy audit and specify the terms and conditions of any Government payments and performance guarantees. Any such performance guarantee shall provide that either the Government or the contractor is responsible for maintenance and repair services for any energy related equipment, including computer software systems. (c) Limitation on Annual Contract Payments.--Aggregate annual payments by the Secretary to a contractor for energy, operations, and maintenance under an energy savings performance contract may not exceed the amount that the Department of Defense would have paid for energy, operations, and maintenance in the absence of the contract (as estimated through the procedures developed pursuant to this section) during term of the contract. The contract shall provide for a guarantee of savings to the Department, and shall establish payment schedules reflecting such guarantee, taking into account any capital costs under the contract. (d) Rulemaking.--Not later than 90 days after the date of the enactment of this Act, the Secretary, with the concurrence of the Federal Acquisition Regulatory Council, shall issue final rules to establish the procedures and methods for use by the Department of Defense to select, monitor, and terminate energy savings performance contracts in accordance with laws governing Federal procurement that will achieve the intent of this section in a cost-effective manner. In developing such procedures and methods, the Secretary, with the concurrence of the Federal Acquisition Regulatory Council, shall determine which existing regulations are inconsistent with the intent of this section and shall formulate substitute regulations consistent with laws governing Federal procurement. (e) Implementation Procedures and Methods.--The procedures and methods established by rule under subsection (d) shall-- (1) provide for the calculation of energy savings based on sound engineering and financial practices; (2) allow the Secretary to request statements of qualifications, which shall, at a minimum, include prior experience and capabilities of contractors to perform the proposed types of energy savings services and financial and performance information from firms engaged in providing energy savings services; (3) allow the Secretary to presume that a contractor meets the requirements of paragraph (2) if the contractor either-- (A) has carried out contracts with a value of at least $1,000,000,000 with the Federal Government over the previous 10 years; or (B) is listed by a Federal agency pursuant to section 801(b)(2) of the National Energy Policy Act (42 U.S.C. 8287(b)(2)); (4) allow the Secretary to, from the statements received, designate and prepare a list, with an update at least annually, of those firms that are qualified to provide energy savings services; (5) allow the Secretary to select firms from such list to conduct discussions concerning a particular proposed energy savings project, including requesting a technical and price proposal from such selected firms for such project; (6) allow the Secretary to select from such firms the most qualified firm to provide energy savings services based on technical and price proposals and any other relevant information; (7) allow the Secretary to permit receipt of unsolicited proposals for energy savings performance contracting services from a firm that the Department of Defense has determined is qualified to provide such services under the procedures established pursuant to subsection (d) and require facility managers to place a notice in the Commerce Business Daily announcing they have received such a proposal and invite other similarly qualified firms to submit competing proposals; (8) allow the Secretary to enter into an energy savings performance contract with a firm qualified under paragraph (7), consistent with the procedures and methods established pursuant to subsection (d); and (9) allow a firm not designated as qualified to provide energy savings services under paragraph (4) to request a review of such decision to be conducted in accordance with procedures, substantially equivalent to procedures established under section 759(f) of title 40, United States Code, to be developed by the board of contract appeals of the General Services Administration. (f) Transition Rule for Certain Energy Savings Performance Contracts.--In the case of any energy savings performance contract entered into by the Secretary, or the Secretary of Energy, before October 1, 2003, for services to be provided at Department of Defense facilities, the Secretary may issue additional task orders pursuant to such contract and may make whatever contract modifications the parties to such contract agree are necessary to conform to the provisions of this section. (g) Pilot Program for Nonbuilding Applications.-- (1) In general.--The Secretary may carry out a pilot program to enter into up to 10 energy savings performance contracts for the purpose of achieving energy savings, secondary savings, and benefits incidental to those purposes, in nonbuilding applications. (2) Selection.--The Secretary shall select the contract projects to demonstrate the applicability and benefits of energy savings performance contracting to a range of non- building applications. (3) Report.--Not later than three years after the date of the enactment of this Act, the Secretary shall submit to Congress a report on the progress and results of the pilot program. The report shall include a description of projects undertaken; the energy and cost savings, secondary savings and other benefits that resulted from such projects; and recommendations on whether the pilot program should be extended, expanded, or authorized. (h) Definitions.--In this section: (1) Energy savings.--The term ``energy savings'' means a reduction in the cost of energy, from a base cost established through a methodology set forth in the energy savings performance contract, utilized in an existing federally owned building or buildings or other federally owned facilities as a result of-- (A) the lease or purchase of operating equipment, improvements, altered operation and maintenance, increased capacity or payload, or technical services; or (B) the increased efficient use of existing energy sources by cogeneration or heat recovery, excluding any cogeneration process for other than a federally owned building or buildings or other federally owned facilities. (2) Energy savings performance contract.--The term ``energy savings performance contract'' means a contract that provides for the performance of services for the design, acquisition, installation, testing, operation, and, where appropriate, maintenance and repair of an identified energy conservation measure or series of measures at one or more locations. Such contracts-- (A) may provide for appropriate software licensing agreements; and (B) shall, with respect to an agency facility that is a public building, as defined in section 13(l) of the Public Buildings Act of 1959 (40 U.S.C. 612(l)), be in compliance with the prospectus requirements and procedures of section 7 of the Public Buildings Accountability Act of 1959 (40 U.S.C. 606). (3) Nonbuilding application.--The term ``nonbuilding application'' means-- (A) any class of vehicles, devices, or equipment that is transportable under its own power by land, sea, or air that consumes energy from any fuel source for the purpose of such transportability, or to maintain a controlled environment within such vehicle, device, or equipment; or (B) any Federally owned equipment used to generate electricity or transport water. (4) Secondary savings.--The term ``secondary savings'' means additional energy or cost savings that are a direct consequence of the energy savings that result from the energy efficiency improvements that were financed and implemented pursuant to the energy savings performance contract. Such secondary savings may include energy and cost savings that result from a reduction in the need for fuel delivery and logistical support, personnel cost savings and environmental benefits. In the case of electric generation equipment, secondary savings may include the benefits of increased efficiency in the production of electricity, including revenue received by the Federal Government from the sale of electricity so produced. (5) Secretary.--The term ``Secretary'' means the Secretary of Defense.

National Defense Energy Savings Act of 2004 - Authorizes the Secretary of Defense to: (1) enter into an energy savings performance contract in order to achieve energy savings and ancillary benefits; (2) incur obligations under the contract to finance energy conservation measures so long as guaranteed savings exceed the debt service requirements; and (3) implement a pilot program to enter into up to ten energy savings performance contracts for the purpose of achieving energy savings, secondary savings, and incidental benefits, in nonbuilding applications. Sets forth implementation guidelines, including contract terms and conditions.

accurate segregation of the genetic material during cell division requires that sister kinetochores attach to microtubules emanating from opposite spindle poles . merotelic kinetochore orientation is an error in which a single kinetochore is attached to microtubules emanating from both spindle poles . if a merotelically attached kinetochore remains uncorrected , it causes the chromatid to lag on the anaphase spindle , hindering its poleward segregation ( figure 1 ) . it is important to understand how cells prevent and correct merotelic kinetochore attachments because merotely represents a major mechanism of aneuploidy in mitotic cells and is the primary mechanism of chromosomal instability in cancer cells [ 38 ] . several proteins have been implicated in correcting or preventing merotelic attachments , including condensin and the fission yeast pcs1/mde4 complex , a homolog of the budding yeast monopolin complex [ 913 ] . two recent studies provide important insights into how pcs1/mde4 and condensin prevent merotelic kinetochore attachments . previous studies suggested that both the csm1/lrs4 monopolin subcomplex in the budding yeast saccharomyces cerevisiae and its counterpart pcs1/mde4 in the fission yeast schizosaccharomyces pombe act at kinetochores as molecular clamps which lock together microtubule attachment sites . while the pcs1/mde4 complex clamps together microtubule attachment sites on a single kinetochore in order to prevent merotelic attachments , the csm1/lrs4 complex clamps together microtubule binding sites from sister kinetochores during meiosis i in order to establish mono - orientation ( attachment of sister kinetochores to microtubules emanating from the same pole ) . although this model was consistent with the experimental data and nicely explained the mutant phenotype observed in cells lacking csm1/lrs4 or pcs1/mde4 , it was rather speculative . a strong argument in favour of the . showed that the csm1/lrs4 complex has a distinctive v - shaped structure , with two pairs of kinetochore - binding domains positioned about 10 nm apart . thus , a plausible model for csm1/lrs4-mediated mono - orientation of sister kinetochores is that these two pairs of kinetochore - binding domains bind across sister kinetochores , bringing them so close together that they effectively prevent bi - orientation ( attachment of sister kinetochores to microtubules emanating from the opposite poles ) . . showed that the s. pombe pcs1/mde4 complex has the same general architecture as csm1/lrs4 , suggesting that both csm1/lrs4 and its s. pombe counterpart pcs1/lrs4 may function as molecular clamps or crosslinkers at kinetochores . although the clamp model is now supported by structure function analyses , it has been challenged by a recent study from tada et al . , who showed that the role of pcs1 and mde4 is to recruit condensin to kinetochores and proposed that condensin at kinetochores clamps together microtubule attachment sites . chromatin immunoprecipitation experiments clearly showed that kinetochore condensin localization is diminished in pcs1 cells and , notably , artificial targeting of condensin to kinetochores largely suppressed the growth defect and halved the incidence of lagging chromosomes in pcs1 cells . these observations are consistent with previous studies showing that both pcs1/mde4 and condensin are important for preventing merotelic attachments and that in budding yeast , monopolin proteins csm1 and lrs4 are required for recruitment of condensin to ribosomal dna . however , other studies showed that condensin associates with kinetochores independently of csm1 and lrs4 and that condensin is not an obligate component of a system preventing merotelic attachments in vertebrate kinetochores . these apparent discrepancies in the literature further underscore the importance of the tada et al . study . does the pcs1/mde4 complex act as a microtubule site clamp ( figure 2a ) , or does it prevent merotelic attachments solely by recruiting condensin to kinetochores ( figure 2b ) ? although tada et al . nicely showed that pcs1 and mde4 act as a condensin recruiter at kinetochores and that this is an important mechanism for preventing merotelic attachments , further experiments are needed to establish whether condensin recruitment is the only role of the pcs1/mde4 complex in preventing merotely , or whether pcs1/mde4 also functions as a microtubule site clamp , as suggested by previous studies ( figure 2 ) . elegant experiments in which kinetochore condensin was specifically inactivated by proteolytic cleavage showed that this disturbed the structure of centromeric chromatin , and frequent separation of core and pericentromeric domains was observed . it is likely that this defect contributes to the high incidence of merotelic attachments observed in condensin mutant cells ; therefore , it will be important to determine whether the absence of pcs1 or mde4 leads to a similar phenotype . moreover , the distinct v - shape structure of the monopolin complex makes important predictions about its putative clamping function . using this structure as a guide , mutations that prevent the clamping ability should be designed and tested in vivo . finally , in order to extend the current studies to other organisms , it will be important to identify counterparts of the fission yeast pcs1/mde4 complex in higher eukaryotes . although structural and sequence analyses showed that the pcs1/mde4 complex shares similar features with the conserved kinetochore complex spc24/spc25 , it is not known whether in higher eukaryotes the spc24/spc25 complex took over the function of the pcs1/mde4 or whether there are true homologs of pcs1/mde4 which have not been identified yet . in summary , mounting evidence suggests that both the pcs1/mde4 and condensin complexes are required to prevent merotely . whereas the clamp model suggests that pcs1/mde4 complex itself acts as a molecular clamp which locks together microtubule attachment sites ( figure 2a ) , an alternative model suggests that the pcs1/mde4 complex prevents merotely indirectly by recruiting condensin to kinetochores and that condensin acts as a molecular clamp which locks together microtubule attachment sites ( figure 2b ) . these two models are not mutually exclusive and it is possible that both pcs1/mde4 's clamping activity and its role as a condensin recruiter are required to efficiently prevent merotelic kinetochore attachments . further studies are needed to unveil molecular details of how kinetochore pools of pcs1/mde4 and condensin complexes prevent merotely . given the importance of this process for our understanding of how cells ensure faithful segregation of chromosomes , it is likely that this will continue to be an area of intense research in the future .

summaryto segregate chromosomes properly , the cell must prevent merotely , an error that occurs when a single kinetochore is attached to microtubules emanating from both spindle poles . recent evidence suggests that cooperation between pcs1/mde4 and condensin complexes plays an important role in preventing merotely .

orthodontic force application leads to periodontal ligament tissue injury and the initiation of acute inflammatory processes . subsequent production of pro - inflammatory mediators such as prostaglandins , substance p and cytokines plays an important role in the mediation of orthodontic pain.1 therefore , it is recommended that light force should be used during orthodontic treatment to minimize tissue damage and subsequent pain and discomfort.25 multistranded stainless steel and nickel titanium ( niti ) alloy archwires are commonly used during the initial levelling and aligning phase of fixed orthodontic treatment because these wires are closest to fulfilling the ideal requirements of an initial archwire.6 previous authors have failed to demonstrate a significant difference in the aligning capabilities of superelastic nickel titanium and multistranded stainless steel archwires.7,8 these findings have been confirmed by recent clinical9 and laboratory10 studies using a pre - adjusted edgewise appliance ( 0.022-inch slot ) system during alignment of the mandibular anterior segment . these studies9,10 highlight the fact that superelastic nickel titanium wires are not superior to multistranded stainless steel , even in the mandibular anterior segment where small inter - bracket widths decrease the relative length of the archwire , which might be expected to favour superelastic nickel titanium archwires.8 besides clinical efficiency , another important consideration for initial arch wire selection should be minimal pain and discomfort because the prevalence of pain during the initial phase of fixed orthodontic treatment is high.11,12 surprisingly , this important topic has been largely ignored in clinical practice as well as research , as evidenced by the scarcity of publications . in the last 20 years , no study has compared these two archwire types for pain , though the effect of bracket design on pain during the initial phase of fixed orthodontic treatmenthas been investigated.13,14 only one clinical trial15 published in 1992 compared superelastic nickel titanium and multistranded stainless wires for orthodontic pain . however , it is unclear whether their sample size was based on priori power analysis and whether groups were appropriately balanced for demographic and clinical characteristics . as pain is a subjective response , it can be significantly influenced by several factors , including age15 and sex16 and clinical characteristics such as orthodontic force level.17 the degree of crowding has a direct effect on inter - bracket distance , which can significantly influence deactivation forces of initial archwires.18 therefore , the present study was designed as a stratified ( age , sex and initial crowding ) randomized clinical trial to investigate and compare the effects of superelastic nickel titanium and multistranded stainless steel archwires on orthodontic pain over a period of 2 weeks . we conducted a single - centre , double - blind , parallel two - arm ( 11 allocation ratio ) stratified randomized controlled trial in india between december 2010 and june 2012 . a total of 96 participants met all inclusion criteria and were enrolled in the study after providing written informed consent . the study protocol was approved by a local ethics review committee of the indian medical association in jalandhar , punjab , india on 20 december 2010 . inclusion criteria were : ( 1 ) 11- to -17-year - old male and females who required fixed orthodontic treatment ; ( 2 ) moderate - to - severe crowding ( 49 mm ) in the mandibular anterior segment that was not severe enough to prevent bracket engagement , patients with severe crowding related to one or two teeth ( such as blocked out lateral incisors ) were not included ; ( 3 ) eruption of all mandibular anterior teeth ; ( 4 ) no history of medical problems / medication that could influence pain perception ; and ( 5 ) informed and witnessed consent from the minor participant and their parent / guardian . exclusion criteria were : ( 1 ) presence of a severe deep bite that could affect bracket placement on the mandibular anterior teeth ; ( 2 ) malocclusion correction required treatment procedures other than continuous arch wire mechanics ; ( 3 ) participants taking pain medications for chronic pain ; ( 4 ) participants with a positive history of dental pain or pain in the orofacial region ; ( 5 ) a medical condition that precluded the use of a fixed orthodontic appliance ( e.g. allergy to nickel , recent history of epileptic seizure or physician s consent could not be obtained , etc . ) . initial crowding assessment was done by using little s irregularity index.19 decisions regarding extraction , as and when required , were based on comprehensive diagnosis and treatment planning . after extractions , participants were scheduled for appointments at least 2-week post - extraction to allow a standardized minimum healing time since one of the prerequisites before trial initiation was that participants should be pain free . on the first day of orthodontic treatment but before the bonding procedure , booklets containing the pain assessment scale and written instructions were provided to participants for the baseline pain assessment . verbal instructions and guidance during the baseline assessment were provided to familiarize the participants with the pain assessment procedure . for all participants , the bonding procedure and initial wire placement were carried out between 10 and 11 o clock in the morning , though on different days . this was to ensure that the follow - up time points for pain assessment were the same . preadjusted edgewise appliances ( pea ) with 0.0220.028-inch slot twin brackets ( roth prescription , gemini metal brackets ; 3 m unitek corporation , monrovia , ca , usa ) were bonded directly to the mandibular dentition using light - cure composite resin ( transbond xt ; 3 m unitek corporation ) . we employed either 0.0175-inch multistranded stainless steel ( six - stranded , unitek coaxial wire ; 3 m unitek corporation ) or 0.016-inch superelastic nickel titanium ( austenitic active , preformed ovoid , superelastic arch wire ; 3 m unitek corporation ) as interventions . intervention and follow - up were done by the first and second authors , who are both qualified orthodontists . after initial arch wire placement , participants were discharged with the booklets containing the pain assessment scale and written instructions . participants were requested to report back after 14 days ( follow - up period ) , unless they experienced an emergency , such as mucosal injury or damage to the appliance . outcome was assessed by using the visual analogue scale ( vas ) , which is a 100-mm long horizontal line where one end corresponds to no pain and the other end indicates worst pain possible.20 the vas is a valid and reliable scale for pain assessment.21 pain was assessed at baseline and at 32 pre - specified follow - up ( post - wire placement ) time points . although the literature shows that there are varying pain perceptions during different dental occlusal positions , we decided to assess pain only at the rest position because participants showed a reluctance to record multiple measurements during the pilot study . assessing pain at the rest position , while touching the front teeth , and while touching the back teeth triples the number of pain assessments at each time point , which could make patients unenthusiastic and , therefore , could affect cooperation during the trial , especially in one that has multiple time points . participants marked a line across the scale corresponding to perceived pain at each time point . the mark was measured from the left margin of the line to the nearest millimetre to quantify the pain and recorded a vas score in mm . the vas score was measured by trained dental assistants ( blinded to the study ) using a manual 0.1-mm calibrated vernier caliper ( manual type ) . the first and second authors measured 20 randomly selected vas scales , independently , and the intraclass correlation coefficient of 0.95 suggested excellent reproducibility and reliability . for pain relief , participants were allowed to take any over - the - counter analgesic . however , participants were asked to record pain ( vas score ) before taking the medication in order to minimize the effect of the analgesic on the pain recording . it is quite possible that analgesic consumption , especially before recording the pain , could lead to bias in pain assessment . however , it is unethical to ask the participant not to take medication or to control the timing or frequency of analgesic consumption . sample size was based on power analysis ( stata / se 10.0 software , college station , tx , usa ) for a repeated measure design with 1 baseline and 32 follow - up repeated measurements ( r = 0.15 ) to detect a 3-mm ( sd 10 for each group , cohen s effect size 0.3 ) mean difference on a 100-mm vas . the sample size determining assumptions , such as effect size and correlation coefficient ( r ) between follow - up repeated measurement , were based on pilot study results . we determined that 42 participants per group ( 84 in total ) were required to achieve 90% power with a significance level of 0.05 . considering possible drop out of 1015% during follow - up , it was decided to enrol at least 95 participants . the randomization schedule was prepared by using ralloc procedure ( stata / se 10.0 software ) to enrol 96 participants into superelastic nickel titanium and multistranded stainless steel groups using stratified block ( size 4 ) randomization . a statistician generated the random allocation sequence , and the dental assistant helped enrol and conceal participant allocation using the opaque sealed envelope method . the stratification factors for randomization were age , sex , and initial crowding ( moderate 46 mm , severe > 69 mm ) . age groups 1114 and 1417 years were selected because these represent preadolescent and adolescent age groups , respectively.22 data was analysed with sas 9.2 software ( sas institute inc . , cary , nc , usa ) demographic and clinical characteristics , including frequency , arithmetic mean and standard deviation calculated using descriptive statistics . mixed model analysis ( proc mixed ) was employed to analyse repeated measure data ( vas score ) by using the restricted maximum likelihood method of estimation.23 both random and repeated statements were used to model the variance and covariance structures , respectively . random intercept was used with unstructured variance matrix for random effects , whereas sp(pow ) ( spatial power law ) covariance structure was used for repeated measures . to fit a time - series - type covariance structure for unequally spaced longitudinal repeated measurements in which the correlations between follow - up measurements change rapidly as a function of time , the spatial structures such as sp(pow ) ( spatial power law ) , sp(gau ) ( gaussian ) and sp(sph ) ( spherical ) are appropriate for modelling covariance structures.23 these covariance structures were evaluated , and the best - fitting model was selected based on log likelihood ratio test and akaike s information criterion ( aic ) , aic small sample corrected and bayesian information criterion ( smaller is better ) . the sp(pow ) structure was the best fitting covariance structure , which is a direct generalization of the autoregressive first order ar ( 1 ) covariance structure for equally spaced data.23 the tukey - kramer method was used to adjust p - values of pairwise comparisons of ls - means ( ls - means ) , as recommended by westfall et al.24 for unbalanced design . data was analysed with sas 9.2 software ( sas institute inc . , cary , nc , usa ) demographic and clinical characteristics , including frequency , arithmetic mean and standard deviation calculated using descriptive statistics . mixed model analysis ( proc mixed ) was employed to analyse repeated measure data ( vas score ) by using the restricted maximum likelihood method of estimation.23 both random and repeated statements were used to model the variance and covariance structures , respectively . random intercept was used with unstructured variance matrix for random effects , whereas sp(pow ) ( spatial power law ) covariance structure was used for repeated measures . to fit a time - series - type covariance structure for unequally spaced longitudinal repeated measurements in which the correlations between follow - up measurements change rapidly as a function of time , the spatial structures such as sp(pow ) ( spatial power law ) , sp(gau ) ( gaussian ) and sp(sph ) ( spherical ) are appropriate for modelling covariance structures.23 these covariance structures were evaluated , and the best - fitting model was selected based on log likelihood ratio test and akaike s information criterion ( aic ) , aic small sample corrected and bayesian information criterion ( smaller is better ) . the sp(pow ) structure was the best fitting covariance structure , which is a direct generalization of the autoregressive first order ar ( 1 ) covariance structure for equally spaced data.23 the tukey - kramer method was used to adjust p - values of pairwise comparisons of ls - means ( ls - means ) , as recommended by westfall et al.24 for unbalanced design . out of 168 participants assessed for eligibility , 96 met the inclusion criteria and enrolled in the trial . one participant was lost to follow up , and 10 were excluded from the analysis due to bond failure or incomplete questionnaires . therefore , a total of 85 participants ( 42 males and 43 females ; mean age 14.12.0 years ) were included in the analysis as shown in the consort flow diagram ( figure 1 ) . least square means ( ls - means ) profile plot of vas scores ( please refer to table 2 for the description of time points ) data numbers ( % ) or means ( sd ) . time had the most significant effect on pain ( f value = 146.63 , df = 2501 , p<0.0001 ) . there was no statistically significant difference between superelastic nickel titanium and multistranded stainless steel wires for mean average vas score across all time points ( f value = 2.65 , df = 92.6 , p = 0.1071 ) . however , the significant interaction between group and time ( f value = 1.57 , df = 2501 , p = 0.0226 ) highlights the fact that the difference for vas score between superelastic nickel titanium and multistranded stainless steel wires was not insignificant across all the time points . this implies that there was a significant difference between these two wires for pain during the trial period . the results of pairwise comparisons for vas score at each time point are shown in table 4 . titanium wires was significantly greater at 12 h ( t = 2.34 , p = 0.0193 ) and on the morning ( t = 2.21 , p = 0.0273 ) , afternoon ( t = 2.11 , p = 0.0346 ) and bedtime ( t = 2.03 , p = 0.042 ) of day 1 . no harm was done to the participants in terms of pain experienced , which was similar to what it would have been if participants were not part of the study . there was no effect on total duration of treatment because the most recent clinical study concluded that both wire types are equally efficient with a pea.9 in this clinical trial , orthodontic pain began 1 h after initial arch wire placement , reached a peak on the morning of day 1 ( 24 h ) , and gradually decreased thereafter . however , even after 14 days , the mean vas score did not reach zero ( figure 2 ) . there was no statistical significant difference between superelastic nickel titanium and multistranded stainless steel wire for overall pain during the entire study . however , compared to multistranded stainless steel wire , subjects who received superelastic nickel titanium wire reported greater pain at peak from 12 h after placement to bedtime on day 1 . the observed trend of pain perhaps reflect the underlying biological responses to orthodontic force application . interleukin-1beta ( il-1beta ) is the first mediator to regulate bone remodelling in response to orthodontic force , and it also plays a significant role in orthodontic pain by inducing the secretion of pain - producing pro - inflammatory mediators.1,25 a recent study17 demonstrated that the il-1beta concentration increases after 1 h of orthodontic force application , peaks after 24 h , and subsequently declines approximately to baseline in 1-week to 1-month time period . in another study,26 the concentration of il-1beta declined to normal only towards the end of the 3-week study period . these findings could explain the pain trend observed in the present trial , where pain started 1 h after initial arch wire placement , peaked after 24 h , then began to decline . however , pain did not decrease to baseline ( zero ) , even after 2 weeks of force application . the findings of our trial both support and refute results from a previous clinical trial investigating pain during initial orthodontic tooth alignment with fixed appliances.15 the results are in accordance in that we did not find a statistically significant difference between the two wires for overall pain experience . the previous study15 reported that from days 2 to 5 , there was less pain associated with the superelastic nickel titanium wire . however , subjects who received this wire in the present investigation did not report less pain at any assessment ( figure 2 ) . furthermore , the previous study reported no significant difference in pain between the two wires during the entire study . titanium wires produced greater pain , especially at peak plateau from 12 h to bedtime of day 1 ( table 4 and figure 2 ) . these differences between the previous report15 and our trial could be explained by the fact that different arch wire material and dimensions were used in these studies . the previous study compared 0.014-inch superelastic nickel titanium and 0.015-inch , three - stranded twistflex multistranded stainless steel wires . in contrast , we compared 0.016-inch superelastic nickel titanium and 0.0175-inch , six - stranded , coaxial wire ( five strands wrapped around a core wire ) . the variations in the wire dimensions and multistranded wire design can influence the force they deliver . titanium wires of the same diameter , in general an increase in superelastic nickel titanium wire diameter from 0.014 to 0.016 inch increases the force level by 50%.27 in comparison , an increase in multistranded wire diameter from 0.015 to 0.0175 inch only increases the force by 2030%.28 therefore , the increase in superelastic nickel titanium diameter from 0.014 to 0.016 inch might have resulted in a substantial ( 50% ) increase in force level compared to only a 2030% increase for multistranded wires with an increase in diameter from 0.015 to 0.0175 inch . furthermore , the 2030% increase in force level for the multistranded wire could have been negated to some extent because coaxial wires deliver less force than twisted wires,28 and the increase in the number of strands ( from three strands to six strands ) makes multistranded wires more flexible and lessens the force.29 there is much controversy regarding the question of whether light versus heavy forces have any effect on orthodontic tooth movement and associated pain . various histological studies and clinical trials suggest that light forces are capable of producing efficient tooth movement with less tissue damage and subsequent pain , whereas heavy forces cause greater periodontal compression and thus more pain.25 however , few authors reported that application of heavier forces per unit area increases the rate of biological response,30 and there are no statistically significant correlations among the initial tooth positions , applied force levels and experienced pain.31 however , one of the most recent studies carried out to examine the relationship between amount of force ( heavy versus low ) concluded that application of heavy force does not significantly enhance the rate of tooth movement , but compared to light force , it does produce significantly greater pain at the peak level of pain , i.e. 24 h after force application.17 the study further concluded that the effect of heavy forces on orthodontic pain was due to significantly greater increase in il-1beta concentration as compared to light forces . perhaps this could explain the difference with regard to pain among superelastic nickel titanium wire and multistranded stainless steel wires at the peak level observed in the present trial . titanium is around 133 g of force over a deflection of 4 mm.27 at a similar deflection of 3 mm , the force produced by 0.0175-inch six - stranded coaxial multistranded stainless steel wire is around 95 g.28 the greater force level associated with superelastic nickel titanium wire 2729 could have resulted in increased concentrations of il-1beta at peak level , which could cause increased pain . since there was a plateau of peak - level pain , it is quite possible that the concentration of il-1beta might have been higher from 12 h to bedtime on day 1 . unfortunately , the previous study17 examined il-1beta concentrations at 1 h , 24 h , 1 week , and so on ; therefore , further studies are required to explore the precise relationships among orthodontic force level , il-1beta concentration and orthodontic pain . we compared the two most commonly used initial archwires in moderate - to - severe crowding conditions that are commonly encountered during orthodontic treatment . therefore , our findings can be generalized to most settings involving the levelling and alignment phase of fixed orthodontic treatment . furthermore , robust conclusions can be drawn from the results because the sample size was based on the priori power analysis , randomization was stratified on known confounding factors , the longitudinal data were comprised of a large number of repeated measures ; and the statistical analysis involved a mixed - effect model analysis that considered the correlated nature of data and inter - individual variations in the form of random effects . the weaknesses and limitations of this study mostly pertain to the non - consideration of a few factors that could have influenced the outcome . although an attempt was made to control all such factors ( age , sex and initial crowding ) , psychological factors such as anxiety / depression and hormonal fluctuation in females during menstruation cycle were not taken into account and could have influenced the outcome of the trial . furthermore , as and when required use of analgesics could have also affected the results . future studies should take into account all such factors that can influence pain perception . during the initial levelling and aligning phase of fixed orthodontic treatment , the initial wire should exert light continuous forces to facilitate the most efficient tooth movement with the least possible tissue damage and pain . because recent clinical9 and laboratory10 studies have concluded that both wire types are equally efficient , the wire choice could be selected based on patient pain and discomfort . our study , perhaps for the first time , demonstrates that during the peak level of pain , multistranded stainless steel wire produces significantly less pain compared to superelastic nickel titanium archwires . therefore , multistranded stainless steel wires can be an important and viable alternative to superelastic nickel titanium during the initial levelling and aligning phase of fixed orthodontic treatment because pain produced by these wires at the peak level is less than that produced by superelastic nickel titanium . during the peak level of pain following the placement of an initial aligning archwire ( 12 h to day 1 bedtime ) , subjects with superelastic nickel titanium wire reported significantly greater pain compared to those with multistranded stainless steel . however , there was no statistically significant difference between these archwires for mean average pain across all time points .

objective : to investigate and compare the effects of superelastic nickel titanium and multistranded stainless steel archwires on pain during the initial phase of orthodontic treatment.design:a double - blind two - arm parallel design stratified randomized clinical trial.setting:a single centre in india between december 2010 and june 2012 . a total of 96 participants ( 48 male and 48 females ; 14.12.1 years old ) were randomized ( stratified on age , sex and initial crowding ) to superelastic nickel titanium or multistranded stainless steel archwire groups using a computer - generated allocation sequence.methods:we compared 0.016-inch superelastic nickel titanium and 0.0175-inch multistranded stainless steel wires in 0.022-inch slot ( roth prescription ) preadjusted edgewise appliances . the follow - up period was 14 days . outcome was assessed with a visual analogue scale at baseline and 32 pre - specified follow - up points . data was analyzed using mixed - effects model analysis.results:one participant was lost to follow up and 10 were excluded from the analysis due to bond failure or incomplete questionnaire answers . ultimately , 85 participants ( 42 males and 43 females ; 14.12.0 years old ) were analysed for the final results . no statistically significant difference was found for overall pain [ f value = 2.65 , degrees of freedom ( df ) = 92.6 ; p = 0.1071 ] . however , compared to multistranded stainless steel wires , pain in subjects with superelastic nickel titanium archwires was significantly greater at 12 h ( t = 2.34 ; p = 0.0193 ) , as well as at day 1 in the morning ( t = 2.21 , p = 0.0273 ) , afternoon ( t = 2.11 , p = 0.0346 ) and at bedtime ( t = 2.03 , p = 0.042).conclusion : for overall pain , there was no statistically significant difference between the two wires . however , subjects with superelastic nickel titanium archwires had a significantly higher pain at peak level .

non radial oscillations of compact stars can be excited in several astrophysical events . for instance , after a neutron star ( ns ) is formed in a gravitational collapse , or in processes that may occur during its subsequent evolution ; these include starquakes , glitches , interactions with a stellar companion , or phase transitions to quark matter or to a kaon and/or pion condensate , that may arise in the inner core of a ns if the density exceeds some critical value . all these phenomena induce perturbations which set the star in oscillation and , according to general relativity , gravitational waves ( gws ) are one of the channels through which energy is dissipated . in addition , due to rotation some modes may grow unstable through the chandrasekhar - friedman - schutz mechanism ( cfs instability ) @xcite ; these instabilities may have important effects on the subsequent evolution of the star , and they may be associated to a further emission of gws , the amount of which would depend on when and whether the growing modes are saturated by non - linear couplings or dissipative processes . it is therefore important to know at which frequencies a star pulsates emitting gravitational waves , and to study under which conditions the corresponding modes become unstable . if one assumes that the star does not rotate , the mode frequencies can easily be computed by solving the equations of stellar perturbations , which have been formulated in the sixties @xcite and further developed in later years @xcite . these equations have been integrated for a large variety of equations of state proposed to describe matter in a ns @xcite . these studies show that the identification of the frequency corresponding to the excitation of a stellar mode ( for instance the fundamental mode which is likely to be the most energetic ) in a detected gravitational signal , would allow to infer interesting information on the composition of the inner core of a ns and on the equation of state of matter at supranuclear densities . however , all stars rotate , and our present knowledge of the quasi - normal mode ( qnm ) spectrum of rotating stars is far to be complete . the perturbative approach which works so fine in the non rotating case , when generalized to include rotation shows a high degree of complexity , even if the star is only slowly rotating @xcite . a major difficulty arises because , when using the standard spherical harmonics decomposition of the perturbed tensors , modes with different harmonic indexes couple , giving rise to an infinite set of dynamical , coupled equations . for this reason , in all studies based on this approach simplifying assumptions are introduced : either the couplings between oscillations with different values of the harmonic index @xmath1 are neglected , or cowling s approximation is used ( i.e. spacetime perturbations are neglected ) @xcite . to our knowledge , the only place where the oscillations of a slowly rotating star are studied without making use of any of these restrictive assumptions is in @xcite where , however , only @xmath2-modes have been considered . an alternative approach consists in solving the equations describing a rotating and oscillating star in full general relativity , in time domain . however , current studies based on this approach also make use of strong simplifying assumptions , or restrict to particular cases . for instance , the cowling approximation has been used in several papers @xcite ; in @xcite only quasi - radial modes ( @xmath3 ) have been considered ; in @xcite only the neutral mode ( zero - frequency mode in the rotating frame ) has been studied ; in @xcite only axisymmetric ( @xmath4 ) modes have been analysed , using the conformal flatness condition . in @xcite , the frequencies of axisymmetric modes ( @xmath4 ) with @xmath3 to @xmath5 have been computed for rapidly rotating relativistic polytropes , using the cowling approximation ; a comparison of the results for @xmath3 obtained in the cowling approximation in @xcite , with those found in full gr in @xcite , shows that cowling s approximation introduces large errors in the determination of the fundamental mode frequency . in this article we develop a general method to find the quasi - normal mode frequencies of a rotating star . we perturb einstein s equations about a stationary , axisymmetric background describing a rotating star . the perturbed quantities are expanded in circular harmonics @xmath6 . as we are looking for quasi - normal modes , we assume a time dependence @xmath7 , with @xmath8 complex . due to the background symmetry , perturbations with different values of @xmath8 and @xmath9 are decoupled ; thus , for assigned values of @xmath10 , the perturbed equations to solve are a 2d - system of linear , differential equations in @xmath2 and @xmath11 . in this paper we do not derive explicitly the perturbed equations in the general case of rapidly rotating stars , since they will be studied in a subsequent paper . our goal here is to describe the general method . two are the main ingredients on which our method is based : i ) the perturbed equations are integrated using spectral methods ; ii ) the boundary conditions at the center of the star and at radial infinity are implemented by suitably generalizing the standing wave approach which has been used to find the qnm frequencies of non - rotating stars @xcite . these points will be described in section [ method ] . to test our approach , in section [ slowly ] we find the frequency of the fundamental mode of a slowly rotating , constant density star , as a function of the rotation rate . concluding remarks are in section [ conclusions ] . the metric which we consider as a background is stationary and axially symmetric . it can be cast in the general form @xcite @xmath12 where @xmath13 , @xmath14 , @xmath15 , @xmath16 are functions of the coordinates @xmath17 , @xmath18 . in ( [ rotmet1 ] ) there is still some gauge freedom , which allows to write the metric in a simpler form , like @xmath19 as in @xcite , or like @xmath20 as in @xcite , @xcite . in the following we shall not specify explicitly the gauge , but we will require that some properties are satisfied ; in particular we require : i ) that the spacetime is described by the coordinates @xmath21 , ii ) that @xmath22 , @xmath23 are killing vectors associated with stationarity and axisymmetry respectively , and iii ) that @xmath24 are polar coordinates on spheres , i.e. that the surfaces @xmath25 , @xmath26 are diffeomorphic ( but not isomorphic ) to @xmath27-spheres . as a consequence of these assumptions ( that are fulfilled by ( [ rotmet2 ] ) and ( [ rotmet3 ] ) ) any tensor field defined on one of these surfaces can formally be expanded in tensor spherical harmonics , even if the spacetime is not spherically symmetric ; this property will be useful in section [ standingrot ] . the metric and fluid velocity perturbations can be considered as tensor fields in this background ; they are expanded in circular harmonics @xmath6 , and fourier - transformed in time . since perturbations belonging to different @xmath9 and different frequency @xmath8 do not couple , in what follows @xmath9 and @xmath8 will be considered as fixed , and perturbed quantities will be decomposed as follows @xmath28 the frequency @xmath8 is , in general , complex . by fixing the gauge , imposing @xmath29 and assigning an equation of state which relates @xmath30 and @xmath31 , the sixteen quantities @xmath32 , @xmath33 , @xmath34 , @xmath35 reduce to ten @xmath36 . a possible gauge choice , which we call _ generalized regge - wheeler gauge _ , is described in appendix [ genrw ] ; however , other gauges can be considered ( see for instance @xcite ) . for simplicity of notation , to hereafter we shall assume that the quantities @xmath37 are scalars with respect to rotation ( as they are , indeed , in the generalized regge - wheeler gauge , see appendix [ genrw ] ) ; however , every step of the approach we will describe can be applied also to tensorial quantities by a suitable generalization . einstein s equations , linearized about our stationary axisymmetric background , reduce to a system of partial differential equations ( pde ) for the functions @xmath37 in @xmath2 and @xmath11 . to find the qnm frequencies , for assigned values of @xmath9 and @xmath8 , we solve these equations by imposing that all metric functions are regular near the center of the star , that the lagrangian perturbation of the pressure vanishes on the stellar surface , and that the solution at infinity behaves as a pure outgoing wave . the conditions at the center and at the surface of the star can be fulfilled for every value of @xmath8 , but the outgoing wave condition at infinity is only consistent with a discrete set of ( complex ) frequencies @xmath38 ; such frequencies are the qnm . we will now describe how to implement the boundary condition at infinity , and the numerical approach we use to solve the perturbed equations . in this section we shall generalize to the rotating case the _ standing wave _ approach @xcite used to find the qnm frequencies of non rotating stars . to this purpose , it is useful to remind how this method works . first of all it is worth stressing that by this approach @xcite one can only determine the qnm frequencies of slowly damped modes , like the @xmath39- , @xmath40- , and @xmath2-modes ; it can not be applied to highly damped modes , like stellar @xmath41-modes or black hole s qnm . it is known that the equations describing the perturbations of a non rotating , spherical star can be separated by expanding the perturbed tensors in tensorial spherical harmonics ; outside the star these equations reduce to those describing schwarzschild perturbations , and they can be reduced to the regge - wheeler @xcite and the zerilli @xcite equations , for two suitably defined functions which we both indicate as @xmath42 . the two wave equations have the following form @xmath43 z^{lm}(r,\omega)=0,\qquad\quad l\ge 2~ , \label{rwzer}\ ] ] where @xmath44 is the usual tortoise coordinate and @xmath45 is a short range potential . the qnm frequencies are the values of the complex frequency @xmath8 for which the solutions of equation ( [ rwzer ] ) , found by imposing appropriate boundary conditions at the surface of the star , behave as pure outgoing waves at radial infinity , i.e. @xmath46 the standing wave approach consists in the following . let us assume that @xmath42 is an analytic function of the complex variable @xmath47 , and be @xmath48 the frequency of a qnm , with @xmath49 . in general , at radial infinity the solution of equation ( [ rwzer ] ) is a superposition of ingoing and outgoing waves , i.e. @xmath50 if @xmath51 , by definition @xmath52 ; since @xmath53 is analytic and since @xmath49 , we can expand @xmath54 near the real @xmath55 as follows @xmath56 where `` @xmath57 '' indicates differentiation with respect to @xmath58 ; then , by imposing @xmath59 we find @xmath60 using this relation the function @xmath54 , near @xmath61 ( with @xmath58 and @xmath55 real ) , can be written as @xmath62\ , , \label{parcompl}\end{aligned}\ ] ] from which it follows @xmath63~ , \label{stanwav}\ ] ] where @xmath64 is a constant which does not depend on @xmath58 . thus , to find the frequencies of the qnm it is sufficient to integrate the wave equation ( [ rwzer ] ) for _ real _ values of the frequency @xmath58 , and find the values @xmath65 for which the amplitude of the standing wave ( [ stanwav ] ) has a minimum : these are the qnm frequencies . the corresponding damping times @xmath66 can be found through a quadratic fit of @xmath67 . let us now consider a rotating star . as discussed above , with a suitable choice of the gauge the relevant perturbed quantities reduce to a set of quantities which behave as scalars with respect to rotation : @xmath36 ( @xmath8 complex ) . they must satisfy a set of pde , obtained by linearizing einstein s equation , which can be integrated once the values of these quantities are assigned at the center of the star , i.e. on a sphere of radius @xmath68 ( hereafter @xmath69 is the stellar radius ) @xmath70 the @xmath71 are subject to constraints , which arise from the analytical expansion in powers of @xmath2 of the perturbed equations , from the assumption of regularity of the spacetime as @xmath72 , and from the requirement that the lagrangian pressure perturbation must vanish on the surface of the star . these constraints reduce the number of independent quantities from the ten @xmath71 to a smaller number , say @xmath73 , i.e. @xmath74 . being these quantities defined on a sphere @xmath75 , they can formally be decomposed in spherical harmonics @xmath76 where the expansion is truncated at @xmath77 . therefore the independent solutions of the perturbed equations correspond to the following set of @xmath78 $ ] constants @xmath79 given these constants , the perturbed equations for the functions @xmath80 can be integrated for @xmath81 . in the wave zone , far away from the star , the far field limit expansion of the metric describing a rotating star shows that the metric reduces to the schwarzschild solution ( see for instance @xcite , chap . this occurs because terms due to rotation decrease faster than the `` schwarzschild - like '' components . therefore , as when dealing with schwarzschild perturbations , in this asymptotic region we can define the gauge invariant zerilli and regge - wheeler functions , @xmath82 and @xmath83 , in terms of the perturbed metric tensor , expanded in tensorial spherical harmonics with @xmath84 . this tensor is found by integrating the equations describing the perturbed spacetime outside the rotating star . the well known asymptotic behaviour of @xmath82 and @xmath83 is @xmath85 a ( complex ) frequency @xmath86 belongs to a quasi - normal mode if , for an assigned value of @xmath9 , the following condition is satisfied for _ any _ @xmath1 : @xmath87 i.e. if the set of @xmath88 $ ] constants @xmath89 vanishes . it should be stressed that this is a big difference with respect to the non rotating case : in that case each mode belongs to a single , assigned value of @xmath1 , and there is degeneracy in @xmath9 . for each assigned value of @xmath9 , we define the vectors @xmath90 the dimensionality of which is @xmath78 $ ] and @xmath88 $ ] , respectively . since the perturbed equations are linear , these vectors are related by the matrix equation @xmath91 the constants @xmath92 do not depend on @xmath8 . the coefficients of the complex matrix @xmath93 have to be evaluated by integrating the perturbed equations . equation ( [ eqmoderot0 ] ) , which identifies the qnm eigenfrequencies , can be written as @xmath94 a discrete set of qnm s exists if the matrix @xmath95 is square , i.e. if @xmath96 . thus , equation ( [ eigeneqn ] ) is equivalent to impose @xmath97 as we will show in the appendices , by counting the number of independent equations in the cases of spherical stars and of slowly rotating stars we find indeed @xmath96 . we expect the same to hold also for rapidly rotating stars . we now summarize the procedure to solve the 2d - perturbed equations using _ spectral methods_. they are , indeed , very powerful to solve 2d - differential equations , and particularly useful to implement boundary conditions . for a general discussion on spectral methods we refer the reader to @xcite . we expand all functions of @xmath2 in chebyshev polynomials : @xmath116 which satisfy the orthogonality relations @xmath117 ( @xmath118 , @xmath119 ) . the variable @xmath120 $ ] is related to @xmath121 $ ] by the following equation @xmath122\,.\label{rescale}\ ] ] * integrals on chebyshev polynomials can be evaluated using the gaussian quadrature method @xcite : truncating the polynomial expansion at @xmath123 we get @xmath124 where the collocation points are @xmath125 * the derivative of a function can be expressed as follows @xmath126 with @xmath127\label{defder}\,.\end{aligned}\ ] ] * given a function @xmath128 , and a function @xmath129 with chebyshev expansion @xmath130 the expansion of @xmath131 is @xmath132 where @xmath133 with @xmath134 we expand all functions of @xmath11 in the basis of the associated legendre polynomials @xmath135 with @xmath136\ ] ] and @xmath9 fixed . they are related to scalar spherical harmonics : @xmath137 therefore , expanding a function in circular harmonics @xmath6 and in associated legendre polynomials is equivalent to expand it in spherical harmonics . @xmath138 s are eigenfunctions of the laplacian operator , @xmath139 and , assuming for simplicity of notation @xmath140 , have the following asymptotic behaviour near the @xmath141-axis ( see ( [ defp0 ] ) ): @xmath142 this is the asymptotic behaviour of any function of @xmath11 which is regular on the @xmath141-axis . let us consider a function @xmath143 , regular in @xmath144 and on the @xmath141-axis ; let us expand it in circular harmonics @xmath145 the regularity of @xmath143 near the @xmath141-axis implies that ( see for instance @xcite ) @xmath146 therefore , the @xmath147 can be expanded in the polynomials @xmath148 with @xmath9 fixed : @xmath149 thus , associated legendre polynomials @xmath138 ( with @xmath9 fixed ) are a complete basis for all functions of @xmath11 with the asymptotic behaviour ( [ asymptax ] ) . in order to apply the gaussian quadrature method to associated legendre s polynomials , we notice that the polynomials @xmath150 form , for each @xmath9 , a complete basis , with orthogonality relation @xmath151 the @xmath152 s are a particular case of jacobi s polynomials @xmath153 defined by @xcite @xmath154 where @xmath155 . therefore , gaussian integration takes the form @xmath156 where @xmath157 and @xmath158 are the collocation points and weights for the jacobi polynomials with @xmath155 . in particular , the coefficients of the expansion ( [ fap ] ) are @xmath159 let us consider a one - dimensional , first order , differential equation @xmath160 with @xmath161 $ ] . if we expand @xmath162 in the basis of chebyshev polynomials , @xmath163 , truncating the expansion at @xmath123 , i.e. @xmath164 the differential equation ( [ zpvz ] ) becomes an algebraic equation : @xmath165 where @xmath166 and @xmath167 are defined in ( [ defder ] ) , ( [ vnm ] ) . the boundary conditions needed to solve equation ( [ zpvz ] ) can be implemented using the so - called @xmath168-_method _ : we cut the last row of ( [ dva ] ) , i.e. we set @xmath169 and replace the row with the boundary condition ; for instance , if we know that @xmath170 , the last row of the matrix equation will be replaced with @xmath171 the differential equation ( [ zpvz ] ) , with the boundary condition @xmath170 , thus reduces to a matrix equation which can be solved by @xmath172 decomposition @xcite . this approach can easily be generalized to higher order differential equations ( by replacing more rows for the associated boundary conditions ) , to systems of coupled differential equations , and to partial differential equations in @xmath173 . in this case , each function is expanded in the basis @xmath174 as follows @xmath175 where sums over chebyshev s and associated legendre s polynomials are truncated to the orders @xmath176 and @xmath177 , respectively ; the coefficients @xmath178 can be organized as the components of a vector , defining the collective index @xmath179(k+1)+n+1=1,2,\dots,\left[l-|m|+1\right](k+1)\ ] ] and setting @xmath180 in terms of the expansion ( [ doubleexp ] ) , pdes in @xmath173 ( in our case , the equations which describe the perturbations of rotating stars ) transform into an algebraic equation . as an example of the double expansion ( [ doubleexp ] ) , in appendix [ rwspher2d ] we show how to solve the regge - wheeler equation as a partial differential equation in @xmath173 . as a test of our method , we have solved the equations which describe the perturbations of a slowly rotating stars . following @xcite , in this case the metric and fluid velocity of the unperturbed star are @xmath181 where @xmath182 describes the dragging of the inertial frames , and all quantities are expanded at first order in the angular velocity of the star , @xmath183 . we introduce a rotation parameter @xmath184 defined by @xmath185 in the metric ( [ slowstar ] ) spherical symmetry is broken only by the term @xmath8 ; when einstein s equations are perturbed about ( [ slowstar ] ) , only terms which are linear in @xmath8 are retained , i.e. we keep terms up to order @xmath186 . as a consequence , perturbations with index @xmath1 are coupled with perturbations with indexes @xmath187 through terms that are of order @xmath186 , the analytical form of which can explicitly be derived . therefore , when we transform the perturbed equations using the double spectral decomposition described in section [ spectral ] , the resulting algebraic equations have a particularly simple form : the relevant matrix is `` almost - block - diagonal '' , each block corresponding to one value of @xmath1 ; the off - diagonal blocks couple @xmath188 . these equations can also be obtained in a different way , i.e. by expanding in chebyshev polynomials the system of ordinary differential equations in @xmath2 derived by kojima in @xcite ( hereafter , k1 ) . this follows from the fact that kojima s equations are derived by expanding the perturbed einstein s equations in spherical harmonics . the general structure of kojima s equations is the following : @xmath189 & = & m{\cal e}[h_0^{lm},k^{lm};\sigma ] + { \cal f}^{(\pm)}[z_{rw}^{l\pm1\,m};\sigma]\nonumber\\ { \cal l}^{ax}[z_{rw}^{lm};\sigma]&= & m{\cal n}[z_{rw}^{lm};\sigma]+ { \cal d}^{(\pm)}[h_0^{l\pm1\,m},k^{l\pm1\,m};\sigma ] . \label{kojstruct}\end{aligned}\ ] ] here @xmath190 , @xmath191 are operators of order @xmath192 , which describe the perturbations of the star in the non rotating case ; @xmath193 , @xmath194 , @xmath195 , @xmath196 are @xmath197 operators , which provide the corrections due to rotation . these equations have been integrated numerically in @xcite ( see also @xcite ) using a very strong simplification : the couplings @xmath198 were neglected ( i.e. @xmath194 and @xmath199 were set to zero ) . moreover , the equations were solved iteratively , finding the solution for @xmath200 first , and then replacing it in the terms @xmath201 $ ] and @xmath202 $ ] of eqs . ( [ kojstruct ] ) . in this way , the right - hand sides of eqs . ( [ kojstruct ] ) become source terms . we stress that with our approach we do not need these simplifications anymore ; in particular , we do not need to neglect the couplings , because we can handle the mixing among perturbations with different @xmath1 s using the spectral methods and the generalized standing wave approach . it should also be mentioned that , when coupling terms are included in the perturbed equations , in order to have a good numerical behaviour of the perturbations near the center of the star we need to use a set of variables ( in particular the @xmath197 terms ) different from that used in @xcite . the equations for the new variables are given explicitly in appendix [ couplkoj ] . as mentioned above , in @xcite ( hereafter k2 ) the equations of stellar perturbations have been integrated for a slowly rotating star , neglecting @xmath198 couplings , and the qnm frequencies have been found ; to reproduce these results we have used the same set of variables as in k1 , the same equation of state ( eos ) i.e. the polytropic eos @xmath203 , and we have computed the fundamental mode ( @xmath39-mode ) frequency , @xmath204 . in k2 the real and imaginary parts of @xmath204 are fitted as functions of the rotation parameter @xmath184 as follows : @xmath205 the value of @xmath206 we find , properly normalized , is plotted versus the stellar compactness , @xmath207 , in figure [ koj93nu ] a ) . the values are in excellent agreement with the results shown in figure 1 of k2 , for @xmath208 . the correction due to rotation , @xmath209 , is plotted versus @xmath207 in figure [ koj93nu ] b ) for different values of @xmath184 . we find that for @xmath210 the corresponding curves are indistinguishable , and coincide with the @xmath208 curve shown in figure 1 of k2 . however , for @xmath211 different @xmath184 correspond to different curves , and the fit ( [ fitdecoupl ] ) becomes inaccurate : @xmath209 is no longer a constant , and further corrections to ( [ fitdecoupl ] ) are of order @xmath212 , as expected theoretically . -mode frequency of a non rotating , polytropic star with @xmath208 , is plotted as a function of the stellar compactness @xmath207 ( a ) ; the frequency shift due to rotation , @xmath209 is plotted versus compactness for different values of @xmath184 ( b ) . as in k2 , couplings among different @xmath1 s are neglected . [ koj93nu],title="fig:",width=226 ] -mode frequency of a non rotating , polytropic star with @xmath208 , is plotted as a function of the stellar compactness @xmath207 ( a ) ; the frequency shift due to rotation , @xmath209 is plotted versus compactness for different values of @xmath184 ( b ) . as in k2 , couplings among different @xmath1 s are neglected . [ koj93nu],title="fig:",width=226 ] -mode frequency ( a ) and the corrections due to rotation ( b ) are plotted as in figure [ koj93nu ] . , title="fig:",width=226 ] -mode frequency ( a ) and the corrections due to rotation ( b ) are plotted as in figure [ koj93nu ] . , title="fig:",width=226 ] in figure [ koj93damp ] we plot the imaginary part of the @xmath39-mode frequency , @xmath213 , and the corresponding rotational correction , @xmath214 , as in figure [ koj93nu ] . @xmath214 is plotted only for @xmath215 , because for smaller values our numerical approach becomes inaccurate . they agree with the values given in figure 2 of k2 , with differences of order @xmath212 . we now apply our method to solve eqs . ( [ kojstruct ] ) in full , i.e. including couplings among different @xmath1 s . the numerical implementation of the equations presents a problem : there are terms in the equations which depend on @xmath216 and on @xmath217 , which strongly diverge on the stellar surface . this divergence is particularly problematic when spectral methods are used , but it can be cured through a regularization procedure @xcite . such regularization goes beyond the scope of the present paper , where we only want to discuss a simple implementation of our approach . therefore , we solve the perturbed equations in the case of a constant density , slowly rotating star , such that the divergent terms vanish . we consider two background models : @xmath218 , with @xmath219 and @xmath64 , with @xmath220 . mass and radius for assigned values of the central density are given in table [ taba ] . .parameters of the constant density stellar models @xmath218 and @xmath64 we use as a background . [ taba ] [ cols="^,^,^,^,^",options="header " , ] the explicit form of the equations and the boundary conditions in @xmath144 and @xmath221 are discussed in appendix [ couplkoj ] . as mentioned above , when couplings are included the equations derived in k1 are very unstable when integrated near the center . for this reason we introduce a new set of variables , which satisfy a new set of equations shown in appendix [ couplkoj ] ; the appropriate boundary conditions in @xmath144 and @xmath221 are also shown . once we assign the value of the harmonic index @xmath9 , these equations couple polar and axial perturbations with @xmath222 . the equations have been integrated for @xmath223 . we do not set @xmath224 because in that case dipolar ( @xmath225 ) perturbations have to be taken into account , which are described by equations different from those we consider in this paper . we would like to stress that rotational corrections to mode frequencies with @xmath226 are much larger than those to mode frequencies with @xmath4 . in k2 , kojima suggested that , at lowest order in @xmath184 , the frequency shift is proportional to @xmath9 . this is consistent with the results of our numerical integration : the relative frequency shifts found in @xcite , where @xmath4 perturbations were studied in full general relativity , are an order of magnitude smaller than the relative shifts we find for @xmath227 . if the star does not rotate , for any assigned value of @xmath1 there is a corresponding @xmath39-mode frequency , which is the same for all @xmath9 s . if the star rotates , due to the couplings the @xmath39-mode belonging to an assigned @xmath1 acquires contributions from different @xmath1 s , and its frequency and damping time change . furthermore , the degeneracy in @xmath9 is broken by rotation . the real part of the @xmath39-mode frequency , @xmath228 , is plotted as a function of the rotation parameter in figure [ fmode ] for the two considered stellar models . the solid line represents the frequency of the @xmath229 @xmath39-mode of the non - rotating star . the dashed lines are the frequencies of the lowest lying fundamental mode of the rotating star , with @xmath230 and @xmath231 , assuming @xmath232 . our calculations refer to @xmath233 , since for higher values the slow rotation approximation becomes inaccurate and the results can not be trusted anymore . -mode frequency , @xmath228 , is plotted versus the rotation parameter @xmath184 . the data refer to two models of constant density star ( see text ) . we include couplings up to @xmath234 . the dashed line refers to the non rotating star ; the dotted lines refer to the modes @xmath235 of the slowly rotating star . [ fmode ] , title="fig:",width=226 ] -mode frequency , @xmath228 , is plotted versus the rotation parameter @xmath184 . the data refer to two models of constant density star ( see text ) . we include couplings up to @xmath234 . the dashed line refers to the non rotating star ; the dotted lines refer to the modes @xmath235 of the slowly rotating star . [ fmode ] , title="fig:",width=226 ] figure [ detail ] shows , in a smaller range of the rotation parameter , the frequency @xmath236 computed by truncating the expansion in @xmath1 at @xmath237 ( i.e. without couplings ) , @xmath238 and @xmath232 . it is evident that for slowly rotating stars the contribution of the couplings is a small correction , and that there is convergence as @xmath177 grows . : we show the contribution of the different couplings to the @xmath39-mode frequency , for model @xmath218 . the different curves are obtained by including in the perturbed equations couplings up to @xmath77 . [ detail],title="fig:",width=226 ] : we show the contribution of the different couplings to the @xmath39-mode frequency , for model @xmath218 . the different curves are obtained by including in the perturbed equations couplings up to @xmath77 . [ detail],title="fig:",width=226 ] the relative frequency shift due to the couplings is well approximated by a quadratic behaviour in @xmath184 : @xmath239 as shown in figure [ couplings ] . ) for model a.[couplings],width=226 ] therefore , the contribution of the couplings is of order @xmath212 , as argued by kojima in k2 , and @xmath240 is well described by a quadratic fit of the form @xmath241 where we should remind that terms of order @xmath212 are of the same order of the terms which we are neglecting in the perturbed equations ab initio . , plotted as functions of the rotation rate for model @xmath218.[coefficients],width=226 ] this fit is accurate up to @xmath242 ; for larger values @xmath243 and @xmath244 are no longer constant , as shown in figure [ coefficients ] : as @xmath184 grows , @xmath243 changes linearly , and the change is negative if @xmath245 , positive if @xmath246 , yielding in both cases a shift to lower values of the total frequency @xmath58 . this explains the small asymmetry between @xmath247 and @xmath248 shown in figure [ fmode ] . notice that deviations from the fit ( [ fitcoupl ] ) are always of order @xmath212 , consistently with our approximation scheme . for @xmath249 , the coefficients @xmath244 are @xmath250 ( if @xmath230 ) and @xmath251 ( if @xmath231 ) ; for @xmath252 they are too small to be correctly extrapolated with our codes . finally , the damping time of the @xmath39-mode is shown in figure [ tau ] as a function of the rotation rate . -mode as a function of the rotation rate , for model @xmath218.[tau],title="fig:",width=226 ] + it is worth stressing that , as the stellar rotation increases , the frequency of the counterrotating ( i.e. @xmath231 ) mode decreases faster than expected by the simple linear fit ( [ fitdecoupl ] ) . furthermore , figure [ tau ] shows that the damping time of the counterrotating mode increases sharply , even for small rotation rates . this indicates that the cfs instability may occur for values of the rotation rate lower than expected by simple linear estimates . it should be mentioned that the equations derived for the perturbations of a slowly rotating star in @xcite and in appendix [ couplkoj ] , are not appropriate to study the @xmath2-modes , because the frequency @xmath58 , which is a dimensionful scale of the problem , is of the same order as the `` small '' parameter @xmath184 . the shift of the @xmath2-mode frequency due to slow rotation in a relativistic star has been studied in @xcite , taking into account the couplings between perturbations with different @xmath1 s . in this paper we propose a new approach to find the quasi - normal mode frequencies of rotating relativistic stars . we describe the main features of the general method , and test it in the particular case of slowly rotating stars . the application of our method to rapidly rotating stars will be discussed in a forthcoming paper . we give explicit formulae ( whose numerical implementation is straightforward ) which allow to transform functions of @xmath173 in vectors , and systems of coupled differential equations ( involving derivatives in @xmath173 ) in algebraic , matrix equations . furthermore , we show that , once the 2d - equations describing stellar perturbations have been solved , the frequencies and damping times of slowly damped , quasi - normal modes can be found by looking for the minima of the determinant of a properly defined matrix , evaluated as function of real frequency , thus generalizing the standing wave approach @xcite to rotating stars . we have tested the method in the case of slow rotation ; the system of partial differential equations from which we start is formally the same as in @xcite ( apart from a redefinition of some variables described in appendix [ couplkoj ] ) . however , in our approach we transform that differential system in a system of algebraic , coupled equations ; thus , the advantage of our method is that it is much easier to handle the couplings among different values of @xmath1 , which in @xcite correspond to couplings between different partial differential equations . for this reason we are able to study the shift of the fundamental mode due to rotation , taking into account the @xmath198 couplings , to our knowledge for the first time in the literature . in this paper we show that , as the rotation parameter @xmath184 increases , the frequency of counterrotating modes decreases at a rate higher than linear in @xmath184 . furthermore , the corresponding damping time sharply increases , even for small rotation rates . this suggests that the cfs instability for a generic mode should occur for values of the rotation rate lower than expected by simple linear estimates . this result complements what found in @xcite , where the equations of stellar perturbations where integrated in full general relativity looking for neutral modes , and it was shown that the cfs instability sets in for smaller rotation rates than in newtonian gravity . it should be mentioned that an alternative approach to find the qnm frequencies , based on a characteristic formulation of the perturbed equations and a complexification of the radial coordinate , which could be generalized to rotating stars , has recently been proposed @xcite . we are grateful to kostas kokkotas for suggesting us to generalize the standing wave approach to rotating stars . we thank loic villain for useful suggestions about the spectral methods , and jos pons for useful discussions . is supported by a `` virgo ego scientific forum ( vesf ) '' grant . in this appendix we denote with @xmath253 the coordinates @xmath254 , and with @xmath255 the coordinates @xmath24 ; we define @xmath256 . the relation between ( [ gengauge ] ) and ( [ propt ] ) is trivial , but to show that ( [ intcond ] ) implies ( [ gengauge ] ) is less obvious . if we integrate by parts ( [ intcond ] ) , we find @xmath263=0\,.\ ] ] as it holds for all @xmath1 s , the term in square brackets must vanish identically , i.e. @xmath264 therefore we can express the four quantities @xmath265 in terms of two scalar functions @xmath266 such that : @xmath267 this , together with ( [ propt ] ) , gives ( [ gengauge ] ) . this gauge choice is implicit in the formulation used in k1 to describe the perturbations of slowly rotating stars . it can , in principle , also be chosen to describe perturbations of rapidly rotating stars . we stress that the existence of the generalized regge - wheeler gauge , in which all perturbations are expressed in terms of functions that are scalar with respect to rotation , is important because it provides a solid basis to the approach described in this paper . indeed , it guarantees that expanding the perturbations in tensorial spherical harmonics is equivalent to expand in circular harmonics @xmath268 firstly , and then to expand the functions appearing in the resulting equations in @xmath0 , in associate legendre polynomials , @xmath269 . in order to better understand how the gauge ( [ gengauge ] ) is related to the regge - wheeler ( rw ) gauge , we now expand @xmath270 in tensor spherical harmonics . this is always possible ( on a surface @xmath271 , @xmath272 ) , but typically it is not useful if the background is non - spherical , since the dynamical equations couple perturbations with different @xmath1 s . anyway , for slowly rotating stars the couplings are small , and the spherical harmonics expansion , as described in appendix [ couplkoj ] and in @xcite , turns out to be useful . by expanding the perturbed metric tensor in tensor spherical harmonics , before any gauge fixing we find @xmath273 where @xmath274 are the axial vector harmonics , and @xmath275 and @xmath276 are tensor harmonics satisfying @xmath277 , with polar and axial parity , respectively . the rw - gauge for a spherical background , imposes @xcite : @xmath278 if we consider ( [ rwgauge ] ) in the case of a non - spherical background , we see that it is equivalent to the gauge ( [ gengauge ] ) . indeed , expanding @xmath279 in vector spherical harmonics , we find @xmath280\,,\ ] ] which , if @xmath281 , reduces to @xmath282 where we have defined the scalar functions @xmath283 we conclude this section with a simple exercise . choosing the gauge ( [ gengauge ] ) , we derive the equations which describe the axial perturbations of a non rotating star , i.e. the equations for @xmath284 ( in this case fluid perturbations are decoupled from metric perturbations ) , and we show how to solve them using spectral methods . we shall follow the lines of the well - known derivation of the regge - wheeler equation @xcite , with one difference : we do not expand the perturbations in spherical harmonics . by defining the function @xmath285 from einstein s equations we find @xmath286 where ` ' indicates differentiation with respect to @xmath2 . @xmath287 satisfies the partial differential equation @xmath288 where the coordinate @xmath44 is defined by @xmath289 in this formulation , @xmath290 is a differential operator : @xmath291\,.\label{v2d}\ ] ] the usual one - dimensional regge - wheeler equation can easily be recovered by expanding @xmath287 in scalar spherical harmonics : @xmath292 where @xmath293 and @xmath294 is the standard regge - wheeler function . let us briefly describe how equation ( [ rw2d ] ) can be integrated using spectral methods and the standing wave approach . we shall integrate this equation for real values of the frequency , therefore in the following we shall set @xmath295 . the integration range in @xmath44 is @xmath296 $ ] , i.e. given @xmath297 we want to know @xmath298 . the starting point @xmath299 corresponds to a small sphere near the center of the star , with @xmath300 , where the regge - wheeler function is given by an analytical expansion ( see below ) . the final point , @xmath301 , corresponds to a point in the wave zone , @xmath302 , where the ingoing and outgoing amplitudes can be extracted . we rescale the variables @xmath44 and @xmath11 as follows : @xmath303\,\nn\\ y&=&\cos\theta\in[-1,1]\,,\end{aligned}\ ] ] so that @xmath299 corresponds to @xmath304 , and @xmath301 to @xmath305 . then , we perform the double expansion ( [ doubleexp ] ) of the regge - wheeler function @xmath306 defined in ( [ deffz ] ) , for assigned values of @xmath9 , @xmath58 : @xmath307 the expansions in chebyshev s and associated legendre s polynomials are truncated at @xmath176 and @xmath177 , respectively ( for instance , @xmath308 ) . the boundary conditions at the center of the star are imposed by assigning @xmath309 and its derivative at @xmath304 : @xmath310 where the analytic expansion of the regge - wheeler equation gives @xcite @xmath311\nn\\ x^l_{in}(\sigma)&\equiv&\frac{(l+2)\left[\frac{1}{3}(2l-1 ) \rho(0)-p(0)\right]-\sigma^2e^{\nu(0)}}{2(2l+3)}\end{aligned}\ ] ] ( note that while in @xmath312 and @xmath313 , the index @xmath1 is a superscript , in @xmath314 it is an exponent ) . the constants @xmath315 form a vector @xmath316 which can be freely assigned ; for each vector @xmath109 we have one solution of the equation . notice that we have one constant @xmath317 for each value of @xmath1 i.e. , in the language of section [ standingrot ] , @xmath318 for the axial parity perturbations . if , in addition to axial perturbations , polar parity perturbations are considered , described outside the star by the zerilli equation , then there is another constant to be assigned for each value of @xmath1 . therefore , if all metric perturbations are considered , @xmath96 as discussed in section [ standingrot ] . we now project equation ( [ rw2d ] ) in the basis of chebyshev s and associate legendre s polynomials . the operator @xmath319 is diagonal in the @xmath138 basis , with eigenvalue @xmath320 . therefore , in this basis the operator @xmath290 defined in ( [ v2d ] ) reduces to the one - dimensional regge - wheeler potential @xmath321 ( [ zy ] ) . we introduce ( as in in section [ cheby ] , equations ( [ defder ] ) , ( [ vnm ] ) ) the derivative matrix @xmath322 and the potential matrix @xmath323 obtained projecting @xmath321 on chebyshev polynomials . to write the matrix equation we define the collective index @xmath324\ ] ] with @xmath325 , and we define the @xmath195-dimensional vector of components @xmath326 the matrix equation has the block - diagonal form @xmath327 with @xmath328 the boundary conditions are implemented by replacing the last two lines of each block , i.e. each @xmath329-th and @xmath330-th lines , with the conditions at the center in terms of the vector @xmath331 : @xmath332 by inverting the matrix equation ( [ la2d ] ) we find the coefficients @xmath333 and then @xmath334 . in this way , for each choice of @xmath335 , and of the vector @xmath336 of initial conditions , we can integrate from @xmath337 to @xmath338 . the ingoing amplitude at infinity @xmath339 can be found using the algorithm described in @xcite . therefore , for each choice of the vector of initial conditions @xmath331 , we have the vector of ingoing amplitudes at infinity @xmath340 this procedure is linear at any step , thus , repeating it for all @xmath98 : @xmath341 we find the expression of the matrix @xmath342 defined by @xmath343 as explained in section [ standingrot ] , near a mode @xmath114 the modulus of the determinant of this matrix behaves as @xmath344 and the frequency @xmath55 and the damping time @xmath345 of the mode can be found by a quadratic fit in @xmath58 . this derivation of the equations describing the perturbations of a slowly rotating star is based on the work of kojima @xcite , denoted as k1 . as discussed above , since we are considering slowly rotating stars , we can first expand the perturbations in spherical harmonics , getting a system of coupled ode in @xmath2 , and then expand this system in chebyshev polynomials , getting an algebraic matrix equation . the first step of this program is equivalent to the derivation of k1 , with one difference : we are going to reformulate the equations in terms of a different set of variables , which are numerically well behaved near the center of the star . following k1 , we shall assume @xmath346 . the background configuration , describing a slowly rotating , stationary and axially symmetric star is given by equation ( [ slowstar ] ) . the pressure @xmath40 and the energy density @xmath347 are found by solving the tov equations ; we assume that the equation of state of matter in the star is barotropic , @xmath348 ; therefore , @xmath349 . the perturbations of the background ( [ slowstar ] ) can be written as @xmath350 with @xmath58 real . the linearized einstein equations for the radial part of these quantities are ordinary differential equations in @xmath2 . as explained in section [ slowly ] , the general structure of these equations is : @xmath189 & = & m{\cal e}[h_0^{lm},k^{lm};\sigma ] + { \cal f}^{(\pm)}[z_{rw}^{l\pm1\,m};\sigma]\nn\\ { \cal l}^{ax}[z_{rw}^{lm};\sigma]&= & m{\cal n}[z_{rw}^{lm};\sigma]+ { \cal d}^{(\pm)}[h_0^{l\pm1\,m},k^{l\pm1\,m};\sigma]\,.\label{kojstruct2}\end{aligned}\ ] ] the quantities @xmath351 , @xmath352 , @xmath353 , @xmath354 , @xmath355 , @xmath356 , @xmath357 can be expressed in terms of @xmath358 , once equations ( [ kojstruct2 ] ) have been solved . the equations for polar perturbations inside the star are a system of two second order ode in @xmath359 , @xmath360 : @xmath361&\equiv&(k^{lm}-h_0^{lm } ) '' -\frac{e^\lambda}{r^2}[2r-10m+4\pi(\rho-5p)r^3](k^{lm}-h_0^{lm})'\nn\\ & & + \frac{e^\lambda}{r^2}(\sigma^2 e^{-\nu}r^2 - 2n)(k^{lm}-h_0^{lm})\nn\\ & & + 4\frac{e^\lambda}{r^4}[3mr-4\pi\rho r^4-e^\lambda(m+4\pi pr^3)^2 ] h_0^{lm}=0\label{in1norot}\\ l_{int}^{(2)lm}[h_0,k]&\equiv&k^{lm\ , '' } -\frac{e^\lambda}{r^2}[(r-3m-4\pi pr^3)c_s^{-2}-3r+5m+4\pi\rho r^3 ] k^{lm\,'}\nn\\ & & + \frac{e^\lambda}{r^2}[\sigma^2e^{-\nu}r^2c_s^{-2}-n(c_s^{-2}+1)]k^{lm } + \frac{c_s^{-2}-1}{r}h_0^{lm\,'}\nn\\ & & + \frac{e^\lambda}{r^3}[(nr+4m+8\pi pr^3)c_s^{-2}-(n+2)r + 8\pi\rho r^3]h_0^{lm}=0\,.\label{in2norot}\end{aligned}\ ] ] once @xmath360 , @xmath359 have been determined , @xmath351 and @xmath362 can be computed through the following relations : @xmath363 other relations ( see k1 ) give the fluid perturbations @xmath353 , @xmath354 , @xmath355 , @xmath356 , @xmath357 in terms of the metric perturbations . outside the star , the polar perturbations reduce to a system of three first order ode in @xmath359 , @xmath351 and @xmath360 : @xmath364&\equiv & k^{lm\,'}+\frac{e^\lambda(r-3m)}{r^2}k^{lm}-\frac{1}{r}h_0^{lm } -\frac{n+1}{r}\tilde h_1^{lm}=0\label{out1norot}\\ l_{ext}^{(2)lm}[h_0,\tilde h_1,k]&\equiv & -r\tilde h_1^{lm\,'}+e^\lambda(k^{lm}+h_0^{lm})- \frac{2me^\lambda}{r}\tilde h_1^{lm}=0\label{out2norot}\\ l_{ext}^{(3)lm}[h_0,\tilde h_1,k]&\equiv & h_0^{lm\,'}+\frac{e^\lambda(r-3m)}{r^2}k^{lm } -\frac{e^\lambda(r-4m)}{r^2}h_0^{lm}\nn\\ & & + \left(\sigma^2 re^\lambda-\frac{n+1}{r}\right)\tilde h_1^{lm}=0\ , , \label{out3norot}\end{aligned}\ ] ] where we have defined @xmath365 in order to have equations with real coefficients . furthermore , there is an algebraic constraint : @xmath366&\equiv & ( \sigma^2r^4e^\lambda - nr^2-mr+m^2e^\lambda)k^{lm}\nn\\ & & + ( nr+3m)rh_0^{lm}-[\sigma^2r^4-(n+1)mr]\tilde h_1^{lm}=0\,.\nn\\ \label{algebraicnorot}\end{aligned}\ ] ] equations ( [ out1norot])-([out3norot ] ) are equivalent to the zerilli equation , but they have the advantage to be easily generalizable to rotating stars , as we will see below . the zerilli function @xmath105 can be computed in terms of @xmath176 , @xmath367 : @xmath368 the axial perturbations are described by the regge - wheeler equation @xmath369\equiv \frac{d^2}{dr_*^2}z_{rw}^{lm } + \left[\sigma^2-e^\nu \left(\frac{l(l+1)}{r^2}-\frac{6m}{r^3}+4\pi(\rho - p)\right)\right ] z_{rw}^{lm}=0\,,\label{rwinnorot}\ ] ] where the coordinate @xmath44 has been defined in ( [ tortoise ] ) and @xmath370 an analytical expansion of equations ( [ in1norot ] ) , ( [ in2norot ] ) , ( [ rwinnorot ] ) near the center of the star gives , for each value of @xmath1 , three independent conditions at the center : @xmath371 where the expressions for @xmath372 , @xmath373 , @xmath374 can be evaluated from the analytical expansion . we notice that @xmath359 and @xmath360 behave , as @xmath375 , like @xmath376 , while the combination @xmath377 behaves as @xmath378 . consequently , when we expand @xmath359 and @xmath360 in powers of @xmath2 about @xmath144 , we find that the leading terms are coincident . in other words , the differential equations for the variables @xmath359 , @xmath360 and @xmath379 are linearly dependent near the origin ( see the discussion in @xcite ) . to avoid this problem , we use as integration variables @xmath377 , @xmath359 and @xmath379 . we define @xmath381 the perturbed equations inside the star have the form @xmath382&=&-\frac{m}{(n+1)\sigma } e^{(j)lm}[h_0,k]\nn\\ & & + e^{-(\lambda+\nu)/2 } \left[\frac{\ii q_{l-1\,m}d^{(j)l-1\,m}[z_{rw}]}{\sigma(n - n_-)}+ \frac{\ii q_{l+1\,m}d^{(j)l+1\,m}[z_{rw}]}{\sigma(n - n_+)}\right]\nn\\ l^{lm}[z_{rw}]&=&\frac{m}{\sigma}n^{lm}[z_{rw}]+e^{(\lambda+3\nu)/2 } \left[\frac{\ii q_{l-1\,m}f^{l-1\,m}[h_0,k]}{\sigma(n - n_-)}+ \frac{\ii q_{l+1\,m}f^{l+1\,m}[h_0,k]}{\sigma(n - n_+)}\right ] \label{inrot0}\end{aligned}\ ] ] ( @xmath383 ) , where @xmath384 $ ] , @xmath385 $ ] are the operators defined in equations ( [ in1norot ] ) , ( [ in2norot ] ) , ( [ rwinnorot ] ) and @xmath386 $ ] , @xmath387 $ ] , @xmath388 $ ] , @xmath389 $ ] are operators at first order in @xmath184 , whose explicit expressions are given in k1 . the operators @xmath387 $ ] , @xmath389 $ ] couple perturbations belonging to different @xmath1 s , and were neglected in the numerical integration of k2 . in order to have equations with real coefficients , we need to get rid of the factors @xmath390 in ( [ inrot0 ] ) . to this purpose , we redefine the regge - wheeler function by a factor @xmath391 @xmath392 thus equations ( [ inrot0 ] ) become @xmath382&=&-\frac{m}{(n+1)\sigma } e^{(j)lm}[h_0,k]\nn\\ & & + e^{-(\lambda+\nu)/2 } \left[\frac{q_{l-1\,m}d^{(j)l-1\,m}[z_{rw}]}{\sigma(n - n_-)}+ \frac{q_{l+1\,m}d^{(j)l+1\,m}[z_{rw}]}{\sigma(n - n_+)}\right]\nn\\ l^{lm}[z_{rw}]&=&\frac{m}{\sigma}n^{lm}[z_{rw}]-e^{(\lambda+3\nu)/2 } \left[\frac{q_{l-1\,m}f^{l-1\,m}[h_0,k]}{\sigma(n - n_-)}+ \frac{q_{l+1\,m}f^{l+1\,m}[h_0,k]}{\sigma(n - n_+)}\right]\ , . \label{inrot}\end{aligned}\ ] ] this rescaling consistently eliminates all imaginary units from the equations . the numerical integration of equations ( [ inrot ] ) presents a serious problem . if we perform an analytical expansion near the center of ( [ inrot ] ) , we find that the coupling terms @xmath393 $ ] become larger than @xmath394 $ ] as @xmath375 . the reason behind this pathological behaviour is that near the center of the star @xmath395 if we use as integration variable @xmath352 instead of @xmath360 ( notice that while in the non rotating case @xmath396 , if the star rotates @xmath397 ) this problem is overcome , since @xmath398 consequently , the coupling terms in the perturbed equations are smaller than @xmath399 $ ] . for this reason , we have expressed our equations inside the star in terms of @xmath400 , @xmath359 , @xmath379 : @xmath401&=&-\frac{m}{(n+1)\sigma } \tilde e^{(j)lm}[h_2,k]\nn\\ & & + e^{-(\lambda+\nu)/2 } \left[\frac{q_{l-1\,m}\tilde d^{(j)l-1\,m}[z_{rw}]}{\sigma(n - n_-)}+ \frac{q_{l+1\,m}\tilde d^{(j)l+1\,m}[z_{rw}]}{\sigma(n - n_+)}\right]\nn\\ l^{lm}[z_{rw}]&=&\frac{m}{\sigma}n^{lm}[z_{rw}]-e^{(\lambda+3\nu)/2 } \left[\frac{q_{l-1\,m}f^{l-1\,m}[h_2,k]}{\sigma(n - n_-)}+ \frac{q_{l+1\,m}f^{l+1\,m}[h_2,k]}{\sigma(n - n_+)}\right]\ , . \label{inrotnew}\end{aligned}\ ] ] the operators @xmath402 , @xmath403 are different from @xmath404 , @xmath405 given in k1 . their expressions are the following : @xmath406&=&\frac{\ii\sigma}{2}\left[2f^{lm\,\prime\prime}(r ) + \left(4\nu'-\lambda'-\frac{6}{r}\right)f^{lm\,\prime}(r)\right.\nn\\ & & \left.-\left(\frac{2e^\lambda}{r^2}(n+1)-(\nu')^2+\frac{4}{r}\left(2\nu'- \lambda'-\frac{2}{r}\right)-32\pi pe^\lambda\right)f^{lm}(r)\right]\nn\\ & & + \ii\sigma\left(2n\xi^{(1)lm\,\prime}(r)-\tilde\beta^{(1)lm\,\prime}(r ) -\zeta^{(1)lm\,\prime}(r)\right)\nn\\ & & -\frac{\ii\sigma}{2}\left(\frac{2}{r}+\lambda'-2\nu'\right ) \left(2n\xi^{(1)lm}(r)-\tilde\beta^{(1)lm}(r)-\zeta^{(1)lm}(r)\right)\nn\\ & & + \ii\sigma(n+1)e^\lambda c^{(3)lm}(r)-\ii\sigma(n+1)c^{(2)lm}(r ) \label{e1lm}\\ \tilde e^{(2)lm}[h_2,k]&=&-\frac{\ii\sigma}{r}c_s^{-2}\left[f^{lm\,\prime}(r ) + \left(\nu'-\frac{2}{r}+(n+1)\frac{e^\lambda}{r}\right)f^{lm}(r)\right]\nn\\ & & -\frac{\ii\sigma}{r}c_s^{-2}\left(2n\xi^{(1)lm}(r)-\tilde\beta^{(1)lm}(r ) -\zeta^{(1)lm}(r)\right)\nn\\ & & -\frac{\ii\sigma}{2}(n+1)c_s^{-2}c^{(2)lm}(r)+ \frac{\ii\sigma}{2}(n+1)e^{\lambda-\nu}c^{(0)lm}(r)\label{e2lm}\\ \tilde d^{(1)l\pm1\,m}[z_{rw}]&=&\ii\sigma e^{(\lambda+\nu)/2}\left[2g^{l\pm1\,m\,\prime\prime}(r ) + \left(4\nu'-\lambda'-\frac{6}{r}\right)g^{l\pm1\,m\,\prime}(r)\right.\nn\\ & & \left.-\left(\frac{2e^\lambda}{r^2}(n+1)-(\nu')^2+\frac{4}{r}\left(2\nu'- \lambda'-\frac{2}{r}\right)-32\pi pe^\lambda\right)g^{l\pm1\,m}(r)\right]\nn\\ & & + 2\ii\sigma e^{(\lambda+\nu)/2}\left[-2(n-2n_\pm-2 ) \chi^{(1)l\pm1\,m\,\prime}(r)+(n - n_\pm-1)\tilde\alpha^{(1)l\pm1\,m\,\prime}(r ) -\eta^{(1)l\pm1\,m\,\prime}(r)\right]\nn\\ & & -\ii\sigma e^{(\lambda+\nu)/2}\left(\frac{2}{r}+\lambda ' -2\nu'\right)\left[-2(n-2n_\pm-2)\chi^{(1)l\pm1\,m}(r)\right.\nn\\ & & \left.+(n - n_\pm-1)\tilde\alpha^{(1)l\pm1\,m}(r)-\eta^{(1)l\pm1\,m}(r ) \right]\nn\\ & & + \ii\sigma e^{(3\lambda+\nu)/2}\left[(n - n_\pm)\tilde a^{(3)l\pm1\,m}(r)+(n - n_\pm)(n - n_\pm-1)b^{(3)l\pm1\,m}(r ) \right]\nn\\ & & -\ii\sigma e^{(\lambda+\nu)/2}\left[(n - n_\pm)\tilde a^{(2)l\pm1\,m}(r)+(n - n_\pm)(n - n_\pm-1)b^{(2)l\pm1\,m}(r ) \right]\label{d1lm}\\ \tilde d^{(2)l\pm1\,m}[z_{rw}]&=&-\ii\sigma \frac{2e^{(\lambda+\nu)/2}}{r}c_s^{-2 } \left[g^{lm\,\prime}(r)+\left(\nu'-\frac{2}{r}+(n+1 ) \frac{e^\lambda}{r}\right)g^{lm}(r)\right]\nn\\ & & -\ii\sigma\frac{2e^{(\lambda+\nu)/2}}{r}c_s^{-2 } \left[-2(n-2n_\pm-2)\chi^{(1)l\pm1\,m}(r)\right.\nn\\ & & \left.+(n - n_\pm-1)\tilde\alpha^{(1)l\pm1\,m}(r)-\eta^{(1)l\pm1\,m}(r ) \right]\nn\\ & & -\ii\sigma\frac{e^{(\lambda+\nu)/2}}{2}c_s^{-2}\left[(n - n_\pm)\tilde a^{(2)l\pm1\,m}(r)+(n - n_\pm)(n - n_\pm-1)b^{(2)l\pm1\,m}(r ) \right]\nn\\ & & + \ii\sigma\frac{e^{(3\lambda-\nu)/2}}{2}\left[(n - n_\pm)\tilde a^{(0)l\pm1\,m}(r)+(n - n_\pm)(n - n_\pm-1)b^{(0)l\pm1\,m}(r ) \right]\label{d2lm}\end{aligned}\ ] ] where @xmath407 are quantities which depend on the perturbations @xmath352 , @xmath359 , etc . , and which are given in appendix b of k1 . at the surface of the star we compute @xmath360 and the other perturbations in terms of @xmath352 , @xmath359 , @xmath379 . we impose the vanishing of the lagrangian pressure perturbation ( see @xcite ) . this reduces the number of freely assigned constants from three ( times @xmath408 ) , which correspond to the three independent solutions ( [ condcenter1])-([condcenter3 ] ) , to two ( times @xmath408 ) , i.e. @xmath96 as discussed in section [ standingrot ] . finally , the equations in vacuum are , as in k1 , @xmath409 & = & \frac{\omega}{\sigma}\left(m\hat e^{(j)lm}[h_0,\tilde h_1,k ] + \frac{q_{l-1\,m}\hat d^{(j)l-1\,m}[z_{rw}]}{n - n_-}+ \frac{q_{l+1\,m}\hat d^{(j)l+1\,m}[z_{rw}]}{n - n_+ } \right)\label{outrot}\\ l^{lm}[z_{rw}]&=&\frac{\omega}{\sigma}\left(m\hat n^{lm}[z_{rw } ] -\frac{q_{l-1\,m}\hat f^{l-1\,m}[h_0,k]}{n - n_-}- \frac{q_{l+1\,m}\hat f^{l+1\,m}[h_0,k]}{n - n_+}\right)\label{rwoutrot}\end{aligned}\ ] ] ( @xmath410 ) where @xmath411 $ ] , @xmath385 $ ] are the operators defined in ( [ in1norot])-([algebraicnorot ] ) , ( [ rwinnorot ] ) , and the expressions of @xmath412 $ ] , @xmath413 $ ] , @xmath414 $ ] , @xmath415 $ ] are given in k1 . when @xmath416 , the background spacetime is with good approximation spherically symmetric , because the terms due to rotation decrease faster than the `` schwarzschild - like '' components ( see for instance @xcite , chap . 19 ) . therefore , spacetime perturbations satisfy the zerilli and the regge - wheeler equations . in this limit , equation ( [ rwoutrot ] ) becomes the regge - wheeler equation for the function @xmath379 , whereas the zerilli function @xmath417 is related to the solution of equation ( [ outrot ] ) by ( [ defzer ] ) . at radial infinity , the amplitude of the stationary wave @xmath418 can be computed in terms of @xmath417 and @xmath379 . we can then apply the stationary wave approach described in section [ standingwave ] and in appendix [ rwspher2d ] . equations ( [ inrotnew ] ) , ( [ outrot ] ) , ( [ rwoutrot ] ) can be integrated using the spectral decomposition in chebyshev s polynomials as explained in section [ spectral ] . there is a main difference with respect to the example described in appendix [ rwspher2d ] , which refers to the axial equation for a non rotating star . while the matrix ( [ matrixl ] ) is block - 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we propose a new method to study the quasi - normal modes of rotating relativistic stars . oscillations are treated as perturbations in the frequency domain of the stationary , axisymmetric background describing a rotating star . the perturbed quantities are expanded in circular harmonics , and the resulting 2d - equations they satisfy are integrated using spectral methods in the @xmath0-plane . the asymptotic conditions at infinity , needed to find the mode frequencies , are implemented by generalizing the standing wave boundary condition commonly used in the non rotating case . as a test , the method is applied to find the quasi - normal mode frequencies of a slowly rotating star .

