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the six cellulolytic fungi , trichoderma harzianum , penicillium citrinum , curvularia lunata , aspergillus flavus and alternaria alternata were grown in basal synthetic medium described by chahal and gray ( 1969 ) . one hundred grams of air dried rice stubble , 2~3 cm in length were autoclaved with 1.8 litres of 1% sodium hydroxide at 121 under 15 lbs for one hour . the procedure for estimation of soluble crude protein production by these six cellulolytic fungi was used as suggested by dhillon et al . the stubble was thoroughly washed with distilled water till neutral and dried at 60. the pre - treated and dried rice straw ground to 60-mesh was used as sole source of carbon . four 250 ml erlenmeyer flasks containing 50 ml basal synthetic medium along with fungal culture and 500 mg delignified rice residue were incubated on a rotary shaker at 28 1. five days after incubation the contents of the flasks were filtered through tared whatman filter no . 1 to determine the weight of the fungal mycelia and undigested cellulosic materials . the dried biomass was analyzed for its nitrogen content through kjeldhal method ( jackson , 1973 ) . to get the protein value t. harzianum was incubated separately on basal synthetic medium for eight days to find the effective day of incubation on scp production . we tried eight different sources , ammonium nitrate , ammonium chloride , ammonium sulphate , ammonium dihydrogen phosphate , diammonium hydrogen phosphate , potassium nitrate , sodium nitrate and urea to find out the most suitable nitrogen source of scp production . the amount of nitrogen added to medium was equivalent to 400 mg of nitrogen / litre of medium . the six cellulolytic fungi , trichoderma harzianum , penicillium citrinum , curvularia lunata , aspergillus flavus and alternaria alternata were grown in basal synthetic medium described by chahal and gray ( 1969 ) . one hundred grams of air dried rice stubble , 2~3 cm in length were autoclaved with 1.8 litres of 1% sodium hydroxide at 121 under 15 lbs for one hour . the procedure for estimation of soluble crude protein production by these six cellulolytic fungi was used as suggested by dhillon et al . the stubble was thoroughly washed with distilled water till neutral and dried at 60. the pre - treated and dried rice straw ground to 60-mesh was used as sole source of carbon . four 250 ml erlenmeyer flasks containing 50 ml basal synthetic medium along with fungal culture and 500 mg delignified rice residue were incubated on a rotary shaker at 28 1. five days after incubation the contents of the flasks were filtered through tared whatman filter no . 1 to determine the weight of the fungal mycelia and undigested cellulosic materials . the dried biomass was analyzed for its nitrogen content through kjeldhal method ( jackson , 1973 ) . to get the protein value t. harzianum was incubated separately on basal synthetic medium for eight days to find the effective day of incubation on scp production . we tried eight different sources , ammonium nitrate , ammonium chloride , ammonium sulphate , ammonium dihydrogen phosphate , diammonium hydrogen phosphate , potassium nitrate , sodium nitrate and urea to find out the most suitable nitrogen source of scp production . the amount of nitrogen added to medium was equivalent to 400 mg of nitrogen / litre of medium . the data shown in table 1 reveals that six cellulolytic fungi tested on delignified cellulose as a carbon source varied widely in soluble crude protein ( scp ) production . t. harzianum resulted in the highest scp production which was significantly superior to other fungi . p. citrinum and c. lunata brought about significant increase in scp compared to the rest of the fungi but varied significantly between themselves . the scp production efficiency of cellulolytic fungi was in order of t. harzianum > p. citrinum > c. lunata > a. flavus > a. alternata > a. niger . similar results were earlier reported by chahal and gray ( 1969 ) and dhillon et al . have been reported to be main sources of cellulase , amylase , hemicellulase , catalase , pectinase and xylanase ( hamlyn , 1998 ) . the maximum biomass production was achieved by a. niger and minimum by t. harzianum but biomass weight loss was reverse . this is consistent with the findings of chahal and gray ( 1969 ) and hobbie et al . rapid and higher production of scp by fungi from delignified cellulose may be ascribed to increased availability of amorphous form of cellulose owing to delignification with sodium hydroxide . ( 1971 ) from their detailed studies of decomposition of delignified cellulose reported that delignification of residue with sodium hydroxide results in increased cellulose to amorphous form which is readily attacked by fungi . ( 1980 ) proposed similar reason for increase in scp from delignified cellulose with sodium hydroxide . iyayi ( 2004 ) reported that the highest percentage increase in protein was obtained with a. niger when wheat offal inoculated with the fungus . on the basis of scp production , the t. harzianum was selected for further study . from the data , it was evident that the maximum scp ( 28% ) was produced 5 days after incubation ( table 2 ) . furthermore , increase in incubation period did not enhance scp production rather slight decrease in scp production was observed . this might be due to autolysis of the fungal mycelium and similar to the previous results ( sekhon , 1975 ; dhillon et al . , 1980 ) . ofuya and nwanjiuba ( 1990 ) have reported that fungal enzyme - controlled degradation responds to incubation time , ph and temperature of the medium . with fungal biomass increase , the nutrients in the substrate medium are quickly used up . among eight different sources , the most suitable nitrogen source ( potassium nitrate ) was found to be the best for maximum scp production , followed by ammonium nitrate and urea ( table 3 ) . on the basis of scp production , the t. harzianum was selected for further study . from the data , it was evident that the maximum scp ( 28% ) was produced 5 days after incubation ( table 2 ) . furthermore , increase in incubation period did not enhance scp production rather slight decrease in scp production was observed . this might be due to autolysis of the fungal mycelium and similar to the previous results ( sekhon , 1975 ; dhillon et al . , 1980 ) . ofuya and nwanjiuba ( 1990 ) have reported that fungal enzyme - controlled degradation responds to incubation time , ph and temperature of the medium . with fungal biomass increase , among eight different sources , the most suitable nitrogen source ( potassium nitrate ) was found to be the best for maximum scp production , followed by ammonium nitrate and urea ( table 3 ) .

the investigation was undertaken to enhance the decomposition process by pre - treatment of rice stubble , having higher concentration of lignin . air - dried rice stubble was treated with 1.8 liter of 1% naoh and autoclaved . six cellulolytic fungi , trichoderma harzianum , penicillium citrinum , curvularia lunata , aspergillus flavus and alternaria alternata were grown in basal synthetic medium along with delignified rice - residue as carbon source for production of soluble crude protein . though the loss of cellulose has been observed by all of them but having a considerable status in the presence of t. harzianum and t. harzianum yielded highest percentage of crude protein ( 27.99% ) with biomass of 375 mg , whereas the lowest protein value ( 17.91% ) was recorded in case of a. niger with biomass of 422 mg . among the imperfect fungi , t. harzianum was the most potent . effects of incubation period and nitrogen sources on soluble crude protein production by t. harzianum were also undertaken in this study . fifth day of incubation period and potassium nitrate as nitrogen source among other nitrogen sources was found most appropriate for soluble crude protein production by the mentioned organism .

chronic renal disease is a health problem in today s world . in the end - stages of renal disease patients however , dialysis causes several stressors on physical , mental and social performance of patients . the present study aimed to review and compare the self - concept in patients undergoing hemodialysis and peritoneal dialysis . this was a case - control study including two groups of patients , undergoing hemodialysis and peritoneal dialysis , who referred to al - zahra and ali asghar hospitals , which are affiliated to isfahan university of medical sciences . data were collected through completing the form of demographic characteristics and a questionnaire , written by the researcher , pertaining to the self - concept which was collected by the samples . anova ( analysis of variance ) showed that statistically there was a significant difference between mean score of self - concept in the three physical ( body - image ) , psychological , and social self aspects in the two groups of hemodialysis and peritoneal dialysis with the control group ; however , duncan s post - hoc analysis showed no significant difference between mean score of self - concept in the three mentioned aspects in the two groups of hemodialysis and peritoneal dialysis . furthermore , anova ( analysis of variance ) showed that there was no significant difference between mean score of the spiritual aspect of the self - concept in the two groups of hemodialysis and peritoneal dialysis with the control group . duncan s post - hoc analysis also showed no significant difference in this aspect between the two groups of hemodialysis and peritoneal dialysis . patients undergoing dialysis have many psychological disorders and the type of dialysis is not of much importance in this regard ; therefore , adequate education and information for clients in order to use appropriate methods of adaptation as well as appropriate social relationship , continuing social support and developing health policies seem necessary in order to prevent mental disorders and providing required services and supports for patients . chronic kidney disease is a health issue in today s world which brings about a threatening situation for the economic , social and health status of the diseased individual , and his / her family and society . thus , in the past few years , it has drawn considerable attention to itself particularly in advanced countries . the importance of such a disease is the dynamic nature of the disease over time and the fact that it will eventually lead to end - stage renal disease . end - stage renal disease is a clinical condition in which the kidneys will not be able to maintain metabolic tasks and keep the balance of the body s fluids and electrolytes . the prevalence rate of end - stage renal disease has been reported to be 242 cases per one million people and this amount is annually rising by 8% . currently , there are more than 450,000 people with end - stage renal disease only in the u.s . according to the statistics in iran , 1200 to 1600 people are annually infected by this disease . according to the report of the principle of the management center for specific diseases in the ministry of health and medical education , the population of patients with end - stage renal disease is 32,000 people in iran which seems to have increased to 40,000 people by 2010 . moreover , according to the studies in iran , the prevalence rate of end - stage renal disease has increased from 234.49 patients per one million people in the year 2000 to 357.63 patients per one million in 2006 . one of the alternative renal therapies is dialysis , of which there are different types . the aim of undergoing dialysis is to create a balance between acid and base status of blood fluids and electrolytes , as well as to remove the blood s metabolic waste . more than 60 percent of patients with end - stage renal disease in the u.s . are treated by hemodialysis . according to the statistics by the ministry of health and medical education in iran , 163,372 patients underwent dialysis in 2008 , of whom 15,172 patients they also reported that 2000 people are annually added to the number of patients undergoing hemodialysis and the number of patients treated by dialysis will be doubled in the next five years . peritoneal dialysis is the optional treatment of those patients with chronic kidney disease who are unable or unwilling to undergo hemodialysis . however , only 8.4 percent of patients with end - stage renal disease tend to perform peritoneal dialysis . in many cases , diagnosis of chronic renal disease and the necessity of implementing dialysis are a cause of concern for patients and their families and will lead to major changes in the individual s lifestyle . dialysis enables greater survival rate of patients , however it causes several stressors on physical , mental and social performance of patients . current complicated therapeutic methods in iran have strongly limited the activity of patients undergoing dialysis and have caused a decrease in their energy level , inability , lose of independence , financial stress , sexual dysfunctions , reduction of self - esteem , change in self - concept , and disruption in their family life . for example , they are fully adapted to the stressors and feel they are different from others ; therefore , one of the concepts inside patients which is disrupted severely by undergoing dialysis is self - concept . the self - concept is one of the profound psychological concepts which is very influential in the patient s attitude toward a healthy relationship with others , life expectancy , and adaptability to circumstances . self - concept does not exist from birth , but is acquired during mutual contact with others or with the environment . self - concept is all the ideas and desires someone has about the identity , values , abilities , and limitations and is changeable . carson believes that the self - concept has four physical , psychological , social and spiritual aspects . carson also believes that the image each person has about her / his own physical image is called the mental image of body . any change in mental image from body would seriously disrupt the balance of the individual ; these changes can be caused by accidents , diseases , or evolutionary changes in the structure and function of the body . psychological self or personal identity is the combination of perceptual , cognitive , and emotional perceptions someone has of themselves ; moreover , sexual identity is also part of an overall sense of identity as well as the self - image someone has as a male or female person . role is defined as the pattern of expected behavior related to the individual s function in a group which is largely influenced by culture . finally , the spiritual self helps the individual communicate with god so that his / her life is meaningful . this dimension of the self - concept includes the individual s beliefs about the universe and the position she / he has , and a great sense of hope and love . chronic renal disease and dialysis therapy have many adverse effects on the mental and physical conditions of people and cause different kinds of deprivations and lifestyle changes such as dependency on others , sexual problems , inadaptability to new conditions and social attitudes , financial problems , lack of employment , limitation in liquid intake and diet , change in familial roles and tasks and reduction in ability to achieve life s long - term goals , anger , depression , anxiety , denial , lack of cooperation , and stress due to physical complications , sense of inefficiency or incompetency , and fear of death . studies have indicated that people with chronic diseases could have better adaptability to the disease if they have a positive self - concept . however , their self - esteem would be decreased if they have a sense of uncertainty from the new identity , a negative self - concept , which this negative evaluation would cause . the fact that an individual is the only valid and authoritative reference for his / her own health assessment is gaining the attention of more researchers every day . , however , the occurrence of disease will largely destroy the individual s self - concept . there are some differences between hemodialysis and peritoneal dialysis in terms of satisfaction of patients , dependency on others , physical changes , ease of implementation , economic status , employment and etcetera . moreover , peritoneal dialysis is a relatively newer method than hemodialysis . also due to the existence of differences in ethnic , cultural and social attitudes in iran , as well as various available resources and facilities for such patients , the present study aimed to review and compare the self - concept in patients undergoing hemodialysis and peritoneal dialysis ; because the improvement and promotion of patients self - concept can be done only by the identification of these problems . this was a case - control quantitative - analytical study conducted in 2010 in al - zahra and ali asghar hospitals , which are affiliated to isfahan university of medical sciences . sampling in the peritoneal dialysis group was done randomly among the patients undergoing peritoneal dialysis who had the inclusion criteria . sampling of the hemodialysis group was done in the same way as the peritoneal dialysis group . for selecting the samples of the control group , the two peritoneal dialysis and hemodialysis groups were randomly asked to introduce some healthy relatives and friends who were close to them in terms of demographic characteristics , socio - cultural and economic conditions , and had no history of renal disease . thereafter , the introduced individuals ( who were 44 people in each group ) were asked to complete the demographic data form and a questionnaire . the inclusion criteria were : iranian nationality , moslem , persian speaker , having an active hospital record , within the age range of 1875 , ability to complete the questionnaire or interview , no physical or mental disability , lack of acute physical or mental diseases during the study , bmi less than 30 , no severe crisis in their life during the past six months , treated by dialysis for at least three months and no renal transplantation surgery . provided that due to any reason , any of the patients who was not willing to continue the participation , and/or did not answer the questionnaire completely , or had the inclusion criteria but was about to perform the kidney transplant , was excluded from the study . form included age , marital status , bmi , education , current employment status , family income , and the cause of their end - stage renal disease . the used questionnaire was written by the researcher and was pertaining to self - concept in patients undergoing dialysis . the researchers designed the questionnaire by referring to the existing scientific resources and articles , and inspiration by the self - image inventory from rogers and beck self - concept scale . scoring was done based on the 5-degree likert scale ( from zero to four representing never , seldom , sometimes , often , and always ) so that score 4 was the most desirable score and zero was as the most unfavorable score in each question . validity of the tool was determined through the comments of experts and scientists in this regard , and content validity . all the obtained data were encoded through inferential and descriptive statistical methods and were analyzed by the software spss version 18 . anova ( analysis of variance ) was used to compare the mean score of self - concept in different aspects in the three groups . mean age ( sd ) in the hemodialysis , peritoneal dialysis and control groups was 45.6 ( 15.2 ) , 48.2 ( 12.7 ) and 43.8 ( 14.8 ) years , respectively . in the groups undergoing hemodialysis , and peritoneal dialysis and the control group there were 21 ( 46.7% ) female and 24 male ( 53.3% ) , 16 female ( 35.6% ) and 29 male ( 64.4% ) and 24 female ( 54.5% ) and 20 male ( 45.5% ) participants , respectively . in total there were 61 female ( 45.5% ) and 73 male ( 54.5% ) participants . the majority of the participants in hemodialysis , peritoneal dialysis and control groups were married ( 80.7% , 57% , and 75% , respectively ) . mean ( sd ) bmi in hemodialysis , peritoneal dialysis and control groups was 23.5 ( 4.5 ) , 24.7 ( 2.7 ) , and 25 ( 2.9 ) kg / m , respectively . in the hemodialysis group , 25 samples were below the high school graduate level ( 51.1% ) , and 22 were high school graduates and higher ( 48.8% ) . in the peritoneal dialysis group , 26 samples were below the high school graduate level ( 57.8% ) , and 19 were high school graduates and higher ( 42.3% ) . in the control group , 23 samples were below high school graduate level ( 51.1% ) , and 22 were high school graduates and higher ( 48.8% ) . twenty one samples ( 46.7% ) in the hemodialysis group reported their family income to be less than their expenses and 22 samples ( 48.9% ) reported it to be the same as their expenses however , in the peritoneal dialysis group , 30 samples ( 66.7% ) reported their family income less than their expenses and 15 samples ( 33.3% ) reported it to be the same as their expenses . sixteen samples ( 35.6% ) in the control group also reported their family income less than their expenses and 29 samples ( 64.4% ) reported it as the same as their expenses . in the hemodialysis and peritoneal dialysis groups , 32 ( 71.1% ) and 31 ( 68.8% ) samples were unemployed respectively , while 20 samples ( 44.4% ) were unemployed in the control group . the most common cause of end - stage renal disease in both groups was diabetes ( 27% and 47.7% frequency in hemodialysis and peritoneal dialysis groups , respectively ) . the results of anova test indicated that statistically there was a significant difference between the mean score of self - concept in physical , psychological and social self in the three hemodialysis , peritoneal dialysis and control groups ( p < 0.05 ) . however , duncan s post hoc test showed that mean score of self - concept in the mentioned aspects had no significant difference in the hemodialysis and peritoneal dialysis groups ( p > 0.05 ) . in other words , mean score of self - concept in aspects , mentioned above , in hemodialysis and peritoneal dialysis groups was significantly lower than in the control group . furthermore , the minimum score of self - concept , in above mentioned aspects , in patients of the peritoneal dialysis group was greater than patients of the hemodialysis group . however , mean score of self - concept statistically had no significant difference between the three groups in terms of spiritual self aspect ( p = 0.144 ) ( table 1 ) . comparing the mean score of self - concept in different aspects in the studied subjects of the three groups the results of this study showed that mean score of self - concept in the three physical , psychological and social self aspects was different for the hemodialysis , peritoneal dialysis and control groups . in other words , mean score of self - concept in physical , psychological and social self aspects for hemodialysis and peritoneal dialysis groups was lower than for the control group . however , mean score of self - concept in each three aspects in the hemodialysis and peritoneal dialysis groups had no significant difference . in line with the results of the present study , partridge and robertson found that disturbance level in body - image for male and female participants undergoing dialysis was significantly higher than that of the healthy population of society in addition , rezai et al . found that 56% of subjects undergoing hemodialysis had a completely negative mental image of their own appearance and physiological activities , 57.3% had a completely negative mental image of their own daily activities against social and personal stimuli ( e.g. daily activities and business tasks ) , 70.7% had a relatively negative mental image of family and society s reactions toward themselves , and 20% had a completely negative mental image of their communication and presence in the society . the results obtained from juergensen et al . also indicated that patients undergoing peritoneal dialysis had more satisfaction with their body - image , social and family life compared to those undergoing hemodialysis . however , it was only in the social and family life that a statistically meaningful difference was observed between the two groups . a 612 month follow - up by koike in the u.s . showed that the depression level in patients with chronic physical illness was significantly greater than others . the findings of bao et al . also indicated that in the group undergoing hemodialysis , the prevalence of erectile dysfunction was significantly higher and the score of erectile dysfunction was considerably lower in the control group and this issue had overwhelmed these patients mentaly . they believed that the iranian culture causes patients to try to hide their illness from others which will lead to social isolation and will subsequently reduce patients social interaction with others . stewart stated that there was a relationship between sexual dysfunction in male patients undergoing hemodialysis with reduction in social interactions , social functioning and role - related limitations . the results of hojjati et al . showed that patients undergoing hemodialysis who had higher frequency of prayer had higher spiritual health . all the above mentioned studies were in accordance with the results of the present study . however , wu et al . found that patients undergoing peritoneal dialysis had higher rates of disorder in special aspects of body - image due to the existence of permanent catheter and dialysate in the peritoneal cavity . yaziciet al . also reported a depression level of 43.8% , 75.3% and 4.2% in female patients undergoing hemodialysis , peritoneal dialysis and within the control groups , respectively . juergensen et al . also showed that patients undergoing hemodialysis had lower satisfaction from religion and spirituality than patients undergoing peritoneal dialysis and there was a significant statistical difference between the two groups . it seems using different tools , unjustified number of subjects , research on one gender in the studied groups and ethnic , cultural , social and spiritual differences between the nations were the cause of the inconsistency of these studies with the present study . generally , the stressors challenge the individual s adaptability capacities . changes in physical , mental , emotional , sexual , familial , and socio - cultural health will influence the self - concept . therefore , patients undergoing dialysis may suffer from injuries in many aspects of their lives such as losing their job , role reduction , functional and nutritional limitations , change in sexual function , potential damage to independence , social isolation , changes in appearance of body due to the nature of the disease and undergoing dialysis , and consequently changes in self - concept which may result in irreversible consequences . in addition to the results of the study , perhaps it can be said that patients undergoing dialysis have issues with their self - concept due to stresses and disorders caused by treatment , and are weaker in different aspects of self - concept compared to the control group . moreover , it seems that the type of dialysis does not cause much difference ; therefore , appropriate education and adequate information for patients with end - stage renal disease to use appropriate methods of adaptation as well as appropriate social relationships , continuing social support , and developing health policies seem necessary to prevent mental disorders and provide the required services and supports for patients .

background : chronic renal disease is a health problem in today s world . in the end - stages of renal disease patients depend upon alternative therapies including dialysis for their survival . however , dialysis causes several stressors on physical , mental and social performance of patients . the present study aimed to review and compare the self - concept in patients undergoing hemodialysis and peritoneal dialysis.materials and methods : this was a case - control study including two groups of patients , undergoing hemodialysis and peritoneal dialysis , who referred to al - zahra and ali asghar hospitals , which are affiliated to isfahan university of medical sciences . these groups were compared to the control group . data were collected through completing the form of demographic characteristics and a questionnaire , written by the researcher , pertaining to the self - concept which was collected by the samples . the data were analyzed by the software spss version 18.findings:anova ( analysis of variance ) showed that statistically there was a significant difference between mean score of self - concept in the three physical ( body - image ) , psychological , and social self aspects in the two groups of hemodialysis and peritoneal dialysis with the control group ; however , duncan s post - hoc analysis showed no significant difference between mean score of self - concept in the three mentioned aspects in the two groups of hemodialysis and peritoneal dialysis . furthermore , anova ( analysis of variance ) showed that there was no significant difference between mean score of the spiritual aspect of the self - concept in the two groups of hemodialysis and peritoneal dialysis with the control group . duncan s post - hoc analysis also showed no significant difference in this aspect between the two groups of hemodialysis and peritoneal dialysis.conclusions:patients undergoing dialysis have many psychological disorders and the type of dialysis is not of much importance in this regard ; therefore , adequate education and information for clients in order to use appropriate methods of adaptation as well as appropriate social relationship , continuing social support and developing health policies seem necessary in order to prevent mental disorders and providing required services and supports for patients .