in recent years considerable efforts have been done to extend concepts and results from the euclidean / hilbert context to settings with no vector space structure . the motivation of such studies comes from nonlinear phenomena which require the presence of a non - positively curved structure for the ambient space ; see jost @xcite , kristly @xcite , kristly , rdulescu and varga @xcite , li , lpez and martn - mrquez @xcite , nmeth @xcite , udrite @xcite and references therein . the purpose of the present paper is to point out some conceptual mistakes within the class of hadamard manifolds where some authors used equivalences between _ convexity notions _ which basically reduce the geometric setting to the euclidean one . thus , in all these papers the corresponding results and their consequences are nothing but previously well known facts in the euclidean case . to be more precise , let @xmath4 be a hadamard manifold ( i.e. , simply connected , complete riemannian manifold with non - positive sectional curvature ) . according to the cartan - hadamard theorem , the exponential map @xmath5 is a global diffeomorphism for every @xmath6 . let @xmath6 be fixed arbitrarily . by using the exponential map , three convexity notions are recalled in the sequel , mentioning also their sources without sake of completeness : * _ affinity . _ a map @xmath7 is called affine if @xmath8\to \mathbb r$ ] is affine in the usual sense on @xmath9 $ ] for every geodesic segment @xmath10\to m.$ ] papa quiroz @xcite and papa quiroz and oliveira @xcite claimed that @xmath11 is affine for every @xmath12 and they used this property to prove convergence of various algorithms on hadamard manifolds . this statement is also used in colao , lpez , marino and martn - mrquez @xcite , and zhou and huang @xcite . * _ geodesics . _ let @xmath13 be two fixed points . by construction , the unique minimal geodesic @xmath10\to m$ ] joining these points is given by @xmath14 yang and pu @xcite claimed that the curve @xmath9\ni t\mapsto \exp_p((1-t)\exp_p^{-1}(q_1)+t\exp_p^{-1}(q_2))$ ] is also a minimal geodesic segment on @xmath15 joining the points @xmath16 and @xmath17 * _ convex hull . _ by definition ( see @xcite ) , the convex hull c@xmath18 of a set @xmath19 is the smallest convex subset of @xmath15 containing @xmath20 instead of the convex hull , yang and pu @xcite introduced the _ geodesic convex hull _ gc@xmath21 of a set @xmath22 with respect to @xmath6 in the following way @xmath23,\sum_{i=1}^m\lambda_i=1\right\}.\ ] ] it is claimed in @xcite that c@xmath24 for every @xmath6 and @xmath25 we provide below a concrete counterexample in the hyperbolic plane which shows that the aforementioned claims are based on a fundamental misconception . consider the poincar upper half - plane model @xmath26 endowed with the riemannian metric defined for every @xmath27 by @xmath28 @xmath29 is a hadamard manifold with constant sectional curvature @xmath30 and the geodesics in @xmath31 are the semilines and the semicircles orthogonal to the line @xmath32 . the riemannian distance between two points @xmath33 is given by @xmath34 fix @xmath35 . by some elementary calculations ( see also @xcite ) we have that for each @xmath36 , @xmath37 where @xmath38 and @xmath39 in other words , @xmath40 belongs to the semiline @xmath41 or a semicircle orthogonal to the line @xmath32 that contains @xmath42 and for which the direction of the tangent in @xmath42 is given by the vector @xmath43 . moreover , @xmath44 . let @xmath45 , @xmath46 and take @xmath47 . then , @xmath48 , v > 0\}.\ ] ] the geodesic segment joining @xmath42 and @xmath16 belongs to the semicircle @xmath49 . denote @xmath50 and @xmath51 with @xmath52 ( see also ( * ? ? ? * section 5 ) for the general expression of the inverse exponential map ) . let @xmath53 and @xmath54 . then @xmath55 . thus , @xmath56 actually , since @xmath57 , the set @xmath58 consists of the points @xmath59 , with @xmath60 $ ] , see figure [ fig:1 ] . note that the above fact also shows that the curve @xmath9\ni t\mapsto \exp_p((1-t)\exp_p^{-1}(q_1)+t\exp_p^{-1}(q_2))$ ] is not the minimal geodesic joining @xmath16 and @xmath61 . it is well known that any affine mapping defined on @xmath31 is constant . in particular , one can choose @xmath62 such that the mapping @xmath63 is not constant and so it is not affine . this fact can be checked directly as well . moreover , it is also obvious that @xmath64 is not a global isometry . as the main result of this paper we prove the following rigidity theorem . * the map @xmath11 is affine for every @xmath67 * for every @xmath13 , the curve @xmath9\ni t\mapsto \exp_p((1-t)\exp_p^{-1}(q_1)+t\exp_p^{-1}(q_2))$ ] is the minimal geodesic segment joining the points @xmath16 and @xmath68 * for every non - empty set @xmath69 , c@xmath70 * the map @xmath5 is a global isometry@xmath71 * the sectional curvature on @xmath4 is identically zero @xmath72i.e . , @xmath4 is isometric to the usual euclidean space @xmath73 [ choquet theorem ; see ( * ? ? ? * theorem 6.5)][choquet ] an @xmath65dimensional riemannian manifold @xmath4 is the riemannian product of an @xmath74dimensional riemannian manifold and the euclidean space @xmath75 @xmath72at least locally@xmath76 if and only if the vector space of all affine functions on @xmath15 has dimension @xmath77 @xmath78 in particular , the sectional curvature restricted to the components of @xmath75 is identically zero.@xmath79 $ ] [ see ( * ? ? ? * lemma 3.3.1)][convex - hull - character ] the convex hull c@xmath18 of a set @xmath69 is @xmath80 where @xmath81 and for every @xmath82 , @xmath83 is the union of all geodesic segments between points of @xmath84 ( ii)@xmath86(i ) let @xmath12 be fixed arbitrarily ; for convenience , let @xmath88 be defined by @xmath89 . by assumption , any geodesic segment in @xmath15 can be represented by @xmath90 , where @xmath91 , @xmath92 $ ] for some @xmath93 then , @xmath94 which is an affine function on @xmath9 $ ] in the usual sense . ( i)@xmath86(v ) we show that the dimension of the space of affine functions on @xmath15 is @xmath95 by assumption , @xmath89 is an affine function on @xmath15 for every @xmath96 . in particular , it follows that @xmath97 since @xmath98 is both convex and concave , see @xcite . since hess@xmath99 for every vector fields @xmath100 on @xmath15 , the latter relation implies in particular that grad@xmath98 is a parallel vector field along any geodesic of @xmath15 . since dim@xmath101 , we may fix @xmath102 such that in every @xmath103 , the set @xmath104 forms a basis of the tangent space @xmath105 ( basically , it is enough to guarantee this property just in one point and use parallel transport at any fixed point ) . in this manner , we constructed exactly @xmath106 non - constant , linearly independent affine functions @xmath107 on @xmath15 , @xmath108 corresponding to the elements @xmath102 . moreover , we may add to this set also a constant function which is affine and linearly independent of @xmath109 therefore , the vector space of all affine functions on @xmath15 has dimensional @xmath110 . according to choquet theorem ( see proposition [ choquet ] ) , we also have that @xmath111 . therefore , @xmath112 and again by choquet theorem and from the fact that @xmath4 is a hadamard manifold , it follows that @xmath15 is globally represented as @xmath113 whose sectional curvature is identically zero . ( iii)@xmath86(ii ) let @xmath13 and @xmath47 . on the one hand , by the definition of the geodesic convex hull , since @xmath114 contains just two elements , we clearly have that @xmath115,\ \lambda_1+\lambda_2=1\right\ } \\ & = & \left\{\exp_p\left((1-t ) \exp_p^{-1}(q_1)+t \exp_p^{-1}(q_2)\right):t\in [ 0,1]\right\}.\end{aligned}\ ] ] on the other hand , if @xmath81 , then the set @xmath116 in proposition [ convex - hull - character ] is precisely the image of the unique minimal geodesic segment @xmath10\to m$ ] joining the points @xmath16 and @xmath61 . moreover , if we take any two points in @xmath117 and join them by a geodesic segment , the minimality of @xmath118 implies that the image of the latter geodesic will be a subset of @xmath119 . therefore , @xmath120 . consequently , @xmath121 since by assumption @xmath122 one obtains ( ii ) . @xmath123 further definitions and open questions concerning the convex hull on non - positively curved spaces can be found in the literature , see ledyaev , treiman and zhu ( * ? ? ? * conjecture 1 ) and nava - yazdani and polthier @xcite . it would be interesting to study the relationship between these notions and the geometric structure of the ambient space . * acknowledgment . * a. kristly was supported by a grant of the romanian ministry of education , cncs - uefiscdi , project number pn - ii - ru - te-2011 - 3 - 0047 . c. li and g. lpez were supported by dges ( grant mtm2012 - 34847-c02 - 01 ) . a. nicolae was supported by a grant of the romanian ministry of education , cncs - uefiscdi , project number pn - ii - ru - pd-2012 - 3 - 0152 . part of this work was carried out while some of the authors were visiting the university of seville supported by dges ( grant mtm2012 - 34847-c02 - 01 ) . a. krist ' aly , v. rdulescu , cs . varga , variational principles in mathematical physics , geometry , and economics , cambridge university press , encyclopedia of mathematics and its applications , no . 136 , cambridge , 2010 .

various results based on some convexity assumptions ( involving the exponential map along with affine maps , geodesics and convex hulls ) have been recently established on hadamard manifolds . in this paper we prove that these conditions are mutually equivalent and they hold if and only if the hadamard manifold is isometric to the euclidean space . in this way , we show that some results in the literature obtained on hadamard manifolds are actually nothing but their well known euclidean counterparts . what do ` convexities ' imply on hadamard manifolds ? + alexandru kristly@xmath0 , chong li@xmath1 , genaro lopez@xmath2 , adriana nicolae@xmath3 + + @xmath1 department of mathematics , zhejiang university , hangzhou 310027 , p. r. china + email address : [email protected] + @xmath2 departamento de anlisis matemtico , universidad de sevilla , apdo . 1160 , 41080-sevilla , spain + email address : [email protected] + @xmath3 department of mathematics , babe - bolyai university , koglniceanu 1 , 400084 cluj - napoca , romania + and + simion stoilow institute of mathematics of the romanian academy , research group of the project pd-3 - 0152 , p.o . box 1 - 764 , ro-014700 bucharest , romania + email address : [email protected] _ keywords _ : hadamard manifold ; convexity . + _ msc _ : 53c23 ; 53c24 .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Protecting the U.S. Corporate Tax Base Act of 2016''. SEC. 2. INCLUSION IN SUBPART F INCOME OF INVESTMENTS BY CONTROLLED FOREIGN CORPORATIONS WITH RESPECT TO MEMBERS OF FOREIGN GROUP WHICH INCLUDES UNITED STATES SHAREHOLDER. (a) In General.--Section 956(a)(1)(A) of the Internal Revenue Code of 1986 is amended to read as follows: ``(A) such shareholder's pro rata share of the sum of-- ``(i) the average of the amounts of United States property held (directly or indirectly) by the controlled foreign corporation as of the close of each quarter of such taxable year, and ``(ii) in the case of a controlled foreign corporation which is a member of an expanded affiliated group the common parent of which is not a domestic corporation, the average of the amounts of foreign group property held (directly or indirectly) by the controlled foreign corporation as of the close of each quarter of such taxable year, over''. (b) Foreign Group Property.--Section 956 of such Code is amended by redesignating subsections (d) and (e) as subsections (e) and (f), respectively, and by inserting after subsection (c) the following new subsection: ``(d) Foreign Group Property; Expanded Affiliated Group.--For purposes of this section-- ``(1) Foreign group property.-- ``(A) In general.--The term `foreign group property' means any stock or obligation of any foreign person which is not a controlled foreign corporation. ``(B) Exceptions.--Such term shall not include-- ``(i) the stock or obligation of any entity if less than 25 percent of the total combined voting power of such entity, immediately after the acquisition of any stock in such entity by the controlled foreign corporation, is owned (directly or indirectly) by the common parent referred to in subsection (a)(1)(A)(ii), and ``(ii) property described in subparagraph (C), (I), (J), (K) or (L) of subsection (c)(2), applied-- ``(I) by substituting `foreign person' for `United States person' in such subparagraphs (C), (J), and (L), ``(II) by substituting `foreign corporation' for `domestic corporation' in subsection (c)(2)(L)(i), and ``(III) by treating a foreign person as a United States shareholder described in subsection (c)(2)(L)(ii)(I) if such foreign person would be so described if such person were a United States person. ``(C) Limitation on treatment as a controlled foreign corporation.--A foreign corporation shall not be treated as a controlled foreign corporation for purposes of subparagraph (A) unless more than 50 percent of the total combined voting power of all classes of stock of such corporation entitled to vote, and more than 50 percent of the total value of the stock of such corporation, is owned (directly or indirectly) by United States persons described in subparagraph (A) or (C) of section 7701(a)(30). ``(D) Foreign person.--For purposes of this paragraph, the term `foreign person' means any person who is not a United States person (as defined in section 7701(a)(30)). ``(2) Expanded affiliated group.--The term `expanded affiliated group' means an affiliated group as defined in section 1504(a), determined-- ``(A) by substituting `more than 50 percent' for `at least 80 percent' each place it appears, and ``(B) without regard to paragraphs (2) and (3) of section 1504(b). A partnership or any other entity (other than a corporation) shall be treated as a member of an expanded affiliated group if such entity controls (as determined under section 954(d)(3)), or is controlled by (as so determined), members of such group (including any entity treated as a member of such group by reason of this sentence). ``(3) Application to non-corporate entities.--In the case of any entity which is not a corporation-- ``(A) any reference in this subsection to stock shall be treated as a reference to any equity or profits interest in such entity, and ``(B) except as otherwise provided by the Secretary, paragraph (1)(B)(i) shall be applied by substituting `25 percent (by value) of the beneficial interests in such entity' for `25 percent of the total combined voting power of such entity'.''. (c) Application of Rules for Pledges and Guarantees.--Section 956(e) of such Code, as so redesignated, is amended to read as follows: ``(e) Pledges and Guarantees.--For purposes of subsection (a), a controlled foreign corporation shall, under regulations prescribed by the Secretary, be considered as holding-- ``(1) an obligation of a United States person if such controlled foreign corporation is a pledgor or guarantor of such obligation, and ``(2) an obligation of a foreign person if such controlled foreign corporation or, to the extent provided under such regulations, any United States shareholder of such controlled foreign corporation, is a pledgor or guarantor of such obligation.''. (d) Termination of Rule Which Permits Use of Related-Party Transactions To Avoid Treatment as a Controlled Foreign Corporation.-- Section 958(b)(4) of such Code is amended by inserting ``if such stock was acquired by such person on or before May 17, 2016'' before the period at the end. (e) Application of Limitation on Amount of Foreign Taxes Deemed Paid With Respect to Section 956 Inclusions.--Notwithstanding section 214(b) of Public Law 111-226, section 960(c) of the Internal Revenue Code of 1986 shall apply to acquisitions of foreign group property (as defined in 956(d) of such Code, as amended by this section) after December 31, 2010, in addition to acquisitions of United States property (as defined in section 956(c) of such Code) after such date. (f) Effective Date.-- (1) In general.--Except as provided in paragraph (2), the amendments made by this section shall apply to taxable years of controlled foreign corporations ending after the date of the enactment of this Act and to taxable years of United States shareholders in which or with which such taxable years of controlled foreign corporations end. (2) Termination of rule which permits use of related-party transactions to avoid treatment as a controlled foreign corporation.--The amendment made by subsection (d) shall apply to taxable years of controlled foreign corporations ending on or after May 17, 2016, and to taxable years of United States shareholders in which or with which such taxable years of controlled foreign corporations end.

Protecting the U.S. Corporate Tax Base Act of 2016 This bill amends the Internal Revenue Code to revise the rules for taxing the earnings and determining the stock ownership of certain controlled foreign corporations (CFCs). The bill provides that, in the case of certain CFCs, subpart F income (income of a CFC earned outside the United States that is not tax deferred) includes a U.S. shareholder's pro rata share of any increase in the CFC's investment of earnings in certain foreign property. The bill also revises the rules for determining stock ownership to prohibit a CFC from transferring stock to a foreign affiliate to reduce the portion of stock owned by U.S. shareholders below the level required to be considered a CFC.

The green glass paten, measuring 22 centimetres in diameter, is the earliest depiction of Jesus found in Spain. Photo: FORVM MMX One of the world's earliest representations of Christ has been unearthed in southern Spain by a team of archaeologists, a glass plate which shines new light on the arrival of Christianity in Spain. The green glass paten, the plate which holds the Holy Eucharist in churches, is the earliest depiction of Jesus found in Spain and is in excellent condition compared to similar pieces discovered around Europe. “We know it dates back to the 4th century, in part because popes in the following centuries ordered all patens to be made out of silver,” Marcelo Castro, head of the Forum MMX excavation project, told The Local. The team of archaeologists have so far managed to find 81 percent of the paten at the site of a religious building in Cástulo, an ancient Iberian town in the province of Jaén, Andalusia. Measuring 22 centimetres in diameter, it shows three beardless men with short hair and halos over their heads. According to Castro, the figures are Jesus and the apostles Paul and Peter as depicted in Christ in Majesty, an early Christian art form which copied Roman and Byzantine styles. The Forum MMX team have been able to establish the paten was made in the 300s thanks to coins and ceramic objects found at the same site. “We were wary about presenting the paten as a 4th century piece in case it clashed with previous studies into the chronology of Christianity in Spain,” Castro explained. But their estimates coincide with the rule of Constantine, the first Roman emperor to claim conversion to Christianity, who also ensured the religion's clandestine followers were no longer persecuted. The paten was put on display on Wedneday at the Archaeological Museum of Linares (Jaén), alongside other ancient pieces such as a mosaic of Cupid (Mosaico de los Amores), unearthed in 2012 and named as one of the discoveries of the year by National Geographic. ||||| Starting in 1996, Alexa Internet has been donating their crawl data to the Internet Archive. Flowing in every day, these data are added to the Wayback Machine after an embargo period. ||||| Image copyright FORVM MMX Archaeologists in Spain say they have found one of the world's earliest known images of Jesus. It is engraved on a glass plate dating back to the 4th Century AD, reports from Spain say. The plate is believed to have been used to hold Eucharistic bread as it was consecrated in early Christian rituals. It measures 22cm in diameter and fragments of it were unearthed outside the southern Spanish city of Linares, ABC newspaper reports. Scientists working for the FORVM MMX project found it inside a building used for religious worship in what remains of the ancient town of Castulo. The find made scientists "review the chronology of early Christianity in Spain", FORVM MMX project director Marcelo Castro told El Mundo newspaper. The pieces were in an excellent state of preservation - 81% of its original area has now been pieced together by scientists. Image copyright FORVM MMX In the image, Jesus Christ is flanked by two apostles, believed to be Peter and Paul. "The scene takes place in the celestial orb, framed between two palm trees, which in Christian iconography represent immortality, the afterlife and heaven, among other things," ABC writes. El Mundo notes that Christ looks very different from later depictions: he has no beard, his hair is not too long and he is wearing a philosopher's toga. Image copyright FORVM MMX Image caption A reconstruction of images on the plate Use #NewsfromElsewhere to stay up-to-date with our reports via Twitter.

– Jesus shaved. Archaeologists in Spain have unearthed what they say is one of the earliest images of him, but you wouldn't know it from a quick glance. The engraving on a glass plate from the 4th century depicts a short-haired Jesus without a beard; he's joined by two men believed to be the apostles Peter and Paul, reports the BBC. The Local reports that the plate is in fragments, and 81% of it has been recovered by the archaeologists. The BBC picked up the report from two Spanish-language sites, including ABC.es, which writes of the plate: "The scene takes place in the celestial orb, framed between two palm trees, which in Christian iconography represent immortality, the afterlife and heaven, among other things." The 9-inch plate, found at a dig site in what was once the ancient town of Castulo, was likely used in religious services to hold Eucharistic bread. The BBC has images. (A scientist, meanwhile, is hoping to resurrect King David's wine.)

soft hadronic scattering , characterized by long distance phenomena , is one of the great challenges in high - energy physics . the difficulty arises from the fact that perturbative qcd can not be applied to these processes and , presently , we do not know even how to calculate elastic hadron - hadron scattering amplitudes from a pure non - perturbative qcd formalism . however , progresses have been achieved through the approach introduced by landshoff and nachtmann @xcite , developed by nachtmann @xcite and connected with the stochastic vacuum model ( svm ) @xcite . in that formalism the low frequencies contributions in the functional integral of qcd are described in terms of a stochastic process , by means of a cluster expansion . the most general form of the lowest cluster is the gauge invariant two - point field strength correlator @xcite @xmath1(1-{\kappa})d_{1 } ( { z^2/a}^{2})\ } , \end{aligned}\ ] ] where @xmath2 is the two - point distance , @xmath3 is a characteristic correlation length , @xmath4 a constant , @xmath5 the gluon condensate and @xmath6 the number of colours ( @xmath7 ) . the two scalar functions @xmath8 and @xmath9 describe the correlations and they play a central role in the application of the svm to high energy scattering @xcite . once one has information about @xmath8 and @xmath9 , the svm leads to the determination of the elementary quark - quark scattering amplitude , which constitutes important input for models aimed to construct hadronic amplitudes . numerical determinations of the above correlation functions , in limited interval of physical distances , exist from lattice qcd in both quenched approximation ( absence of fermions ) @xcite and full qcd ( dynamical fermions included ) @xcite . in a previous paper , we determined the elementary amplitudes from lattice qcd in the quenched approximation @xcite , using as framework the svm . in this communication , we apply the same procedure , now taking into account the lattice results in full qcd . our main goal is to investigate the differences in the elementary amplitudes associated with quenched theory and full qcd and also the effect of different bare quark masses . in addition , we obtain analytical parametrizations for the amplitudes that are suitable for phenomenological uses , and discuss in some detail the region of validity of all the results . the manuscript is organized as follows . in sec . ii we recall the main formulas related with the elementary amplitudes in the context of the svm and in sec . iii we review the parametrizations for the correlators from numerical simulations on the lattice . in sec . iv we present the results for the elementary amplitudes from full qcd with different quark masses and discuss the similarities and differences with our previous result in the quenched approximation . the conclusions and some final remarks are the contents of sec . v. in this section we briefly review the main steps of the calculation scheme that allows the determination of the elementary amplitudes through the svm @xcite . we refer the reader to @xcite for more details concerning specific calculation . the elementary amplitude @xmath10 in the momentum transfer space may be expressed in terms of the elementary profile @xmath11 in the impact parameter space , through the symmetrical two - dimensional fourier transform @xmath12 where @xmath13 is the momentum transfer , @xmath14 the impact parameter and @xmath15 is a bessel function . in the nachtmann approach @xcite , the study of the elementary scattering is based on the amplitude of quarks moving on lightlike paths in an external field , picking up an eikonal phase in traveling through the nonperturbative qcd vacuum . in order to have gauge invariant dirac s wave function solutions a wilson loop is proposed to represent each quark . in this context the no - colour exchange parton - parton ( loop - loop ) amplitude can be written as @xcite @xmath16tr[{\cal{p}}e^{-ig{\int}_{loop2}d { \sigma}_{\rho\sigma}f_{\rho \sigma}(y;w)}-1]{\rangle } , \nonumber\end{aligned}\ ] ] where @xmath17 means the functional integration over the gluon fields ( the integrations are over the respective loop areas ) , and @xmath18 is a common reference point from which the integrations are performed . this expression is simplified in the krmer and dosch description by taking the wilson loops on the light - cone . in the svm the _ leading order _ contribution to the amplitude is given by @xcite @xmath19 where @xmath20 is a constant depending on normalizations and @xmath21 here @xmath22 is the minkowski version of the gluon correlator . after a two - dimensional integration , @xmath23 may be expressed in terms of the correlation functions in ( 1 ) by @xcite @xmath24 where @xmath25(b'),\end{aligned}\ ] ] @xmath26(b ) , \label{epsilonii}\end{aligned}\ ] ] for @xmath27 or @xmath28 , @xmath29 $ ] , where @xmath30 denotes a n - dimensional fourier transform . with the above formalism , once one has inputs for the correlation functions @xmath31 and @xmath32 , the elementary amplitude in the momentum transfer space , eq . ( 2 ) , may , in principle , be evaluated through eqs . ( 3 - 6 ) . it is important to stress that , as constructed , this approach is intended for the high energy limit and small momentum transfer region , namely , @xmath33 , where @xmath34 is the c.m . energy and @xmath35 gev@xmath0 . the determination of the correlation functions through numerical simulation on a lattice is made by means of the cooling technique , a procedure that removes the effects of short - range fluctuations on large distance correlators . the numerical results with the associated error are usually parametrized with the functions @xcite @xmath36 @xmath37 where @xmath38 in the non - perturbative exponential terms is the correlation length of the gluon field strengths . discussions on these choices , including the perturbative - like divergence at short distances , may be found in refs . @xcite and @xcite . these correlation functions were first determined in the quenched su(3 ) theory and in the interval of physical distances ( euclidean space ) between 0.1 and 1 fm @xcite . after that , the effects of dynamical fermions have also been included ( full qcd ) , for bare quark masses @xmath39 and @xmath40 ( @xmath3 is the lattice spacing ) and physical distances between 0.3 and 0.9 fm @xcite . the above parametrizations are the same in all these cases and the numerical values of the parameters , obtained from references @xcite and @xcite , are displayed in table 1 . [ cols="^,^,^,^ " , ] and quenched approximation , in the region of large ( a ) and small ( b ) momentum transfer.,title="fig:",width=321,height=226 ] and quenched approximation , in the region of large ( a ) and small ( b ) momentum transfer.,title="fig:",width=321,height=226 ] .,title="fig:",width=321,height=226 ] .,title="fig:",width=321,height=226 ] an immediate conclusion from these results is the presence of an additional component in the case of full qcd . this is a central point that we shall discuss in certain detail in what follows . let us start with the components with the highest slopes , which appear in both cases in the small momentum transfer region , namely , below @xmath41 gev@xmath0 ( figs . 3 and 4 ) . as mentioned before , the real " lattice results correspond to sets of discrete theoretical points with errors , in a finite interval of physical distances , roughly 0.1 - 1.0 fm . therefore , the parametrizations ( 7 ) and ( 8) extrapolate this interval down and above . the highest physical distance reached in the simulations was 0.85 fm , which corresponds to @xmath42 gev@xmath0 . therefore , we conclude that the components with the highest slopes in figs 3 and 4 ( @xmath43 gev@xmath0 ) are associated with the extrapolations above the physical region with real " lattice results . in the same manner , the components with the smallest slopes are connected with extrapolations down the real " lattice points in physical distances and they are the responsible for the amplitudes in high momentum region ( @xmath44 gev@xmath0 in figs . 3 and 4 ) ; therefore , they are outsite the region of validity of the svm , namely , @xmath35 gev@xmath0 . we conclude that in this context only the intermediate components , predominant in the interval , let us say , @xmath45 gev@xmath0 , can have physical meaning in the sense of being in agreement with the svm and the real " lattice results in both full qcd and quenched approximation . from figs . 3 and 4 this secure " region is characterized by only one component in the case of the quenched approximation and two components in full qcd . the transition between these two components occurs at @xmath46 gev@xmath0 ( fig . 4 - left ) , a limit region for which the svm is intended for . in this work we have obtained analytical parametrizations for the quark - quark scattering amplitudes in a nonperturbative qcd framework ( svm ) and using as inputs the correlation functions , determined from numerical simulation on a lattice , in both quenched approximation and full qcd . the formalism is intended for small momentum transfer ( @xmath35 gev@xmath0 ) , asymptotic energies @xmath33 and physical distances between 0.1 and @xmath47 0.9 fm . as discussed in sec . iv , these conditions put some restrictions in the physical interpretations and , therefore , in the practical phenomenological uses of these amplitudes . however , even under the above strictly conditions we can surely extract some novel results : ( 1 ) the amplitudes decrease smoothly as the momentum transfer increases and they do not present zeros ; ( 2 ) the decreasing is faster when going from quenched approximation to full qcd ( with decreasing quark masses ) , and this effect is associated with the increase of the correlation lengths ( @xmath38 and @xmath48 ) ; ( 3 ) the dynamical fermions generate two contributions in the region of small momentum transfer , which are of the same order at @xmath49 1 gev@xmath0 ( only one contribution is present in the case of quenched approximation ) . we understand that result ( 3 ) may suggest some kind of change in the dynamics at the elementary level , near @xmath49 1 gev@xmath0 and at asymptotic energies . if that is true , some signal could be expected at the hadronic level . one possibility is that this effect can be associated with the position of the dip ( or beginning of the shoulder " ) in the hadronic ( elastic ) differential cross section data . the asymptotic condition embodied in our result indicates that @xmath49 1 gev@xmath0 seems in agreement with limit of the shrinkage of the diffraction peak , empirically verified when the energy increases in the region 23 gev @xmath50 1.8 tev . at last it should be noted that if there is no new effect above the physical distances presently investigated on the lattice ( @xmath51 0.9 fm ) , the extrapolations can be considered as a good representation of the lattice results . in this case our analytical parametrizations may be usefull inputs for phenomenological uses in the region of small momentum transfer and asymptotic energies . we are thankful to professor a. di giacomo for valuable discussions and suggestions and to dr . j. montanha neto for reading the manuscript . this work was supported by fapesp ( contract n. 01/08376 - 2 and 00/04422 - 7 ) .

making use of the stochastic vacuum model and the gluon gauge - invariant two - point correlation function , determined by numerical simulation on the lattice in both quenched approximation and full qcd , we calculate the elementary ( quark - quark ) scattering amplitudes in the momentum transfer space and at asymptotic energies . our main conclusions are the following : ( 1 ) the amplitudes decrease monotonically as the momentum transfer increases ; ( 2 ) the decreasing is faster when going from quenched approximation to full qcd ( with decreasing quark masses ) and this effect is associated with the increase of the correlation lengths ; ( 3 ) dynamical fermions generate two components in the amplitude at small momentum transfer and the transition between them occurs at momentum transfer near 1 gev@xmath0 . we also obtain analytical parametrizations for the elementary amplitudes , that are suitable for phenomenological uses , and discuss the effects of extrapolations from the physical regions investigated in the lattice . _ to be published - physics letters b _

for the next generation cosmic microwave background ( cmb ) experiment , polarbear-2 @xcite , we will build a receiver that has 7,588 tes bolometers coupled to two - band ( 95 and 150 ghz ) polarization - sensitive antennas . the kilopixel arrays are necessary to achieve the required sensitivity and our science goals . polarbear-2 is an upgraded experiment based on polarbear-1 , which has measured the b - mode power spectrum @xcite , the deflection power spectrum @xcite and its cross - correlation with cosmic infrared background @xcite . polarbear-1 is using a readout system with a multiplexing factor of 8 in the frequency domain , with the bolometers biased up to 1 mhz . polarbear-1 is using analog flux - locked loop ( fll ) to read out the current through the squid amplifier . the polarbear-2 focal plane is an order of magnitude larger than currently deployed tes arrays . this requires a large multiplexing factor due to limitations on thermal loading from signal cables . we are developing readout electronics , which multiplexes 40 tes bolometers through a single superconducting quantum interface device ( squid ) . extending that architecture to 40 bolometers requires an increase in the bandwidth of the squid electronics , above 4 mhz . since the analog fll limits the usable bandwidth up to 1 mhz , we use digital active nulling ( dan ) @xcite @xcite on the digital frequency - domain multiplexing platform for multiplexing 40 bolometers , as shown in fig . [ fig : circuit_diagram ] . with dan , digital feedback is calculated for each bolometer , extending the useful bandwidth of the squid amplifier . in this paper , we will describe cryogenic readout electronics , lc filters and cold cables , which are also important for achieving the high multiplexing factor . we are developing 40-channel lc filters and low - inductance superconducting cables . detailed descriptions of the lc filters are found in @xcite . this paper gives an overview of the cryogenic readout and its requirements for cmb observations . using the new readout components and the modified wiring , we will show the performance of bolometers biased at high frequency ( @xmath0 3 mhz ) . [ width=0.85 , bb=0 0 794 396 ] pb2_circuit_ppt.pdf since the resistance of a tes bolometer is small , it is important to design the cryogenic readout electronics carefully , and suppress the series impedance to voltage - bias the tes bolometers . in the following sections , we will give an overview of requirements placed on the series impedance . a component that mainly contributes to the series resistance is an equivalent series resistance ( esr ) of a capacitor forming an lc filter . as dielectric loss in the capacitors become larger at a higher frequency , controlling the esr becomes more important for a readout with a large multiplexing factor , which requires a wide bandwidth . the series resistance causes instability in electrothermal feedback when @xmath1 with loop gain @xmath2 , where @xmath3 is a series resistance , and @xmath4 is a tes resistance @xcite . even with @xmath5 , a non - linear response of the tes bolometer is caused and can create systematic errors with cmb observations . assuming that @xmath6 for our tes bolometers , the non - linear response of the voltage - biased bolometer at a frequency , @xmath7 , @xmath8 where @xmath9 is the current through the tes , @xmath10 is input power , @xmath11 is the loop gain , and @xmath12 is the time constant at @xmath13 . this equation can be derived using equations shown in @xcite . the equation is valid for cmb observations since we only use frequencies where @xmath7 for data analysis . if the loop gain @xmath14 is infinite and the series resistance @xmath3 is zero , the gain @xmath15 is constant and the bolometer response is linear . the series resistance varies the gain as the input power @xmath10 changes . considering the first order of taylor series , the change in current as a function of input power is @xmath16\bigr| _ { \delta p = 0 } \delta p \bigr ] , \label{eq : taylor_series2}\ ] ] we used a constant - voltage biased condition , @xmath17 , to derive eq . [ eq : taylor_series2 ] . the first term expresses linear response and other terms express the non - linear response . when the loop gain is infinite and the series resistance is zero , the non - linear terms become zero and the response is linear . the second and the last terms in eq . [ eq : taylor_series2 ] are proportional to the series resistance . the second term can not be mitigated even with the infinite loop gain . our goal is @xmath18 , achieved by the polarbear-1 readout , to maintain the non - linearity in the same level . components that contribute to the series resistance are ( 1 ) equivalent series resistance ( esr ) of a capacitor for an lc filter @xcite ( 2 ) flex cables with copper lines which connect the wafer and the lc filters ( 3 ) contact resistance of connectors ( 4 ) copper traces on printed circuit boards where squids are mounted ( 5 ) a resistor biasing the bolometers ( 30 m@xmath19 ) . in fig . [ fig : circuit_diagram ] , the resistive bridge consisting of @xmath20 and @xmath21 , where @xmath22 , is equivalent to a voltage - source with @xmath21 in series according to thevenin s theorem . since readout lines on the wafer and cables between the lc boards and the squid mounting boards are superconducting , they do nt contribute to the series resistance . in sec . [ sec : testing ] , we present measurements of the total series resistance . though the series inductance can also break the constant voltage - biasing condition , most of the inductance in series with the bolometer can be mitigated and does nt appear in eq . [ eq : responsivity ] . most of the series inductance can be cancelled by choosing the resonant frequency of the lc filter shifted by the series inductance . however , contribution to cross talk between neighboring channels in frequency space @xcite can not be mitigated . the change in the current through the series inductance @xmath23 in fig . [ fig : circuit_diagram ] modulates the voltage across the entire lcr circuit , deposits electronic power to the bolometers and leads to cross talk . the series resistance @xmath24 shown in fig . [ fig : circuit_diagram ] also contributes to the voltage modulation . at high frequency , the series impedance @xmath25 is much higher than @xmath24 , and the series resistance is negligible . note that the current through the squid input coil is cancelled by dan , such that @xmath26 , and the squid input impedance @xmath27 does nt contribute to cross talk . the electrical cross talk should be smaller than the @xmath28 1% specification set by the size of the cmb signals being measured . we chose logarithmic spacing to maintain cross talk across the entire readout bandwidth @xcite . we set targeted series inductance to 60 nh , considering the length of the cold cables ( about 60 cm ) and an achievable inductance ( about 1 nh / cm ) . based on the series inductance and the acceptable cross talk , the peak frequencies of the lc filters are from 1.6 mhz to 4.2 mhz . the frequency schedule allows a margin of error of resonant frequencies of the lc filters . in this section , we present the evaluations of our cryogenic readout in a laboratory fmux setup , shown in fig . [ fig : circuit_diagram ] . we used a low inductance cable to connect the lcr circuit ( 0.3 k ) to the bias resistor ( 4 k ) . the cable consists of two segments : a low - inductance broadside - coupled stripline which has copper lines and high thermal conductivity , and a nbti stripline with a similar geometry . the nbti stripline was used to isolate the 4 k and 0.3 k stages thermally . the total inductance for the cryogenic cable was @xmath29 90 nh . we are developing a nbti stripline with a thinner substrate to achieve the targeted series inductance , 60 nh . the resonant peaks of the lc filters were measured by sweeping a small amplitude probe in frequency , as shown in fig . [ fig : netanal ] . we used the width of a resonant peak , @xmath30 , to measure a resistance in series with an lc filter . when the tes is superconducting , the measured resistance is equal to the sum of the series resistance , @xmath31 . figure [ fig : rs ] shows the series resistance obtained by fitting the peaks in fig . [ fig : netanal](b ) . this is the sum of resistances for all the cryogenic readout electronics , and is higher than the equivalent series resistance of the capacitors in the lc filters , shown in @xcite . the error bars in fig . [ fig : rs ] could be originated from a fit function describing a single lcr leg , not considering the stray capacitance , the inductance and the leakage current through neighboring channels in frequency spacing . the measured resistance meets the requirements , @xmath18 , where @xmath4 in transition is about 1 @xmath19 . using the new cryogenic readout , we sucessfully tuned the bolometers into the middle of transition . figure [ fig : rp ] shows examples of the transition curves . controlling the series resistance and inductance is important to reduce systematic errors for cmb observations . even a small series resistance changes performance of the tes bolometer and creates non - linearity , which leads to systematic errors . we successfully reduced the series resistance using low - loss capacitors . to reduce it further , we will implement micro - d connectors , which have a low - contact resistance and are robust mechanically . though their disadvantage is a high inductance , we will use the lower - inductance stripline under development to compensate the increase in inductance . we have demonstrated tuning bolometers into transition at a high frequency using legacy warm electronics , which multiplexes up to 16 channels . new warm electronics allowing a larger multiplexing factor have been developed @xcite and we will test the cold readout with them . the polarbear project is funded by mext kakenhi grant number 21111002 , the national science foundation ast-0618398 , nasa grant nng06gj08 g , and the simons foundation . the mcgill authors acknowledge funding from the natural sciences and engineering research council of canada , the canada research chairs program , and canadian institute for advanced research . tes bolometers , lithographed capacitors and inductors were fabricated at the berkeley marvell nanofabrication laboratory .

the readout of transition - edge sensor ( tes ) bolometers with a large multiplexing factor is key for the next generation cosmic microwave background ( cmb ) experiment , polarbear-2 @xcite , having 7,588 tes bolometers . to enable the large arrays , we have been developing a readout system with a multiplexing factor of 40 in the frequency domain . extending that architecture to 40 bolometers requires an increase in the bandwidth of the squid electronics , above 4 mhz . this paper focuses on cryogenic readout and shows how it affects cross talk and the responsivity of the tes bolometers . a series resistance , such as equivalent series resistance ( esr ) of capacitors for lc filters , leads to non - linear response of the bolometers . a wiring inductance modulates a voltage across the bolometers and causes cross talk . they should be controlled well to reduce systematic errors in cmb observations . we have been developing a cryogenic readout with a low series impedance and have tuned bolometers in the middle of their transition at a high frequency ( @xmath0 3 mhz ) .