Megyn Kelly ಮರುಟ್ವೀಟಿಸಿದ್ದಾರೆ Breaking911 This has to stop. Who are we? What are we becoming? @ TuckerCarlson is tough & can handle a lot, but he does not deserve this. His family does not deserve this. It’s stomach-turning.https://twitter.com/breaking911/status/1060329164367167488 … ||||| Tweet with a location You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| On Wednesday night, a group of leftwing protestors gathered outside of Tucker Carlson‘s home. The group “Smash Racism DC” shared video of protestors ringing the doorbell and getting no response (Carlson likely wasn’t home due to the taping of his show). and one of them used a megaphone to shame the Fox News host and ordered him to “leave town.” “We know where you sleep at night,” the protestor warned Carlson. Out of respect and safety of Tucker Carlson, Mediaite has chosen not to publish the footage from the protest. Twitter has taken down Smash Racism DC’s thread which also published Carlson’s home address. This group was also behind the ambush Sen. Ted Cruz (R-TX) and his wife at a Washington D.C. restaurant. Many in conservative media have condemned the latest mob activity. This is revolting, and frightening. https://t.co/LotbWuwB5L — Brit Hume (@brithume) November 8, 2018 This article says ⁦@SmashRacismDC⁩ posted ⁦@TuckerCarlson⁩ ‘s address and Twitter removed after ⁦@DailyCaller⁩ made inquiries. Why is their account still allowed despite egregiously violating TOS? cc @jack ⁦@TwitterSafety⁩ https://t.co/TGr3rVxqAM — Dana Loesch (@DLoesch) November 8, 2018 These people are animals. Animals. Yes, animals. https://t.co/qgi7Ulqjco — Dan Bongino (@dbongino) November 8, 2018 Before wrapping his show Wednesday night, Carlson told his viewers that he was taking the next two days off and that he’d be back on Monday. Tucker Carlson signing off his show: “I’m taking two days off. I’ll see you Monday.” — Amanda Prestigiacomo (@AmandaPresto) November 8, 2018 It is unclear if his hiatus has anything to do with tonight’s protest. [images via screengrab] Have a tip we should know? [email protected] ||||| A self-described left-wing Antifa group posted videos of a mob outside the Washington, D.C., home of Fox News’ Tucker Carlson Wednesday evening, chanting, “Tucker Carlson, we will fight. We know where you sleep at night.” The now-deleted video was posted on social media by Smash Racism, D.C. The same group made headlines in September after activists confronted Sen.Ted Cruz, R-Texas, and his wife inside a restaurant during Brett Kavanaugh's Supreme Court confirmation hearings. The group posted on Facebook that Carlson spreads "fear into our homes," and said it wanted to even the score. "Each night you remind us that we are not safe. Tonight, we remind you that you are not safe either," the group posted. They also chanted, "Racist s---bag, leave town." The post was later removed. Carlson, host of "Tucker Carlson Tonight," was not home at the time. He said his wife, Susie, was home alone and heard the commotion from the kitchen. She called the police and locked herself into a pantry, he said. His brother -- who lives close by -- arrived about the same time as law enforcement. The host said activists rang his doorbell, broke his oak door and one protester was apparently caught on security video mentioning a pipe bomb. D.C. police did not immediately respond to a Fox News email early Thursday. Carlson said he was at the Fox News office in Washington working on his opening monologue when neighbors texted him about the commotion outside his home. His wife of 22 years did not contact him because she didn’t want to distract him before he went on air, he said. The group eventually scattered. It was unclear if there were any arrests. Carlson said the group posted online the home addresses of his brother and his former college roommate, Neil Patel, who co-founded the Daily Caller with Carlson. Carlson said he is used to being confronted in public and has no interest in playing the role of victim, but he said his wife and his four children should not have to be exposed to the aggression while at home. “Here’s the problem, I have four children,” he said by phone. “I never thought twice about leaving them home alone, but this is the reaction because this group doesn’t like my TV show.” Twitter reportedly removed a photo of Carlson’s home address that was posted by the group. Smash Racism DC's account was suspended early Thursday. Brit Hume, a Fox News commentator, took to Twitter to denounce the protest as “revolting, and frightening.” ||||| BREAKING: A mob has gathered outside Tucker Carlson’s home demanding his family leave DC because he is a "racist scumbag." "Every night you spread fear into homes — we remind you that you are not safe either" Tucker has 4 children. The Left is sick. https://dailycaller.com/2018/11/07/protesters-tucker-carlson-house/ …pic.twitter.com/1R9O9UcTYM

– Current and former Fox News personalities are blasting what they say was a terrifying display at the Washington, DC, home of Tucker Carlson Wednesday night. Carlson wasn't home but says his wife called police and locked herself in a pantry when protesters from a group called Smash Racism, DC, arrived, rang the doorbell, and began chanting: "We will fight. We know where you sleep at night." They also referred to Carlson as a "racist scumbag" and ordered that he leave town, per Fox News. "Each night you remind us that we are not safe. Tonight, we remind you that you are not safe either," the antifa-linked group added on social media. It shared Carlson's home address and a video of the scene before its Twitter account was suspended early Thursday (you can see video here). Carlson also said that one protester mentioned a pipe bomb, and that the group also shared the addresses of his brother and Daily Caller co-founder Neil Patel. "This is the reaction because this group doesn't like my TV show," the host tells Fox. "This is revolting, and frightening," tweets Fox News political analyst Brit Hume. "Who are we? What are we becoming?" adds Megan Kelly. "He does not deserve this. His family does not deserve this. It's stomach-turning." The protesters dispersed as police arrived, though it's unclear if any arrests were made. Meanwhile, Carlson used his sign-off on Wednesday's Tucker Carlson Tonight to announce he'd be taking two days off before returning Monday, per Mediaite. (Expect two books from Carlson.)