networks describing complex systems in the real world are quite inhomogeneous and complicated @xcite . the number of edges from a node , namely degree , for example , is widely distributed in a network . in fact , many real - world complex networks have asymptotically power - law degree distributions , which is called the scale - free property @xcite . in addition , the degrees of adjacent nodes via an edge are usually correlated . such nearest neighbor degree correlations can be described by the joint probability @xmath0 of a randomly chosen edge connecting two nodes with degrees @xmath1 and @xmath2 . it has been empirically known that nodes in social networks tend to be connected to nodes with similar degrees ( assortative mixing ) while technological or biological networks show the opposite tendency ( disassortative mixing ) @xcite . network complexity is also characterized by the shortest path distance ( number of edges along the shortest path ) between nodes . from this point of view , most of real - world networks can be classified into two classes @xcite , namely , small - world networks @xcite and fractal networks @xcite . in a small - world network , the shortest path distance averaged over all node pairs increases logarithmically ( or more slowly ) with the total number of nodes . in other words , the minimum number of subgraphs @xmath3 covering the entire network decreases exponentially ( or faster ) with the subgraph diameter , that is , @xmath4 where @xmath5 is the maximum distance between any nodes in the subgraph ( subgraph diameter ) and @xmath6 is a constant . it has been shown that many real - world networks possess the small - world property @xcite . for a fractal network , on the other hand , the number of covering subgraphs decreases with @xmath5 in a power - law manner , i.e. , @xmath7 where @xmath8 is the fractal dimension of the network . this relation has been observed also in a diverse range of networks from the world wide web to some kinds of cellular networks @xcite . the origin of the fractal property in complex networks is still an open question @xcite , though the mechanism of the small - world network formation has been found in the existence of short - cut edges . it has , however , been empirically demonstrated that real - world and synthetic fractal scale - free networks have _ disassortative _ degree correlations @xcite . if the converse is also true , that is , disassortative mixing makes a scale - free network fractal , the origin of fractality would be found in the degree correlation . disassortativity is a local property characterizing nearest neighbor degree correlations , while fractality is a consequence of long - range structural correlations . this fact seems to deny the above possibility . it is , however , known that if edges in a scale - free network are rewired to maximize or minimize the assortativity @xmath9 while keeping the degree sequence ( and hence the degree distribution ) then the maximally assortative or disassortative network becomes to possess a long - range correlation @xcite . the assortativity @xmath9 is the pearson s correlation coefficient for degrees and defined by @xcite @xmath10^{2 } } { \displaystyle \sum_{(i , j)\in e}(k_{i}^{2}+k_{j}^{2})-\frac{1}{2m}\left[\sum_{(i , j)\in e}(k_{i}+k_{j})\right]^{2 } } , \label{eq_assortativity}\ ] ] where @xmath11 is the degree of node @xmath12 , @xmath13 is the total number of edges , and @xmath14 is the set of undirected edges in the network . a maximally assortative network has an onionlike structure consisting of communities of regular subgraphs @xcite . such a network displays a long - range structural correlation in which maximum degree nodes are distant from minimum degree ones . a maximally disassortative ( md ) network also shows a community structure . in each community , all nodes with a specific low degree and higher degree nodes are connected alternately @xcite . thus , a minimum ( or maximum ) degree node is located far away from an intermediate degree node in the md network , which implies a long - range correlation . therefore , there is a possibility that even short - range disassortative degree mixing induces the long - range fractal correlation , as pointed out by ref . @xcite through the analysis of random critical branching trees . furthermore , considering the entropic origin of disassortativity @xcite , we can discuss the formation mechanism of fractal scale - free networks in connection with a process maximizing the entropy . in this paper , we examine the possibility that a negative degree correlation between nearest neighbor nodes makes a scale - free network fractal . to this end , we first prepare an uncorrelated scale - free network that is guaranteed to become fractal by rewiring edges . then , this network is again rewired so that the nearest neighbor degree correlation becomes maximally negative . if the rewired md network exhibits the fractal nature , one can conclude that fractality of scale - free networks is induced by disassortative degree mixing . our results , however , show that disassortativity does not always make scale - free networks fractal . we also suggest that fractality seems to require a long - range repulsive correlation between similar degree nodes . the rest of this paper is organized as follows . in sec . [ sec:2 ] , we explain how to prepare the initial network @xmath15 that can be fractal scale free by rewiring edges . the rewiring method to obtain md networks is also described in this section . our results on the fractal property of rewired disassortative networks are presented in sec . [ sec:3 ] . a long - range degree correlation is also argued . section [ sec:4 ] is devoted to the summary and remarks . we investigate the fractal property of md networks formed by rewiring edges while keeping the degree distribution of a given initial uncorrelated scale - free network @xmath15 . in this section , we explain how to prepare the initial network @xmath15 and how to rewire it so as to realize a md network . the initial uncorrelated scale - free network @xmath15 must be guaranteed to become fractal by rewiring edges . such a network can be constructed by rewiring randomly edges of an original scale - free fractal network @xmath16 . we adopt the @xmath17-flower with @xmath18 as the network @xmath16 @xcite . in the @xmath17-flower model , we start with the cycle graph consisting of @xmath19 nodes and edges [ the first generation @xmath17-flower ] . the @xmath20th generation @xmath17-flower @xmath21 is obtained by replacing each edge in @xmath22 by two parallel paths of @xmath23 and @xmath24 edges . the number of nodes @xmath25 and the number of edges @xmath13 in @xmath21 are given by @xmath26 the degree of a node in this network falls into any of @xmath27 with @xmath28 , and the number of nodes @xmath29 with the degree @xmath30 is given by @xmath31 which specifies the degree sequence of the network . thus , the degree distribution function @xmath32 for @xmath33 of @xmath21 with large @xmath20 is proportional to @xmath34 , where @xmath35 the network with @xmath36 exhibits fractality with the fractal dimension @xcite , @xmath37 the @xmath38th generation @xmath39-flower with @xmath40 nodes and @xmath41 edges is depicted in fig . [ fig:1](a ) . th generation @xmath39-flower with @xmath42 nodes and @xmath43 edges . ( b ) a network formed by @xmath44 operations of rr for the network shown by ( a).,scaledwidth=48.0% ] the initial network @xmath15 is formed by rewiring randomly edges in the scale - free fractal @xmath17-flower as @xmath16 . the random rewiring ( rr ) procedure is performed as follows : \(i ) choose randomly two edges @xmath45 and @xmath46 with four different end nodes , namely @xmath47 . \(ii ) rewire these edges to @xmath48 and @xmath49 , if this rewiring process does not make multiple edges . \(iii ) repeat ( i ) and ( ii ) enough times . since the above rewiring preserves the degree of each node , the degree sequence ( and thus the degree distribution ) of the network after rr s does not change from the original one . if the number of repetition times is much larger than the number of edges @xmath13 , the rewired network @xmath15 possesses essentially the same statistical properties as the configuration model @xcite with the degree sequence specified by eq . ( [ uv_nkm ] ) . therefore , @xmath15 has no degree correlations , as well as no structural correlations such as fractality . it should be , however , emphasized that the network @xmath15 is guaranteed to become fractal by rewiring edges . as an example of @xmath15 , the network shown in fig . [ fig:1](b ) is formed by the rr procedure ( i)-(iii ) from the @xmath39-flower of fig . [ fig:1](a ) . in order to make md networks @xmath50 from an initial network @xmath15 , we first quantify the degree of assortative mixing in a network . the assortativity @xmath9 defined by eq . ( [ eq_assortativity ] ) is widely used for this purpose . if @xmath9 is positive , the network is assortatively mixed on degrees of nodes , while a network with a negative @xmath9 shows disassortative mixing . it has been , however , pointed out that @xmath9 strongly depends on the network size and can not be negative for infinitely large scale - free networks if the degree distribution decays asymptotically more slowly than @xmath51 @xcite . to overcome this problem , the spearman s rank correlation coefficient @xmath52 for degrees has been proposed for measuring assortative ( or disassortative ) mixing @xcite . this quantity is defined by @xmath53^{2 } } { \displaystyle \sum_{(i , j)\in e}(r_{k_{i}}^{2}+r_{k_{j}}^{2})-\frac{1}{2m}\left[\sum_{(i , j)\in e}(r_{k_{i}}+r_{k_{j}})\right]^{2 } } , \label{eq : rho}\ ] ] where @xmath54 is the rank of the degree of node @xmath12 and the meaning of the summation is the same as in eq . ( [ eq_assortativity ] ) . from the above definition , it is clear that @xmath52 is the pearson s correlation coefficient for degree ranks . there are several ways to determine the rank @xmath55 if plural nodes in a network have the same degree . to avoid this problem , litvak _ et al_. @xcite resolve the rank degeneracy for the same degree nodes by using random numbers . this method , however , makes it difficult to calculate analytically @xmath52 even for a deterministic network such as the @xmath17-flower . an alternative way of ranking is to rank degrees of @xmath56 end nodes in ascending order with assigning the average rank of degenerated degrees to them @xcite . in this case , the rank of an end node with degree @xmath1 is given by @xmath57 where @xmath58 is the number of nodes with degree @xmath1 . using this ranking , the spearman s rank correlation coefficient @xmath52 can be written as @xmath59 where we use @xmath60 . it should be noted that topologies of networks with a specific degree sequence are reflected only in the first term @xmath61 of the numerator . since the rank @xmath55 one - to - one corresponds to @xmath1 , analytical calculations of @xmath52 are possible for some deterministic networks . for example , @xmath52 for the @xmath20th generation @xmath17-flower @xmath21 with @xmath36 and @xmath62 is presented by ( see the appendix ) @xmath63 where @xmath64 is less than or equal to @xmath65 . for an infinitely large @xmath17-flower ( @xmath66 ) , @xmath67 is negative for any @xmath68 as expected from fig . [ fig:1](a ) , while the assortativity @xmath9 for @xmath69 with @xmath70 becomes zero as shown in the appendix . we construct a md network @xmath50 by rewiring edges of @xmath15 so as to minimize the spearman s rank correlation coefficient @xmath52 . the actual rewiring procedure is as follows : \(i ) choose randomly two edges @xmath45 and @xmath46 with four different end nodes . \(ii ) rewire these edges to @xmath48 and @xmath49 , if this rewiring does not make multiple edges and not increase the spearman s rank correlation coefficient @xmath52 . \(iii ) repeat ( i ) and ( ii ) until @xmath52 can not be decreased anymore by rewiring . this disassortative rewiring ( dr ) also does not change the degree sequence . therefore , @xmath29 of @xmath50 is still given by eq . ( [ uv_nkm ] ) . for some degree sequences , the rank correlation @xmath52 can not reach its minimum value by the above dr scheme because of local minimum trap . in such a case , an optimization algorithm based on simulated annealing @xcite must be employed instead of the present dr . however , the above simple dr can minimize @xmath52 at least for the degree sequence specified by eq . ( [ uv_nkm ] ) , as mentioned later . as a function of the number of dr steps @xmath71 starting from the initial networks ( @xmath15 ) formed by @xmath44 operations of rr for the 4th ( solid line ) , 5th ( dashed line ) , and 6th ( dotted line ) generation @xmath39-flowers ( @xmath16 ) , where @xmath13 is the number of edges in the networks . the horizontal dotted line indicates the value of @xmath72.,scaledwidth=45.0% ] figure [ fig:2 ] shows how the rank correlation coefficient @xmath52 decreases with the dr step @xmath71 starting from @xmath15 . initial networks @xmath15 are formed by @xmath44 operations of rr for @xmath39-flowers ( @xmath16 ) , where @xmath13 is the number of edges . solid , dashed , and dotted curves in fig . [ fig:2 ] represent the results for the 4th , 5th , and 6th generation @xmath39-flowers as @xmath16 . the numbers of nodes @xmath25 and edges @xmath13 are @xmath42 , @xmath73 , and @xmath74 and @xmath43 , @xmath75 , and @xmath76 for the 4th , 5th , and 6th generations , respectively . the initial values of @xmath52 at @xmath77 ( i.e. , @xmath52 for @xmath15 ) are slightly negative even though @xmath15 is randomly rewired enough times . this is because self - loops and multiple edges are not allowed in @xmath15 . since the probability to have such edges by rr with allowing them decreases with the network size , @xmath52 for @xmath15 becomes close to zero as the generation increases . the rank correlations @xmath52 monotonically decrease with the dr step , and reach negative constant values . these convergence values coincide with @xmath78 presented by eq . ( [ eq : uv - rho ] ) , namely , @xmath79 , @xmath80 , and @xmath81 ( indicated by the horizontal dotted line in fig . [ fig:2 ] ) . the rank correlations never diminish from these values even if repeating dr operation many times . we can show that the above convergence value @xmath82 gives the minimum @xmath52 among networks with the degree sequence specified by eq . ( [ uv_nkm ] ) , that is , networks with @xmath82 are nothing but md networks . for simplicity , let us discuss the case of @xmath78 and define two sets , @xmath83 and @xmath84 , of networks derived from the @xmath20th generation @xmath39-flower . the set @xmath83 includes all networks with the degree sequence specified by eq . ( [ uv_nkm ] ) , while @xmath84 is a proper subset of @xmath83 in which every network is composed of edges connecting two nodes with the lowest degree @xmath85 and a higher degree @xmath30 with @xmath86 . namely , a network in @xmath84 has the joint probability @xmath0 for @xmath87 given by @xmath88 where @xmath29 is presented by eq . ( [ uv_nkm ] ) and @xmath89 is the number of edges . the rank correlation coefficient @xmath52 takes a constant value for networks in @xmath84 because @xmath52 of eq . ( [ eq : rho2 ] ) is uniquely determined by @xmath0 and @xmath55 and the rank @xmath55 defined by eq . ( [ eq : rank ] ) does not change for networks in @xmath83 . since the @xmath39-flower is an element of @xmath84 , this constant value is equal to @xmath78 . if a network with the degree sequence @xmath29 given by eq . ( [ uv_nkm ] ) has a joint probability @xmath0 different from eq . ( [ eq : pkk ] ) , the network possesses edges connecting lowest degree nodes to each other . in order to prove that @xmath52 of such a network is larger than @xmath78 , let us consider a network @xmath90 formed by rewiring two edges @xmath91 and @xmath92 of a network @xmath93 to @xmath94 and @xmath95 . here , the degrees of these end nodes are @xmath96 and @xmath97 . the network @xmath90 has the same @xmath55 as @xmath98 because @xmath99 , while @xmath0 for @xmath90 is slightly different from eq . ( [ eq : pkk ] ) . for both @xmath98 and @xmath90 , we have @xmath100 and @xmath101 , because @xmath55 is a monotonically increasing function of @xmath1 . these relations for @xmath55 give the inequality , @xmath102 the left - hand side of the above inequality represents the contribution to the first term in the numerator of eq . ( [ eq : rho2 ] ) from the edges @xmath94 and @xmath95 of @xmath90 , while the right - hand side is that from the edges @xmath91 and @xmath92 of @xmath98 . other edges of @xmath98 and @xmath90 give the same contribution to this term . the remaining terms of eq . ( [ eq : rho2 ] ) do not change between @xmath98 and @xmath90 . therefore , the above inequality shows that the rank correlation @xmath103 for the network @xmath98 is less than @xmath104 for @xmath90 . this implies that @xmath78 provides the minimum value @xmath105 of @xmath52 for networks in @xmath83 . in other words , @xmath84 is the set of md networks ( @xmath50 ) within @xmath83 . in the case of fig . [ fig:2 ] , @xmath52 reaches @xmath105 at @xmath106 , @xmath107 , and @xmath108 for the 4th , 5th , and 6th generations , respectively . further dr operations after these steps realize different topology networks @xmath50 s in @xmath84 . the above argument for @xmath78 can be easily generalized to @xmath82 . and ( b ) @xmath109 operations of dr from the network shown by fig . [ fig:1](b).,scaledwidth=48.0% ] examples of md networks formed by dr s from @xmath15 shown in fig . [ fig:1](b ) are presented in fig . [ fig:3 ] . these networks seem to be very different from the @xmath38th generation @xmath39-flower ( @xmath16 ) shown in fig . [ fig:1](a ) , though the nearest - neighbor degree correlations are the same as @xmath16 . in order to quantify such differences in network topology , we employ two indices . one is the spectral distance @xmath110 between networks @xmath98 and @xmath111 with the same size @xmath25 @xcite . the distance @xmath110 is defined by @xmath112 } . \label{eq : spec_dist}\ ] ] here , @xmath113 and @xmath114 are the @xmath115th eigenvalues ( in ascending order ) of the adjacency matrix @xmath116 $ ] and the laplacian matrix @xmath117 $ ] , respectively , where @xmath118 if the nodes @xmath12 and @xmath119 are connected in @xmath98 , @xmath120 otherwise , and @xmath121 . since @xmath110 is invariant under the similarity transform , @xmath122 for networks @xmath98 and @xmath111 being isomorphic to each other . it should be remarked , however , that two cospectral networks providing @xmath122 are not always isomorphic . although @xmath110 becomes large when the topology of @xmath111 largely deviates from @xmath98 , it is not clear what type of topological differences strongly affects @xmath110 . thus , we introduce another measure , the correlation distance @xmath123 , to quantify the topological difference between networks . the quantity @xmath123 is defined as @xmath124 where @xmath125 is the joint probability that randomly chosen two nodes have the degrees @xmath1 and @xmath2 and are separated by the shortest path distance @xmath126 to each other . similar to @xmath110 , @xmath123 takes the minimum value @xmath127 if @xmath128 . @xmath123 becomes maximum if two distribution functions @xmath125 and @xmath129 have no overlap , and isbounded by @xmath130 because of the normalization condition@xmath131 . a large correlation distance @xmath123 implies that @xmath111 displays very different ( long - range ) degree correlations from @xmath98 . ( black line ) and correlation distance @xmath132 ( red line ) rescaled by @xmath133 and @xmath134 , respectively , where @xmath16 is the 4th generation @xmath39-flower , and @xmath15 is the network after @xmath135 operations of rr from @xmath16 . the left panel displays the distances during @xmath44 operations of rr starting from @xmath16 , while the right panel shows the distance changes by dr s starting from @xmath15.,scaledwidth=48.0% ] we examined how largely md networks are different from the @xmath17-flower by computing the above topological distances . the left panel of fig . [ fig:4 ] shows @xmath136 and @xmath132 as a function of the number of rr steps @xmath71 , where @xmath16 is the original 4th generation @xmath39-flower @xmath137 and @xmath138 is the network after @xmath71 operations of rr from @xmath16 . the right panel depicts the same quantities , but @xmath71 is the number of dr steps starting from @xmath15 , and @xmath138 is the network after @xmath71 operations of dr from @xmath15 . in this panel , data for @xmath139 represent the topological distances of md networks from @xmath137 . the topological distances must become zero at some values of @xmath71 in this region because the @xmath137 included in @xmath84 is reachable from any md network by dr s . nevertheless , both the spectral and correlation distances never drop to zero , at least within the present window of @xmath71 . this implies that the topology of md network in @xmath84 is diverse and most of md networks have very different structures from the @xmath17-flower . the diverse topologies of md networks can be readily understood through the idea of _ unit rewiring_. the @xmath20th generation @xmath17-flower @xmath21 is composed of @xmath140 pieces of @xmath141 ( @xmath142 ) . if we regard @xmath141 as a superedge of @xmath21 , @xmath21 is equivalent to @xmath143 with superedges . let us perform rr operations for @xmath143 with superedges , which corresponds to rr s in units of the subgraph @xmath141 in @xmath21 . we call such a rewiring a unit rewiring ( ur ) . as examples , networks after @xmath144 and @xmath145 operations of ur in units of @xmath146 and @xmath147 starting from @xmath137 are depicted in figs . [ fig:5](a ) and 5(b ) , respectively . it should be emphasized that the network after ur s has the same @xmath0 , and thus @xmath52 , as the original network @xmath21 . therefore , all networks formed by ur s are elements of @xmath84 . the number of networks formed by ur operations in units of @xmath141 starting from @xmath21 is equivalent to the number of networks with the same degree sequence as @xmath143 . since even this number is quite large @xcite , the number of elements in @xmath84 that includes unit - rewired networks as a part of it rises astronomically . and ( b ) @xmath145 operations of ur in units of @xmath146 and @xmath147 starting from @xmath137 , respectively.,scaledwidth=48.0% ] considering the property of unit rewiring , in a network @xmath148 formed by ur operations in units of @xmath141 , the degree - degree correlation or other structural correlations in units of @xmath141 can not extend beyond the scale of them . this implies that the network @xmath148 ( @xmath149 ) does not possess the fractal property as a long - range structural correlation . thus , we can conclude that disassortative degree mixing does not always make a scale - free network fractal . although the @xmath17-flower in @xmath84 has surely a fractal structure , it can be demonstrated that fractal networks are rather rare in the set @xmath84 . in the right panel of fig . [ fig:6 ] , the number of covering subgraphs @xmath3 [ see eqs . ( [ eq : def_sw ] ) and ( [ eq : def_fr ] ) ] is plotted as a function of @xmath5 for @xmath38 topologically very different networks in @xmath84 , by employing the compact - box - burning algorithm @xcite . these results show that @xmath150 decreases exponentially with @xmath5 . in addition to these @xmath38 examples , we examined @xmath150 for totally @xmath151 md networks with different topologies to each other . our results show that @xmath150 for every network obeys eq . ( [ eq : def_sw ] ) , which implies that most of md networks with the scale - free property are not fractal , but have the small - world property . as a function of the subgraph diameter @xmath5 for the original 6th generation @xmath17-flower @xmath152 ( gray circles in the left panel ) , @xmath15 formed by rr s from @xmath152 ( gray squares in the left panel ) , and four topologically different networks in @xmath84 formed by dr s from @xmath15 ( black symbols in the right panel ) . the results are vertically shifted for graphical reasons . lines in the left panel are guides to the eye.,scaledwidth=43.0% ] for the 6th generation @xmath39-flower @xmath152 ( top ) , networks ( @xmath153 ) formed by rewiring edges while keeping @xmath0 starting from @xmath152 ( middle ) , and networks ( @xmath15 ) formed by rr s starting from @xmath152 ( bottom ) . the results for @xmath153 and @xmath15 are averaged over @xmath151 connected samples . the inset shows @xmath154 for the www ( @xmath155 ) with @xmath156 nodes and @xmath157 edges @xcite ( red circles ) , a network ( @xmath153 ) formed by rewiring edges while keeping @xmath0 starting from @xmath155 ( green triangles ) , and a network ( @xmath158 ) formed by rr s starting from @xmath155 ( blue squares ) . curves are guides to the eye.,scaledwidth=46.0% ] does the degree correlation have nothing to do with the fractal property of a scale - free network ? our results demonstrate that at least the nearest neighbor disassortative degree correlation can not be the origin of fractality in scale - free networks . however , as seen in fig . [ fig:1](a ) , the @xmath17-flower has a distinguishing feature of a long - range repulsive correlation between the same degrees . this is not found in a typical md network shown in fig . [ fig:3 ] . in particular , the long - range repulsion between hub nodes is found not only in the @xmath17-flower but also in other synthetic scale - free fractal networks @xcite . in order to quantify the repulsive correlation between hubs , we introduce the conditional probability @xmath159 of randomly chosen two nodes with degrees @xmath1 and @xmath2 being separated by the distance @xmath126 to each other . if setting @xmath160 , this probability indicates the distribution of shortest path distance among nodes with the largest degree @xmath161 and gives information on the hub - hub repulsion . to improve the statistical reliability of this distribution , we define the distance distribution function @xmath162 , where @xmath32 is the degree distribution , @xmath163 represents the summation over degrees of the top 2% of high degree nodes , and @xmath164 is the normalization constant . as expected , @xmath154 for the @xmath17-flower shown in the top panel of fig . [ fig:7 ] is distributed in a wide range of @xmath126 , which implies that high degree nodes are likely to be largely separated from each other . the middle panel of fig . [ fig:7 ] indicates @xmath154 for networks ( @xmath153 ) formed by rewiring many edges while keeping @xmath0 starting from the @xmath17-flower , where we should note that @xmath153 is a md network . the actual rewiring process can be done as follows : first we choose randomly two edges @xmath45 and @xmath46 with four different end nodes , where the degree of node @xmath165 is equal to the degree of node @xmath166 , then rewire them to @xmath48 and @xmath49 . the function @xmath154 for @xmath153 is distributed in a narrow range of small @xmath126 . the width of the distribution is , however , slightly wider than that for @xmath15 ( bottom panel of fig . [ fig:7 ] ) formed by rr s starting from the @xmath17-flower . this is because higher degree nodes are never directly connected in @xmath153 . in addition to the @xmath17-flower , we examined @xmath154 for the www @xcite as a real - world scale - free fractal network . this network exhibits disassortative degree mixing ( @xmath167 ) and is known to have the fractal dimension @xmath168 @xcite . as shown in the inset of fig . [ fig:7 ] , @xmath154 for the www has a long tail . if the network is rewired while keeping @xmath0 , @xmath154 becomes much narrower than that for the original www as seen by triangles in the inset and the network loses fractality . these results suggest that the fractal property of a scale - free network requires a long - range repulsive correlation between similar degree nodes , particularly hub nodes . we have studied the relation between fractality of scale - free networks and their degree correlations . real - world and synthetic fractal scale - free networks are known to exhibit disassortative degree mixing in common . it is , however , not obvious whether a negative correlation between nearest neighbor degrees causes the fractal property of a scale - free network , though the possibility of disassortativity being the origin of fractality is suggested . in order to clarify this point , we examined maximally disassortative ( md ) networks prepared by rewiring edges while keeping the degree sequence . for the preparation of md networks , uncorrelated networks are first formed by rewiring randomly edges of the @xmath17-flower then , these networks are again rewired to minimize the rank correlation coefficient @xmath52 . our results show that there exist a huge number of md networks with different topologies but most of them are not fractal . therefore , it is concluded that negative correlations between nearest neighbor degrees can not be the origin of fractality of scale - free networks . this can be readily understood if we consider md networks formed by unit rewiring operations starting from the @xmath17-flower , because unit - rewired networks can not have any structural correlations beyond the scale of the rewiring unit . in addition , we studied the long - range repulsion between hub nodes in fractal scale - free networks and their rewired networks while keeping the joint probability @xmath0 . the results for the @xmath17-flower and a real - world fractal scale - free network show that distances between large degree nodes in fractal scale - free networks are much longer than those in their rewired networks . this fact prompts the speculation that fractality of scale - free networks requires a long - range repulsive correlation in similar degrees . we should point out that networks treated in this work are a bit special . as mentioned in sec . [ sec:1 ] , md networks are generally composed of communities in each of which all nodes with a specific low degree and higher degree nodes are connected alternately . this gives md networks a long - range degree correlation . on the other hand , an md network with the same degree sequence as the @xmath17-flower ( @xmath169 ) consists of only one community , because the total number of spokes from the lowest degree nodes is equal to or larger than that from all remaining higher degree nodes . we then can not expect the long - range degree correlation in md networks with the same degree sequence as the @xmath17-flower . nevertheless , our conclusion is considered to be still valid even for more general networks . this is because disassortative degree mixing does not introduce any long - range repulsive correlations between similar degree nodes in a community of a general md network . therefore , the md network is not fractal at least below the scale of the community . our speculation about the long - range repulsive correlation between similar degree nodes for fractal scale - free networks should be checked by further investigations . for this purpose , it is significant to define a new index characterizing the strength of such a repulsive correlation . it is interesting to identify whether a network formed by rewiring edges to maximize this index becomes fractal . the authors thank s. tomozoe for fruitful discussions . this work was supported by a grant - in - aid for scientific research ( no . 16k05466 ) from the japan society for the promotion of science . here , we derive eq . ( [ eq : uv - rho ] ) for the @xmath20th generation @xmath17-flower with @xmath36 and @xmath62 . at first , we determine the rank @xmath170 for the degree @xmath30 ( @xmath171 ) in the @xmath17-flower . for the @xmath17-flower , eq . ( [ eq : rank ] ) can be written as @xmath172 where @xmath173 is the total number of spokes from nodes with degree @xmath174 . since @xmath29 is given by eq . ( [ uv_nkm ] ) , we have @xmath175 where @xmath176 . therefore , the rank of degree @xmath174 is presented by @xmath177 + \frac{1}{2 } & ( 1\le m < n ) , \\[10pt ] \displaystyle 2w^{n}-2^{n-1}w+\frac{1}{2 } & ( m = n ) . \end{cases } \label{eq : rkm2}\ ] ] to calculate @xmath52 by eq . ( [ eq : rho2 ] ) , we need to evaluate @xmath178 and @xmath179 for the @xmath17-flower . considering that nodes with degree @xmath174 for @xmath86 always connect to the lowest degree nodes with degree @xmath85 , the number of edges whose end nodes have the degree ranks @xmath180 and @xmath181 is @xmath182 . the remaining @xmath183/2 $ ] edges connect the lowest degree nodes to each other . thus , the quantity @xmath184 is presented by @xmath185r_{k_{1}}^{2}. \label{eq : x_2}\ ] ] using eqs . ( [ eq : skm ] ) and ( [ eq : rkm2 ] ) , the quantity @xmath184 is calculated as @xmath186 where @xmath187 and the number of edges @xmath13 is given by @xmath188 . the summation over edges in eq . ( [ eq : y ] ) is also rewritten as @xmath189 and @xmath190 can be calculated as @xmath191 the calculations of eqs . ( [ eq : x_3 ] ) and ( [ eq : y_3 ] ) become easier if we utilize the obvious relations @xmath192 and @xmath193 . from eqs . ( [ eq : rho2 ] ) , ( [ eq : x_3 ] ) and ( [ eq : y_3 ] ) , the rank correlation coefficient @xmath82 for the @xmath20th generation @xmath17-flower is then calculated as @xmath194 which is identical to eq . ( [ eq : uv - rho ] ) . for the @xmath39-flower , for example , @xmath78 is calculated as @xmath195^{-1 } , \label{rho_for_22-flower}\ ] ] which gives @xmath196 for @xmath66 . the assortativity @xmath9 defined by eq . ( [ eq_assortativity ] ) for the @xmath20th generation @xmath17-flower with @xmath36 and @xmath197 can be calculated by a similar way . the result is given by @xmath198 \displaystyle -\frac{(n+1)^{2}-4n}{(3\cdot 2^{n}-2)-(n+1)^{2 } } & ( w=4 ) , \\[15pt ] \displaystyle -\frac{4^{n-1}-2^{n}+1}{4^{n-1}(3n-8)+3\cdot 2^{n}-1 } & ( w=8 ) , \end{cases } \label{eq : r_uv}\ ] ] where @xmath199 and @xmath200 for @xmath66 , the assortativity @xmath201 converges as @xmath202 since the scale - free exponent @xmath203 given by eq . 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fractal scale - free networks are empirically known to exhibit disassortative degree mixing . it is , however , not obvious whether a negative degree correlation between nearest neighbor nodes makes a scale - free network fractal . here we examine the possibility that disassortativity in complex networks is the origin of fractality . to this end , maximally disassortative ( md ) networks are prepared by rewiring edges while keeping the degree sequence of an initial uncorrelated scale - free network that is guaranteed to become fractal by rewiring edges . our results show that most of md networks with different topologies are not fractal , which demonstrates that disassortativity does not cause the fractal property of networks . in addition , we suggest that fractality of scale - free networks requires a long - range repulsive correlation in similar degrees .

Crawl of outlinks from wikipedia.org started March, 2016. These files are currently not publicly accessible. Properties of this collection. It has been several years since the last time we did this. For this collection, several things were done: 1. Turned off duplicate detection. This collection will be complete, as there is a good chance we will share the data, and sharing data with pointers to random other collections, is a complex problem. 2. For the first time, did all the different wikis. The original runs were just against the enwiki. This one, the seed list was built from all 865 collections. ||||| After rumors that the gorgeous couple was on the rocks, it's official. Another one bites the dust in the wake of George Clooney's bachelor ways -- this time it's Elisabetta Canalis."We are not together anymore. It's very difficult and very personal, and we hope everyone can respect our privacy," the ex-pair said in a joint statement released on Wednesday.We can't say we didn't see this coming. The Italian actress and model, 32, recently told an Italian magazine that she had no plans to live the bachelorette life forever and knew that she wanted to be married at some point -- a revelation that most likely sent Clooney, 50, who has vowed to never marry again, running.

– Big Hollywood breakup today: George Clooney and Italian girlfriend Elisabetta Canalis have called it quits after two years, reports People. They issued a joint statement short on specifics: "We are not together anymore. It's very difficult and very personal, and we hope everyone can respect our privacy." Canalis's rep says she will be "taking some time" before talking to the press. They celebrated his 50th birthday in LA last month. (Click to read about an interview that PopEater notes could have led to the split.)

there is compelling evidence that massive black holes ( mbhs ) lie in the centers of all galaxies @xcite , including in the center of our galaxy @xcite . the mbh affects the dynamics and evolution of the galaxy s center as a whole ( e.g. @xcite ) and it also strongly affects individual stars or binaries that approach it . such close encounters , which may be extremely energetic , or involve non - gravitational interactions , or post - newtonian effects , have been the focus of many studies ( see review by @xcite ) . these processes include the destruction of stars by the mbh , either by falling whole through the event horizon , or by being first tidally disrupted and then accreted ( e.g. @xcite ) ; tidal scattering of stars on the mbh @xcite ; the capture and gradual inspiral of stars into the mbh , accompanied by the emission of gravitational waves or by tidal heating ( e.g. @xcite ) ; or dynamical exchange interactions in which incoming stars or binaries energetically eject a star tightly bound to the mbh and are captured in its place very near the mbh ( e.g. @xcite ) . the interest in such processes is driven by their possible implications for the growth of mbhs , for the orbital decay of a mbh binary , for the detection of mbhs , for gravitational wave ( gw ) astronomy , as well as by observations of unusual stellar phenomena in our galaxy , e.g. the puzzling young population of b - star very near the galactic mbh @xcite , or the hyper - velocity b stars at the edge of the galaxy @xcite , possibly ejected by 3-body interactions of a binaries with the mbh @xcite . here we focus on close encounters with the mbh whose ultimate outcome ( `` event '' ) is the elimination of the incoming object from the system , whether on the short infall ( dynamical ) time , if the event is prompt ( e.g. tidal disruption or 3-body exchange between a binary and the mbh ) , or on the longer inspiral time , if the event progresses via orbital decay ( e.g. gw emission or tidal capture and heating ) . such processes are effective only when the incoming object follows an almost zero angular momentum ( `` loss - cone '' ) orbit with periapse closer to the mbh than some small distance @xmath5 . to reach the mbh , or to decay to a short period orbit , both the infall and inspiral times must be much shorter than the system s relaxation time @xmath6 @xcite . the fraction of stars initially on loss - cone orbits is very small and they are rapidly eliminated . subsequently , the close encounter event rate is set by the dynamical processes that refill the loss - cone . the loss - cone formalism used for estimating the event rate ( @xcite ) usually assumes that the system is isolated and that the refilling process is 2-body relaxation . this typically leads to a low event rate , set by the long 2-body relaxation time . two - body relaxation , which is inherent to stellar systems , ensures a minimal loss - cone refilling rate . other , more efficient but less general refilling mechanisms were also studied with the aim of explaining various open questions ( e.g. the stalling problem of mbh binary coalescence , @xcite , or mbh feeding , @xcite ) or in the hope that they may lead to significantly higher event rates for close encounter processes . these mechanisms include chaotic orbits in triaxial potentials @xcite ( the presence of a mbh may however destroy the triaxiality near the center ; @xcite ) ; increased fraction of low angular momentum orbits in non - spherical potentials @xcite ; accelerated resonant relaxation of angular momentum near the mbh where the orbits are keplerian @xcite ; perturbations by a massive accretion disk or an intermediate mass black hole ( imbh ) companion @xcite . most of these mechanisms require special circumstances to work ( e.g. specific asymmetries in the potential ) , or are short - lived ( e.g. the imbh will eventually coalesce with the mbh ) . here we explore another possibility , which is more likely to apply generally : accelerated relaxation and enhanced rates of close encounters driven by massive perturbers ( mps ) . efficient relaxation by mps was first suggested by @xcite to explain stellar velocities in the galactic disk . mps remain an important component in modern models of galactic disk heating ( see e.g. @xcite and references therein ) . a similar mechanism was suggested to explain the spatial diffusion of stars in the inner galactic bulge @xcite . in addition to dynamical heating , efficient relaxation by mps was suggested as a mechanism for loss cone replenishment and relaxation , both in the context of scattering of oort cloud comets to the sun @xcite and the scattering of stars to a mbh in a galactic nucleus @xcite . @xcite suggested mps as a mechanism for establishing the @xmath7 relation @xcite by fast accretion of stars and dark matter . they also noted the possibility of increased tidal disruption flares and accelerated mbh binary coalescence due to mps . in this study we investigate in detail the dynamical implications of loss - cone refilling by mps . we evaluate its effects on the different modes of close interactions with the mbh , in particular 3-body exchanges , which were not considered by @xcite , and apply our results to the galactic center ( gc ) , where observations indicate that dynamical relaxation is very likely dominated by mps . this paper is organized as follows . in [ s : outline ] we present the main concepts and procedures of our calculations . the observational data and theoretical predictions about mps in the inner @xmath8 pc of the gc are reviewed in [ s : gc_mps ] . in section [ s : interact ] we explore the implications of relaxation by mps for various types of interactions with the mbh . we summarize our results in [ s : summary ] . in addition to stars , galaxies contain persistent dense structures such as molecular clouds , open clusters and globular clusters with masses up to @xmath9@xmath10 . such structures can perturb stellar orbits around the mbh much faster than 2-body stellar relaxation ( hereafter `` stellar relaxation '' ) , provided they are numerous enough . this condition can be quantified by considering a test star randomly scattered by perturbers with masses in the interval ( @xmath11 ) and number density @xmath12 , approaching it with relative velocity @xmath13 on orbits with impact parameters in the interval ( @xmath14).@xmath15 the minimal impact parameter still consistent with a small angle deflection is @xmath16 ( the capture radius ) , where @xmath13 is of the order of the local velocity dispersion @xmath17 . defining @xmath18 , the encounter rate is then @xmath19\mathrm{d}m_{p}2\pi b\mathrm{d}b\,.\end{aligned}\ ] ] the total rate is obtained by integrating over all mp masses and over all impact parameters between @xmath20 and @xmath21 . here we are interested in perturbations in the specific angular momentum @xmath22 of a star relative to the central mbh , and so @xmath23 , the radial distance of the star from the center . mps with substantially larger impact parameters are much less efficient because their effect on the mbh - star pair is tidal rather than direct . the relaxation rate due to all mps at all impact parameters is then @xmath24 where @xmath25 ) is the coulomb logarithm ( here the dependence of @xmath26 and @xmath13 on @xmath27 is assumed to be negligible ) . for stars , typically @xmath28@xmath29 ; the omission of large angle scattering by encounters with @xmath30 is thus justified because it introduces only a relatively small logarithmic correction . this formulation of the relaxation time is equivalent to its conventional definition ( @xcite ) as the time for a change of order unity in @xmath31 by diffusion in phase space due to scattering , @xmath32 , where @xmath33 is the diffusion coefficient . if the stars and mps have distinct mass scales with typical number densities @xmath34 and @xmath35 and rms masses @xmath36 and @xmath37 ( @xmath38 ) , then mps dominate if the ratio of the 2nd moments of the mp and star mass distributions , @xmath0 , satisfies @xmath1 ( note that for a continuous mass spectrum , this condition is equivalent to @xmath39 ) . as discussed in detail in [ s : gc_mps ] , the central @xmath40 of the galactic center ( gc ) contain @xmath41 solar masses in stars , and about @xmath42 solar masses in mps such as gmcs or open clusters of masses @xmath43 @xcite . an order of magnitude estimate indicates that mps in the gc can reduce the relaxation time by several orders of magnitude , @xmath44^{-1}\left[\frac{(m_{p}/{m_{\star}})}{10^{5}}\right]\,.\end{aligned}\ ] ] note that @xmath45 does not include possible modifications in the value of @xmath26 for mps due to their much larger size , which may decrease this ratio by @xmath46 . this estimate is borne by more detailed calculations ( fig . [ f : tr ] and table [ t : models ] ) , using the formal definition @xmath47 with @xmath48 ( e.g. @xcite , eqs . 8 - 69 to 8 - 70 ) . a similar result is indicated by simulations of spatial diffusion of stars in the central 100 pc @xcite . the fokker - planck approach to the loss - cone problem ( e.g. @xcite ) assumes that the effects of multiple small perturbations on the orbit of a test star dominate over the rarer strong close encounters ( @xmath49 , and that the cumulative effect can be described as diffusion in phase space . the change in the angular momentum of the test star then grows non - coherently , @xmath50 . the change over one orbital period @xmath51 is @xmath52 , where @xmath53 is the maximal ( circular ) angular momentum for a stellar orbit of specific relative energy @xmath54 , and @xmath55 is the negative of the gravitational potential , so that @xmath56 for bound orbits . the magnitude of @xmath57 relative to the @xmath22-magnitude of the loss - cone , @xmath58 determines the mode of loss - cone refilling . the relative volume of phase space occupied by the loss - cone , @xmath59 , increases with @xmath60 ( decreases with @xmath61 ) while @xmath51 decreases . near the mbh ( high @xmath60 ) @xmath62 , stars diffuse slowly into the loss - cone , and are promptly destroyed over an orbital period , leaving the loss - cone always nearly empty . in this empty loss - cone regime , the loss - cone is relatively large , but the refilling rate is set by the long relaxation timescale ( e.g. @xcite ) , @xmath63}\frac{n_{\star}(e)}{p(e)}\,,\label{e : gempty}\end{aligned}\ ] ] where @xmath64 is the stellar number density per energy interval . far from the mbh ( low @xmath60 ) @xmath65 , stars diffuse across the loss - cone many times over one orbit , and the loss cone is always nearly full . in this full loss - cone regime the refilling rate is set by the short orbital time , but the loss cone is relatively small , @xmath66 note that here and elsewhere we make the simplifying approximation that the period is a function of energy only , which is true only for motion in a keplerian potential . the total contribution to loss - cone refilling is dominated by stars with energies near the critical energy @xmath67 ( equivalently , critical typical radius @xmath68 ) separating the two regimes ( @xcite ; see [ s : interact ] ) . within @xmath68 ( @xmath69 ) , an object , once deflected into the loss cone , can avoid being scattered out of it before reaching the mbh is determined by the condition @xmath70 over the inspiral time , rather than the much shorter orbital period , which results in a much smaller @xmath68 than for direct infall . inspiraling stars with @xmath69 can avoid being scattered directly into the mbh before completing the orbital decay . there is no contribution to inspiral events from regions outside @xmath68 ( @xmath71 ) , since the probability of an object to remain on its low-@xmath22 trajectory over the many orbital periods required to complete the inspiral , is vanishingly small . ] . the empty and full loss - cone regimes of infall processes can be interpolated to give a general approximate expression for the differential event rate for these non - coherent encounters ( e.g. @xcite),@xmath72 with @xmath73\,,\ ] ] where @xmath74 is the loss - cone limited angular momentum change per orbit , which expresses the fact that the loss - cone can at most be completely filled during one orbit . the loss - cone formalism can be generalized to deal with mps in an approximate manner with only few modifications . the capture radius for mps may be smaller than their size . since the mp mass profile is centrally concentrated , we adopt the modified definition @xmath75 where @xmath76 . this results in @xmath77 for mps , less than the typical value for relaxation by stars . nevertheless , the error introduced by neglecting encounters with @xmath30 is still not very large because penetrating encounters are much less efficient . however , the assumption of multiple non - coherent encounters with mps over one orbital period is not necessarily justified because of their small number density . to address this , we modify the treatment of the empty loss - cone regime ( the contribution to the event rate from regions where the loss - cone is already filled by stellar relaxation can not be increased by mps , see [ s : interact ] ) . we define rare encounters as those with impact parameters @xmath78 , where @xmath79 is defined by @xmath80 the differential rate is estimated simply by @xmath81 . when @xmath82 , with @xmath83 , all encounters with @xmath84 are defined as frequent encounters that occur more than once per orbit , and add non - coherently or @xmath85 , all encounters are considered rare . ] . note that even when @xmath82 for all mps , perturbations by rare , very massive mps may still occur less than once per orbit . our treatment is approximate . a complete statistical treatment of this situation lies beyond the scope of this study . when the typical number of encounters per orbit is less than one , the fractional contributions from different individual encounters , @xmath86 , should be averaged coherently ( @xmath87 ) , subject to the limit that each encounter can at most fill the loss - cone . the loss - cone limited change in angular momentum per orbit due to rare encounters is therefore @xmath88^{2}\,.\label{e : jr}\ ] ] in contrast , frequent uncorrelated collisions add up non - coherently ( @xmath50 ) , and it is only their final value that is limited by the loss - cone ( individual steps @xmath86 may exceed @xmath89 , but can then be partially cancelled by opposite steps during the same orbit ) . the loss - cone limited change in angular momentum per orbit due to frequent encounters is therefore @xmath90\,.\label{e : jf}\ ] ] the total loss - cone limited angular momentum change per orbit is then approximated by @xmath91 and the differential event rate is calculated by eq . ( [ e : dgde ] ) , @xmath92n_{\star}(e)/p(e)$ ] . the contribution of rare encounters is evaluated in the impulse approximation by setting @xmath93 in eq . ( [ e : jr ] ) . we find that the this contribution by gc mps ( [ s : gc_mps ] ) is generally small . frequent encounters are the regime usually assumed in the fokker - planck treatment of the loss - cone problem ( e.g. @xcite ) . to evaluate the contribution of frequent encounters , we do not calculate @xmath86 directly , but instead calculate the sub - expression @xmath94 in eq . ( [ e : jf ] ) in terms of the @xmath95-averaged diffusion coefficient @xmath96 , after averaging over the orbit between the periapse @xmath97 and apoapse @xmath98 and averaging over the perturber mass function ( this is essentially equivalent to the definition of @xmath57 in terms of @xmath6 , [ ss : noncoherent ] ) , @xmath99 the assumptions involved in the last approximate term ( @xcite ) are that the star is on a nearly radial orbit ( @xmath100 , @xmath101 , @xmath102 ) and that @xmath103 ) ( the diffusion coefficient of the transverse velocity relative to the mbh ) can be approximated by @xmath104 ( the diffusion coefficient of the transverse velocity relative to the stellar velocity @xmath105 ) , given explicitly by ( @xcite , eq . 8 - 68 ) @xmath106 where @xmath107 and where a spatially homogeneous distribution of mps with a maxwellian velocity distribution of rms 1d velocity @xmath17 was assumed . to summarize , the event rates are calculated as follows . for each perturber model ( table [ t : models ] ) , we integrate over the stellar distribution ( @xmath108 , for @xmath109 and @xmath110 ) in terms of @xmath61 , using @xmath34 to derive the appropriate density of perturbed objects ( single stars [ ss : single ] or binaries [ ss : binary ] ) . at each @xmath61 we calculate @xmath20 ( eq . [ e : bmin ] ) , @xmath79 ( eq . [ e : b1 ] ) , @xmath111 ( eq . [ e : jr ] ) and @xmath112 ( eq . [ e : jf ] ) . the integral @xmath113 ( eq . [ e : if ] ) is evaluated by taking @xmath114 and correcting approximately for the difference relative to the exact calculation . we use @xmath74 ( eq . [ e : jtot ] ) to calculate the differential event rate @xmath115 ( eq . [ e : dgde ] ) , with the _ ansatz _ @xmath116 where @xmath117 is an effective semi - major axis , which is motivated by the fact that for a keplerian isothermal eccentricity distribution , @xmath118 . the total event rate is calculated by carrying the integration over @xmath61 in the region where mps exist , between @xmath119 and @xmath120 ( [ s : gc_mps ] ) . mps can dominate relaxation only when they are massive enough to compensate for their small space densities . here we consider only mps with masses @xmath121 . such mps could be molecular clouds of different masses , in particular giant molecular clouds ( gmcs ) , open or globular stellar clusters , and perhaps also imbhs . as discussed below , observations of the galaxy reveal enough mps to dominate relaxation in the central 100 pc . we adopt here a conservative approach , and include in our modeling only those mps that are directly observed in the galaxy , namely gmcs and young clusters . we discuss briefly theoretical predictions for two other classes of mps : dynamically evolved `` submerged '' clusters and imbhs , that could well be common in galactic centers and contribute to efficient relaxation . the dynamically dominant mps are gmcs . emission line surveys of the central @xmath8 pc reveal @xmath8 gmcs with estimated masses in the range @xmath9@xmath122 and sizes of @xmath123 @xcite . we selected individual , reliably identified gmcs in the central @xmath124 of the galaxy ( @xmath8 pc of the gc ) , from the sample observed by @xcite . figure [ f : mp - mf ] shows the empirical gmc mass function using their virial mass estimates as an upper mass limit and adopting a lower limit 10 times smaller , following @xcite who found that lte mass estimates are typically an order of magnitude lower than the virial ones . note that the more recent gmc co1 - 0 molecular line observations by @xcite , which we use here , indicate a more massive and flatter mass function than that derived for their earlier cs1 - 0 molecular line observations @xcite . this is probably due to the higher sensitivity of the co1 - 0 line to lower - density molecular gas ( m. tsuboi , priv . comm . ) . inside the inner @xmath125 of the gc ( a volume smaller or comparable to that of a gmc or a stellar cluster ) , the most massive local structures are the molecular gas clumps observed in the circumnuclear gaseous disk ( cnd ) and its associated spiral - like structures @xcite . their size are @xmath126 pc and their masses are estimated to be in the range @xmath127@xmath128 , where the lower estimates are based on the assumption of optically thin hcn(1 - 0 ) line emission and the upper estimates are based on the optically thick assumption , which also coincides with the virial estimates . it is possible to obtain a model - independent estimate of the effect of the _ observed _ mps on the relaxation time by the directly derived value @xmath129 , which is listed in table [ t : models ] . the observed gmc masses show that @xmath130 on the 100 pc scale , and @xmath131 on the 5 pc scale , a clear indication that mps dominate the relaxation on all relevant lengthscales . where mps exist . for the purpose of our numeric calculations below , it is convenient to describe the differential mass function analytically . here we adopt a power - law @xmath132 parameterization ( or a lognormal probability distribution function ( lnpdf ) in the appropriate cases @xmath133 , where@xmath134 is the log mean and @xmath17is the log standard deviation ) . figure [ f : mp - mf ] shows that the power law distibution is a good fit for the gmcs mass function @xcite , and for the lower estimates of the clusters and gas clumps . for the upper estimates of the clusters and the molecular gas clumps the mfs were found to be better fit by a lognormal distribution , which we used in these cases . it should be emphasized that our results and conclusions are determined primarily by the large values of @xmath45 , and not by the detailed form of the mass function . we repeated our calculations with several alternative distributions and found qualitatively similar results . the assumed high mass cutoff of the mf is important , as it determines the magnitude of @xmath45 . figure [ f : mp - mf ] shows that our models do not extrapolate beyond the maximum observed mp masses ( and even fall below them for gmcs ) . we obtained best fit power indices @xmath135 and lnpdf indices @xmath134and @xmath17 for the lower and upper estimates . the cumulative mass functions and best fits are shown in fig . ( [ f : mp - mf ] ) and listed in table [ t : mps ] . we find @xmath136 for both the lower mass range ( @xmath137 ) and the upper gmc mass range ( @xmath138 ) . the clump mass function has @xmath139 for the lower mass range ( @xmath140 ) and @xmath141 ( @xmath142 for the best power law fit ) for the upper mass range ( @xmath143 ) ( fig . [ f : mp - mf ] and table [ t : mps ] ) . the space density of such clumps falls rapidly inside the inner @xmath144 . stellar clusters are another class of mps , which are of minor dynamical significance in this context . about @xmath145 young stellar clusters with masses in the range @xmath146@xmath128 and sizes of order @xmath147 pc were observationally identified @xcite . again , we fit the lower and upper mass estimates of these clusters ( with mass ranges @xmath148 and @xmath149 , respectively ) with a power - law mass function of a lnpdf , and find @xmath150 and @xmath151 ( @xmath152 for the best power law fit ; see fig . [ f : mp - mf ] and table [ t : mps ] ) . it is interesting to note in passing that both the gmcs and gas clumps and the clusters have bery similar mass functions distributions , but the clusters have a lower mass range , as might be expected if these gmcs are the progenitors of young gc clusters , similar to the relation observed between galactic disk clusters and gmcs @xcite . based on the current observations of the 9 confirmed clusters in the gc , we find that they are dynamically insignificant compared to the gmcs . note however that their contribution to the relaxation is comparable to that of the stars , even when the lower mass estimate is assumed . when the upper mass estimate is assumed , clusters shorten the relaxation time by a factor of 10 ( fig . [ f : tr ] and table [ t : models ] ) . clusters could play a larger role in relaxation if there are many more yet undiscovered ones in the gc . based on dynamical simulations , @xcite suggest that there may be @xmath153 evolved young clusters in the region , undetected against the field stars because of their low surface density . however , @xcite argue that these massive clusters , it they exist , should have been observed . two young gc cluster candidates were recently discovered by @xcite , one of which may be more massive than @xmath154 . it is thus possible that the gc harbors some additional undetected massive clusters , although probably not as many as suggested by @xcite . such young clusters may grow imbhs by runaway stellar collisions ( e.g. @xcite ) , which would then sink to the center by dynamical friction , dragging with them the cluster core . @xcite estimate that many imbhs may have migrated to the central 10 pc of gc in this way , however there is as yet no observational evidence supporting this idea . the mbh s dynamical influence extends up to a radius @xmath155 containing @xmath156 ) mass in stars , which in the gc falls in the range @xmath157@xmath158 pc , depending on the operative definition of @xmath155 and the uncertainties in the value of @xmath159 and of the density of the surrounding stellar cluster ( see @xcite , sec 3.1.2 ) . thus most galactic mps , and in particular the massive ones , lie outside @xmath155 . table ( [ t : mps ] ) summarizes the estimated properties of the observed mps . [ cols="<,^,^,^,^,^,^,^,<",options="header " , ] the maximal differential loss - cone refilling rate , which is also the close encounters event rate , @xmath160 , is reached when relaxation is efficient enough to completely refill the loss cone during one orbit ( eq . [ e : dgde ] ) . further decrease in the relaxation time does not affect the event rate at that energy . mps can therefore increase the differential event rate over that predicted by stellar relaxation , only at high enough energies , @xmath69 ( equivalently , small enough typical radii , @xmath161 ) , where slow stellar relaxation fails to refill the empty loss - cone . the extent of the empty loss - cone region increases with the maximal periapse @xmath5 , which in turn depends on the close encounter process of interest . for example , the tidal disruption of an object of mass @xmath162 and size @xmath163 occurs when @xmath164 , the tidal disruption radius , @xmath165 this approximate disruption criterion applies both for single stars ( @xmath166 , @xmath167 ) and for binaries , where @xmath162 is the combined mass of the binary components and @xmath163 is the binary s semi - major axis , @xmath168 . stellar radii are usually much smaller than typical binary separations , but stellar masses are only @xmath169 times smaller than binary masses . binaries are therefore disrupted on larger scales than single stars . in the gc this translates to an empty ( stellar relaxation ) loss - cone region extending out to @xmath170 pc for single stars and out to @xmath171 pc for binaries . in the gc @xmath172 , and so mps are expected to increase the binary disruption rate by orders of magnitude , but increase the single star disruption rate only by a small factor . this is depicted qualitatively in figure ( [ f : bin ] ) , which shows the local rates ( @xmath173 ) for disruption of single stars and binaries due to stellar relaxation or relaxation by a simplified one component mp model . c + figure ( [ f : bin ] ) also shows that the mp - induced disruption rate is dominated by binaries originating near the _ inner _ cutoff @xmath174 ( in the following discussion the initial orbital energy of the disrupted objects is expressed by the corresponding radius of a circular orbit , @xmath175 ) . this is qualitatively different from the usual case of stellar tidal disruption induced by stellar relaxation , which mainly occurs inside @xmath176 and is dominated by stars originating near the _ outer _ limit @xmath177 ; usually @xmath178 @xcite . the difference can be understood by considering the @xmath61-dependence of @xmath179 . neglecting logarithmic terms , the empty and full local loss - cone rates are , respectively ( eqs . [ e : gempty ] , [ e : gfull])@xmath180\left(\frac{q}{r}\right)\frac{{n_{\star}}(<\ ! r)}{p(r)}\,,\end{aligned}\ ] ] where @xmath181 is the number of stars enclosed within @xmath61 . inside @xmath155 , the potential is dominated by the mbh ( @xmath182 ) , @xmath183 with @xmath184 for most dynamical scenarios ( e.g. @xcite ) and the velocity dispersion is keplerian , @xmath185 . the orbital period scales as @xmath186 and @xmath187 $ ] . the local disruption rates are then @xmath188 and @xmath189 . for plausible values of @xmath190 , @xmath191 increases with @xmath61 whereas @xmath192 decreases with @xmath61 , so the rate is dominated by stars near @xmath68 @xcite . outside @xmath155 , the stellar distribution is usually assumed to be near isothermal , @xmath193 with @xmath194 and a velocity dispersion @xmath195 , and the potential is dominated by the stars ( @xmath196 ) . the orbital period scales as @xmath197 and @xmath198 . the local disruption rates are then @xmath199 and @xmath200 . for @xmath201 both rates increase toward small radii . since for most galactic mp types @xmath202 , the disruption rate is dominated by stars near @xmath119 . for example , when the loss - cone is empty , @xmath203 of the total rate is due to mps at @xmath204 ; when the loss - cone is full , @xmath205 of the total rate is due to mps at @xmath204 . gmcs , gas clumps and clusters in the gc are abundant only beyond the central @xmath206 pc , whereas the empty loss - cone regime for tidal disruption of single stars extends only out to @xmath170 pc . for inspiral processes such as gw emission , @xmath68 is @xmath8 times smaller still @xcite . the effect of such mps on close encounter events involving single stars is thus suppressed ( weaker tidal effects by mps at @xmath207 are not considered here ) . this is contrary to the suggestion of @xcite , who assumed that the effect of mps fully extends to the empty loss - cone regime . we find that the enhancement of mps over stellar relaxation to the single stars disruption rate is small , less than a factor of @xmath208 , and is due to stars scattered by gas clumps in the small empty - loss cone region between @xmath209 and @xmath210 . a possible exception to this conclusion is the hypothesized population of imbhs @xcite , not modeled here , whose distribution could extend to the inner pc ( e.g. the imbh candidate in irs 13 , @xcite , but see @xcite and @xcite ) . the empty loss cone region for binary - mbh interactions extends out to @xmath211 pc because of their large tidal radius . on these large scales mps are abundant enough to dominate the relaxation processes . here we focus on 3-body exchange interactions @xcite , which lead to the disruption of the binary , the energetic ejection of one star , and the capture of the other star on a close orbit around the mbh . various phenomena associated with such exchange interactions were suggested and explored . @xcite and later @xcite , @xcite , @xcite and @xcite , studied hyper - velocity stars ejected from the gc following tidal disruption by the mbh . @xcite suggested this mechanism to explain the origin of the young stars near the galactic mbh . @xcite proposed that compact objects captured following a binary disruption event will eventually be sources of gws from zero - eccentricity orbits , in contrast to high - eccentricity sources typical of single star inspiral @xcite . the event rates estimated by these authors vary substantially . @xcite assumed a full loss - cone and a fraction @xmath212 of the stars in binaries with small enough semi - major axis to produce a high - velocity star ( @xmath213 ) , and derived a 3-body exchange rate of @xmath214 . @xcite took into account the empty loss cone regime , and argued for a higher fraction of relevant binaries ( @xmath215 for binaries with @xmath216 that can survive 0.8 pc from the mbh ) , thereby obtaining a rate of @xmath217 , 3 orders of magnitude smaller than that estimated by hills . these calculations assumed the same binary separation for all binaries and a constant binary fraction at all distances from the mbh ( two possibilities were considered , @xmath218 and @xmath219 ) . the binary fraction and typical binary semi - major axis depend on the binary mass , and on the rate at which binaries evaporate by encounters with other stars . this depends in turn on the stellar densities and velocities , and therefore on the distance from the mbh . here we take these factors into account and estimate in detail the 3-body exchange rate for mp - driven relaxation . the rate is proportional to the binary fraction in the population , which is the product of the poorly - known binary imf in the gc and the survival probability against binary evaporation . we assume for simplicity equal mass binaries , @xmath220 , since the observations indicate that moderate mass ratios dominate the binary population @xcite . the evaporation timescale at distance @xmath61 from the center for a binary of semi - major axis @xmath168 composed of two equal mass stars of mass @xmath221 and lifetime @xmath222 is ( e.g. @xcite ) @xmath223 the coulomb factor for binary evaporation , @xmath224 , expresses the fact that the binary is only affected by close perturbations at distances smaller than @xmath225 . the mps considered here are extended objects ( table [ t : models ] ) and therefore do not affect the binary evaporation timescale ( imbh mps could be a possible exception ) . although binary evaporation is a stochastic process and the actual time to evaporation differs from binary to binary , we expect a small scatter in the evaporation rate , @xmath226 , because evaporation is a gradual process caused by numerous weak encounters . evaporation is thus better approximated as a fixed limit on the binary lifetime , rather than as a poisson process ( where @xmath227 ) . the maximal binary lifetime is then @xmath228 $ ] , where @xmath229 is the hubble time , taken here to be the age of the galaxy . it is well established that the central @xmath230@xmath231 of the gc have undergone continuous star formation over the lifetime of the galaxy @xcite . assuming a constant star formation rate over time @xmath229 , the differential binary distribution at time @xmath232 is @xmath233 , where @xmath234 is the normalized initial semi - major axis distribution , which can be observed in binaries in low - density environments where @xmath235 , and @xmath236 is the single star formation rate , which is normalized to the observed present day stellar density by setting @xmath237 and taking @xmath235 for singles , so that @xmath238 . the present - day binary semi - major axis distribution is therefore @xmath239}\right\ } \,.\label{e : fhard}\end{aligned}\ ] ] the capture probability and the semi - major axis distribution of captured stars were estimated by simulations @xcite . numeric experiments indicate that between @xmath240@xmath241 of the binaries that approach the mbh within the tidal radius @xmath242 ( eq . [ e : rt ] ) are disrupted . here we adopt a disruption efficiency of @xmath243 . the harmonic mean semi - major axis for 3-body exchanges with equal mass binaries was found to be @xcite @xmath244 where @xmath168 is the semi - major axis of the infalling binary and @xmath245 that of the captured star ( the mbh - star `` binary '' ) . most values of @xmath245 fall within a factor @xmath157 of the mean . this relation maps the semi - major axis distribution of the infalling binaries to that of the captured stars : the harder the binaries , the more tightly bound the captured stars . the velocity at infinity of the ejected star ( neglecting the galactic potential ) is @xmath246 ( an equal mass binary with periapse at @xmath247 is assumed ; @xcite ) . the harder the binary , the higher is @xmath248 . the periapse of the captured star is at @xmath247 , and therefore its eccentricity is very high @xcite , @xmath249 for values typical of the gc . we now consider separately the implications of 3-body exchange interactions of the mbh with old ( @xmath250 ) binaries and massive young ( @xmath251 yr ) binaries . the properties of binaries in the inner gc are at present poorly determined . the period distribution of solar neighborhood binaries can be approximated by a log normal distribution with a median period of 180 years ( @xmath252 au ) @xcite . the total binary fraction of these binaries is estimated at @xmath253 @xcite . adopting these values for the gc , the total binary disruption rate by the mbh can then be calculated , as described in [ s : outline ] , by integrating @xmath254 ( eqs . [ e : fhard ] ) over the binary @xmath168 distribution and over the power - law stellar density distribution of the gc up to 100 pc @xcite . table ( [ t : bin ] ) lists the capture rates for the different perturber models , assuming a typical old equal - mass binary of @xmath255 . the old , low - mass binary disruption rate we derive for stellar relaxation alone is @xmath256 , @xmath257 times lower , but still in broad agreement with the result of @xcite . their rate is somewhat higher because they assumed a constant binary fraction and a constant semi - major axis for all binaries , even close to the mbh , where these assumptions no longer hold . mps increase the binary disruption and high - velocity star ejection rates by factors of @xmath258 and effectively accelerate stellar migration to the center . this can modify the stellar distribution close to the mbh by introducing a `` source term '' to the stellar current into the mbh . low - mass stars are at present too faint to be directly observed in the gc . however , such a source term may have observable consequences since it can increase the event rate of single star processes such as tidal disruption , tidal heating and gw emission from compact objects , in particular from compact objects on zero - eccentricity orbits @xcite ( in contrast , gw from inspiraling single stars occur on high - eccentricity orbits , @xcite ) . we calculated numerical solutions of the fokker - planck equation for the stellar distribution around the mbh with a captured stars source term . these preliminary investigations ( perets , hopman & alexander , in prep . ) confirm that the total accumulated mass of captured stars does not exceed the dynamical constraints on the extended mass around the mbh @xcite , because 2-body relaxation and likely also resonant relaxation @xcite scatters enough of them into the mbh or to wider orbits . > p0.6inccccc model & & young stars@xmath259 & young stars@xmath259 & young hvss@xmath260 + & @xmath261 & @xmath262 & @xmath261 & @xmath263 & + gmc1 & @xmath264 & @xmath265 & @xmath266 & @xmath267 & 342 + gmc2 & @xmath268 & @xmath269 & @xmath270 & @xmath271 & 49 + clusters1 & @xmath272 & @xmath273 & @xmath274 & @xmath275 & 1.9 + clusters2 & @xmath276 & @xmath277 & @xmath278 & @xmath279 & 0.1 + stars & @xmath280 & @xmath281 & @xmath282 & @xmath283 & 1.3 + observed & ? & ? & @xmath284 & @xmath285 & @xmath286 + + + + + mps may be implicated in the puzzling presence of a cluster of main sequence b - stars ( @xmath287 ) in the inner @xmath288 ( @xmath289 pc ) of the gc . this so - called `` s - cluster '' is spatially , kinematically and spectroscopically distinct from the young , more massive stars observed farther out , on the @xmath290@xmath240 pc scale , which are thought to have formed from the gravitational fragmentation of one or two gas disks @xcite . there is however still no satisfactory explanation for the existence of the seemingly normal , young massive main sequence stars of the s - cluster , so close to a mbh ( see review of proposed models by @xcite ; also a recent model by @xcite ) . here we revisit an idea proposed by @xcite , that the s - stars were captured near the mbh by 3-body exchange interactions with infalling massive binaries . originally , this exchange scenario lacked a plausible source for the massive binaries . @xcite speculated that they originated in an unusually dense and massive young cluster on an almost radial infall trajectory , but concluded that such a finely - tuned scenario seems unlikely . furthermore , a massive cluster is expected to leave a tidally stripped tail of massive stars beyond the central @xmath240 pc @xcite , which are not observed @xcite . alternatively , it must contain an unusually massive central imbh to hold it together against the tidal field of the gc @xcite . however , such a massive imbh is well beyond what is predicted by simulations of imbh formation by runaway collisions @xcite , or anticipated by extrapolating the @xmath291 relation @xcite to clusters . mp - driven 3-body exchanges circumvent the problems of the cluster infall scenario by directly bringing massive _ field _ binaries to @xmath247 , without requiring massive clusters of unusual , perhaps even impossible properties . the ongoing star formation in the central @xmath8 pc implies the presence of a large reservoir of massive stars there , which are indeed observed in the central @xmath292 pc both in dense clusters and in the field @xcite . it is plausible that a high fraction of them are in binaries . we model the binary population of the gc in the s - stars mass range , @xmath293 , by assuming equal mass binaries that follow the single star mass function with an initial binary fraction of @xmath294 , as observed elsewhere in the galaxy ( @xcite ) . because the stellar evolutionary lifespan of such stars is relatively short , massive binaries are essentially unaffected by dynamical evaporation . we assume star formation at a constant rate for 10 gyr with a miller - scalo imf @xcite , and use a stellar population synthesis code @xcite with the geneva stellar evolution tracks @xcite to estimate that the present day number fraction of stars in the s - star mass range is @xmath295 ( and less than 0.01 of that for @xmath296 stars ) . note that if star formation in the gc is biased toward massive stars @xcite , this estimate should be revised upward . we adopt the observed solar neighborhood distribution of the semi - major axis of massive binaries , which is log - normal with @xmath2970.6 au ( i.e. 63% of the binaries with @xmath298 au ; 91% with @xmath299 au ) @xcite . massive binaries are thus typically harder than low - mass binaries , and will be tidally disrupted ( eq . [ e : rt ] ) closer to the mbh and leave a more tightly bound captured star . we represent the massive binaries by one with equal mass stars in the mid - range of the s - stars masses , with @xmath300 and @xmath301 , and integrate over the stellar distribution and the binary @xmath168 distribution as before , to obtain the rate of binary disruptions , @xmath302 , the mean number of captured massive stars in steady state , @xmath303 , and their semi - major axis distribution ( eq . [ e : afinal ] ) . table ( [ t : bin ] ) compares the number of captured young stars in steady state , for the different mp models , on the @xmath261 scale ( the s - cluster ) and @xmath304 pc scale ( the stellar rings ) with current observations @xcite . the s - stars are found in the central @xmath305 pc @xcite . if they were captured by binary disruptions , they must have originated from massive binaries with @xmath306 au . this is consistent with semi - major axis distribution of massive binaries . the number of captured massive stars falls rapidly beyond @xmath307 pc ( table [ t : bin ] ) because wide massive binaries are rare . this capture model thus provides a natural explanation for the central concentration of the s - cluster ( fig [ f : scluster ] ) . the absence of more massive stars in the s - cluster ( @xmath296 , spectral type ov ) is a statistical reflection of their much smaller fraction in the binary population . figure ( [ f : scluster ] ) and table ( [ t : bin ] ) compare the cumulative semi - major axis distribution of captured b - stars , as predicted by the different mp models , with the total number of young stars observed in the inner 0.04 pc ( @xmath308 stars , @xcite ) . of these , only @xmath309 have full orbital solutions ( in particular @xmath168 and @xmath310 ) at present . for the others we assume the _ ansatz _ that @xmath168 is similar to the observed projected position . the numbers predicted by the gmc - dominated mp models are consistent with the observations , unlike the stellar relaxation model that falls short by two orders of magnitude . the binary capture model predicts that captured stars have very high initial eccentricities . most of the solved s - star orbits do have @xmath311 , but a couple have @xmath312@xmath313 @xcite . normal , non - coherent stellar relaxation is slow , even after taking into account the decrease in @xmath6 toward the center due to mass segregation @xcite . it is unlikely that it could have decreased the eccentricity of these stars over their relatively short lifetimes . however , the much faster process of resonant relaxation @xcite may be efficient enough to randomize the eccentricity of a fraction of the stars , and could thus possibly explain the much larger observed spread in eccentricities @xcite . additional orbital solutions and a better estimate of the efficiency of resonant relaxation in the gc are required for more detailed comparisons between observations and the mp model predictions . each captured star is associated with an ejected companion , which in some cases is launched with a very high velocity . the one - to - one correspondence between the number of captured s - stars and the number of early - type hyper - velocity stars ( hvss ) is thus a generic prediction of binary capture models . the mp capture scenario specifically implies the continuous and isotropic ejection of both young and old hvss from the gc . recent observations of hvss @xcite are consistent with a gc origin and favor a steady state temporal distribution and an isotropic spatial distribution over a burst - like non - spherical distribution that is expected for hvss triggered by the infall of a cluster @xcite . two of the recently observed hvss ( @xmath314@xmath315 , @xcite ) were spectrally identified as late bv young massive stars ( masses of @xmath208@xmath316 , ms lifespans of @xmath317@xmath318 yr and number fraction @xmath319 in the population ) , implying a total population of @xmath320 such hyper - velocity stars in the galaxy @xcite . we model the parent binaries of these hvss by equal mass binaries of @xmath321 and @xmath322 . the ejection velocity was found in numerical simulations @xcite to scale as@xmath323 to reproduce the high hvs velocities we consider binaries with @xmath324 au , which are tidally disrupted at @xmath325 pc and eject a hvs with @xmath326 , the escape velocity from the bulge @xcite . taking only the gmcs into account , we predict that tens to hundreds such hvss exist in the galaxy , in agreement with the deduced hvs populations , whereas stellar relaxation predicts only 1.3 such stars ( see table [ t : bin ] ) . we note @xcite used the @xmath327 total rate of hyper - velocity star ejection calculated by @xcite ( including binaries of all stellar types , assuming stellar relaxation only and normalized to a fiducial 10% binary fraction ) to estimate the number of late bv hvss in a salpeter imf at @xmath145@xmath328 . this theoretical prediction seems in rough agreement with the observations ( and contradicts our much lower estimate of 1.3 hvss ) . however , the rates of yu & tremaine are inapplicable here and lead to a significant over - estimate of the number of hvss because their binary population model is not appropriate for massive binaries in the gc . on the one hand , the young binary population does not extend all the way to the center , as assumed by yu & tremaine for the general binary population ( following @xcite who do not find any bv stars between 0.51 pc of the gc , we truncate the massive binary population inside 1.5 pc ) . the massive binary population in the gc is @xmath329 times smaller than implied by a simple scaling of the yu & tremaine general binary population . on the other hand , the binary fraction of young massive binaries is 70% rather than 10% ( [ sss : youngbin ] ) . we conclude that the agreement found by brown et al . is accidental , and that binary disruption by stellar relaxation is insufficient to explain the number of observed hvss , whereas mp - induced relaxation can reproduce the observations . relaxation by mps dominates relaxation by 2-body stellar interactions when the ratio between the 2nd moments of their respective mass functions satisfies @xmath330 . we show that galactic mps ( stellar clusters , gmcs and smaller molecular gas clumps that exist outside the inner few pc ) dominate and accelerate relaxation in the inner @xmath8 pc of the gc . this is plausibly the case in the centers of late - type galaxies in general . there is also evidence for molecular gas in the centers of late - type galaxies ( e.g. @xcite ) , which suggests that mps may dominate relaxation there as well , and lead to the relaxation of the central regions of galactic bulges in general . relaxation determines the rate at which stars and binaries are deflected to near radial ( loss - cone ) orbits that bring them closer to the mbh than some critical periapse @xmath5 , where they undergo a strong destructive interaction with it . the size of @xmath5 depends on the nature of the interaction of interest ( e.g. tidal disruption , 3-body exchange ) . it is much larger for binaries than for single stars due to the binary s larger effective size . we extend loss - cone theory to approximately treat rare encounters with mps , and apply it to explore the implications of mps on the rates of different types of close encounters . the rate reaches its maximum when loss - cone orbits are replenished by scattering within an orbital time ( the full loss - cone regime ) . this is more easily achieved when the phase - space volume of the loss - cone is small , that is , when @xmath5 is small . mps thus affect only those processes with large @xmath5 whose loss - cone is too large to be efficiently replenished by stellar encounters ( the empty loss - cone regime ) . we show that mps will not contribute much to the disruption of single stars in the gc , whose loss - cone is efficiently replenished by stars outside the central @xmath169 pc ( mps may accelerate the consumption of stars by more massive mbhs , where @xmath5 is significantly larger , or the capture of stars in accretion disks ) . however , mps will enhance by factors of 101000 the tidal disruption rate of infalling binaries , which result in the capture of one of the stars on a tight orbit around the mbh , and the ejection at high velocity of the other star @xcite . the enhancement of the event rates is dominated by the innermost mps , and so the uncertainty in the mp distribution on the smallest scales dominates the uncertainties in the total event rate . detailed observations of mps in the inner gc allow us to robustly predict their effects in the galaxy . we show that mp - induced disruptions of relatively rare massive binaries can naturally explain the puzzling presence of normal - appearing main sequence b stars in the central @xmath307 pc of the gc @xcite , and at the same time can account for the observed hvss well on their way out of the galaxy @xcite . tidal disruptions of the many more faint low - mass binaries can efficiently supply single stars on very eccentric tight orbits near the mbh . such an increase in the numbers of stars in tight orbit near the mbh may increase the rates of single star processes such as tidal disruption and heating or gw emission from tightly bound compact objects @xcite . finally , mp - induced interactions also have cosmological implications for the coalescence of binary mbhs following galactic mergers @xcite . we suggest that mps can accelerate the dynamical decay of binary mbhs by efficiently supplying stars for the slingshot mechanism , and thereby help solve the `` last parsec '' stalling problem . mp - driven loss - cone refilling will operate even in the case of a spherical potential , where other suggested mechanisms are inefficient , thus allowing mbhs to coalesce on the dynamical timescale of the galactic merger . a detailed treatment of this idea will be presented elsewhere ( perets & alexander , in prep . ) . , t. , genzel , r. , martins , f. , nayakshin , s. , beloborodov , a. m. , levin , y. , trippe , s. , eisenhauer , f. , ott , t. , gillessen , s. , abuter , r. , cuadra , j. , alexander , t. , & sternberg , a. 2006 , , 643 , 1011 , j. a. 2002 , in the shapes of galaxies and their dark halos , proceedings of the yale cosmology workshop the shapes of galaxies and their dark matter halos , new haven , connecticut , usa , 28 - 30 may 2001 . edited by priyamvada natarajan . singapore : world scientific , 2002 , isbn 9810248482 , p.123 , ed . p. natarajan , 123+

we study the role of massive perturbers ( mps ) in deflecting stars and binaries to almost radial ( `` loss - cone '' ) orbits , where they pass near the central massive black hole ( mbh ) , interact with it at periapse , and are ultimately destroyed . mps dominate dynamical relaxation when the ratio of the 2nd moments of the mp and star mass distributions , @xmath0 , satisfies @xmath1 . we compile the mp mass function from published observations , and show that mps in the nucleus of the galaxy ( mainly giant molecular clouds ) , and plausibly in late type galaxies generally , have @xmath2 . mps thus shorten the relaxation timescale by @xmath3 relative to 2-body relaxation by stars alone . we show this increases by @xmath4 the rate of _ large_-periapse interactions with the mbh , where loss - cone refilling by stellar 2-body relaxation is inefficient . we extend the fokker - planck loss - cone formalism to approximately account for relaxation by rare encounters with mps . we show that binary stars mbh exchanges driven by mps can explain the origin of the young main sequence b stars that are observed very near the galactic mbh , and increase by orders of magnitude the ejection rate of hyper - velocity stars . in contrast , the rate of _ small_-periapse interactions of single stars with the mbh , such as tidal disruption , is only increased by a factor of a few . we suggest that mp - driven relaxation plays an important role in the 3-body exchange capture of single stars on very tight orbits around the mbh . these captured stars may later be disrupted by the mbh via tidal orbital decay or direct scattering into the loss cone ; captured compact objects may inspiral into the mbh by the emission of gravitational waves from zero - eccentricity orbits .