it was suspected as long as 150 years ago that something was blocking the light of stars on its way to earth , but it was nt until the early twentieth century that the work of barnard and trumpler confirmed the existence of obscuring clouds of interstellar dust ( whittet 1992 and references therein ) . trumpler found that the wavelength dependence of interstellar extinction is proportional to @xmath0 implying submicron size dust grains . despite these early advances , we , in the early twenty - first century , are still struggling to understand the nature of cosmic dust . the chemical composition of the dust grains has been the most difficult problem to address since the available observational data do not provide strong constraints . many solids have been suggested including ices , silicates , various carbon compounds , metals and complex organic molecules . graphite has been a popular grain constituent since it was associated with the 2175 extinction bump ( stecher & donn 1965 ) . two silicate features in the ir are widely observed providing one of the few firm identifications of a grain material ( woolf , & ney 1969 ; gillett , & forrest 1973 ) . the best diagnostic for determing the sizes of interstellar dust grains is the wavelength dependence of extinction ( mathis 2000 ) . a wealth of observational data now exists which characterizes extinction properties from the uv to the ir along sightlines in various dust grain environments . this combined with better constraints on the abundances of elements available for condensation into grains in the interstellar medium makes a study of the distribution of sizes of the dust grains into perhaps a slightly more tractable problem than it previously was . when data on the extinction were only available at visible wavelengths , the proposed size distribution was flat up to some cutoff size ( oort & van de hulst 1946 ) . the addition of data in the uv and ir wavelength regions in the last 40 years has revolutionized the study of the size distribution of dust grains , putting much more stringent constraints on the upper and lower size cutoffs and on the slope of the size dependence . the modern era of grain modeling was ushered in by mathis , rumpl , & nordsieck ( 1977 [ mrn ] ) . their grain model consisted of power - law size distributions of separate populations of bare spherical silicate and graphite grains . it is a testament to the groundbreaking nature of this work that today , twenty - five years later , it has not been fully superseded by later studies . mrn - type analyses must make assumptions regarding a particular model of the size - dependence of the dust grains . one is now able to circumvent such issues through a solution of the inverse problem using the maximum entropy method ( mem ) ( e.g. , kim , martin , & hendry 1994 ) . the versatility of this technique allows one to easily include a range of grain models in the analysis : from the simple mrn - like approach to more realistic composite grains which can include the effects of porosity , solid inclusions ( silicate , graphite , superparamagnetic etc . ) , and alignment . in this work , we present some preliminary efforts to extract mem size distributions of dust grains in the local group using `` basis sets '' of grain cross - sections for several composite grain models , each of which satisfies cosmic abundance constraints . most studies of grain size over the last half century have assumed a size distribution which is either a power law or a power law with exponential decay ( ped ) . in addition , most calculations have used mie theory assuming spherical grains . these power laws have been utilized for two reasons . first , they provide a good fit to the observed extinction wavelength dependence with as few as two populations of grains . second , formation and destruction processes such as shattering and coagulation which modify grain sizes along many sightlines may naturally produce a power law size distribution ( biermann & harwit 1980 ; hayakawa & hayakawa 1988 ; odonnell & mathis 1997 ) . this type of study began with oort & van de hulst ( 1946 ) who fit extinction at visible wavelengths assuming ice grains and a size distribution resembling a ped . greenberg ( 1968 ) greatly expanded this work using spheres , cylinders and spheroids , combined with many different materials and grain orientations limited only by lack of computing power available at the time . greenberg utilized the oort & van de hulst size distribution almost exclusively . this brings us to mrn who found that a very good fit could be made to the uv and visible extinction using separate populations of bare silicate and graphite grains with a power law distribution of sizes where n(a ) @xmath1 @xmath2 . the graphite grains range in size from 0.005 to 1 and the silicate grains from 0.025 to 0.25 . mathis & wallenhorst ( 1981 ) expanded on mrn by showing that they could fit various high @xmath3 sightlines with peculiar " extinctions such as @xmath4 sco , @xmath5 oph and @xmath6 ori by raising the lower size cutoff to 0.04 and sometimes also raising the upper size cutoff . this suggested that small silicates are missing along these lines of sight . greenberg & chlewicki ( 1983 ) claimed that grains responsible for bump and fuv extinction are two independent populations and that mrn violates this condition . however , cardelli , clayton , & mathis ( 1989 [ ccm ] ) showed that the greenberg & chlewicki result is spurious due to having an @xmath3 dependence in one ratio and not in the other . the lack of accurate optical constants for silicates and graphite have cast doubts on the significance of the good fits to extinction data with mrn - type models . in the absence of laboratory data on graphite , mrn adjusted the optical constants to make the bump lie at 2175 a. the situation improved with the work of draine & lee ( 1984 ) who synthesized dielectric functions for graphite and astronomical " silicate on the assumptions that mrn is valid . the polycyclic aromatic hydrocarbon ( pah ) absorption cross - section was established based on the interstellar 2175 bump profile ( li & draine 2001 ) . as data from the mid- and far - ir became available , it became evident that significant numbers of small grains and large molecules such as pahs were needed to account for emission features and excess continuum emission from single - photon heating ( draine & anderson 1985 ; desert , boulanger , & puget 1990 ) . the iras data imply a need to push the lower size cutoff of mrn down to @xmath70.0003 . ccm suggested that all populations of grains are subject to the same processes in a systematic way across the whole size distribution . they found that there is an average milky way extinction relation , a(@xmath8)/a(v ) , over the wavelength range 0.125 @xmath9 m to 3.5 @xmath9 m , which is applicable to a wide range of interstellar dust environments , including lines of sight through diffuse dust , dark cloud dust , and star formation ( ccm ; cardelli & clayton 1991 ; mathis & cardelli 1992 ) . the extinction relation is a function of one parameter , chosen to be r@xmath10 . the existence of this relation , valid over a large wavelength interval , suggests that the environmental processes which modify the grains are efficient and affect all grains . mathis & whiffen ( 1989 ) suggested that many grains are composite , perhaps like interplanetary grains with many individual grains of different materials including silicates and amorphous carbon stuck together in grains with significant amounts of vacuum . in their model , small bare graphite grains are still needed to explain the bump and pahs for the ir . mrn - type fits and the draine & lee optical constants have also been applied to sightlines in the the magellanic clouds . pei ( 1992 ) constructed one characteristic curve for each of the galaxy , lmc and smc even though large variations are seen from sightline to sightline in the smc and lmc let alone the milky way . he used data from koornneef ( 1982 , 1983 ) , rieke & lebofsky ( 1985 ) , morgan & nandy ( 1982 ) , nandy , morgan , & houziaux ( 1984 ) and bouchet et al . this study did not use the best extinction curve data available even at that time . the wavelength dependence of uv extinction in the lmc and smc are much better characterized now ( gordon & clayton 1998 ; misselt , clayton , & gordon 1999 ; gordon et al . pei ( 1992 ) uses the same exponent , and upper and lower cutoffs as mrn then varies the relative abundances of carbon and silicon in the three galaxies to get the best fit . he finds minor differences between the best fits and the measured curves , and suggests that changing the exponent and upper and lower cutoffs would nt improve on the fits presented . pei finds it,remarkable that all three parameters are roughly optimized for all three galaxies . " the standard silicate / graphite model appears to account well for all of pei s average curves with only the adjustment of the graphite to silicate ratio . aannestad ( 1995 ) expanded on mrn and extended fitting the extinction curve out to 925 using voyager data . he used both mie calculations for spheres plus the discrete dipole approximation ( dda ) for graphite disks . large and small silicates and carbon grains , and pahs were included along with organic refractory mantles ( jenniskens 1993 ) . aannestad suggests that the very small grains are made up of graphite , amorphous carbon , and diamond . as with previous studies , the higher @xmath3 extinction curves are fit by eliminating small grains . he also finds that 2:1 oblate graphite disks are better than spherical graphite for fitting the bump . aannestad suggests that radiation pressure could be responsible for changing grain size distributions in addition to shattering and coagulation . aannestad s study along with two that followed it ( mathis 1996 ; li & greenberg 1997 ) represent attempts to update mrn by addressing the complexities of fitting the uv to the far - ir extinction while staying within the constraint of the available abundances of various elements . the latter two studies use a ped for defining the size distribution . mathis ( 1996 ) uses mie theory but does nt attempt to include very small grains . li & greenberg ( 1997 ) employ finite cylinders for modeling the core - mantle grains . they state that their model uses less carbon than other models and so is nt so constrained by the carbon abundance . dwek et al . ( 1997 ) fit dust models to ir emission from 3.5 to 1000 using iras and cobe data . the iras data first showed cirrus emission with an excess at 12 and 25 caused by fluctuations in small grains down to 3 in size . these may be the same as the pahs that cause uir bands . the dwek et al . model uses bare silicate and graphite grains and pahs . they make a fit to 14 parameters , 8 fixed and 6 varying , using mie theory with the draine & lee constants . once the ir emission was fit they calculated the predicted uv extinction for their derived size distribution . in addition to the many mrn - like studies outlined above , two other methods have been suggested for deriving the dust grain size distribution by solving the inverse problem . zubko , krelowski , & wegner ( 1996a , 1998 ) suggest regularization where once a grain model is assumed then a unique size distribution is derived . it is not restricted by any a priori relation such as a power law . however , like most of the other studies above , zubko et al . use bare spherical grains ( astronomical silicate , graphite , ac , sic and water ice ) and mie theory to calculate the extinction efficiencies . their best fit models are silicate / graphite / ice mixtures although , as they note , the 3.1 ice feature is not seen in diffuse dust . zubko et al . say the results are essentially different from the mrn power law . his method results in size distributions with more structure than a simple power law . they are qualitatively similar to the results of the mem method described below . the regularization method has also been applied to the smc extinction ( zubko 1999 ) . the other derivation of the size distribution is through the maximum entropy method ( mem ) . kim et al . ( 1994 ) use the mem method with mrn - type bare spherical silicate , graphite and amorphous carbon particles for two cases with @xmath3 = 3.1 and 5.3 . the main constraint applied is the wavelength dependence of interstellar extinction . a second constraint is the abundance of various elements . this is combined with an assumed gas - to - dust ratio , @xmath11 . their results are similar to mrn but the resulting size distribution has more structure . the upper size cutoff in mrn was a subjective choice . mem results show a smooth decrease starting at 0.2 . the amounts of carbon and silicon used are similar to mrn . solar abundances as defined by grevesse & anders ( 1989 ) were used to constrain their models . kim & martin ( 1996 ) expanded the mem work to a wider range of @xmath3 values . they fit @xmath3 = 2.7 to 5.3 , while trying to minimize amount of carbon used . they limited the mass to that used by @xmath3=3.1 . they also found that fitting the extinction curve for @xmath5 oph needs more large particles in a bimodal distribution . recently , weingartner & draine ( 2001 ) expanded on mrn by establishing a multifunctional form of the grain sizes including two log - normal size distributions , peds and curvature terms . it involves 6 adjustable parameters for carbon grains and five for silicates . the fits are also constrained by @xmath3 and the available carbon abundance . they fit extinction curves by varying the powers , the curvature parameters , the transition sizes , the upper cutoff parameters and the total volume per h atom in both the carbon and silicate grain distributions , respectively . they include sufficient numbers of small grains to account for observations of ir emission . they find carbon and silicate grain size distributions that can account for both the uv to ir extinction and the ir emission . an important constraint on the composition of interstellar grains is the cosmic abundance of various elements . a proposed grain constituent can not use more of any element than is available in the interstellar medium . so a set of reference abundances , that represent the typical ism in a given galaxy , is needed . this set represents the total abundance of elements in the gas and dust . if these reference values are known , then a measurement of the gas phase abundances will reveal how much is missing , i.e. , how much has condensed to form dust grains . in the last few years , new data have put much more stringent constraints on the reference abundances in the interstellar medium of the galaxy ( e.g. , spitzer & fitzpatrick 1993 ; cardelli et al . 1993 , 1994 ; sofia , cardelli , & savage 1994 ; snow & witt 1996 ) . in particular , there was a move away from the use of solar abundances . this was motivated by the fact that solar abundances implied more oxygen than could be accounted for by the gas and solid phases of the ism . as a result , it was suggested that all abundances may be about 60% of solar . other abundance sources such as b stars have been used instead . one impact of this has been the so - called `` carbon crisis '' , in which there may be less carbon available than is needed for various models of the interstellar extinction including mrn . in fact , mathis ( 1996 ) shows this paucity of carbon would likely play a large role in constructing and validating grain models . recently , however , it has become apparent that that the `` crisis '' may be due to problems with the solar abundances . the measurements of the abundance of oxygen in the sun have been dropping and now stand at about two thirds of its former value ( sofia & meyer 2001 ) . there is now no good argument for adopting a reference that is two - thirds the solar abundance ( sofia & meyer 2001 ) . therefore , solar abundances have been adopted as the standard for the the galactic sightlines in this study . see table 1 . in the magellanic clouds , the relative abundances between the elements are similar to those found in the local ism ( russell & dopita 1992 ; welty et al . 1997 ; venn 1999 ) however , the metallicities in the lmc and smc are 0.3 and 0.6 0.7 dex lower , respectively , than in the local ism in the galaxy ( welty et al . 2001 ) . metallicity and the gas - to - dust ratio are correlated , so the amount of dust per hydrogen column is lower in the magellanic clouds . the observed gas - phase abundances of various elements in the ism should be just the reference abundance minus any depletion into dust grains . in the galaxy , several depletion patterns have been associated with different environments ( savage & sembach 1996 ; welty et al . for example , the depletions range from -0.8 [ mg , si / zn ] and -1.8 [ fe , ni / zn ] to - 0.2 [ mg , si / zn ] and -0.5 [ fe , ni / zn ] for cold dense clouds and the galactic halo , respectively , with the warm diffuse ism depletions lying in between . the relative gas - phase abundances in the magellanic clouds resemble those in the galactic halo implying that the depletion patterns in the ism of those galaxies may be similar to those in the galaxy despite the known differences in gas - to - dust ratio and metallicity ( welty et al . however , for at least three smc sightlines , the depletion pattern shows one important difference . silicon appears to be almost undepleted ( @xmath12 0.2 dex ) . almost every grain model for the ism from mrn to the present time includes silicates as an in important constituent . in particular , grain models of the smc have emphasized the importance of silicates since the role of carbon seems to be less important as measured by the strength of the 2175 feature ( pei 1992 ; zubko 1999 ; weingartner & draine 2001 ) . so , if silicon is indeed relatively undepleted in the smc , the grain models will have to be reassessed ( welty et al . low dispersion short and long wavelength iue spectra , combined with bvjhk photometry were used to construct the extinction curves in this study . the spectra were downloaded from the mast iue archive . the archive spectra were reduced using newsips and then were recalibrated using the method developed by massa & fitzpatrick ( 2000 ) . the short and long wavelength spectra for each star were co - added , binned to the instrumental resolution ( @xmath75 ) and merged at the maximum wavelength of the short wavelength spectrum . extinction curves were constructed using the standard pair method ( e.g. , massa , savage & fitzpatrick 1983 ) . uncertainties in the extinction curves contain terms that depend both on the broadband photometric uncertainties as well as those in the iue fluxes , which are calculated directly in newsips . our error analysis is described in detail in gordon & clayton ( 1998 ) . the sample includes early - type supergiants which may be used with the same accuracy as main sequence stars in calculating extinction ( cardelli , sembach , & mathis 1992 ) . table 2 lists the sightlines being analyzed for this study . the extinction curves have been fitted using the fitzpatrick & massa ( 1990 , hereafter fm ) parameterization . fm have developed an analytical representation of the shape of the extinction curves using a small number of parameters . this was done using linear combinations of a drude bump profile , @xmath13 , a linear background and a far - uv curvature function , @xmath14 , where @xmath15 . there are 6 parameters determined in the fit : the strength , central wavelength , and width of the bump , @xmath16 , @xmath17 , and @xmath18 , the slope and intercept of the linear background , @xmath19 and @xmath20 , and the strength of the far - uv curvature , @xmath21 . the fm best fit parameters to the sightlines are given in table 3 . extinction data have been obtained from the literature for the lmc , smc and some galactic sightlines ( gordon & clayton 1998 ; misselt et al . 1999 ; clayton , gordon , & wolff 2000 ) . various `` average '' curves have been calculated which generally represent extinction characteristics of groups of sightlines . in the smc , only four suitable early - type stars have been observed that are significantly reddened and also had well matched comparison stars ( gordon & clayton 1998 ) . three stars lie in the smc bar , and the line of sight for each of them passes through regions of recent star formation . the fourth star belongs to the smc wing and its line - of - sight passes though a much more quiescent region . in the lmc , the sample contains 12 stars in the 30 dor region and 7 stars outside 30 dor ( misselt et al . 1999 ) . while the extinction properties of the 30 dor and non-30 dor samples as defined are both inhomogeneous , a group of stars with similar reddenings and bump strengths were found lying in or near the region occupied by the supergiant shell ( lmc 2 ) . the average extinction curves inside and outside lmc 2 show a very significant difference in 2175 bump strength , but the far - uv extinctions are very similar . an `` average '' extinction curve for the galaxy is included in tables 2 and 3 . it is representative of a typical diffuse interstellar sightline . it has been constructed by making an fm fit to a ccm curve with @xmath3=3.1 ( misselt et al . another average curve is included which represents dust characteristics along extremely long path length , low - density sightlines in the galaxy from the sample of sembach & danks ( 1994 , sd region ) ( clayton et al . in addition , several individual sightlines are included in this study which are representative of the range of extinction characteristics seen in the galaxy . they are listed in table 2 . these extinction curves have been constructed as described above ( valencic et al . extinction curves have been presented for these stars previously : hd 29647 , hd 62542 ( cardelli & savage 1988 ) ; hd 37022 , hd 147889 , hd 204827 ( fitzpatrick & massa 1990 ) ; hd 147165 ( clayton & hanson 1993 ) ; hd 210121 ( larson , whittet , & hough 1996 ) ; and the sd region ( clayton et al . 2000 ) . these sightlines comprise values r@xmath10 from 2.1 to 5.5 . the sample includes the standard " ccm curve ( @xmath3 = 3.1 ) as well as those with steep ( hd 210121 , sd region , hd 204827 ) and flat ( hd 37022 , hd 147165 , hd 147889 ) uv rises , normal and weak ( hd 29647 , hd 62542 ) bumps . these sightlines represent all the physical environments accessible to uv observations including dense clouds , star - forming regions and the diffuse ism . in addition , we include average sightlines for the two extinction - curve types seen in each of the smc and lmc . we employ a ( slightly ) modified version of the mem extinction fitting algorithm developed by kim et al . ( 1994 , and references within ) . instead of using the number of grains as a constraint , the algorithm employs the mass distribution : m(a ) da = mass of dust grains per h atom in the size interval a to a+da . thus , the traditional mrn - type model becomes @xmath22 . we use a ped as the template function for each component . the data are examined at 34 wavelengths and the grain cross sections are computed over the range 0.0025 - 2.7 with 50 logarithmically - spaced bins . the shape of the mass distribution is strongly constrained only for data over the region 0.04 - 1 . below 0.04 , the rayleigh scattering behavior constrains only total mass ; above 1 , the `` gray '' nature of the dust opacity also forces the mem algorithm to simply adjust the total mass , using the shape of the template function to specify the size - dependence of the distribution . the total mass of dust is constrained using both the gas - to - dust ratio and cosmic " abundances ( i.e. , we try not to use more carbon or silicon than is available ) ; see table 1 . as a first step , we consider only three - component models of homogeneous , spherical grains : modified astronomical silicate " ( weingartner & draine 2001 ) , amorphous carbon ( zubko et al . 1996b ) , and graphite ( laor & draine 1993 ) . we modeled all the individual and average sightlines for the galaxy and the magellanic clouds listed in table 2 . the results are presented in figures 1 - 3 . for each sightline , two plots have been produced . the first shows the amount of extinction provided by each of the three materials , the total extinction of the model compared to the measured extinction curve . the fraction of the adopted abundance available for each material ( table 1 ) which is needed for the best model fit , is also listed . the second plot shows the resultant mass distribution for different sizes of grains of each material relative to the mass of hydrogen . figures 1 and 2 present the three - component models for a selection of galactic sightlines including the standard " curve ( @xmath3 = 3.1 ) . figure 3 presents three - component models for the smc and lmc curves described above . the mem fits to all of the sightlines considered here show the same general behavior with the dust grain mass distributed across a wide range of sizes up to some upper size cutoff . as described above , the mem model is not well constrained for very large and very small grains . one would naively think that as @xmath3 gets larger and the uv extinction gets flatter that the relative amount of mass in small grains would go down and large grains would go up ; for steeper curves , the opposite would happen . these effects are seen in figures 1 - 3 but no simple correlation with @xmath3 or far - uv steepness is seen . similarly , sightlines with weak bumps use relatively less mass in the likely bump grains . one trend is that sightlines with higher than average gas - to - dust ratios lie below the average galactic curve at all grain sizes . this is just due to the fact that the the masses in the figures are normalized to the mass of hydrogen . the fraction of the available silicon and carbon used in the mem fits to the various sightlines covers a very wide range . three general factors determine the fraction of silicon and carbon that any individual sightline will use . first , the higher the gas - to - dust ratio is , the more metals are available in the gas phase . second , the higher the abundances of metals are , the more material is available . finally , high values of @xmath3 imply a greater than average mass fraction in larger grains . the extinction due to large grains is not as efficient per unit mass as smaller grains since the mass goes as @xmath23 while the surface area goes as @xmath24 . hd 37022 which has normal galactic abundances and gas - to - dust ratio but the highest value of @xmath3 in our sample , requires more than 100% of the available silicon and carbon . similarly , the other high @xmath3 sightlines , hd 147889 , hd 147165 and hd 29647 all require large fractions of the available metals . the smc wing which has a low gas - to - dust ratio and low abundances also uses more than 100% of the available silicon and carbon . on the other hand , the sd region with a high gas - to - dust ratio , normal abundances and a low @xmath3 uses less than half of the silicon and carbon . the lmc2 and the smc bar regions both have low abundances and high gas - to - dust ratios . both use 50% or less of the available silicon and 60 - 80% of the carbon . the smc bar uses a larger fraction of both elements because of its higher normalized extinction , requiring more dust grains . the relationship between elemental fraction used and the gas - to - dust ratio is illustrated in figure 4 . all extinction models rely heavily on silicates , yet recent observations suggest that silicon is relatively undepleted in the smc bar ( welty et al . it should be noted that the sightlines investigated by welty et al . do not have extinction curves due to their small reddenings . however , mem model fits to the average smc bar extinction indicate that the curve can not be fit with carbon grains alone . since there is almost no bump in the smc bar extinction that may also imply the presence of fewer graphite grains . carbon grains are responsible for most of the visible extinction and silicon grains for most of the uv extinction . so , in general , both species of grains are needed along any sightline to get a good fit to the extinction curve . at least , the mem fit for the smc bar requires a smaller fraction of silicon and carbon than almost any other sightline modeled . a quick look at the figures shows that the hd 210121 and smc bar sightlines are the most unusual in their grain size distributions . both differ strongly from the ccm curve . these two sightlines also have the steepest far - uv extinction . the model fits show a deficit of large silicate and amorphous carbon grains for both sightlines . the hd 210121 sightline which , unlike the smc bar , has a significant bump , shows a slightly larger size cutoff for graphite grains . the next steepest sightlines , in the lmc and in the sd region in the galaxy do not show much difference from the average curve once the gas - to - dust ratio differences are taken into account . the importance of small grains in the steep uv rise for several sightlines ( including hd 204827 ) is also quite evident . larson et al . ( 2000 ) also did mem modeling for hd 210121 with similar results . the largest @xmath3 sightline , toward hd 37022 , also shows large deviations from the average galactic curve . the mem fit to the hd 37022 sightline shows a large deficit of small graphite and silicate grains . kim et al . ( 1994 ) found that extinction with @xmath3=5.3 requires a similar dust mass to extinction with @xmath3=3.1 . there is a great reduction in the number of grains with sizes less than 0.1 and some increase in larger particles for the model with the larger value of @xmath3 . among the fits to other large @xmath3 sightlines , hd 147165 shows trends similar to the hd 37022 fit while the fit to hd 147889 is not significantly different from the average galactic fit . the mass distributions , found in this study , show significant departures from power - law ( and even ped ) behavior . this is an important distinction to make in light of the work by pei ( 1992 ) , which extends mrn to the same environments by changing only the end points of the grain size range . as an interesting exercise , we constructed a composite model along the lines of mathis ( 1998 ) . however , given our interest in increasing the cross section per unit volume while also minimizing the amounts of si and c used , we chose to explore the use of pyroxene and oxides . in other words , by freeing up some of the [ fe , mg ] normally used in olivine - like astronomical silicate , one is able to form oxides without consuming any additional cosmic fe or mg ( as compared to olivine ) . briefly , our composite grain component consists of ( by volume ) 28.5% pyroxene ( @xmath25sio_3 $ ] ) , 16.5% amorphous carbon , 5% oxide ( @xmath26o$ ] ) , and 50% vacuum . the elemental budget for this component is [ c / h ] = 1.05e-4 and [ si / h ] = 2.9e-5 . defining a molecule " of this material to have 1 si atom , one derives a molecular weight of 213 and density of 1.45 g/@xmath27 . the dust mass densities used in this study are @xmath28= 3.3 g @xmath29 , @xmath30= 2.3 g @xmath29 and @xmath31= 1.8 g @xmath29 . we included small silicates and small carbon ( graphite ) grains in our composite model , in addition to the composite grain component itself . following the lead of mathis ( 1998 ) , we computed the optical properties using a geometric mean of two effective medium mixing rules : bruggeman and an extension by ossenkopf ( 1991 ) . the dielectric functions for the individual components were taken from the following sources : amorphous carbon - be form of zubko et al . ( 1996b ) ; oxide - henning et al . ( 1995 ) , and pyroxene - dorschner et al . unfortunately , the latter two are limited to wavelengths above 0.22 ( we discarded the 0.2 point ) . for the purpose of this exercise , we assumed that the uv behvior of the materials will be similar to that of astronomical silicates ( i.e. , the fe component is dominant in this regime ) . so , we extended the dielectric function to the 0.08 - 0.2 region by scaling the imaginary component ( @xmath32 ) of astronomical silicates to match smoothly with that of each material at 0.22 . we then computed the real component ( @xmath33 ) using a subtractive kramers - kronig ( skk ) algorithm , implementation kindly supplied by kelly snook ( snook 1999 ; see also warren 1984 ) . the fixed - point value of @xmath33 needed for the skk calculations is adopted from the visible measurements of each material at a wavelength of 0.5 . the model fits are shown in figure 5 . this result is intriguing as it indicates that the composite grains may require a smaller fraction of the available silicon and carbon . weingartner & draine ( 2001 ) note that kim et al . ( 1994 ) make more efficient use of the grain volume by using mem to construct more complicated size distributions . they find this `` fine - tuning unappealing . '' however , their own models have trouble staying within the standard abundance / depletion limits . weingartner & draine suggest that it is more likely that the abundance constraints are too stringent and the real galactic abundances are higher than solar . as can be seen in figures 1 and 3 of this paper , the mem model fits sometimes require 100% or more of the available silicon and carbon assuming the new " old solar abundances . weingartner & draine fit the galactic average extinction curve as well as the average lmc , lmc2 and smc bar sightlines . a comparison of their results with ours shows significant differences , in particular , in the upper size cutoffs of silicate and carbon grains . for example , weingartner & draine also fit the hd 210121 sightline . their two - component fit has upper size cutoffs of @xmath70.3 for the silicates and @xmath71 for carbonaceous grains . in our three - component fit , we find the opposite , @xmath70.3 for amorphous carbon and @xmath71 for silicate grains . we also include graphite with an upper cutoff of @xmath70.3 . dwek et al . ( 1997 ) used ir emission at mid - ir wavelengths to constrain the size distribution and then predicted the uv extinction . they find a size distribution for silicates not too different from mrn and include two power laws for graphite . their predicted uv extinction curve is steeper in the uv than the @xmath3=3.1 extinction curve . the cirrus , modeled by dwek et al . ( 1997 ) , is located at high latitude so may have extinction more like that seen toward hd 210121 . the differences among these studies reinforce the fact that while the model results are useful , they are not unique . li & greenberg ( 1998 ) fit the extinction curve of hd 210121 using both an mrn power - law with silicates and graphite , and a core - mantle model . most previous papers that calculate the size distributions assume just one average " extinction curve to fit ( i.e. , mathis 1996 ) . in this paper , we present a uniform set of mem model fits , all using the same grain materials , optical constants and abundance constraints . in addition , we are taking advantage of improved uv and ir data and better estimates of the gas - to - dust ratio . the model fits cover the entire range of extinction properties that have been seen in the galaxy and the magellanic clouds . clearly , more work needs to be done : the derived mass distributions will need to be tested in other observational regimes , such as thermal ir and linear polarization . more sophisticated cross sections need to be included , both in terms of grain topology and composition . the next step will include composite grains , as well as both aligned and randomly - oriented spheroids . in addition , more extensive galactic studies need to be undertaken . specifically , attempts to tie sightline characteristics such as depletion patterns , molecular abundances , etc . to specific extinction features ( i.e. , steep uv rise , weak bump ) . aannestad , p.a . 1992 , apj , 443 , 653 biermann , p. & harwit , m. 1980 , apj , 241 , l105 bohlin , r. c. , savage , b. d. , & drake , j. f. 1978 , , 224 , 132 bouchet , p. , lequeux , j. , maurice , e. , prevot , l. , & prevot- burnichon , m.l . 1985 , a&a , 149 , 330 cardelli , j.a . , & clayton , g.c . 1991 , aj , 101 , 1021 cardelli , j. a. , clayton , g. c. , & mathis , j. s. 1989 , , 345 , 245 cardelli j.a . , mathis , j.s . , ebbets , d.c . , & savage , b.d . 1993 , apj , 402 , l17 cardelli , j. a. , & savage , b.d . 1988 , apj , 325 , 864 cardelli , j.a . , sembach , k.r . , & mathis , j.s . 1992 , aj , 104 , 1916 cardelli j.a . , sofia , u.j . , savage , b.d . , keenan , f.p . , & dufton , p.l . 1994 , apj , 420 , l29 clayton , g.c . , gordon , k.d . , and wolff , m.j . 2000 , apjs , 129 , 147 clayton , g.c . , & hanson . 1993 , a.j . , 105,1880 clayton , g. c. , wolff , m. j. , allen , r. g. , & lupie , o. l. 1995 , , 445 , 947 clayton , g. c. , wolff , m. j. , gordon , k.d . , & misselt , k.a . 2000 , asp conf . ser . , 196 , 41 desert , f .- x . , boulanger , f. , & puget , j.l . 1990 , a&a , 237 , 215 dorschner j. , begemann b. , henning th . , jaeger , c. , & mutschke , h. 1995 , a&a , 300 , 503 draine , b.t . , & anderson , n. 1985 , apj , 292 , 494 draine , b.t . , & lee , h.m . 1984 , apj , 285 , 89 dwek , e. et al . 1997 , apj , 475 , 565 fitzpatrick , e. l. 1985 , , 299 , 219 fitzpatrick , e. l. & massa , d. 1990 , , 72 , 163 gillett , f.c . , & forrest , w.j . 1973 , apj , 179 , 483 gordon , k. d. & clayton , g.c . 1998 , , 500 , 816 gordon , k. d. , clayton , g.c . , misselt , k.a . , wolff , m.j . , & landolt , a.u . 2002 , apj , submitted greenberg , j.m . 1968 , in nebulae and interstellar matter , ed . middlehurst and l.h . aller ( chicago : university of chicago press ) , p. 221 greenberg , j.m . , & chlewicki , g. 1983 , apj , 272 , 563 grevesse , n . , & anders , e. 1989 , in cosmic abundances of matter , aip conf . proc . , 183 , 1 gunderson , k. a. , clayton , g. c. , & green , j. 1998 , , 110 , 60 hayakawa , h. , & hayakawa , s. 1988 , pasj , 40 , 341 henning th . , begemann b. , mutschke h. , & dorschner j. , 1995 , a&as , 112 , 143 jenniskens , p. 1993 , a&a , 274 , 653 kim , s .- h . & martin , p. g. 1995 , , 442 , 172 kim , s .- h . & martin , p. g. 1996 , , 462 , 296 kim , s .- h . , martin , p. g. , & hendry , p.d . 1994 , , 422 , 164 koornneef , j. 1982 , a&a , 107 , 247 koornneef , j. 1983 , a&a , 128 , 84 laor , a. & draine , b. t. 1993 , , 402 , 441 larson , k.a . , whittet , d.c.b . , & hough , j.h . 1996 , apj , 472 , 755 larson , k.a . , wolff , m.j . , roberge , w.g . , whittet , d.c.b . , & he , l. 2000 , apj , 532 , 1021 li , a. , & draine , b.t . 2001 , apj , 554 , 778 li , a. , & greenberg , j.m . 1997 , a&a , 323 , 566 li , a. , & greenberg , j.m . 1997 , a&a,339 , 591 martin . n. , maurice , e. , & lequeux , j. 1985 , a&a , 215 , 219 massa , d. , & fitzpatrick , e. l. 2000 , apjs , 126 , 517 massa , d. , savage , b. d. , & fitzpatrick , e. l. 1983 , , 266 , 662 mathis , j. s. 1996 , apj , 472 , 643 mathis , j. s. 1998 , , 497 , 824 mathis , j. s. 2000 , jgr , 105 , 10269 mathis , j. s. , & cardelli 1992 , apj , 398 , 610 mathis , j. s. , rumpl , w. & nordsieck , k.h . 1977 , apj , 217 , 425 mathis , j. s. , & wallenhorst , s.g . 1981 , apj , 244 , 483 mathis , j. s. , & whiffen , g. 1989 , apj , 341 , 808 misselt , k. a. , clayton , g. c. , & gordon , k. a. 1999 , , 512 , 128 morgan , d.h . , & nandy , k. 1982 , mnras , 199 , 979 nandy , k. , morgan , d.h . , & houziaux , l. 1984 , mnras , 211 , 895 odonnell , j.e . , & mathis , j.s 1997 , apj , 479 , 806 oort , j.h . , & van de hulst , h.c . 1946 , ban , 10 , 187 ossenkopf , v. 1991 , a&a , 251 , 210 pei , y. c. 1992 , , 395 , 130 rieke , g.h . , & lebofsky , m.j . 1985 , apj , 288 , 618 rouleau & martin 1991 , , 377 , 526 russell , s. c. & dopita , m. a. 1992 , , 384 , 508 savage , b.d . , drake , j.f . , buditch , w. , & bohlin , r.c . 1977 , apj , 215 , 788 savage , b.d . , & sembach , k.r . 1996 , ara&a , 34 , 279 sembach , k.r . , & danks , a.c . 1994 , a&a , 289 , 539 snook , k. j. , 1999 , ph.d thesis , stanford university , stanford , california snow , t.p . , & witt , a.n . 1996 , apj , 468 , l65 + sofia , u.j . , cardelli , j.a . & savage , b.d . 1994 , apj , 430 , 650 + sofia , u.j . , & meyer , d.m . 2001 , apj , 554 , l221 spitzer , l. , & fitzpatrick , e.l . 1993 , apj , 409 , 299 + stecher , t.p . , & donn , b. 1965 , apj , 142 , 1681 valencic , l. et al . 2002 , in preparation venn , k.a . 1999 , apj , 518 , 405 warren , s. , 1984 , appl , 23 , 1206 weingartner , j.c . , & draine , b.t . 2001 , apj , 548 , 296 welty , d. e. , lauroesch , j.t . , blades , j.c . , hobbs , l.m . , & york , d.g . 1997 , apj , 489 , 672 welty , d. e. , lauroesch , j.t . , blades , j.c . , hobbs , l.m . , & york , d.g . 2001 , apj , 554 , l75 whittet , d.c.b . 1992 , dust in the galactic environment , ( iop : bristol ) whittet , d.c.b . , gerakines , p.a . , hough , j.h . , & shenoy , s.s . 2001 , apj , 547 , 872 whittet , d.c.b . , martin , p.g . , fitzpatrick , e.l . , & massa , d. 1993 , apj , 408 , 573 woolf , n.j . , & ney , e.p . 1969 , apj , 155 , l181 zubko , v.g . 1999 , apj , 513 , l29 zubko , v.g . , krelowski , j. , & wegner , w. 1996a , mnras , 283 , 577 zubko , v.g . , krelowski , j. , & wegner , w. 1998 , mnras , 294 , 548 zubko , v.g . , mennella , v. , colangeli , l. , & bussoletti , e. 1996b , mnras , 282 , 1321 lcccl smc bar & 2.7&0.18&3.6e+22&1,2,18 + smc wing & 2.1&0.24&1.5e+21&1,3,18 + lmc & 3.4&0.25&1.1e+22&4,5,18 + lmc 2 & 2.8&0.19&1.9e+22&4,5,18 + average galactic&3.1 & & 5.8e+21&6,7 + hd 29647&3.6&1.00&5.8e+21&6,12 + hd 37022&5.5&0.34&5.8e+21&6,7 + hd 62542 & 3.2&0.33&5.8e+21&6,11,13 + hd 147165&3.8&0.40&5.9e+21&7,14,15 + hd 147889&4.2&1.09&5.8e+21&7 + hd 204827&2.6&1.10&5.8e+21&6,8 + hd 210121&2.1&0.38&5.8e+21&9,10 + sd region&2.7&0.24&1.2e+22&16,17 + lccccccc smc bar & -4.47 @xmath34 0.19 & 2.35 @xmath34 0.18 & 0.08 @xmath34 0.01 & -0.22 @xmath34 0.004 & &&1 smc wing & -1.00 @xmath34 0.15 & 1.17 @xmath34 0.12 & 3.49 @xmath34 0.19 & 0.17 @xmath34 0.04 & 4.69 @xmath34 0.0001 & 1.17 @xmath34 0.05&1lmc & -1.28 @xmath34 0.34 & 1.11 @xmath34 0.10 & 2.73 @xmath34 0.37 & 0.64 @xmath34 0.06 & 4.596 @xmath34 0.017 & 0.91 @xmath34 0.05&2lmc 2 & -2.16 @xmath34 0.36 & 1.31 @xmath34 0.08 & 1.92 @xmath34 0.23 & 0.42 @xmath34 0.08 & 4.626 @xmath34 0.010 & 1.05 @xmath34 0.07&2milky way&0.12 @xmath34 0.11&0.63 @xmath34 0.04&3.26 @xmath34 0.11&0.41 @xmath34 0.02&4.596 @xmath34 0.002&0.96 @xmath34 0.01&2hd 29647 & -0.02 @xmath34 0.20 & 0.82 @xmath34 0.02 & 3.06 @xmath34 0.26 & 0.61 @xmath34 0.25 & 4.64 @xmath34 0.03 & 1.45 @xmath34 0.003&4hd 37022 & 2.06 @xmath34 0.35 & 0.004 @xmath34 0.003 & 2.14 @xmath34 0.06 & 0.53 @xmath34 0.04 & 4.56 @xmath34 0.002 & 1.04 @xmath34 0.02&4hd 62542 & -1.31 @xmath34 0.06 & 1.31 @xmath34 0.09 & 2.64 @xmath34 0.10 & 1.36 @xmath34 0.12 & 4.61 @xmath34 0.01 & 1.37 @xmath34 0.02&4hd 147165 & 1.07 @xmath34 0.20 & 0.31 @xmath34 0.02 & 4.03 @xmath34 0.12 & 0.04 @xmath34 0.003 & 4.59 @xmath34 0.002 & 1.09 @xmath34 0.02&4hd 147889&1.89 @xmath34 0.20 & 0.09 @xmath34 0.018 & 4.77 @xmath34 0.05 & 0.92 @xmath34 0.04 & 4.62 @xmath34 0.01 & 1.08 @xmath34 0.01 & 4 hd 204827&-0.74 @xmath34 0.08 & 1.10 @xmath34 0.01 & 3.11 @xmath34 0.11 & 0.86 @xmath34 0.16 & 4.60 @xmath34 0.01 & 1.16 @xmath34 0.02&4hd 210121&-3.15 @xmath34 0.09 & 1.96 @xmath34 0.15 & 2.94 @xmath34 0.15 & 1.05 @xmath34 0.11 & 4.57 @xmath34 0.01 & 1.11 @xmath34 0.02&4sd region & -1.83 @xmath34 0.14 & @xmath35 @xmath34 0.20 & @xmath36 @xmath34 0.27 & @xmath37 @xmath34 0.10 & @xmath38 @xmath34 0.02 & @xmath39 @xmath34 0.02 & 3

employing the maximum entropy method algorithm , we fit interstellar extinction measurements which span the wavelength range 0.125 - 3 . we present a uniform set of mem model fits , all using the same grain materials , optical constants and abundance constraints . in addition , we are taking advantage of improved uv and ir data and better estimates of the gas - to - dust ratio . the model fits cover the entire range of extinction properties that have been seen in the galaxy and the magellanic clouds . the grain models employed for this presentation are the simplistic homogeneous spheres models ( i.e. , mathis , rumpl , & nordsieck 1977 ) with two ( graphite , silicate ) or three ( graphite , silicate , amorphous carbon ) components . though such usage is only a first step , the results do provide interesting insight into the use of grain size as a diagnostic of dust environment . we find that the smc bar extinction curve can not be fit using carbon grains alone . this is a challenge to the recent observational result indicating little silicon depletion in the smc .