novae are all semi - detached binary systems where a late - type star transfers mass to a white dwarf companion @xcite . a thermonuclear runaway eventually ensues in the material accreted onto the surface of the white dwarf resulting in the nova explosion @xcite . the resulting release of energy ( @xmath4 @xmath5 @xmath6 ergs ) is sufficient to expel the accreted envelope and drive substantial mass loss ( @xmath7@xmath8 m@xmath9 ) from the system at high velocities ( @xmath4several hundreds to a few thousand km s@xmath10 ; * ? ? ? novae exhibit outburst amplitudes of roughly 10 to 20 mag , and can reach peak luminosities as high as m@xmath11 , second only to grb and supernovae in the energetics of their outbursts , but far more frequent in a given galaxy than either . their high luminosities and rates ( @xmath12 yr@xmath10 in a galaxy like m31 [ shafter & irby 2001 ; darnley et al . 2006 ] ) , make novae powerful probes of the properties of binary star systems in different ( extragalactic ) stellar populations . the rapid formation of copious amounts of dust in many novae post - outburst also makes them unique laboratories in which to explore cosmic dust grain formation @xcite . models show that properties of the eruption ( e.g. the peak luminosity and the decline rate ) are strongly dependent on parameters such as the accretion rate , and the mass and luminosity of the white dwarf ( e.g. , * ? ? ? * ) , some or all of which may vary systematically with the underlying stellar population . the strength of the nova outburst is most sensitive to the mass of the accreting white dwarf , with the increased surface gravity of a more massive white dwarf resulting in a higher pressure at the base of the accreted envelope at the time of thermonuclear runaway and a more violent outburst . in addition , since a smaller mass of accreted material is required to achieve the critical temperature and density necessary for a runaway , nova outbursts produced on massive white dwarfs are expected to have shorter recurrence times and faster light curve evolution @xcite . further , since the mean white dwarf mass in a nova system is expected to decrease as a function of the time elapsed since the formation of the progenitor binary ( e.g. , * ? ? ? * ; * ? ? ? * ) the proportion of fast and bright novae is expected to be higher in a younger stellar population , which should contain on average more massive white dwarfs . @xcite became the first to formally postulate the existence of two populations of novae : a relatively young population of `` disc novae '' , which are found in the solar neighborhood and in the lmc , and `` bulge novae '' , which are concentrated towards the galactic center and in the bulge of m31 , and are characterized by generally slower outburst development . the argument in favor of two nova populations was further developed by @xcite , who showed that the average scale height above the galactic plane for `` fast '' novae ( @xmath13 d is the time in days a nova takes to decline by two magnitudes from maximum light . ] ) is smaller than for novae with slower rates of decline . at about the same time , @xcite was proposing that classical novae could be divided into two classes based on their spectral properties : specifically , the relative strengths of either their fe ii or he and n emission lines . novae with prominent fe ii lines ( `` fe ii novae '' ) usually show p cygni absorption profiles , tend to evolve more slowly , have lower expansion velocities , and have a lower level of ionization , compared with novae that exhibit strong lines of he and n ( `` he / n novae '' ) . in addition , the latter novae display very strong neon lines , but not the forbidden lines that are often seen in the fe ii novae . following up on their earlier work , @xcite noted that galactic novae with well determined distances that were classified as he / n were concentrated near the galactic plane , and tended to be faster , and more luminous compared with their fe ii counterparts . infrared observations offer another avenue for the study of nova populations . models for thermonuclear runaways on the surfaces of white dwarfs predict that the ejecta will contain not only accreted gas , but material dredged up from the white dwarf as well . thus , spectroscopic analysis of the ejecta offers an opportunity to distinguish between eruptions that occur on co white dwarfs and those occurring on more massive one white dwarfs @xcite . eruptions occurring on co white dwarfs are expected to produce a significant amount of dust , mainly in the form of carbon grains that shroud the central source , and result in warm ( @xmath41000 k ) blackbody emission that peaks in the near ir ( @xmath14 ) @xmath15 months after eruption ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? on the other hand , eruptions seated on the more massive one white dwarfs are believed to produce strong forbidden lines of neon ( [ ne ii ] @xmath2 and [ ne vi ] @xmath16 ) , but little or no dust . the first observational support for a class of novae occurring on massive one white dwarfs was found more than twenty years ago when @xcite discovered that the [ ne ii ] @xmath2 emission line in qu vul ( @xmath17 ) reached a flux level @xmath18 times that of the free - free continuum more than four months after eruption . at the time , this was the strongest @xmath2 emission line seen in any astrophysical object . since that time several additional galactic novae with an overabundance of ne have been discovered , and they are collectively referred to as `` neon '' novae @xcite . it appears that up to one - third of novae are of this type , with the remainder being co novae . although much can and has been learned from the study of galactic novae , the nearby spiral m31 , where more than 800 nova candidates have been discovered over the past century ( e.g. * ? ? ? * and references therein ) , offers a unique opportunity to study an equidistant sample of novae from differing stellar environments ( bulge and disk ) while minimizing some of the uncertainties that plague galactic observations ( e.g. , highly variable extinction along the lines of sight to different novae ) . with this motivation in mind , we are currently involved in a multi - wavelength program of photometric and spectroscopic follow - up observations of novae discovered in m31 @xcite . as a part of this effort focusing on the nature of the white dwarfs ( co vs one ) , we have obtained both ir photometric and spectroscopic observations of a sample of 10 novae in m31 using the irac and irs instruments on board the _ spitzer _ space telescope . here , we present the results of our survey . in order to search for dust formation in a sample of m31 novae we initiated a program of _ spitzer _ infrared array camera ( irac ; * ? ? ? * ) and infrared spectrograph ( irs ; * ? ? ? * ) observations in early 2007 and 2008 . our observing strategy called for the observations to be triggered approximately three months after discovery of a nova . however , due to the vagaries of _ spitzer _ scheduling , our observations were typically executed anywhere from 3 to as long as 7 months after eruption . during the first year of observations , the same 4 novae were observed with both irac and the irs . the results from the irs observations were disappointing , with no line emission detected in any nova , and continuous emission detected in just two of the novae . we concluded that most novae had likely faded beyond detectability by the time the irs observations were scheduled . in order to increase the probability of detection , in the second epoch of observations , we were able to modify our irs target list to include two more recent novae for observation : m31n 2007 - 11d and 2007 - 11e , resulting in line emission being detected in one of these novae . our _ spitzer _ observations are summarized in table [ spitzersummary ] . irac data were obtained in all four irac bands ( @xmath19 , @xmath20 , @xmath21 , @xmath22 ) . the irac observations consisted of a 12 point reuleaux dither pattern with a medium scale factor . a single 100 sec frame was obtained at each dither position , resulting in a total of @xmath41200 sec of exposure in each band . source extraction and photometry were performed on the post - bcd ( basic calibrated data ) mosaics produced by the _ science center ( ssc ) , pipeline version 18.5 . the extractions and determination of uncertainties were performed using version 2.1 of the idl program atv , written and maintained by @xcite . due to the crowded nature of the observed fields along with rapidly varying background levels , it was necessary to use apertures of minimal size to avoid contamination from neighboring objects . therefore we chose an aperture size of radius 2 pixels for each extraction . we used the nominal positions of the novae as determined by visual photometric observations , along with an atv 3-pixel - radius centering box , to determine the center for each aperture used in extraction . aperture correction factors , derived by the ssc and provided in the irac data handbook 3.0 , were then used to estimate the true flux of the novae based on the measured flux in each aperture . finally , we determined the background level for each aperture using an annulus of inner radius of 2 pixels and outer radius 6 pixels . the energy distributions for the six novae detected by irac are shown in figure [ iracsed ] and summarized in table [ iractab ] . irs data were obtained in the low resolution sl1 module , covering a wavelength range of @xmath23 . the irs data were obtained using 24 cycles of 60 sec ramps . as each cycle of an irs observation consists of two nod positions , this resulted in a total of @xmath42880 sec of on - source integration time per target . the irs data were analyzed in the smart package @xcite using optimal extraction @xcite . the bcd ( basic calibrated data ) products were cleaned using the irsclean tool with campaign specific masks before all 2d spectra at a given nod position were combined into a single image . for our observations , this resulted in two @xmath41440 sec cleaned two dimensional spectra . prior to spectral extraction , the two nod positions were subtracted from each other to remove the background and mitigate rogue pixels not present in the masks . the spectral extraction was performed on these background subtracted images . for each object , we selected the `` manual optimal extraction '' option in smart . the position of the irs slit was projected on our irac images to verify that we were extracting spectra for the correct object . a visual inspection of the two dimensional spectra revealed that only 2 objects ( m31n 2006 - 09c and 2006 - 10a ) had clear traces at the nominal source position . for the remaining objects ( with the exception of m31n 2007 - 11e , see below ) , we extracted spectra at the nominal source position in each nod position . as expected from the visual inspection of the two dimensional spectra , no sources were detected . in the case of m31n 2006 - 09c , the nova was the only detected source . the spectrum of m31n 2006 - 09c was extracted using the optimal extraction algorithm with a background order of one ; even though background subtraction was accomplished to first order by subtracting nod positions , residual structure was still present owing to the variation of the local background between the nod positions . in the case of m31n 2006 - 10a , there were two objects detected , the brighter nova at the nominal position in the slit as well as a fainter source offset by @xmath43 pixels ( @xmath45 ) . to extract m31n 2006 - 10a , two sources were specified and the extraction algorithm was allowed to fit the trace within one pixel of the nominal position ( for the nova ) and between one and four pixels from the nominal position for the contaminating source . in the case of m31n 2007 - 11e , no source was apparent save for a faint line at the position of [ ne ii ] @xmath2 . for m31n 2007 - 11e , we forced the extraction aperture to be centered on the nominal source position for each nod . for all three objects , spectra extracted at each nod position were clipped at the order edges and combined . the spectra extracted for m31n 2006 - 09c and 2006 - 10a are shown in figure [ irsed1 ] and the extracted spectrum of m31n 2007 - 11e is shown in figure [ irsed2 ] . to complement our _ spitzer _ observations , we attempted to obtain optical photometric time - series of several novae in our survey using the liverpool telescope ( lt , * ? ? ? * ) , primarily to measure the peak nova brightness and rate of decline ( @xmath24 ) . the lt data were reduced using a combination of iraf and starlink software . these data were calibrated with standard stars from @xcite and checked against secondary standards from @xcite , @xcite , and @xcite . these observations were augmented by the extensive photometric database compiled by one of us ( kh ) as part of an on - going program to monitor nova light curves in m31 . the latter observations include both survey and targeted images taken with the 0.35-m telescope of private observatory of kh at lelekovice , the 0.65-m telescope of the ondejov observatory ( operated partly by the charles university , prague ) , and the 0.28-m telescope of the zln observatory . standard reduction procedures for raw ccd images were applied ( bias and dark - frame subtraction and flat - field correction ) using sims and munipack programs . reduced images of the same series were co - added to improve the s / n ratio ( total exposure time varied from ten minutes up to about one hour ) . the gradient of the galaxy background of co - added images was flattened by a spatial median filter using sims . these processed images were then used to search for novae . photometry was performed using `` optimal photometry '' ( based on fitting of psf profiles ) in gaia , and calibrated with standard stars from @xcite . of the ten novae observed by _ spitzer _ we were successful in obtaining a series of photometric observations for five of the novae . the results of these observations are summarized in tables [ phot1 ] [ phot5 ] , with the resulting light curves shown in figures [ lc1 ] [ lc3 ] . in addition to our ground - based photometric observations , we also attempted to obtain optical spectroscopic observations of each nova using the low resolution spectrograph ( lrs ; * ? ? ? * ) on the hobby - eberly telescope ( het ) . we used either the @xmath25 grating with a 1.0@xmath26 slit and the gg385 blocking filter covering 415011000 at a resolution of @xmath27 , or the @xmath28 grating with a 2.0@xmath26 slit and the gg385 blocking filter , covering 42757250 at a resolution of @xmath29 . when employing the lower - dispersion @xmath25 grating , we limited our analysis to the 41509000 wavelength range where the effects of order overlap are minimal . the spectra were reduced using standard iraf routines to flat - field the data and to optimally extract the spectra . a summary of all the het observations is given in table [ hettab ] . because the observations were made under a variety of atmospheric conditions with the stellar image typically overfilling the spectrograph slit , our data are not spectrophotometric . thus , the data have been displayed on a relative flux scale . spectra were successfully obtained for eight of the ten novae observed by _ these data , which were obtained primarily to ascertain the spectroscopic classes @xcite and ejection velocities of the novae , are shown in figures [ het1 ] [ het3 ] , and are summarized in tables [ emission ] and [ spatpos ] . spectroscopic classes for the two novae that we were unable to observe , m31n 2007 - 07f and 2007 - 08a , were available through spectra obtained by @xcite and @xcite , respectively . seven of the ten novae in our sample clearly belong to the fe ii class , which is characterized by relatively narrow balmer and fe ii emission . of the remaining three , m31n 2006 - 10b was a hybrid " nova ( a broad - lined fe ii system that later evolved into a he / n system ) , while m31n 2007 - 08a was described by @xcite as an fe ii ( or possibly a hybrid ) nova . the large balmer emission line widths seen in m31n 2006 - 10b are typical of what is found in he / n novae ; however , the relatively narrow lines exhibited by 2007 - 08a are more characteristic of the fe ii class . the remaining nova , m31n 2007 - 10a , is quite peculiar spectroscopically ( see figure [ het2 ] ) . the spectrum displays narrow emission characteristic of the fe ii novae , but in addition to balmer emission , shows prominent he i lines rather than fe ii emission . the spatial positions of the 10 novae in our _ spitzer _ sample are shown in figure [ spat ] . as has been demonstrated by @xcite from a larger sample of novae , there is no evidence that the spatial distribution of fe ii and he / n novae differ in m31 ( see also * ? ? ? of the 8 novae observed by irac , only m31n 2006 - 10a shows clear evidence of an infrared excess in the irac bands , peaking at @xmath30 ( see fig . [ irsed1 ] ) . m31n 2007 - 07f shows evidence for a rather weaker , slightly longer wavelength excess ( see fig . [ iracsed ] ) . we may associate such excess emission with that from dust grains condensing in the ejecta of each nova , as has been observed in many galactic novae see section 1 . both m31n 2006 - 10a and 2007 - 07f belong to the fe ii spectroscopic class , and both can be considered relatively slow " novae with decay times of @xmath31 and @xmath3250 days , respectively . to further explore the relationship between dust formation timescales and nova speed class , we have augmented our m31 sample with available data on galactic dust - forming novae . a summary is presented in table [ dust ] . in figure [ tcond ] we have plotted the condensation time , @xmath33 , of dust grains in galactic novae against @xmath34 . dust condensation times for this plot have been taken from table 13.1 of @xcite and times of dust breaks in d - type novae from @xcite . in general , these are consistent within a few days , but we have taken the earlier quoted time in each case , if they are both available for a given nova . speed class , in terms of @xmath34 , has been taken from @xcite . we have also plotted the two suspected dusty m31 novae on figure [ tcond ] , where @xmath33 is likely to be an upper limit in both instances ( i.e. we have not necessarily observed the onset of the dust formation event ) . note that for m31n 2006 - 10a and 2007 - 11d , we have used @xmath34(@xmath35 ) but as this was unavailable for the other m31 novae , we have used @xmath34(@xmath36 ) . there is a clear trend for the galactic novae in the sense that the faster novae tend to form grains earlier than the slow novae . an outlier is nova pw vul . @xcite note that this nova had a very erratic early optical light curve which resembled dq her , but showed no deep minimum as did the latter , archetypal dust - forming nova . indeed pw vul s dust shell was also low mass and optically thin and the quoted value of @xmath37 days was calculated by @xcite from the angular expansion rate of the pseudo - photosphere and the maximum flux of the outburst . this is consistent with the time of first condensation being in the observational gap between 100 and 290 days post - outburst . also shown as a lower limit on this plot is the dust condensation time for qu vul , given by @xcite as 40200 days ( we will return to this object below ) . marking an extreme point on the plot is nova v445 pup . a dust extinction dip is clearly seen in its light curve and ( relatively sparse ) infrared photometry thereafter confirms the presence of an extensive dust shell , but this is an example of a very rare helium nova outburst ( see * ? ? ? * and references therein ) . the apparent correlation between @xmath33 and @xmath24 is perhaps surprising . if we assume a constant central source luminosity , @xmath38 , and outflow velocity , @xmath39 , for a given nova , and that the grain condensation temperature , @xmath40 , is constant from nova to nova , we can write ( e.g. , * ? ? ? * ) : @xmath41 adopting available empirical relations between @xmath39 and @xmath24 , and between @xmath38 and @xmath24 ( the maximum - magnitude vs rate - of - decline relation ) such as those given in @xcite , we find that @xmath42 and @xmath43 . after inserting these relations into eqn ( 1 ) , it appears that @xmath33 should be essentially independent of nova speed class ! clearly , the empirical correlation shown in figure [ tcond ] justifies further investigation , but as pointed out by @xcite , dust grain nucleation and growth rely on a complex set of parameters . finally , it should be noted that not all novae form detectable amounts of dust , with examples at both ends of the range of speed class ( e.g. v1500 cyg versus hr del ; * ? ? ? the reasons for this have been explored by various authors ( e.g. , * ? ? ? * ; * ? ? ? * ) but are not fully understood . figure [ tirmax ] shows a plot of nova speed class versus the time of maximum infrared flux , @xmath44 , as observed in galactic novae . since @xmath44 is not available for our m31 novae , we have instead plotted the speed class and time after discovery ( approximate optical maximum ) for the novae observed with irac . both m31n 2006 - 10a and 2007 - 07f are marked on the plot . again there appears to be a trend of increasing @xmath44 with speed class for the galactic novae , with the exception of qu vul . we may note however that this is the time of the maximum flux observed in the @xmath45 silicate feature in this nova by @xcite at @xmath46 days , and not necessarily the time of maximum continuum emission from grains in the expanding shell , which may have been ( much ) earlier . indeed , an observation on day 206 for this nova by @xcite showed that at this time emission from graphitic dust clearly dominated the @xmath45 continuum in qu vul . from figure [ tirmax ] , it appears that m31n 2006 - 10a may have been observed by _ spitzer _ nearer the time of the infrared emission maximum than 2007 - 07f , which again is consistent with the higher dust shell luminosity and inferred dust temperature in 2006 - 10a compared to 2007 - 07f . indeed , m31 2006 - 10a might have been observed not too long after @xmath33 at around the time of @xmath44 . evidence for this comes from its position on figs . [ tcond ] and [ tirmax ] , coupled with @xmath47 ( @xmath48k ) being much lower than @xmath40 ( @xmath49k ) . there is in fact a steep drop in observed effective dust grain temperature in well observed dusty novae coinciding approximately with infrared maximum arising from what @xcite termed the infrared pseudo - photosphere " in the optically thick ( in the infrared ) dust shells of prolific dust formers such as nq vul @xcite . as the dust formation rate reduces in the expanding shell , the observed optical depth also reduces and @xmath47 increases again . @xcite found even better agreement with observations if grains were subject to some size reduction around the time of infrared maximum , possibly due to sputtering . in nq vul the temperature minimum lasted from around 62 to 130 days post - outburst . all but one of the faster m31 novae lie above the region occupied by the galactic novae at infrared maximum ( the exception being m31n 2006 - 11a ) . the non - detection of dust emission in these objects may then be due to them either being observed well after dust emission maximum , or the fact that they did not produce large amounts of dust in the first place . the latter appears to be the case for 2006 - 11a at least , as it does lie in the region of the plot occupied by the dusty galactic novae . we may estimate the total mass of dust in m31n 2006 - 10a , @xmath50 , assuming an isothermal , optically - thin dust shell of uniform spherical grains of radius @xmath51 from the equation @xmath52 where @xmath53 is the distance , @xmath54 the bulk density of the grain material , @xmath55 the observed flux density at wavelength @xmath56 , @xmath57 the planck function at @xmath56 and grain temperature @xmath58 , and @xmath59 the grain absorption coefficient . if @xmath60 for small dielectric absorbers , it can be shown that @xmath61 where @xmath62 is the wavelength of maximum emission in @xmath63 . in the case of m31n 2006 - 10a , the irs spectrum in figure[irsed1 ] shows no apparent @xmath45 silicate feature , and the emitting grains are more likely carbon - based , as seen at some point in the evolution of most dust - forming novae @xcite . taking for simplicity graphite spheres of size small compared with the wavelength of emission , then @xmath64 @xcite . thus with @xmath65 , @xmath66 k , and if @xmath67 , then @xmath68 ( * ? ? ? * although this neglects any temperature dependence of the absorption coefficient ) . taking @xmath69 kg m@xmath70 @xcite , and a distance to m31 of 780 kpc @xcite then @xmath71 m@xmath72 . this is consistent with the range of dust masses derived for galactic novae , particularly the more prolific dust - formers ( see e.g. , * ? ? ? we have conducted the first infrared survey of novae in the nearby spiral , m31 , using the _ spitzer _ space telescope . the primary motivation behind the survey was to determine the feasibility of using _ spitzer _ observations of m31 novae to study dust formation property as a function of nova speed class and spectroscopic type . we observed a total of 10 novae in m31 with _ spitzer _ over a two year period : m31n 2006 - 09c , 2006 - 10a , 2006 - 10b , 2006 - 11a , 2007 - 07f , 2007 - 08a , 2007 - 08d , 2007 - 10a , 2007 - 11d , and 2007 - 11e . eight of these novae were observed with irac ( all but m31n 2007 - 11d and 2007 - 11e ) and 8 with the irs ( all but m31n 2007 - 07f and 2007 - 08a ) , with 6 novae observed with both instruments . observations of galactic novae show that dust formation typically occurs with a timescale , @xmath33 , of between @xmath73 and @xmath74 months post - eruption ( mean @xmath75 months ) , depending on the speed class of the nova . for a typical nova , the peak infrared signature occurs shortly thereafter , with the time to infrared maximum , @xmath44 , averaging about 3 months post - eruption . thus , our observing strategy was to schedule our _ spitzer _ observations approximately 3 months post discovery when the infrared signature due to dust formation was expected to reach a maximum . unfortunately , the constraints imposed by the _ spitzer _ scheduling process did not allow us to time our observations as precisely as we would have liked , and our observations occurred anywhere between @xmath0 and @xmath1 months post eruption . our principal conclusions can be summarized as follows : * ( 1 ) * we were able to detect six of the eight novae observed with irac . of these , only m31n 2006 - 10a showed clear evidence for an infrared excess peaking at @xmath30 . the irs spectrum of this nova showed no evidence of silicate emission features and thus we assume that the dust was carbon - based in this case . we were then able to estimate the total mass of dust formed to be @xmath76 m@xmath9 . this is comparable to the mass of dust found in galactic novae forming the more extensive dust shells . another nova , m31n 2007 - 07f , showed evidence of possible dust formation through a weaker infrared excess detected to peak at longer wavelength . our observations of these two novae occurred 116 and 203 days post discovery , respectively . thus , it is plausible that that our observations of m31n 2007 - 07f occurred after the peak ir flux was achieved as suggested by our comparison with the times of infrared maximum in galactic dust - forming novae . both novae are fe ii systems with relatively slow light curve evolution : @xmath77 d and @xmath78 d , respectively . * ( 2 ) * we find a surprising correlation between the condensation time for dust grains ( @xmath33 ) and nova speed class ( @xmath24 ) for galactic novae ( see fig . [ tcond ] ) . although upper limits , the values of @xmath33 for the two m31 novae with detected ir excesses are consistent with this correlation . most of the m31 novae in our sample , which have @xmath79 , were likely observed too long after dust condensation for us to detect an ir excess in our data . one exception is m31n 2006 - 11a , which is a moderate - speed - class , fe ii nova observed less than 3 months after discovery . a comparison with galactic dust - forming novae ( see fig [ tirmax ] ) shows that an ir excess likely would have been visible assuming dust formation had taken place . * ( 3 ) * three of the eight novae observed with the irs were detected : m31n 2006 09c and 2006 - 10a showed only continuum emission , while 2007 - 11e revealed a [ ne ii ] @xmath2 emission feature characteristic of the class of neon novae " . other than its neon emission , m31n 2007 - 11e , is fairly unremarkable in other respects , being neither a particularly fast or slow fe ii system . our preliminary survey has demonstrated that ir observations can be used to detect dust formation in m31 novae . it is likely that those novae that went undetected were observed too long after maximum light when the dust had cooled sufficiently to render the ir flux below our limit of detection . future observations , possibly from the ground , of a larger sample of novae will be required to further characterize the relationship between nova speed class , spectroscopic type , and dust formation timescales . the correlations we find between speed class and @xmath33 and @xmath44 will greatly assist observational planning . the work presented here is based in part on observations obtained with the hobby - 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24 june 1994 publisher : dordrecht kluwer academic publisher : s , 1995 . edited by a. bianchini , m. della valle , and m. orio . astrophysics and space science library , vol . 205 , p.495 . warner , b. 1995 , in _ cataclysmic variable stars _ , cambridge university press . warner , b. 2008 , in classical novae , 2nd ed . , edited by m. bode and a. evans , cambridge university press , p. 16 williams , r. e. 1992 , , 104 , 725 woudt , p. a. , et al . 2009 , , 706 , 738 -band light curves for four novae observed by _ spitzer_. the @xmath81 symbols refer to lower limits on the @xmath36 magnitudes . the light curves yield @xmath82 d , @xmath83 d , @xmath84 d , and @xmath85 d for m31n 2006 - 09c , 2006 - 10a , 2006 - 10b , and 2007 - 08d , respectively . [ lc1 ] ] and @xmath35 light curves for m31n 2006 - 10a obtained with the liverpool telescope ( the @xmath35 light curve is shown in grey ) . arrows are upper limits . from these light curves we derive @xmath86 d and @xmath31 d. [ lc2 ] ] and @xmath35 light curves for m31n 2006 - 10b obtained with the liverpool telescope ( the @xmath35 light curve is shown in grey ) . arrows are upper limits . maximum light was missed in @xmath35 , but the @xmath57 light curve yields @xmath87 d. [ lc3 ] ] , versus nova speed class ( @xmath88 $ ] , except for m31n 2007 - 07f , which is @xmath89 $ ] ) . data for galactic novae are given as open triangles , with the two suspected dust - forming novae in m31 shown as filled red squares . these , and the special cases of the galactic novae pw vul and v445 pup , are discussed more fully in the text . ] , versus nova speed class for galactic novae ( open triangles , @xmath44 data from * ? ? ? * see also table [ dust ] ) . an outlier is qu vul , which is discussed more thoroughly in the text . red squares denote the observations of novae in m31 @xmath90 days after discovery ( near optical maximum ) with objects of particular interest noted ( see text for details ) . values of @xmath24 are from @xmath35-band measurements for m31n 2006 - 10a and the galactic novae , while the m31 novae are mainly based on @xmath36-band measurements ( again see text for details ) . ] lccccrl m31n 2006 - 09c & 00:42:42.38 & + 41:08:45.50 & 3996.64 & 4151.25 & 154.61 & 16.5(w ) + m31n 2006 - 10a & 00:41:43.23 & + 41:11:45.90 & 4034.31 & 4149.85 & 115.54 & 18.6(r ) + m31n 2006 - 10b & 00:39:27.46 & + 40:51:10.10 & 4039.59 & 4149.82 & 110.23 & 16.4(w ) + m31n 2006 - 11a & 00:42:56.61 & + 41:06:18.20 & 4064.97 & 4151.22 & 86.25 & 17.3(w ) + m31n 2007 - 07f & 00:38:42.20 & + 40:52:56.10 & 4292.48 & 4495.03 & 202.55 & 17.4(w ) + m31n 2007 - 08a & 00:40:54.40 & + 40:53:50.30 & 4318.80 & 4498.70 & 179.90 & 17.6(w ) ? + m31n 2007 - 08d & 00:39:30.27 & + 40:29:14.20 & 4336.58 & 4495.06 & 158.48 & 18.1(r ) + m31n 2007 - 10a & 00:42:55.95 & + 41:03:22.00 & 4379.11 & 4498.73 & 119.62 & 16.3(r ) ? 2006 - 09c & 00:42:42.38 & + 41:08:45.50 & 3996.64 & 4142.04 & 145.40 & 16.5(w ) + m31n 2006 - 10a & 00:41:43.23 & + 41:11:45.90 & 4034.31 & 4141.99 & 107.68 & 18.6(r ) + m31n 2006 - 10b & 00:39:27.46 & + 40:51:10.10 & 4039.59 & 4142.08 & 102.49 & 16.4(w ) + m31n 2006 - 11a & 00:42:56.61 & + 41:06:18.20 & 4064.97 & 4141.95 & 76.98 & 17.3(w ) + m31n 2007 - 08d & 00:39:30.27 & + 40:29:14.20 & 4336.58 & 4519.34 & 182.76 & 18.1(r ) + m31n 2007 - 10a & 00:42:55.95 & + 41:03:22.00 & 4379.11 & 4519.30 & 140.19 & 16.3(r ) ? + m31n 2007 - 11d & 00:44:54.90 & + 41:37:39.60 & 4421.02 & 4519.43 & 98.41 & 14.9(w ) + m31n 2007 - 11e & 00:45:47.74 & + 42:02:03.50 & 4432.58 & 4519.39 & 86.81 & 16.6(w ) + lcccc m31n 2006 - 09c & @xmath91 & @xmath92 & @xmath93 & @xmath94 + m31n 2006 - 10a & @xmath95 & @xmath96 & @xmath97 & @xmath98 + m31n 2006 - 10b & @xmath99 & @xmath100 & @xmath101 & + m31n 2006 - 11a & @xmath102 & @xmath103 & @xmath104 & + m31n 2007 - 07f & @xmath105 & @xmath106 & @xmath107 & @xmath108 + m31n 2007 - 08a & & & & + m31n 2007 - 08d & @xmath109 & @xmath110 & @xmath111 & @xmath112 + m31n 2007 - 10a & & & & + crccc 3993.376 & @xmath113 & r & kh & lelekovice 0.35-m + 3996.404 & @xmath114 & r & p. kunirk & ondejov 0.65-m + 3999.609 & @xmath115&r & p. kunirk & ondejov 0.65-m + 4000.317 & @xmath116 & r & kh & lelekovice 0.35-m + 4000.590 & @xmath117&r & m. wolf & ondejov 0.65-m + 4001.360 & @xmath118 & r & kh & lelekovice 0.35-m + 4002.302 & @xmath119 & r & kh & lelekovice 0.35-m + 4002.329 & @xmath120 & r & kh & lelekovice 0.35-m + 4005.312 & @xmath121 & r & kh & lelekovice 0.35-m + 4007.312 & @xmath122 & r & kh & lelekovice 0.35-m + 4014.295 & @xmath123 & r & kh & lelekovice 0.35-m + 4017.258 & @xmath124 & r & kh & lelekovice 0.35-m + 4019.319 & @xmath125 & r & kh & lelekovice 0.35-m + 4024.383 & @xmath126 & r & kh & lelekovice 0.35-m + 4026.330 & @xmath126 & r & kh & lelekovice 0.35-m + 4026.364 & @xmath126 & r & kh & lelekovice 0.35-m + 4034.312 & @xmath127 & r & kh & lelekovice 0.35-m + + 4256.677 & @xmath128 & b & mfb , mjd , aws , kam & lt 2.0-m + 4260.700 & @xmath129 & b & mfb , mjd , aws , kam & lt 2.0-m + + 4260.705 & @xmath130 & v & mfb , mjd , aws , kam & lt 2.0-m + + 4260.690 & @xmath131 & r & mfb , mjd , aws , kam & lt 2.0-m + + 4260.695 & @xmath132 & i & mfb , mjd , aws , kam & lt 2.0-m + crccc 4019.319 & @xmath133 & r & kh & lelekovice 0.35-m + 4024.383 & @xmath134 & r & kh & lelekovice 0.35-m + 4026.330 & @xmath135 & r & kh & lelekovice 0.35-m + 4031.251 & @xmath136 & r & kh & lelekovice 0.35-m + 4034.312 & @xmath137 & r & kh & lelekovice 0.35-m + 4034.470 & @xmath138 & r & p. kunirk & ondejov 0.65-m + 4035.360 & @xmath139 & r & kh & lelekovice 0.35-m + 4043.331 & @xmath122 & r & kh & lelekovice 0.35-m + 4047.288 & @xmath140 & r & kh & lelekovice 0.35-m + 4048.324 & @xmath126 & r & kh & lelekovice 0.35-m + 4055.296 & @xmath141 & r & kh & lelekovice 0.35-m + 4055.262 & @xmath142 & r & p. caga & zln 0.28-m + 4070.308 & @xmath143 & r & m. wolf , p. zasche & ondejov 0.65-m + 4071.385 & @xmath144 & r & p. kunirk & ondejov 0.65-m + 4078.308 & @xmath139 & r & kh & lelekovice 0.35-m + 4078.343 & @xmath145 & r & kh & lelekovice 0.35-m + 4080.306 & @xmath146 & r & kh & lelekovice 0.35-m + 4084.212 & @xmath144 & r & kh & lelekovice 0.35-m + 4093.174 & 19.5 : & r & kh & lelekovice 0.35-m + 4096.325 & @xmath147 & r & kh & lelekovice 0.35-m + 4097.222 & @xmath148 & r & kh & lelekovice 0.35-m + 4115.194 & @xmath149 & r & kh & lelekovice 0.35-m + 4121.381 & @xmath150 & r & kh & lelekovice 0.35-m + 4122.331 & @xmath151 & r & kh & lelekovice 0.35-m + 4122.377 & @xmath152 & r & kh & lelekovice 0.35-m + + 4044.337 & @xmath153 & b & mfb , mjd , aws , kam & lt 2.0-m + 4050.589 & @xmath154 & b & mfb , mjd , aws , kam & lt 2.0-m + 4056.585 & @xmath155 & b & mfb , mjd , aws , kam & lt 2.0-m + 4062.606 & @xmath156 & b & mfb , mjd , aws , kam & lt 2.0-m + 4069.484 & @xmath157 & b & mfb , mjd , aws , kam & lt 2.0-m + 4071.549 & @xmath158 & b & mfb , mjd , aws , kam & lt 2.0-m + 4074.575 & @xmath159 & b & mfb , mjd , aws , kam & lt 2.0-m + 4077.542 & @xmath160 & b & mfb , mjd , aws , kam & lt 2.0-m + 4084.460 & @xmath161 & b & mfb , mjd , aws , kam & lt 2.0-m + 4092.454 & @xmath162 & b & mfb , mjd , aws , kam & lt 2.0-m + 4099.407 & @xmath163 & b & mfb , mjd , aws , kam & lt 2.0-m + 4101.393 & @xmath164 & b & mfb , mjd , aws , kam & lt 2.0-m + 4114.372 & @xmath165 & b & mfb , mjd , aws , kam & lt 2.0-m + 4120.432 & @xmath166 & b & mfb , mjd , aws , kam & lt 2.0-m + 4254.685 & @xmath167 & b & mfb , mjd , aws , kam & lt 2.0-m + + 4044.334 & @xmath168 & v & mfb , mjd , aws , kam & lt 2.0-m + 4050.586 & @xmath169 & v & mfb , mjd , aws , kam & lt 2.0-m + 4056.582 & @xmath170 & v & mfb , mjd , aws , kam & lt 2.0-m + 4062.604 & @xmath171 & v & mfb , mjd , aws , kam & lt 2.0-m + 4069.481 & @xmath172 & v & mfb , mjd , aws , kam & lt 2.0-m + 4071.546 & @xmath173 & v & mfb , mjd , aws , kam & lt 2.0-m + 4074.572 & @xmath174 & v & mfb , mjd , aws , kam & lt 2.0-m + 4077.539 & @xmath175 & v & mfb , mjd , aws , kam & lt 2.0-m + 4084.457 & @xmath176 & v & mfb , mjd , aws , kam & lt 2.0-m + 4092.451 & @xmath177 & v & mfb , mjd , aws , kam & lt 2.0-m + 4099.404 & @xmath178 & v & mfb , mjd , aws , kam & lt 2.0-m + 4101.391 & @xmath179 & v & mfb , mjd , aws , kam & lt 2.0-m + 4114.370 & @xmath180 & v & mfb , mjd , aws , kam & lt 2.0-m + 4120.429 & @xmath181 & v & mfb , mjd , aws , kam & lt 2.0-m + 4254.692 & @xmath182 & v & mfb , mjd , aws , kam & lt 2.0-m + + 4254.671 & @xmath183 & r & mfb , mjd , aws , kam & lt 2.0-m + crccc 4043.888 & @xmath184 & b & mfb , mjd , aws , kam & lt 2.0-m + 4049.001 & @xmath185 & b & mfb , mjd , aws , kam & lt 2.0-m + 4057.034 & @xmath186 & b & mfb , mjd , aws , kam & lt 2.0-m + 4062.963 & @xmath187 & b & mfb , mjd , aws , kam & lt 2.0-m + 4068.945 & @xmath188 & b & mfb , mjd , aws , kam & lt 2.0-m + 4071.940 & @xmath189 & b & mfb , mjd , aws , kam & lt 2.0-m + 4074.973 & @xmath190 & b & mfb , mjd , aws , kam & lt 2.0-m + 4083.911 & @xmath191 & b & mfb , mjd , aws , kam & lt 2.0-m + 4098.938 & @xmath192 & b & mfb , mjd , aws , kam & lt 2.0-m + 4105.915 & @xmath193 & b & mfb , mjd , aws , kam & lt 2.0-m + 4113.883 & @xmath194 & b & mfb , mjd , aws , kam & lt 2.0-m + 4119.958 & @xmath195 & b & mfb , mjd , aws , kam & lt 2.0-m + 4248.204 & @xmath196 & b & mfb , mjd , aws , kam & lt 2.0-m + + 4048.998 & @xmath197 & v & mfb , mjd , aws , kam & lt 2.0-m + 4053.817 & @xmath198 & v & mfb , mjd , aws , kam & lt 2.0-m + 4057.031 & @xmath199 & v & mfb , mjd , aws , kam & lt 2.0-m + 4062.960 & @xmath200 & v & mfb , mjd , aws , kam & lt 2.0-m + 4068.942 & @xmath201 & v & mfb , mjd , aws , kam & lt 2.0-m + 4071.937 & @xmath202 & v & mfb , mjd , aws , kam & lt 2.0-m + 4074.970 & @xmath203 & v & mfb , mjd , aws , kam & lt 2.0-m + 4083.908 & @xmath204 & v & mfb , mjd , aws , kam & lt 2.0-m + 4098.936 & @xmath205 & v & mfb , mjd , aws , kam & lt 2.0-m + 4101.885 & @xmath206 & v & mfb , mjd , aws , kam & lt 2.0-m + 4105.912 & @xmath207 & v & mfb , mjd , aws , kam & lt 2.0-m + 4107.986 & @xmath208 & v & mfb , mjd , aws , kam & lt 2.0-m + 4113.880 & @xmath209 & v & mfb , mjd , aws , kam & lt 2.0-m + 4119.955 & @xmath210 & v & mfb , mjd , aws , kam & lt 2.0-m + 4248.209 & @xmath211 & v & mfb , mjd , aws , kam & lt 2.0-m + + 4248.193 & @xmath212 & r & mfb , mjd , aws , kam & lt 2.0-m + + 4248.199 & @xmath213 & i & mfb , mjd , aws , kam & lt 2.0-m + crccc 4048.324 & @xmath150 & r & kh & lelekovice 0.35-m + 4055.296 & @xmath150 & r & kh & lelekovice 0.35-m + 4070.263 & @xmath214 & r & m. wolf , p. zasche & ondejov 0.65-m + 4070.308 & @xmath215 & r & m. wolf , p. zasche & ondejov 0.65-m + 4078.308 & @xmath216 & r & kh & lelekovice 0.35-m + 4078.343 & @xmath217 & r & kh & lelekovice 0.35-m + 4080.306 & @xmath218 & r & kh & lelekovice 0.35-m + 4084.212 & @xmath214 & r & kh & lelekovice 0.35-m + 4093.174 & @xmath219 & r & kh & lelekovice 0.35-m + 4096.325 & @xmath220 & r & kh & lelekovice 0.35-m + 4097.222 & @xmath220 & r & kh & lelekovice 0.35-m + 4115.194 & @xmath125 & r & kh & lelekovice 0.35-m + 4121.381 & @xmath144 & r & kh & lelekovice 0.35-m + 4122.331 & @xmath136 & r & kh & lelekovice 0.35-m + 4122.377 & @xmath221 & r & kh & lelekovice 0.35-m + 4126.289 & @xmath222 & r & kh & lelekovice 0.35-m + 4126.339 & @xmath221 & r & kh & lelekovice 0.35-m + 4128.275 & @xmath136 & r & kh & lelekovice 0.35-m + 4135.298 & @xmath223 & r & kh & lelekovice 0.35-m + 4135.334 & @xmath224 & r & kh & lelekovice 0.35-m + 4141.362 & @xmath225 & r & kh & lelekovice 0.35-m + 4146.295 & @xmath226 & r & kh & lelekovice 0.35-m + 4149.273 & @xmath226 & r & kh & lelekovice 0.35-m + 4166.247 & @xmath227 & r & kh & ondejov 0.65-m + 4167.366 & @xmath228 & r & kh & ondejov 0.65-m + 4170.264 & @xmath229 & r & kh & ondejov 0.65-m + 4173.269 & @xmath230 & r & p. kunirk , t. henych & ondejov 0.65-m + 4174.268 & @xmath133 & r & kh & lelekovice 0.35-m + 4240.561 & @xmath149 & r & kh & ondejov 0.65-m + + 4140.868 & @xmath231 & b & mfb , mjd , aws , kam & lt 2.0-m + + 4140.872 & @xmath232 & v & mfb , mjd , aws , kam & lt 2.0-m + + 4140.856 & @xmath233 & r & mfb , mjd , aws , kam & lt 2.0-m + + 4140.862 & @xmath234 & i & mfb , mjd , aws , kam & lt 2.0-m + crccc 4380.401 & @xmath145 & r & kh , p. kunirk & ondejov 0.65-m + 4380.424 & @xmath235&r & kh , p. kunirk & ondejov 0.65-m + 4382.235 & @xmath236&r & kh , p. kunirk & ondejov 0.65-m + 4387.219 & @xmath151 & r & kh , p. kunirk & ondejov 0.65-m + 4387.231 & @xmath237 & r & kh , p. kunirk & ondejov 0.65-m + 4387.561 & @xmath238 & r & kh & ondejov 0.65-m + 4388.227 & @xmath230&r & kh , p. kunirk & ondejov 0.65-m + 4388.626 & @xmath239&r & kh & ondejov 0.65-m + 4389.233 & @xmath240 & r & kh , p. kunirk & ondejov 0.65-m + 4389.646 & @xmath229 & r & kh & ondejov 0.65-m + lcccccc m31n 2006 - 09c & 00 42 42.38 & 41 08 45.5 & 24.18 sep 2006 & 1800 & 42757250 & spec + m31n 2006 - 10a & 00 41 43.23 & 41 11 45.9 & 30.31 oct 2006 & 1500 & 42757250 & spec + m31n 2006 - 10b & 00 39 27.38 & 40 51 09.8 & 23.24 nov 2006 & 1200 & 42757250 & phot + m31n 2006 - 11a & 00 42 56.81 & 41 06 18.4 & 28.23 nov 2006 & 1200 & 42757250 & spec + m31n 2007 - 08d & 00 39 30.27 & 40 29 14.2 & 13.44 sep 2007 & 1200 & 42757250 & spec + m31n 2007 - 10a & 00 42 55.95 & 41 03 22.0 & 19.13 oct 2007 & 1400 & 42757250 & phot + m31n 2007 - 11d & 00 44 54.60 & 41 37 40.0 & 04.22 dec 2007 & 1200 & 41008900 & phot + m31n 2007 - 11e & 00 45 47.74 & 42 02 03.5 & 05.23 dec 2007 & 1200 & 41008900 & phot + lrrrr m31n 2006 - 09c & @xmath241 & @xmath242 & 1910 & 1920 + m31n 2006 - 10a & @xmath243 & @xmath244 & 950 & 810 + m31n 2006 - 10b & @xmath245 & @xmath246 & 3030 & 3562 + m31n 2006 - 11a & @xmath247 & @xmath248 & 1420 & 1120 + m31n 2007 - 07f & @xmath249 & @xmath250 & 1340 & 1110 + m31n 2007 - 08a & & @xmath251 & & 1880 + m31n 2007 - 08d & @xmath252 & @xmath253 & 1160 & 1180 + m31n 2007 - 10a & @xmath254 & @xmath255 & 470 & 500 + m31n 2007 - 11d & @xmath256 & @xmath257 & 2060 & 2260 + m31n 2007 - 11e & @xmath258 & @xmath259 & 1750 & 1600 + lrrrll m31n 2006 - 09c & @xmath260 & @xmath261 & 11.61 & fe ii & 1,2 + m31n 2006 - 10a & @xmath262 & @xmath263 & 17.31 & fe ii & 1 + m31n 2006 - 10b & @xmath264&@xmath265 & 63.14 & he / n & 1 + m31n 2006 - 11a & 2.35 & @xmath266 & 20.46 & fe ii & 1 + m31n 2007 - 07f & @xmath267&@xmath268 & 81.74 & fe ii & 3 + m31n 2007 - 08a & @xmath269&@xmath270 & 30.49 & fe ii ? & 4 + m31n 2007 - 08d & @xmath271&@xmath272 & 59.56 & fe ii & 1 + m31n 2007 - 10a & 2.19 & @xmath273 & 27.57 & fe ii ? & 1 , 5 + m31n 2007 - 11d & 24.34 & 21.60 & 34.03 & fe ii & 1 , 6 , 7 + m31n 2007 - 11e & 34.06 & 46.07 & 57.52 & fe ii & 1 , 8 + lccccr v1370 aql & 15 & @xmath274 & 37 & & he / n + v1419 aql & 25 & @xmath490 & 40 & & fe ii + os and & 11 & 22 & & & fe ii + t aur & 80 & 87 & & & fe ii + v705 cas & 33 & 63 & 100 & & fe ii + v842 cen & 43 & 36 & 87 & & fe ii + v476 cyg & 7 & 40 & & & fe ii + v1668 cyg & 11 & 33 & 57 & & fe ii + v2274 cyg & 22 & 40 & & & fe ii + dq her & 76 & 105 & & & fe ii + v827 her & 21 & 43 & & & + v838 her & 1.2 & 18 & 25 & & he / n + v445 pup & 215 & 218 & & & + v732 sgr & 65 & 73 & & & + fh ser & 49 & 60 & 90 & & fe ii + lw ser & 32 & 23 & 75 & & fe ii + v992 sco & 100 & 93 & & & fe ii + nq vul & 21 & 62 & 80 & & fe ii + pw vul & 44 & 154 & 280 & & fe ii + qu vul & 20 & 40 & 240 & & fe ii + qv vul & 37 & 56 & 115 & & fe ii + lmc 1998#1 & 23 & 59 & 57 & & + m31n 2006 - 09c & @xmath275 & & & 154.61 & fe ii + m31n 2006 - 10a & @xmath276 & @xmath277 & & 116 & fe ii + m31n 2006 - 10b & @xmath278 & & & 110.23 & he / n + m31n 2006 - 11a & @xmath279 & & & 86.25 & fe ii + m31n 2007 - 07f & @xmath280 & @xmath281 & & 203 & fe ii + m31n 2007 - 08a & 2 & & & 158.48 & fe ii ? + m31n 2007 - 08d & @xmath282 & & & 179.9 & fe ii + m31n 2007 - 10a & 7 & & & 119.62 & fe ii ? + m31n 2007 - 11d & @xmath283 & & & 98.37 & fe ii + m31n 2007 - 11e & @xmath284 & & & 86.8 & fe ii +

we report the results of the first infrared survey of novae in the nearby spiral galaxy , m31 . both photometric and spectroscopic observations of a sample of 10 novae ( m31n 2006 - 09c , 2006 - 10a , 2006 - 10b , 2006 - 11a , 2007 - 07f , 2007 - 08a , 2007 - 08d , 2007 - 10a , 2007 - 11d , and 2007 - 11e ) were obtained with the _ spitzer _ space telescope . eight of the novae were observed with the irac ( all but m31n 2007 - 11d and 2007 - 11e ) and eight with the irs ( all but 2007 - 07f and 2007 - 08a ) , resulting in six in common between the two instruments . the observations , which were obtained between @xmath0 and @xmath1 months after discovery , revealed evidence for dust formation in two of the novae : m31n 2006 - 10a and ( possibly ) 2007 - 07f , and [ ne ii ] @xmath2 line emission in a third ( 2007 - 11e ) . the _ spitzer _ observations were supplemented with ground - based optical photometric and spectroscopic data that were used to determine the speed classes and spectroscopic types of the novae in our survey . after including data for dust - forming galactic novae , we show that dust formation timescales are correlated with nova speed class in that dust typically forms earlier in faster novae . we conclude that our failure to detect the signature of dust formation in most of our m31 sample is likely a result of the relatively long delay between nova eruption and our _ spitzer _ observations . indeed , the two novae for which we found evidence of dust formation were the two slowest " novae in our sample . finally , as expected , we found that the majority of the novae in our sample belong to the fe ii spectroscopic class , with only one clear example of the he / n class ( m31n 2006 - 10b ) . typical of an he / n system , m31n 2006 - 10b was the fastest nova in our sample , not detected with the irs , and just barely detected in three of the irac bands when it was observed @xmath3 months after eruption .

laparoscopic cholecystectomy ( lc ) has been a standard operation and replaced the open cholecystectomy ( oc ) rapidly because the technique resulted in less pain , smaller incision , and faster recovery . from 1987 , in which year mouret performed the first lc , the new technique developed fast . despite the benefits of lc , there is still concern about some severe complications of this technique , especially bile duct injury ( bdi ) . in order to reduce bdi , surgeons must expose calot 's triangle clearly without a sense of touch in lc . one is energized dissection , such as electric coagulation , monopolar electrosurgery , and ultrasonic scalpel . based on some reports of multicenter , large - sample trial studies , the rate of bdi in lc was 0.100.42% around the world . our center firstly used blunt dissection by flushing and aspiration to expose calot 's triangle and had a satisfactory result . from 2003 to 2015 , lc was performed on 21,497 patients in 12 years . the calot 's triangle was exposed by blunt dissection routinely before transecting the cystic duct . above all cases , bdi was diagnosed in 20 patients ( 0.09% ) . in this study , we were to introduce the technique of blunt dissection and to show the bdi cases in our institution . from 2003 to 2015 , 21,497 lcs were performed in department of general surgery , sir run run shaw hospital of zhejiang university . there were 7470 males and 14,027 females , aged 50.3 years ( 1484 years ) . in all the cases , 19,343 patients were diagnosed as cholecystolithiasis , including 16,754 chronic cholecystolithiasis and 2589 acute cholecystolithiasis ; 2154 patients were diagnosed as cholecystic polypus . the technique of blunt dissection with flushing and aspiration was used in each operation to expose calot 's triangle . patients were placed in supine position and 4 entries ( 1 umbilical , 1 epigastric , and 2 in the right flank ) were made . a veress needle was inserted directly under the umbilicus to allow for the flow of carbon dioxide into the peritoneal cavity , and the pneumoperitoneum was established at 1214 mmhg . the cystic artery and cystic duct were ligated with clips after the cystic duct , the common hepatic duct , and the common hepatic duct were identified [ figure 1 ] . the main equipment of the technique is laparoscopic suction and irrigation tubes . in the picture , we identified the cystic duct ( a ) , the common hepatic duct ( b ) and the common hepatic duct ( c ) . prophylactic antibiotics were used in all operated patients ( half an hour before surgery , intravenously ) . in cases of conversion from lc to oc , the preferred incision was a subcostal incision . as inflammation around the gallbladder , the laparoscopic cholecystitis grading ( lcg ) was classified into four grades ( g0g3 ) [ table 1 ] . laparoscopic cholecystitis grading the strasberg classification was used to describe the type of bdi ( based on surgical and cholangiographic findings ) and the dindo - clavien classification was used to stratify the severity of complications [ tables 2 and 3 ] . type of bile duct injury the dindo - clavien classification cns : central nervous system ; ic : intermediate care ; icu : intensive care unit . patient demographics include age and gender ; operation time , rate of conversion , surgeon ; the hospitalization days , complications , and types and treatments of bdi . from 2003 to 2015 , 21,497 lcs were performed in department of general surgery , sir run run shaw hospital of zhejiang university . there were 7470 males and 14,027 females , aged 50.3 years ( 1484 years ) . in all the cases , 19,343 patients were diagnosed as cholecystolithiasis , including 16,754 chronic cholecystolithiasis and 2589 acute cholecystolithiasis ; 2154 patients were diagnosed as cholecystic polypus . the technique of blunt dissection with flushing and aspiration was used in each operation to expose calot 's triangle . patients were placed in supine position and 4 entries ( 1 umbilical , 1 epigastric , and 2 in the right flank ) were made . a veress needle was inserted directly under the umbilicus to allow for the flow of carbon dioxide into the peritoneal cavity , and the pneumoperitoneum was established at 1214 mmhg . the cystic artery and cystic duct were ligated with clips after the cystic duct , the common hepatic duct , and the common hepatic duct were identified [ figure 1 ] . the main equipment of the technique is laparoscopic suction and irrigation tubes . in the picture , we identified the cystic duct ( a ) , the common hepatic duct ( b ) and the common hepatic duct ( c ) . prophylactic antibiotics were used in all operated patients ( half an hour before surgery , intravenously ) . in cases of conversion from lc to oc , the preferred incision was a subcostal incision . as inflammation around the gallbladder , the laparoscopic cholecystitis grading ( lcg ) was classified into four grades ( g0g3 ) [ table 1 ] . the strasberg classification was used to describe the type of bdi ( based on surgical and cholangiographic findings ) and the dindo - clavien classification was used to stratify the severity of complications [ tables 2 and 3 ] . type of bile duct injury the dindo - clavien classification cns : central nervous system ; ic : intermediate care ; icu : intensive care unit . patient demographics include age and gender ; operation time , rate of conversion , surgeon ; the hospitalization days , complications , and types and treatments of bdi . during the 12-year study period , 21,497 lcs were performed by blunt dissection with flushing and aspiration , operation time 45 ( range : 20300 minutes ) minutes , average bleeding 14 ml . mean hospitalization days were 2.1 days , and about 46% had hospitalization days of 1 day or less . two hundred and thirty - nine cases had conversion because of severe adhesion , carcinoma of the gallbladder , gallbladder - intestine fistula , and bdi . twenty patients had diagnosis of bdi , representing an incidence of 0.09% . in 11 cases ( 55% ) , three patients were acute cholecystolithiasis , and 17 patients were chronic cholecystolithiasis . based on the lcg , there were 8 g1 , 7 g2 , and 5 g3 . the operating surgeon was a senior hpb staff in 17 cases ( 85% ) , an hpb surgery fellow in 2 cases ( 10% ) , and a general surgery resident in 1 case ( 5% ) . the bdis in these 20 cases were as follows : 6 cases of common bdi ( 4 cases of lateral injury and 2 circumferential injury ) , 2 of common hepatic duct injury , 1 of right hepatic duct injury , 1 of accessory right hepatic duct , 1 of aberrant bdi , 1 of biliary stricture , 1 of biliary duct perforation , 3 of hemobilia , and 4 of bile leakage . one case of right hepatic duct injury and 1 case of common hepatic duct injury were caused by thermal damage of electric coagulation . according to strasberg - bismuth classification of bdi , there were 4 type a ( 20% ) , 1 type b ( 5% ) , 1 type c ( 5% ) , 10 type d ( 50% ) , and 1 type e2 ( 5% ) . operative data and overall perioperative outcomes in patients with bdi after lc chd : common hepatic duct ; cbd : common bile duct ; bdi : bile duct injury ; lcg : laparoscopic cholecystitis grading ; lc : laparoscopic cholecystectomy ; ss : secondary surgery ; ryh : roux - en - y hepaticojejunostomy . seven cases were diagnosed bdi after operations and had conservative treatment . above the 20 cases , 17 cases ( 85% ) were selective operations ( 8 cases [ 47% ] were converted to repair bdi , 2 cases received second surgeries ) and 3 cases were emergency operations ( 2 cases [ 67% ] were converted to repair bdi ) . ten cases were converted to open surgery ( 6 cases of common bdi , 2 of common hepatic duct injury , 1 of right hepatic duct injury , and 1 of accessory right hepatic duct ) . the most common procedure performed was a primary closure in 8 with t - tube placement , and 2 roux - en - y hepaticojejunostomies ( 2 with a circumferential injury of the common bile duct ) . two cases ( 1 biliary duct perforation and 1 bile leakage ) received the second surgery : 1 case of biliary duct perforation was performed roux - en - y hepaticojejunostomy and stayed in intensive care unit ( icu ) for more than 2 weeks ; 1 case of bile leakage was performed peritoneal lavage and drainage . one patient had jaundice after surgery and was diagnosed biliary stricture by magnetic resonance cholangiopancreatography . the other 6 cases ( 3 bile duct bleeding and 3 bile leakage ) also had conservative treatment with ultrasound guided percutaneous puncture catheter drainage and achieved remission of symptoms [ tables 4 and 5 ] . twelve cases ( 60% ) were grade ii and 6 cases ( 30% ) of leakage or bleeding required ultrasound guided percutaneous puncture catheter drainage ( grade iiia ) . common bile duct perforation with bile leakage developed in 1 case ( iv b ) , which received the second surgery to do roux - en - y hepaticojejunostomies and stayed in icu for more than 1 month because of multiorgan dysfunction . the other one had a bile leakage with severe infection and received the second surgery to lavage and drainage ( iiib ) . mean hospitalization days was 21 days ( range : 5158 days ) , and all the patients were fully recovered . three patients were acute cholecystolithiasis , and 17 patients were chronic cholecystolithiasis . based on the lcg , there were 8 g1 , 7 g2 , and 5 g3 . the operating surgeon was a senior hpb staff in 17 cases ( 85% ) , an hpb surgery fellow in 2 cases ( 10% ) , and a general surgery resident in 1 case ( 5% ) . the bdis in these 20 cases were as follows : 6 cases of common bdi ( 4 cases of lateral injury and 2 circumferential injury ) , 2 of common hepatic duct injury , 1 of right hepatic duct injury , 1 of accessory right hepatic duct , 1 of aberrant bdi , 1 of biliary stricture , 1 of biliary duct perforation , 3 of hemobilia , and 4 of bile leakage . one case of right hepatic duct injury and 1 case of common hepatic duct injury were caused by thermal damage of electric coagulation . according to strasberg - bismuth classification of bdi , there were 4 type a ( 20% ) , 1 type b ( 5% ) , 1 type c ( 5% ) , 10 type d ( 50% ) , and 1 type e2 ( 5% ) . operative data and overall perioperative outcomes in patients with bdi after lc chd : common hepatic duct ; cbd : common bile duct ; bdi : bile duct injury ; lcg : laparoscopic cholecystitis grading ; lc : laparoscopic cholecystectomy ; ss : secondary surgery ; ryh : roux - en - y hepaticojejunostomy . seven cases were diagnosed bdi after operations and had conservative treatment . above the 20 cases , 17 cases ( 85% ) were selective operations ( 8 cases [ 47% ] were converted to repair bdi , 2 cases received second surgeries ) and 3 cases were emergency operations ( 2 cases [ 67% ] were converted to repair bdi ) . ten cases were converted to open surgery ( 6 cases of common bdi , 2 of common hepatic duct injury , 1 of right hepatic duct injury , and 1 of accessory right hepatic duct ) . the most common procedure performed was a primary closure in 8 with t - tube placement , and 2 roux - en - y hepaticojejunostomies ( 2 with a circumferential injury of the common bile duct ) . in 1 case ( aberrant bdi ) , the injury was repaired laparoscopically . nine cases were diagnosed after operations . two cases ( 1 biliary duct perforation and 1 bile leakage ) received the second surgery : 1 case of biliary duct perforation was performed roux - en - y hepaticojejunostomy and stayed in intensive care unit ( icu ) for more than 2 weeks ; 1 case of bile leakage was performed peritoneal lavage and drainage . one patient had jaundice after surgery and was diagnosed biliary stricture by magnetic resonance cholangiopancreatography . this patient received conservative treatment and achieved remission of symptoms in 1 week . the other 6 cases ( 3 bile duct bleeding and 3 bile leakage ) also had conservative treatment with ultrasound guided percutaneous puncture catheter drainage and achieved remission of symptoms [ tables 4 and 5 ] . twelve cases ( 60% ) were grade ii and 6 cases ( 30% ) of leakage or bleeding required ultrasound guided percutaneous puncture catheter drainage ( grade iiia ) . common bile duct perforation with bile leakage developed in 1 case ( iv b ) , which received the second surgery to do roux - en - y hepaticojejunostomies and stayed in icu for more than 1 month because of multiorgan dysfunction . the other one had a bile leakage with severe infection and received the second surgery to lavage and drainage ( iiib ) . mean hospitalization days was 21 days ( range : 5158 days ) , and all the patients were fully recovered . the rate of bdi in lc was 0.100.42% , and common bdi and common hepatic duct injury were the most common types , ranged from 61.0% to 77.5% . before the adoption of this technique , 14,302 cases of laparoscopic cholecystectomies were performed in our institute by the conventional procedure and the occurrence rate of biliary injury was 0.37% which was significant higher than that reported in the current study ( p < 0.05 , chi - square analysis ) , but we did not use this comparison to approve the advantage of the current procedure because of the potential impact of the learning curve . we reviewed large - series reports of lc , which had more than 10,000 cases on pubmed [ table 6 ] . the occurrence rate of biliary injury in our series is lower than that in these reports that might account for the potential advantage of this procedure . according to these reports , causes of bdi include : ( 1 ) severe adhesion , it is difficult to expose calot 's triangle clearly ; ( 2 ) abnormal anatomy of bile duct ; ( 3 ) improper operation , such as thermal injury by electric coagulation , monopolar electrosurgery , and ultrasonic scalpel , bile duct stricture caused by clips ; ( 4 ) surgeons are not trained well . showed an rct study in 2014 , the use of energetic dissection in lc , like electric coagulation and ultrasonic scalpel , was associated with higher risk of complication . reported that the rate of bdi in surgeon s first lc was 1.7% , but in one 's 50 lc the rate reduced to 0.17% . so in lcs , experienced and well - trained surgeons are very important . besides , the most important measure to avoid bdi was exposing the calot 's triangle clearly . in conclusion , our center firstly used blunt dissection by flushing and aspiration to expose the calot 's triangle . the technique has two advantages : ( 1 ) blunt dissection , which can avoid thermal injury by using energetic dissection and reduce injury by sharp dissection ; ( 2 ) the equipment is cheap , simple , and easy for young surgeons to learn . surgeons use laparoscopic suction and irrigation tubes to flush and aspirate the calot 's triangle repeatedly . two hundred and thirty - nine cases ( 1.1% ) were converted to open , 20 cases ( 0.09% ) were bdi and 11 cases of bdi ( 55% ) were diagnosed in operations . compared with other institution around the world ( over 10,000 lcs ) , we had a significantly lower incidence of bdi in lcs [ table 6 ] . in the 20 cases , there were 17 senior surgeons , 2 fellows , and 1 resident . above all , we found that the rate of bdi and converted using our blunt dissection were both less than other large sample trial studies around the world . according to the analysis of surgeons , 85% cases were performed by senior surgeons and only 15% cases were performed by junior surgeons . so we believed that the technique of blunt dissection with flushing and aspiration is the best and easiest solution for surgeons to expose the calot 's triangle and reduce the incidence of bdi . it has three advantages : ( 1 ) laparoscopic suction and irrigation tubes are blunt tools and have a high safety in dissection ; ( 2 ) it is easy for surgeons to control and it can flush and aspirate repeatedly to keep operation field clear without changing equipment frequently ; and ( 3 ) laparoscopic suction and irrigation tubes are cheap and available equipments , it can reduce the cost of operations . the technique of blunt dissection by flushing and aspiration to expose the calot 's triangle is safe and simple . detailed operation procedures : first step is open a hole in the anterior sheath over the calot 's triangle wall by dissecting forceps , then using laparoscopic suction and irrigation tubes to flush and aspirate the calot 's triangle repeatedly through the anterior sheath hole until we see the cystic duct clearly . second step is flushing and aspiration in a direction parallel to the cystic duct , from its length down toward the junction of the cystic duct , common bile duct , and common hepatic duct until exposing the bile duct clearly . third , in order to expose the cystic artery and abnormal anatomy , we can use the same way to flush and aspirate the tissue in the calot 's triangle and identify all the location of main arteries and bile ducts . if the calot 's triangle can not be dissected clearly with severe adhesion , in our experience , we can not cut - off the arteries and bile ducts blindly , and we can use intraoperative cholangiography to locate bile ducts . so we believe that blunt dissection by flushing and aspiration is an effective solution to expose bile ducts and arteries , especially abnormal anatomy . besides , based on our experience , there were some notices for prevention of bdi : ( 1 ) check carefully before operations and evaluate the abnormal anatomy ; ( 2 ) do not cut - off the ducts before the main bile ducts are not clear ; ( 3 ) reduce the use of energetic dissection ; ( 4 ) intraoperative cholangiography can show the bile ducts clearly and prevent bdi , but now many experts considered that it is unnecessary for surgeons to perform intraoperative cholangiography in all the lcs . in conclusion , blunt dissection by flushing and aspiration to expose calot 's triangle , and results proved it to be a valuable method to avoid bdi .

background : laparoscopic cholecystectomy ( lc ) has been a standard operation and replaced the open cholecystectomy ( oc ) rapidly because the technique resulted in less pain , smaller incision , and faster recovery . this study was to evaluate the value of blunt dissection in preventing bile duct injury ( bdi ) in laparoscopic cholecystectomy ( lc).methods : from 2003 to 2015 , lc was performed on 21,497 patients , 7470 males and 14,027 females , age 50.3 years ( 1484 years ) . the calot 's triangle was bluntly dissected and each duct in calot 's triangle was identified before transecting the cystic duct.results:two hundred and thirty - nine patients ( 1.1% ) were converted to open procedures . the postoperative hospital stay was 2.1 ( 0158 ) days , and cases ( 46% ) had hospitalization days of 1 day or less , and 92.8% had hospitalization days of 3 days or less ; bdi was occurred in 20 cases ( 0.09% ) including 6 cases of common bdi , 2 cases of common hepatic duct injury , 1 case of right hepatic duct injury , 1 case of accessory right hepatic duct , 1 case of aberrant bdi 1 case of biliary stricture , 1 case of biliary duct perforation , 3 cases of hemobilia , and 4 cases of bile leakage.conclusion:exposing calot 's triangle by blunt dissection in laparoscopic cholecystectomy could prevent intraoperative bdi .

luminous red galaxies ( lrgs ) are particularly suited to the study of clusters . these elliptical galaxies are typically the most luminous and massive galaxies at redshifts @xmath14 , strongly tracing their underlying dark matter halos . furthermore , their uniform spectral energy distribution ( sed ) and characteristic spectral features have allowed for simplified selection and accurate redshift determination at @xmath15 @xcite . this previous work takes advantage of a strong break in the sed of lrgs that occurs at @xmath16 . as objects at higher redshift are considered however , this method becomes limited , as the @xmath16 feature passes into the _ i _ band at @xmath17 . in order to efficiently select lrgs at higher redshifts , new techniques must be used . this paper presents a publicly available catalog of massive galaxy candidates , with redshifts @xmath10 . galaxies are chosen based on photometric selection methods aimed to select higher redshift lrgs by combining optical and infrared surveys , developed by @xcite and further improved by @xcite . this work extends these previous results to include massive blue galaxies in addition to lrgs , and optimizes the selection cut using receiver operating characteristic ( roc ) curves to target objects above @xmath10 . optical data used is from the sloan digital sky survey ( sdss ; * ? ? ? * ) and infrared data used is from a catalog of forced photometry derived from the wide - field infrared survey explorer ( wise ; * ? ? ? * ; * ? ? ? the resulting catalog s redshift distribution is tested using spectroscopic and photometric redshifts , and restframe @xmath2 are used to determine lrg selection efficiency . a full description of the data sets used in this work is presented in [ sec : data ] . selection technique and optimization are discussed in [ sec : selection ] . the properties of the resulting catalog , and its comparison to similar work by @xcite , are described in [ sec : results ] . infrared and optical data used in this work are provided by the publicly available forced photometry catalog developed by @xcite . the catalog provides improved photometry for wise , at the positions of over 400 million primary sources from sdss - iii data release 10 @xcite . taking advantage of the higher resolution of sdss as a means to find sources in wise , photometry is extracted using _ the tractor _ image modeling code from `` unwise '' unblurred coadds of wise imaging . this unwise imaging preserves the original resolution of the survey , and allows for a higher signal - to - noise . for a detailed overview of the `` unwise '' imaging , see @xcite . the resulting catalog provides a consistent set of sources between sdss and wise . forced photometry may also be obtained for sources which , although blended in wise , are resolved in sdss . the sdss was conducted using a dedicated 2.5-meter telescope at the apache point observatory , new mexico . the telescope is equipped with two multi - object spectrographs as well as a 120-megapixel wide - field camera @xcite performing 5-band _ ugriz _ photometry at wavelengths 3551 , 4686 , 6165 , 7481 , 8931 @xmath18 @xcite . to date , sdss has made public twelve data releases @xcite . this work uses the @xmath19 and @xmath20 bands . wise is a full - sky cryogenic survey , carried out in 2010 over four simultaneously observing bands centered at 3.4 , 4.6 , 12 , and 22 @xmath21 . the survey achieved unprecedented sensitivity and angular resolution over the full sky ; the most recent allwise data release attained 5@xmath22 point source sensitivities better than 0.054 , 0.071 , 0.730 and 5 mjy in unconfused regions on the ecliptic , where sources can be distinguished from background noise , as well as 6.1 `` , 6.4 '' , 6.5 `` , and 12.0 '' angular resolution , in each of the four bands . for a full description of wise , see @xcite . this work uses the @xmath23 ( w1 ) band . we use objects in the unwise catalog that are marked as galaxies in the sdss _ photoobj _ catalog files , with clean photometry flag set to 1 . the catalog is then masked to ensure we are only using regions with good sdss observing conditions : objects not contained within imaging masks provided by @xcite are excluded from the analysis . the photometry is then corrected for galactic extinction following @xcite . values of @xmath24 are obtained from dust maps provided by @xcite , and extinction value @xmath25 for each band is calculated using @xmath26 of 2.751 , 2.086 , and 0.234 for @xmath19 , @xmath20 , and w1 , respectively ] . extinction corrected magnitudes are then given by the apparent magnitude , subtracted by the extinction value . in the optical , @xmath19 and @xmath20 band magnitudes are assumed to be consistent with ab magnitudes . in the infrared band , wise apparent magnitudes are converted from vega to ab magnitudes , using the following magnitude offset in the w1 band ] . @xmath27 we limit the @xmath19 , @xmath20 , and w1 band ( ab ) magnitudes to 22.9 , 21.8 , and 20.5 , respectively . magnitude errors in each band are restricted to values below 0.2 , corresponding to a 5@xmath22 detection . in regions of the surveys with shallower photometry , it is more difficult to reach this limit ; these cuts perform best in regions with deeper photometry ( e.g. stripe 82 ) . the deep2 galaxy redshift survey is the second phase of the deep extragalactic evolutionary probe ( deep ) survey conducted using the keck ii telescope , utilizing the deimos spectrograph @xcite . the most recent fourth data release contains all data from previous releases , providing spectra for @xmath2850,000 galaxies , selected using bri optical catalogs by @xcite . the deep2 dr4 redshift catalog contains 50,319 unique entries with @xmath29 , and covering @xmath30 over four separate 120 by 30 fields . in particular , we use the field centered at @xmath31 , + @xmath32 , coincident with the extended groth strip ( egs ) . the redshift catalog also contains @xmath2 restframe colors obtained from @xcite . we consider redshift value _ zbest _ , which is corrected for heliocentric motion , and restframe @xmath2 color , for sources with _ zquality _ flag of 3 or 4 that are cross - matched to within 10 of objects in the sdss / wise catalog . for more details on the deep2 survey , see @xcite . furthermore , we make use of a 2d selection function map of the egs region to determine the completeness of the estimated properties of our sample . the map contains the probability that an object meeting the deep2 target - selection criteria is selected for observation and successfully yielded a redshift . the selection function maps are described in @xcite , @xcite , and @xcite . the cosmological evolution survey ( cosmos ) photometric redshift catalog is an accurate , magnitude - limited photo - z redshift catalog extending to @xmath33 . redshifts are calculated using 30 bands in the uv ( galaxy evolution explorer ) , visible near - ir ( subaru , cfht , united kingdom infrared telescope , and national optical astronomy observatory ) , and mid - ir ( spitzer / irac ) , over a @xmath34 region of the sky . for more information , see @xcite . we consider redshift value _ zp_best _ for sources that are cross - matched to within 10 of objects in the sdss / wise catalog . to ensure reliable redshifts , we consider only objects in the photo - z catalog where @xmath35 , @xmath36 , @xmath37 , @xmath38 , and @xmath39 to be sure that the objects are not masked in any optical band . furthermore , we limit the photo - z catalog to @xmath40 . we use star - galaxy classifications developed in the 2006 may release of @xcite , contained within the cosmos zurich structure and morphology catalog and described in @xcite . we select a subset of the catalog where @xmath41 , and cross - match sources to within 10 of objects in the sdss / wise catalog . the @xmath42 flag is used as an indicator of star - galaxy classification . in sdss and wise . the `` @xmath43 bump '' manifests itself as a peak in infrared - to - optical flux for lrgs at @xmath44 . centered in each arcmin squared image , the lrg is shown as seen in sdss dr10 image single field search in the @xmath19 band ( left ) , and wise image service in the @xmath23 w1 band ( right ) . this property allows for selection of lrgs with @xmath1 through a simple cut in @xmath45 vs @xmath46 . ] , comprised of two lines ( line 1 and line 2 ) that are varied as discussed in [ sec : selection ] . the figure shows 5039 objects that are cross - matched with the cosmos zurich structure and morphology catalog , colored by star / galaxy classification , of which 1648 are selected ( above line 1 and line 2 ) by the cut . photometry is provided by the `` unwise '' forced photometry catalog , with ( ab ) magnitudes @xmath47 , @xmath48 , @xmath49 and their respective errors below 0.2 . stellar contamination is found to be less than @xmath50 . for comparison , a similar selection cut targeting @xmath51 , by @xcite is shown . ] vs @xmath52 absolute @xmath53 band ( ab ) magnitudes provided by the deep2 redshift survey catalog along the egs field , for objects contained in sdss and wise . two populations are visible , corresponding to red and blue sequence galaxies , with red galaxies lying above @xmath54 . objects selected by the cut correspond to more massive objects with red and blue color . ] we seek to photometrically select a catalog of massive galaxies with redshift @xmath55 , building on the lrg selection technique described by @xcite and @xcite . unable to rely on the @xmath16 spectral feature used in previous lrg selection techniques ( e.g. , * ? ? ? * ) , this new method takes advantage of the presence of cool , old stellar populations and low star formation of lrgs at @xmath56 . at these redshifts , lrgs exhibit a spectral feature known as the `` @xmath43 bump '' . at restframe wavelength @xmath57 , the sed of cool , old stars exhibit a local maximum due to a local minimum opactity of @xmath58 ions @xcite ; this is observable , for lrgs at redshifts @xmath59@xmath60 , as a peak in infrared to optical flux at wavelengths of @xcite . figure [ r_and_w_images ] shows an example lrg as observed in the @xmath19 and w1 bands . by combining optical and infrared imaging data , color - color cuts can therefore be made to select high redshift lrgs . analysis by @xcite tests this selection technique using the all - wavelength extended groth strip ( egs ) international survey ( aegis ; * ? ? ? * ) , which provides deep imaging data over all wavelengths in the egs . the data set includes publicly available optical imaging from the canada - france hawaii telescope legacy survey ( cfht ls ; * ? ? ? * ) , infrared imaging from the _ spitzer _ infrared array camera ( irac ; * ? ? ? * ) and redshifts and restframe @xmath2 colors from the deep2 redshift survey @xcite to test the selection technique . the adopted method outlined in @xcite can be summarized as a simple cut in @xmath61 $ ] vs @xmath46 , both selecting lrgs at the desired redshift and eliminating galaxies with bluer seds . here , _ r _ and _ i _ represent the optical _ r _ and _ i _ bands of the cfht ls . the selection proposes @xmath19 and @xmath20 band cutoffs of 22.5 and 21.5 , respectively , and yields 420 objects per square degree with @xmath62 < 18.9 $ ] and 1120 objects per square degree with @xmath62 < 19.4 $ ] , based on a @xmath63 area within the egs , with 10 - 15% uncertainty due to cosmic variance . as described by @xcite , the lowest band in wise at @xmath23 is particularly suited to this color - color cut , as it coincides with the @xmath43 bump at @xmath64 . furthermore , a cut in this @xmath65 $ ] vs @xmath46 color - color space also allows for the separation of stars and galaxies , in order to select of a catalog with low stellar contamination . @xcite presents a thorough analysis of these methods using optical photometry from cfht ls , and infrared photometry from wise . the cut was optimized to select lrgs with @xmath51 , by varying the intersection of a vertical line with a sloped line using the roc curve and figure of merit ( fom ) statistics . the result of this analysis can be summarized by two requirements : @xmath66 > 2.0 \times ( r - i ) \end{gathered}\ ] ] the analysis in @xcite is intended to be used for target selection of lrgs in spectroscopic surveys such as the extended baryon oscillation spectrscopic survey ( eboss ) and the dark energy spectroscopic instrubent ( desi ) survey . for further details on eboss target selection of lrgs using these cuts , see @xcite . the work presented in this paper uses extinction corrected infrared data from the @xmath23 band of wise forced photometry , and extinction corrected @xmath19 and @xmath20 bands from sdss . model magnitudes are used to calculate @xmath46 . in the case of @xmath65 $ ] , however , the @xmath67 flag from @xcite indicates which @xmath19 band magnitude to use . if wise objects were treated as point sources for the purposes of forced photometry , we use psf magnitudes in the @xmath19 band . for those which are treated as extended objects , we use composite model ( cmodel ) magnitudes in the @xmath19 band . in figure [ split_by_stargal ] , the final selection cut is shown , as well as star - galaxy separation . the color - magnitude diagram of figure [ color - mag - plot ] shows the separation of red and blue sequence galaxies with restframe @xmath2 . in figure [ fig : split ] , we show how the redshift and restframe @xmath2 vary across the color - color space , where restframe @xmath54 are indicative lrg - like sed . [ cols= " < " , ] stellar contamination is estimated using the @xmath42 flag contained within the cosmos zurich structure & morphology catalog described in [ subsubsec : zurich ] . over the cosmos area , 1,648 objects are cross - matched to within 10 of the selected objects , with a completeness of @xmath68 . we estimate a stellar contamination of @xmath69 . we include , for comparison , the selection cut developed by @xcite , shown in figure [ split_by_stargal ] . the cut performs best for a threshold @xmath70 , and yields a more peaked redshift distribution closer to @xmath71 . in figure [ z_hist ] we show the resulting redshift distribution by @xcite applied to our data . however , as seen in figure [ z_hist ] , the cut presented in this work does not reject as many massive blue galaxies . because the cut is wider , we are also able to select a much larger number of galaxies . we have efficiently selected a catalog of massive galaxies optimized to select objects with @xmath55 , using optical and infrared photometry . in deep2 , the resulting catalog has average redshift @xmath3 , with standard deviation @xmath4 . in cosmos , the resulting catalog has average redshift @xmath7 , with standard deviation @xmath8 . average restframe @xmath5 , with @xmath6 . the catalog contains primarily lrgs , although an estimated @xmath72 of the selected objects are bluer galaxies . we anticipate these to be massive galaxies in our targeted redshift range that will be equally cosmologically useful . we find that only @xmath11 of the catalog are bluer sources with redshift @xmath12 . moreover , the selection yields a higher number of galaxies than previous work by @xcite . stellar contamination is estimated to be @xmath13 . we anticipate a large signal from cross - correlations with cmb lensing , detections of the sunyaev - zeldovich effect , and the integrated sachs - wolfe effect . the catalog will be publicly available ] . this work was begun as an undergraduate senior thesis at princeton university , under the supervision of david n. spergel and with the support of nsf grant ast-1311756 . this work was partially funded by a fulbright grant under the u.s . student program to chile . we would like to thank rolando dnner for his many useful discussions throughout the development of this project . this work was also supported by nasa 12-euclid11 - 0004 and nsf ast1517593 , under the supervision of shirley ho . we would like to thank david wake for his contributions in the early stages of this work . lastly , we would like to thank dustin lang for his help in accessing the unwise data . funding for the sdss and sdss - ii has been provided by the alfred p. sloan foundation , the participating institutions , the national science foundation , the u.s . department of energy , the national aeronautics and space administration , the japanese monbukagakusho , the max planck society , and the higher education funding council for england . the sdss web site is http://www.sdss.org/. the sdss is managed by the astrophysical research consortium for the participating institutions . the participating institutions are the american museum of natural history , astrophysical institute potsdam , university of basel , university of cambridge , case western reserve university , university of chicago , drexel university , fermilab , the institute for advanced study , the japan participation group , johns hopkins university , the joint institute for nuclear astrophysics , the kavli institute for particle astrophysics and cosmology , the korean scientist group , the chinese academy of sciences ( lamost ) , los alamos national laboratory , the max - planck - institute for astronomy ( mpia ) , the max - planck - institute for astrophysics ( mpa ) , new mexico state university , ohio state university , university of pittsburgh , university of portsmouth , princeton university , the united states naval observatory , and the university of washington . funding for sdss - iii has been provided by the alfred p. sloan foundation , the participating institutions , the national science foundation , and the u.s . department of energy office of science . the sdss - iii web site is http://www.sdss3.org/. sdss - iii is managed by the astrophysical research consortium for the participating institutions of the sdss - iii collaboration including the university of arizona , the brazilian participation group , brookhaven national laboratory , carnegie mellon university , university of florida , the french participation group , the german participation group , harvard university , the instituto de astrofisica de canarias , the michigan state / notre dame / jina participation group , johns hopkins university , lawrence berkeley national laboratory , max planck institute for astrophysics , max planck institute for extraterrestrial physics , new mexico state university , new york university , ohio state university , pennsylvania state university , university of portsmouth , princeton university , the spanish participation group , university of tokyo , university of utah , vanderbilt university , university of virginia , university of washington , and yale university . this publication makes use of data products from the wide - 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we present the development of a photometrically selected massive galaxy catalog , targeting luminous red galaxies ( lrgs ) and massive blue galaxies at redshifts @xmath0 . massive galaxy candidates are selected using infrared / optical color - color cuts , with optical data from sloan digital sky survey ( sdss ) and infrared data from `` unwise '' forced photometry derived from the wide - field infrared survey explorer ( wise ) . the selection method is based on previously developed techniques to select lrgs with @xmath1 , and is optimized using receiver operating characteristic ( roc ) curves . the catalog contains 16,191,145objects , selected over the full sdss dr10 footprint . the redshift distribution of the resulting catalog is estimated using spectroscopic redshifts from the deep2 galaxy redshift survey and photometric redshifts from cosmos . restframe @xmath2 colors from deep2 are used to estimate lrg selection efficiency . using deep2 , the resulting catalog has average redshift @xmath3 , with standard deviation @xmath4 , and average restframe @xmath5 , with standard deviation @xmath6 . using cosmos , the resulting catalog has average redshift @xmath7 , with standard deviation @xmath8 . we estimate @xmath9 of the catalog to be blue galaxies with @xmath10 . an estimated @xmath11 of selected objects are blue sources with redshift @xmath12 . stellar contamination is estimated to be @xmath13 . catalogs cosmology : observations galaxies : colors , distances and redshifts galaxies : photometry methods : data analysis galaxies : general

the nucleus @xmath0th is located in a region where strong octupole correlations are important in the properties already of the low - lying excitations . besides the interplay of collective and single - particle excitations , which takes place in deformed rare earth nuclei , the reflection asymmetry additionally complicates the picture of excitations . already in an earlier publication @xcite , a conclusion was made that the nature of the first excited 0@xmath4 states in the actinide nuclei is different from that in the rare earth region , where they are due to the quadrupole vibration . the strong excitations in the ( p , t)-reaction suggest that these states represent a collective excitation different from the @xmath5-vibration . decay modes of the levels of the band on the first excited 0@xmath4 state in @xmath0th have led to the suggestion that this band might predominantly have an octupole two - phonon structure @xcite . one has to expect a complicated picture at higher excitations : residual interactions could mix the one - phonon and multiphonon vibrations of quadrupole and octupole character with each other and with quasiparticle excitations . detailed experimental information on the properties of such excitations is needed . on the experimental side , two - neutron transfer reactions are very useful . on the theoretical side , a test of the advanced interacting boson model ( ibm ) and a microscopic approach , such as the quasiparticle - phonon model ( qpm ) , would be very interesting . after the first observation of a large number of excitations with the @xmath6 transfer in the ( p , t ) reaction seen in the odd nucleus @xmath3pa @xcite , it was logical to investigate such excitations in the even - even nucleus @xmath0th , since @xmath3pa corresponds to @xmath0th + p , as well as in other actinide nuclei . such measurements were carried out for the nuclei @xmath0th , @xmath7th and @xmath8u , and the results of a limited analysis have been published in @xcite ( besides the earlier preliminary study of @xmath0th and @xmath9u in @xcite ) . the paper @xcite concentrated only on the energies of the excited @xmath1 states in these actinide nuclei and the ( p , t ) transfer strengths to these states . the ( p , t ) reaction , however , gives much more extensive information on specific excitations in these nuclei , which was not analyzed previously . such information was obtained for @xmath7th in our paper @xcite after detailed analysis of the experimental data from the ( p , t ) reaction . for the @xmath1 excitation , we were able to derive additional information on the moments of inertia , which can be useful in clarifying the structure of these excitations . in this paper we present the results of a careful and detailed analysis of the experimental data from the high - resolution study of the @xmath7th(p , t)@xmath0th reaction carried out to obtain deeper insight into all excitations in @xmath0th . the total picture for @xmath0th has to differ from the one for @xmath7th , since the first one is considered as an octupole soft and the latter as a vibration - like nucleus . it would be interesting to compare the @xmath1 excitations in the even nucleus @xmath0th and the odd nucleus @xmath3pa , the data for which in the low - energy part of excitations are known from the publication @xcite . information on excited states of @xmath0th prior to this study was obtained mainly from the @xmath10-decay of @xmath8u , the @xmath5- and ec - decay of @xmath0ac and @xmath0pa , as well as from the ( @xmath10 , xn@xmath11)-reaction . the most complete information was obtained from the @xmath5-decay of @xmath0ac reported by dalmasso et al . @xcite and from the ec - decay study of @xmath0pa by weber et al . @xcite . the lowest collective bands in @xmath0th were studied in the ( @xmath10 , xn@xmath11)-reaction @xcite . a total of 58 levels were reported in @xcite and 80 levels were observed in @xcite below 2.1 mev , connected by more than 240 @xmath11-rays that were established in these studies . present results , derived from the @xmath7th(p , t)@xmath0th reaction , lead to about 163 levels in the energy range up to 3.25 mev . unfortunately , during the experiment the radioactive target was destroyed and assignments were made only for 106 levels in the range up to 2.5 mev . energies and cross sections for one angle were obtained additionally for 57 levels . besides 0@xmath4 excitations , where the number of reliable assignments could be increased for five states in comparison with the preliminary analysis in publication @xcite , information on the spins for many other states was obtained . this information was essentially complementary to what was known from publications @xcite . some levels are grouped into rotational bands , thus allowing to derive the moment of inertia for some @xmath1 , @xmath12 and @xmath13 , @xmath14 , @xmath15 , @xmath16 bands . one of the results of ref . @xcite was the establishment of the one - phonon octupole - quadruplet with @xmath17 states . in this paper we suggested the two - phonon octupole - quadruplet with @xmath18 states . a radioactive target of 100 @xmath19g/@xmath20 @xmath7th with half - life t@xmath21 = 8@xmath22 years , evaporated on a 22 @xmath19g/@xmath20 thick carbon backing , was bombarded with 25 mev protons at an intensity of 1 - 2 @xmath19a from the tandem accelerator of the maier - leibnitz - labor of the ludwig - maximilians - universitt and technische universitt mnchen . the isotopic purity of the target was about 99% . the tritons were analyzed with the q3d magnetic spectrograph and then detected in a focal plane detector . the focal plane detector is a multiwire proportional chamber with readout of a cathode foil structure for position determination and de / e particle identification @xcite . the acceptance of the spectrograph was 11 msr , except for the most forward angle of 5@xmath23 with an acceptance of 6 msr . the resulting triton spectra have a resolution of 47 kev ( fwhm ) and are background - free . the angular distributions of the cross sections were obtained from the triton spectra at ten laboratory angles from 5@xmath23 to 40@xmath23 for energies up to 1800 kev , but only at five angles from 7.5@xmath23 to 30@xmath23 for energies from 1800 to 2500 kev . the energies and cross sections for the states from 2500 kev to 3250 kev were measured only for 10@xmath23 . a triton energy spectrum measured at a detection angle of 10@xmath23 is shown in fig . [ fig : specth228_10deg ] . the analysis of the triton spectra was performed with the program gaspan @xcite . measurements were carried out with two magnetic settings : one for excitations up to 1.75 mev , and another one for the energy region from 1.6 mev to 3.3 mev , respectively . for the calibration of the energy scale , the triton spectra from the reactions @xmath24w(p , t)@xmath25w , @xmath26w(p , t)@xmath24w and @xmath27u(p , t)@xmath8u were measured at the same magnetic settings . the levels in @xmath7th known from the study @xcite were also included in the calibration . from 106 levels identified in the spectra , 60 levels were identified for all ten angles and 46 levels only for 5 angles . they are listed in table [ tab : expei ] . the energies and spins of the levels as derived from this study are compared to known energies and spins , mainly from the published data @xcite . they are given in the first four columns . the ratios of cross sections at angles 7.5@xmath23 and 26@xmath28 to the one at 16@xmath28 , given in the next two columns , help to highlight the @xmath1 excitations ( large values ) . the column labelled @xmath29 gives the cross section integrated in the region from 7.5@xmath28 to 30@xmath28 , where the cross sections are measured for all level energies . the column titled @xmath30 gives the ratio of the integrated cross sections , from experimental values and calculations in the dwba approximation ( see sec . [ sec : dwba ] ) . the last column lists the notations of the schemes used in the dwba calculations : sw.jj means one - step direct transfer of the @xmath31 neutrons in the ( p , t ) reaction ; notations of the multi - step transfers used in the dwba calculations are displayed in fig . [ fig : schemes ] . additionally , energies of 57 levels seen only in the spectrum measured at 10@xmath23 and corresponding cross sections are listed in table [ tab : expesigma ] . + ll l ccc cc r c c + + & & & & & ratio&way of + & & [ 2,7 ] & this work&&(7.5@xmath32/16@xmath32 ) & ( 26@xmath32/16@xmath32)&[@xmath19b ] & @xmath33&fitting + + + + & & & & & ratio&way of + & & [ 2,7 ] & this work&&(7.5@xmath32/16@xmath32 ) & ( 26@xmath32/16@xmath32)&[@xmath19b ] & @xmath33&fitting + + 0.0 _ 2 & & 0.00 & @xmath1 & @xmath1 & & 5.83 & 5.61 & 165.56 & 6.20 & sw.gg + 57.8 _ 2 & & 57.76 & @xmath12 & @xmath12 & & 1.59 & 0.68 & 37.07 & 8.30&m1a.gg + 186.8 _ 2 & & 186.83 & @xmath34 & @xmath34 & & 0.74 & 0.38 & 9.07 & 1.90&m1a.gg + 328.0 _ 2 & & 328.00 & @xmath14 & @xmath14 & & 0.45 & 0.66 & 0.82 & 0.50&m2a.gg + 378.2 _ 2 & & 378.18 & @xmath2 & @xmath2 & & 0.58 & 0.71 & 4.48 & 1.60&m2a.gg + 396.9 _ 2 & & 396.08 & @xmath16 & @xmath16 & & 0.54 & 0.33 & 2.89 & 0.56&m3a.gg + 519.2 _ 3 & & 519.20 & @xmath35 & ( @xmath35 ) & & 1.23 & 1.33 & 0.43 & 0.90&sw.gg + 622.5 _ 4 & & 622.50 & @xmath36 & @xmath37 & & 0.20 & 0.94 & 0.26 & & + 695.6 _ 3 & & 695.50 & @xmath38 & @xmath39 & & 0.15 & 0.41 & 0.37 & & + 831.9 _ 2 & & 831.83 & @xmath1 & @xmath1 & & 12.06 & 7.50 & 39.10 & 360 & sw.ii + 874.4 _ 2 & & 874.42 & @xmath12 & @xmath12 & & 1.22 & 0.58 & 9.57 & 160 & m1a.ii + 911.6 _ 5 & & 911.80 & @xmath40 & & & & & & & + 920.6 _ 5 & & 920.80 & @xmath41 & & & & & & & + 938.7 _ 2 & & 938.55 & @xmath1 & @xmath1 & & 18.38 & 7.21 & 6.83 & 8.20 & sw.ii + 943.8 _ 4 & & 944.19 & @xmath14 & @xmath14 & & 0.12 & 0.67 & 0.37 & 1.00 & sw.gg + & & 968.33 & @xmath15 & & & & & & & + & & 968.43 & @xmath34 & & & & & & & + 968.8 _ 2 & & 968.97 & @xmath12 & @xmath12 & & 0.67 & 0.47 & 20.0 & 132&sw.ig + 979.4 _ 2 & & 979.50 & @xmath12 & @xmath12 & & 0.78 & 0.59 & 9.25 & 55.6&sw.ig + 1016.4 _ 2 & & 1016.43 & @xmath42 & @xmath16 & & 0.80 & 0.47 & 5.37 & 1.10&m3a.gg + & & 1022.53 & @xmath43 & & & & & & & + & & 1059.93 & @xmath44 & @xmath45 & & & & & & + 1074.8 _ 3 & & 1074.8 & @xmath34 & @xmath34 & & 0.74 & 1.32 & 1.62 & 0.26 & m1a.gg + 1091.0 _ 3 & & 1091.01 & @xmath34 & @xmath34 & & 0.74 & 0.44 & 0.42 & 0.10 & m1a.gg + 1105.5 _ 3 & & & & @xmath2 & & 0.61 & 0.56 & 0.77 & 21.0 & sw.ii + 1120.1 _ 3 & & 1120.1 & @xmath1 & @xmath1 & & 2.63 & 3.71 & 1.24 & 0.04 & sw.gg + & & 1122.95 & @xmath15 & & & & & & & + 1142.8 _ 3 & & 1143.2 & @xmath35 & @xmath35 & & 0.80 & 0.98 & 1.10 & 26.0 & sw.jj + 1153.3 _ 3 & & 1153.48 & @xmath12 & @xmath12 & & 0.65 & 0.49 & 23.89 & 140 & sw.ig + 1168.0 _ 4 & & 1168.37 & @xmath16 & @xmath16 & & 0.36 & 0.58 & 0.68 & 1.00 & w.gg + & & 1174.52 & @xmath46 & & & & & & & + 1175.2 _ 4 & & 1175.40 & @xmath12 & @xmath12 & & 1.05 & 0.91 & 2.09 & 13.0 & sw.ig + 1201.0 _ 9 & & 1200.54 & @xmath43 & @xmath43 & & 0.31 & 1.10 & 0.40 & 0.56 & m2a.gg + 1225.7 _ 6 & & & & @xmath34 & & 1.00 & 0.64 & 0.25 & 1.75 & sw.jj + & & 1226.55 & @xmath45 & & & & & & & + 1261.6 _ 3 & & 1261.5 & @xmath34 & @xmath34 & & 1.33 & 1.12 & 3.64 & 67.0 & sw.ii + 1270.2 _ 6 & & 1270.0 & & @xmath2 & & 0.40 & 0.97 & 0.31 & 0.15 & sw.gg + 1290.4 _ 3 & & 1290.2 & @xmath34 & @xmath34 & & 1.14 & 0.88 & 3.59 & 67.0 & sw.ii + 1296.0 _ 5 & & 1297.34 & @xmath35 & @xmath47 & & 1.33 & 1.23 & 0.50 & 1.00 & sw.gg + 1319.2 _ 4 & & & & @xmath48 & & 0.74 & 1.08 & 0.24 & 1.50 & sw.ig + 1343.9 _ 5 & & 1344.03 & @xmath16 & @xmath16 & & 0.77 & 0.33 & 0.31 & 0.08 & m3a.gg + & & 1393.4 & @xmath49 & @xmath50 & & & & & & + 1415.8 _ 6 & & 1415.92 & @xmath42 & @xmath51 & & 1.15 & 1.20 & 0.05 & 2.80 & sw.jj + 1423.8 _ 5 & & & & @xmath48 & & 2.20 & 1.33 & 0.16 & 0.03 & m1a.gg + 1432.1 _ 5 & & 1431.98 & @xmath52 & @xmath34 & & 1.61 & 1.17 & 0.21 & 6.80 & sw.ii + & & 1448.80 & @xmath53 & & & & & & & + & & 1450.29 & @xmath54 & & & & & & & + 1453.5 _ 5 & & & & @xmath51 & & 0.61 & 0.63 & 1.34 & 1.80 & sw.jj + 1470.0 _ 5 & & & & @xmath55 & & 0.94 & 1.81 & 0.19 & 0.01 & m3a.gg + 1497.4 _ 4 & & 1497.7 & @xmath56 & @xmath47 & & 1.07 & 0.91 & 0.37 & 0.56 & sw.gg + 1511.2 _ 3 & & & & @xmath1 & & 7.96 & 6.96 & 2.13 & 1.10 & sw.ig + 1531.7 _ 3 & & & & @xmath1 & & 2.21 & 0.83 & 0.47 & 2.60 & sw.ii + plus & & 1531.48 & @xmath43 & @xmath43 & & & & & 0.02 & m2a.gg + & & 1539.13 & @xmath57 & & & & & & & + 1544.4 _ 3 & & & & @xmath12 & & 1.27 & 0.65 & 1.61 & 1.53 & m1a.gg + & & 1581.0 & @xmath58 & & & & & & & + 1586.9 _ 4 & & & & @xmath12 & & 0.98 & 0.71 & 0.31 & 1.00 & sw.jj + & & 1588.33 & @xmath45 & & & & & & & + 1613.0 _ 5 & & & & @xmath34 & & 1.06 & 1.26 & 0.54 & 12.0 & sw.ii + 1618.3 _ 5 & & 1617.74 & ( @xmath59 & @xmath34 & & 0.88 & 0.76 & 1.22 & 0.16 & m2a.ii + 1627.9 _ 3 & & & & @xmath1 & & 7.44 & 5.21 & 9.66 & 10.0 & sw.ig + 1638.4 _ 4 & & 1638.25 & @xmath12 & @xmath12 & & 0.59 & 0.37 & 1.45 & 23.5 & sw.ii + & & 1643.18 & @xmath60 & & & & & & & + 1643.8 _ 3 & & 1643.8 & @xmath61 & @xmath34 & & 1.58 & 1.08 & 8.54 & 160 & sw.ii + & & 1645.89 & @xmath43 & & & & & & & + 1651.4 _ 3 & & & & @xmath51 & & 0.08 & 0.79 & 0.86 & 1.20 & sw.gg + 1667.3 _ 5 & & 1667.3 & & @xmath12 & & 0.71 & 0.61 & 3.17 & 46.0 & sw.ii + 1672.3 _ 5 & & & & @xmath12 & & 0.91 & 0.53 & 1.85 & 3.80 & sw.jj + 1678.4 _ 5 & & 1678.4 & @xmath62 & @xmath12 & & 0.88 & 0.75 & 1.48 & 19.5 & sw.ii + & & 1682.70 & @xmath63 & & & & & & & + & & 1683.74 & @xmath64 & & & & & & & + & & 1688.39 & @xmath43 & & & & & & & + 1691.3 _ 4 & & & & @xmath1 & & 2.66 & 2.06 & 1.26 & 0.75 & sw.ig + & & 1707.2 & @xmath65 & & & & & & & + 1710.7 _ 6 & & & & @xmath1 & & 1.38 & 1.86 & 0.54 & 0.02 & sw.gg + 1724.6 _ 4 & & 1724.29 & @xmath12 & @xmath12 & & 1.06 & 0.66 & 2.73 & 5.50 & sw.ii + 1733.8 _ 4 & & 1735.62 & @xmath34 & @xmath34 & & 1.13 & 0.86 & 2.28 & 3.50 & sw.ij + 1742.8 _ 4 & & 1743.86 & @xmath66 & @xmath34 & & 0.81 & 0.56 & 1.36 & 0.16 & m2a.gg + 1750.7 _ 3 & & & & @xmath1 & & 1.27 & 1.84 & 1.75 & 0.70 & sw.jj + 1758.1 _ 3 & & 1757.9 & @xmath67 & @xmath12 & & 0.85 & 0.75 & 4.35 & 26.0 & sw.ig + & & 1758.24 & @xmath63 & & & & & & & + & & 1760.25 & @xmath61 & & & & & & & + & & 1795.9 & @xmath68 & & & & & & & + 1796.8 _ 3 & & 1796.4 & @xmath69 & @xmath34 & & 1.40 & 0.83 & 6.47 & 89.0 & sw.ig + & & 1797.65 & @xmath70 & & & & & & & + 1803.0 _ 4 & & 1802.9 & @xmath71 & @xmath12 & & 0.65 & 0.49 & 15.34 & 90.0 & sw.ig + & & 1804.60 & @xmath72 & & & & & & & + & & 1811.5 & @xmath71 & & & & & & & + 1812.7 _ 4 & & & & @xmath55 & & 1.35 & 1.63 & 0.62 & 0.04 & sw.ig + & & 1817.43 & @xmath45 & & & & & & & + & & 1823.4 & @xmath73 & & & & & & & + 1826.2 _ 4 & & & & @xmath72 & & 1.16 & 0.83 & 1.91 & 7.50 & sw.ij + 1840.3 _ 8 & & 1842.2 & @xmath42 & & & 1.41 & 0.33 & 0.21 & & + 1858.6 _ 5 & & & & @xmath55 & & 0.65 & 1.19 & 1.28 & 0.06 & sw.ig + 1863.9 _ 5 & & 1864.8 & @xmath71 & @xmath48 & & 0.75 & 0.79 & 1.47 & 8.10 & sw.ig + & & 1876.5 & @xmath74 & & & & & & & + 1878.9 _ 5 & & 1879.0 & @xmath74 & @xmath51 & & 1.05 & 0.91 & 1.93 & 110 & sw.ii + & & 1892.98 & @xmath43 & & & & & & & + 1898.2 _ 4 & & 1899.98 & @xmath12 & @xmath48 & & 0.84 & 0.81 & 2.55 & 140 & sw.ii + & & 1901.90 & @xmath34 & & & & & & & + 1903.9 _ 4 & & & & ( @xmath2 ) & & 0.69 & 1.58 & 1.54 & 0.07 & sw.gg + & & 1906.78 & @xmath70 & & & & & & & + & & 1908.4 & @xmath16 & & & & & & & + 1908.9 _ 7 & & & & @xmath1 & & 2.17 & 1.91 & 4.56 & 1.30 & sw.jj + & & 1924.1 & @xmath75 & & & & & & & + & & 1924.6 & @xmath76 & & & & & & & + 1925.4 _ 4 & & 1925.20 & @xmath34 & @xmath56 & & 0.61 & 1.73 & 0.54 & 21.0 & sw.ii + & & 1928.54 & @xmath43 & & & & & & & + & & 1937.16 & @xmath63 & & & & & & & + 1938.3 _ 4 & & 1938.9 & @xmath34 & ( @xmath34 ) & & 1.06 & 0.76 & 1.99 & 0.67 & m2a.gg + & & 1944.85 & @xmath43 & & & & & & & + & & 1945.8 & @xmath56 & & & & & & & + 1947.8 _ 7 & & & & ( @xmath12 ) & & 1.02 & 0.75 & 0.77 & 3.50 & sw.ig + & & 1949.7 & @xmath77 & & & & & & & + 1959.7 _ 6 & & 1958.5 & @xmath12 & @xmath48 & & 0.10 & 1.69 & 0.43 & 1.50 & sw.ig + & & 1964.90 & @xmath48 & & & & & & & + 1971.7 _ 4 & & & & @xmath78 & & 0.66 & 0.81 & 0.79 & 3.10 & sw.ig + & & 1974.20 & @xmath34 & & & & & & & + 1981.9 _ 4 & & 1981.97 & @xmath66 & @xmath51 & & 1.68 & 0.77 & 1.70 & 2.60 & sw.gg + & & 1987.46 & @xmath34 & & & & & & & + 1993.9 _ 5 & & & & ( @xmath16 ) & & 0.97 & 0.72 & 1.80 & 2.80 & sw.gg + 2010.4 _ 6 & & 2010.15 & @xmath79 & @xmath48 & & 0.46 & 0.43 & 0.76 & 13.0 & sw.ig + & & 2013.6 & @xmath63 & & & & & & & + & & 2016.75 & @xmath56 & & & & & & & + & & 2022.73 & @xmath12 & & & & & & & + 2030.3 _ 4 & & 2029.6 & @xmath48 & @xmath12 & & 0.54 & 0.23 & 0.84 & 16.0 & sw.ig + & & 2037.0 & @xmath63 & & & & & & & + 2044.7 _ 5 & & & & @xmath1 & & 9.22 & 4.56 & 0.57 & 3.10 & sw.ii + 2052.1 _ 4 & & & & ( @xmath2 ) & & 0.72 & 1.30 & 3.70 & 180 & sw.ii + 2069.6 _ 5 & & & & @xmath12 & & 0.76 & 0.56 & 1.38 & 6.10 & sw.ig + 2079.9 _ 5 & & & & @xmath1 & & 17.08 & 13.13 & 4.62 & 25.9 & sw.ii + 2091.2 _ 7 & & & & @xmath55 & & 0.62 & 0.82 & 1.20 & 35.0 & sw.ii + 2111.6 _ 5 & & & & @xmath48 & & 0.70 & 0.71 & 2.57 & 11.0 & sw.ig + & & 2123.1 & @xmath78 & & & & & & & + 2131.3 _ 6 & & & & @xmath1 & & 6.84 & 4.53 & 24.80 & 120 & sw.ii + 2152.8 _ 4 & & & & @xmath72 & & 1.30 & 0.90 & 4.13 & 98.0 & sw.ii + 2159.4 _ 6 & & & & @xmath1 & & 3.78 & 1.54 & 1.18 & 8.10 & sw.ii + 2170.3 _ 4 & & & & @xmath48 & & 1.00 & 0.85 & 5.61 & 26.0 & sw.ig + 2198,2 _ 4 & & & & @xmath12 & & 0.59 & 0.62 & 3.81 & 19.5 & sw.ig + 2215.9 _ 4 & & & & ( @xmath34 ) & & 1.40 & 1.15 & 6.00 & 130 & sw.ii + 2235.2 _ 7 & & & & ( @xmath34 ) & & 0.98 & 0.86 & 2.82 & 61.0 & sw.ii + 2290.0 _ 7 & & & & @xmath1 & & 9.96 & 5.75 & 11.00 & 61.0 & sw.ii + 2302.9 _ 5 & & & & @xmath72 & & 1.09 & 0.84 & 2.75 & 62.0 & sw.ii + 2323.2 _ 5 & & & & @xmath12 & & 0.41 & 0.62 & 2.24 & 16.0 & sw.ig + 2335.9 _ 5 & & & & ( @xmath34 ) & & 2.13 & 1.65 & 17.10 & 370 & sw.ig + & & & & ( @xmath1 ) & & & & 4.50@xmath80 & 25.0 & sw.gg+14 + 2344.2 _ 5 & & & & ( @xmath16 ) & & 0.77 & 0.58 & 6.65 & 10.0 & sw.gg + 2356.2 _ 5 & & & & ( @xmath12 ) & & 0.63 & 0.61 & 4.61 & 21.5 & sw.ig + 2375.5 _ 8 & & & & ( @xmath12 ) & & 0.78 & 0.60 & 4.87 & 22.0 & sw.ig + 2398.3 _ 9 & & & & ( @xmath16 ) & & 0.76 & 0.75 & 7.36 & 11.0 & sw.gg + 2408.8 _ 9 & & & & ( @xmath34 ) & & 1.87 & 1.28 & 2.34 & 60.0 & sw.ii + 2441.7 _ 5 & & & & ( @xmath12 ) & & 0.71 & 0.51 & 10.32 & 47.0 & sw.ig + 2456.8 _ 5 & & & & @xmath1 & & 16.18 & 1.27 & 0.53 & 5.20 & sw.ii + 2476.7 _ 5 & & & & ( @xmath12 ) & & 0.62 & 0.52 & 10.38 & 48.0 & sw.ig + 2494.1 _ 5 & & & & ( @xmath12 ) & & 0.65 & 0.47 & 12.74 & 63.5 & sw.ig + + _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ @xmath80 the value after subtracting a constant of 14 @xmath19b ( see text in sec . [ sec : dwba ] for explanation . + lclclc + e [ kev ] & @xmath81 & e [ kev ] & @xmath81 & e [ kev ] & @xmath81 + + + 2513.5 _ 7 & 2.00 & 2742.3 _ 4 & 5.50 & 3035.6 _ 9 & 0.95 + 2531.5 _ 7 & 6.60 & 2763.7 _ 4 & 8.60 & 3046.4 _ 6 & 2.10 + 2536.8 _ 9 & 3.20 & 2781.4 _ 5 & 1.75 & 3059.2 _ 5 & 2.15 + 2542.4 _ 9 & 1.85 & 2798.6 _ 8 & 1.55 & 3075.2 _ 5 & 2.20 + 2554.5 _ 5 & 6.00 & 2805.6 _ 7 & 2.00 & 3085.2 _ 8 & 1.25 + 2566.3 _ 6 & 2.20 & 2821.0 _ 5 & 2.90 & 3097.0 _ 6 & 3.10 + 2595.4 _ 5 & 5.40 & 2839.3 _ 6 & 1.30 & 3104.7 _ 6 & 3.40 + 2606.1 _ 5 & 23.5 & 2853.7 _ 5 & 2.75 & 3112.7 _ 11 & 1.70 + 2615.1 _ 9 & 0.15 & 2868.1 _ 5 & 3.20 & 3119.9 _ 9 & 2.30 + 2634.8 _ 5 & 1.60 & 2877.5 _ 8 & 1.80 & 3128.2 _ 10 & 1.25 + 2644.0 _ 3 & 9.20 & 2883.7 _ 9 & 1.60 & 3158.8 _ 8 & 1.50 + 2657.1 _ 4 & 5.20 & 2918.8 _ 6 & 1.85 & 3165.7 _ 6 & 2.00 + 2660.1 _ 5 & 6.00 & 2927.4 _ 5 & 3.25 & 3186.0 _ 6 & 2.00 + 2667.1 _ 5 & 3.30 & 2936.8 _ 9 & 1.40 & 3195.2 _ 6 & 2.60 + 2676.0 _ 6 & 67.2 & 2945.3 _ 9 & 1.35 & 3209.6 _ 12&1.40 + 2688.4 _ 4 & 2.10 & 2955.1 _ 8 & 1.25 & 3214.8 _ 9 & 2.20 + 2695.6 _ 7 & 1.10 & 2993.1 _ 12 & 1.00 & 3225.0 _ 20 & 0.50 + 2705.5 _ 5 & 1.35 & 2999.5 _ 10 & 1.50 & 3232.9 _ 13 & 1.20 + 2718.4 _ 5 & 2.10 & 3014.3 _ 11 & 0.80 & 3239.9 _ 8 & 3.40 + _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ the spins of the excited states in the final nucleus @xmath0th were assigned via an analysis of the angular distributions of tritons from the ( p , t ) reaction . the angular distributions for @xmath1 excitations have a steeply rising cross section at very small reaction angles , and a sharp minimum at a detection angle of about 14@xmath23 . this pronounced feature helped to identify most of these states in complicated and dense spectra , even without fitting experimental angular distributions . no complication of the angular distributions was expected , since the excitation of @xmath1 states predominantly proceeds via a one - step process . this is not the case for the excitation of states with other spins , where multi - step processes could play a very important role . the identification of these states is possible by fitting the experimental angular distributions with those calculated in the distorted - wave born approximation ( dwba ) . the potential parameters suggested by becchetti and greenlees @xcite for protons and by flynn _ @xcite for tritons were used in the calculations . these parameters have been tested via their description of angular distributions for the ground states of @xmath0th , @xmath7th and @xmath8u @xcite . minor changes of the parameters for tritons were needed only for some @xmath16 states , particularly for the states at 396.9 and 1016.4 kev . for these states , the triton potential parameters suggested by becchetti and greenlees @xcite were used . for each state the binding energies of the two neutrons are calculated to match the outgoing triton energies . the corrections to the reaction energy are introduced depending on the excitation energy . for more details see @xcite . a problem arising in such calculations is the lack of prior knowledge of the microscopic structure of these states . we can assume , however , that the overall shape of the angular distribution of the cross section is rather independent of the specific structure of the individual states , since the wave function of the outgoing tritons is restricted to the nuclear exterior and therefore to the tails of the triton form factors . to verify this assumption , dwba calculations of angular distributions for different @xmath31 transfer configurations to states with different spins were carried out in our previous paper @xcite . the coupled - channel approximation ( chuck3 code of kunz @xcite ) was used in these calculations . indeed , the calculated angular distributions are very similar . nevertheless , they depend to some degree on the transfer configuration , the most pronounced being found for the 0@xmath4 states , what is confirmed by the experimental angular distributions . the best reproduction of the angular distribution for the ground state was obtained for the transfer of the @xmath82 configuration in the one - step process . this orbital is close to the fermi surface and was considered as the most probable one in the transfer process . other transfer configurations that might be of importance are @xmath83 and @xmath84 , also near the fermi surface . better reproduction of the angular distribution for some @xmath1 states is obtained just for these configurations . the main features of the angular distribution shapes for 2@xmath4 and 4@xmath4 states are even more weakly dependent on the transfer configurations . nevertheless the @xmath82 , @xmath83 and @xmath84 configuration , alone or in combination , were used in the calculations for these states too . results of fitting the angular distributions for the states assigned as @xmath1 excitations are shown in fig . [ fig : angl_distr_0 + ] . the agreement between the fit and the data is excellent for most of the levels . remarks are needed only for the levels at 1531.7 and 2335.9 kev . the spin @xmath43 was assigned to the level at 1531.47 kev in @xcite . a level at the close - lying energy of 1531.7 kev has been observed also in the ( p , t ) reaction , but the angular distribution of tritons can not be fitted by calculations for transition to the @xmath43 state . the maximum cross section for forward angles suggests the presence of a @xmath1 excitation , though the angular distribution fitted by a calculation for transfer of the @xmath83 configuration to the @xmath1 state is not perfect . a satisfactory fit of the experimental angular distribution was obtained assuming overlapping states with spins @xmath1 and @xmath43 ( fig . [ fig : angl_distr_0 + ] ) , thus confirming the assignment for both states . an ambiguous picture is observed for the 2335.9 kev state , where the angular distribution is measured for a limited range of angles . the fitting agreement is perfect for a transition to the 4@xmath4 state , but the cross section is surprisingly large for a 4@xmath4 state , twice larger than for the @xmath34 member of the g.s . band . therefore , the possibility of a 0@xmath4 excitation can not be excluded , but the experimental angular distribution is fitted for a @xmath1 state only with adding a constant of 14 @xmath19b . this ambiguity can be resolved by measurements in wider angular regions . thus we can make firm @xmath1 assignments for 17 states for energies excitations below 2.5 mev , in comparison with 12 states found in the preliminary analysis of the experimental data @xcite . of course , some higher lying 0@xmath4 levels are lost because of the cutoff of the investigated energy region . but as follows from a similar study for @xmath7th , only a few @xmath1 states are observed above 2500 kev , where the density of @xmath1 excitations decreases for higher energies ( or else that the cross section of such excitations is very low and they are hidden in very dense and complicated spectra ) . therefore , we can compare 24 @xmath1 states in @xmath7th with only 17 @xmath1 states in @xmath0th in the same energy region . similar to @xmath1 excitations , the one - step transfer calculations give a satisfactory fit of angular distributions for about 80% of the states with spins different from @xmath1 , but about 20% of these states need the inclusion of multi - step excitations . multi - step excitations have to be included to fit the angular distributions already for the @xmath12 , @xmath34 and @xmath2 states of the g.s . band . [ fig : schemes ] shows the schemes of the multi - step excitations , tested for every state in those cases , where one - step transfer did not provide a successful fit . [ fig : angl_distr_natur ] demonstrates the quality of the fit of some different - shaped angular distributions for the excitation of states with spin @xmath12 by calculations assuming one - step and one - step plus two - step excitations , respectively . results of similar fits for the states assigned as @xmath34 , @xmath2 and @xmath14 , @xmath16 , @xmath35 excitations are shown in fig . [ fig : angl_distr_unnatur ] . the assignments of the spins resulting from such fits are presented in table [ tab : expei ] , together with other experimental data . special comments are needed for the column displaying the ratio @xmath85 . calculated cross sections for the specific transfer configurations differ very strongly . since we have no a priori knowledge of the microscopic structure of the excited states , and thus do not know the relative contributions of the specific @xmath31 transfer configurations to each of these states , these ratios can not be considered as spectroscopic factors . nevertheless , a very large ratio , such as in the case of the @xmath83 transfer configurations used in the calculation for some @xmath1 and even @xmath12 and @xmath34 states , is unexpected . surprisingly , the shape just for this neutron configuration gives the best agreement with experiment . some additional comments on table [ tab : expei ] are needed . in all cases , where the firm assignment were known from the previous studies @xcite , they are confirmed by the ( p , t ) angular distribution analysis . in those cases , where two or three possible spin assignments were proposed earlier , the ( p , t ) angular distribution analysis allows to select only one assignment almost in all cases . for the energies above 2030 kev only the assignments from the ( p , t ) reaction are possible at present . the following remarks are needed in those cases , where the assignments from different publications are in contradiction , which can be removed using the data from the ( p , t ) reaction . _ 938.7 kev . _ spin @xmath15 was assigned for this level in @xcite . our fit of the angular distribution gives reliably spin @xmath1 in agreement with @xcite . _ 943.8 kev . _ spin @xmath12 was assigned for this level in @xcite . the angular distribution rejects this value and agrees with the assignment of spin @xmath14 accepted in @xcite . _ 968 - 969 kev . _ three levels around 968 kev with spins @xmath86 were identified in @xcite and two levels with spins @xmath87 in @xcite . there is a discrepancy in assignment for the 968.33 kev level as @xmath16 in @xcite and as @xmath15 in @xcite . this line is masked in the ( p , t ) spectrum by a strong line from the transition to the 969 kev level . but since the angular distribution is very well described by a calculation leading to a @xmath12 state and is not disturbed by a transition to spin @xmath16 , the assignment @xmath15 is preferable ( transition is weak ) . _ 1016.4 kev . _ the discrepancy in assignment for the 1016.4 kev level as @xmath12 in @xcite and as @xmath16 in @xcite can not be removed by the ( p , t ) angular distribution , since it can be fitted by a transition sw.ig to @xmath12 and m3a.gg to @xmath16 , respectively . however , transitions seen in the decay of @xmath0pa @xcite from this state to the @xmath35 and @xmath34 states leads to the assignment of @xmath16 . we accepted this spin also due to strong arguments in @xcite , including the assignment of spins @xmath15 and @xmath14 to the levels at 968.3 kev and 943.8 kev as members of the @xmath88 band . _ 1059.9 kev . _ from the tentative assignments @xmath89 in @xcite and the firm assignment @xmath45 in @xcite for this level , the latter has to be additionally supported by the fact , that the corresponding line in the ( p , t ) spectrum was not seen ( transition to the state of unnatural parity ) . _ 1225.7 and 1226.56 kev . _ spin @xmath45 was assigned for the level 1226.56 kev in both @xcite and @xcite . the level with the close energy 1225.7 kev is seen in the ( p , t ) reaction , but the angular distribution agrees with the assignment of spin @xmath34 . therefore both levels are present in table [ tab : expei ] . _ 1393.4 kev_. this level was observed in the decay of @xmath0pa with restriction of the spin - parity to @xmath90 , @xmath91 and @xmath16 by its population and depopulation @xcite . additional restriction from the @xmath92 angular distribution ratio indicates that this level has most likely @xmath93 and that the @xmath12 and @xmath16 assignments are nearly excluded . this level was not observed in the ( p , t ) reaction , thus supporting such conclusion . _ 1415.8 kev . _ spin @xmath12 was assigned to this level in @xcite and spins @xmath12 or @xmath16 were allowed in @xcite . the angular distribution of tritons gives preference to spin @xmath16 . _ 1432.1 kev . _ the discrepancy between @xmath43 in @xcite and @xmath34 in @xcite for the 1432.1 kev level is removed already by the fact of the excitation of this state in the ( p , t ) reaction , and additionally by the angular distribution leading to the @xmath34 assignment . also additional lines observed in the decay of @xmath0pa @xcite , leading to the 6@xmath4 level , confirm this assignment . _ 1450.29 kev . _ spin @xmath16 was assigned to this level in @xcite and spin @xmath45 in @xcite . the fact that this level is not observed in the ( p , t ) reaction gives preference for an assignment of spin @xmath45 not excluding spin @xmath16 . _ 1531.7 kev . _ spin @xmath43 was assigned for the level at 1531.47 kev both in @xcite and @xcite . however , the angular distribution of tritons for the level with the close - lying energy 1531.7 kev indicates another spin value . it has a steeply rising cross section at small angles as for a @xmath1 excitation , however , the minimum at a detection angle about @xmath94 is not sharp . therefore we assumed an overlapping of peaks of two levels , one of which is a @xmath1 level . _ 1643.8 kev . _ there are two close - lying levels at 1643.18 kev with spin 2@xmath95 or 3@xmath95 identified both in @xcite and @xcite and 1643.8 kev , respectively , as identified in @xcite with an assignment of possible spins ( 2,3,4)@xmath4 . only the level at 1643.8 kev is observed in the ( p , t ) reaction with clear assignment of spin 4@xmath4 . _ 1733.8 kev . _ we assumed that the level at 1735.6 kev , identified as a 4@xmath4 state in @xcite and as 2@xmath4,3,4@xmath4 state in @xcite , and the level at 1733.8 kev seen in the ( p , t ) reaction with an assignment of spin 4@xmath4 are identical , though the energy difference is larger than the energy error . _ 1742.8 kev . _ spin 3 was assigned to the level at 1743.86 kev in @xcite and spin 4@xmath4 in @xcite . the angular distribution from the ( p , t ) reaction prefers the assignment of spin 4@xmath4 . _ 1758 - 1760 kev . _ several close - lying levels were identified at 1757.9 kev with spin @xmath71 @xcite , at 1758.24 kev with spin ( 3,4)@xmath4 @xcite , at 1760.25 kev with spin 4@xmath4 @xcite and with spin @xmath96 @xcite . different @xmath11-lines were used in the identification of the levels at 1757.9 and 1758.24 kev : 741.9 , 1361.4 , 1430.0 kev for the first one and 1571.52 and 1700.59 kev for the latter . at the same time , in @xcite the line at 1430.0 kev was used for the identification of another level at 1617.74 kev , and the important line at 1758.24 kev was used for the identification of the level at 1944.85 kev . the line at 1758.11 kev can be attributed to the decay of the level at 1758.24 kev , then the spin of this state distinctly has to be @xmath12 . the ambiguity can not be solved with the ( p , t ) data . therefore we put the level at 1758.1 kev with an assignment of spin @xmath12 from the ( p , t ) study in correspondence with the level at 1757.9 kev in @xcite , but for the level at 1758.24 kev in @xcite we do not exclude the spin @xmath12 , too . as far as the level at 1760.25 kev is concerned , a spin @xmath12 can be nearly excluded , since this line is not observed in the ( p , t ) reaction . _ 1796.8 kev . _ two close - lying levels were identified : 1795.9 kev with an assignment @xmath89 in @xcite and 1796.4 kev with an assignment as @xmath69 in @xcite . the level at 1796.8 kev with spin @xmath34 is observed in the ( p , t ) reaction . it is problematic to put this level in correspondence with one of the observed ones in decay , considering the assignments . therefore only energetic proximity was taken into account . _ 1908.9 kev . _ the level at 1908.4 kev , @xmath51 was identified in @xcite , however , a level with almost the same energy of 1908.9 kev as observed in the ( p , t ) reaction was clearly identified as a @xmath1 state , they must be considered as a different levels . _ 2010.4 kev . _ there is discrepancy in the assignment of spin to the level at 2010.15 kev : @xmath97 in @xcite and @xmath34 in @xcite . the angular distribution from the ( p , t ) reaction prefers spin @xmath48 . + cccccccccc + @xmath1 & @xmath90 & @xmath12 & @xmath43 & @xmath34 & @xmath46 & @xmath2 & @xmath98 & @xmath99 & + + 0.0 & & 57.8 & & 186.8 & & 378.2 & & 622.5 & + 831.9 & & 874.4 & & 968.4 & & 1105.5 & & 1281 & + & & 968.8 & 1022.5 & 1091.0 & 1174.5 & 1270.2 & 1380 & 1497 & + & & 1153.5 & 1200.5 & 1261.5 & & & & & + 938.6 & & 979.5 & & 1074.8 & & & & & + 1120.1 & & 1175.4 & & 1290.2 & & 1470.0 & & & + & & 1319.2 & & 1432.0 & & & & & + 1511.2 & & 1544.4 & & 1618.3 & & & & & + & & 1638.3 & 1688.4 & 1760.2 & & & & & + & & & & 1643.8 & & ( 1812.7 ) & & & + ( 1531.7 ) & & 1586.9 & & & & & & & + 1627.9 & & 1667.3 & & 1742.8 & & 1858.6 & & & + & & & & 1796.8 & & 1903.9 & & & + & & 1724.6 & 1760.3 & 1826.2 & & & & & + & & 1803.0 & & 1938.3 & & & & & + & & 1898.2 & 1937.2 & 1987.5 & & & & & + & & 1899.98 & 1944.85 & ( 2010.17 ) & & & & & + 1908.9 & & 1947.8 & & 2037.0 & & & & & + 2079.9 & & 2111.6 & & & & & & & + 2131.3 & & 2170.3 & & & & & & & + 2290.0 & & 2323.2 & & & & & & & + ( 2335.9 ) & & 2375.5 & & & & & & & + + @xmath100 & @xmath14 & @xmath15 & @xmath16 & @xmath45 & @xmath35 & @xmath101 & @xmath38 & @xmath102 & @xmath41 + + @xmath13 & 328.0 & & 396.9 & & 519.2 & & 695.6 & & 920.6 + @xmath14 & 943.8 & 968.3 & 1016.4 & 1059.2 & 1143.2 & & & & + @xmath15 & & 1122.9 & 1168.4 & 1226.6 & 1297.3 & & & & + @xmath16 & & & 1344.0 & & 1497.7 & & & & + after the assignment of spins to all excited states , those sequences of states can be identified , which show the characteristics of a rotational band structure . an identification of the states attributed to rotational bands was made on the basis of the following conditions : \a ) the angular distribution for a band member candidate state is fitted by dwba calculations for the spin necessary to put this state in the band ; \b ) the transfer cross section in the ( p , t ) reaction to states in the potential band has to decrease with increasing spin ; \c ) the energies of the states in the band can be fitted approximately by the expression for a rotational band @xmath103 with a small and smooth variation of the inertial parameter @xmath104 . collective bands identified in such a way are shown in fig . [ fig : bands ] and are listed in table [ tab : bands ] ( for a calculation of the moments of inertia ) . the procedure can be justified in that some sequences meeting the above criteria are already known from gamma - ray spectroscopy to be rotational bands @xcite , so similar sequences are rotational bands , too . the straight lines in fig . [ fig : bands ] strengthen the argument for these assignments . it is worth mentioning , that the assignments of @xmath1 even for the states at 1531.7 and 2335.9 kev are supported by one @xmath12 state on top of them . the bands built on states of one - phonon octupole - quadruplet ( the band @xmath88 was not correctly identified in @xcite ) , the band with @xmath105 , 831.9 kev @xcite , @xmath105 , 938.6 , 1120.1 kev @xcite and @xmath106 , 968.8 and 1153.5 kev @xcite were identified earlier . additional levels are added to these bands from the ( p , t ) study ( table [ tab : bands ] ) . two bands with @xmath106 are added in table [ tab : bands ] , based only on the analysis of the decay of @xmath0ac @xcite : at 1638.23 kev and at 1899.98 kev . there is only contradiction in the spin assignment for the 2010.17 kev level . the ( p , t ) data do not support spin @xmath34 and prefer a @xmath12 assignment instead . in fig . [ fig : moments ] we present moments of inertia ( moi ) obtained by fitting the level energies of the bands displayed in fig . [ fig : bands ] by the expression @xmath107 for close - lying levels , i.e. they were determined for band members using the ratio of @xmath108 and @xmath109 $ ] , thus saving the spin dependence of the moi . this procedure is valid for all bands except the 943.8 kev , @xmath14 band . the usual procedure leads to strongly staggering values . in the case of the @xmath110 and @xmath111 bands , the coriolis interaction mixes the band members only for @xmath112 odd . the @xmath112 even members of the @xmath111 band remain unperturbed . in a simple two level model ( @xmath110 and @xmath111 bands ) the following expression can be obtained for the band energies @xmath113 where @xmath114 and @xmath115 , @xmath116 and @xmath117 are the intrinsic bandhead energies , @xmath118 is the inertial parameter and @xmath119 is the strength of the coriolis interaction , which is believed to be small . an effective parameters of inertia behaves then as @xmath120 + fitting these expressions to the experimental data gives the smoothly changing values of the moment of inertia between 76.9 and 78.6 as shown in fig.[fig : moments ] with parameter @xmath121 ( thus staggering is removed ) . in most cases moi slightly increase with the increasing spin . there are few cases of @xmath1 bands where moi are sloping down . this can be explained as an effect of the coriolis interaction of a 2qp @xmath122 band with a nearby lying 2qp @xmath123 band ( not seen in the ( p , t ) reaction ) . a similar effect was observed e.g. in @xmath124er for the @xmath16 and @xmath45 2qp bands @xcite . in @xmath0th an additional moi even - odd spin staggering is expected for the @xmath123 band similar to that for the octupole @xmath88 band since the odd spin states of the @xmath123 band have no counterparts in the @xmath105 band . the obtained moi cover a broad range , from @xmath12550 mev@xmath126 to @xmath125100 mev@xmath126 . the negative parity bands based on the states with spin 1@xmath95 , interpreted as the octupole - vibrational bands @xcite , have high moi . the @xmath1 band at 1120.1 kev , considered as @xmath5 - vibrational band , has the smallest moi , close to the one of the ground - state band . at this stage , it is difficult to state a complete correlation between the intrinsic structure of the bands and the magnitude of their moi . nevertheless , one can assume for the @xmath1 bands that some of the larger moi could be related to the two - phonon octupole structure and the smallest moi could be related to the one - phonon quadrupole structure . the bands with intermediate values of the moi could be based on the two - phonon quadrupole excitations . if the moments of inertia do indeed carry information on the inner structure of the bands , then the number of excitations with a structure as in the g.s . or @xmath5-vibrational states in @xmath0th is small . the lowest negative - parity excitations with @xmath17 are generally interpreted as octupole vibrational . they are one - phonon octupole excitations . the corresponding energies in @xmath0th as 328.0 , 944.2 , 1123.0 , and 1344.0 kev were established already in @xcite . here we confirmed these assignments after the removal of some ambiguities . they are the bandheads of the rotational bands which are displayed in fig . [ fig : quadruplet ] together with the ( p , t ) cross sections and their parameters @xmath104 . in the case of @xmath7th , the assumption was made that the strongly excited first 0@xmath4 state , together with also strongly excited states with spins 2@xmath4 and 4@xmath4 , accompanied by somewhat weaker excited state with spin 6@xmath4 , belong to the two - phonon octupole quadruplet @xcite . strong excitations and close rotational parameters were the arguments for assigning the same structure to these states . as one can see in fig . [ fig : strength ] , the first 0@xmath4 state in @xmath0th at 831.9 kev is also strongly excited . taking into account the decay properties of the band on this 0@xmath4 state , the suggestion was made that this band has an octupole two - phonon structure @xcite . the picture for other states is not so transparent . there is no prominent excitation strength of the @xmath12 and @xmath34 states just above this 0@xmath4 state . the first excited 2@xmath4 state , which is not a member of the 0@xmath4 band , is the state at 968.8 kev . but the de - excitation of the band built on this state demonstrates the properties expected for a @xmath11-vibrational band . moreover , its moment of inertia is much smaller than the one derived for the 0@xmath4 band at 831.9 kev . for the band built on the @xmath12 state at 1153.3 kev , the moment of inertia is close to the one of the band built on the @xmath1 state at 831.9 kev and the state at 1153.3 kev is relatively strong excited in the ( p , t ) reaction . the @xmath34 and @xmath2 states , which do not belong to rotational bands , which are strongly excited in the ( p , t ) reaction and could be members of the two - phonon octupole quadruplet , are the states at 1643.8 and 1905.8 kev . the level at 1812.7 kev , tentatively assigned as a @xmath2 state , can be attributed to the band based on the @xmath34 state , the corresponding inertial parameter again is very close to the one for @xmath1 and @xmath12 bands . no members of a rotational band can be related to the @xmath2 band head at 1905.8 kev . in the interacting boson model ( ibm ) , the positive - parity states are described by introducing @xmath127 and @xmath128 bosons , while for the negative parity states one has to introduce additional bosons with odd values of angular momentum ( at least one @xmath129 boson ) . in the region of transitional actinides , where octupole deformation might develop , the ibm-@xmath130 ( which uses @xmath131 and @xmath129 bosons ) was applied with success in refs . @xcite . in the present paper , we adopt the ibm-@xmath130 framework for calculating the low - lying positive and negative parity states in @xmath0th . in ref . @xcite , the ibm calculations for this nucleus have been already performed . however , these calculations used only a simplified hamiltonian to describe the existing ( up to that date ) electromagnetic data . more recent calculations ( which also used a simplified hamiltonian ) @xcite indicated that ibm fails completely to reproduce the ( p , t ) spectroscopic factors . the calculated first excited states were found with a transfer strength of @xmath1321@xmath133 of that of the ground state and the higher states were even weaker , whereas experimentally the first excited state is seen with @xmath13230@xmath133 of the ground - state intensity . in order to treat these spectroscopic observables in a reasonable approach , we used the method suggested in ref . @xcite , where it was shown that the addition of the second - order o(5 ) casimir operator in the hamiltonian can account for the observed ( p , t ) spectroscopic factors . the hamiltonian employed in the present paper is similar to the one used in refs . @xcite and is able to describe simultaneously the positive and negative parity states : @xmath134^{(0)}\label{eq1},\end{aligned}\ ] ] where @xmath135 , @xmath136 , and @xmath137 are the boson energies and @xmath138 , @xmath139 , and @xmath140 are the boson number operators , @xmath141 is the quadrupole - quadrupole interaction strength and @xmath142 is the strength of the o(5 ) second order casimir operator . in the @xmath130 model , the quadrupole operator is considered as being @xcite : @xmath143^{(2)}\nonumber\\ + \chi^{(2)}_{pf } \left\ { \frac{9\sqrt{3}}{10}(p^{\dagger}\tilde{p})^{(2)}+\frac{3\sqrt{42}}{10}(f^{\dagger}\tilde{f})^{(2)}\right\}\label{eq2}\end{aligned}\ ] ] the quadrupole electromagnetic transition operator is : @xmath144 where @xmath145 represents the boson effective charge . to ensure no - vanishing e2 transitions between the states containing no @xmath146 bosons and those having @xmath147 components we follow the approach described in refs . @xcite , where the mixing of different positive parity - states with different @xmath146 components is achieved by introducing in the hamiltonian a dipole - dipole interaction term of the form : @xmath148 where @xmath149^{(1 ) } + \sqrt{5}[{s}^{\dagger}\tilde{p}+{p}^{\dagger}\tilde{s}]^{(1)}\\\nonumber + \sqrt{7}[{d}^{\dagger}\tilde{f}+{f}^{\dagger}\tilde{d}]^{(1)}\label{eq7}\end{aligned}\ ] ] is the dipole operator arising from the @xmath150(4 ) dynamical symmetry limit , which does not conserve separately the number of positive and negative parity bosons @xcite . this term will also be important later in the calculations of the two - neutron transfer intensities . the interaction strength is given by the @xmath10 parameter and is chosen to have a very small value , @xmath10=0.0005 mev , similar to refs . @xcite . for the @xmath151 transitions , a linear combination of the three allowed one - body interactions was taken : @xmath152\label{eq4},\end{aligned}\ ] ] where @xmath153 is the effective charge for the @xmath151 transitions and @xmath154 and @xmath155 are model parameters . the goal of the present paper is to describe simultaneously both the existing electromagnetic and the hadronic ( transfer strength ) data . to achieve this goal , two - neutron transfer intensities between the ground state of the target nucleus and the excited states of the residual nucleus were also calculated . the l=0 transfer operator may contain various terms , but we shall restrict our operator to the following form : @xmath156 where @xmath157 is the pair degeneracy of neutron shell , @xmath158 is the number of neutron pairs , @xmath159 is the total number of bosons , and @xmath160 , @xmath161 , and @xmath162 are constant parameters . the l=0 transfer operator contains two additional terms beside the leading order term , proportional to the bosonic @xmath163 operator @xcite . details about the contributions of different terms in calculating the ( p , t ) spectroscopic factors will be given in a forthcoming paper @xcite . the calculations were performed using the computer code octupole @xcite . the hamiltonian is diagonalized in a hilbert space with a total number of bosons @xmath164 . for the present calculations we used an extended basis allowing up to three negative parity bosons ( @xmath165=3 ) . the vibrational strengths used in the calculations are @xmath135=0.2 mev , @xmath136=1.0 mev , and @xmath137=1.1 mev , while the quadrupole - quadrupole interaction strength has a value of @xmath141=-21 kev . the strength of the o(5 ) second order casimir operator is set to @xmath166=0.053 mev , while the quadrupole operator parameters are ( @xmath167=-1.09 , @xmath168=-1 ) . the full spectrum of excited 0@xmath169 states obtained in the present experiment is displayed in fig . [ fig10 ] in comparison to the corresponding calculated values . in the energy range covered experimentally ( up to 2.5 mev ) , the ibm-@xmath130 calculations predict 10 excited 0@xmath169 states in comparison to the 17 experimentally observed 0@xmath169 excitations ( firm spin assignment ) . given that there was no attempt to fine tune the calculations to the empirical 0@xmath169 states , there is no point in invoking a precise energy cutoff for the ibm calculations . therefore , it is appropriate to look also above 2.5 mev , where there is a continuous spectrum of 0@xmath169 states consisting of 20 states up to 3.3 mev and as many as 30 up to 4 mev . the ibm predicts that some of these states are having 2@xmath146 bosons in their structure and are related ( according to ref . @xcite ) to the presence of double dipole / octupole excitations . for example , the boson admixtures for the first excited @xmath1 state are @xmath170=4.2 , @xmath171=1.4 , @xmath172=0.6 in comparison with those for the @xmath5-vibrational state as @xmath170=4.5 , @xmath171=0.006 , @xmath172=0.001 . however , the present data can not allow for a final decision on the nature of the 0@xmath169 states . additional experimental information is needed to measure the branching ratios and the absolute transition probabilities stemming from these states . in fig . [ fig10 ] , the 2@xmath169 and 4@xmath169 levels revealed in the present experiment are also compared to the predictions of the ibm . the experiment revealed 33 excited 2@xmath169 and 25 excited 4@xmath169 states up to 2.5 mev . in the same energy range , the calculations produced only 16 excited 2@xmath169 states and 15 4@xmath169 excitations . if one looks above this limit , the ibm predicts 32 excited 2@xmath169 states and 33 excited 4@xmath169 states up to 3.3 mev . .[be_ibm ] experimental and calculated b(e1)/b(e2 ) transition ratios in @xmath0th . the parameters of the @xmath151 operator are fitted to the experimental data available . [ cols="^,^,^,^,^,^,^",options="header " , ] in @xmath0th there are no lifetimes measured for the negative - parity states , hence no absolute transition probabilities could be extracted . therefore we would restrict the present discussion to reproducing the b(e1)/b(e2 ) ratios . a detailed comparison between the experimental data and the present calculations is presented in table [ be_ibm ] . the agreement is obtained by using @xmath153=0.005 @xmath173fm and @xmath145=0.19 @xmath173b as the effective charges in eq.([eq4 ] ) and ( [ eq3 ] ) , respectively . the remaining @xmath151 parameters are @xmath174=0.4 and @xmath175=-1.4 . the b(e1)/b(e2 ) ratios discussed in table [ be_ibm ] belong to the @xmath176=0@xmath177 ( the predicted double - octupole phonon band ) and @xmath176=0@xmath178 ( @xmath5-vibrational ) bands . the comparison between them is important , because it can be used as a tool for providing additional information about the nature of the @xmath176=0@xmath177 band . all the states belonging to this band are having 2 @xmath146 bosons in their structure in the ibm calculations and are supposed to have a double - octupole phonon character . further information confirming this hypothesis comes from the analysis of the @xmath151 and @xmath179 branching ratios . if the picture proposed by the ibm is correct , the states belonging to the @xmath176=0@xmath177 band will show strong transitions into the negative - parity states ( if they have a double - octupole character ) , while the levels stemming from the @xmath176=0@xmath178 ( @xmath5-band ) will show very weak @xmath151 transitions to these states . the experimental values in table [ be_ibm ] fully confirm this hypothesis , showing that the b(e1)/b(e2 ) ratios are at least one order of magnitude larger for the @xmath176=0@xmath177 band . in fig . [ fig11 ] , we display the calculated two - neutron intensities for @xmath0th in comparison to the integrated experimental cross sections normalized to that of the ground state . the calculations reproduce the strong excitation of the first 0@xmath4 state at 832 kev in good agreement with the experiment . the experimental spectrum of 0@xmath169 states is dominated also by a single state located at an energy of 2.1 mev , showing a high cross section of about 15@xmath133 of that of the ground state . in the ibm , there is predicted a state located at 2.1 mev , which have the transfer intensities of about 18@xmath133 . this state has a double - octupole phonon structure . another state at 2.29 mev with a relative cross section of about 7@xmath133 can be put in correspondence to the predicted in the ibm state at 2.2 mev also with a double - octupole phonon structure . the running sum in fig . [ fig11 ] is taken up to 3.25 mev , where another group of states with significant transfer strength is predicted by the ibm . the parameters from eq.([eq5 ] ) were estimated from the fit of the known two - neutron transfer intensities ( integrated cross sections ) in table [ tab : expei ] . the values employed in the present paper are @xmath160=1.3 mb / sr , @xmath161=-0.4 mb / sr , and @xmath162=0.03 mb / sr . the location and transfer intensity of the strongest states is very well reproduced by the calculations . because the calculated energy distribution of the 0@xmath169 states is underestimating the experimental data , this also affects the fragmentation of the transferred strength . however , the main characteristics are well reproduced by the present calculations . ( color online ) comparison between the experimental two - neutron transfer intensities ( panel ( a ) ) for the 0@xmath169 states and the ibm predictions ( panel ( b ) ) . in panel ( c ) the experimental versus computed running sum of the ( p , t ) strengths is given.,width=8 ] the ibm is a phenomenological approach . to gain a detailed information on the properties of the states excited in the ( p , t ) reaction , a microscopic approach is necessary . the ability of the qpm to describe multiple @xmath1 states ( energies , @xmath179 and @xmath180 strengths , two - nucleon spectroscopic factors ) was demonstrated for @xmath181gd @xcite . an extension of the qpm to describe the @xmath1 states in the actinides @xcite was made after our publication on the results of a preliminary analysis of the experimental data @xcite . these calculations are used to compare to the present detailed analysis of the experimental data for @xmath0th . as for the theoretical basis of the calculations , we refer to the publications @xcite . the experimental spectrum of the @xmath182 relative level reaction strength for the ( p , t ) transfer ( the ratios of the ( p , t ) strength for every state to those for the ground state ) is compared to the results of the qpm calculations in fig . [ fig : compil - zeroqpm ] . the ( p , t ) normalized transfer spectroscopic strengths in the qpm are expressed also as ratios @xmath183 ^ 2.\ ] ] the amplitude @xmath184 refers to the transitions to the @xmath112 members of the ground - state rotational band , i.e. to the ground state at an analysis of the @xmath1 excitations . the amplitude @xmath185 includes the transitions between the ground state and the one- and two - phonon components of the wave function . the numerical results of the calculations obtained according to the qpm investigation in the publication @xcite are provided to us by a. v. sushkov @xcite . the qpm generates 15 @xmath1 states below 2.5 mev , in fair agreement with the 17 firmly assigned states . the calculations reproduce the strong excitation of the first 0@xmath4 state in accordance with the experiment . in fig . [ fig : compil - zeroqpm ] , we present also the increments of the ( p , t ) strength ratios in comparison to those of the qpm calculated normalized spectroscopic strengths . as one can see , the calculations are in fair agreement with the experiment . the ( p , t ) strength for the questionable 0@xmath4 state at 2335.9 kev does not influence considerably the results of comparison ( hence it is not included in the comparison ) . visible deviation of calculated strength from experiment is seen above 2 mev . theory predicts many @xmath1 excitations at higher energies ( more than 80 states in the energy range below 4 mev ) , but with small strength . at the same time , two strong excitations are observed in the experiment at 2.13 and 2.29 mev ( see table [ qpm_structure ] ) , respectively . it is interesting to note that both the ibm and the qpm predict two strongly excited states and therefore a jump in the increments of the ( p , t ) strength in the vicinity of 2 mev , thus reproducing partly the sharp increase in the experimental increment . in these qpm calculations , the dominant phonon structure of the 0@xmath4 states in low part of energies is the one - phonon quadrupole nature . for higher energies admixtures of two quadrupole and two octupole phonons are present in the structure of these states , and for some of the states they became dominant . the relatively modest role of the octupole phonons in the structure of the low energy @xmath1 states is explained in @xcite by the enforcement of the pauli principle , leading to a spreading of the lowest two octupole phonon components among several qpm @xmath1 states and pushing them to higher energies . ccccccl @xmath186 & @xmath187 & @xmath188 & @xmath189 & @xmath190 & @xmath191 & structure from @xcite structure from@xcite + + 0@xmath192 & 0.832 & 0.8 & 0.724 & 0.236 & 0.281 & @xmath193 @xmath1940.3 $ ] + 0@xmath195 & 0.939 & 1.0 & 1.496 & 0.041 & 0.002 & @xmath196 @xmath1970.7 $ ] + 0@xmath198 & 1.120 & 1.2 & 1.570 & 0.008 & 0.001 & @xmath199 @xmath200 + 0@xmath201 & 1.511 & 1.4 & 1.831 & 0.013 & 0.021 & @xmath20221 $ ] @xmath203 + 0@xmath204 & 1.532 & & & 0.003 & & + 0@xmath205 & 1.628 & 1.6 & 1.950 & 0.058 & 0.089 & @[email protected] $ ] + 0@xmath208 & 1.691 & 1.7 & 1.962 & 0.008 & 0.046 & @xmath2096$]@xmath2104 $ ] + 0@xmath211 & 1.710 & 1.8 & 2.138 & 0.003 & 0.001 & @xmath2124$]@xmath2130.2 $ ] + 0@xmath214 & 1.750 & & & 0.011 & & + 0@xmath215 & 1.909 & 1.9 & 2.162 & 0.028 & 0.016 & @xmath2164;[(30)_1(30)_1]23$]@xmath217 + 0@xmath218 & 2.045 & & 2.190 & 0.003 & 0.008 & @xmath21987 $ ] + 0@xmath220 & 2.080 & & 2.270 & 0.028 & 0.013 & @xmath22132 $ ] + 0@xmath222 & 2.131 & & 2.290 & 0.150 & 0.008 & @xmath2236;[(31)_1(31)_1]7 $ ] + 0@xmath224 & 2.159 & & 2.334 & 0.007 & 0.001 & @xmath22587 $ ] + 0@xmath226 & 2.290 & & 2.350 & 0.067 & 0.003 & @xmath22765 $ ] + 0@xmath228 & 2.456 & & 2.359 & 0.003 & 0.001 & @xmath2293;[(30)_1(30)_3]3 $ ] + 0@xmath230 & 0.328 & 0.5 & & 0.005 & & @xmath231 + 1@xmath230 & 0.944 & 1.0 & & 0.002 & & @xmath232 + 3@xmath230 & 1.344 & 1.4 & & 0.002 & & @xmath2333 $ ] + 2@xmath192 & 0.969 & 1.0 & & 0.121 & & @xmath234 + 2@xmath195 & 1.153 & 1.3 & & 0.145 & & @xmath235 + 4@xmath192 & 1.432 & 1.5 & & 0.001 & & @xmath236 + @xmath237 data are taken from @xcite . @xmath238 data are taken from @xcite + crccrccrcccc k@xmath239 & e@xmath240 & i@xmath240 & & e@xmath241 & i@xmath241 & & e@xmath242 & i@xmath242 & & exp . ( 10@xmath243 b@xmath126 ) & qpm ( 10@xmath243 b@xmath126 ) + + 0@xmath169 & 831.8 & 0@xmath169 & & 328.0 & 1@xmath244 & & 57.8 & 2@xmath169 & & 5.1(4 ) & 2.25 + 0@xmath169 & 938.6 & 0@xmath169 & & 328.0 & 1@xmath244 & & 57.8 & 2@xmath169 & & 6.7(6 ) & 54.8 + 0@xmath169 & 1175.5 & 2@xmath169 & & 328.0 & 1@xmath244 & & 186.8 & 4@xmath169 & & 0.06(3 ) & 1.45 + besides the publication @xcite , other calculations of the same dubna group were carried out for a microscopic description of the level structure , and transition rates between excited states in @xmath0th , observed in the decay of @xmath0pa @xcite . the wave functions , the level energies from two publication in correspondence to the experimental ones and to the transfer factors are given in table [ qpm_structure ] . the transfer factors and also the moments of inertia are taken into account to put in correspondence the experimental and calculated levels . the large difference in the transfer factors is seen only for two levels at 2131 and 2290 kev . there is an essential difference in the energies of the lowest @xmath1 states in two publications , as they are more close to the experimental ones in @xcite . this is caused by the choice of the isoscalar quadrupole - quadrupole interaction strength stronger than the critical value in ref . @xcite . as a consequence the energy of the lowest collective @xmath1 state becomes imaginary and its properties such as the structure , e2 reduced transition probabilities and the transfer factor are partially transferred to the next @xmath1 collective state . among the transition properties , the calculated b(e1)/b(e2 ) ratios at the decay of some 0@xmath4 states are of special interest in this publication . we present here some data on the b(e1)/b(e2 ) ratios , in order to note the difference in the explanation of the experimental data by the qpm and the ibm . the calculated ratios for transitions from the @xmath245 , @xmath246 , and @xmath247 states to the octupole @xmath248 state and the ground state band are compared to experimental ratios in table [ be_qpm ] . as one can see from table [ qpm_structure ] and table [ be_qpm ] , the small admixtures of the octupole two - phonon components to the wave functions of the @xmath245 and @xmath246 states are responsible for the fast @xmath151 transitions . in the ibm , similar results are obtained for the @xmath245 state , having 2 @xmath146 bosons in their structure and which are supposed to have mainly a double - octupole phonon character ( see table [ be_ibm ] and corresponding discussion ) . at the same time , the b(e1)/b(e2 ) ratio is considerably smaller for the decay of the @xmath247 state , which is a @xmath5-vibrational state , again in agreement with the experiment . the same result is obtained in the ibm . generally , the qpm is quite accurate in nuclei with small ground - state correlations . these correlations increase with the collectivity of the first one - phonon states , which is exactly the case of the @xmath249 octupole phonon state in @xmath0th . to decrease the correlations the value of the octupole - octupole isoscalar interaction strength was diminished so that the calculated energy of the @xmath249 state was almost 200 kev higher than the experimental value @xcite . in addition , the effect of multi - phonon admixtures ( three and more phonons ) that pushes two - octupole phonon poles and consequently two - octupole phonon energies to lower values was then underestimated . in summary , the accuracy of the calculations of @xmath0th as stated in ref . @xcite is worse due to the increased ground - state correlations and the shift of two - phonon poles towards smaller energies . in future qpm studies one also has to take into account the spin - quadrupole interaction that is known to increase the density of low - lying @xmath1 states @xcite . at a microscopic approach there can be a few situations of structure of the @xmath182 states . a @xmath5-vibrational mode can be characterized by the relatively small two - nucleon transfer strength and a relatively large b(e2 ) value with a moment of inertia close to the one of the ground state . the large ratio b(e1)/b(e2 ) and the increase of the moment of inertia indicate the presence of the octupole two - phonon component . if a state has a relatively weak b(e2 ) value and also a weak two - nucleon transfer strength , but exhibits an increase of the moment of inertia , it should be a state with one dominant 2qp configuration . the pairing vibrational excitations can be characterized by their large two - nucleon transfer strengths and relatively small b(e2 ) values . it is clear that the first and second @xmath1 excited states can not be the @xmath5-vibrational states as usually is observed in deformed rare - earth nuclei since their moments of inertia are much larger than those of the ground state and also their ( p , t ) strengths are large . the actual @xmath5-vibrational state is observed at 1120 kev and it is excited very weakly in the ( p , t ) reaction . as we have seen , both the ibm and the qpm reproduce the @xmath182 relative level reaction strength for the ( p , t ) reaction and the b(e1)/b(e2 ) ratios of the decay of the lowest @xmath1 states reasonably well . at the same time , the nature of @xmath1 excitations in the qpm differs significantly from the one in the _ spdf_-ibm . in all low - lying states of the qpm calculations , quadrupole phonons are dominant and the octupole phonons are predicted to play a relatively modest role , whereas the ibm predicts the lowest @xmath1 state as having mainly 2@xmath146 bosons in their structure @xcite . the analysis of the lowest quadrupole phonon wave function in the qpm reveals that the backward rpa amplitudes @xmath250 contribute considerably to the relative ( p , t ) reaction strength thus indicating that the lowest excited @xmath1 state describe pairing vibrations arising from ground state fluctuations @xcite . for an additional hint to the nature of the lowest @xmath1 states , we include fig . [ fig : b(e1)-b(e2 ) ] with the b(e1)/b(e2 ) ratio stemming from the lowest excited states in @xmath0th and @xmath7th . intuitively , one would expect that a large b(e1)/b(e2 ) ratio might be characteristic for a two - octupole - phonon excitation , whereas a small ratio might indicate a shape oscillation . such a picture is observed for @xmath0th : large b(e1)/b(e2 ) ratios for the @xmath245 and @xmath246 states , and vanishing values for @xmath5- and @xmath11-vibrational states . the assumption in @xcite that just the two - phonon structure is a reason of the very strong excitation of the @xmath245 state in the ( p , t ) reaction has to be rejected , since the b(e1)/b(e2 ) ratio for the @xmath245 state in @xmath7th is small at strong excitation in the ( p , t ) reaction ( or the b(e1)/b(e2 ) ratio is no reliable manifestation of the two - phonon nature of a state ) . . in this aspect a comparison of the relative transfer strengths in the ( p , t ) reaction leading to the @xmath1 states in @xmath0th and the @xmath251 states in @xmath3pa ( data are taken from @xcite ) has to be considered additionally ( see fig . [ fig : b(e1)-b(e2 ) ] ) . since the ground - state spin in the target nucleus @xmath252pa is @xmath251 , just these spins are excited in a two - neutron @xmath253 transfer . @xmath3pa can be regarded as @xmath0th plus a strongly coupled proton . the rotational band built on the first @xmath251 excited state in @xmath3pa at 11.6 kev @xcite corresponds to the g.s . band in @xmath0th and is excited very strongly . the main component in the structure of the ground state in the target nucleus @xmath252pa is 1/2[530 ] @xcite . therefore the levels excited in the @xmath253 transfer are @xmath254 states and they are members of collective bands based on the state originating from coupling the @xmath255 state to the @xmath0th core - excited states . such bands , as identified in @xcite , can be used to derive the moments of inertia for at least three @xmath251 states . values of @xmath256 in mev@xmath126 are given below ( energies in @xmath3pa are relative to the lowest @xmath251 state ) + @xmath3pa : * 79.2*(0.0 kev ) , * 78.4*(703 kev ) , * 127.5*(830 kev ) + ( 1524 kev ) . + @xmath0th : * 51.9*(0.0 kev ) , * 70.3*(832 kev ) , * 73.2*(939 kev ) . + the moments of inertia in @xmath3pa are larger than those in @xmath0th which is a manifestation of the contribution of the odd proton . the large moment of inertia for the 830.5 kev state can probably be explained ( at least partly ) by neglecting the coriolis coupling when fitting the energies of the corresponding band . nevertheless the increment of the moment of inertia for the state at 830.5 kev relative to other states in @xmath3pa can be put in correspondence to similar increments for the states at 831.8 and 938.6 kev relative to the g.s . in @xmath0th . but this state , as well as other low - lying states in @xmath3pa , are only weakly excited in contrast to the strong excitation of the state 831.8 kev in @xmath0th . at the same time , the @xmath251 state at 1523.7 kev is excited strongly , but it can not be put in correspondence to the first excited state in @xmath0th : there is practically no increment of its moment of inertia relative to the lowest 3/2@xmath95 state . besides that , its energy is almost twice larger than the first excited @xmath1 state in @xmath0th . from the insufficient information we can only conclude that the 831.8 kev state in @xmath0th has the largest pairing vibrational component and in @xmath3pa the additional proton has the effect that the largest pairing vibrational component is moved to the 1523.7 kev state . no theoretical explanation was undertaken since the publication of the experimental results on @xmath3pa @xcite . it would be interesting to undertake the theoretical analysis of the excitations with the @xmath6 transfer in odd nuclei and first of all in the @xmath3pa nucleus . experimental study of excitations in other odd nuclei , as we have seen , may promise unexpected phenomena . as for the experimental evidence of the nature of other @xmath1 states , we have only the moments of inertia derived from the sequences of states treated as rotational bands and thus only tentative conclusions can be drawn about their structure . in contrast to @xmath7th @xcite , for which they are distributed almost uniformly over the region from 47 to 98 mev@xmath126 , the moments of inertia in @xmath0th have values close to 50 mev@xmath126 only for the g.s . , @xmath5-vibrational @xmath1 states and for the state at 1531.7 kev , all other @xmath1 states have larger values from 70 to 95 mev@xmath126 . this fact can indicate that corresponding states are possibly of two - phonon nature too , or two quasi - particle states with an admixture of the pairing vibrations . excited states in @xmath0th have been studied in ( p , t ) transfer reactions . 106 levels were assigned , using a dwba fit procedure , additionally only the energies are determined for 57 states . among them , 17 excited @xmath1 states have been found in this nucleus up to an energy 2.5 mev , most of them have not been experimentally observed before . their accumulated strength makes up for more than 70% of the ground - state strength . firm assignments have been made for most of the 2@xmath4 and 4@xmath4 states and for some of the 6@xmath4 states . these assignments allowed to suggest multiplets of states , which can be treated as one- and two - phonon octupole quadruplets , and to identify the sequences of states , which have the features of rotational bands with definite inertial parameters . moments of inertia are derived from these sequences . only for the g.s . and @xmath5-vibrational states and additionally for the state at 1531.7 kev ( for which the shape of the angular distribution is different from most other ones ) , the moments of inertia are about 50 mev@xmath126 . for all other states they are larger than 70 mev@xmath126 , i.e. the value for the first excited @xmath1 state . this information , together with the spectroscopic information on some @xmath257-transitions , were used for conclusions on the nature of the @xmath1 states . the experimental data have been compared to _ spdf_-ibm and qpm calculations . spectroscopic factors from the ( p , t ) reaction , and the trend in their change with excitation energy , are approximately reproduced by both the ibm and qpm for the 0@xmath4 states . a remarkable feature of the ibm and qpm is the prediction of strong first vibrational excitations , close in magnitude and position to the experimental ones . giving also an approximately correct number of @xmath1 states , these models provide different predictions for the structure of these states . the lack of additional information does not allow for final conclusions on the validity of the theoretical approaches . challenging experiments on gamma spectroscopy following ( p , t ) reactions would give much needed information . the work was supported by the dfg ( c4-gr894/2 - 3 , gu179/3 , jo391/2 - 3 , zl510/4 - 2 ) , mll , and us - doe , contract number de - fg02 - 91er-40609 , and cz.1.05/2.1.00/03.0082 . wirth , g. graw , s. christen , d. cutoiu , y. eisermann , c. gnther , r. hertenberger , j. jolie , a. i. levon , o. mller , g. thiamova , p. thirolf , d. tonev , and n. v. zamfir , phys . c * 69 * , 044310 ( 2004 ) . p. schuler , ch . lauterbach , y. k. agarwal , j. de boer , k. p. blume , p. a. butler , k. euler , ch . fleischmann , c. gnther , e. hauber , h. j. maier , m. marten - tolle , ch . schandera , r. s. simon , r. tolle , and p. zeyen , phys . b174 * , 241 ( 1986 ) . f. d. becchetti and g. w. greenlees , proc . third int . symp . on polarization phenomena in nuclear reactions , medison , 1970 , ed . h. h. barshall and w. haeberli ( university of wisconsin press , medison , 1971 ) p.68 g. graw , y. eisermann , r. hertenberger , h .- f.wirth , s. christen , o. moeller , d. tonev , j. jolie , c. guenther , a. i. levon , and n. v. zamfir , int . conf . on nucl . reaction mechanisms , varenna , italy , june 9 - 13 , 2003 .