SECTION 1. SHORT TITLE. This Act may be cited as the ``District of Columbia and United States Territories Circulating Quarter Dollar Program Act''. SEC. 2. ISSUANCE OF REDESIGNED QUARTER DOLLARS HONORING THE DISTRICT OF COLUMBIA AND EACH OF THE TERRITORIES. Section 5112 of title 31, United States Code, is amended by inserting after subsection (m) the following new subsection: ``(n) Redesign and Issuance of Circulating Quarter Dollar Honoring the District of Columbia and Each of the Territories.-- ``(1) Redesign in 2009.-- ``(A) In general.--Notwithstanding the fourth sentence of subsection (d)(1) and subsection (d)(2) and subject to paragraph (6)(B), quarter dollar coins issued during 2009 shall have designs on the reverse side selected in accordance with this subsection which are emblematic of the District of Columbia and the territories. ``(B) Flexibility with regard to placement of inscriptions.--Notwithstanding subsection (d)(1), the Secretary may select a design for quarter dollars issued during 2009 in which-- ``(i) the inscription described in the second sentence of subsection (d)(1) appears on the reverse side of any such quarter dollars; and ``(ii) any inscription described in the third sentence of subsection (d)(1) or the designation of the value of the coin appears on the obverse side of any such quarter dollars. ``(2) Single district or territory design.--The design on the reverse side of each quarter dollar issued during 2009 shall be emblematic of one of the following: The District of Columbia, the Commonwealth of Puerto Rico, Guam, American Samoa, the United States Virgin Islands, and the Commonwealth of the Northern Mariana Islands. ``(3) Selection of design.-- ``(A) In general.--Each of the 6 designs required under this subsection for quarter dollars shall be-- ``(i) selected by the Secretary after consultation with-- ``(I) the chief executive of the District of Columbia or the territory being honored, or such other officials or group as the chief executive officer of the District of Columbia or the territory may designate for such purpose; and ``(II) the Commission of Fine Arts; and ``(ii) reviewed by the Citizens Coinage Advisory Committee. ``(B) Selection and approval process.--Designs for quarter dollars may be submitted in accordance with the design selection and approval process developed by the Secretary in the sole discretion of the Secretary. ``(C) Participation.--The Secretary may include participation by District of Columbia or territorial officials, artists from the District of Columbia or the territory, engravers of the United States Mint, and members of the general public. ``(D) Standards.--Because it is important that the Nation's coinage and currency bear dignified designs of which the citizens of the United States can be proud, the Secretary shall not select any frivolous or inappropriate design for any quarter dollar minted under this subsection. ``(E) Prohibition on certain representations.--No head and shoulders portrait or bust of any person, living or dead, and no portrait of a living person may be included in the design of any quarter dollar under this subsection. ``(4) Treatment as numismatic items.--For purposes of sections 5134 and 5136, all coins minted under this subsection shall be considered to be numismatic items. ``(5) Issuance.-- ``(A) Quality of coins.--The Secretary may mint and issue such number of quarter dollars of each design selected under paragraph (4) in uncirculated and proof qualities as the Secretary determines to be appropriate. ``(B) Silver coins.--Notwithstanding subsection (b), the Secretary may mint and issue such number of quarter dollars of each design selected under paragraph (4) as the Secretary determines to be appropriate, with a content of 90 percent silver and 10 percent copper. ``(C) Timing and order of issuance.--Coins minted under this subsection honoring the District of Columbia and each of the territories shall be issued in equal sequential intervals during 2009 in the following order: the District of Columbia, the Commonwealth of Puerto Rico, Guam, American Samoa, the United States Virgin Islands, and the Commonwealth of the Northern Mariana Islands. ``(6) Other provisions.-- ``(A) Application in event of admission as a state.--If the District of Columbia or any territory becomes a State before the end of the 10-year period referred to in subsection (l)(1), subsection (l)(7) shall apply, and this subsection shall not apply, with respect to such State. ``(B) Application in event of independence.--If any territory becomes independent or otherwise ceases to be a territory or possession of the United States before quarter dollars bearing designs which are emblematic of such territory are minted pursuant to this subsection, this subsection shall cease to apply with respect to such territory. ``(7) Territory defined.--For purposes of this subsection, the term `territory' means the Commonwealth of Puerto Rico, Guam, American Samoa, the United States Virgin Islands, and the Commonwealth of the Northern Mariana Islands.''.

District of Columbia and United States Territories Circulating Quarter Dollar Program Act - Authorizes the Secretary of the Treasury to issue during 2009 redesigned quarter dollars commemorating the District of Columbia and the U.S. Territories.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Parental Involvement Enhancement Act''. SEC. 2. FINDINGS. The Congress finds the following: (1) Research indicates that, regardless of economic, ethnic, or cultural background, parental involvement in a child's education is a major factor in determining success in school. (2) Parental involvement in a child's education contributes to such positive outcomes as improved grades and test scores, higher expectations for student achievement, better school attendance, improved rates of homework completion and graduation from secondary schools, decreased violence and substance abuse, and higher rates of graduation from and enrollment in postsecondary schools. (3) According to the Department of Education study entitled ``Strong Families, Strong Schools'', in elementary schools where parents were actively involved, the average fourth grade reading scores were 17 points above the national average. (4) According to the National Commission on Children, more than 70 percent of students ages 10 to 13, and more than 50 percent of students ages 14 to 17, would like to talk to their parents more about school and schoolwork. (5) Ninety-five percent of parents strongly agree that parental involvement is as important a factor as quality of teachers in ensuring student success in school, and 69 percent of parents believe that in order to improve public schools, more opportunities for parental involvement are necessary. (6) Of the 800 parents questioned under the National Parent Teacher Association's 1998 survey of public school parents, more than half stated that low levels of parental involvement and the inability of schools to keep parents informed are serious problems. (7) Teachers rank strengthening parental roles in their children's education as an important issue that should receive the highest priority in the formulation of public education policy over the next few years. SEC. 3. GRANT PROGRAM. (a) In General.--Title I of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6301 et seq.) is amended by adding at the end the following new part: ``PART G--PARENTAL INVOLVEMENT ``SEC. 1701. PARENTAL INVOLVEMENT GRANT PROGRAM. ``(a) In General.--In accordance with this section, the Secretary may make grants to elementary schools or secondary schools to promote the involvement of parents in the education of their children. ``(b) Use of Funds.--Each school receiving a grant under this section may use the proceeds of such grant only-- ``(1) for educational or outreach materials or resources designed to increase parental involvement in their children's education; or ``(2) to pay the salary or benefits of an individual who is an eligible parent liaison as described in subsection (c). ``(c) Eligible Parent Liaisons.--For the purposes of this section, an individual shall be an eligible parent liaison if the individual is employed by the school to be a parent liaison and meets each of the following criteria: ``(1) The individual holds a degree in social work, counseling, psychology, human resources, or any other field that the school considers relevant to performing the functions described in paragraph (3). ``(2) The individual is bilingual or multilingual, if appropriate for the needs of the school. ``(3) The individual is responsible for-- ``(A) facilitating communication between the school's teachers and the parents of the school's students, especially parents who have limited English proficiency; ``(B) if national or State tests or assessments are conducted at the school, explaining to such parents how such tests or assessments work and what the results mean; and ``(C) if the school provides report cards, explaining to such parents what such report cards mean. ``(4) The individual maintains a flexible schedule that allows the individual to perform the functions described in paragraph (3) while accommodating the needs of working parents. ``(d) Application.-- ``(1) In general.--Each school seeking a grant under this section shall submit to the Secretary an application that includes-- ``(A) a description of the school's student population, including information on the socioeconomic status and the English-speaking ability of the students; ``(B) a plan describing how the school seeks to increase parental involvement at the school, including information on-- ``(i) the number of eligible parent liaisons the school plans to employ; ``(ii) the activities the school plans to conduct to increase parental involvement; and ``(iii) the materials or resources that the school plans to acquire to increase parental involvement; and ``(C) a description of how the school will evaluate the materials and resources acquired, and the success of the activities carried out, with the grant. ``(2) Parental input.--Each application submitted under this paragraph (including the plan described in paragraph (1)(B)) shall be developed with the input of parents of students at the school submitting the application. ``(e) Selection Criteria.--In making grants under this section, the Secretary shall give preference-- ``(1) to schools that have a large percentage of students whose parents have limited English proficiency; and ``(2) to schools at which the involvement of parents in the education of their children has traditionally been low. ``(f) Parental Involvement in Hiring Decisions.--As a condition of the receipt of funds made available under this section, the Secretary shall require that each school receiving such funds involve each of the following when making a hiring decision with respect to an eligible parent liaison hired with such funds: ``(1) The parents of the students at the school. ``(2) Any local parent organization active in the affairs of the school.''. (b) Authorization of Appropriations.--Section 1002 of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 6302) is amended by adding at the end the following new subsection: ``(h) Parental Involvement.--There is authorized to be appropriated to carry out part G $100,000,000 for fiscal year 2002.''.

Parental Involvement Enhancement Act - Amends the Elementary and Secondary Education Act of 1965 to establish a Parental Involvement grant program. Authorizes the Secretary of Education to make such grants to elementary and secondary schools. Allows use of such grant funds only for: (1) educational or outreach materials or resources designed to increase parental involvement in their children's education; or (2) the salary or benefits of an individual who is an eligible parent liaison. Requires the Secretary, in making such grants, to give preference to: (1) schools with a large percentage of students whose parents have limited English proficiency; and (2) schools at which the involvement of parents in the education of their children has traditionally been low. Requires grantee schools to involve students' parents and parent organizations in hiring decisions regarding eligible parent liaisons.

the recurrent laryngeal nerve ( rln ) injury during surgeries on thyroid and parathyroid remains the most significant commonly found complication of endocrine surgery in the neck , and it can result in significant morbidity including temporary or permanent paralytic dysphonia and dysphagia . rates of nerve injury published in the literature typically range from 1% to 2% and are significantly higher for re - operation . it has long been accepted that anatomic identification of both the rln and the external branch of the superior laryngeal nerve ( ebsln ) is the safest way to reduce nerve injury rates to a minimum and certainly injury rates are lowest when surgery is carried out by experienced endocrine surgeons or thyroid surgeons in specialized centers with high caseloads . nonetheless , identification and preservation of the rln an anatomically intact nerve may still show altered function postoperatively due to multiple factors , such as neural stretch during goiter retraction . the study group comprised of forty - seven patients who underwent thyroid or parathyroid surgery at tulane university medical center from october of 2007 to april of 2009 . the protocol for assessment of the laryngeal nerves included routine preoperative and postoperative laryngoscopy at one to two weeks . stroboscopy and electromyography ( emg ) assessment were not used in this study . a standard mivat / p gasless approach to the thyroid gland was performed under general anesthesia . the surgeon stands at the lesion side , the camera operator on the other side , and an assistant at the patient 's head . all vessel ligation during the procedure was done using the harmonic scalpel ( ethicon , nj ) . additionally , the harmonic scalpel was also used to divide the isthmus in lobectomies , to isolate the gland from the trachea . after routine attempted anatomical observation of the rln , stimulation of the nerve was done with a hand - held nerve stimulator with either the medtronic varistim iii nerve stimulator ( medtronic inc . , minneapolis , mi , usa ) or the nervona system ( nervona , ca , usa ) at currents of 1 to 2 ma on completion of dissection [ 2 , 5 ] . the rln was stimulated at the most proximal exposed site of the nerve ( figure 1 ) . data for continuous variables are expressed as median and range , unless specified otherwise . the outcome measures primarily the morbidity and mortality . a total of seventy - seven nerves in forty - seven patients were included in this study . there were twenty - three total thyroidectomies ( 48.9% ) , nineteen hemithyroidectomies ( 41.3% ) , 10.6% and ten parathyroidectomies ( 10.6% ) . out of seventy - seven rlns , there was one permanent unilateral rln injury ( 1.29% ) in a patient with advanced papillary thyroid cancer managed by postoperative cord injection . no hemorrhage or cervical hematoma was observed , and none of our cases developed wound infection ( figure 2 ) . one of the most common operations throughout the world is thyroidectomy , and it has a low morbidity rate if performed by skilled surgical teams . conventional thyroidectomy requires a transverse cervical incision that leaves a visible scar on the anterior surface of the neck . the application of minimally invasive techniques for thyroid surgery was primarily motivated by the attempt to improve the cosmetic result of this operation . the aesthetic point of view is particularly important for young women , who constitute a large part of patients affected by thyroid diseases . most mivat / p allows for a prompt postoperative recovery and is performed as an outpatient procedure in some clinical settings . it has been recently demonstrated that endoscopic and video - assisted [ 911 ] procedures for thyroid and parathyroid surgery have some advantages over conventional methods of surgery in terms of not only cosmetic results but also analgesic requirements and postoperative recovery . on the other hand , it should be pointed out that these procedures are not easy or feasible in all clinical settings . they are technically demanding and require a surgical team skilled in both endocrine and endoscopic surgery . the endoscopic and video - assisted procedures require learning and a training period that can be time consuming , especially at the beginning of the experience . however , with training , learning , and experience , along with the continuous development in scientific medical technologies , mivat / p will be done in more centers and more candidates will be qualified for these kinds of surgeries . the recurrent branch of the laryngeal nerve ( rln ) innervates all of the laryngeal muscles except the cricothyroid muscle , which regulates the tension of the vocal cords and is innervated by the external branch of superior laryngeal nerve . if damage to the rln is unilateral , the patient may present with voice changes including hoarseness . bilateral nerve damage can result in breathing difficulties and aphonia , the inability to speak . the right recurrent laryngeal nerve is more susceptible to damage during thyroid surgery due to its relatively medial location . the nerve injury in this series was on the right side . such anomalies include nonrecurrence of the rln , rln displacement by thyroid nodularity or paratracheal lymphadenopathy , extralaryngeal branching of the rln , and variations of the nerve course in relation to the inferior thyroid artery and ligament of berry . in a recent analysis of rln anatomy in 491 thyroid surgery cases , 60.8% of rlns were found in the expected tracheoesophageal groove position , whereas 4.9% were lateral and 28.3% were posterior to the trachea . of greatest concern are those cases where the rln is found on the anterior surface of the thyroid gland , a particularly high - risk area for nerve injury . the surgical importance of this nerve relates to its proximity to the superior thyroid vessels . to preserve the rln , most surgeons tend to avoid rather than expose the nerve , suggesting selective ligation of the upper pedicle vessels . miccoli and colleagues introduced the minimally invasive video - assisted thyroidectomy procedure in 1998 . during mivat /p , most surgeons do not use ionm to search for the rln . in our series consisting of forty - seven operations , we were able to visualize the rln in 100% of the cases . among these , the nerve ran entirely medial and separate to the superior thyroid artery in most of the patients . ionm of the rln during thyroid and parathyroid surgeries has been claimed in some studies to reduce the rate of nerve injury [ 15 , 16 ] ; however , other studies have shown it to be of no benefit and no reduction in the risk of rln injury [ 1720 ] compared with anatomic identification . however , hermann et al . showed that ionm could be useful in identifying the rln especially when anatomically altered by prior surgery or large masses . numerous studies have shown that only routine exposure of the rln is associated with very low rates of injury in high - volume centers ( less than 0.3% ) . during mivat / p , the surgical incision is really small in most cases to allow palpation of the nerve or the larynx as methods of identification . in our institution , we have been using ionm as a method of rln identification during mivat / p operations . now we are reporting our experience retrospectively . at the beginning of implementing both technologies together , we hypothesized that this method of monitoring the rln would decrease / prevent the risk of iatrogenic injury with lesser risk to the patient . our initial clinical results were very promising showing that the use of ionm is easy and feasible in mivat / p , and it was rather safe with no intraoperative complications or conversion to traditional open approach . though the operating space in these kinds of endoscopic surgeries is relatively narrow , there was no difficulty using the ionm simulator probe . the tip of the monopolar probe is flexible , which helped the surgeon to go beyond the view of his field . the rln may get injured while it still looks intact without the nerve being actually cut . this can be caused by different sorts of injuries , which include , but are not limited to , traction , pressure , ischemia , ligation , crush , electrical or suction injury [ 23 , 24 ] . the role of ionm is not only during surgical dissection . its role extends after the operation as it can help detect how the rln is functioning at the end of the procedure . this provides the opportunity to stage contralateral surgery in case of suspected rln injury , thus avoiding the risk of rln injury bilaterally . we also would like to mention that in our experience , we never had device failure or any unexpected events with the use of ionm during mivat / p . our experience of ionm with mivat / p showed that ionm could be a very useful adjunctive method for rln identification besides endoscopic visualization and magnification . this possibly will decrease rln injury and improve the quality and outcomes of mivat / p operations . kern discussed an important point that nerve monitoring during surgeries can possibly decrease the medico - legal liability . however , the literature needs a study with a wider scale of patients to accurately prove our citations . to show a decrease in rln paralysis rates from 2% to 1% per nerves at risk , a study group of approximately 1,000 patients would be necessary . standardization of the technique and wider availability of these technologies in centers performing these kinds of operations would be of great benefit .

objective . our goal is to study the feasibility of using intraoperative neuromonitoring ( ionm ) in minimally invasive video - assisted thyroidectomy and parathyroidectomy ( mivat / p ) with emphasis given to the identification of recurrent laryngeal nerve ( rln ) . methods . consecutive series of forty - seven patients with seventy - seven recurrent laryngeal nerves at risk undergoing both mivat / p and ionm were enrolled in this retrospective , nonrandomized analysis study . all operations were performed by the same surgeon within an academic institution setting . all patients underwent vocal cord evaluation postoperatively . demographics and intraoperative and postoperative complications following surgery were collected . results . out of seventy - seven rlns , there was one permanent unilateral rln injury ( 1.29% ) in a patient with advanced papillary thyroid cancer , managed by cord injection . there was another transient rln paresis that resolved spontaneously ( 1.29% ) . there were no instances of equipment malfunction or interference . conclusions . to our knowledge , this is the first reported mivat / p series from the united states of america with a standardized ionm technique . the technical feasibility of ionm seems acceptable and may serve as a meaningful adjunct to the visual identification of nerves . neuromonitoring during mivat / p is effective in providing identification of laryngeal nerves and enables surgeons to feel more comfortable with mivat / p . comparative series are needed for further evaluation .