the excitation spectra in the deformed nucleus @xmath0th have been studied by means of the ( p , t ) reaction , using the q3d spectrograph facility at the munich tandem accelerator . the angular distributions of tritons were measured for about 110 excitations seen in the triton spectra up to 2.5 mev . firm @xmath1 assignments are made for 17 excited states by comparison of experimental angular distributions with the calculated ones using the chuck3 code . assignments up to spin @xmath2 are made for other states . sequences of states are selected which can be treated as rotational bands and as multiplets of excitations . moments of inertia have been derived from these sequences , whose values may be considered as evidence of the two - phonon nature of most @xmath1 excitations . experimental data are compared with interacting boson model ( ibm ) and quasiparticle - phonon model ( qpm ) calculations and with experimental data for @xmath3pa .

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It’s clear, London has broken out from the mono rules about coffee just being black or white. Follow Susannah Butter: @susannahbutter ||||| Share this article with Google Plus Whatever people do to coffee, one thing tends to remain the same – its distinctly brown colouring. However much milk you might add, it’ll still stay on the brown side of beige. Free doughnuts are being given away next Friday on Shaftesbury Avenue And for those of us who like it pure, that rich burnt umber colour is part of the enjoyment of black coffee. All this time, we’ve taken the intrinsic brownness of coffee for granted. Until now. Someone has come up with Clear Coffee – ‘the first colourless coffee drink in the world’. It looks like water and supposedly tastes like coffee. It’s made from Arabica coffee beans and water and claims to be ‘produced by methods which have never been used before’. How does it taste? It’s odd but not unpleasant. In fact, it’s very drinkable. Imagine making a caffeine of coffee and then forgetting to wash it out. The next day, you add cold water to get the very last dregs of flavour out of the wet beans – and that’s what this tastes like. Water…but an aftertaste of coffee. Other hot takes from the desk include: Ellen (who doesn’t like coffee) – ‘I don’t mind it’. Rebecca (again, not a massive coffee-head): ‘it has the aftertaste of cheap wine and I can think of things I’d less rather drink. But it would taste delicious with a splash of rum’. It does strike me as solving an issue that probably didn’t need to be solved but nonetheless, it’s novel and refreshing. Founded by David Nagy and his brother Adam, CLR CFF – the company behind the coffee – claims that it’s ‘due to this combination of technology and high-quality ingredients (that) a drink has been developed which is unique in taste and flavour’. ‘If you are looking for a refreshing coffee but you want to keep your smile white, then Clear Coffee is perfect for you!’ David says that they came up with the idea for colourless coffee after struggling with teeth stains from his heavy coffee habit. They wanted to create a drink which would still satisfy the coffee cravings whilst being low in calories and kinder on enamel. Confusing. Very confusing. MORE: Apparently we should be adding salt – not sugar – to our coffees MORE: How to make your coffee truly Instagrammable according to an award-winning latte artist

– Two Slovakian brothers are promising to protect coffee lovers from stained teeth with a concoction they're calling the world's "first colorless coffee drink." It looks like a bottle of water, but CLR CFF is a "potent, cold brew," per the Evening Standard. Self-described heavy coffee drinker David Nagy says he came up with the idea with brother Adam while in London, and the brothers aren't sharing their production process except to say it involves methods never used before. They say it's safe, however, with arabica beans, water, and no chemicals or sweeteners. The label notes that a 200ml bottle has 100mg of caffeine, on par with a typical cup of coffee. So how does it taste? Metro UK proclaims it "odd but not unpleasant. In fact, it's very drinkable." But one of its tasters detects "the aftertaste of cheap wine" and suggests it would go well with a "splash of rum." In fact, mixologists are already putting the vowel-challenged beverage to that use, notes Refinery29. If you want to sample it, you'll have to go to London (Whole Foods is among the retailers stocking it there), or order it online, where a two-pack of 200ml bottles costs $7.50. Buzz is apparently growing, because the site warns that delivery could take up to four weeks thanks to a "huge amount of orders." (And introducing ... mushroom coffee.)

in this section we will derive some properties of squeezed states , mentioned in the main text , using algebraic properties of the creation - annihilation operators . first we will show the equivalence of the two alternative forms of squeezed states and second we will derive their coordinate space representation . _ to see that the state ( [ psit ] ) can also be written in the form @xmath45 for a suitable value @xmath106 and vice versa , one may notice that , due to the commutation relations ( [ ccr ] ) , the operators @xmath107 satisfy the @xmath105 algebra : @xmath108=\pm k_\pm$ ] and @xmath109=2k_0 $ ] , i.e. they are generators of the @xmath110 group . this allows us to `` _ _ disentangle _ _ '' the exponential operator @xmath111 , i.e. , to write it as a product of exponential operators @xmath112 . the values of the coefficients @xmath113 and @xmath114 as functions of @xmath115 can be derived , for example , by considering a finite matrix representation of the @xmath116 group ( whose algebra is trivially related to that of @xmath110 which , being a non - compact lie group , has no finite representation ) and simply solving a small set of equations @xcite @xmath117 it is then trivial to see that the disentangled operator acting on @xmath40 yields @xmath118 which is exactly ( [ psit ] ) for @xmath106 given by @xmath119 for the initial state wavefunction @xmath120 , noticing that the amplitude @xmath64 is real , and therefore so is @xmath49 , and that @xmath50 is essentially the generator of uniform coordinate scalings , we find from ( [ gsw ] ) and the above results @xmath121/4 } e^{\xi n [ 1+\ell ( n-1)]/2 -\frac12 { \omega}e^{2\xi } \sum_i x_i^2 } \delta(\{x_i\})^\ell { { \nonumber}\\ } & = \mathcal{n}_{n,\ell } \ ; { \omega}_0^{n[1+\ell ( n-1)]/4 } e^{-\frac12 { \omega}_0 \sum_i x_i^2 } \delta(\{x_i\})^\ell { { \nonumber}\\ } & = \psi_{gs}({\omega}_0;\{x_i\ } ) \label{a3}\end{aligned}\ ] ] which verifies that the squeezed vacuum state ( [ psi ] ) gives the correct pre - quench ground state wavefunction . we saw that the initial state @xmath33 corresponds , in coordinate space , to the wavefunction of the post - quench ground state rescaled by a factor @xmath47 . for the evolved state ( [ psit ] ) the amplitude @xmath122 is complex and the calculation of its coordinate space wavefunction is more elaborate . we first write the squeeze operator as @xmath123 and apply the disentanglement procedure to split it into separate exponential operators @xmath124 whose action on a coordinate space wavefunction is transparent . we find @xmath125 from which the evolved wavefunction turns out to be @xmath126}^{n [ 1+\ell ( n-1)]/4 } e^{-\frac12 { \left ( } \frac{1+\eta(t)}{1-\eta(t ) } { \right ) } { \omega}\sum_i x_i^2 } \delta(\{x_i\})^\ell \label{a5}\end{aligned}\ ] ] with @xmath127 , i.e. ( [ 5 ] ) in the main text . from the definition @xmath58 of the density moments and our result ( [ omegat ] ) for the density @xmath57 , we can derive their evolution in time @xmath128 as well as the corresponding time averages @xmath129 where @xmath130 . the @xmath131 s can be calculated explicitly @xmath132}\label{bn}\ ] ] where @xmath133 is the hypergeometric function . note that @xmath104 scales as @xmath134 in the thermodynamic limit , as expected . another interesting observable is the correlation of the positions of different particles @xmath135 which is @xcite @xmath136 after time averaging we have @xmath137 in contrast to the moments @xmath104 the above correlations do not depend explicitly on @xmath1 therefore they are relatively unimportant in the thermodynamic limit . [ [ derivation - of - the - expansion - of - time - averaged - moments - in - terms - of - the - iom ] ] derivation of the expansion of time averaged moments in terms of the iom ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ we will show that in the harmonic calogero model the set of time averaged observables @xmath97 can be expressed in terms of the integrals of motion @xmath138 with @xmath139 and their products @xmath140 with @xmath141 . it is instructive to start with the single harmonic oscillator case first , i.e. @xmath101 and @xmath142 . the operator @xmath143 is @xmath144 where @xmath145 and @xmath146 . evolving the operators in time ( in the heisenberg picture ) according to @xmath147 and @xmath148 and taking the time average , we notice that only the ( @xmath149 in number ) terms with equal number of @xmath150 and @xmath151 operators contribute @xmath152 these terms can be re - ordered , using the ccr , as alternating sequences of @xmath151 and @xmath150 , therefore giving @xmath153 for some appropriate combinatorial coefficients @xmath154 . one way to derive the latter is by first normal - ordering the terms in ( [ 2 ] ) and then re - expressing them in terms of @xmath155 . both steps are known in the literature @xcite @xmath156 and @xmath157 where @xmath158 are the stirling numbers of the first kind , so that @xmath159 from which we can read off the coefficients @xmath154 introduced above @xmath160 we can easily generalise to the case of @xmath161 noninteracting bosons , for which the above results give @xmath162 note that the knowledge of the values @xmath138 is equivalent to the information of how many particles occupy each of the excitation levels of the trap , since from their generating function @xmath163 one can derive the occupation number operator of the @xmath102-th level as @xmath164 where @xmath165 is the projector on the @xmath102-th level eigenstate of the @xmath15-th boson . in @xcite the set of iom used in the construction of the gge is the free fermion analogue of these occupation number operators of the trap levels . therefore for the gge in the interacting case , it is natural to choose the set ( [ iom1 ] ) which is the generalisation of the free boson or fermion sets . the interacting case @xmath100 is however different : due to the non - trivial commutation relations ( [ ccr ] ) , each time a swapping of two adjacent operators is needed in order to bring a term of ( [ 2 ] ) into the required alternating form , additional lower order terms appear that involve a sum over the exchange operator @xmath13 . for example , let us consider the term @xmath166 which needs only one swap of the 3rd and 4th operators in order to be brought into the right form . by doing so we get the extra term @xmath167 . moving the exchange operator to the left or right i.e. to the bra or ket , on which its action gives simply 1 , we change the particle index of the intermediate string of operators from @xmath14 to @xmath15 and as a result the final expression is @xmath168 , instead of @xmath169 as it would be if there was no exchange operator . in general we now have , apart from all previous terms , also all possible products @xmath170 where @xmath87 is any partition of the integer @xmath171 , thus leading to ( [ taevo ] ) in the main text . the combinatorial coefficients @xmath85 and @xmath86 at leading order in @xmath1 for the first few moments are @xmath172 where @xmath173 . in order to calculate the values of the iom @xmath75 in the initial state @xmath33 we could use the expansion ( [ psi ] ) of the latter in terms of the post - quench excitations on which the @xmath75 are diagonal . however the eigenvalues of @xmath75 on a general eigenstate are given only implicitly in the literature @xcite . an alternative route is instead to express the @xmath75 in terms of the pre - quench creation - annihilation operators using the inverse of the bogoliubov transformation ( [ bog ] ) , then normal - order the result using the pre - quench version of the ccr ( [ ccr ] ) and act on @xmath33 . we can omit all terms that would be impossible to contribute to the final expressions for the expectation values at _ leading order _ in @xmath1 . we observe that the leading order in @xmath1 contribution to the expectation values comes from all terms that when normal - ordered give the maximal power @xmath174 of the operator @xmath175 ( like e.g. the alternating term @xmath176 ) which in turn when acting on @xmath33 give simply @xmath177 . in other words , we find that @xmath178 for a suitable function @xmath179 . in the last equation the dots `` ... '' denote pre - quench excitations that are accompanied by coefficients of lower order in @xmath1 and do not contribute to the leading order expressions when we apply the state @xmath180 on the left . according to the above , the leading order expectation values of the iom on the initial state are @xmath181 next we consider the products of iom . if we start with a product of two iom @xmath182 we can readily see that , always to leading order in @xmath1 @xmath183 i.e. in general , products of iom can be constructed by introduction of @xmath184 between @xmath185 operators . therefore their study too reduces to a direct application of the previous observation and we have @xmath186 which proves the factorisation of the iom in the initial state at leading order in @xmath1 . as a verification of the consistency of our results , we compare the gge values of the first four moments , as given by ( [ mom ] ) along with ( [ iom2 ] ) , with the actual time averaged values , as given by ( [ mom0 ] ) and ( [ bn ] ) from which we have @xmath188 the agreement between these two independently derived results is indeed exact .

we consider a quantum quench of the trap frequency in a system of bosons interacting through an inverse - square potential and confined in a harmonic trap ( the harmonic calogero model ) . we determine exactly the initial state in terms of the post - quench eigenstates and derive the time evolution of simple physical observables . since this model possesses an infinite set of integrals of motion that allow its exact solution , a generalised gibbs ensemble ( gge ) , i.e. a statistical ensemble that takes into account the conservation of all integrals of motion , can be proposed in order to describe the values of local physical observables long after the quench . even though , due to the presence of the trap , physical observables do not exhibit equilibration but periodic evolution , such a gge may still describe correctly their time averaged values . we check this analytically for the local boson density and find that the gge conjecture is indeed valid , in the thermodynamic limit . _ introduction_. sparked by experimental findings in the field of ultracold atoms out - of - equilibrium @xcite , questions about the time evolution of quantum systems have become the subject of intense study . without doubt , the investigation of whether _ thermalization _ or some more general _ equilibration _ occurs when starting from an out - of - equilibrium initial state , has been established as the main objective ( @xcite for a review ) . a common protocol for the preparation of the initial state is a _ quantum quench _ , i.e. an instantaneous change of the parameters of the hamiltonian of the system so that the initial state is the ground state of the pre - quench hamiltonian . in integrable systems , i.e. 1d systems possessing an infinite number of local integrals of motion ( iom ) , the evolution is constrained by the extra conservation laws and thermalization is prevented . however a generalized relaxation incorporating the extra constraints is still possible and in fact it has been demonstrated that such a _ generalized gibbs ensemble _ ( gge ) describes the large time values of _ local _ physical observables in various settings @xcite . most analytical demonstrations of the validity of the gge refer to non - interacting systems or systems that can be mapped into non - interacting ones via some suitable nontrivial transformation @xcite with the few exceptions that refer to genuine interacting systems ( i.e. described by nontrivial scattering phase shifts ) , restricting to special classes of initial states @xcite . for such genuinely interacting systems even the derivation of gge predictions is a difficult task that has been accomplished for some models only recently @xcite . a common obstacle in the study of quantum quenches in these systems is the derivation of the expansion of the initial state on the eigenstates of the post - quench hamiltonian @xcite . despite the technical difficulties , testing the gge conjecture for a quantum quench in a genuinely interacting system is necessary , especially since in a non - interacting system the verification is somewhat expected because all observables can typically be derived by the iom themselves . moreover , unlike the physics of ground state or thermal equilibrium of an interacting system which is governed by its low energy properties that usually can be effectively described by a non - interacting model , this is certainly not true after a quantum quench , as far as the question of equilibration is concerned , since the high energy excitations play in general a significant role . in this letter we consider the harmonic calogero model ( hcm ) @xcite , i.e. a system of harmonically trapped particles interacting via an inverse - square potential . we restrict our attention to the case of bosonic elementary particles . the calogero model in infinite space and its variants in a harmonic trap or on a circle ( calogero - moser - sutherland models @xcite ) possess an infinite set of iom and , even though genuinely interacting , are well - known for exhibiting effectively free behaviour with generalized particle statistics @xcite . in the harmonic trap , the spectrum is equidistant and the hamiltonian can be diagonalised by means of creation - annihilation operators satisfying generalised canonical commutation relations ( ccr ) @xcite . this allows the exact derivation of the initial state after a quench of the trap frequency and the study of the subsequent time evolution . the existence of an infinite set of iom suggests that a gge may be applicable . however , due to the presence of the trap , the excitation levels are equidistant and the periodicity of the evolution does not allow equilibration of observables , even in the thermodynamic limit @xcite . in this case one may still apply a weak version of the gge conjecture ( cf . @xcite ) stating that it describes the _ time averages _ of local observables . despite the fact that in a trapped system the _ locality _ of the iom ( which is a characteristic feature of quantum integrability @xcite and is typically considered as a condition for the validity of the gge @xcite ) is lost or ambiguous , this conjecture has been recently verified in the case of the essentially non - interacting tonks - girardeau gas in a quenched trap @xcite . we derive analytically the gge predictions for the time averaged values of the local density of particles and compare them with their actual values . we show that the gge predicts _ correctly _ the actual values , when the thermodynamic limit is taken into account . _ the model_. the hcm is described by the hamiltonian @xmath0 where @xmath1 is the number of particles and @xmath2 the trap frequency . the interaction constant is more conveniently parametrized as @xmath3 . its ground state is given by the wavefunction @xmath4/4 } e^{-\frac12 \omega \sum_i x_i^2 } \delta(\{x_i\})^\ell \label{gsw}\ ] ] where @xmath5 is the vandermonde determinant and @xmath6 a normalisation constant . the ground state energy is @xmath7 $ ] . the local density in the ground state @xmath8 is given for large @xmath1 by the _ wigner semicircle _ distribution @xcite @xmath9 and zero otherwise . notice that the density is independent of @xmath10 , except through the cloud radius @xmath11 . one method to study this model and derive its energy eigenstates is by using the _ dunkl _ or _ exchange operator _ formalism @xcite , in which the interaction term is written as @xmath12 where @xmath13 is the so - called exchange operator that permutes the coordinates of two particles @xmath14 and @xmath15 . assuming that all particles are bosonic , the introduction of the exchange operator does not alter the physics . @xmath13 satisfies the properties @xmath16 , @xmath17 = 0 $ ] if @xmath18 distinct , @xmath19 if @xmath20 distinct and @xmath21 if @xmath20 distinct , @xmath22 for any operator @xmath23 . now defining creation - annihilation operators @xmath24 where @xmath25 , we find that they satisfy generalized canonical commutation relations ( ccr ) @xmath26 & = [ a_i^{\dagger},a_j^{\dagger}]=0 { { \nonumber}\\}[a_i , a_i^{\dagger } ] & = 1+\ell { \textstyle \ , \sum_{j\neq i } m_{ij } } { { \nonumber}\\}[a_i , a_j^{\dagger } ] & = -\ell m_{ij } \quad \text { if } i\neq j \label{ccr}\end{aligned}\ ] ] using the above definitions , the hamiltonian can be cast in the diagonal form @xmath27 . there are several alternative but equivalent ways to write the set of commuting iom for this model . a common choice is @xcite @xmath28 with @xmath29 . these constitute a minimal complete set of iom since all higher ones are algebraically dependent on the lowest @xmath1 . another choice is @xcite @xmath30 . it should be emphasised that _ none _ of these sets of iom are local _ nor _ manifestly equivalent to local ones , as typically required by the gge conjecture @xcite . to the best of our knowledge , no definition of a set of local iom exists for the hcm . _ trap quench and the initial state_. now we consider a quantum quench of the trap frequency from @xmath31 to @xmath32 and wish to write the initial ground state @xmath33 in terms of the post - quench eigenstates . from ( [ xp ] ) we find that the post - quench creation - annihilation operators @xmath34 are related to the pre - quench ones @xmath35 by a _ bogoliubov transformation _ , as in the non - interacting case @xcite @xmath36}\label{bog}\ ] ] which means that @xmath33 satisfies the equation @xmath37 where @xmath38 , from which we can find its expansion on post - quench eigenstates . remarkably , regardless the nontrivial form of the ccr ( [ ccr ] ) , the initial state turns out to be of the same _ squeezed coherent _ form as in the non - interacting case @xcite @xmath39 where @xmath40 is the post - quench ground state ( @xmath41 ) . written in this form , the state can be readily evolved in time @xmath42 states of the form above are well - known as _ squeezed vacua _ , they are produced by the action of the _ squeeze operator _ $ ] on the vacuum @xcite and , equivalently , have the characteristic property of being annihilated by a _ squeezed annihilation operator _ @xmath44 , like the one of ( [ bog ] ) . indeed , as shown in @xcite , the state ( [ psit ] ) can also be written in the form @xmath45 for @xmath46 . _ coordinate space representation of the wavefunction_. squeezed coherent states , like coherent states too , have a simple interpretation when seen as wavefunctions in coordinate ( or in phase ) space . obviously by its definition , the initial state @xmath33 corresponds in coordinate space to the wavefunction of the post - quench ground state rescaled by a factor @xmath47 . an elegant way to see this from ( [ psi ] ) is by using its alternative form @xmath48 and noticing that @xmath49 is real and @xmath50 is essentially the generator of uniform coordinate scalings @xcite . for the evolved state ( [ psit ] ) the amplitude @xmath51 is complex and the calculation is more elaborate . the final result @xcite is @xmath52}^{n [ 1+\ell ( n-1)]/4 } \times { { \nonumber}\\ } & \times \exp{\left [ } -\frac12 { \omega}{\left ( } \frac{1+\eta(t)}{1-\eta(t ) } { \right ) } \sum_i x_i^2 { \right ] } \delta(\{x_i\})^\ell \label{5}\end{aligned}\ ] ] this expression is in agreement with and can be derived in a completely different way by using a scaling transformation to solve the problem of a system confined in a time - dependent harmonic trap @xcite and specialising to the quench protocol ( cf . @xcite for the tonks - girardeau limit ) . _ time evolution of observables_. knowing the evolution of the system s state we proceed to calculate the expectation values of physical observables . since our aim is to compare with the gge predictions , we will focus on the density profile @xmath53 which is a _ local _ observable , and calculate its time average @xmath54 in the thermodynamic limit . however we will also derive its moments @xmath55 , i.e. the expectation value of the operators @xmath56 of any of the particles , which are nonlocal observables but related to @xmath57 through @xmath58 , so that the latter can be reconstructed when all of @xmath55 are known . the thermodynamic limit for trapped systems is defined so that the system size and number of particles tend to infinity , but the density ( at any point in the bulk or averaged over all space ) remains finite . this requirement is fulfilled when the trap frequency ( in our case both @xmath31 and @xmath32 ) scales like @xmath59 @xcite . since the density does not scale with @xmath1 in this limit , the moments scale like @xmath60 and this leading order is the only one we are interested in . since the evolved state wavefunction ( [ 5 ] ) is a scaling transformation of that of the ground state , we can readily show that the corresponding density profile @xmath57 is also given by the wigner semicircle ( [ dens ] ) after replacing @xmath32 in @xmath11 by @xmath61 i.e. @xmath62 ( cf . @xcite ) . as expected , the density profile exhibits oscillatory ( `` breathing '' ) behaviour . the time averaged density profile @xmath63 is evaluated numerically and plotted in fig . [ f : rho ] for several values of @xmath64 . from the above results it is easy to calculate explicitly the moments of @xmath57 and their time averaged values @xcite . _ top : _ time - averaged density profile @xmath63 ( in units @xmath65 ) as a function of the position @xmath66 ( in units @xmath67 ) for fixed pre - quench trap frequency @xmath68 and variable post - quench trap frequency @xmath69 . the dashed curve indicates the initial wigner - semicircle density profile @xmath70 . _ bottom : _ time evolution of the cloud edges @xmath71 for the corresponding values of @xmath2 . the vertical dotted lines indicate the positions of the extrema of @xmath72 . ] _ generalised gibbs ensemble_. having found the time averages of observables we can now compare them with the corresponding gge predictions . it is convenient to use as test observables the moments @xmath73 from which the local observable @xmath74 can be reconstructed . to construct the gge density matrix we use the iom @xmath75 given by ( [ iom1 ] ) . this choice of iom corresponds to the ones used in the exact solution of the classical version of the hcm @xcite . besides , it is a natural generalisation @xcite of the set considered in @xcite which is the only other existing demonstration of the gge conjecture in a trapped system . the corresponding gge density matrix is @xmath76 where @xmath77 and the lagrange multipliers @xmath78 are determined by the condition that the gge values of the iom are equal to their values in the initial state , i.e. @xmath79 . however deriving the @xmath78 is not a necessary step , since it is possible to directly express the moments in terms of the iom and their products , which can be calculated in the gge without explicit knowledge of the @xmath78 . indeed , by expanding the operator @xmath80 and evolving in time ( in the heisenberg picture ) we realise that _ only _ terms with equal number of @xmath81 and @xmath82 s contribute to the time averaged expectation values , since only those are unaccompanied by oscillatory phase factors . but these terms can be recast as powers and products of the operators @xmath83 using the commutation relations ( [ ccr ] ) so that in the end we find @xcite @xmath84 for suitable coefficients @xmath85 and @xmath86 , where @xmath87 is a partition of @xmath88 in terms of @xmath89 numbers , i.e. @xmath90 . obviously the expectation values of the iom and their products are calculated in the initial state , as the index `` 0 '' indicates . note that the presence of correlators of iom products is an effect of the non - trivial form of the ccr ( [ ccr ] ) for @xmath91 . on the other hand , using the same expansion to calculate the gge averages @xmath92 we find that it is exactly those _ same _ terms with equal number of @xmath81 and @xmath82 s that contribute , since only those have non - zero traces in the basis of post - quench eigenstates . therefore @xmath93 is given by the rhs of ( [ taevo ] ) but with the expectation values of the iom and their products calculated now in the gge instead of the initial state . the values of the iom in the initial state and in the gge are by definition equal to each other @xmath94 . on the other hand , their products are uncorrelated in the gge in the thermodynamic limit , i.e. @xmath95 . this statement is based on the fundamental concept of statistical physics that , in the thermodynamic limit , the expectation value of some operator in a statistical ensemble equals its value on a single eigenstate ( microstate ) that is _ representative _ of the ensemble @xcite ( the relative fluctuations about these values scale to zero with @xmath1 ) . since the iom are diagonal on the eigenstates , their products factorise . therefore what determines the validity of the gge conjecture is whether this property holds also in the initial state . this turns out to be true , when we consider the thermodynamic limit . to see this @xcite , we first have to calculate the values of the iom and their products in the initial state by using the inverse of the bogoliubov transformation ( [ bog ] ) and normal - ordering according to the ccr ( [ ccr ] ) . keeping only terms that contribute to leading order in @xmath1 we verify that for an arbitrary product of iom we have @xmath96 @xcite . according to the above , it finally follows that the gge predicts _ correctly _ the values of @xmath97 and therefore of @xmath98 . _ conclusions . _ the above analysis shows that the gge conjecture is valid for a quantum quench of the trap frequency in the hcm . it should be stressed that the thermodynamic limit was an essential step in the course of this verification . finite size corrections coming from lower order contributions in @xmath1 would spoil the crucial property of the iom products to have uncorrelated values in the initial state . the same could happen if a different initial state was considered , since this property is not necessarily true for any initial state . in this case the gge would not predict correctly the @xmath97 since it would miss information about the initial correlations between the iom . in order to correct the gge , one would have to generalise it so that ( [ rhogge ] ) includes not only the iom but also all products of them , with the values of the corresponding additional @xmath99 s fixed independently from the initial condition @xcite . also note that the above refer to the general case @xmath100 ; in the trivial case of noninteracting bosons , i.e. @xmath101 , the gge is correct anyway , since all terms involving products of iom in ( [ taevo ] ) disappear and the equality of the values of the iom in the initial state and in the gge is sufficient to ensure its validity . another remark based on ( [ taevo ] ) is that in order to correctly predict @xmath97 it is sufficient to use a _ truncated _ gge @xcite with only the lowest @xmath102 iom fixed by the initial conditions . in particular , a measurement of @xmath103 _ only _ , would lead to the misconception that the system is described by a gibbs ensemble . this is not in contradiction with the gge conjecture , since the latter refers to local observables while the moments are global ones . in order to correctly predict the time averaged local density profile @xmath63 instead , we need all of its moments @xmath104 and therefore the _ full _ gge is required , i.e. including all infinite iom . notice that in ( [ rhogge ] ) we used only the @xmath1 lowest iom : including all higher ones as well would be equivalent to including all products of the @xmath1 lowest ones , since the higher are algebraically dependent on the lower ones . however , as discussed above , in the thermodynamic limit the products of iom do not need to be included in the gge , because their values in the initial state become uncorrelated and therefore are already predicted correctly by the gge ( [ rhogge ] ) . even though an experimental implementation of the hcm remains elusive so far , we expect that the general conclusions drawn above will serve as guidelines to experimentalists working on the verification of the gge conjecture , since the need of a confining trap ( that breaks the integrability of other models , like the lieb - 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portal vein tumor thrombosis ( pvtt ) , a common complication of hepatocellular carcinoma ( hcc ) with a reported incidence of 34% to 50% in patients with advanced hcc , is one of the most negative prognostic factors . however , survival duration in patients with pvtt is very heterogeneous , depending on other clinical characteristics and/or hepatic function . several staging systems have already been used in determination of prognosis and identification of optimal treatment modalities for hcc patients [ 1,4 - 7 ] . however , hcc patients with pvtt can not be stratified using these systems [ 8 - 10 ] . more precise stratification would be helpful in identification of patients who might benefit from specific treatments . to address this shortcoming , in a previous study we proposed a prognostic index for pvtt in patients with hcc ( pith ) who were treated with radiotherapy ( rt ) . however , it was a retrospective single - institution study , which was inherently influenced by selection bias . therefore , the pith staging system is currently not considered reliable enough for direct application in clinical situations . the purpose of the current study is to validate the pith staging system and compare it with other known systems in order to determine which system enables the most accurate prediction of survival through a retrospective analysis of patients from the korean radiation oncology group ( krog ) . in our previous study we proposed the pith staging system based on the clinical outcomes of 281 patients with combined hcc and main and/or first branch pvtt who were treated with rt at samsung medical center . this system is based on seven pretreatment factors : eastern cooperative oncology group ( ecog ) performance status , child - pugh classification , tumor size , tumor multiplicity , site of pvtt involvement , degree of occlusion of portal flow , and the presence of lymph node metastasis . of those factors , degree of occlusion of portal flow was excluded in the current study due to diagnostic obscurity and differences among institutional imaging work - up protocols . this study was approved and exempted from permission by the institutional review board of samsung medical center , sungkyunkwan university school of medicine ( irb no . 2011 - 10 - 057 ) . to validate the pith staging system we enrolled patients with hcc combined with main and/or first branch pvtt who were treated with rt from january 1998 to october 2011 at 10 korean institutions of the krog . because other local treatment modalities can be considered when pvtt is confined to segmental branches ( i.e. , portal vein branches other than the main or first branch ) , we excluded those patients in order to maintain homogeneity of the study . the diagnosis of hcc was based on histology of tumor tissue or reliable clinical criteria , largely in accordance with guidelines proposed by the korean liver cancer study group ( klcsg ) , as follows : liver nodules in a high - risk group ( association with liver cirrhosis or viral hepatitis ) with one typical dynamic imaging finding and a trend of increasing elevated serum -fetoprotein ( afp ) level above 400 ng / ml , or two typical dynamic imaging findings without afp increase . after 2009 , the cutoff value of afp was lowered to 200 ng / ml . pvtt was identified using helical computed tomography ( ct ) scans with contrast enhancement , magnetic resonance imaging scans , or angiography . on contrast - enhanced ct scans , pvtt was identified by the presence of a low - attenuation intraluminal filling defect adjacent to the primary tumor with contrast enhancement . thrombi located in the bilateral first branches and the main trunk were categorized as main pvtt . tumor size was defined as the length of the longest diameter of the primary tumor with pvtt . the rt protocol , which included fractionated 3d conformal radiation therapy ( 3d - crt ; 1.8 gy or 2.0 gy / fraction ) , hypofractionated rt ( 2.0 to 5.0 gy / fraction ) , or stereotactic body rt ( sbrt , more than 5.0 gy / fraction with fewer than five fractions ) was not a criterion for eligibility for evaluation by the pith system provided that the other eligibility criteria of this study were met . recurrence and type of treatment before and after rt were also not considered in determining eligibility . data from 1,050 patients were gathered from the 10 institutions of the krog . among these , 56 patients could not be analyzed due to missing data that were requisite for this study ( 24 patients due to inaccessibility of rt history and 32 patients due to lack of information on performance status ) . all patients were categorized according to the cancer of the liver italian program ( clip ) , japanese integrated staging ( jis ) , okuda , and pith staging systems based on their clinical and laboratory characteristics before rt . because all patients enrolled in this study were stage c according to the barcelona clinic liver cancer ( bclc ) staging system , we did not compare the bclc with the pith system . pvtt response after rt was determined using serial ct scans 4 to 12 weeks after completion of treatment , and the modified response evaluation criteria in solid tumors ( mrecist ) were used for measurement of response . patient overall survival ( os ) was the single end point used to assess the performance of the different staging systems . os was measured from the date of the start of rt to the date of death or the last follow - up visit . os data were plotted using the kaplan - meier method and compared using the log - rank test . homogeneity of the staging systems ( i.e. , a small difference in survival among patients in the same classification within each system ) was determined by the likelihood ratio and akaike information criterion ( aic ) was also used to evaluate the discriminatory ability of the given models by the cox proportional hazards model , which was tested using the schoenfeld residuals method . finally , time - dependent receiver operating characteristics ( roc ) curve estimation and prediction error curve analysis were used to evaluate the discriminatory and stratification abilities in the different staging systems . a staging system is considered to have a better performance if there is a higher likelihood ratio and time - dependent area under curve ( auc ) , and a lower aic . low integrated brier score ( ibs ) , which is the area under the curve of the prediction error curve analysis , is regarded as a prerequisite for a good staging system . chicago , il ) except for time - dependent roc curve estimation and prediction error curve analysis , which were performed using r statistical package 1.0.4 . in our previous study we proposed the pith staging system based on the clinical outcomes of 281 patients with combined hcc and main and/or first branch pvtt who were treated with rt at samsung medical center . this system is based on seven pretreatment factors : eastern cooperative oncology group ( ecog ) performance status , child - pugh classification , tumor size , tumor multiplicity , site of pvtt involvement , degree of occlusion of portal flow , and the presence of lymph node metastasis . of those factors , degree of occlusion of portal flow was excluded in the current study due to diagnostic obscurity and differences among institutional imaging work - up protocols . this study was approved and exempted from permission by the institutional review board of samsung medical center , sungkyunkwan university school of medicine ( irb no . to validate the pith staging system we enrolled patients with hcc combined with main and/or first branch pvtt who were treated with rt from january 1998 to october 2011 at 10 korean institutions of the krog . because other local treatment modalities can be considered when pvtt is confined to segmental branches ( i.e. , portal vein branches other than the main or first branch ) , we excluded those patients in order to maintain homogeneity of the study . the diagnosis of hcc was based on histology of tumor tissue or reliable clinical criteria , largely in accordance with guidelines proposed by the korean liver cancer study group ( klcsg ) , as follows : liver nodules in a high - risk group ( association with liver cirrhosis or viral hepatitis ) with one typical dynamic imaging finding and a trend of increasing elevated serum -fetoprotein ( afp ) level above 400 ng / ml , or two typical dynamic imaging findings without afp increase . after 2009 , the cutoff value of afp was lowered to 200 ng / ml . pvtt was identified using helical computed tomography ( ct ) scans with contrast enhancement , magnetic resonance imaging scans , or angiography . on contrast - enhanced ct scans , pvtt was identified by the presence of a low - attenuation intraluminal filling defect adjacent to the primary tumor with contrast enhancement . thrombi located in the bilateral first branches and the main trunk were categorized as main pvtt . tumor size was defined as the length of the longest diameter of the primary tumor with pvtt . the rt protocol , which included fractionated 3d conformal radiation therapy ( 3d - crt ; 1.8 gy or 2.0 gy / fraction ) , hypofractionated rt ( 2.0 to 5.0 gy / fraction ) , or stereotactic body rt ( sbrt , more than 5.0 gy / fraction with fewer than five fractions ) was not a criterion for eligibility for evaluation by the pith system provided that the other eligibility criteria of this study were met . recurrence and type of treatment before and after rt were also not considered in determining eligibility . data from 1,050 patients were gathered from the 10 institutions of the krog . among these , 56 patients could not be analyzed due to missing data that were requisite for this study ( 24 patients due to inaccessibility of rt history and 32 patients due to lack of information on performance status ) . all patients were categorized according to the cancer of the liver italian program ( clip ) , japanese integrated staging ( jis ) , okuda , and pith staging systems based on their clinical and laboratory characteristics before rt . because all patients enrolled in this study were stage c according to the barcelona clinic liver cancer ( bclc ) staging system , we did not compare the bclc with the pith system . pvtt response after rt was determined using serial ct scans 4 to 12 weeks after completion of treatment , and the modified response evaluation criteria in solid tumors ( mrecist ) were used for measurement of response . patient overall survival ( os ) was the single end point used to assess the performance of the different staging systems . os was measured from the date of the start of rt to the date of death or the last follow - up visit . os data were plotted using the kaplan - meier method and compared using the log - rank test . homogeneity of the staging systems ( i.e. , a small difference in survival among patients in the same classification within each system ) was determined by the likelihood ratio and akaike information criterion ( aic ) was also used to evaluate the discriminatory ability of the given models by the cox proportional hazards model , which was tested using the schoenfeld residuals method . finally , time - dependent receiver operating characteristics ( roc ) curve estimation and prediction error curve analysis were used to evaluate the discriminatory and stratification abilities in the different staging systems . a staging system is considered to have a better performance if there is a higher likelihood ratio and time - dependent area under curve ( auc ) , and a lower aic . low integrated brier score ( ibs ) , which is the area under the curve of the prediction error curve analysis , is regarded as a prerequisite for a good staging system . chicago , il ) except for time - dependent roc curve estimation and prediction error curve analysis , which were performed using r statistical package 1.0.4 . table 1 summarizes the characteristics of the 994 patients from the 10 institutional databases who were used for external validation . the median age of the patients was 54 years ( range , 23 to 84 years ) . there were 102 patients ( 10.3% ) with an ecog performance status of 2 or higher . main pvtt was observed in 50.0% of the patients , and the primary tumor and pvtt were irradiated simultaneously in 476 patients ( 47.9% ) . of the 994 patients , one or more treatments were administered in 822 patients ( 82.7% ) . the distribution of specific treatment modalities administered prior to rt was as follows ( patients who received two or more treatment modalities were counted separately for each one ) : surgical resection ( n=45 , 4.5% ) , radiofrequency ablation ( rfa ; n=54 , 5.4% ) , percutaneous ethanol injection ( n=25 , 2.5% ) , transcatheter arterial embolization or chemoembolization ( tae or tace ; n=713 , 71.7% ) , transcatheter arterial chemoinfusion ( taci ; n=67 , 6.7% ) , chemotherapy ( n=27 , 2.7% ) . six patients ( 0.6% ) had undergone previous rt . the primary gross tumor and pvtt were simultaneously irradiated in 476 patients ( 47.9% ) , and only pvtt was targeted in 427 patients ( 43.0% ) because of their hepatic and tumor condition ( e.g. , large tumor [ more than two - thirds of the liver ] with severe liver cirrhosis , child - pugh class c , large tumor with main pvtt in both lobes of the liver , numerous intrahepatic metastases ) . a median daily dose of 2.5 gy ( range 1.8 to 17.0 gy ) was administered , yielding a total dose of 45.0 gy ( range 7.2 to 66.0 gy ) , which translates to a biologic effective dose of 56.25 gy10 ( 8.5 to 137.7 gy10 as the /=10 ) . conventional fractionated 3d - crt ( 1.8 - 2.0 gy / fraction ) was used in 392 patients ( 39.4% ) . hypofractionated rt ( 2.22 - 5.0 gy / fraction ) was the most common dosing scheme ( n=581 , 58.5% ) . sbrt ( more than 5.0 gy / fraction with fewer than five fractions ) was administered to 21 patients ( 2.1% ) . chemotherapy was administered concomitantly with rt in 110 patients ( intra - arterial in 75 , sorafenib in 21 , systemic in 4 ) . after rt , among patients who received two or more treatment modalities , 49 patients ( 4.9% ) received other local treatments ( such as surgery , rfa , percutaneous ethanol injection therapy ) and tae / tace / taci were performed on 534 patients ( 53.7% ) . chemotherapy ( arterial or systemic ) was administered in 111 patients ( 11.2% ) and 62 ( 6.2% ) received sorafenib . the median survival was 9.2 months and the actuarial 6- , 12- , 18- , and 24-month os rates were 65.7% , 40.0% , 25.2% , and 18.1% , respectively . with the exception of 46 patients ( 4.6% ) who were not evaluated due to lack of follow up , complete response of the pvtt was observed in 50 patients ( 5.0% ) , partial response in 405 patients ( 40.7% ) , stable disease in 408 patients ( 41.0% ) , and progressive disease in 85 patients ( 8.6% ) , yielding an objective response rate of 45.7% . the median survival duration of the patients who showed complete response and partial response was 32 months and 13.1 months , respectively ( fig . 1 ) . patient distribution and survival rate according to each staging system are shown in table 2 and fig . the clip and pith staging systems showed a more even patient distribution than the other staging systems . the subgroup of patients with a score of zero experienced a significantly longer survival ( median , 17.2 months ) than the subgroup with a score of 4 to 6 , who experienced a median survival of less than six months . comparison between the best prognostic subgroups of each system showed that a jis score of 1 was associated with superior survival ( median 57.2 months and 80.0% os at 12 months ) ; however , only five patients from the current group were classified as this subgroup . with the exception of this result , the pith staging system stratified subgroups better than any other staging system . nearly 70% of patients with a pith score of zero had survival durations longer than 12 months and more than one - third of these patients had survival duration longer than two years . in addition , it clearly classified the worst prognostic subgroup ; patients with a pith score of 4 to 6 had median survival durations shorter than six months . furthermore , significant differences in the survival curves were observed among pith stage i , ii , iii , and iv , whereas no difference was observed between okuda stage ii and iii ( fig . as shown in table 3 , the likelihood ratio ( 28.812 ) for the pith staging system was higher than those of the other staging systems , indicating that pith has better homogeneity , and the aic ( 10,042.002 ) was the lowest for the pith staging system , indicating that pith is more informative than other systems with regard to prediction of survival . time - dependent roc curve and ibs of prediction error curve analysis were also analyzed , and the auc and ibs values were compared . although not all values reached generally accepted discriminatory levels , pith showed the highest auc ( 0.593 ) and lowest ibs ( 0.082 ) . table 1 summarizes the characteristics of the 994 patients from the 10 institutional databases who were used for external validation . the median age of the patients was 54 years ( range , 23 to 84 years ) . there were 102 patients ( 10.3% ) with an ecog performance status of 2 or higher . main pvtt was observed in 50.0% of the patients , and the primary tumor and pvtt were irradiated simultaneously in 476 patients ( 47.9% ) . of the 994 patients , one or more treatments were administered in 822 patients ( 82.7% ) . the distribution of specific treatment modalities administered prior to rt was as follows ( patients who received two or more treatment modalities were counted separately for each one ) : surgical resection ( n=45 , 4.5% ) , radiofrequency ablation ( rfa ; n=54 , 5.4% ) , percutaneous ethanol injection ( n=25 , 2.5% ) , transcatheter arterial embolization or chemoembolization ( tae or tace ; n=713 , 71.7% ) , transcatheter arterial chemoinfusion ( taci ; n=67 , 6.7% ) , chemotherapy ( n=27 , 2.7% ) . the primary gross tumor and pvtt were simultaneously irradiated in 476 patients ( 47.9% ) , and only pvtt was targeted in 427 patients ( 43.0% ) because of their hepatic and tumor condition ( e.g. , large tumor [ more than two - thirds of the liver ] with severe liver cirrhosis , child - pugh class c , large tumor with main pvtt in both lobes of the liver , numerous intrahepatic metastases ) . a median daily dose of 2.5 gy ( range 1.8 to 17.0 gy ) was administered , yielding a total dose of 45.0 gy ( range 7.2 to 66.0 gy ) , which translates to a biologic effective dose of 56.25 gy10 ( 8.5 to 137.7 gy10 as the /=10 ) . conventional fractionated 3d - crt ( 1.8 - 2.0 gy / fraction ) was used in 392 patients ( 39.4% ) . hypofractionated rt ( 2.22 - 5.0 gy / fraction ) was the most common dosing scheme ( n=581 , 58.5% ) . sbrt ( more than 5.0 gy / fraction with fewer than five fractions ) was administered to 21 patients ( 2.1% ) . chemotherapy was administered concomitantly with rt in 110 patients ( intra - arterial in 75 , sorafenib in 21 , systemic in 4 ) . after rt , among patients who received two or more treatment modalities , 49 patients ( 4.9% ) received other local treatments ( such as surgery , rfa , percutaneous ethanol injection therapy ) and tae / tace / taci were performed on 534 patients ( 53.7% ) . chemotherapy ( arterial or systemic ) was administered in 111 patients ( 11.2% ) and 62 ( 6.2% ) received sorafenib . the median survival was 9.2 months and the actuarial 6- , 12- , 18- , and 24-month os rates were 65.7% , 40.0% , 25.2% , and 18.1% , respectively . with the exception of 46 patients ( 4.6% ) who were not evaluated due to lack of follow up , complete response of the pvtt was observed in 50 patients ( 5.0% ) , partial response in 405 patients ( 40.7% ) , stable disease in 408 patients ( 41.0% ) , and progressive disease in 85 patients ( 8.6% ) , yielding an objective response rate of 45.7% . the median survival duration of the patients who showed complete response and partial response was 32 months and 13.1 months , respectively ( fig . patient distribution and survival rate according to each staging system are shown in table 2 and fig . 2 . the clip and pith staging systems showed a more even patient distribution than the other staging systems . the subgroup of patients with a score of zero experienced a significantly longer survival ( median , 17.2 months ) than the subgroup with a score of 4 to 6 , who experienced a median survival of less than six months . comparison between the best prognostic subgroups of each system showed that a jis score of 1 was associated with superior survival ( median 57.2 months and 80.0% os at 12 months ) ; however , only five patients from the current group were classified as this subgroup . with the exception of this result , the pith staging system stratified subgroups better than any other staging system . nearly 70% of patients with a pith score of zero had survival durations longer than 12 months and more than one - third of these patients had survival duration longer than two years . in addition , it clearly classified the worst prognostic subgroup ; patients with a pith score of 4 to 6 had median survival durations shorter than six months . furthermore , significant differences in the survival curves were observed among pith stage i , ii , iii , and iv , whereas no difference was observed between okuda stage ii and iii ( fig . as shown in table 3 , the likelihood ratio ( 28.812 ) for the pith staging system was higher than those of the other staging systems , indicating that pith has better homogeneity , and the aic ( 10,042.002 ) was the lowest for the pith staging system , indicating that pith is more informative than other systems with regard to prediction of survival . time - dependent roc curve and ibs of prediction error curve analysis were also analyzed , and the auc and ibs values were compared . although not all values reached generally accepted discriminatory levels , pith showed the highest auc ( 0.593 ) and lowest ibs ( 0.082 ) . as reported in several studies , the presence of pvtt in hcc patients remains one of the most negative prognostic factors [ 1 - 3 ] . in the absence of any treatment modality , patient survival in this setting is less than three months . as a result , most staging systems include this factor as a criterion and assign these patients to a poor prognostic group [ 1,4 - 6,16 ] . however , the survival duration in these patients has been shown to vary widely , from less than five months to more than five years depending on patient and tumor characteristics . previous staging systems do not take into account these variations [ 1,4 - 7 ] . in the bclc staging system , all of these patients are designated as stage c , and sorafenib is the only recommended treatment [ 6,19 - 21 ] . because pvtt is a heterogeneous entity with significant prognostic variation , there are likely to be some patients who will benefit from local therapy rather than sorafenib . theoretically , locoregional therapies such as tace , radioembolization , and/or rt could suppress pvtt progression and delay intravascular tumor growth and the deterioration of liver function by maintaining adequate portal flow . in fact , rt has been reported to yield fair outcomes with an objective response rate of approximately 40% to 50% and a median survival duration of 9 to 10 months . these results suggest that rt is effective in patients with hcc and pvtt , and , based on these findings , the korean liver cancer study group recommends sorafenib and rt as standard therapies for hcc with pvtt . to address the lack of an effective staging system for hcc combined with pvtt , we conducted this validation study in order to obtain a more definitive conclusion regarding the clinical utility of the pith staging system , which was originally developed using pretreatment tumors and pvtt characteristics obtained retrospectively from a single institution . from 10 korean institutions within the krog , 994 patients with hcc and main and/or first branch pvtt who were treated with rt from january 1998 to october 2011 were analyzed . during the validation process , we found that patients were more evenly distributed by the clip and pith staging systems than by other systems . the patient distribution within each pith score , an important feature of a good prognostic system , was much better than that in the other staging systems . specifically , pith showed a clearer division of the subgroups with the best and worst prognosis . based on statistical analysis of likelihood ratio , aic , time - dependent roc curve estimation , and prediction error curve , the pith system showed better homogeneity and discriminatory ability compared with other systems . compared with the other staging systems , two - thirds of patients with a pith score of zero had survival durations longer than 12 months . in contrast , patients with a pith score of 4 to 6 had survival durations shorter than six months , although pith could not stratify them specifically . in the former group , there might be the potential to extend survival by combining treatment modalities , whereas in the latter group , it might be appropriate to reconsider rt . our findings indicate that the pith staging system might be helpful when planning rt in patients with hcc combined with pvtt . first , due to the retrospective nature of the study , the potential for selection bias can not be excluded . second , the wide heterogeneity in rt regimens and additional treatment after rt could be confounding factors . however , such heterogeneity is an essential component of treatment decisions in actual practice , and additional treatments after rt may be administered when they offer the possibility of improving clinical outcome . the pith system could be used more comfortably in such situations because specific restrictions were not applied in the current study to exclude patients receiving rt . third , we only included patients who received rt ; therefore , it is difficult to generalize our finding to patients undergoing other treatment modalities . like other staging systems , pith included performance status ( ecog ) , liver function ( child - pugh class ) , and extent of primary tumor . however , pith also considered the extent and position of the pvtt . the status of pvtt might be particularly important in patients treated with rt , and the slightly better performance of the pith system in these patients could reflect consideration of pvtt . conduct of a larger prospective validation study is required in order to broaden the applicability of this staging system . this study successfully validated the pith staging system in a study group obtained in a multicenter retrospective fashion . pith showed better stratification ability than the okuda , clip , and jis systems . compared with previous systems , pith may be helpful to oncologists in more accurate determination of prognosis and selection of more appropriate treatment options through more effective stratification of patients with hcc and pvtt based on risk .

purposewe previously reported on a staging system and prognostic index ( pith ) for portal vein tumor thrombosis ( pvtt ) in hepatocellular carcinoma ( hcc ) patients treated with radiotherapy ( rt ) at a single institution . the aim of this study is to validate the pith staging system using data from patients at other institutions and to compare it with other published staging systems.materials and methodsa total of 994 hcc patients with pvtt who were treated with rt between 1998 and 2011 by the korean radiation oncology group were analyzed retrospectively . all patients were staged using the cancer of the liver italian program ( clip ) , japanese integrated staging ( jis ) , okuda , and pith staging systems , and survival data were analyzed . the likelihood ratio , akaike information criteria ( aic ) , time - dependent receiver operating characteristics , and prediction error curve analysis were used to determine discriminatory ability for comparison of staging systems.resultsthe median survival was 9.2 months . compared with the other staging systems , the pith score gave the highest values for likelihood ratio and lowest aic values , demonstrating that pith may be a better prognostic model . although the values were not significant and differences were not exceptional , the pith score showed slightly better performance with respect to time - dependent area under curve and integrated brier score of prediction error curve.conclusionthe pith staging system was validated in this multicenter retrospective study and showed better stratification ability in hcc patients with pvtt than other systems .

Media Misperceptions Venezuela: The Spin vs. The Truth As demonstrated in numerous examples in “South of the Border,” major U.S. media outlets have distorted their audiences’ perceptions of Venezuela and the government of Hugo Chávez. Most media reports on Venezuela frame their stories in ways that are likely to make American audiences distrustful and apprehensive of Venezuela. These frames are reinforced by commonly repeated media myths and inaccuracies that further tend to portray the Venezuelan government as an enemy of the United States, and as an increasingly totalitarian government that is stifling dissent, cracking down on the press, and eroding democratic freedoms. These frames and myths – “spin,” in public relations-speak – overlook an abundance of evidence to the contrary. Spin: Hugo Chávez is a dictator. Truth: The government of Venezuela has held, and Chávez and his party have won, repeated elections throughout his time in office. These elections have been considered free and fair by the Organization of American States (OAS), the European Union (EU) and the Carter Center — three major electoral observation bodies. Some criticize the Chávez government because his political party has near total control over the National Assembly; however this is a direct result of the opposition’s actions. Just days before the 2005 legislative elections most of the opposition decided to stage a boycott of the vote. This came only a few days after their representatives had told the OAS and other electoral observers that conditions had been met for their participation. The move handed almost complete control in the National Assembly to Chávez’s allies while failing to delegitimize the legislature internationally. Prior to these elections, the opposition held significant power in the National Assembly, which allowed them to block many of the Chávez administration’s policies. Real attacks on democracy have come from sectors of the Venezuelan opposition. In April 2002, a broad group of opposition forces directly supported and participated in a short-lived coup d’etat against the elected government. In late 2002 and early 2003, opposition groups paralyzed the oil industry and provoked a deep recession, in a second attempt to force President Chávez from power. In 2005, the country’s main opposition parties tried to provoke a destabilizing political crisis by boycotting the legislative elections. All of these undemocratic actions only succeeded in further discrediting an opposition movement that many Venezuelans identify with the failed policies of the unpopular governments of the past. The Chávez government continues to enjoy an overwhelming majority support of voters in most national elections. In the 2006 presidential election, in which a record number of voters participated, Chávez won with 63 percent of the vote, and in the 2008 regional elections his party won in 17 of 22 states. The next legislative elections are in September, and the opposition is expected to significantly increase its presence in the National Assembly. However the opposition remains divided and trails far behind the government in terms of popular support. Democratic participation has increased greatly under Chávez as well. For example, while turnout was around 54 percent in the 1998 elections in which Chávez was first elected, in the 2006 presidential election, voter participation jumped to 75 percent. For perspective, in the 2008 U.S. presidential election, voter participation was around 60 percent, and this was one of the highest totals in some 40 years. The Chávez administration has made it a priority to promote electoral participation within poor communities that traditionally had a low voter turnout; this has included large voter registration drives and the creation of voting centers in poor areas. Despite media reports to the contrary Venezuelans are satisfied with their democracy. The Chilean Latinbarómetro, one of the most exhaustive and well respected polling companies in the region, consistently shows that Venezuela ranks near the top of countries in the hemisphere in terms of the level of satisfaction with democracy. Spin: Chávez is clamping down on freedom of the press. The Truth: Venezuela continues to have strong opposition broadcast and print media, as any casual visitor to Venezuela can plainly see. The supposed deterioration of freedom of the press under the Chávez government is a favorite theme of U.S. media coverage of Venezuela, and it is regarding this topic that the gap between reality and media claims is usually at its widest. Anyone who travels to Venezuela will easily find numerous front-page criticisms and broadcast denunciations of the Chávez government that go well beyond the sort of attacks on Obama that appear in the U.S. press. Yet that Chávez is attempting to “eliminate independent media”[1] by “muzzling the press”[2] are favorite themes for U.S. editorial pages, with news articles chiming in that “Chavez’s administration is moving to tighten its grip over Venezuela’s media industry.”[3] U.S. media coverage has often also distorted the facts regarding the Venezuelan government’s conflicts with opposition media outlets, some of which have openly supported undemocratic and extra-constitutional means to undermine or even overthrow the government. Claims that Chávez is an enemy of press freedom reached a peak in 2007 when the Venezuelan government chose not to renew the broadcast license of opposition TV station RCTV. U.S. media and commentators claimed that RCTV was being “censored”[4] and “shut down”[5], but in reality, RCTV continued to broadcast via cable and Internet with large audience numbers, and maintaining its anti-Chávez line. While opponents of the government criticized the decision to allow RCTV’s license to expire, it is important to note that a TV station that had done even some of the things that RCTV had done would never obtain a broadcast license in the United States or any European democracy. Most importantly – as was admitted in news articles on the controversy,[6] RCTV openly supported the 2002 coup against Chávez by encouraging people to participate in opposition protests, by reporting the false information that Chávez had resigned,[7] and then, when Chávez returned to power, by airing Disney cartoons rather than report this news.[8] RCTV head Marcel Granier met with coup president Pedro Carmona during the coup, as Carmona enlisted the media’s help in attempting to ensure the coup’s success.[9] RCTV also actively promoted the oil strike (2002-2003) that attempted to topple the government, and other, legal political and electoral campaigns. Even some observers who harshly criticized the government’s decision on RCTV admitted that the issue was much more complicated, and that RCTV was not automatically entitled to its license. “Broadcasting companies in any country in the world, especially in democratic countries, are not entitled to renewal of their licenses,” José Miguel Vivanco of Human Rights Watch explained. “The lack of renewal of the contract, per se, is not a free speech issue. Just per se.”[10] In the years since the RCTV decision, instead of correcting its hyperbolic claims of Venezuelan censorship, U.S. media outlets have continued the theme. The new focus is on broadcaster Globovisión, routinely described as “Venezuela’s only remaining opposition TV television station on the open airwaves.”[11] This characterization is simply false, as numerous local TV stations in Venezuela have an opposition political line (and national broadcasters such as Televen continue to run programs with a strong opposition slant). The great majority of Venezuelan media continues to be privately owned, and the opposition dominates the newspaper industry as well. As Human Rights Watch – a frequent critic of freedom of the press in Venezuela – noted in a 2008 report, “the balance of forces in the print media has not changed significantly”, with the majority of Venezuelan newspapers continuing to be privately-owned and two of the three top newspapers maintaining an opposition political line (the third is neutral).[12] U.S. press reports also frequently describe a shift among some opposition media, such as TV station Venevisión, towards being less critical of the government.[13] While U.S. media often suggests that this could be out of fear of “censorship,” Venezuela-analyst Greg Wilpert offers another theory: “I think some of the TV stations have slightly moderated [their opposition to the government] not because of intimidation, but because they were losing audience share. Over half of the population is supportive of Chávez. They’ve reduced the number of anti-Chávez programs that they used to have. But those that continue to exist are just as anti-Chávez as they were before.”[14] Spin: Poverty has worsened under Chávez. The Truth: Poverty has fallen dramatically in Venezuela since Hugo Chávez was elected president. While poverty did rise overall from 1999 – 2003, this was largely due to the economic impact of the coup d’etat in 2002 and the severely damaging oil lockout in late 2002/early 2003. The resulting recession was extreme: a 24 percent loss of GDP from the third quarter of 2002 until the first quarter of 2003. Media outlets in the past used poverty data from 2003 or 2004 to “prove” that poverty increased under Chávez – even when more recent poverty data was available. This distorted the reality of what happened. From the first half of 2003 to the second half of 2009 the percentage of households below the poverty line declined from 54 percent to just 24.2 percent, a 55 percent decrease. Extreme poverty has also declined precipitously, from 30.2 percent in 2003 to 7.4 percent in 2009, a decline of over 75 percent. It is important to note that these poverty measures only include income measures and do not take into account the non-income benefits generated by numerous social programs that have benefited the poor. Access to health care, education and discounted food all contribute to improving the conditions of Venezuela’s poor. In addition, Venezuela has made important strides in reducing inequality. From 2002-2008, Venezuela led Latin America in decreased inequality, and currently has the most equitable distribution of income in the region. Spin: Chávez’s spend-happy policies have led to dangerously high inflation, leading to serious economic problems. The Truth: While the inflation rate in Venezuela is relatively high, it has not reached dangerous levels, as is often reported. Inflation was 31 percent in 2008, however much of this was in the first half of the year due to temporary price shocks. In 2009, inflation slowed to around 26 percent. To put this in perspective, when Chávez took office inflation was 29.5 percent, and reached 100 percent in 1996. Over the last seven years inflation has averaged roughly 21 percent per year, but this is barely over the threshold of 20 percent inflation that research has shown to negatively effect growth. The minimum wage has also largely tracked inflation. In addition, while some goods have increased more in price than the general index, some important goods have not. For instance, since December 2007, the cost of housing, household services, clothing, communications, and education have all increased less than the general rate of inflation. While food and health have both increased more, these are areas where the government of Venezuela has increased access and affordability for the poor. Spin: Venezuela’s economic growth is the result of an “oil boom” that’s headed for a bust. The Truth: While the rise in the price of oil clearly contributed to Venezuela’s strong growth, it was not the only reason and there are signs that the economy can withstand fluctuations. After the oil lock-out and subsequent recession the economy took off, growing 95 percent over the following five and half years. At the same time world oil prices continued to sharply rise. This led many media commentators to claim that Venezuela’s growth is dependent on an unsustainable oil boom. However, during those five years of rapid growth it was in fact non-oil GDP that was the prime contributor to GDP growth. In fact, from 2005-2007 the oil sector was actually a drag on growth, decreasing around two percent a year, while on the other hand non-oil GDP was growing at around ten percent during the same period. Looking at the current recession in Venezuela also provides evidence that the economy is not based on an oil boom. While Venezuela saw negative growth in 2009, this did not have to be so bad. The country has accumulated massive international reserves, and when oil prices dropped and the economy began to slow, the government could have used these reserves to fund stimulus measures to make up for the loss in demand. With relatively low levels of public debt, Venezuela also could have borrowed money internationally to finance counter-cyclical spending. Further evidence of this is that despite that the economy shrank 3.3 percent, poverty rates continued to decline and unemployment was less affected than in many other countries hit by the global recession. Spin: Venezuela supports terrorist groups including the FARC. The Truth: No specific proof of Venezuelan support for terrorist groups has ever been presented. Groups and individuals opposed to the Venezuelan government, both in Venezuela and internationally, have continually made allegations that the Venezuelan government supports groups on the State Department list of terrorist organizations, most commonly the FARC. Despite this, no specific, verifiable proof has ever been presented; indeed many of the allegations are based on a single, discredited source (see below). Venezuela and Colombia share a border of more than 2000 km, much of which is dense, sparsely populated jungle; it is likely that the FARC operates on both sides of the border area. A new round of allegations of Venezuelan support for the FARC occurred after a March 2008 raid on a FARC camp in the eastern jungle of Ecuador near the Colombian border. Although the bombing raid killed 26 people and destroyed much of the camp, the Colombian military (itself responsible for horrific human rights abuses and ties to right wing paramilitaries) claims to have recovered laptops, hard drives and memory cards that were not damaged in the raid. The Colombian government has since made numerous allegations of Venezuelan (and Ecuadorean) support for the FARC based on these files. Colombian officials have leaked excerpts of the documents, exaggerating the significance of the contents for possible political purposes. Colombia also made a number of other allegations that stemmed from the laptops regarding an alleged FARC “dirty bomb” and the FARC’s ties to Ecuador, both of which were quickly proven false. Some experts expressed skepticism regarding the laptop documents in part due to how quickly Colombia appeared to find incriminating information. An Interpol analysis stated that it would take more than one thousand years to read through it all, at a rate of a hundred pages per day, yet Colombia began releasing some of what would be the most damning evidence within just days of the raid. Yet the Colombian authorities continued to claim to find evidence from the computer files linking not only the Venezuelan and Ecuadorian governments to the FARC, but also investigative journalists, activists, and others. Recently released Colombian government documents show that some of these individuals were the targets of “smear campaigns” by the Colombian presidency and the intelligence agency. The allegation that received the most press coverage was that Chávez had offered some $300 million in support to the FARC. This turned out, however, to be based on a far-reaching interpretation of sections of the files, and it is also possible that various alleged communications between the FARC and Venezuelan government actually related to Venezuela’s role in the months just prior to the raid in negotiating the release of high-profile hostages from the FARC. After a phone call from President George W. Bush, Colombian President Alvaro Uribe abruptly ended Chávez’s official mediation role. The released hostage Pablo Moncoyo, after being freed following over a decade in captivity, thanked Chávez but not Uribe for his release. Although the U.S. and Colombia have both cited the laptops as evidence of Venezuelan support for the FARC, most other countries and international bodies have not, and in April 2008 OAS Secretary General Jose Miguel Insulza testified before the House Subcommittee on Western Hemispheric Affairs that there was no evidence of Venezuelan support for the FARC. An Interpol analysis of the laptops concluded that because of the handling of the evidence by the Colombian government for days before it was turned over, that it would not hold up in judicial proceedings. The computers and other devices were in control of the Colombia military for two days until they were handed over to computer experts, and then it was another week before they were given to Interpol. Interpol did not analyze the contents of the documents, in fact they had non-Spanish speakers evaluate the contents, despite that most – if not all – of the emails and other text was in Spanish. Recently, further allegations have been made about Venezuelan support for both the FARC and the ETA (the Basque separatist group that is also labeled a terrorist organization). This made a splash in the media in March 2010 when a Spanish judge brought charges against Venezuela claiming Venezuelan support for the ETA. The evidence cited was again from the recovered FARC laptops, and during a recent hearing before the Senate Armed Service Committee, Douglas Fraser, the U.S. Commander of the U.S. Southern Command, testified that he was not aware of any evidence of Venezuelan support for the ETA. Although he later recanted these statements after meeting with the U.S. State Department, this seems more political than factual. It is unlikely that the head of the U.S. military in Latin America would not be aware of this evidence, had if it existed. Spin: Hugo Chávez controls everything that happens in Venezuela in a “top-down” fashion. The Truth: Venezuela’s “Bolivarian Revolution” empowers communities to make decisions and exert more control over their lives in a “bottom-up” distribution of power. Most media coverage of Venezuela focuses on the role of president Chávez, framing coverage of developments in Venezuela whereby decision-making appears to be unilaterally made by Chávez. This ignores, however, the efforts that have been made in Venezuela to increase political participation and empower grassroots organizations, not to mention the role of the legislature, the judiciary, government agencies, and political parties – both Chávez’s and independent parties. Democratic participation has increased greatly under Chávez. As noted above, voter participation increased from 54 percent to 73 percent from the 1998 presidential election to the 2006 election. This was the result of policies such as voter registration drives that allowed millions of previously disenfranchised voters to have a voice in politics. Participation extends beyond elections, with community councils being a main source for grassroots empowerment. The new Constitution in 1999 formed the legal basis for a participatory democracy through the codification of Local Public Planning Councils. In 2006 the law was modified to give more power and control directly to Community Councils; there are an estimated 20,000 of these in Venezuela. The councils can plan and implement community projects, and can request funding from the state. They have drastically changed the previous system, where the decision-making process in such projects was concentrated in the hands of local and national authorities. Self-organization has been a dominant theme throughout the Chávez administration, and was the primary force that overturned the April 2002 coup d’etat. After the military ousted Chávez in April 2002, and the coup leaders dissolved the nation’s institutions, it was the grassroots that took to the streets demanding that democracy be respected. The successful mobilization led to the rapid overturning of the coup and the return of the democratically-elected Chávez to power. The roots of these grassroots efforts come from an event in 1989 in Venezuela which became known as the Caracazo. Former president Carlos Andrés Pérez, at the urging of the International Monetary Fund, implemented austere economic policies in the face of high inflation and high unemployment. When bus fares were raised in the capital city of Caracas, popular protests ensued. The government responded with a harsh military crackdown, resulting in the death of at least 450 Venezuelans. Resources: Online: Venezuela Analysis Jules Boykoff, “Devil or Democrat? Hugo Chávez and the US Prestige Press.” New Political Science, Volume 31, Issue 1 March 2009 , pages 3 – 26. (A shortened version of this article was posted on Venezuela Analysis.) Dan Beeton, “Wrong Numbers: Distorting Venezuela’s record on poverty,” Extra!, November/December 2006 Lee Salter, “A Decade of Propaganda? The BBC’s Reporting of Venezuela.” Venezuelanalysis.com, December 14th 2009 Mark Weisbrot’s op-ed’s and columns on Venezuela, Center for Economic and Policy Research. [1] The Washington Post, “Meddle With Mr. Chavez.” (Editorial) March 1, 2003. [http://www.washingtonpost.com/ac2/wp-dyn?pagename=article&node=&contentId=A18965-2003Feb28¬Found=true] Accessed April 27, 2010. [2] The Los Angeles Times, “Hugo Chavez flexes his muzzle.” (Editorial) January 26, 2010. [http://articles.latimes.com/2010/jan/26/opinion/la-ed-rctv26-2010jan26] Accessed April 27, 2010. [3] Darcy Crowe, “Venezuela’s Chavez Moves to Tighten Control Over Private Media.” The Wall Street Journal. July 9, 2009 [http://online.wsj.com/article/SB124717745352519889.html] Accessed April 27, 2010. [4] Miguel Perez, “Muzzling the news media broadcasts a loss of Venezuela democracy.” Chicago Sun-Times. January 9, 2007. Reposted at http://www.creators.com/opinion/miguel-perez/say-adios-to-venezuelan-democracy.html . Accessed April 27, 2010. [5] Andres Oppenheimer, “OAS silence on Venezuela censorship scary.” The Miami Herald. June 7, 2007. Reposted at http://www.hacer.org/current/Vene145.php. Accessed April 27, 2010. [6] Simon Romero, “Nonrenewal of TV License Stokes Debate in Venezuela.” New York Times, January 1, 2007. [http://www.nytimes.com/2007/01/01/world/americas/01venez.html?_r=1] Accessed April 26, 2010. [7] Carlos Chirinos, “Venezuela investiga el “Carmonazo”.” BBC Mundo, October 5, 2004. [http://news.bbc.co.uk/hi/spanish/latin_america/newsid_3718000/3718810.stm] Accessed April 27, 2010. [8] David Adams and Phil Gunson, “Media accused in failed coup.” St. Petersburg Times, April 18, 2002. [http://www.stpetersburgtimes.com/2002/04/18/Worldandnation/Media_accused_in_fail.shtml] Accessed April 27, 2010. [9] On the Media (NPR), “Pulling the Plug.” May 18, 2007. [http://www.onthemedia.org/transcripts/2007/05/18/05] Accessed April 27, 2010. [10] Patrick McElwee, “Is Free Speech Really at Stake? Venezuela and RCTV.” VenezuelaAnalysis.com. May 23rd 2007. [http://venezuelanalysis.com/analysis/2398] Accessed April 26, 2010. [11] Christopher Toothaker, “Last Anti-Chavez TV Station Faces Probe, Shutdown.” Associated Press. May 16, 2009. [http://abcnews.go.com/International/wireStory?id=7604504] Accessed April 27, 2010. [12] Human Rights Watch, “A Decade Under Chávez: Political Intolerance and Lost Opportunities for Advancing Human Rights in Venezuela.” September 18, 2008 . (footnote 184, p.74; footnote 181, p.73) [http://www.hrw.org/sites/default/files/reports/venezuela0908web.pdf] Accessed April 27, 2010. [13] Simon Romero, “Chávez Looks at His Critics in the Media and Sees the Enemy.” The New York Times. June 1, 2007. [http://www.nytimes.com/2007/06/01/world/americas/01venez.html] Accessed April 27, 2010. [14] McElwee. ||||| When this and several other discrepancies were pointed out to Mr. Stone in the interview, his attitudes varied. “I’m sorry about that, and I apologize,” he said about the 1998 election. But he also complained of “nitpicking” and “splitting hairs” and said that it was not his intention to make either a program for C-Span or engage in what he called “a cruel and brutal” Mike Wallace-style interrogation of Mr. Chávez that the BBC broadcast this month. “We are dealing with a big picture, and we don’t stop to go into a lot of the criticism and details of each country,” he said. “It’s a 101 introduction to a situation in South America that most Americans and Europeans don’t know about,” he added, because of “years and years of blighted journalism.” Photo “I think there has been so much unbalance that we are definitely a counter to that,” he also said. Tariq Ali, the British-Pakistani historian and commentator who helped write the screenplay, added: “It’s hardly a secret that we support the other side. It’s an opinionated documentary.” Initial reviews of “South of the Border” have been tepid. Stephen Holden in The New York Times called it a “provocative, if shallow, exaltation of Latin American socialism,” while Entertainment Weekly described it as “rose-colored agitprop.” Some of the misinformation that Mr. Stone, who consistently mispronounces Mr. Chávez’s name as Sha-VEZ instead of CHA-vez, inserts into “South of the Border” is relatively benign. A flight from Caracas to La Paz, Bolivia, flies mostly over the Amazon, not the Andes, and the United States does not “import more oil from Venezuela than any other OPEC nation,” a distinction that has belonged to Saudi Arabia during the period 2004-10. But other questionable assertions relate to fundamental issues, including Mr. Stone’s contention that human rights, a concern in Latin America since the Jimmy Carter era, is “a new buzz phrase,” used mainly to clobber Mr. Chávez. Mr. Stone argues in the film that Colombia, which “has a far worse human rights record than Venezuela,” gets “a pass in the media that Chávez doesn’t” because of his hostility to the United States. Advertisement Continue reading the main story As Mr. Stone begins to speak, the logo of Human Rights Watch, which closely monitors the situation in both Colombia and Venezuela and has issued tough reports on both, appears on the screen. That would seem to imply that the organization is part of the “political double standard” of which Mr. Stone complains. “It’s true that many of Chávez’s fiercest critics in Washington have turned a blind eye to Colombia’s appalling human rights record,” said José Miguel Vivanco, director of the group’s Americas division. “But that’s no reason to ignore the serious damage that Chávez has done to human rights and the rule of law in Venezuela,” which includes summarily expelling Mr. Vivanco and an associate, in violation of Venezuelan law, after Human Rights Watch issued a critical report in 2008. Photo A similarly tendentious attitude pervades Mr. Stone’s treatment of the April 2002 coup that briefly toppled Mr. Chávez. One of the key events in that crisis, perhaps its instigation, was the “Llaguno Bridge Massacre,” in which 19 people were shot to death in circumstances that remain murky, with Chávez supporters blaming the opposition, and vice versa. Mr. Stone’s film includes some new footage from the confrontation at the bridge, but its basic argument hews closely to that of “The Revolution Will Not Be Televised,” a film the Chávez camp has endorsed. That documentary, however, has been subject to rebuttal by another, called “X-Ray of a Lie,” and by Brian A. Nelson’s book “The Silence and the Scorpion: The Coup Against Chávez and the Making of Modern Venezuela” (Nation Books), neither of which Mr. Stone mentions. Instead Mr. Stone relies heavily on the account of Gregory Wilpert, who witnessed some of the exchange of gunfire and is described as an American academic. But Mr. Wilpert is also the husband of Mr. Chávez’s consul-general in New York, Carol Delgado, and a longtime editor and president of the board of a Web site, Venezuelanalysis.com, set up with donations from the Venezuelan government, affiliations that Mr. Stone does not disclose. Newsletter Sign Up Continue reading the main story Please verify you're not a robot by clicking the box. Invalid email address. Please re-enter. You must select a newsletter to subscribe to. Sign Up You will receive emails containing news content , updates and promotions from The New York Times. You may opt-out at any time. You agree to receive occasional updates and special offers for The New York Times's products and services. Thank you for subscribing. An error has occurred. Please try again later. View all New York Times newsletters. Like Mr. Stone’s take on the Kennedy assassination, this section of “South of the Border” hinges on the identity of a sniper or snipers who may or may not have been part of a larger conspiracy. As Mr. Stone puts it in the film, “Shots were fired from the rooftops of buildings, and members from both sides were hit in the head.” In a telephone interview this week, Mr. Wilpert acknowledged that the first shots seem to have been fired from a building known as La Nacional, which housed the administrative offices of Freddy Bernal, the pro-Chávez mayor of central Caracas. In a congressional investigation following the coup, Mr. Bernal, who led an elite police squadron before taking office, was questioned about a military officer’s testimony that the Defense Ministry had ordered Mr. Bernal to fire on opposition demonstrators. Mr. Bernal described that charge as “totally false.” “I did not know about that, I didn’t even know it was a Chávista building,” Mr. Stone said initially, before retreating to his original position. “Show me some Zapruder footage, and it might be different,” he said. The second half of “South of the Border” is a road movie in which Mr. Stone, sometimes accompanied by Mr. Chávez, meets with leaders of Bolivia, Argentina, Paraguay, Brazil, Ecuador and Cuba. But here, too, he bends facts and omits information that might undermine his thesis of a continent-wide “Bolivarian revolution,” with Mr. Chávez in the forefront. Photo Visiting Argentina, for example, he accurately describes the economic collapse of 2001. But then he jumps to Néstor Kirchner’s election to the presidency in May 2003 and lets Mr. Kirchner and his successor — and wife — Cristina Fernández de Kirchner claim that “we began a different policy than before.” Advertisement Continue reading the main story In reality, Mr. Kirchner’s presidential predecessor, Eduardo Duhalde, and Mr. Duhalde’s finance minister, Roberto Lavagna, were the architects of that policy shift and the subsequent economic recovery, which began while Mr. Kirchner was still the obscure governor of a small province in Patagonia. Mr. Kirchner was originally a protégé of Mr. Duhalde’s, but the two men are now political enemies, which explains the Kirchners’ desire to write him out of their version of history. Trying to explain the rise of Evo Morales, the president of Bolivia who is a Chávez acolyte, Mr. Ali refers to a controversial and botched water privatization in the city of Cochabamba. “The government decided to sell the water supply of Cochabamba to Bechtel, a U.S. corporation,” he says, “and this corporation, one of the things it got the government to do was to pass a law saying that from now on it was illegal for poor people to go out onto the roofs and collect rainwater in receptacles.” In reality, the government did not sell the water supply: it granted a consortium that included Bechtel a 40-year management concession in return for injections of capital to expand and improve water service and construction of a dam for electricity and irrigation. Nor is the issue of water collection by the poor exactly as Mr. Ali presents it. “The rainwater permit issue always comes up,” Jim Shultz, a water privatization critic and co-editor of “Dignity and Defiance: Stories of Bolivia’s Challenge to Globalization” (University of California Press), said in an e-mail message. “What I can say is that the privatization of the public water system was accompanied by a government plan to require permits in order to dig wells and such, and that it could have potentially granted management concessions to Bechtel or others.” But “it never got that far,” he added, and “it remains unclear to me to this day what type of water collection systems would have been included.” He concluded: “Many believed that would have included some rain collection systems. That could also easily be hype.” Asked about the discrepancy, Mr. Ali replied that “we can talk about all this endlessly,” but “the aim of our film is very clear and basic.” In “South of the Border,” he added: “We were not writing a book, or having an academic debate. It was to have a sympathetic view of these governments.” ||||| New York Times reporter Larry Rohter turned in a factually challenged fact-check of Oliver Stone's new film South of the Border. So Stone and the film's co-writers Mark Weisbrot and Tariq Ali wrote a devastating rebuttal. A reader passed along a link to that piece to Rohter, suggesting that he "should be embarrassed" by his review. Unsurprisingly, Rohter would not seem to be embarrassed at all, judging his reply email, which FAIR has received: Dear Mr. Fuentes: Actually, it's Oliver Stone and company who need to heed your advice. I've been scrupulously honest in my reporting and writing, and they are offended and embarrassed at having their many errors and inaccuracies disclosed. Rather than owning up to those mistakes, they've chosen to double down and up the ante. Where they might merely have been mistaken before, they are now lying outright, the letter you link to below being the prime example. Don't take my word for it. I urge you to go back and look at what Stone and his screenwriters are saying in that letter. As regards the issue of U.S. oil imports from OPEC countries, for example, go ahead and click on the two links that Stone & Weisbrot provide and look at the numbers contained there. You will see that the United States has imported more oil from Saudi Arabia than Venezuela every year since 2000. So no matter how Stone and company want to slice, dice bend or twist it, the assertion they make in the film about U.S. oil imports is simply wrong. The numbers are clear and indisputable. Same thing goes for the 1998 Venezuela presidential race. The numbers don't lie: Irene Saez got only 3 percent of the vote, compared to 40 percent for Henrique Salas Romer, yet she is Chavez's "main opponent" and he is not? Let's apply that same pretzel logic to some other elections and see what we come up with. Was George Bush's "main opponent" in 2000 Al Gore or Ralph Nader? Was Harry Truman's "main opponent" in 1948 Thomas E. Dewey or the Dixiecrat Strom Thurmond? Was Jimmy Carter's "main opponent" in 1980 Ronald Reagan or John Anderson? It's also worthwhile using a little bit of simple logic to analyze the issue of the Cochabamba water privatization. Tariq Ali's argument seems to be that there is no substantial difference between a sale and a 40 year lease. Granted that the notion of private ownership may be anathema to someone with his ideological leanings, and therefore his understanding of different property regimens may be flawed. But the outright sale of an asset is not the same as granting a concession to use that asset for a fixed period of time, as anyone who has ever leased a car knows well. The devil is in the details, and Stone and company have chosen to ignore those. I could subject each of their other wild and erroneous claims to the same kind of dissection for you, but I trust you get the picture from the examples I've cited. Thank you for writing. Talk about doubling down. Rohter, for some reason, decided that this passing comment in the film deserved to be debunked: "We import more oil from Venezuela than any other OPEC nations." As the film makes clear, that comment was made by an oil industry analyst in a 2002 TV appearance, though Rohter's Times piece oddly cited 2004-10 data to contradict him. Stone and co. cite 1997-2001 as a more relevant time frame; in that period, the United States did in fact buy more oil from Venezuela than from Saudi Arabia (though in 2000-01, Saudi Arabia was the bigger supplier). In his emailed response, Rohter ignores this explanation, and says the links provided by Stone, Weisbrot and Ali don't support their point. It would seem that they do. It's a strange item to seize on, anyway; the filmmakers included the oil analyst to make the point that various business interests--including oil companies--supported the coup against Chavez, which is not at all controversial. Rohter's complaint about Chavez's 1998 election is similarly tendentious. Irene Saez was considered by many observers to be Chavez's main rival in the presidential campaign. That's what reporter Bart Jones says in the documentary; it's also what the New York Times reported shortly after Chavez's victory (12/9/98): Until last spring, Irene Saez, a former Miss Universe, had been leading in voter surveys, peaking at 35.7 percent to Mr. Chavez's 20.6 percent. Then the price of oil, which underpins Venezuela's entire economy, fell steeply. "We went from an optimistic country to a pessimistic one," said Luis Vicente Leon, director of the Datanalysis polling agency. The following month, Miss Saez accepted a lukewarm endorsement from one of the two traditional parties. The backing compromised her claims to being an outsider and her popularity ratings slid into the single digits. On the debate over Bolivian water rights, the matter seems hardly worth reviewing; it comes down to how one chooses to characterize a deal that would hand a private company 40-year control over a nation's water supply. Apparently in Rohter's mind, calling such a deal "privatization" is evidence that someone has the wrong "ideological leanings" to understand complex financial transactions. Rohter assures that he "could subject each of their other wild and erroneous claims to the same kind of dissection for you." I think we've seen enough.

– Oliver Stone and a New York Times movie critic are feuding over a scathing review of Stone's documentary on Hugo Chavez, South of the Border. It began when the Times' Larry Rohter wrote this piece, in which he accuses Stone of "mistakes, misstatements, and missing details." Stone fired back with this detailed rebuttal, telling Rohter to get his own facts straight. And now, of course, Rohter has responded with a rebuttal of his own, reprinted at the Huffington Post. "I've been scrupulously honest in my reporting and writing, and (Stone and company) are offended and embarrassed at having their many errors and inaccuracies disclosed," writes Rohter. Stone, meanwhile, accuses his critic of "animus and conflict of interest," because the documentary criticizes both the Times coverage of Venezuela and Rohter's own "anti-Chavez" reporting from years earlier. "The Times should apologize for having published it," he concludes.

Human rights group hail statement by international body about ‘its own involvement’ in crisis which experts say still has not received proper attention Human rights groups working with thousands of victims of cholera in Haiti have reacted with jubilation to the United Nation’s first tacit admission that it was to blame for the devastating outbreak of the disease that has claimed as many as 30,000 lives and infected more than two million people. For the past six years, the world body has doggedly refused to address the issue of how its own peacekeepers, relocated from Nepal to Haiti in 2010 in the wake of a major earthquake, imported the deadly cholera bacterium with them. Studies have found that the UN troops could have been screened for the illness, and the disaster averted, for as little as $2,000 (then £1,400). In a statement first reported by the New York Times, the office of the secretary-general of the UN, Ban Ki-moon, said that the organization had decided to step up its efforts to fight back cholera in one of the world’s poorest countries. “Over the past year the UN has become convinced that it needs to do much more regarding its own involvement in the initial outbreak and the suffering of those affected by cholera,” said Farhan Haq, Ban’s deputy spokesman. The reference to the UN’s “involvement in the initial outbreak” was greeted as a breakthrough by groups working with cholera victims. “This is a groundbreaking first step towards justice,” said Beatrice Lindstrom of the Institute for Justice & Democracy in Haiti (IJDH), which is pursuing a class-action lawsuit against the UN to try to force it to accept responsibility for the disaster and to pay compensation. The world body has consistently refused any claim for compensation, claiming it is immune from legal action. Lindstrom added that the real test of the UN’s intentions was what comes next. “The UN must follow this announcement with action, including issuing a public apology, establishing a plan to provide compensation to the victims who have lost so much, and ensuring that cholera is eliminated in Haiti through robust investment in water and sanitation infrastructure. We will keep fighting until it does.” The UN’s top diplomat appears to have been bounced into making a clearer recognition of responsibility than ever before by the advent of a new draft report from one of its own special advisers looking into how the UN handled the crisis. According to the New York Times, the draft report states directly that the cholera epidemic would not have happened without the actions of the world organization. UN's own experts chastise Ban Ki-moon over handling of Haiti cholera outbreak Read more The author of the report, Philip Alston, the UN’s special rapporteur on extreme poverty and human rights, was one of five experts working for the UN who earlier this year wrote a heavily critical letter to Ban in which the secretary-general’s resistance to accepting any responsibility was torn apart. The five special rapporteurs accused the UN chief executive, in essence, of stripping hundreds of thousands of Haitians of their right to justice. In his statement, the UN’s deputy spokesman said: “The UN has been heavily engaged in cholera eradication since the 2010 outbreak.” But that claim conflicts with the testimony of health experts who say that the world organization has consistently dropped the ball over the cholera epidemic. Dr Renaud Piarroux, a pediatrician who was among the first to sound the alarm over the outbreak of cholera, recently visited the country and reported that the incidence of the disease and the lack of any infrastructure to deal with its spread were still alarming. Piarroux’s report concludes that Haiti’s cholera epidemic is by far the largest the world has faced in recent decades, and yet there has been no concerted effort to eradicate it by the UN or any other international body. “That the current response is not up to the challenge is an understatement,” writes Piarroux, whose work in exposing the UN’s role in bringing cholera to Haiti and the world body’s efforts to cover up its complicity is profiled in the book Deadly River by Ralph Frerichs. The French epidemiologist goes on to say that “neither local politicians nor the international community seem to have taken the measure of the seriousness of the situation”. ||||| U.N. Admits Role In Haiti Cholera Outbreak That Has Killed Thousands Enlarge this image toggle caption Hector Retamal/AFP/Getty Images Hector Retamal/AFP/Getty Images In the fall of 2010, months after a devastating earthquake struck Haiti, a new disaster began: a cholera outbreak that killed thousands of people and continues to sicken people across the country. Experts determined that the source of the disease was a U.N. peacekeeping camp. And now, nearly six years later, the United Nations has admitted it played some role in the deadly outbreak. At a briefing Thursday, U.N. spokesman Farhan Haq said that over the course of the past year, "the U.N. has become convinced that it needs to do much more regarding its own involvement in the initial outbreak and the suffering of those affected by cholera." He said the U.N. would announce new actions to address the issue within the next two months. "Our legal position on this issue has not changed," Haq said, adding that the U.N. was not describing any of its actions as "reparations." The U.N.'s acknowledgement was first reported by the New York Times, which notes that the statement from Haq "stopped short of saying that the United Nations specifically caused the epidemic." The newspaper adds: "Nor does it indicate a change in the organization's legal position that it is absolutely immune from legal actions. ... But it represents a significant shift after more than five years of high-level denial of any involvement or responsibility of the United Nations in the outbreak, which has killed at least 10,000 people and sickened hundreds of thousands." Cholera, as our Goats and Soda blog has explained, is an infectious disease that causes severe, watery diarrhea. It spreads through contaminated water. The illness causes dehydration and can lead to death, sometimes in just a few hours, if left untreated. The beginning of the epidemic in Haiti was swift and catastrophic. Here's how Richard Knox described the outbreak for NPR in 2013: "Suddenly, the first cases appeared in the central highlands near a camp for United Nations peacekeeping forces. ... "The disease struck with explosive force. Within two days of the first cases, a hospital 60 miles away was admitting a new cholera patient every 3 1/2 minutes. " 'Part of the reason we think the outbreak grew so quickly was the Haitian population had no immunity to cholera,' says Daniele Lantagne, an environmental engineer at Tufts University. 'Something like when the Europeans brought smallpox to the Americas, and it burned through the native populations.' " Before 2010, cholera had been unknown in Haiti for at least a century. And the impoverished, earthquake-devastated country was already struggling with water and sanitation. A panel of experts appointed by the U.N. found that the strain of cholera that popped up in Haiti was "a perfect match" for a strain found in Nepal. Nepalese peacekeepers were staying at the U.N. camp, and poor sanitation sent sewage from the camp into local waterways. In 2013, activists sued the U.N. over the cholera outbreak. Earlier this year, NPR's Jason Beaubien offered an update on that case: "A three-judge federal appeals court panel held a hearing March 1 on whether the U.N. should be held accountable for Haiti's devastating epidemic. "A federal district judge last year dismissed the class-action suit, ruling that international treaties immunize the U.N. from lawsuits. The plaintiffs appealed the lower court's dismissal, resulting in this month's hearing. The United States is defending the U.N., since the agency is headquartered in New York. "The lawsuit was brought by the Boston-based Institute for Justice and Democracy in Haiti and a sister group in Haiti on behalf of 5,000 cholera victims. They want the U.N. to end cholera by installing a national water and sanitation system; pay reparations to cholera victims and their families; and publicly apologize for bringing cholera to Haiti. "The plaintiffs contend the U.N. forfeited its legal immunity when it failed to launch an internal process to adjudicate the plaintiffs' claims, as they say its own commitments require. " 'The U.N.'s conditional immunity does not authorize impunity,' plaintiffs' attorney Beatrice Lindstrom told the three-judge appeals panel." As the Times noted, the U.N. did not walk back its claim of immunity in its acknowledgement of some responsibility in the outbreak. As Jason reported, U.N. officials are concerned that if the U.N. is held responsible for the cholera outbreak, it will be vulnerable to lawsuits around the world over actions of its peacekeeping forces. Some of the U.N.'s own special rapporteurs have sharply criticized that stance and say U.N. efforts to address the crisis are "clearly insufficient." Again, the cholera crisis that began in 2010 continues. The disease is now endemic in the country; thousands of people are sickened every year.

– After six years, the UN has admitted it is at least partially responsible for the cholera outbreak ravaging Haiti, the New York Times reports. The epidemic started in 2010 near a base where UN peacekeepers from Nepal had just arrived. Nepal was experiencing an outbreak of cholera at the time, and waste from the base in Haiti got into a nearby river. According to NPR, experts hired by the UN found the strain of cholera in Haiti matched the one in Nepal. And scientists agreed the base was the only realistic source of the outbreak. Regardless, the UN continued to deny any responsibility as cholera killed at least 10,000 Haitians and sickened hundreds of thousands more. The Guardian puts those numbers even higher at 30,000 and 2 million respectively. On Thursday, UN secretary general Ban Ki-moon for the first time said the UN played a role in the cholera outbreak and called for a "significant new set of UN actions to stop it." His spokesperson admitted some UN "involvement in the initial outbreak." This change in tack follows a confidential report from a UN adviser that stated the cholera epidemic "would not have broken out but for the actions of the United Nations." Still, the UN resisted taking full responsibility for the outbreak and continued to insist it can't be held legally responsible. Studies show it would have cost the UN as little as $2,000 to screen its peacekeepers for cholera and protect Haitians, who have no immunity to cholera and were already dealing with a devastating earthquake.

solar granulation is one of the most studied phenomena in the lower solar atmosphere and its properties are thought to be well understood @xcite . spectral and imaging observational data have allowed solar granulation to be studied in detail . commonly considered parameters include sizes and lifetimes of granules , velocity and intensity fluctuations together with their correlations , proper motions of individual features , etc . ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? at the same time , state of the art simulations of solar convection and magneto - convection reproduce very satisfactorily many observational granulation properties , which has made it possible to explain self - consistently the mean shapes of spectral line profiles @xcite . simulations have shown that parameters as micro- and macroturbulent velocities ( used widely in the past to match the spectral lines shapes to observations ) are not necessary any more as the spectral lines are broadened by the velocity field of the convection motions . in this letter , we report on spatially resolved observations of the line broadening by the granular velocity field ( or , equivalently , the spatially resolved action of solar microturbulence ) . the data used in the letter were obtained with the imaging magnetograph experiment ( imax ; see * ? ? ? * ) that flew on board the sunrise balloon telescope in june , 2009 @xcite . we study the spatial variations of the full width at half maximum ( fwhm ) of the 5250.2 line . we found that the fwhm is larger in intergranular lanes and smaller in granules . but the most interesting finding is that the fwhm is particularly small in narrow lanes located at granular / intergranular borders . we found only few works that discuss the relation between the line fwhm and granulation @xcite , pointing out that the fwhm is anti - correlated with brightness . the observations of @xcite were interpreted in terms of supersonic flows , which was questioned by @xcite . we did not find any previous mention of the detection of the narrow regions with extremely small fwhm adjacent to intergranular borders . the aim of this letter is to describe their properties and to offer an explanation for their origin . the imax instrument and the details of the data acquisition and reduction are described in @xcite . here we use a time series of images of about 23 min duration taken near the solar disc center ( ut 00:37 ) . the observational sequence consists of five polarized filtergrams taken at @xmath0 , @xmath1 and @xmath2 m from the 5250.2 line center . we use level 2 data ( reconstructed by deconvolution ) . the spatial resolution of the reconstructed data is estimated to be 015 . the field of view is about 33@xmath3 33 ( after removing the apodized areas ) , with a pixel size of 0055 . we use the following parameters extracted from the stokes @xmath4 data : continuum intensity , line of sight velocity , and fwhm . the latter two parameters were calculated from gaussian fits to the five intensity wavelength points . the statistical errors of the fitting procedure were within the range of 2040 for the velocities and a few m to 10 m ( at most ) for the fwhm . figure [ fig : fwhm ] shows an image of the fwhm at one moment of time . this image demonstrates clearly that the width of the 5250.2 intensity profile follows the granulation structure . the fwhm increases in intergranular lanes ( appearing as bright regions ) and becomes smaller in granules . a more careful inspection of the image reveals that adjacent to almost each intergranular lane there are narrow black regions ( that also have elongated lane - like shapes ) of smaller widths . the average fwhm of the 5250.2 line in the granular regions is of 120 m , in intergranular regions is of 140 m , but only 100 m at the borders between granules and intergranular lanes . the unsharp mask filter applied to this image enhances the gradients and makes the locations with extremely small fwhm more evident ( fig . [ fig : fwhm]b ) . panels c and d with enlarged view of the region of 6 mm @xmath3 6 mm size ( marked by the white squares in figs . [ fig : fwhm]a and b ) give some very clear examples of the dark lanes surrounding bright intergranular spaces . these dark features sometimes appear only on one side of the bright intergranular lane , and sometimes on both sides . in many cases they appear in regions where the normalized continuum intensity @xmath5 , i.e. just at the borders between granules and intergranular lanes . the width of these dark features is about @xmath6 imax pixels , i.e. @xmath702 . their lifetime is the same as the lifetime of the intergranular lane they are attached to , see fig . [ fig : time ] ( left and middle panels ) . these dark lanes in the fwhm image appear also in the non - reconstructed data ( with less contrast ) , proving that they are not artifacts of the phase diversity reconstruction procedure . to find the origin of these dark lanes in fwhm images , we have performed spectral line synthesis of the 5250.2 line in a snapshot of magneto - convection simulations @xcite . we considered a simulation run with a bi - polar magnetic field structure and an average unsigned magnetic field in the box of 30 g , corresponding to a quiet solar region ( for more details on this simulation snapshot see * ? ? ? * ) . the grid size of the simulations is about 20 km . the synthesis was done in lte using the sir code @xcite . no additional line broadening mechanisms , such as macro- or microturbulence were introduced . we found that the areas with extremely narrow intensity profiles adjacent to intergranular lanes also appear in the simulations . for an adequate comparison with the observations we have degraded the simulation spectra in the following way . firstly , we performed a convolution of each monochromatic image with an airy function imitating the action of a 100 cm telescope . secondly , we convolved the spectra in wavelength with the transmission profiles of the imax etalon . finally , we fit a gaussian function to the five wavelength points and calculated the width of the gaussian profiles as a proxy to the intensity profile width , as well as velocity , similar to the observations . the resulting image of the simulated fwhm is shown in figure [ fig : fwhm_sims]a . the fwhm image shows structures similar to the observed ones , i.e. larger fwhm in intergranular lanes and very low fwhm in the narrow regions adjacent to lanes . note that the average value and the range of variations agree very well in the simulations and observations . similar to the observations , the dark lanes in the fwhm image correspond to the normalized continuum intensity around unity , i.e. they mark the transition between granules and intergranular lanes ( fig . [ fig : fwhm_sims]b ) . their width is a few pixels ( @xmath702 ) . due to the small width of these dark lanes , about 02 , high resolution and image stability are required for their detection . figure [ fig : fwhm_sims]c shows the fwhm after the simulated spectra were degraded to hinode resolution and pixel size ( note that the 6301.5 is used in this case ) . this image preserves brightenings in intergranular lanes corresponding to large fwhm , but the adjacent dark lanes do not show up at this resolution . on the one hand , this comparison demonstrates that imax / sunrise data quality is necessary to detect these features . on the other hand , it proves that the instrument reached indeed very high spatial resolution @xcite . the imax spectral line of 5250.2 at is sensitive to the velocity broadening , but also to magnetic fields via the zeeman effect , and to temperature . to find out which effect is primarily responsible for the spatial variations of the fwhm , we performed additional calculations . we repeated the spectral synthesis for three cases : ( 1 ) magnetic field was set to zero , preserving the variations in the rest of the variables ; ( 2 ) horizontal variations of the temperature and gas pressure were set to zero using for all the points the mean stratification , but preserving variations of the velocity and magnetic field ; ( 3 ) velocity was set to zero at all points , while preserving variations in the rest of the variables . we found that the magnetic field s influence on the horizontal variations of the fwhm is negligible except for a few isolated locations in intergranular lanes where the field reaches kg values . there the fwhm is additionally enhanced by the zeeman broadening . figure [ fig : std ] gives the variations of the fwhm in the cases ( 2 ) and ( 3 ) . case ( 2 ) , where only velocity variations are preserved , looks almost identical to the original case in fig . [ fig : fwhm_sims]a . while case ( 3 ) , where only variations of the thermodynamic variables are preserved , looks very different , showing almost an opposite behaviour to the case ( 2 ) . note that , curiously , in the case ( 3 ) the broadening due to magnetic field becomes evident in some intergranular lanes where the field is strongest ( locations at @xmath8 mm ; @xmath9 mm and @xmath10 mm ; @xmath11 mm in the right panel of fig.[fig : std ] ) . the broadening due to magnetic field is much weaker compared to the velocity broadening , but is comparable in magnitude to the thermal broadening . the average value of the fwhm and its standard deviation is much lower for the case ( 3 ) as compared to the case ( 2 ) and to the observations . thus , we conclude that velocity broadening is the prime responsible for the horizontal variations of the fwhm . figure [ fig : flows ] shows several examples of the velocity field at the locations marked by letters in fig . [ fig : fwhm_sims]b . at these locations the red line crosses an intergranular lane with enhanced fwhm as well as the transition between granule and intergranule with very low fwhm . as follows from fig . [ fig : flows ] , all these locations have features in common . at the center of an intergranular lane , in the deep photospheric layers , the vertical velocity is mainly a downflow with a magnitude reaching about @xmath6 . the intergranular lanes are also characterized by a strong vertical velocity gradient . in a few hundred kilometers , the velocity decreases from @xmath6 to zero , following the change of its sign at the top of the atmosphere . these strong velocity gradients have immediate implications on the width of the 5250.2 line profiles , whose core forms around 400 km @xcite . the action of these vertical velocity gradients over the height range of formation of the line is similar to the action of microturbulence velocity , producing additional broadening of the profiles . we conclude that the large fwhm in intergranular lanes is produced by a microturbulence - like effect due to strong vertical velocity gradients , unlike the mechanism based on super - sonic flows proposed by @xcite . similar conclusion , as for the enhancement of the fwhm in intergranular lanes , was previously reached in the work of @xcite from studying the line - parameter variations in the two - dimensional hydrodynamic simulations . figure [ fig : flows ] shows that the regions with extremely low fwhm correspond to the locations where the granular flow bends . these locations are the transitions from granules with upflowing velocities to intergranular lanes with downflows . as the velocity vector bends there , the vertical velocity component is close to zero and the vertical velocity gradient is very small as well . it makes the velocity broadening at these transition locations extremely low , thus producing narrow profiles , as detected in the imax observations . in fig . [ fig : fwhm_sims]b the red dashed contours mark the location with zero vertical velocity in simulations . it shows that almost always these locations coincide with dark lanes in fwhm image . the imax data only have five points in wavelength , making it impossible to check the conclusions about the velocity gradients , obtained from simulations . however , the absolute values of the los velocities are reliably obtained from these data . according to simulations , the regions with extremely low fwhm correspond to locations with almost zero vertical velocities . in fig . [ fig : time ] ( right panel ) , we plot the los velocity histograms obtained from the imax data over the whole time series . this figure shows the existence of the three distinct families of features . granules , selected as locations with @xmath12 , have the velocity histogram peak at @xmath13 . intergranular lanes , selected as locations with @xmath14 , show downflowing velocities with the histogram peak at 0.4 . this histogram almost coincides with the one obtained by selecting locations with enhanced fwhm given by white regions in fig . [ fig : fwhm]b . finally , there is a third distribution corresponding to the borders between granules and intergranular lanes . it is obtained by selecting locations with low fwhm given by the black regions in fig . [ fig : fwhm]b . its maximum appears at zero los velocity . this observational confirmation supports the conclusion based on simulations that the regions with extremely small fwhm correspond to locations where the velocity vector bends , producing a zero los velocity component . in this letter we have investigated the spatial distribution of the full width at half maximum of the 5250.2 intensity profiles in the imax / sunrise data . we have shown that the fwhm becomes large in intergranular lanes and is very small in narrow 02 wide strips adjacent to the lanes . the lifetime of these narrow regions is the same as the intergranular lanes they are attached to and they evolve in parallel . based on the similarity between imax observations and simulations of magneto - convection , we have offered an explanation for the formation of these profiles with small fwhm . we suggest that these profiles appear in regions where the granular flow bends . there , the velocity broadening is extremely small , as the los velocity component is close to zero and has very small gradients . this conclusion is supported by the analysis of the los velocity histograms in the imax data . we claim that the sunrise / imax resolution and image stability is the necessary condition to detect these narrow transition zones between granules and intergranular lanes . the german contribution to sunrise is funded by the bundesministerium fr wirtschaft und technologie through deutsches zentrum fr luft- und raumfahrt e.v . ( dlr ) , grant no . 50 ou 0401 , and by the innovationsfond of the president of the max planck society ( mpg ) . the spanish contribution has been funded by the spanish micinn under projects esp2006 - 13030-c06 and aya2009 - 14105-c06 ( including european feder funds ) . the hao contribution was partly funded through nasa grant number nnx08ah38 g . this work has been partially supported by wcu grant no . r31 - 10016 funded by the korean ministry of education , science , and technology .

based on imax / sunrise data , we report on a previously undetected phenomenon in solar granulation . we show that in a very narrow region separating granules and intergranular lanes the spectral line width of the 5250.2 line becomes extremely small . we offer an explanation of this observation with the help of magneto - convection simulations . these regions with extremely small line widths correspond to the places where the granular flows bend from mainly upflow in granules to downflow in intergranular lanes . we show that the resolution and image stability achieved by imax / sunrise are important requisites to detect this interesting phenomenon .

blockade or destruction of portions of trigeminal nerve distal to the gasserian ganglion is a well - demonstrated procedure to manage neuralgic pain in the distribution of the nerve . mandibular nerve block with alcohol is a frequently implemented procedure customarily in an outpatient context with minimal monitoring to treat trigeminal neuralgia with predominant pain in mandibular region . this procedure is periodically used and is generally considered a safe procedure resulting in desiderata pain control . the reported complications of mandibular nerve block are less than 1% and those described in the literature are intravascular injection , hypoesthesia , dysesthesia , sensory and motor loss in the mandibular nerve distribution , prolonged vertigo , facial swelling , diplopia , etc . here , we present a case of an elderly edentulous patient with trigeminal neuralgia who suffered recurrent temporomandibular joint ( tmj ) dislocation following mandibular nerve block . while difficulty in chewing due to masseter muscle weakness is a common complaint in these patients , but tmj dislocation is hardly seen . this case focuses on the preponderance of clinical evaluation and accentuates need for additional forethought to be taken during pain procedures , particularly in geriatric population . an 85-year - old male patient , a known case of trigeminal neuralgia , presented to ourpain clinic with complaints of sharp , lancinating pain in left jaw and face , agnate to the distribution of left mandibular division of trigeminal nerve since last 10 years . the previous magnetic resonance imaging of the patient was normal and there was no evidence neural compression by vascular loop . in contempt of regular medical therapy with carbamazepine 200 mg his symptoms hadexacerbated in last few days and the pain became obstinate to treatment and patient was reluctant to increase the dose of drugs as it resulted in excessive sedation . written informed consent was received and the patient was taken up in the procedure room and standard monitors attached . after preparing the left side of the face with povidone iodine , sterile rapes were placed . the patient was placed in a supine position with head tilted to the left side . after aseptic preparation and draping of the part , a 9.0 cm 22 gauge ( g ) needle was introduced perpendicularly in the middle of the coronal process at midpoint of the inferior border of the right zygomatic arch . the needle was advanced to hit the lateral pterygoid plate . the needle was withdrawn slightly and directed posteriorly toward the ear so that it passed the posterior border of the pterygoid plate . the needle was then carefully advanced 0.5 cm each time till the nerve stimulation was obtained . the mandibular nerve was stimulated at 1 ma for 0.1s stimulus duration with the help of a nerve stimulator , following which 2 ml of 2% lignocaine was injected after ensuring negative aspiration , which was followed by 1.0 ml absolute alcohol injection ( 1-butanol , usp ; merck specialties , mumbai , india ) . the procedure was uneventful and patient had immediate pain relief on the left side , but started complaining of mild pain on the right side of the face in preauricular region . in the absence of apparent physical findings we assumed it to be two days post block , the patient presented with complaints of severe pain , inability to close mouth , and eat food since 2 days . on physical examination the patient was positioned horizontal with the doctor standing behind the head of the patient . the thumbs were placed upon the ridge of the edentulous mandible intraorally , with the fingers swaddled externally around the mandible . firm , passive and unwavering pressure was applied in a downward and posterior direction until the jaw came back into place . a barton 's bandage was then applied to prevent another dislocation and the patient was cautioned to avoid opening the mouth wide . he was asked to come up for a follow - up in the maxillofacial outpatient department ( opd ) . radiographic investigations were done , which showed deepened glenoid fossa and steep articular eminence [ figure 1 ] . the patient and his family were not amenable for the surgical treatment for dislocation , so it was decided to treat the recurrent dislocation by autologous blood injection . local anesthesia ( 2% lignocaine ) was injected into the preauricular site , and a 21 gauge needle was inserted into the superior articular cavity of right side tmj . five milliliter blood was collected from a peripheral vein . of this , 3 ml was injected into the superior articular activity and 1 ml was injected around the articular capsule . further , subluxation reoccurred over the next several days , but then desists after some days . patient was pain free and able to carry out his normal daily activities like chewing , yawning , and mouth opening with reasonable ease 6 months post procedure [ figure 2 ] . treatment done did not seem to affect his daily life , so it was decided not to perform further treatment . neurolytic alcohol blocks are commonly used in patients with trigeminal neuralgia pertaining to mandibular distribution of the nerve . usually done as an outpatient procedure with minimal complications and good pain relief for considerable time . however , these blocks offer limited pain relief and repeated blocks are less successful and associated with higher risk of neuritis . this case reports occurrence of rare but disabling complication which happened not because of the neural blockade , but as a consequence of pain relief . usual complications of mandibular nerve block are hypoesthesia , dysesthesia , sensory loss in mandibular nerve distribution , facial swelling , and masseter muscle weakness , but dislocation of the joint following mandibular nerve block for inferior alveolar nerve neuralgia is never reported in the literature . . tmj dislocation is a painful condition occurring due to fixation of mandibular condyle in the anterosuperior aspect of the articular eminence . we assume that in this case , patient restrained his mouth opening while laughing , yawning , or biting due to severe neuralgic pain . but once there was pain relief following mandibular nerve block , the mobility across tmj was regained and due to previous excessive looseness / laxity of the mandibular and capsular ligaments , dislocation occurred . this laxity of ligaments attributed to hypermobility of the mandible along with the presence of steep articular eminence in old age precipitating dislocation additionally , patients with weakness of the joint capsule , anatomic aberration of the joint , or injury to the associated ligaments are at greater risk of dislocation . role of muscles and their tone for control of tmj movements and possibility of loss of tone adding to recurrent dislocations can not be ruled out . autologous blood is a lucid and minimally invasive method for the treatment for recurrent tmj dislocation . the contingent mechanism of action is that blood injected would result in formation of local bed for fibrous tissue , that will eventually lead to the embodiment of adhesions in the cavity . this is a unique case report of occurrence of rare complication like temporomandibular dislocation following peripheral trigeminal nerve block procedure . the intent of reporting this case is to raise the alertness of probableserious complication like tmj dislocation , especially in edentulous geriatric patients following pain relief due to peripheral mandibular nerve blocks which are customarily contemplated as minor outpatient procedures .

mandibular nerve block is periodically used procedure used to treat neuralgic pain in the distribution of trigeminal nerve . it is a commonly performed block in outpatient settings at our institute . we present a case of an elderly edentulous patient with trigeminal neuralgia who suffered recurrent temporomandibular joint ( tmj ) dislocation following mandibular nerve block . the patient presented with complaints of severe pain , inability to close mouth , and eat food since 2 days . anterior closed reduction of tmj resulted in reduction of joint and immediate pain relief . however , the maneuver failed due to recurrent dislocation of the joint . a barton dressing was applied to prevent another dislocation . this was followed by autologous blood injection into the joint . this case focuses on the preponderance of clinical evaluation and accentuates the need for additional forethought to be taken during pain procedures , particularly in the geriatric population .