merging ( or inspiralling ) dns systems are one of the prime targets for ground - based gravitational - wave ( gw ) interferometers such as geo600 , tama , virgo , and ligo ( the laser interferometer gravitational - wave observatory ) @xcite . event rates of the dns inspiral searches by these detectors can be inferred using the rate estimates with an extrapolation out to the maximum detection distances for any detector under consideration . before 2003 , the galactic dns merger rate had been estimated between @xmath4 yr@xmath2 ( see kalogera et al . 2001 and references therein ) . at that time , there were only two systems available for empirical studies , psrs b1913 + 16 @xcite and b1534 + 12 @xcite . we calculated the pdf of galactic dns merger rates , @xmath5 , based on these two systems ( see kim et al . 2003 , hereafter kkl , for further discussions ) . soon after the discovery of the highly relativistic system psr j0737@xmath33039 , we were able to revise @xmath5 including psr j0737@xmath33039 in collaboration with the observation team@xcite . the discovery of j0737@xmath33039 , resulted in a significant increase in the estimated galactic dns by a factor of @xmath06 . this implies a boost in event rates for dns searches for gw interferometers . in this paper , we present our recent results on : ( i ) the pdf of galactic dns merger rate estimates with updated observations ; ( ii ) the _ global _ pdf of rate estimates considering the systematic uncertainties ; ( iii ) constraints on upper limits for rate estimates based on the observed supernova rate incorporated with our theoretical understanding of the sn - dns relation ; ( iv ) the approximate contribution of j1756@xmath32251 to the galactic dns merger rates and uncertainties in our assumptions on the efficiency of the acceleration searches for parkes multibeam pulsar survey ( pmps ) . finally , we discuss implications of the most recently discovered pulsar binary j1906 + 0746 @xcite . here , we describe the main components of the calculation of the combined @xmath6 considering the three observed dns systems in the galactic disk . the merger rate of a given population _ i _ can be defined by @xmath7 where @xmath8 represents the number of pulsars in our galaxy with pulse and orbital characteristics _ similar _ to an observed sample _ ( e.g. psr j0739@xmath33039 ) and @xmath9 is a correction factor to take into account pulsar beaming ( typically @xmath10 ) . @xmath11 is the lifetime of system _ i _ based on its observed properties . in order to calculate @xmath8 , we distribute a large population of pulsars _ all _ similar to the system _ i _ , in a model galaxy assuming spatial and luminosity distributions . since pulsar luminosities are drawn from a distribution , the observed flux and estimated distance for the dns system are not relevant in our calculation . moreover , the selection effects for faint pulsars are implicitly taken into account . once we generate a pulsar population with a size @xmath12 , we can then calculate the number of pulsars detected ( @xmath13 ) by large - scale pulsar surveys . we repeat the survey simulations with a detailed modeling of selection effects for observed dns systems . for a fixed @xmath12 , we find that @xmath13 follows a poisson distribution , p(@xmath14 ) , where @xmath15 is a mean value of @xmath13 for a given population size ( @xmath12 ) . we require @xmath16 , i.e. , we consider only one observed system , and calculate the best - fit value of @xmath15 . with a wide range of @xmath12 , we find @xmath17 as expected where c is a constant . applying bayes theorem to these results , we calculate a p(@xmath12 ) , a pdf for the population size of a given system _ i _ knowing that there is one observation . the calculation @xmath5 from @xmath18 is straightforwad , and the full derivation and formula can be found in appendix a of kim et al . ( 2004 ) . the lifetime of a dns system is defined by @xmath19 , where @xmath20 is the spin - down age of a recycled pulsar @xcite and @xmath21 is the remaining lifetime until the two neutron stars merge @xcite . based on the most recent observations , we estimate the lifetime of j0737@xmath33039 to be @xmath0230myr @xcite . this is the shortest among the three observed systems . the beaming correction factor @xmath22 is defined as the inverse of the fractional solid angle subtended by the pulsar beam . its calculation requires detailed geometrical information on the beam . following kalogera et al . ( 2001 ) and updating the values with recent observations , we calcualte @[email protected] for psr b1913 + 16 @xcite and @xmath06.0 for psr b1534 + 12 @xcite without good knowledge of the geometry of j0737@xmath33039 , we assume @xmath23 to be the average value of the other two systems ( @xmath24 ) . is shown on a log scale . the thick solid line is the galactic rate estimate overlapped with results for individual observed systems ( dashed lines ) . dotted lines indicate confidence intervals for the rate estimates . the same results are shown on a linear scale in the small inset . all results are from our reference model.,width=275 ] in fig . 1 , we show @xmath6 for a reference model ( model 6 in kkl ) . we obtain the most likely value of @xmath25 , larger by a factor of @xmath26 than the rate estimated before the discovery of j0737@xmath33039 . the increase factor is found similar for all pulsar population models we examined . the increased merger rates imply a boost in the inferred detection rate of gws from dns inspirals for ground - based gw interferometers such as ligo . in order to calculate the detection rate ( @xmath27 ) , we assume a homogeneous distribution of galaxies in nearby universe and a spherical symmetry in detector sensitivity . then , we can write @xmath28 , where @xmath29 is the number of galaxies in the detection volumne ( @xmath30 ) . we calculate the number density of galaxies derived by the observed blue luminosity density , ( @xmath31myr@xmath32 ( see phinney ( 1991 ) and kalogera et al . ( 2001 ) for more details ) . the detection volume of ligo can then be defined as a sphere for a given detection distance ( 20 mpc and 350 mpc for the inital and advanced ligo , respectively ) , and the number of galaxies within @xmath30 is simply @xmath33 . for our reference model , we find that the most probable event rates are about 1 per 30yrs and 1 per 2 days , for initial and advanced ligo , respectively . at the 95% confidence interval , the most optimistic predictions for the reference model are 1 event per 9yrs and 1.6 events per day for initial and advanced ligo , respectively . more details can be found in kalogera et al . ( 2004 ) . as shown in the fig . 1 , the galactic dns merger rate is dominated by psr j0737@xmath33039 . recently , lorimer et al . ( 2005a ) suggested that the current age of j0737@xmath33039 is @xmath34 myr . this implies a even shorter lifetime ( @xmath35 myr ) knowing that the estimated merger timescale of this system is @xmath085 myr . based on their results , we find the most likely value of @xmath36 for the reference model is @xmath37myr@xmath2 . the beaming correction for j0737@xmath33039 is not yet constrained and we assume msps discovered in dns systems are not very different . as a conservative lower limit , without any beaming corrections for all observed systems for a reference model , we obtain @xmath38 myr@xmath2 with a 95% confidence interval . the corresponding detection rates for initial and advanced ligo are @xmath39 yr@xmath2 and @xmath40 yr@xmath2 , respectively . only when the axis geometry of j0737 - 3039 becomes available , we will be able to constrain the uncertainties of the beaming fraction , and in turn , the rate estimates . in kkl , we showed that empirical dns merger rates are strongly dependent on the assumed luminosity distribution function for pulsars , but not on the pulsar spatial distribution . therefore , we can consider only the rate dependence on the pulsar luminosity function for simplicity . here , we describe how we can incorporate the systematic uncertainties from these models and calculate , @xmath41 , a _ global _ pdf of rate estimates . note that the results available on prior functions for pulsar luminosity distribution are currently out of date . specific quantitative results could change when constraints on the luminosity function are derived from the current pulsar sample . we assume a power - law luminosity distribution for a radio pulsar luminosity function @xmath42 . this function is defined by two parameters : the cut - off luminosity @xmath43 and power - index @xmath44 . we assume prior distributions for these two parameters and calculate @xmath45 . we fit the marginalised likelihood of @xmath43 and @xmath44 presented by @xcite and obtain the following analytic formulae for prior functions , i.e. @xmath46 and @xmath47 : @xmath48 and @xmath49 , where @xmath50 and @xmath51 are coefficients we obtain from the least - square fits and the functions are defined over the intervals @xmath52 $ ] mjy kpc@xmath53 and @xmath54 $ ] . we note that , although cordes and chernoff ( 1997 ) obtained @xmath46 over @xmath55 $ ] mjy kpc@xmath53 centered at 1.1 mjy kpc@xmath53 , we consider @xmath46 with a peak at @xmath56mjy kpc@xmath53 considering the discoveries of faint pulsars with l@xmath57 below 1 mjy kpc@xmath53 @xcite . next we calculate @xmath45 as follows : @xmath45 + @xmath58 . on a linear scale ( lower panel ) and the assumed intrinsic distributions for @xmath43 and @xmath44 ( upper panels ) . dotted lines represent the lower ( @xmath59 ) and upper ( @xmath60 ) bounds on the observed sn ib / c rate scaled by 5% of the observed sn ib / c rates , @xmath61 myr@xmath2 ( see text).,width=275 ] in fig . 2 , we show the distributions of @xmath43 and @xmath44 adopted ( top panels ) and the resulting global distribution of galactic dns merger rate estimates ( bottom panel ) . we find the peak value of @xmath45 at _ only _ around 13myr@xmath2 . we note that this is a factor @xmath62 smaller than the result from the reference model ( @xmath6371myr@xmath2 ) . at the 95% confidence interval , we find that the _ global _ galactic dns merger rates lie in the range @xmath0 1145myr@xmath2 . these imply ligo event rates in the range @xmath64yr@xmath2 ( initial ) and @xmath65yr@xmath2 ( advanced ) . since 1997 , the number of known millisecond pulsars has more than doubled , and therefore , constraints on @xmath43 and @xmath44 and their pdfs based on the most up - to - date pulsar sample are urgently needed . according to the standard binary evolution scenario , the progenitor of the second neutron star is expected to form during a type ib / c supernova . therefore , the empirical estimates for the type ib / c sn rate in our galaxy can be used to set upper limits on the dns merger rate estimates . based on cappellaro et al . ( 1999 ) , we adopt @xmath66myr@xmath2 considering sbc sd galaxies , a hubble constant @xmath67km / s / mpc and the blue luminosity of our galaxy @xmath68 . we calculate the fraction of sn ib / c actually involved in the formation of dns with a binary evolution code startrack @xcite and estimate the rate ratio : @xmath69/@xmath70 . motivated by this result , we adopt the empirical @xmath71 assuming @xmath72 and compare the value with the global pdf ( fig . [ cols= " < , > , > , < , < , < " , ] @xmath73 pulsar spin period + @xmath74 orbital period + @xmath75 eccentricity + @xmath76 lifetime of a system + @xmath77 population size for a given dns system + @xmath78 approximate @xmath79 . results depend on the survey modeling ( see text ) . + @xmath80 the nature of the companion is not yet clear . @xmath80 @xmath81 where @xmath82 is a death - time of the pulsar . + we note that our most optimistic dns merger rate is @xmath83 myr@xmath2 at a 95% confidence interval ( model 15 in kkl ) . we obtain @xmath84 with respect to the center value of the empirical sn type ib / c rate ( @xmath85 myr@xmath2 ) and the upper limit of @xmath86 at the 95% confidence interval ( @xmath87 myr@xmath2 ) . this corresponds to @xmath88 for a sn type ii rate , which is factor 6.1 larger than that of sn type ib / c . in both cases , the most optimistic model is lower than the current empirical supernova rate estimates , but not really consistent with the results of population synthesis calculations . if we consider a upper limit of @xmath86 at the 95% confidence interval from the global pdf , we obtain @xmath89 13% and 2% for the center value of sn type ib / c ( 1100 myr@xmath2 ) and ii , respectively . recently , faulkner et al . ( 2005 ) discovered psr j1756@xmath32251 , the 4th merging dns in the galactic disk from the parkes multibeam pulsar survey ( pmps ) . the standard fourier method failed to find this pulsar and they reanalysed the pmps data with an acceleration search ( or a ` stack search ' as described in their paper ) . in order to calculate the merger rate including psr j1756@xmath32251 , a detailed simulation is necessary to calculate the effect of the acceleration search with the pmps . however , the approximate contribution of psr j1756@xmath32251 to the galactic merger rate can be easily obtained . we find the total rate increases by only @xmath90 due to the new discovery . this is expected because psr j1756@xmath32251 can be identified as a member of the b1913 + 16-like population , which has already been taken into account in the calculation . only future detections of pulsars from a significantly different population ( compared to the known systems ) , or from the most relativistic systems , will result in a non - trivial contribution to the rate estimates . finally , we note the implications of j1906 + 0746 on the pulsar binary merger rates . this system has drawn attention due to the extremely young age of the pulsar ( characteristic age of @xmath0 112 kyr ; lorimer et al . if the companion is another neutron star , j1906 + 0746 would be the first discovery of a non - recycled component in a dns system . currently , the nature of the companion is totally unknown , and it can be either a light neutron star , or heavy ( o - mg - ne ) white dwarf . assuming j1906 + 0746 is a dns system , we calculate its contribution to the galactic merger rate . because of its short lifetime ( @xmath082myr ) , j1906 + 0746 can increase the galactic dns merger rate by about a factor 2 . this implies that the current estimated dns merger rate including j0737@xmath33039 can still be doubled ! if j1906 + 0746 is an eccentric ns wd system , such as j1141 - 6545 @xcite or b2303 + 46 @xcite , it will be as important as j1141 - 6545 , which is currently dominate the birthrate of eccentric ns - wd binaries . in table 1 , we summarize some important properties of observed merging dns systems , which used in the calculation of @xmath91 in this paper . we summarize our results on the galactic merger rate of double neutron stars ( dns ) in view of the recent discovery of psr j0737 - 3039 . we update the results based on the most recent observations . global _ pdf of rate estimates incorporates the already known systematics due to the radio pulsar luminosity function . the most likely value obtained from the global distribution is at only @xmath0 13 myr@xmath2 , and a reanalysis of the _ current _ pulsar sample and radio luminosities is needed for a reliable assessment of the best fitting distribution . the dns merger rate can be constrained by empirical type ib / c supernova rates , and we compare the supernova rate with the global pdf . recent discoveries of relativistic systems , such as j1756@xmath32251 and j1906 + 0746 are important for the reduction of the uncertainties associated with the empirical rate estimates . as for j1756@xmath32251 , we expect their contribution to the galactic dns merger rate is negligible , and this pulsar can be seen another sample of b1913 + 16-like population . it is not clear whether the companion of j1906 + 0746 is a neutron star or a white dwarf . this system may increase the estimated merger rate of the relevant population by a factor of 2 whether it is a dns or another eccentric ns - wd binary . this research is partially supported by nsf grant 0353111 , and a packard foundation fellowship in science and engineering to vk . drl is a university research fellow supported by the royal society .

we present the current estimates of the galactic merger rate of double - neutron - star ( dns ) systems . using a statistical analysis method , we calculate the probability distribution function ( pdf ) of the rate estimates , which allows us to assign confidence intervals to the rate estimates . we calculate the galactic dns merger rate based on the three known systems b1913 + 16 , b1534 + 12 , and j0737 - 3039 . the discovery of j0737 - 3039 increases the estimated dns merger rate by a factor @xmath06 than what is previously known . the most likely values of dns merger rate lie in the range @xmath1 myr@xmath2 depending on different pulsar models . motivated by a strong correlation between the peak rate estimates and a pulsar luminosity function , we calculate a _ global _ probability distribution as a single representation of the parameter space covered by different pulsar population models . we compare the global pdf with the observed supernova ib / c rate , which sets an upper limit on the dns merger rate . finally , we remark on implications of new discoveries such as of j1756@xmath32251 , the 4th dns in the galactic disk , and j1906 + 0746 , a possible dns system . method : statistical ; stars : binary ; pulsars : individual ( psr j0737 - 3039 ) ; gravitational waves

SECTION 1. SHORT TITLE. This Act may be cited as the ``Dirty Bomb Prevention Act''. SEC. 2. RADIATION SOURCE PROTECTION. (a) Amendment.--Chapter 14 of the Atomic Energy Act of 1954 (42 U.S.C. 2201 et seq.) is amended by adding at the end the following new section: ``Sec. 170C. Radiation Source Protection.-- ``a. Task Force on Sealed Source Protection.-- ``(1) Establishment.--There is hereby established a task force on sealed source protection. ``(2) Membership.--The task force shall be headed by the Chairman of the Commission or his designee. Its members shall be the following: ``(A) The Secretary of Defense or his designee. ``(B) The Secretary of Transportation or his designee. ``(C) The Attorney General or his designee. ``(D) The Secretary of State or his designee. ``(E) The Director of the Central Intelligence Agency or his designee. ``(F) The Director of the Federal Emergency Management Agency or his designee. ``(G) The Director of the Federal Bureau of Investigation or his designee. ``(H) The Homeland Security Officer or his designee. ``(3) Duties.-- ``(A) In general.--The task force, in consultation with other State, Federal, and local agencies and members of the public, as appropriate, shall evaluate and provide recommendations to ensure the security of sealed sources from potential terrorist threats, including acts of sabotage, theft, or use of such sources in a radiological dispersal device. ``(B) Recommendations to congress and the president.--Not later than 180 days after the date of the enactment of this section, and not less than once every 3 years thereafter, the task force shall submit a report to Congress and to the President, in unclassified form with a classified annex if necessary, providing recommendations, including recommendations for appropriate regulatory and legislative changes, for-- ``(i) the establishment of or modifications to a classification system for sealed sources based on their potential attractiveness to terrorists and the extent of the threat to public health and safety, taking into account sealed source radioactivity levels, dispersability, chemical and material form, and other factors as appropriate; ``(ii) the establishment of or modifications to a national system for recovery of sealed sources that have been lost or stolen, taking into account the classification system established under clause (i); ``(iii) the storage of sealed sources not currently in use in a safe and secure manner; ``(iv) the establishment of or modification to a national tracking system for sealed sources, taking into account the classification system established under clause (i); ``(v) the establishment of or modifications to a national system to impose fees to be collected from users of sealed sources, to be refunded when the sealed sources are returned or properly disposed of, or any other method to ensure the return or proper disposal of sealed sources; ``(vi) any modifications to export controls on sealed sources necessary to ensure that foreign recipients of sealed sources are able and willing to control United States-origin sealed sources in the same manner as United States recipients; ``(vii) whether alternative technologies are available that can perform some or all of the functions currently performed by devices that employ sealed sources, and if so, the establishment of appropriate regulations and incentives for the replacement of such devices with alternative technologies in order to reduce the number of sealed sources in the United States; and ``(viii) the creation of or modifications to procedures for improving the security of sealed sources in use, transportation, and storage, which may include periodic Commission audits or inspections to ensure that sealed sources are properly secured and can be fully accounted for, Commission evaluation of security measures, increased fines for violations of Commission regulations relating to security and safety measures applicable to licensees who possess sealed sources, background checks for certain individuals with access to sealed sources, assurances of the physical security of facilities that contain sealed sources, and the screening of shipments to facilities particularly at risk for sabotage of sealed sources to ensure that they do not contain explosives. ``b. Commission Actions.--Not later than 60 days after receipt by Congress and the President of the report required under subsection a.(3)(B), the Commission, in accordance with the recommendations of the task force, shall take any appropriate actions, including commencing revision of its system for licensing sealed sources, and shall take necessary steps to ensure that States that have entered into an agreement under section 274 b. establish compatible programs in a timely manner. ``c. National Academy of Sciences Study.--Not later than 60 days after the date of the enactment of this section, the Commission shall enter into an arrangement with the National Academy of Sciences for a study of industrial, research, and commercial uses for sealed sources. The study shall review the current uses for sealed sources, identifying industrial or other processes that utilize sealed sources that could be replaced with economically and technically equivalent (or improved) processes that do not require the use of radioactive materials. The Commission shall transmit the results of the study to Congress within 24 months after the date of the enactment of this section. ``d. Definition.--For purposes of this section, the term `sealed source' means any byproduct material or special nuclear material encased in a capsule designed to prevent leakage or escape of the material, except that such term does not include fuel or spent fuel.''. (b) Table of Sections Amendment.--The table of sections of the Atomic Energy Act of 1954 is amended by adding at the end of the items relating to chapter 14 the following new items: ``Sec. 170B. Uranium supply. ``Sec. 170C. Radiation source protection.''.

Dirty Bomb Prevention Act - Amends the Atomic Energy Act of 1954 to establish a task force on sealed source protection (byproduct material or special nuclear material encased in a capsule designed to prevent leakage or escape of the material).Requires the task force to evaluate and make recommendations to ensure the security of sealed sources from potential terrorist threats, including acts of sabotage, theft, or use of such sources in a radiological dispersal device.Directs the Nuclear Regulatory Commission to arrange with the National Academy of Sciences for a study of industrial, research, and commercial uses for sealed sources.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Public Safety Ex-Offender Self- Sufficiency Act of 2003''. SEC. 2. TEMPORARY EX-OFFENDER LOW-INCOME HOUSING CREDIT. (a) In General.--Subpart D of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 is amended by adding at the end the following new section: ``SEC. 45G. EX-OFFENDER LOW-INCOME HOUSING CREDIT. ``(a) In General.--For purposes of section 38, the amount of the ex-offender low-income housing credit determined under this section for any taxable year in the credit period shall be an amount equal to-- ``(1) the applicable percentage of ``(2) the qualified basis of each qualified ex-offender residential building. ``(b) Applicable Percentage.--In the case of any qualified ex- offender residential building, the term `applicable percentage' has the meaning given such term in section 42(b)(2) with respect to qualified low-income buildings, except that, for the purposes of this subsection, the percentages prescribed by the Secretary under section 42(b)(2)(B) shall yield amounts of credit which have a present value equal to 70 percent of the qualified basis of any qualified ex-offender residential building. ``(c) Qualified Basis.-- ``(1) In general.--For purposes of subsection (a) and except as otherwise provided in this subsection, the term `qualified basis' means the adjusted basis of a qualified ex- offender residential building as of the close of the 1st taxable year of the credit period. ``(2) Qualified basis to include portion of building used to provide ex-offender support services.--The qualified basis of any qualified ex-offender residential building for any taxable year shall be increased by the lesser of-- ``(A) so much of the qualified basis of such building as is used throughout the year to provide ex- offender support services, or ``(B) 20 percent of the qualified basis of such building (determined without regard to this paragraph). ``(3) Special rules.--Rules similar to the rules of paragraphs (4), (5) (other than subparagraph (A) thereof), and (7) of section 42(d) shall apply in determining the adjusted basis of any qualified ex-offender residential building. ``(d) Rehabilitation Expenditures.--Rules similar to the rules of section 42(e) shall apply in determining the treatment of rehabilitation expenditures paid or incurred by the taxpayer with respect to a qualified ex-offender residential building. ``(e) Credit Period.--For purposes of this section, rules similar to the rules of section 42(f) shall apply in determining the credit period with respect to any qualified ex-offender residential building. ``(f) Qualified Ex-Offender Residential Building.--For purposes of this section, the term `qualified ex-offender residential building' means any building which, at all times during the compliance period, meets the following requirements: ``(1) Ex-offender residential units.-- ``(A) In general.--Each residential unit in such building shall be made available for occupancy to not more than 1 ex-offender. ``(B) Residency requirements.--Such ex-offender must-- ``(i) meet the residency requirements under subsection (g); ``(ii) have failed to meet such requirements for fewer than 14 days; or ``(iii) be in the process of being evicted from such building for failing to meet such requirements. ``(C) Flexibility.--A building shall not be determined to fail to satisfy the requirements of this paragraph solely because-- ``(i) some or all of the residential units in such building are single room occupancy (as defined in section (8)(n) of the United States Housing Act of 1937 (42 U.S.C. 1437f(n))), or ``(ii) any unit made available to an ex- offender is also made available to one or more of the ex-offender's sons, daughters, step- sons, or step-daughters. ``(2) Self-sufficiency centers for ex-offenders.--The building shall include a self-sufficiency center for ex- offenders that-- ``(A) is specifically designed to accommodate, and reserved for, the provision of ex-offender support services to residents of the facility and other ex- offenders; ``(B) is made available for rental by providers of such services at a rate determined by the owner of the facility; and ``(C) provides an array of such services sufficient to meet a significant portion of the needs of ex- offenders for ex-offender support services. ``(3) Rent limitations.--The portion of the monthly rent payable by the occupant of each unit in the building may not exceed 30 percent of the adjusted monthly income (as such term is defined in section 3(b) of the United States Housing Act of 1937 (42 U.S.C. 1437a(b)) of the occupant. ``(g) Residency Requirements.-- ``(1) In general.--An ex-offender meets the residency requirements for a qualified ex-offender residential building if such ex-offender-- ``(A) has a low income; ``(B) is participating in an ex-offender support services program as described in paragraph (3)(B); ``(C) has not been prohibited from residency under paragraph (4); and ``(D) commences occupancy of a unit in a qualified ex-offender residential building on a date that is not later than-- ``(i) in the case of an ex-offender who has been discharged from prison, jail, a half-way house, or any other correctional facility, 12 months after such discharge; or ``(ii) in the case of any ex-offender whose sentence did not include confinement to a correctional facility, 12 months after the date of the ex-offender's conviction. ``(2) Low-income.--For purposes of this section, an ex- offender is considered to have a low income if, at the commencement of the ex-offender's occupancy of a residential unit, the income (if any) of the ex-offender does not exceed 60 percent of area median gross income (as determined consistent with section 8 of the United States Housing Act of 1937). ``(3) Participation in ex-offender support services program.-- ``(A) Program.--For purposes of this section, an ex-offender support services program is a program for the provision of specific ex-offender support services for an ex-offender that-- ``(i) is created and managed by a coordinating individual or entity having education, training, and experience with ex- offenders and their support services needs; ``(ii) is specifically designed to meet the needs of the particular ex-offender for ex- offender support services; ``(iii) sets forth a specific duration over which the ex-offender support services are to be provided and goals by which to assess the progress of the ex-offender; and ``(iv) provides for continual oversight to monitor the progress and needs of the ex- offender and to ensure that the ex-offender is being provided the appropriate ex-offender support services and is complying with the requirements of the program. ``(B) Participation.--For purposes of this section, an ex-offender is considered to be participating in an ex-offender support services program if the ex- offender-- ``(i) has entered into a written agreement with the coordinator for the program that-- ``(I) sets forth the ex-offender support services that are appropriate for, and will be made available to, the ex-offender and the duration of the program for the ex-offender; and ``(II) provides that the ex- offender's continued attendance at scheduled program meetings and events and obtaining of program services are a condition of the ex-offender's continued residency in the facility; and ``(ii) is not in default with regard to the ex-offender's obligations under such agreement. ``(C) Ex-offender support services.--For purposes of this section, the term `ex-offender support services' means services that assist ex-offenders to develop skills necessary for life outside of the environment of a correctional institution, and includes-- ``(i) job training; ``(ii) employment counseling and placement; ``(iii) entrepreneurial training; ``(iv) financial management training; ``(v) homeownership and rental counseling; ``(vi) drug and alcohol abuse counseling; ``(vii) self-esteem and peer development assistance; ``(viii) anger management counseling; ``(ix) health care services, including mental health services and behavioral counseling; ``(x) probation services; ``(xi) family and crisis management counseling; and ``(xii) general educational assistance and counseling. ``(4) Limitation on term of residency.--An ex-offender may not reside in an ex-offender residential facility at any time after the expiration of the 2-year period beginning upon the commencement of the ex-offender's occupancy in the ex-offender residential facility. ``(h) Ex-Offender.--For purposes of this section, the term `ex- offender' means any individual who has been convicted of a crime under State or Federal law which is punishable by imprisonment for a maximum term of 6 months or longer. ``(i) Allocation and Determination of Credit.-- ``(1) In general.--Except as otherwise provided in this subsection, rules similar to the rules of section 42(h) (other than subparagraphs (E) and (F) of paragraph (1) thereof) shall apply with respect to allocating and determining any credit under this section. ``(2) State housing credit ceiling.--For purposes of this section: ``(A) In general.--The State housing credit ceiling shall be calculated by substituting the amount determined under section 42(h)(3)(C)(ii) with the State allocation. ``(B) State allocation.-- ``(i) Competitive process.--The State allocation for any State shall be determined by the Secretary, utilizing a competitive application process. ``(ii) Basis for competition.--In determining the State allocation for any State, the Secretary shall consider the following: ``(I) Need, as determined by the ratio between the reported number of sentenced prisoners released from State or Federal jurisdiction in the applicant State during the most recent year for which information is available, and the total population of the applicant State. ``(II) The commitment of Federal and other funds within the applicant State for operating costs and ex- offender support services in projects that are to be funded by the State temporary ex-offender low-income housing credit. ``(III) The applicant's plan to collect available information about the success of the program with respect to increased housing stability and lack of additional incarceration of ex-offeder participants. ``(IV) The applicant's organizational capacity for the successful development or operation of qualified ex-offender residential buildings. ``(V) The goal of making allocations to the largest feasible number of States. ``(iii) Aggregate amount.--The aggregate amount of State allocations for any year shall be $85,000,000. ``(C) Building allocations.--The Secretary may allocate a housing credit dollar amount to any building. In making such allocations, the Secretary shall utilize a competitive application process and shall consider the factors described in subparagraph (B)(ii). Any allocation made under this subparagraph shall be treated for purposes of this subsection as part of the State allocation for the State in which such building is located. ``(D) Unused housing credit carryovers.-- ``(i) In general.--The State housing credit ceiling shall be calculated by substituting the amount determined under section 42(h)(3)(C)(iv) with the State carryover allocation. ``(ii) State carryover allocation.--The State carryover allocation for any State shall be determined by the Secretary in a manner similar to the manner in which the State allocation is determined under subparagraph (B). The aggregate amount of State carryover allocations for any year shall be equal to the aggregate unused housing credit carryovers (within the meaning of section 42(h)(3)(D)) of all States for the preceding calendar year. ``(4) Required involvement of qualified non-profit organizations.--For purposes of this section, section 42(h)(5)(A) shall be applied by substituting `0' for `90'. ``(j) Recapture of Credit.--Rules similar to the rules of subsections (i)(1) and (j) of section 42 shall apply for purposes of this section. ``(k) Application of At-Risk Rules.--Rules similar to the rules of section 42(k) shall apply for purposes of this section. ``(l) Certification and Other Reports to Secretary.--Subject to such regulations as the Secretary may prescribe, rules similar to the rules of section 42(l) shall apply for purposes of this section. ``(m) Responsibilities of the Secretary and Housing Credit Agencies.--Rules similar to the rules of subsections (m) and (n) of section 42 shall apply for purposes of this section.''. (b) Inclusion as Current Year Business Credit.--Section 38(b) of the Internal Revenue Code of 1986 is amended by adding at the end the following new paragraph: ``(13) the ex-offender low-income housing credit under section 45G(a).''. (c) Clerical Amendment.--The table of sections for subpart D of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 is amended by adding at the end the following new item: ``Sec. 45G. Ex-offender low-income housing credit.''. (d) Effective Date.--The amendments made by this section shall apply to property placed in service during taxable years beginning after the date of the enactment of this Act.