3d single - particle imaging with x - ray free - electron lasers ( xfels ) is being actively pursued for its potential biological applications , which notably include determining the structures of single molecules @xcite . it is also one of the most challenging goals in x - ray laser science , because each diffraction measurement provides a very weak signal and is destructive . as few as @xmath0 photons per shannon - nyquist pixel ( at high scattering angles ) are expected for a 500 kda protein @xcite . to overcome low signal - to - noise , the experiment involves a large number of diffraction measurements ( 10@xmath110@xmath2 ) and each measurement must be of a new copy of the particle , which is assumed to have an identical structure . such datasets are achievable because xfels have high repetition rates ( @xmath3 100 hz @xcite ) and serial injection technology has been developed to continuously deliver fresh sample into the beam path @xcite . a consequence of this experimental approach is that particle orientation is not measured and must be determined by analyzing the diffraction data @xcite . in practice , a single orientation is not associated with each diffraction pattern , but rather the low signal per pattern is more effectively handled by treating the data globally to directly obtain a 3d diffraction intensity volume @xcite . this intensity volume in then given as input for a phase retrieval algorithm that produces an image of the particle @xcite . in order to assemble the two - dimensional noisy diffraction patterns into a consistent three - dimensional intensity function , numerous algorithms have been proposed to date . early work from huldt _ et al._@xcite and bortel _ et al._@xcite classified patterns into classes , which were averaged to improve signal - to - noise prior to orienting the classes using common arcs of intersection . however , the classification is not suffiently accurate to handle the low signals expected in experiment @xcite . this approach has since been superseded by a variety of methods that treat the data globally to overcome the issue of noise . fung _ et al._@xcite proposed an algorithm based on a manifold embedding technique . this approach is based on a generative topographic mapping ( gtm ) , where each pattern is considered as a vector of the @xmath4-dimensional space of intensities , with @xmath4 the number of pixels on the detector . since a continuous rotation of the sample implies a continuous variation of the diffraction intensities , the images obtained should span a three - dimensional manifold embedded in @xmath4-dimensional space . the manifold is generated from a large number of diffraction patterns , and averaging out the closest diffraction patterns leads to the expected smooth manifold . however , a large number of diffraction patterns may be required to obtain a sufficiently smooth manifold @xcite . we note that this approach has been developed further recently in @xcite . more recently , diffusion map techniques have been developed to compute low - dimensional manifolds from xfel diffraction data @xcite . in practice , these techniques can generate more than three significant dimensions revealing other experimental variables such as changing beam conditions or sample heterogeneity . the advantage here is that the generation of the manifold is not biased by human assumptions . the challenge is the interpreting the manifold and identifying the correct relationship between the three degrees of freedom on the manifold and the rotation group . one way to explicitly relate the data - space to rotations is via mapping geodesics @xcite . the first attempt to introduce geometrical constraints in the processing of diffraction patterns was taken by saldin _ et al._@xcite , where the three - dimensional intensity function was expanded on the spherical harmonic basis . their approach was based the cross - correlation of the diffraction patterns and exploits the orthogonality of spherical harmonics to obtain a decomposition of the cross - correlation function . it is interesting to note that this method has been tested experimentaly @xcite on large dimers with known structure . for objects of known rotational symmetry , the correlation function can be converted into the 3d single - particle fourier intensity , which can then be converted to an image of the particle via phasing . for some time , it was known how to extend this method to an asymmetric 3d object , but recently an algorithm has been proposed to phase directly from the correlation function @xcite . the correlation function can also be used with molecular replacement techniques @xcite . it has the added advantage that multiple particles can be illuminated per measurement , which not many other algorithms can handle . in ref . @xcite , loh and elser have introduced the expansion - maximization - compression ( emc ) algorithm which relies on an expectation - maximization ( em ) technique . as a bayesian method , it aims to use known information about the noise statistics to handle very low signal - to - noise levels . the algorithm iteratively maximizes the likelihood of the reconstructed intensity given the set of diffraction patterns . the algorithm does not assign a single molecular orientation to each pattern , but rather it estimates the probability for a diffraction pattern to be associated with a certain orientation . recently , this algorithm has proven its feasibility with the reconstruction of mimivirus from experimental data collected at lcls @xcite . the emc algorithm is studied in detail in this work , with the introduction of several improvements . recently , walczak _ et al._@xcite developed the bayesian approach further using seed structural models to speed up convergence and to discriminate between different conformations . finally , we note that tegze and bortel @xcite have proposed a simplified version of the emc algorithm , where the diffraction pattern orientation is fully assigned through the intensity best fit , rather than in a probalistic way . a drawback of the emc algorithm is that it is computationally expensive to implement on large datasets that are expected in experiment . the emc algorithm stores a matrix that grows proportionally with the number of diffraction patterns and must be recalculated at every iteration . this is not a trivial step if there are 10@xmath5 10@xmath2 measured diffraction patterns . hence , there is still scope to develop the emc algorithm further to enable parallelization and efficient computation . another related issue is analyzing smaller datasets at lower resolution , which would be very valuable during an experiment to provide feedback on data collection . algorithms that are readily scaled with the number of patterns and resolution are also valuable . with these considerations in mind , we study here the application of spherical harmonic analysis to the emc algorithm . our goal is to produce an emc algorithm that can be scaled in terms of angular and radial resolution . this facilitates starting with lower resolution reconstruction with less patterns , higher signal and less computational time , before proceeding to higher resolutions . by implementing the algorithm shell by shell , we also enable it to be easily parallelized . after reviewing the relevant properties of spherical harmonics in section [ sec : geom ] , we formulate the emc algorithm for a single q - shell in section [ sec : emc ] and impose an angular bandwidth limit . section [ sec : shell ] describes how reconstructions on neighbouring shells can be aligned via correlations , and finally numerical tests are provided in section [ sec : numeric ] . while our work improves upon the computational requirements for emc , it does not match the computational advantages of correlation methods based on spherical harmonics that do not require more memory as the number of patterns increases@xcite . as described above , however , correlation - based methods have other issues for particles without rotational symmetry , while emc has potential advantages for analyzing low signal data , which contributes to its popularity . explorations of how to retain the advantages of emc at lower computational expense are thus valuable for the development of xfel single particle imaging . the intensity function of a biomolecule @xmath6 is linked to @xmath7 the fourier transform of its 3d electron density @xmath8 , with @xmath9 and @xmath10 respectively the real and reciprocal space coordinates . during xfel experiment , each diffraction pattern is obtained from a randomly rotated copy of the biomolecule . a rotation of the molecule in the real space corresponds to the same rotation around the origin of the ewald sphere in the dual space . the accumulation of thousands of diffraction patterns from rotated molecules can cover a spherical volume in the reciprocal space , in order the reconstruct of the 3d intensity of the biomolecule . with the notation previously introduced , the fourier transform or molecular transform @xmath11 of the three - dimensional electron density of the molecule reads , @xmath12 the intensity function @xmath13 is defined as the square magnitude of the fourier transform of the electron density , up to a constant normalizing factor @xmath14 depending on the experimental conditions @xcite . thus we have the following @xmath15 in what follows , we will be using spherical coordinates for @xmath10 , meaning that its parametrization will be @xmath16 where @xmath17 is the radial coordinate , and @xmath18 are angular coordinates , where the polar angle is relative to the beam axis . in the following we make use of the shorthand notation @xmath19 , where @xmath20 is an unit vector pointing towards angular coordinates @xmath21 . in order to take advantage of the symmetries of the intensity function @xmath13 , we propose to consider it as a set of concentric shells of increasing radii . on such a shell of radius @xmath22 , where @xmath23 stands for the shell number , we define the intensity @xmath24 . in the reconstruction process , the three - dimensional intensity function will be recovered by assembling the reconstructed intensities over spherical shells . the shell - by - shell reconstruction can be made efficient using the fact that each @xmath25 can be decomposed on a spherical harmonic basis . such spherical basis is presented is section [ subsec : harmdcompi ] . before introducing this decomposition , we first present the measurement model . in order to perform shell - by - shell reconstruction of the intensity function , we introduce a measurement model which relates diffraction data to the corresponding part of the intensity on each shell . in this model , as shown in figure [ fig : shellprocessingmethod ] , the corresponding _ diffraction patterns _ on a spherical shell @xmath23 are mono - dimensional , _ i.e. _ circles on this spherical shell . formally , we denote by @xmath26 the _ detector _ on the shell , that is the reference sampling points . @xmath26 is defined as the set of @xmath27 _ pixels _ coordinates on the spherical shell @xmath28 and given by @xmath29 where @xmath30 is given in angular coordinates by @xmath31 $ ] , and @xmath22 is the radius of the spherical shell . the dependence of @xmath32 on the radius @xmath22 is a consequence of the scattering geometry . for completeness we recall that @xmath33 where @xmath34 is defined in terms of the wavelength @xmath35 , @xmath36 . on the detector , the number of pixels contributing to a shell , _ i.e._the number of pixels on a circle on the diffraction pattern increases with the radius @xmath22 . the number of points @xmath27 on the detector are scaled such that : @xmath37 where @xmath38 denotes the ceiling function , and @xmath39 is the reciprocal space pixel size . finally , each measurement @xmath40 , or diffraction pattern on a shell consists in a set of @xmath27 samples @xmath41 , @xmath42 given by a poisson model @xcite ( due to low - photon counts expected in single - particle experiments ) @xmath43 where the random rotation @xmath44 is drawn from the uniform distribution on the rotation group @xmath45 . the intensity on a given shell @xmath23 , _ i.e. _ @xmath28 , can be expanded on the spherical harmonics basis ( see appendix [ appendix_a ] for details ) as follows , @xmath46 where the coefficients @xmath47 are the spherical harmonic coefficients of the intensity function on the shell @xmath23 . it turns out that the spherical harmonic representation provide an efficient way to deal with the symmetries of the intensity functions . in the following , we exploit the physical properties of the intensity function to simplify further the expansion above . first , intensity functions are by definition real - valued functions . as a consequence , its spherical harmonic coefficients exhibits the well - known conjugation property of spherical harmonics @xmath48 moreover , another interesting property is the centro - symmetry of intensity functions , also known as the friedel property . this symmetry property reads @xmath49 and it is straightforward to see that with this constraint every coefficient of odd degree @xmath50 is set to zero , @xmath51 finally , the finite size nature of the molecule in real space implies that the spectral representation on each shell is effectively bandlimited , meaning that the coefficients in the spherical harmonics expansion are non - zero up to a maximum degree @xmath52 @xmath53 where @xmath52 is the bandlimit on the shell @xmath23 , and where the sum has been restricted to even values of the degree @xmath50 . since friedel symmetry imposes condition ( [ eq : friedelsymmetrycoefficients ] ) on the coefficients , the value of @xmath52 is an odd number . it is interesting to note that rotational symmetries of the particle will further reduce the number of independent coefficients . this makes it easier to implement particle symmetry than for the cartesian sample of the intensity function used in the original emc algorithm and may improve performance in the case of highly symmetric particles . we develop in this section extension of the original emc algorithm @xcite to the spherical harmonic basis.precisely , we define an update rule in terms of the spherical harmonic coefficients of the shell intensity , and scale efficiently the computation time in terms of the bandlimit @xmath54 . in what follows , all quantities with superscript @xmath55 denotes the corresponding values at the @xmath56-th iteration of the em algorithm . we start this section by recalling the framework of em algorithms . in general , em algorithms provide an efficient way to deal with missing data @xcite . in our spherical setting , we design an em algorithm which updates the spherical harmonics coefficients at each iteration , namely we write the update rule @xmath57 where @xmath56 denotes the iteration index . note that we distinguish the estimated coefficients @xmath58 from the theoretical ones @xmath59 to avoid confusion . at each iteration of the em algorithm , the likelihood of the estimated parameter @xmath58 given the set of measurements @xmath60 is increased . however , em - algorithms do not work directly with the likelihood function , but rather with the _ intermediate quantity _ @xmath61 , whose value is determined in the expectation step ( e - step ) of the algorithm . for practical purposes , we first introduce the intermediate quantity per pattern @xmath62 , which reads @xmath63p(\bm r\vert \bm y_k , \hat{\bm c}^{(n)})\mathrm{d}\mu(\bm r)\ ] ] where @xmath64 denotes the ( bi)-invariant haar measure on @xmath45 . since the acquisitions @xmath65 are independent from each other , we can express the total intermediate quantity as the sum @xmath66 where the choice of the normalization made here is arbitrary . the maximization step can now be defined as the maximization of the ( total ) intermediate quantity , such that it reads @xmath67 we note here that there are potentialy several values of @xmath58 that maximize the intermediate quantity ; therefore uniqueness is not guaranteed . this is a general property of expectation - maximization algorithms . considering the em algorithm expressed directly with the spherical harmonic coefficients is a complicated task , which leads to intractable maximizations procedures . rather than solving the problem directly in the spherical harmonic domain , we extend the original approach of loh and elser @xcite to a spherical framework . let us introduce a spherical intensity model , denoted by @xmath68 . this spherical intensity model @xmath68 can be expressed using a spherical harmonic expansion similar to ( [ eq : shintensitymodelgeneric ] ) . the corresponding intermediate quantity per pattern reads @xmath69\\ & \times p(\bm r\vert \bm y_k , w^{(n)}_{\bm r})\mathrm{d}\mu(\bm r ) \end{split}\ ] ] where @xmath70 is a shorthand notation for the set @xmath71 . recall that the @xmath72 denote the reciprocal space coordinates of the detector . now , let us give details on the different quantities above . the conditional probabilities read @xmath73 the first equality is simply the definition of the joint probability , whereas the second equality is obtained applying bayes rule . we note that those quantities involve the prior distribution on the orientations , _ i.e. _ @xmath74 since the model @xmath68 is assumed deterministic . we assume there is no preferential orientation of the particle and that the distribution of orientations is uniform , which means with respect to the bi - invariant haar measure on @xmath45 that @xmath75 moreover , the poisson assumption on the photon count and the independence of each pixel yields to @xmath76 which gives the expression of the intermediate quantity per pattern @xmath77\prod_{i=1}^n(w_{i,\bm r}^{(n)})^{y_{ik}}\exp(-w_{i,\bm r}^{(n)})\ ] ] where @xmath78 is a constant only depending on the data @xmath79 ( which is arbitrarly removed hereafter ) , and @xmath80 is a normalization constant given by @xmath81 now , we face the following problem of computing the integrals over the rotation group @xmath45 . unfortunately there is no exact way to do so due to the lack of quadrature formula for probability functions on the rotation group @xmath45 . nevertheless , the integrals above can be approximated via a discrete sum over elements of the rotation group . more precisely , if we suppose that we have some sampling set @xmath82 of size @xmath83 and whose elements are indexed by @xmath84 , the intermediate quantity reads @xmath85\prod_{i=1}^n(w_{ij}^{(n)})^{y_{ik}}\exp(-w_{ij}^{(n)})\ ] ] where @xmath86 are equivalent to quadrature weights such that @xmath87 , @xmath88 , and where @xmath89 is obtained following the same guidelines . since the model @xmath68 is now evaluated at @xmath83 rotated versions of the original detector coordinates , we call it a _ tomographic model_. in a similar way , we define the _ tomographic grid _ coordinates as @xmath90 . in short - form , we can rewrite the latter intermediate quantity as a function of the tomographic model @xmath91 where @xmath92 is given by @xmath93 finally , the corresponding expectation step of the em algorithm is given by @xmath94 the last expressions ( [ eq : definition_proba_pjk ] ) and ( [ eq : intermediate_quantity_lohelser ] ) are exactly the same as in ref . @xcite , as expected . the expression of the intermediate quantity ( [ eq : intermediate_quantity_lohelser ] ) is rather simple and allows for a closed - form maximization procedure , that is @xmath95 we note that in recent papers @xcite , where the emc algorithm is applied to experimental data , an update rule of the fluence in each diffraction pattern is also derived . here we make the simplifying assumption that the fluence in each diffraction pattern is constant . by introducing a tomographic model @xmath68 , the em - procedure has been made easier . however , our goal is to obtain an algorithm which updates the spherical harmonic coefficients up to some degree @xmath96 for the considered shell , and this is done by adding two extra steps , known as expansion and compression . first , we remark that the tomographic grid coordinates are treated independently : therefore there exists a lot of tuples @xmath97 such that the coordinates @xmath98 , @xmath99 are really close . to enforce the consistency of the estimated model , we introduce a _ regular _ spherical grid @xmath100 and the corresponding regular model @xmath101 , whose nodes are given by @xmath102 . note that the grid depends on the bandlimit @xmath54 , allowing efficient scaling of the grid size . if the grid is well chosen and exhibits nice features , then the spherical harmonics coefficients @xmath103 up to some degree @xmath96 can be obtained using a fast implementation of the spherical harmonic transform . the above description actually corresponds to the compression step ( c - step ) , which can be schematically given by @xmath104 whereas the reverse operation is the expansion step ( e - step ) @xmath105 we make use of the material introduced in appendix [ appendix_a ] by choosing the healpix sampling scheme on the sphere for our grid @xmath100 . healpix grid on the sphere provides equal - area pixelization of the sphere , along with hierarchical resolution and numerous features @xcite . the compression step is performed as follows . we first determine the tomographic points @xmath98 belonging to each healpix pixel , and then the intensity value on this pixel is given by inverse distance weighting ( idw ) between the respective @xmath98 and the pixel center @xmath102 , @xmath107 the coefficients @xmath47 are then computed up to order @xmath96 as given by the sampling theorem ( [ eq : appendix_sampling_theorem_healpix ] ) using a fast spherical harmonic transform ( sht ) . the friedel symmetry is restored by canceling the coefficients for odd values of @xmath50 . the expansion step is done by the successive expansion of the coefficients @xmath47 to obtain @xmath101 , then by computation of the tomographic intensities by interpolation on the sphere . precisely the intensity @xmath101 is obtained by inverse sht , again implemented using the healpix package routines . the interpolation from the regular grid @xmath106 to the tomographic grid is done by bilinear interpolation using the four nearest - neighbors on the regular grid . several issues need to be considered when using the proposed spherical emc algorithm and the adaptive spherical emc algorithm given in pseudocode algortihms [ alg1 ] and [ alg2 ] respectively . we discuss thereafter the critical points to control in order to ensure proper behaviour of the reconstruction algorithms . in general , initialization of em - like algorithms is critical . indeed , convergence is often guaranteed only to a local maximum of the likelihood . as a consequence , a bad initialization of the algorithm may lead to local convergence to an undesired non - global minimum . in order to minimize such an effect , an initialization procedure based on the bandlimit adaptive scheme proposed throughout this paper can be used . namely , since the algorithm estimates bandlimited intensity functions with increasing degree , it seems reasonable to initialize the algorithm with the previous estimated model , at bandlimit @xmath108 . at the first stage of the algorithm , corresponding to bandlimit @xmath109 , this is done the following way . first the tomographic model is initialized with the mean photon count ( mpc ) of the diffraction patterns on this shell . note that the mpc is defined here as an average over the detector pixels , not in terms of shannon - nyquist pixels . then , to avoid the algorithm stopping prematurely , we slightly pertubate the mpc . the initialized tomographic model then reads @xmath110 with @xmath111 and where the @xmath112 s are drawn uniformly on the interval @xmath113 $ ] . here @xmath114 is a randomization parameter , @xmath115 . finally , performing one compression step leads to the estimate of initial spherical harmonic coefficients @xmath116 , which completes the initialization step . another important point issue is the convergence assessment of the algorithm . in the general em algorithm setting , this is often done by monitoring the likelihood value , whose increments are given by the so - called _ fundamental inequality of em _ @xcite @xmath117 the em algorithm then stops when likelihood increments become smaller than a certain threshold value . in the emc setting we added two extras steps , expansion and compression respectively , to make the expectation - maximization procedure tractable . this yields to a loss of important properties of the em algorithm , namely the likelihood @xmath118 is not forced to increment at each iteration , and the likelihood value is not directly available . to obtain the likelihood value , it is thus necessary to proceed as follows . first recall that we have only defined the intermediate quantity @xmath119 for now . the likelihood is obtained the following way @xmath120 where the _ entropy _ @xmath121 is defined like in @xcite by @xmath122\\&\times p(\bm r\vert \bm y_k , w^{(n)}_{\bm r})\mathrm{d}\mu(\bm r ) \end{split}\ ] ] we are interested in the likelihood of the model at iteration @xmath56 , denoted by @xmath123 . using the expression above , it reads @xmath124 . using similar arguments as above , the latter quantity can be rewritten the following way @xmath125 we note that the quantity @xmath126 is exactly the _ mutual information _ quantity proposed by loh and elser ( * ? ? ? * equation 19 ) . our stopping criterion is now defined as follows . at each iteration , we compute the relative likelihood variation denoted @xmath127 . when the value of @xmath127 goes below a given threshold @xmath128 , then either the algorithm stops if the current value of @xmath54 is equal to @xmath129 , or restart with an increased bandlimit @xmath54 and uses the previously estimated spherical harmonic coefficients as a starting point . the computational time of the algorithm presented in this paper scales directly with the desired resolution of the desired reconstruction . actually , the most expensive part is the maximization step , which in our case scales as @xmath130 . it thus shows a clear dependence on the bandlimit @xmath54 , and on the number of pixels on the shell . this motivates the shell - by - shell approach : since inner and outer shells show two disjoints set of parameters ( small @xmath54 and @xmath27 for the inner shell , large @xmath54 and @xmath27 for the outer shells ) , it is interesting to gain computation time by parallelization of the shell reconstructions . also , the increasing bandlimit approach is expected to lead to a better conditioning of the algorithm , limiting the number of iterations and improving the quality of the reconstruction . finally , we shall point out that the sampling of the rotation group used here is based upon harmonic analysis results on the rotation group . therefore , one may expect the harmonic approximation of integrals over @xmath45 used in the emc algorithm to perform equally well compared to the @xmath131-cell sampling scheme previously introduced @xcite . [ sec : shell ] since we have considered each shell separately ( which allows an efficient parralelization of the algorithm , and distribution of the data ) , the shells have to be realigned in order to form a consistent 3d function . namely , we want to minimize the quadratic error between two successive shells . the problem can be stated as follows , we need to find the rotation @xmath132 such that @xmath133 where we have introduced the rotation operator @xmath134 defined by @xmath135 . as the features shared by the shell intensities evolve with the radius @xmath22 , the spherical shell alignment problem between two consecutive shells is only significant if these are sufficiently close to each other . the alignment procedure is indeed expected to fail in the case where @xmath136 , that is the shannon - nyquist theorem is no longer verified in the radial direction . in this paper the shell alignment problem is solved using correlations on the rotation group , using an approach proposed by kostelec and rockmore in @xcite . for an overview concerning the so - called _ rotational matching problem _ , see for instance @xcite and reference therein , especially for the rotational matching problem in biophysics . the problem as stated in ( [ eq : position_problem_shell_alignment ] ) is equivalent to maximizing the correlation of the two shell intensities , @xmath137 we remind that the shell intensities are also represented by their estimated spherical harmonic coefficients up to a given bandlimit @xmath54 ) , respectively @xmath138 and @xmath139 . using fourier analysis properties on the rotation group , the correlation above can be expressed the following way @xmath140 where we have introduced the wigner - d functions , @xmath141 , which are detailed in appendix [ appendix_b ] . now , using the same rotation group sampling as in the spherical emc algorithm , one can evaluate the correlation ( [ eq : correlation_practical ] ) efficiently . the rotation @xmath142 that leads to the higher correlation value between the two shells is then used to align the @xmath143 shell with the previous one . namely , the _ aligned _ spherical harmonic coefficients read @xmath144 by repetition of the same procedure for succesive shells , we are able to reconstruct efficiently the full 3d intensity function . finally , a few non trivial points are to be mentioned . first , since the correlation is performed numerically on a discrete rotation sample , it is unlikely that the rotation leading to the higher correlation value will be the _ exact _ one . however , by increasing the size of the rotation sampling , the rotation estimation error will be further reduced . moreover , from a practical perspective , a good approximation of the correlation can be obtained using only spherical harmonics of low degree , even in the case of large bandlimits @xmath54 @xcite . this could be adequatly exploited to obtain low - resolution reconstructions efficiently . finally one can note that a method as been proposed in @xcite to improve the accuracy of the rotation matching , and could be efficiently applied in our context . in this section , we illustrate our approach with simulations . first , we show how the adaptive spherical emc can effectively reconstruct the shell intensity for different bandlimits . we illustrate the potential of the approach by considering three typical shells , an inner , middle and outer shell respectively . theoretical intensity functions corresponding to these three shells are presented in figure [ fig : theoreticalenergydistribution ] . the behavior of the algorithm with respect to the number of observations is also studied in detail . secondly , we investigate the full shell - by - shell reconstruction problem , and analyse the effect of the distance between shells on the resulting resolution . all simulations show results for the satellite tobacco necrosis virus ( stnv , pdb entry : 2buk ) , one of the smallest viruses known to date . the reciprocal space size of a pixel is @xmath145 @xmath146 . simulations are performed for a fluence @xmath14 corresponding to @xmath147 photons per pulse and @xmath148 @xmath149m@xmath150 focal spot area . corresponding mean photon count ( mpc ) per pixel are given in the top of figure [ fig : theoreticalenergydistribution ] . we note that the number of photons per pulse used here ( @xmath147 ) is about ten times higher than those currenlty available at xfel facilities . this choice is motivated here by the fact that it allows us to use less diffraction patterns to reconstruct the biomolecule , as the aim of this work is to demonstrate the feasability of the approach . as it will be seen in the next section , using state of the art photon counts will lead to an higher number of diffraction patterns required for a given bandlimit @xmath54 . in this section we address the important issue of the required number of diffraction patterns in single - particle experiments . namely , we ask the following question : given a specified shell , how many diffraction patterns are needed to reconstruct the intensity defined on this shell , for a given bandlimit @xmath54 ? this question is in general quite complex , and to allow further investigation we need to make some assumptions . the reconstruction of the intensity on the shell is conditional upon the ability to recover the orientation of each diffraction pattern , yet to have sufficient signal - to - noise ratio . it is expected that the number of diffraction patterns required will be governed by a combination of these two factors . when the signal - to - noise ratio is high , as expected for large biomolecules and viruses ( and already shown by a recent experiment @xcite ) , the orientation recovery problem drives predominantly the performances of reconstruction algorithms . in the sequel , we perform numerical analysis addressing the question stated previously , taking into account both orientation recovery issue and sufficient signal - to - noise ratio . let us consider a shell of radius @xmath22 , and that detector coordinates on this shell are given by equation ( [ eq : detector_definition_shell ] ) . we note that the number of pixels on the detector @xmath27 scales with the radius @xmath22 , given the pixel spacing @xmath39 . moreover , we fix a mean photon count per pixel on this shell . now , we define an equal - area grid on the sphere with healpix , with a resolution parameter @xmath151 . we draw an uniform random rotation from @xmath45 , and apply it to the detector coordinates . then , we draw @xmath27 samples from the poisson distribution of parameter @xmath152 . finally , we analyse which healpix pixels are visited by the non - zero pixels of this _ rotated detector _ and keep trace of this visit . the number of runs of this simulation until each pixel has been visited at least once gives us an estimate of the required number of diffraction patterns on this shell , for a given resolution @xmath151 . repeating this algorithm several times gives a fair estimate of this number . here , we only analysed the number of required patterns in terms of the resolution parameter @xmath151 . recalling that @xmath151 is linked to the bandlimit @xmath54 by the approximate sampling theorem ( [ eq : appendix_sampling_theorem_healpix ] ) , we link each @xmath151 value with the maximum bandlimit @xmath54 available for this resolution parameter . extrapolation between missing @xmath54-values gives an estimate of the required diffraction patterns for any @xmath54 value . note that with this choice of detector geometry and for a given shell , the maximum value of @xmath54 available is given by @xmath153 . this simply means that the maximum bandlimit available increases with the shell radius . the results of the simulation are presented in figure [ fig : requiredpatterns ] . in the first row , we analysed the number of diffraction patterns needed in the case of three typical shells , inner , middle , and outer , and for different mpc on these shells . the mpc used here are @xmath154 , @xmath155 , @xmath148 , @xmath156 . first , one sees that for a given shell and bandlimit , the number of required patterns increases as the mpc decreases , as expected . similarly the patterns required increase with the bandlimit @xmath54 , given a certain shell and mpc . for a given bandlimit @xmath54 and a fixed mpc , the required number of patterns reduces as the shell radius increases . this is the expected behaviour , since at @xmath54 fixed , the area of each pixel on the sphere increases . moreover , we note that for each shell , the required number of patterns behaves as a power law of @xmath54 . at the bottom of figure [ fig : requiredpatterns ] , the number of patterns required in the case of the stnv virus are presented . note that the number of required patterns increases with the shell radii , due to a lower mpc in the outer shells . black squares show the theoretical bandlimit of the shell intensity , calculated from figure [ fig : theoreticalenergydistribution ] by thresholding the relative energy per degree below some predefined threshold , typically @xmath157 in our experiments . and mpc , where each plot correspond to different shell radii . in each plot the following mpc values were used @xmath158 , @xmath155 , @xmath148 , @xmath156 . ( bottom ) corresponding required patterns in the case of the stnv virus , using mpc values shown in figure [ fig : theoreticalenergydistribution].,scaledwidth=49.0% ] in the sequel , we investigate the behavior of the algorithm in three typical cases of shell intensity reconstructions : inner , middle and outer shell cases . the simulations presented here have been performed using 500 diffraction patterns for the inner shell case and 1000 diffraction patterns for the middle and outer shell cases . we make use of the adaptive shell emc algorithm presented earlier . this algorithm provides an adaptive reconstruction method based on the spherical harmonic decomposition of the shell intensity up to a maximum bandlimit @xmath129 . the inner shell case is represented in figure [ fig : reconstructioninner ] . from figure [ fig : theoreticalenergydistribution ] , the expected theoretical bandlimit is @xmath159 . one can notice that the likelihood improvements become rapidly very small , and that the number of iterations for each bandlimit @xmath54 is given by the minimum number of iterations imposed ( in our case 4 ) . this behavior is easily seen from the low - bandlimit distribution of the inner shell . as seen in the reconstruction provided , the main features of the shell intensity are already reconstructed at @xmath109 , as expected . the middle shell case is represented in figure [ fig : reconstructionmid ] . again , using figure [ fig : theoreticalenergydistribution ] , we see that the expected theoretical bandlimit is now @xmath160 . the likelihood is improving over the different bandlimits , tending to smaller increments as the bandlimit increases . the reconstructions provided shows how the accumulation of spherical harmonic coefficients of higher degree improves the accuracy of the reconstruction . one can note that low - bandlimit reconstructions exhibit negative values ( up to @xmath161 , included ) ; therefore the negative values are thresholded to some small constant ( here @xmath162 ) . this stems from the fact that truncation of a spherical harmonic expansion of the non - negative function does not preserve the non - negativity of the function . finally , the outer shell case is represented in figure [ fig : reconstructionouter ] . in this case , the theoretical bandlimit is @xmath163 , as seen in figure [ fig : theoreticalenergydistribution ] . here , the likelihood tends to improve constantly as the bandlimit increases before stabilizing from @xmath164 . reconstructions provided show the frequency - like improvement as the bandlimit @xmath54 increases . truncated theoretical intensities for the respective @xmath54 values are also provided . however , one can notice the difference between the theoretical and reconstructed intensities . the reasons are twofold : first when estimating low-@xmath54 intensity functions , there is aliasing of power of higher degree coefficients ( @xmath165 ) , resulting in an higher overall energy in the reconstruction than in the truncated theoretical intensity . this is well shown by results in the cases @xmath166 and @xmath167 . the second results from an insufficient number of diffraction patterns , since for @xmath168 the reconstruction barely improves , whereas the truncated theoretical intensity continues to converge to the theoretical intensity . * 3c + & truncated & theoretical + @xmath109 & 0.152 & 0.171 + @xmath169 & 0.143 & 0.148 + @xmath161 & 0.0979 & 0.0998 + the shell - by - shell approach offers an efficient and faster method to distribute computation of the reconstructions . however , by considering the shells independently the radial information is lost . this radial information has to be retrieved during an alignment process , as described in section [ section : shellalignement ] . using 1000 diffraction patterns , we reconstructed each shell intensity independently up to bandlimit @xmath161 and maximum frequency @xmath170 @xmath146 , for a reciprocal space spacing @xmath171 @xmath146 between the shells . the shells were then realigned using the above mentioned correlation method . results are presented in figure [ figure : fullreconstruction ] . to evaluate numerically the performance of the method , we introduce an error metric based on the well - know @xmath172-factor , which is defined such that @xmath173 where @xmath174 denotes the reconstructed intensity , and @xmath175 is the theoretical intensity . here @xmath102 denotes the 3d - spherical grid points . to illustrate the reconstruction performances with the bandlimit @xmath54 , we have computed the @xmath172-factor for @xmath176 reconstructions . we distinguished two cases , one where the theoretical intensity is truncated up to degree @xmath54 , and the other where the full theoretical intensity is considered . as shown by the results in [ table : rfactors ] , the @xmath172-factor decreases as @xmath54 increases , meaning that the reconstructed intensity function is improved over @xmath54 . also one notices that the @xmath172-factors for the truncated theoretical intensity is smaller than for the full theoretical intensity , which is consistent with the fact that the full intensity function is more _ complex _ than the truncated one . finally , one can note that different sources of estimation error arise in the shell - by - shell approach . one is related to the shell intensity estimation problem , where the finite number of diffraction patterns limits the actual accuracy of the reconstruction . the second one is due to the radial decoupling between the shells , which leads to an realignment error . the latter can be minimized by either increasing the size of the grid on which the @xmath177 correlation is performed , or either by using refinment methods such as in @xcite . as a consequence , the algorithm presented here may not be as accurate as the original emc algorithm in the case of low snr datasets . it is actually expected that the proposed approach is a compromise improved computational performance of a shell - by - shell approach and noise tolerance . here we have shown that a spherical harmonic basis is a convenient way to design an incremental , parallelizable approach to the reconstruction of 3d intensity functions from 2d xfel diffraction patterns . the proposed shell - by - shell algorithm allows control over radial and angular resolution , which can be gradually increased during the reconstruction . as a shell - by - shell approach is intrinsically parallelizable , it is potentially an efficient way to analyse the very large datasets expected in experiment . using numerical simulations , we have studied how the number of patterns required for convergence depends on the signal and resolution . the spherical harmonic functions , or in short spherical harmonics , extend fourier analysis to the 2-sphere @xmath178 . formally , the spherical harmonic of degree @xmath50 and order @xmath179 is given by @xmath180 where @xmath181 is the associated legendre polynomial ( or generalized jacobi polynomial ) . for each integer degree @xmath182 corresponds @xmath183 orders @xmath179 , such that @xmath184 . the spherical harmonic functions form a complete orthonormal basis on the 2-sphere @xmath178 for square integrable functions . as a consequence any square - integrable complex - valued function @xmath185 , @xmath186 can be decomposed onto spherical harmonics , @xmath187 where we have introduced the spherical harmonic coefficients @xmath188 , which are given by projection onto the respective spherical harmonic @xmath189 via the canonical inner product on @xmath190 , @xmath191 these coefficients are complex - valued , and the properties of the function @xmath192 ( real - valued , symmetries ) are encoded in the coefficients . as in classical fourier analysis , spherical harmonics exhibit parseval relation , that is the energy of @xmath192 is preserved in the spherical harmonic domain , @xmath193 it is often convenient to introduce a related rotation - invariant quantity , known as the energy per degree @xmath194 , defined by @xmath195 . for numerical purposes the infinite series expansion in the spherical harmonic decomposition in ( [ eq : appendix_infinite_sh_decomposition ] ) is not desirable . rather , we consider bandlimited functions on the sphere . we say that a function @xmath192 is bandlimited at @xmath54 ( or equivalently @xmath54-bandlimited ) if for all @xmath196 , the spherical harmonic coefficients are identically zero @xmath197 . in the following , we consider @xmath54-bandlimited functions only . the forward and inverse spherical harmonic transform ( sht ) are given by @xmath198 the computation of the forward sht requires the evaluation of an integral over the 2-sphere @xmath178 for each coefficient @xmath188 . the evaluation of such integrals can be done by conveniently sampling the 2-sphere , _ i.e._distributing nodes on the surface on the sphere in order to obtain a quadrature formula . to this aim , a certain number of sampling schemes have been already proposed @xcite , often motivated by the analysis of the cosmic microwave background . in this work , we use the healpix sampling scheme @xcite , which has been designed for high performance , fast and accurate computation of spherical harmonics on the sphere . the sphere is tessellated into curvilinear equal - area pixels , where the pixel centers are distributed on lines of constant latitude allowing faster computation of spherical harmonic functions due to the separation of angular variables in the spherical harmonics . the healpix sampling scheme is hierarchical and provides different levels of resolution through a parameter @xmath151 . the number of pixels @xmath199 at resolution @xmath151 is given by @xmath200 where the parameter @xmath151 is a power of @xmath201 , due to the construction of the grid . although healpix grid do not exhibit an exact sampling scheme , a very accurate estimate of the spherical harmonics coefficients in ( [ eq : appendix_sh_forward ] ) is obtained if the following condition is fulfilled ; @xmath202 this last formula stands for an approximate sampling scheme on the grid . the special orthogonal group in three dimensions @xmath45 denotes the set of real matrices @xmath203 which satisfy @xmath204 where @xmath205 is the transpose of the matrix @xmath132 , @xmath206 its determinant and @xmath207 the @xmath208 identity matrix @xcite . it is commonly parametrized by euler angles , @xmath209 where @xmath210 and @xmath211 . in the @xmath212 convention , the matrix @xmath213 reads @xmath214 where @xmath215 denote rotations around canonical axes @xmath216 and @xmath217 , respectively . these rotations reads explicitely @xmath218 harmonic analysis on the rotation group @xmath45 is conveyed by the irreducible representations of @xmath45 . this is direct consequence of the peter - weyl theorem in the @xmath45 case @xcite . namely , any square - integrable function @xmath219 can be decomposed as @xmath220 where the @xmath221 functions are the wigner - d functions and @xmath222 are the fourier coefficients obtained following @xmath223 the wigner - d functions are conveniently expressed using the @xmath212-euler angles parametrization , that is @xmath224 where @xmath225 is a polynomial in @xmath226 and @xmath227 . let us consider a @xmath54-bandlimited function @xmath192 on the rotation group , that is for all @xmath196 , @xmath228 . it is possible to compute its fourier transform exactly using the following equiangular sampling @xmath229 where the indices @xmath230 . equation ( [ eq : fourier_transform_so3 ] ) then reads @xmath231 where we have introduced a single index @xmath232 . the weights @xmath233 satisfy @xmath234 and read @xmath235\right ) \sin \beta_{j_2}.\ ] ] note that in the emc algorithm , the above sampling set is used to approximate the value of the integral of some function . this operation corresponds actually to computing the first fourier coefficient @xmath236 . it can be shown that using only half the samples in each angle in the sampling described above is sufficient ( aliasing in the higher order coefficients is therefore tolerated ) . this remark allows us to obtain @xmath237 samples instead of @xmath238 , however this was not implemented here since the oversampling of the rotation group allows a better approximation of the intermediate quantity @xmath239 . 37ifxundefined [ 1 ] ifx#1 ifnum [ 1 ] # 1firstoftwo secondoftwo ifx [ 1 ] # 1firstoftwo secondoftwo `` `` # 1''''@noop [ 0]secondoftwosanitize@url [ 0 ] + 12$12 & 12#1212_12%12@startlink[1]@endlink[0]@bib@innerbibempty \doibase http://dx.doi.org/10.1063/1.4918726 [ * * , ( ) , http://dx.doi.org/10.1063/1.4918726 ] @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop ( ) \doibase http://dx.doi.org/10.1016/j.jsb.2009.01.005 [ * * , ( ) ] @noop * * , ( ) @noop * * , ( ) link:\doibase 10.1098/rstb.2013.0326 [ * * ( ) , 10.1098/rstb.2013.0326 ] , @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) link:\doibase 10.1073/pnas.1513738112 [ * * , ( ) ] , @noop * * , ( ) @noop * * , ( ) \doibase http://dx.doi.org/10.1016/j.jsb.2012.04.014 [ * * , ( ) ] @noop * * , ( ) @noop * * , ( ) @noop ( ) @noop * * , ( ) @noop _ _ ( , ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop * * , ( ) @noop ( ) @noop _ _ ( , ) @noop _ _ , vol .

in 3d single particle imaging with x - ray free - electron lasers , particle orientation is not recorded during measurement but is instead recovered as a necessary step in the reconstruction of a 3d image from the diffraction data . here we use harmonic analysis on the sphere to cleanly separate the angular and radial degrees of freedom of this problem , providing new opportunities to efficiently use data and computational resources . we develop the expansion - maximization - compression algorithm into a shell - by - shell approach and implement an angular bandwidth limit that can be gradually raised during the reconstruction . we study the minimum number of patterns and minimum rotation sampling required for a desired angular and radial resolution . these extensions provide new avenues to improve computational efficiency and speed of convergence , which are critically important considering the very large datasets expected from experiment .

why do we see the world around us the way it is ? human eyes can detect electromagnetic waves in a very narrow range of wavelength , @xmath2 , which we call visible light . the light from a source , say the sun , is reflected from the surface of macro - objects and is absorbed by the eye s retina which transforms it into a neural signal going to the brain which forms the picture . the same principle is used in radars which detect reflected electromagnetic waves of a meter wavelength . the only requirement to see " an object is that the length of resolving waves must be comparable to or smaller than its size . the same conditions have to be obeyed in case one wants to study the microworld , e.g. , the structure of macromolecules ( dna , rna ) or assemblies ( viruses , ribosomes ) . obviously , when one puts a chunk of material in front of a source of visible light , see fig . [ crystalography ] , the object merely leaves a shadow on a screen behind it and one does not see its elementary building blocks , i.e. , atoms . obviously , visible light is not capable to resolve the internal lattice structure of a crystal since the size of an individual atom , say hydrogen , is of order @xmath3 and the light does not diffract from it . therefore , to see " atoms in crystals one has to have photons with the wavelength @xmath4 , or equivalently , of the energy @xmath5 . to do this kind of nano - photography " one needs a beam of x - rays which after passing through the crystal creates fringes on a photo - plate , see fig.[crystalography ] . does one get a three - dimensional picture from such a measurement ? unfortunately , no . in order to reconstruct atomic positions in the crystal s lattice one has to perform an inverse fourier transform . this requires knowledge of both the magnitude and the phase of diffracted waves . however , what is measured experimentally is essentially a count of number of x - ray photons in each spot of the photo - plate . the number of photons gives the intensity , which is the square of the amplitude of diffracted waves . there is no practical way of measuring the relative phase angles for different diffracted spots experimentally . therefore , one can not unambiguously reconstruct the crystal s lattice . this is termed as the phase problem " . none of techniques called to tackle the problem provides a parameter - free answer . when we study hadronic matter at the fundamental level we attempt to perform the femto - photography " of the interior constituents ( quarks and gluons ) of strongly interacting elementary " particles such as the nucleon . quantum @xmath6 dynamics , the theory of strong interaction , is not handy at present to solve the quark bound state problem . therefore , phenomenological approaches , based on accurate analyses of high - energy scattering experimental data and making use of rigorous perturbative qcd predictions , are indispensable for a meticulous understanding of the nucleon s structure . as we discuss below most of high - energy processes resolving the nucleon content , such as described in terms of form factors and inclusive parton densities , suffer from the same phase problem " and therefore they lack the opportunity to visualize its three - dimensional structure . a panacea is found in newborn generalized parton distributions @xcite , which are measurable in exclusive leptoproduction experiments . nucleon form factors are measured in the elastic process @xmath7 . its amplitude is given by the lepton current @xmath8 interacting via photon exchange with the nucleon matrix element of the quark electromagnetic current @xmath9 : @xmath10 here the matrix element of the quark current is decomposed in terms of dirac and pauli form factors ( @xmath11 ) , accompanied by the dirac bilinears @xmath12 and @xmath13 . in the breit frame @xmath14 there is no energy exchange @xmath15 and thus relativistic effects are absent . the momentum transfer is three - dimensional @xmath16 , so that @xmath17 \tilde\varphi_1 g_m ( - \vec\delta^2 ) \ , , \end{aligned}\ ] ] are expressed in terms of sachs electric @xmath18 and magnetic @xmath19 form factors . introducing the charge @xmath20 and magnetic moment @xmath21 ( x)$ ] operators , one finds the normalization @xmath22 the interpretation of sachs form factors as fourier transforms of charge and magnetization densities in the nucleon requires to introduce localized nucleon states in the position space @xmath23 as opposed to the plane - wave states used above @xmath24 , @xmath25 here a very broad wave packet @xmath26 is assumed in the momentum space . then the charge density @xmath27 of the nucleon , localized at @xmath28 , is @xmath29 and similar for the magnetic form factor . the famous hofstadter s experiments established that the proton is not a point - like particle @xmath30 which would have @xmath31 , but rather @xmath32 with the mean square radius @xmath33 . the breit frame is not particularly instructive for an interpretation of high - energy scattering . here an infinite momentum frame ( imf ) is more useful , see discussion below . in this frame , obtained by a _ z_-boost , the nucleon momentum is @xmath34 . in the imf one builds a nucleon state localized in the transverse plane at @xmath35 @xmath36 , is given by the two - dimensional fourier transform of form factors @xmath37 as previously one assumes a rather delocalized transverse momentum wave function @xmath38 . thus , we can interpret form factors as describing the transverse localization of partons in a fast moving nucleon , irrespective of their longitudinal momenta and independent on the resolution scale . the deeply inelastic lepton - nucleon scattering @xmath39 probes , via the amplitude @xmath40 the nucleon with the resolution @xmath41 , set by the photon virtuality @xmath42 . recalling that the nucleon s size is @xmath43 , one concludes that for @xmath44 of order of a few gev , the photon penetrates the nucleon interior and interacts with its constituents . the cross section of the deeply inelastic scattering is related , by the optical theorem , to the imaginary part of the forward compton scattering amplitude @xmath45 the very intuitive parton interpretation has its clear - cut meaning in the imf . a typical interaction time of partons is inversely proportional to the energy deficit of a given fluctuation of a particle with the energy @xmath46 and three - momentum @xmath47 into two partons with energies @xmath48 and three - momenta @xmath49 . it scales , for @xmath50 , as @xmath51 therefore , one can treat partons as almost free in the imf due to the time dilation . the virtual photon sees " nucleon s constituents in a frozen state during the time of transiting the target which is , thus , describable by an instantaneous distribution of partons . here again the analogy with x - ray crystallography is quite instructive : recall that an x - ray , scattered off atoms , reveals crystal s structure since rapid oscillations of atoms in the lattice sites can be neglected . atoms can be considered being at rest during the time x - rays cross the crystal . the transverse distance probed by the virtual photon in a lorentz contracted hadron , is of order @xmath52 , see fig . [ partoncontent ] . one can conclude therefore that simultaneous scattering off an @xmath53-parton cascade is suppressed by an extra power of @xmath54 . the leading contribution to @xmath55 is thus given by a handbag diagram , i.e. , the photon single - quark compton amplitude . the character of relevant distances in the compton amplitude ( [ dis - compton ] ) is a consequence of the bjorken limit which implies large @xmath44 ( small distances ) and energies @xmath56 ( small times ) at fixed @xmath57 . by going to the target rest frame one immediately finds that at large @xmath44 the dominant contribution comes from the light - cone distances @xmath58 between the points of absorption and emission of the virtual photon in ( [ dis - compton ] ) because @xmath59 , @xmath60 . since the hard quark - photon subprocess occupies a very small space - time volume but the scales involved in the formation of the nucleon are much larger , hence , they are uncorrelated and will not interfere . the quantum mechanical incoherence of physics at different scales results into the factorization property of the cross section ( [ dis - compton ] ) , @xmath61 where @xmath62 is a parton distribution , the density of probability to find partons of a given longitudinal momentum fraction @xmath63 of the parent nucleon with transverse resolution @xmath64 , @xmath65 no information on the transverse position of partons is accessible here , fig.[partoncontent ] . both observables addressed in the previous two sections give only one - dimensional slices of the nucleon since only the magnitude of scattering amplitudes is accessed in the processes but its phase is lost . these orthogonal spaces are probed simultaneously in generalized parton distributions ( gpds ) , which arise in the description of deeply virtual compton scattering ( dvcs ) @xmath66 in the bjorken limit , see fig . [ lightconedvcs ] . in the same spirit as in deeply inelastic scattering , the latter consists of sending @xmath67 to the deep euclidean domain while keeping @xmath68 small and @xmath69 fixed , @xmath70 . by the reasoning along the same line as in the previous section one finds that the compton amplitude factorizes into gpds parametrizing the twist - two light - ray operator matrix element @xmath71 and a handbag coefficient function , so that one gets from fig . [ lightconedvcs ] @xmath72 where @xmath73 and the contribution from a crossed diagram is omitted . gpds depend on the @xmath74-channel momentum fraction @xmath63 , measured with respect to the momentum @xmath75 , and @xmath76-channel fraction @xmath77 , which is the longitudinal component of the momentum transfer @xmath78 , as well as its square @xmath79 . due to the reality of the final state photon @xmath80 . a geometric picture underlying dvcs is as follows , see fig . [ dvcsgeometry ] . the electric field of lepton s virtual fluctuation @xmath81 accelerates a quark localized in the transverse area @xmath82 at the impact parameter @xmath83 and carrying a certain momentum fraction of the parent nucleon . the accelerated parton tends to emit the energy via electromagnetic radiation and fall back into the nucleon , see fig . [ dvcsgeometry ] . the incoming - outgoing nucleon system is localized at the center of coordinates @xmath84 , however , due to non - zero longitudinal momentum exchange in the @xmath76-channel the individual transverse localizations of incoming and outgoing nucleons are shifted in the transverse plane by amounts . we define the fourier transform with respect to @xmath85 which has its advantages that @xmath83 does not depend implicitly on @xmath86 . ] @xmath87 and @xmath88 , respectively @xcite . generally , gpds are not probabilities rather they are the interference of amplitudes of removing a parton with one momentum and inserting it back with another . in the limit @xmath89 they reduce to inclusive parton densities and acquire the probabilistic interpretation . this is exhibited in a most straightforward way in the light - cone formalism @xcite , where one easily identifies the regions @xmath90 and @xmath91 with parton densities while @xmath92 with distribution amplitudes . this latter domain precludes the density interpretation for @xmath93 . the first moment of gpds turns into form factors ( [ formfactor ] ) . the second moment of eq . ( [ defgpds ] ) gives form factors of the quark energy - momentum tensor , @xmath94 . since gravity couples to matter via @xmath95 , these form factors are the ones of the nucleon scattering in a weak gravitational field @xcite @xmath96 analogously to the previously discussed electromagnetic case , the combination @xmath97 arising in the @xmath98 component measures the mass distribution inside the nucleon @xcite . it is different from the charge distribution due to presence of neutral constituents inside hadrons not accounted in electromegnetic form factors . the gravitomagnetic form factor @xmath99 at zero recoil encodes information on the parton angular momentum @xcite @xmath100 ( x)$ ] expressed in terms of the momentum flow operator @xmath101 in the nucleon and gives its distribution when fourier transformed to the coordinate space . these form factor are accessible once gpds are measured : @xmath102 gpds regain a probabilistic interpretation once one sets @xmath103 but @xmath104 @xcite . when fourier transformed to the impact parameter space they give a very intuitive picture of measuring partons of momentum fraction @xmath63 at the impact parameter @xmath83 with the resolution of order @xmath64 set by the photon virtuality in the localized nucleon state ( [ transverselocalnucleon ] ) , @xmath105 to visualize it , see fig . [ partoncontent ] , one can stick to the regge - motivated ansatz @xmath106 with a linear trajectory @xmath107 where @xmath108 and @xmath109 . the light - cone dominance in dvcs is a consequence of the external kinematical conditions on the process in the same way as in deeply inelastic scattering . therefore , one can expect precocious scaling starting as early as at @xmath110 . it is not the case for hard exclusive meson production , giving access to gpds as well , where it is the dynamical behavior of the short - distance parton amplitude confined to a small transverse volume near the light cone that drives the perturbative approach to the process . here the reliability of perturbative qcd predictions is postponed to larger momentum transfer . although gpds carry information on both longitudinal and transverse degrees of freedom , their three - dimensional experimental exploration requires a complete determination of the dvcs amplitude , i.e. , its magnitude and phase . one way to measure the phase at a given spot is known as holography , for visible light . this technology allows to make three - dimensional photographs of objects , see fig . [ holography ] : the laser beam splits into two rays . one of them serves as a reference source and the other reflects from the object s surface . the reflected beam , which was in phase with the reference beam before hitting the target " , interferes with the reference beam and forms fringes on the plate with varying intensity depending on the phase difference of both . ( unfortunately , the same method can not be used for x - ray holography of crystals and scattering experiments due to the absence of practical splitters " . ) for the exclusive leptoproduction of a photon , however , there are two contributions to the amplitude : the dvcs one @xmath111 , we are interested in , and @xmath112 from the ` contaminating ' bethe - heitler ( bh ) process , in which the real photon spills off the scattered lepton rather than the quark , see fig . [ holography ] . the bh amplitude is completely known since the only long - distance input turns out to be nucleon form factors measured elsewhere . the relative phase of the amplitudes can be measured by the interference of dvcs and bh amplitudes in the cross section @xmath113 and , thus , the nucleon hologram can be taken . the most straightforward extraction of the interference term is achieved by making use of the opposite lepton charge conjugation properties of dvcs and bh amplitudes . the former is odd while the latter is even under change of the lepton charge . the unpolarized beam charge asymmetry gives @xmath114 and measures the real part of the dvcs amplitude modulated by the harmonics of the azimuthal angle between the lepton and photon scattering planes @xmath115 @xcite . if on top of the charge asymmetry one further forms either beam or target polarization differences , this procedure would allow to cleanly extract the imaginary part of the dvcs amplitude where gpds enter in diverse combinations . these rather involved measurements have not yet been done . luckily , since the ratio of bh to dvcs amplitude scales like @xmath116^{1/2}/y$ ] , for large @xmath117 or small @xmath118 , it is safe to neglect @xmath119 as compared to other terms . thus , in such kinematical settings one has access to the interference in single spin asymmetries , @xmath120 which measure gpds directly on the line @xmath121 as shown in fig . [ gpdfromdvcs ] . experimental measurements of these asymmetries were done by hermes @xcite and clas @xcite collabarations . the comparison to current gpd models is demonstrated in fig . [ fig - ssaca ] . in order to go off the diagonal @xmath121 one has to relax the reality constraint on the outgoing @xmath122-quantum , i.e. , it has to be virtual and fragment into a lepton pair @xmath123 with invariant mass @xmath124 . thus , one has to study the process @xmath125 . in these circumstances , the skewedness parameter @xmath86 independently varies for fixed bjorken variable since @xmath126 , and one is able to scan the three - dimensional shape of gpds , see fig . [ gpdfromdvcs ] . unfortunately , the cross section for dvcs lepton pair production is suppressed by @xmath127 as compared to dvcs and also suffers from resonance backgrounds , see , e.g. , @xcite . finally , perturbative next - to - leading ( nlo ) and higher - twist effects are shortly discussed . estimates of the former are , in general , model dependent . nlo contributions to the hard - scattering amplitude @xcite of a given quark species are rather moderate , i.e. , of the relative size of @xmath128 , however , the net result in the dvcs amplitude can be accidentally large @xcite . this can be caused by a partial cancellation that occurs in tree amplitudes . evolution effects @xcite in the flavor non - singlet sector are rather small . in the case of gluonic gpd models we observed rather large nlo corrections to the dvcs amplitude for the naive scale setting @xmath129 @xcite . for such models one also has rather strong evolution effects , which severely affect lo analysis . however , one can tune the factorization scale @xmath130 so that to get rid of these effects . the renormalon - motivated twist - four @xcite and target mass corrections @xcite await their quantitative exploration . d. mller et al . , fortschr . 42 ( 1994 ) 101 ; x. ji , phys . d 55 ( 1997 ) 7114 ; a.v . radyushkin , phys . d 56 ( 1997 ) 5524 . m. diehl , hep - ph/0205208 ; m. diehl et al . b 596 ( 2001 ) 33 ; s.j . brodsky , m. diehl , d.s . hwang , nucl . b 596 ( 2001 ) 99 . x. ji , phys . 78 ( 1997 ) 610 . belitsky , x. ji , phys . b 538 ( 2002 ) 289 . m. burkardt , phys . d 62 ( 2000 ) 071503 ; hep - ph/0105324 ; hep - ph/0207047 . ralston , b. pire , hep - ph/0110075 . belitsky , d. mller , a. kirchner , nucl . b 629 ( 2002 ) 323 . m. diehl et al . , phys . b 411 ( 1997 ) 193 ; a.v . belitsky et al . , nucl . b 593 ( 2001 ) 289 . a.v . belitsky , d. mller , nucl . b 589 ( 2000 ) 611 ; n. kivel et al . , phys . lett . b 497 ( 2001 ) 73 ; a.v . radyushkin , c. weiss , phys . d 63 ( 2001 ) 114012 . a. airapetian et al . 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hard exclusive leptoproductions of real photons , lepton pairs and mesons are the most promising tools to unravel the three - dimensional picture of the nucleon , which can not be deduced from conventional inclusive processes like deeply inelastic scattering . doe / er/40762 - 259 + umd - pp#02 - 059 + * nucleon hologram with exclusive leptoproduction * * a.v . belitsky@xmath0 , d. mller@xmath1 * _ @xmath0department of physics _ _ university of maryland at college park _ _ college park , md 20742 - 4111 , usa _ _ @xmath0fachbereich physik _ _ universitt wuppertal _ _ d-42097 wuppertal , germany _ * abstract * hard exclusive leptoproductions of real photons , lepton pairs and mesons are the most promising tools to unravel the three - dimensional picture of the nucleon , which can not be deduced from conventional inclusive processes like deeply inelastic scattering . _ brief summary of talks given at _ _ 17th summer school hugs@cebaf ( jefferson lab , june 2002 ) _ _ workshop exclusive processes at high momentum transfer " ( jefferson lab , may 2002 ) _ _ workshop qcd structure of the nucleon " ( ferrara , april 2002 ) _ _ workshop testing qcd through spin observables " ( charlottesville , april 2002 ) _ _ conference baryons 2002 " ( jefferson lab , march 2002 ) _ _ electron - ion collider workshop " ( brookhaven lab , february 2002 ) _