Public Safety Ex-Offender Self-Sufficiency Act of 2003 - Amends the Internal Revenue Code to allow a business related tax credit for investment in residential housing units for certain low-income individuals who were convicted of a crime punishable under state or federal law by a prison term of six months or longer (ex-offenders) and who participate in a program of support services, including job and entrepreneurial training, designed to make such ex-offenders self sufficient.

Breaking News Emails Get breaking news alerts and special reports. The news and stories that matter, delivered weekday mornings. / Updated By Elizabeth Chuck Ohio authorities released unnerving 911 calls Saturday that were placed from two of the four homes where eight family members were found dead a day prior. "There's blood all over the house! My brother-in-law's in the bedroom. It looks like someone has beat the hell out of him," a female caller who identifies herself as Bobbi breathlessly says in the first call. "There's blood all over the covers." Officials still have no one in custody in the killings, which happened in Piketon, a rural town east of Cincinnati. The manhunt intensified Saturday for a killer or killers after police interviewed 30 people overnight but made no arrests. The victims were all members of the Rhoden family, police said Friday. Seven were adults, the eighth was a 16-year-old boy. None died by suicide, authorities added. The victims were identified Saturday as: Hannah Gilley, 20; Christopher Rhoden, Sr., 40; Christopher Rhoden, Jr., 16; Clarence "Frankie" Rhoden, 20; Dana Rhoden, 37; Gary Rhoden, 38; Hanna Rhoden, 19; and Kenneth Rhoden, 44. Ohio Attorney General Mike DeWine said Saturday that work at the four crime scenes has been completed. Related: Eight Members of Ohio Family Dead in 'Execution-Style' Killings One victim was a young mom, murdered in bed as she lay with her 4-day-old newborn; the baby, plus two other children, escaped the slaughter. The first call was placed at 7:49 a.m., according to the audio, which was released by DeWine and Pike County Sheriff Charles Reader. The caller tells the 911 dispatcher she arrived to find the home locked, but knew where the key was, so she let herself in. Once inside, she saw her brother-in-law and another man "laying on the floor." "I think they’re both dead. Looks like someone has beat the (expletive) out of them," she said. The call is punctuated by her stopping to catch her breath and crying. The next call was placed at 1:26 p.m. at a different location from a man who identified himself as Kenneth Rhoden. "It's all that stuff that's on the news," he says. "I just found my cousin with a gunshot wound." When asked whether his cousin is alive, he responds, "No. No." This aerial photo shows one of the locations being investigated in Pike County, Ohio, as part of an ongoing homicide investigation, April 22. Lisa Marie Miller / The Columbus Dispatch via AP The first call lasted nearly two-and-a-half minutes. The second was under a minute and 40 seconds. The sheriff said "a specific family that has been targeted." Jeff Ruby, a Cincinnati-area restaurant owner, put up a $25,000 reward on Saturday for any information leading to an arrest, DeWine said. On Friday, DeWine said there could be multiple suspects. "There may be one, there may be two, there may be three, we just don't know," he said. "We're very early in this investigation." Other than the 4-day-old, a 6-month-old and a 3-year-old survived. On Saturday, a woman speaking on behalf of the Rhoden family thanked investigators and said the family had asked for prayers and for anyone with information to contact the state bureau of investigation. Piketon, which has a population of about 2,200, is about 95 miles east of Cincinnati. ||||| Ohio's Attorney General says marijuana grow operations were found at three of the four places where eight relatives were shot dead in "execution type" killings. Authorities did not provide further details. Attorney General Mike DeWine told ABC News earlier that authorities still do not have a suspect description or motive in the Friday killings, saying the suspect or suspects took several steps to cover up their tracks and remove any possible evidence that would help police track them down. He says authorities have received more than 100 tips so far and they are following up on all of them. "These were pre-planned, pre-meditated execution-type killings," DeWine told ABC News today. "Four different homes. A case like this is going to take some time." The victims were all members of the Rhoden family, officials said Saturday. They were identified as: Hannah Gilley, 20; Christopher Rhoden, Sr., 40; Christopher Rhoden, Jr., 16; Clarence "Frankie" Rhoden, 20; Dana Rhoden, 37; Gary Rhoden, 38; Hanna Rhoden, 19; and Kenneth Rhoden, 44. Seven of the victims were found in three homes along the same road in Peebles, a small village about 70 miles east of Cincinnati. The eighth victim was found later than the others in nearby Piketon, officials said. Some of the victims appeared to have been killed in their sleep and were found shot to death in their beds, DeWine said. One victim, who appeared to be a mother, was killed lying in bed with a 4-day-old baby, he said. Three young children -- the 4-day-old baby, a 6-month-old baby and a 3-year-old -- were found unharmed at the various shooting locations, said Pike County Sheriff Charles Reader. At a news conference this afternoon DeWine described the killings as "a sophisticated operation." "They thought this thing through," DeWine said. Cincinnati-area businessman Jeff Ruby has offered $25,000 for information that leads to the gunman's arrest, officials said Saturday. Investigators also released 911 calls that recorded family members finding their relatives dead inside their homes. One woman called 911, sounding frantic and out of breath, telling a dispatcher she had found blood throughout her brother-in-law's house. "I think my brother-in-law's dead," she said. "There's blood all over the house." She then said it looked like someone else was dead there, too, before weeping into the phone. In another 911 call, a man said: "I just found my cousin with a gunshot wound." "Is he alive?" the dispatcher asked. "No, no," the caller said. Sharon Fulton, the wife of a pastor at the Union Hill Church, said there was shock within the small community of Peebles, which had a population of 1,782 at the time of the 2010 census. "When one hurts, we all hurt," she said. ABC News' Alex Perez contributed to this report. Get real-time updates as this story unfolds. To start, just "star" this story in ABC News' phone app. Download ABC News for iPhone here or ABC News for Android here.

– The 911 calls came Friday, from two of the four Ohio homes where eight members of the Rhoden family lay dead in grisly execution-style murders: "There's blood all over the house! My brother-in-law's in the bedroom. It looks like someone has beat the hell out of him," a woman says in the first, at 7:49am, after she let herself into a locked house, per NBC News. "There's blood all over the covers." Kenneth Rhoden made the second call, around 1:30pm: "It's all that stuff that's on the news. I just found my cousin with a gunshot wound." Asked if the man is alive, Rhoden responds, "No, no." Police are still scrambling to find a suspect. "There may be one, there may be two, there may be three, we just don't know," says Ohio AG Mike DeWine. "We're very early in this investigation." A local restaurant owner has offered up a $25,000 reward leading to the suspects, notes ABC News. But the community of tiny Peebles is reeling. "It's sad," says the wife of a local pastor. "We know the grandparents ... they're around our age. ... What if that was my family? I don't know how they're handling this."

In El Salvador, Maria Teresa Rivera was convicted of aggravated homicide after experiencing an obstetrical emergency. She is scheduled to have a new day in court on May 11, when she will argue that there were judicial errors in her original trial. Rivera's sentence is the most extreme of "Las 17," a group of women in the country who have been imprisoned after obstetrical emergencies. Now, she is scheduled to have a new day in court on May 11, when she will argue that there were judicial errors in her original trial. Un flor por las 17 / YouTube In November 2011, Maria Teresa Rivera unexpectedly went into labor, giving birth in the latrine of her home. The birth was dangerous and unattended by any medical professionals; the fetus died. Like many women in El Salvador, where abortion is completely illegal, Rivera’s medical crisis led to her being charged with and convicted of aggravated homicide; she was sentenced in 2012 to 40 years in prison. Rivera’s sentence is the most extreme of “Las 17,” a group of women who have been imprisoned after obstetrical emergencies. Now, she is scheduled to have a new day in court on May 11, when she will argue that there were judicial errors in her original trial. If the judge rules in her favor, she will be freed from prison. Advocates say that her case could influence public sentiment about other similar cases around the country. With the support of the Agrupación Ciudadana por la Despenalización del Aborto, a Salvadoran feminist organization, Rivera has been fighting her case for several years, as reported earlier in Rewire. Along with the rest of Las 17, she requested a pardon from the Salvadoran government in 2014, but her request was denied. Appreciate our work? Rewire is a non-profit independent media publication. Your tax-deductible contribution helps support our research, reporting, and analysis. DONATE NOW “Rivera represents the maximum will of the state to criminalize women in this country,” Morena Herrera, president of the Agrupación, explained in an on-the-ground interview with Rewire. “Her sentence is the longest of any of the women with similar convictions; at 40 years, it is practically a life sentence.” Fortunate To Be Alive Maria Teresa Rivera, who shared her story on camera from prison in 2013, was a 28-year-old factory worker in 2011. She was living with her young son and his grandparents, her ex in-laws, in a very modest home in the outskirts of San Salvador. Rivera, the sole provider for the family, supplemented her factory work with house-cleaning in order to pay $13 a month to keep her son in a neighborhood Catholic school and purchase his asthma medication. One night, according to court documents, Rivera said she awoke with intense thirst. But when she arose from her bed, she felt dizzy and then fainted. When she regained consciousness, she felt a strong urge to defecate and went to the latrine outside the house. As she sat in the latrine, she had intense cramping and “felt as if a little ball fell from her body.” Then she fainted and fell to the ground, where her mother-in-law found her in a pool of blood and called an ambulance to take her to the hospital. No one at the scene—family or paramedics—reported hearing any sounds of a baby, and no one realized she had given birth. Rivera told doctors, attorneys, and others that did not know she was pregnant. She had been experiencing bleeding during the time of the pregnancy, which she interpreted as her menstrual cycle. Neither she nor any friends, relatives, or co-workers noted any physical changes that would indicate a pregnancy. She had also had two doctor visits for other complaints during those months, and no doctor had diagnosed her pregnancy. According to her own estimations, the last sexual contact she’d had that could have resulted in pregnancy had been six months earlier. She arrived at the hospital in a severe state of shock from extreme blood loss, fortunate to still be alive. Doctors told her she had given birth and wanted to know where the baby was. Medical personnel contacted police, who went to her home to locate the deceased fetus. Rivera was detained by police at the hospital and has been imprisoned since that time. Interrogation While Hospitalized Multiple national and international organizations, including Amnesty International and the Center for Reproductive Rights, along with numerous medical, legal, human rights, and academic experts, have analyzed Rivera’s case in the years since her conviction. Harvard University sociologist Jocelyn Viterna and Salvadoran lawyer Jose Santos Guardado Bautista, for example, used parts of Rivera’s story and court documents in their 2014 analysis of systematic gender discrimination toward Las 17 within the judicial system. Viterna and Bautista noted, for example, that the only witness testimony the judge considered credible was a supervisor from human resources at the factory where Rivera worked. Contrary to Rivera’s testimony, the supervisor testified that Rivera asked for time off for doctor appointments in January 2011 because she was pregnant. The judge refused to allow testimony from neighbors and friends who stated that they had never seen Rivera show any signs of pregnancy. “Had Maria Teresa truly reported a pregnancy to her employer in January of 2011, she would have been 11 months pregnant when the birth occurred in November,” Viterna and Bautista observed. “This testimony is nothing short of preposterous. Nevertheless, this is the only witness testimony that the judge deems ‘credible’ in the final sentencing.” According to Viterna and Bautista’s report, “The judge admitted that there was no evidence that Maria Teresa had done anything to hurt her baby. The judge also admitted that there was no evidence of any motive for why she would want to kill her baby.” However, he still convicted her of aggravated homicide. A 2015 resolution from the Salvadoran Attorney General for Human Rights (Procuradoría Para la Defensa de los Derechos Humanos or PDDH in Spanish), which provided a formal opinion on violations of Rivera’s human rights, supports Viterna and Bautista’s findings. The PDDH resolution observed that Rivera faced a slanted system even before she got to court: At the First of May Hospital where Rivera was taken, the criminal investigation was prioritized over her right to health. She was subjected to interrogation when she was still in Intensive Care and without legal representation. In addition, the medical personnel did not seek information about her health history; they limited themselves to examining the birth canal, carrying out the extraction of the remaining placenta, and discharging her the following day, without attending to her overall health. Both the PDDH and Viterna-Bautista reports noted that the judge relied on shoddy, unscientific evidence to convict Rivera. According to court records, the autopsy report for the fetus said its cause of death was “perinatal asphyxia.” “It is perhaps worth reiterating that there were no signs of trauma on the [fetus], either externally or internally. It is perhaps worth reiterating that, despite the judge’s conclusion that the [fetus] died from suffocating within the latrine, the fetal lungs were clean with no sign of fecal matter or other materials inside them. Rather, the autopsy concluded that the [fetus] died of a medical condition—perinatal asphyxiation—that could have occurred before, during, or after the birth. Clearly, there is no evidence in these documents proving homicide,” Viterna and Bautista wrote. “Perinatal asphyxiation,” they said, “is a medical condition.” Still, the judge interpreted the autopsy report to mean that Rivera had carried out an intentional criminal act. He also ignored the portion of the autopsy report stating that the umbilical cord could have been separated by its fall into the latrine. As quoted by the PDDH resolution, he wrote: There is no doubt that the baby was born alive and was full-term and that the detached umbilical cord was cut by the mother …. This judge does not give credibility to what the accused says when she states she did not know she was pregnant …. She knew she was pregnant and that brought with it the obligation to care for and protect this young person she carried in her womb. In this sense, the fact that she went to the latrine, she did it with the intention of violently expelling [it] so that inside the latrine there would be no opportunity to breathe and in that way cause its death and then be able to say it was a [spontaneous] abortion.” The judge also based his conviction, the PDDH resolution said, on the results of a DNA test showing the fetus was genetically related to Rivera. “No evidence was introduced to show that Rivera had taken any intentional action to cause the death,” the PDDH resolution concluded. Convicted by Patriarchy Rivera’s legal representatives will likely use many of these inconsistencies as evidence for procedural judicial error in court this week. A favorable outcome in her trial can represent a significant step forward for women’s human rights, particularly sexual and reproductive rights in El Salvador. The country’s 1997 absolute ban on abortion, along with a 1998 constitutional modification to declare that life begins at conception, created the social, cultural, and legal environment that has justified courts sending women such as Rivera to prison for documented obstetrical emergencies, not even attempted abortion. According to the global organization Ipas, more than 600 women were incarcerated between 1998 and 2013 under the abortion law. As the PDDH resolution noted, “in El Salvador, there exists a culture of the promotion of motherhood as the only form of self-realization for women, and the creation of the binomial ‘woman-mother,’ which locates women as instinctive and not rational. This imposes upon women [duties of] sacrifice, abnegation, and the prioritization of children over their own human conditions, behaviors that are not demanded in equal proportions from men. “Women find themselves with a social expectation to comply with the role ‘woman-mother,’ even in the health system where women should be assured of conditions free of discrimination and obstetric violence,” it continued. Advocates and researchers have argued that this sexist framework contributed to Rivera’s conviction. As Viterna and Bautista wrote, the trial judge claimed that Rivera “‘decided to carry out her criminal plan within the area of her household, looking for a moment during which there weren’t any other persons around to carry out this homicide,’ as if a woman has complete control over when, where and how her body will give birth.” The PDDH concluded that “the judge convicted Rivera under subjective criteria with a heavily sexist ideology,” saying that Rivera’s rights to the presumption of innocence were overruled by such an ideology, unsupported by any medical or scientific evidence. Rivera’s case, along with that of Carmen Guadalupe Vazquez (who was one of Las 17 granted a pardon in 2015 when the Salvadoran Supreme Court recognized judicial errors in her case), is representative of a consistent pattern toward this group of women that the Agrupación has been documenting. “Correcting these judicial errors is very important, first of all for Rivera and her young son, so that she can go free, but also for all the other women in similar circumstances. It’s also necessary for those who work for justice in this country, particularly women’s reproductive justice, to see that the work has concrete results,” Herrera said. Herrera hopes that a positive outcome will continue to make visible this pattern of judicial error and “move other cases [of Las 17] forward more rapidly and bring greater justice to the judicial system.” According to IThe Agrupación is currently representing more than 25 women imprisoned with similar convictions: the original 17, two of whom received pardons, and others who have entered the system more recently. “Maria Teresa’s story illustrates the systematic ways that women’s rights are violated: the right to health, the right to privacy in one’s life, the right to doctor-patient confidentiality, along with all the judicial procedural rights such as the presumption of innocence,” Herrera said in an interview with Rewire. “The judicial system in El Salvador is the part of the state that has changed least since the signing of the 1992 peace accords” that ended the Salvadoran civil war, Herrera said. “Not just in how it deals with women, but how little sensitivity it demonstrates overall with regard to human rights.” ||||| (Updated on 10/27: San Salvador’s Third Criminal Chamber has absolved María Teresa Rivera. She is free.) On an early November morning in 2011, María Teresa Rivera awoke with a twinge in her stomach and hastened through the pre-dawn light to the outhouse behind her home. She hadn’t been feeling well, but didn’t realize she was pregnant. Doubled over in pain, she suffered a miscarriage in her outhouse. She tried to stumble back to her bed, but collapsed on the way. Her mother-in-law found her slumped on the ground, dazed and bleeding, and rushed her to the nearest public hospital. That’s when María Teresa’s morning really got bad. She had a miscarriage and was sentenced to 40 years in prison for murder. Then an appeals judge absolved her. Now the Attorney General wants to send her back to prison for the same crime. The doctor took one look at her, then turned her over to police, who handcuffed her and told her she was under arrest for “aggravated homicide.” Maria Teresa said she was taken from her hospital bed to the police station, then straight to jail. “I never got to talk to a lawyer,” she told me. The whirlwind mockery of due process ended with a judge’s gavel that sentenced Maria Teresa to 40 years in prison. She was only 28 years old at the time, and raising a 7-year-old son by herself. This is what justice looks like in El Salvador, the country with the most draconian anti-abortion laws in the world. Maria Teresa’s head-spinning story may sound unbelievable, but it’s a frighteningly common tale in a country that criminalizes all forms of abortion and mistakes miscarriage for murder. There are currently 25 women—all poor, all young— behind bars in El Salvador for suffering spontaneous abortions. “There is no justice. There is only injustice, especially for poor women, the most vulnerable people in the country. It’s poverty. When you have money, there is no problem. But when you don’t have money, everything is stacked against you.” - Maria Teresa Rivera But even in her darkest hour, María Teresa, who grew up in an orphanage before getting a job hunched over a sewing machine in a Salvadoran sweatshop, remained hopeful that she would get out of jail and reunite with her son. Then last May, after more than four years in prison, the unthinkable happened: An appellate judge agreed to rehear María Teresa’s case, realized she had been railroaded on flimsy murder charges, and ordered her immediate release from jail. It was an unlikely second chance in a country that rarely gives first chances to impoverished single mothers. “It was such a feeling of happiness that I couldn’t even believe it,” Maria Teresa told me when I asked her about the day of her release. “To hug my son again after four and a half years…It was the happiest feeling that I could have felt, something I will never forget.” Amnesty International Tragically, that happy moment could be short-lived. El Salvador’s Attorney General, in an act of mustache-twisting nastiness, is now challenging the judge’s decision to release María Teresa a month after she was granted freedom. The government’s top prosecutor claims the judge did not use “sana crítica” (reasonable review), and that new forensic evidence proving the neonatal death was cased by perinatal asphyxia does not constitute “new facts.” If the Attorney General’s appeal is upheld, María Teresa could be rearrested next week and sent back to jail for the same crime she was already absolved of. This is Kafka on steroids. Maria Teresa’s only “crime” was failing to have a successful pregnancy in a land where machismo has been codified into law. Now the country with the highest murder rate in the world is treating this single mother as if she were public enemy No. 1—a threat that needs to be removed from society and put behind bars for the rest of her life. El Salvador isn’t the only country with punitive and backwards laws against abortion and reproductive rights. Worldwide, there are five countries—all, pathetically, in Latin America—that have total abortion bans, including two of El Salvador’s closest neighbors: Honduras and Nicaragua. The U.S., for all its posturing, is also pretty stupid about reproductive rights. A total of 38 states have fetal homicide laws on the books, according to the National Conference of State Legislatures, although Indiana is apparently the only state that’s actually sentenced a woman to jail time for feticide. But when it comes to punishing pregnant women, no other country is as determinedly misogynistic as little El Salvador. Since criminalizing all forms of abortion in 1998, El Salvador has locked up dozens of women for having unsuccessful pregnancies—and they’re showing no signs of slowing down. The sisterhood of ‘The 17’ To raise awareness about the issue, human rights activists in El Salvador started a campaign in 2014 calling for the release of “The 17,” a group of incarcerated women serving sentences of 12-40 years for having miscarriages or spontaneous abortions. Since the campaign has started, three women have been released or pardoned, but another dozen have been incarcerated on similar charges. Maria Teresa says the incarcerated women have formed a strong sisterhood in El Salvador’s dangerously overcrowded women’s prison, which is reportedly overpopulated by 900%. “We spent a lot of time together, and we talked about our cases. We got along very well. We were all in there for the same reason, 25 women at least. At first we were 17, then we were more,” Maria Teresa told me. She says there were some desperate moments when the women lost hope. “We didn’t see any solution. We thought the world had forgotten about us.” But when El Salvador’s feminist movement started the “Las 17” movement two years ago, it came as “a great relief and a light of hope” for the women in jail, Maria Teresa said. “It gave us strength to keep fighting.” Now that she’s out of jail, María Teresa says she’s determined to remain a free woman so she can raise her son to become a professional one day. Related Teen sentenced to 30 years in jail for having a miscarriage could be pardoned in El Salvador “This is difficult process right now, but things will work out. I trust in God and I know that nothing more will happen; I am not going back, and I trust in God that I won’t go back to jail,” she told me. God might be her last best chance, because Maria Teresa says she has no faith in El Salvador’s justice system. “There is no justice. There is only injustice, especially for poor women, the most vulnerable people in the country,” she said. “It’s poverty. When you have money, there is no problem. But when you don’t have money, everything is stacked against you, and that’s what happens to us women in El Salvador. The Salvadoran women has always been discriminated against. Always trampled on. That’s the huge problem here. Women have no rights. Women’s rights don’t count in this country.” Maria Teresa said her fight is also for all the other women jailed in El Salvador under similar circumstances. “It’s not just me, there are lots of women who are suffering an unjust jail sentence. So I have to fight for them too.” ||||| Looking for news you can trust? Subscribe to our free newsletters. Maria Teresa Rivera didn’t realize she was pregnant in 2011 when she went into early labor. The 28-year-old factory worker in El Salvador, who already had one son, started bleeding heavily late one night, so her family called an ambulance to drive her to the hospital. The next day, Rivera was taken to jail. Her crime? Having a miscarriage. Rivera is one of a number of women in El Salvador incarcerated not for abortion, which is illegal, but as a result of miscarriages. An abortion rights group in the area has identified 17 people convicted of homicide, with sentences upward of 40 years, after facing obstetric emergencies such as miscarriage or stillbirth. After serving four of her 40-year prison sentence for aggravated homicide, Rivera’s conviction was overturned by a judge and she walked free this spring. But the prosecution appealed her release, and this week a three-judge panel will decide whether to hold a new hearing or throw out the charges for good. Only six countries in the world, including El Salvador, ban abortion in all cases, even when the pregnancy is the result of rape or threatens the life of the mother. Nicaragua, Chile, the Dominican Republic, the Vatican city-state, and Malta are the only other places with similar prohibitions. In January, El Salvador’s deputy health minister told women to avoid getting pregnant for two years because of worries over the effects of Zika virus. “A woman who procures herself an abortion is running a very high risk,” Carmen Barroso, the former regional director of the International Planned Parenthood Federation in the Western Hemisphere, told Mother Jones. “She’ll run the risk to her life because she’ll have to have an unsafe abortion because they are so limited in availability. It is tragic.” The ban in El Salvador got international attention in 2013, when the country’s highest court rejected the abortion request of a young woman, known only as Beatriz, with a potentially life-threatening pregnancy, ruling the “rights of the mother cannot be privileged over those” of the fetus. The fetus suffered from anencephaly, a severe congenital disorder where the fetus’ brain and skull stop growing, giving it little chance of surviving outside the womb. The woman survived after getting a controversial caesarian section. Despite the ban, more than 19,000 illegal abortions were reported in El Salvador between 2005 and 2008, according to the Ministry of Health’s Information, Monitoring, and Evaluation Unit, an estimate that advocates say is low. Nearly a third of abortions performed were on adolescents, who make up a large percent of the region’s unplanned pregnancies. According to the World Health Organization, 9 percent of maternal deaths in Central America are the result of illegal abortions. As a result of the criminalization, women in El Salvador frequently face legal scrutiny for abortion-related crimes. According to research done by a Salvadoran advocacy group, between 2000 and 2011 about 130 women were criminally prosecuted for ending their pregnancies. That number doesn’t include cases where the allegations were dropped or cases involving minors, whose records are sealed. Almost 50 women were convicted of either illegal abortion or different degrees of homicide, which carries a sentence of up to 50 years. Then there are the cases of the 17 women who are part of “Las 17,” as they’re known, who are all, like Rivera, young, impoverished, and accused of losing their pregnancies on purpose. Guadalupe Vasquez, a housekeeper, was only 17 years old when she became pregnant from rape. She decided to keep the baby but lost it during labor. After her employer sent her to the hospital, she was reported to the police and eventually sentenced to 30 years behind bars. Many of the women, including Rivera, were reported to the police by medical staff at the hospital. In some cases, neighbors or friends called law enforcement. “I felt the need to go to the bathroom, I pushed, and it was the baby that came out into the latrine,” Rivera said in a video from prison. She passed out from loss of blood and was in the hospital when she woke up. “Then they took me to this place,” she said. Rivera was convicted “despite the complete lack of evidence of any wrongdoing,” according to an analysis of Las 17 cases by a Salvadoran lawyer and a Harvard sociologist. The analysis also concluded that Salvadoran courts systematically discriminated against the women by aggressively pursuing “the mother’s prosecution instead of pursuing the truth.” “In stark contrast to the courts’ findings, our analysis concludes that the legal and medical facts in the majority of these cases correspond with medical emergency—not with homicide,” they wrote. Rivera successfully appealed her conviction and has spent the last two months walking free. “What worries me is leaving my son alone again,” Rivera, who grew up in orphanages, told Rewire after being released in May. “I was forced to abandon him for four and a half years, and he suffered greatly during that time.”

– When Maria Teresa Rivera, a 28-year-old factory worker in El Salvador and single mom of a young boy, began to bleed heavily and collapsed, her family called an ambulance. She had just miscarried a baby she didn't even know she was pregnant with, and the next thing she knew she was in jail, accused of aggravated homicide. Rivera was sentenced to 40 years in prison and had to leave her son behind, reports Mother Jones. "I was forced to abandon him for four and a half years, and he suffered greatly during that time," she told Rewire in May. (Mother Jones notes that 19,000 illegal abortions were reported in El Salvador, which has the world's strictest total abortion ban, between 2005 and 2008, nearly a third of them on adolescents. The World Health Organization reports that 9% of maternal deaths in Central America are from illegal abortions.) But a judge who reviewed her case four years into her sentence ordered her release this past spring, and she enjoyed an entire month of freedom—"To hug my son again after four and a half years … it was the happiest feeling that I could have felt, something I will never forget"—before El Salvador's attorney general challenged the decision in what Fusion is calling "an act of mustache-twisting nastiness." And while Rivera awaits a three-judge panel's decision this week, there is increased attention on "the 17," a group of women serving 12 to 40 years for having miscarriages or spontaneous abortions. While three women have been released since the group formed in 2014, another dozen have been locked up. "I have to fight for them," Rivera says. (One woman's conviction in El Salvador was based solely on her allegedly abusive husband's testimony.)

premature birth is a significant risk factor for adverse motor , coordination , cognitive , and behavioral outcomes in survivors . the prevailing brain pathology in very preterm infants is diffuse white matter injury in the cerebral hemispheres . in addition , a consistent pattern of regionally specific long - term volume reduction and abnormalities in cortical and deep grey matter structures in ex - preterm infants is now recognized [ 3 , 4 ] . injury and impaired development of the cerebellum , involving both white matter and grey matter components as a complication of premature birth , are also becoming increasingly recognized with advanced neonatal brain imaging [ 511 ] . survivors of preterm birth demonstrate a constellation of long - term neurodevelopmental deficits , many of which are potentially related to cerebellar injury , including impaired motor functions such as hypotonia , fine motor incoordination , ataxia , and impaired motor sequencing [ 12 , 13 ] . cerebellar injury has also been implicated in cognitive , social , and behavioral dysfunction among older patients [ 14 , 15 ] and may contribute to the long - term cognitive , language , and behavioral dysfunction seen among 25% to 50% formerly preterm infants [ 1619 ] . the cerebellum is considered particularly vulnerable in the newborn human because of its very rapid growth at that time , a period comparable in the developing animal . the concept of a particular vulnerability of the cerebellum during its phase of rapid growth is documented in experimental models of undernutrition , glucocorticoid exposure , and x - irradiation [ 2022 ] . this article reviews the morphogenesis and histogenesis of the human and rodent developing cerebellum , and its more frequent injuries in preterm . most cerebellar lesions are cerebellar hemorrhage and infarction usually leading to cerebellar abnormalities and/or atrophy but the exact pathogenesis of lesions of the cerebellum is unknown . the different mechanisms involved , infection , inflammation , hypoxia , ischemia , exposure to drugs , and undernutrition , have been investigated with animal models . the cerebellum is composed of three major histological subdivisions : the cortex , the underlying white matter , and the deep cerebellar nuclei . the basic histological layering of the cerebellar cortex is similar in rodents and primates : the deep granular cell layer , the purkinje cell layer , and the superficial molecular layer are shown in the simplified schema in coronal and sagittal planes ( figure 1 ) . from the eight classes of cells found in the cerebellar cortex , only the purkinje cell axons project outside the cortex . the others are local circuit neurons : the granular cells and unipolar brush cells are glutamatergic whereas the others , in particular the stellate , the golgi , and the basket cells , are gabaergic . the two main afferent pathways conveying information to the cerebellar cortex are the climbing and mossy fibers systems that direct their impulses differently to the purkinje cells . the climbing fibers originate from the inferior olivary nucleus and established directed synaptic contacts with dendrites of the purkinje cells . the afferent mossy fibers originate from neuronal populations from various nuclei of the spinal cord , the brain stem , and even the deep cerebellar nuclei . they reach the purkinje cell indirectly through relay cells , the granular cells via their axonal field , and the parallel fibers . the purkinje cells are therefore the pivotal elements around which all the cerebellar circuits are organized by receiving information , processing it , and channeling towards efferent pathways . the characteristic neuronal arrangement consists of a strict positioning of neurons and afferent fibers conferring to the cortex a stereotyped three - dimensional geometry , which is very helpful to analyze any changes which may occur in the properties of neurons and their connectivity . . the cerebral cortical areas of the forebrain make several axonal connections with the cerebellum via the pallidum , the thalamus , and the pons in mammals . whereas in humans unilateral and crossed afferents connections running along the superior peduncle in the cerebellum are the most predominant , these corticopontocerebellar projections are bilateral in the rat brain . contrary to other regions of the central nervous system ( cns ) , cerebellar neurons are generated in two germinative neuroepithelia in two waves of proliferation and migration processes . this development occurs in similar order but at different rates in rodents and primates ( figure 2 ) . during the embryonic period in mammals , the cerebellar primordium arises from both mesencephalic and rhombencephalic vesicles in the isthmic area under the control of the isthmic organizer . the first neurons to be generated are the deep nuclear neurons and all the purkinje cells that migrate immediately after to the cerebellar plate ( figure 3 ) . in parallel , the first granular cell precursors are generated in the rostral rhombic lip ( with other neuronal cell populations ) , and they migrate as precursor granular cells tangentially to cover the superficial zone of the cerebellar plate following a lateromedial and anteroposterior direction ( see ) . the second wave of proliferation occurs in the egl , the secondary germinal zone giving rise to the granular cells which migrate radially inward to their final destination in the internal granular layer ( igl ) . the proliferation of granular cells is regulated by purkinje cells ( pc ) secreting the sonic hedgehog signaling factor . in the molecular layer , the onset of synaptic inputs of the axons of the granular cells ( parallel fibers ) is concomitant with the onset of the final postsynaptic dendritogenesis of the purkinje cells . the synaptic inputs , essentially from the parallel fibers but also from the climbing fibers , are essential for the achievement of the espalier arrangement of the dendritic trees of the purkinje cells . in the rat , although the extension of the lateral domain of the dendritic tree of the pc is achieved at postnatal day 15 ( p15 ) , its final extension , that is , adult size , is reached at p30 . altman and bayer described in the rat a caudorostral gradient of development of the cerebellar cortex . in human , the adult number of folia is achieved around two months postnatally and the egl disappears around the 7th postnatal month . interestingly , in vivo 3-dimensional volumetric imaging techniques shows , an increase in the cerebellar volume of about 5-fold from 24 to 40 gestational weeks ( gw ) [ 29 , 30 ] . lesions such as cerebellar hemorrhage ( cbh ) , infarction , and cerebellar atrophy have been increasingly diagnosed in preterm and term infants using improved neuroimaging techniques [ 4 , 9 , 10 , 17 , 31 , 32 ] . thus , in the study of limperopoulos et al . , the incidence of lesions in infants < 750 g birth weight was 15% , and 2% were seen in those > 750 g to 1499 g. the topography of the cbh is primarily focal , unilateral , and within the peripheral parenchyma of the cerebellar hemisphere . subpial germinal matrix bleeding within the external granular layer may account for some intrahemispheric cbh . the vermis is involved in slightly less than one - third of patients . cases of vermian hemorrhage represent hemorrhage within the germinal matrix located in the subependymal layer of the roof of the fourth ventricle [ 33 , 34 ] . cbh may occur concomitantly with cerebral lesions such as hemorrhagic parenchymal infarction , intraventricular hemorrhage with dilatation , and periventricular leukomalacia . in these last cases , this reduction may be due to a primary cerebellar injury that is not detectable by mr imaging at term - equivalent age or due to wallerian degeneration secondary to cerebral lesions . cerebellar atrophy is usually focal in the unilateral supratentorial lesions and often generalized in the bilateral cerebral lesions . these data suggest important insights into the highly integrated anatomic and functional integrations between the cerebrum and the cerebellum during development , such as trophic transsynaptic effects along the corticopontocerebellar pathway . in preterm of 32 gestational week ( gw ) , neuronal loss and gliosis were detected in dentate nucleus , cerebellar cortex , or the brain stem cerebellar relay nuclei , basis pontis , and inferior olive , in only 5% to 15% of infants , in particularly in presence of leukomalacia . the possibility that cerebellum atrophy in premature infants may be related to adverse blood product as hemosiderin deposit following hemorrhage has been suggested by messerschmidt and colleagues [ 5 , 19 , 33 ] . found that more severe supratentorial intraventricular hemorrhage ( ivh ) was associated with slower growth of cerebellar volumes . no changes in volumes were found with ivh at 30 weeks postmenstrual age ( 95% ci 2633 weeks ) , but volumes by 40 weeks were 1.4 cm lower in premature infants with grade 1 - 2 ivh and 5.4 cm lower with grade 3 - 4 ivh . the same magnitude of decreased volume was found whether the ivh was ipsilateral or contralateral . no association was found with severity of white matter injury ( p = 0.3 ) . whether these blood products are crucial or not in the onset of the cerebellar lesion remain unclear ( see ) . early effects of decreased cerebellar volume associated with supratentorial ivh in either hemisphere may be a result of concurrent cerebellar injury or direct effects of subarachnoid blood on cerebellar development . preterm delivery associated to other adverse insults could disrupt the developmental program of the cerebellum . a recent postmortem study on premature infants who had survived in an exutero environment reports cerebellar abnormalities in the development of granular cells which parallel a decrease of sonic hedgehog in the purkinje cell layer . univariate analyses identified maternal , intrapartum , and early postnatal hemodynamic risk factors ; multivariate regressions indicate that emergent caesarian section , patent ductus arteriosus , and lower 5-day minimum ph independently increased the odds of cerebellar hemorrhage . the correlation of lesions of the cerebellum in preterm with animal models can highlight the precise pathophysiology of these lesions . the damaging influence of hypoxia or hypoxia - ischemia to the cerebellar underdevelopment is suggested by the strong correlation of the cerebellar abnormality with mri - demonstrated supratentorial injury [ 3 , 4 , 9 , 11 , 32 ] . in the largest reported mri series of very preterm and preterm , a decrease in cerebellar volume at term equivalent age correlated with decreasing gestational age . in the pathology of preterm infants , neuronal loss detected in the cerebellum and related brain stem nuclei was essentially confined to the infants with periventricular leukomalacia ( 25% to 30% of infants ) . primary impaired cerebellar development of different origins , such as hypoxia - ischemia , has most often consisted of bilateral , generally symmetric deficits in the cerebellar hemispheric volumes . on the other hand , a recent mri study suggested that unilateral injury confined to the preterm cerebral hemisphere was associated with a significantly decreased volume of the contralateral cerebellar hemisphere . these data suggest that two main mechanisms might induce the impaired cerebellar development of the premature brain : either a direct effect on the development of the cerebellar cortex or remote effects operating via trophic transsynaptic interaction between the telencephalic leukomalacia and the developing cerebellum via the corticopontocerebellar pathway . on the other hand a recent study by tam et al . showed that cerebral white matter injury did not correlate with reductions in cerebellar volume . to address this question a model of the preterm human in neonatal rat pups was developed on postnatal day 2 ( p2 ) which is comparable to 28 weeks of gestation in the human ( figure 2 ) , when the cerebellar cortex is the most vulnerable to insult ( see section 2.4 ) . as mentioned previously , the second wave of neuronal cerebellar proliferation plays a key role in the organization of the cerebellar cortex . in a previous study we demonstrated that global hypoxic injury or forebrain hypoxia - ischemia at p2 in rat pups produce dramatic cellular damages in the cerebellar cortex . interestingly , the addition of forebrain ischemia does not increase the huge cellular damage obtained following hypoxia which contradict the afore mentioned hypothesis about a possible correlation between cerebral and cerebellum . our results showing neuronal and white matter damage in both cerebellar hemispheres following hypoxia alone suggest that systemic hypoxia could adversely affect the developing cerebellum independent of its connections at this developmental stage . the defect in myelination detected following hypoxia alone is even more severe than that following hypoxia - ischemia . the lack of volume loss detected at p21 indicates that there can be significant cellular injury followed by gliosis and postlesional plasticity with axonal and dendritic growth . the presence of increased density of gfap - positive cells and microglial activation in the white matter and cerebellar cortex of both hypoxic and hypoxic - ischemic injured rats supports a pathological event directly affecting the survival and/or maturation of neurons and preoligodendrocytes . these findings may explain some neurodevelopmental abnormalities seen in preterm babies even in the absence of gross cerebellar volume reduction . following hypoxia - ischemia , selective vulnerability of different regions of the brain depends on its maturity and on the severity of the insult . in the p7 hypoxic - ischemic model ( vannucci model ) equivalent of human injury at 3236 weeks of gestation ( figure 2 ) the areas with higher metabolism such as the cerebral cortex , hippocampi , and deep gray nuclei suffer the most after initial ischemic injury . histological brain damage is generally confined to the cerebral hemisphere ipsilateral to the arterial occlusion , and consists of selective cell death or infarction and delayed neurodegeneration depending on the duration of the systemic hypoxia [ 3840 ] . other studies using perinatal hypoxia - ischemia have shown that cell death occurs in brain regions that are not directly affected by the ischemia , such as cerebellum [ 39 , 41 , 42 ] suggesting that neuronal connectivity may play a role in neurodegeneration following hypoxia - ischemia to the immature brain ( p7 age ) . taken together , these findings may reveal the connection networks which could exist between the damaged forebrain and cerebellum in the developing mammal brain . in rodent models , forebrain hypoxia - ischemia may affect differently the corticopontocerebellar connections according to the age of the insult . as aforementioned , these lesions may not occur at p2 but could be present at p7 . in human , the activity in the ipsilateral pons , and also the contralateral cerebellar cortex , is a phenomenon known as crossed cerebellar diaschisis . limperopoulos et al . showed that unilateral injury confined to the preterm cerebral hemisphere was associated with a significantly decreased volume of the contralateral cerebellar hemisphere , and that these effects were evident as early as term gestational age equivalent . limperopoulos et al . hypothesized that the corticopontocerebellar connections are involved in cerebellar damage . a strong relation of maternal intrauterine infection with systemic fetal inflammation or of postnatal neonatal infection with systemic inflammation and the occurrence of periventricular leukomalacia is well documented [ 44 , 45 ] . white matter damage , astrocytosis , and cytokine activation have been demonstrated in experimental model of intrauterine infection , all of which are capable of leading to delays in brain development [ 46 , 47 ] . the cerebellum is particularly vulnerable to infections insults since it is not fully developed until after birth in both humans and rodents [ 22 , 33 ] . due to the nearly 5-fold increase in growth in the cerebellum in the last trimester of pregnancy , intrauterine infection , or activation of the fetal immune system could cause irreparable damage to this structure . experimental studies of e. coli injection administered at gestational day 17 in rats decreased purkinje cell density and volume . the decrease in calbindin in purkinje cells is also accompanied by impairment in motor coordination and balance in rats from the early postnatal period through adulthood . in fetal preterm sheep , exposure to bacterial endotoxin ( lipopolysaccharide ; lps ) cause a diffuse pattern of cerebellar white matter damage [ 50 , 51 ] . injury to the cerebellar white matter involves diffuse loss of oligodendrocytes , associated with apoptotic and/or inflammatory processes , which is similar to the white matter injury observed in the forebrain of preterm infants and in experimental immature animal models . human cytomegalovirus infection of the developing central nervous system ( cns ) is also a major cause of neurological damage in newborn . to investigate the pathogenesis of this human infection , animal models of virus infection of the cns are associated with a delay of the morphogenesis of the cerebellum [ 53 , 54 ] . the defects in cerebellar development in infected animals located in the cerebellar cortex are correlated temporally with virus replication and cns inflammation , spatially unrelated to foci of virus - infected cells . cmv - infected cells are more prevalent in the purkinje cell layer than in the mitotic granule cell layer . in an animal model of lymphocytic choriomeningitis virus astrocytes and bergmann glia cells are the first cells of the brain parenchyma infected with lcmv and the virus spreads across the brain principally via contiguous glial cells . lcmv infects neurons in only four specific brain regions : the cerebellum , olfactory bulb , dentate gyrus , and periventricular region . the cerebellum undergoes an acute and permanent destruction while the olfactory bulb is acutely hypoplastic but recovers fully with age . neurons of the dentate gyrus are unaffected in the acute phase but undergo a delayed - onset mortality . in contrast , the periventricular region has neither acute nor late - onset cell loss . currently , there are no direct data on the role of infection / inflammation in the genesis of cerebellar abnormality of the human premature infant . maternal exposure to nicotine , cocaine , and ethanol during pregnancy is known to be a significant contributor to neurobehavioral deficits in the offspring , and specific studies of the cerebellum in this context are of particular interest . in animal studies , nicotine treatment via injection during gestation has been shown to produce episodic hypoxia in the developing fetus . abdel - rahman et al . evaluated the neurotoxicity in the offspring at pubertal stage of the development following continuous maternal exposure to nicotine via infusion during the gestation period . histopathological findings showed a significant decrease in the surviving purkinje neuronal cells in the cerebellum and ca1 subfield of hippocampus in the offspring on postnatal day 30 and 60 . these pathological findings suggest that the deficits in the cerebellum could persist longer than other brain regions . furthermore , there was a significant increase in gfap immunostaining in both cerebellar white matter and granular cell layer as well as the ca1 subfield of the hippocampus . the mechanisms which alcohol induces their effects on development are unknown . a study by bonthius et al . showed that gestational exposure to ethanol in a nonhuman primate species induced permanent doserelated deficits in the number of cerebellar purkinje cells . the number of purkinje cells and their linear frequencies were significantly reduced in the alcohol - treated subjects , and the deficits were dose - dependent . the findings suggest that alcohol - induced reduction in neuronal number may be an important factor underlying the cns dysfunction in fetal alcohol syndrome . the developmental effects of glucocorticoids on the cerebellum are an important area of study as the cerebellum has the highest levels of glucocorticoid receptors in the brain , localized in the external granular layer [ 61 , 62 ] . studies in human preterm newborns reveal adverse effects of postnatal dexamethasone therapy on brain development , including decreased cerebral and cerebellar tissue volumes . in a recent study by tam et al . , preterm newborns were prospectively studied with serial mri examinations near birth and again near term - equivalent age . adjusting for relevant clinical factors , antenatal betamethasone was not associated with changes in cerebellar volume but postnatal exposure to clinically routine doses of hydrocortisone or dexamethasone was associated with impaired cerebellar growth . animal models demonstrate reduced preterm cerebellar growth after exposure to all glucocorticoids including hydrocortisone , dexamethasone , and corticosterone [ 62 , 65 , 66 ] . in the developing cerebellum , glucocorticoids cause neuronal apoptosis and inhibit proliferation of immature granule neuron precursors . however , although 11--hydroxysteroid dehydrogenase type 2 is capable of degrading hydrocortisone but not dexamethasone , both glucocorticoids result in injury of the external granular layer in wild - type animals . this is suggested by rodent models showing similar effects of corticosterone ( a known substrate of 11--hydroxysteroid dehydrogenase type 2 ) and dexamethasone on granule cell apoptosis with acute glucocorticoid exposure and inhibition of cell proliferation with chronic exposure . heine et al . recently showed that systemic administration of a small - molecule agonist of the sonic hedgehog - smoothened pathway ( sag ) prevents neurotoxic effects of gcs susceptible to metabolism by the enzyme 11-hydroxysteroid dehydrogenase type 2 , but that it does not interfere with beneficial effects of glucocorticoids on lung maturation . these findings suggest the potential of a small molecule agonist of smoothened as a neuroprotective agent in the setting of glucocorticoid - induced neonatal cerebellar injury . in the study of limperopoulos , cerebellar volumes were significantly associated with head circumference and weight at term - equivalent age mri . insufficient postnatal catch - up growth in preterm infants has been significantly associated with adverse neurodevelopmental outcome [ 69 , 70 ] . these data suggest that impaired postnatal growth may be an important marker of impaired central nervous system integrity and , in particular , deficient cerebellar growth at term . however , prospective studies in preterm ( less than 30 weeks ' gestation age ) suggest that suboptimal early nutrition in preterm infants can have a permanent effect on their cognitive function , emphasising the potential importance of dietary management decisions in this population [ 71 , 72 ] . many experimental data show that during its phase of rapid growth , the cerebellum is especially vulnerable to undernutrition [ 21 , 22 , 73 ] . . showed no overt signs of damage in sheep brains and cerebellum from intrauterine growth restricted ( iugr ) fetuses ; however , morphological analysis demonstrated subtle but important alterations in connectivity and function . in the cerebellum , the most important finding was a 20% reduction in the area of arborization of purkinje cell dendrites and a 26% decrease in the total number of dendritic spines . as spines are the sites of synaptic apposition , synaptic input to purkinje cells are reduced with a possible alteration in cerebellar function [ 7476 ] . restricted cerebellar growth and differentiation is also shown in studies of placental insufficiency in fetal sheep and guinea pigs [ 77 , 78 ] . cerebellar injury and disorders of development are now a recognized problem in preterm infants ; these data suggest a potential pathological role in the long - term cognitive , behavioral and motor deficits associated or not with brain injury . the precise pathophysiology of cerebellar injury remains unknown in preterm infants , and it is necessary to interrogate animal models to unravel the main mechanisms . in parallel , sophisticated pathological data on premature cerebellum are necessary to analyze specific human features . in addition , pathological investigations associated with mri studies on the same cerebellum are an essential step to define biomarkers necessary to improve the prognosis of cerebellar damage in preterm infants .

cerebellar injury is increasingly recognized through advanced neonatal brain imaging as a complication of premature birth . survivors of preterm birth demonstrate a constellation of long - term neurodevelopmental deficits , many of which are potentially referable to cerebellar injury , including impaired motor functions such as fine motor incoordination , impaired motor sequencing and also cognitive , behavioral dysfunction among older patients . this paper reviews the morphogenesis and histogenesis of the human and rodent developing cerebellum , and its more frequent injuries in preterm . most cerebellar lesions are cerebellar hemorrhage and infarction usually leading to cerebellar abnormalities and/or atrophy , but the exact pathogenesis of lesions of the cerebellum is unknown . the different mechanisms involved have been investigated with animal models and are primarily hypoxia , ischemia , infection , and inflammation exposure to drugs and undernutrition can also induce cerebellar abnormalities . different models are detailed to analyze these various disturbances of cerebellar development around birth .

in 2014 , more than 200,000 american men will be diagnosed with prostate cancer ( pca ) . it is the most frequently diagnosed solid tumor and the second leading cause of cancer - related deaths amongst men in the united states . it is estimated to cause 28% of the total number of cancer cases and 10% of the total cancer deaths amongst adult male cancer patients . prostate - specific antigen ( psa ) is the biomarker currently being used for pca . usually high preoperative values have been related to advanced disease and a poorer clinical outcome . clinicians initially used psa for monitoring pca patients after treatment to detect disease progression , treatment failure , or potential relapse and then subsequently recommended its use for screening purposes [ 35 ] . since the late 1980s , the introduction of psa screening along with digital rectal exam ( dre ) and transrectal ultrasound ( trus ) in general clinical practice has led to an increase in the documented incidence of pca [ 6 , 7 ] . this trend has been accompanied by an increase in invasive procedures with radical prostatectomy rates nearly six - fold higher in 1990 than in 1984 . while aggressive screening practices in the us resulted in patients getting diagnosed at a much earlier and potentially more curable stage of the disease [ 24 ] , it was followed by widespread criticism of overdiagnosis and overtreatment of indolent tumors . a recent analysis done by draisma et al . ( 2009 ) using different simulation models estimated the overdiagnosis rate for screen detected cancers that otherwise would have never been diagnosed in the absence of screening test to be 23% and 42% . similarly , welch et al . estimated the magnitude of overdiagnosis from randomized trials to be 60% for psa detected pca . even though psa is currently being used as a marker for diagnosis , its values are now being recognized as representing the relative degree of risk for pca . at 4 ng / ml ( upper limit of the reference interval ) psa fails to detect a substantial number of cancers , and the prostate cancer prevention trial has concluded that there is no cutoff value for psa level with simultaneous high sensitivity and high specificity for monitoring healthy men for pca but rather a continuum of prostate cancer risk at all values of psa . the controversy surrounding the use of this marker is currently being debated , because it is still unclear whether psa screening has truly led to a decline in mortality due to pca [ 12 , 13 ] . under normal conditions , the intact architecture of prostate gland keeps psa tightly confined and only low levels of psa can be detected in blood . the increase in serum psa in prostate cancer can not be explained by increased psa expression ; instead it may represent abnormalities in prostate gland architecture and vascularization , although the exact mechanism is unclear . psa screening test carries a sensitivity and specificity in the range of 70% to 90% and 20% to 40% , respectively . the area under the curve ( auc ) of the receiver operating characteristic ( roc ) curve is between 0.55 and 0.70 for the ability of psa to identify patients with pca . it is not specific for pca and more commonly is elevated in noncancerous events such as infections , trauma , benign prostatic hyperplasia ( bph ) , and growth in prostate volume . the positive predictive value for psa - based screening for pca is between 25% and 40% , with patients in the gray zone of 410 ng / ml having a 25% chance of harboring latent pca and about 15% of men with psa concentrations of < 4 ng / ml also displaying pca . these shortcomings of psa as a marker have created a necessity to search for novel markers of pca to better predict disease occurrence , progression , and final outcome as well as avoid overtreatment of latent tumors . this review focuses on those upcoming circulating biomarkers that are being evaluated for their diagnostic , prognostic , therapeutic , and predictive properties . other biomarkers that in recent times have generated considerable interest such as micrornas , dna methylation , exosomes , and platelet sequestered biomarkers specific to pca are also briefly discussed . the national cancer institute defines a biomarker as a biological molecule found in blood , other body fluids , or tissues that is a sign of a normal or abnormal process or of a condition or disease . the level or expression of a biomarker should not only be sensitive and specific to a particular disease ( or natural process ) but also correlate with the progress of the disease or its response to a treatment . to fulfill all of these criteria there is a general consensus that a panel of biomarkers is required rather than an individual biomarker for a particular condition / disease [ 1923 ] . cancer biomarkers can play a crucial role in disease diagnosis and in predicting its outcome . they can potentially provide vital information to determine whom to treat aggressively and whom to follow up with active surveillance . they may also predict who will respond and how much response to expect with the established treatment modalities for a particular cancer . lastly , they may shed some light onto the development of newer , safer , and more efficacious therapies [ 2426 ] . for the purpose of this review we will concentrate on the circulating biomarkers present in bodily fluids that can be evaluated by using either minimally invasive procedures ( blood ) or noninvasive procedures ( urine ) rather than tissue markers . development of a panel of sensitive and specific circulating biomarkers would lead to a tremendous reduction in unnecessary biopsies and will have an added advantage of being repeated at regular intervals and can be utilized for follow - up assessment after radical prostatectomy , radiotherapy , hormone therapy , or chemotherapy . for the purpose of this review paper , candidate circulating biomarkers have been subdivided as ( 1 ) circulating metabolic biomarkers , ( 2 ) circulating protein biomarkers , ( 3 ) circulating genetic / epigenetic biomarkers , and ( 4 ) other potential biomarkers ( figure 1 ) . sarcosine ( n - methylglycine ) is a natural amino acid that is found in muscle and other body tissues . it was shown to induce invasive phenotype in benign prostate epithelial cell and , when detected in urine , it may be used as an indicator of malignant prostate cancer . a difference between benign prostate , clinically localized prostate cancer , and metastatic prostate cancer was also demonstrated based on the levels of sarcosine in urine , blood , and tissues of each subgroup . attenuation in cell invasion was observed in du145 prostate cancer cells after knocking down glycine - n - methyl transferase , the enzyme that catalyzes the production of sarcosine from glycine attenuated prostate cancer invasion . while addition of exogenous sarcosine or knocking down of sarcosine dehydrogenase , the enzyme responsible for sarcosine degradation stimulated an invasive phenotype in primary benign prostate epithelial cells . some experts in this field have pointed to the limitations to these findings , namely , small sample size and the need for independently confirming these results in larger cohorts of patients . ever since these preliminary results were published there have been studies that either challenged or supported the above findings , while others have concluded that neither of these contrasting studies have used validated analytical method to measure sarcosine in urine [ 31 , 32 ] . because of these equivocal findings it is yet to be determined whether sarcosine may play a vital role to promote prostate cancer cells toward invasion and aggressiveness . given the inconclusive results , it is clear that further investigations are needed to determine the role of sarcosine in prostate cancer progression and invasion as well as to establish its potential as a prostate cancer biomarker . -methylacyl coenzyme a racemase ( amacr ) is an isomerase family enzyme primarily located in mitochondria or peroxisomes . amacr overexpression as identified by immunostaining has been reported to be a diagnostic indicator of pca and other solid tumors [ 34 , 35 ] . it has become established as a tissue biomarker for pca and currently amacr detection in pca biopsy samples is regarded as an improvement over the serum psa test . amacr mrna has also been detected in prostatic secretions obtained from postmassage urine specimens . when amacr transcripts ( mrna ) were normalized to psa transcripts it was shown to be predictive of pca . on the contrary , autoantibodies against this protein have also been found in serum and a study from 2004 suggests that it could distinguish cancerous from benign blood samples better than psa . transforming growth factor-1 is a growth factor that is involved in a wide variety of cellular mechanisms including , but not limited to , cell proliferation , differentiation , immune response , and angiogenesis . its increased local expression in pca has been related to higher tumor grade , local invasion , distant metastasis , and biochemical recurrence . in a study by ivanovic , an immunoassay was used to measure preoperative plasma levels of tgf-1 in pca patients . the study correlated increased levels of tgf-1 with invasive pca . while shariat et al . has shown tgf-1 association with extracapsular extension , seminal vesicle invasion , and biochemical recurrence [ 43 , 44 ] . further large scale level studies are needed to validate these findings that can serve to determine its use as a biomarker for disease progression . interleukin-6 ( il-6 ) is a cytokine secreted by a variety of cell types with variable effects on immune and hematopoietic mechanisms . both in vitro and in vivo studies have shown increased expression of il-6 and its soluble receptor ( il-6r ) in pca cells and tissue . nakashima et al . reported that elevated levels of il-6 and its receptor in serum are associated with metastatic and hormone refractory disease [ 48 , 49 ] . based on these findings , kattan et al . validated and enhanced the prognostic ability of an existing preoperative nomogram by adding plasma levels of tgf-1 and soluble il-6r from samples collected prior to radical prostatectomy . a multi - institutional dataset of 423 pca patients treated with radical prostatectomy validated these results , suggesting a potential role for tgf-1 and soluble il-6r to improve risk stratification of biochemical recurrence after radical prostatectomy and help in guiding clinicians to identify patients who need aggressive follow - up . early prostate cancer antigen is a nuclear matrix protein , originally discovered in rat prostate tissue . epca is linked to nuclear transformations that occur in early stages of prostate cancer development . based on immunohistochemical staining , it has been reported by different groups [ 52 , 53 ] to be present in various cancer precursor lesions in addition to prostate cancer tissue . more recently studies [ 54 , 55 ] using epca - based enzyme linked immunosorbent assay have provided substantial data to confirm the potential diagnostic value of serum epca . prostate cancer antigen 3 ( pca3 ) also known as differential display code 3(dd3 ) is a noncoding mrna , which is specifically produced by prostate gland . pca3 has been found to be highly overexpressed in malignant prostate tissue in comparison with benign prostate tissue [ 56 , 57 ] and its yield is improved in urine specimen if preceded by attentive dre / prostate massage . a robust urine test ( hologic gen - probe 's progensa pca3 assay ) its role in predicting tumor volume [ 58 , 59 ] or extracapsular extension on final pathology after prostatectomy has been established . since it has been reported that pca3 holds less sensitivity but high specificity for pca than psa [ 6062 ] , perhaps combining pca3 with psa or other new biomarkers like amcar will improve the sensitivity and help better stratify the patients for specific treatment decisions . golgi phosphoprotein 2 ( golph2 ) , also named as gp73 , is a 73 kda golgi apparatus associated protein that is coded by the golm1 gene located on chromosome 9q21.33 . , it is also overexpressed in hepatocellular carcinoma and adenocarcinoma of the lung [ 6466 ] . while it is still unclear what the exact functions and mechanics of gloph2 regulation are , work by kristiansen et al . suggest that it may be involved in posttranslation protein modification , cell signaling regulation , transport of secretory proteins , or maintenance of golgi apparatus function . a recent study by laxman et al . identified increased urinary golph2 transcriptome along with spink1 , pca3 , and tmprss2-erg as a significant predictor of pca . given the lack of additional data , it is clear that further studies are required to determine the appropriate diagnostic or prognostic value of circulating / excreted golph2 in pca . about 90% of gene fusions in prostate cancer are accounted by the fusion between the transmembrane protease , serine 2 ( tmprss2 ) , that is a strong androgen - regulated gene and the erg gene , a v - ets erythroblastosis virus e26 oncogene homolog ( avian ) . the erg gene belongs to the ets family of transcription regulators , which contributes to carcinogenesis and tumor progression . these gene fusions are presumed to result in overexpression of ets transcription factors under the control of androgen response elements . some studies [ 69 , 70 ] have already investigated the presence of tmprss2-erg mrna in pca patients ' urine samples . since it is absent in about 50% of pca cases , its use lies in combined assays with other biomarkers , such as pca3 . evaluated 1312 prospectively enrolled subjects and established that urine tmprss2-erg along with pca3 enhanced serum psa predicted pca risk and clinically relevant cancer on biopsy . in addition , urine tmprss2-erg levels seem to be associated with indicators of clinically significant prostate cancer at biopsy and prostatectomy such as gleason score , the percent of tumor observed , and number of cores with tumor . in the absence of any ongoing or recently published trials , these biomarkers ( tmprss2-erg & pca3 ) can at the best be used as an adjunct to psa . in addition , urinary mrna for tmprss2-erg or pca3 is measured relative to psa mrna in urine , thus dictating the dependency of these tests on any fluctuation in the levels of urinary mrna for psa . prostate stem cell antigen ( psca ) is a glycosylphosphatidylinositol - anchored cell surface antigen . it has been identified in the epithelium of several organs , such as the prostate , stomach , bladder , and gallbladder [ 7173 ] . psca was detected in pca tissues by immunohistochemistry , and psca rna was found in blood samples of patients diagnosed with pca . increased psca production was correlated with an increased risk of pca , a higher gleason score , a higher stage , seminal vesicle invasion , capsular invasion , and the presence of metastasis [ 71 , 7476 ] . it was observed to be jointly amplified with c - myc in locally advanced prostate cancers [ 77 , 78 ] . when compared with the mrna of other circulating prostate markers like psa and psma , psca displayed inferior sensitivity and considerable inability to distinguish between malignant and benign disease , though its disease specificity and independent predictive value were the highest . by using human psca transfected pc3 cell lines and inoculating subcutaneously in female ncr nude mice , researchers had shown that anti - psca monoclonal antibodies inhibited tumor growth and metastasis formation . it was postulated to be a potential therapeutic target for immunotherapeutic procedures [ 8183 ] . despite these significant findings there are still no definitive conclusions regarding its use in clinic as a serum biomarker for pca . need for additional data as well as validation and reproducibility of the techniques to quantify the serum levels are some of the shortcomings that need to be addressed before psca can be considered as a valuable biomarker for further development . more studies are awaited to further evaluate and determine its effectiveness as a clinical prostate cancer marker . micrornas ( mirnas ) are small endogenous single stranded , noncoding rna molecules of approximately 17- to 27-nucleotide length . though the majority of mirna resides intracellularly , stable mirna has been observed in extracellular body fluids including blood and urine . mirnas seem to play an important role in modulating immune response , dna repair , apoptosis , oxidative stress , carcinogenesis , and cancer progression . extracellularly , mirnas have been implicated to play an important role in distant signaling by modifying gene expression . they tend to negatively regulate the targeted mrnas at the posttranslational level by binding with imperfect complementarities to the sites within the 3 untranslated region ( utr ) of these mrnas . in this manner , they are able to reduce the stability and translational efficiency of target mrnas . like protein - coding rnas , mirnas have the potential to either promote ( oncomirs ) or inhibit ( tumor suppressor mirnas ) cancer [ 86 , 87 ] . a single mirna may target more than 200 different mrnas and , vice versa , a particular target could be regulated by different mirnas . so far , close to 1400 human mirnas have been identified.in a recent study by agaoglu et al . mir-21 ( ar - regulated mirna ) and mir-221 were elevated in the plasma of men with localized pca compared with healthy controls . in addition , mir-141 along with mir-21 and mir-221 were increased in samples from men with bone metastases compared with men with localized / locally advanced disease , and mir-141 could accurately distinguish between these groups ( auc = 0.755 ) . the oncogenic properties of mir-221 have been attributed to its control of cyclin dependent kinase ( cdk ) inhibitors p27kip1 and p57kip2 , effectively controlling the g1-to - s phase transition [ 90 , 91 ] as well as pi3k and pten signaling . likewise , mir-21 's oncogenic effects and drug resistance properties have been attributed to its control of downstream target , programmed cell death 4 ( pdcd4 ) [ 93 , 94 ] . shen et al . also confirmed that mir-20a , mir-21 , mir-221 were differentially expressed based on pca stage or risk assessment by cancer of the prostate risk assessment ( capra ) or d'amico scores . other studies using tissue - based microarrays and pcr tests have reported conflicting results showing loss of mir-221 and mir-222 either during the early stage of cancer or during the aggressive stage [ 97 , 98 ] . such conflicting reports indicate the need for further larger scale investigations and also hint at the idea that expression levels of mirnas might be differentially controlled at different stages of the pca progression . bryant et al . has identified 12 differentially quantitated plasma mirnas between cohorts of pca patients and healthy men with mir-107 showing the highest fold - change . five of the mirnas were also detected in urine and mir-107 and mir-574 - 3p were present at significantly higher concentrations in urine samples from men with pca compared with healthy controls . the authors also went on to identify 16 mirnas , including mir-141 , mir-200b , and mir-375 , at differential levels in the plasma of pca men with either localized or metastatic disease . another group ( nguyen et al . ) reconfirmed similar findings by demonstrating that elevated expression of circulating mir-375 and mir-141 can distinguish patients with metastatic castration - resistant prostate cancer ( crpc ) from those with low - risk , localized prostate cancer . mir-143 , mir-145 , and mir-200 family mirnas have been identified as tumor suppressor mirs and are known to be involved in epithelial - mesenchymal transition ( emt ) either by loss of their suppression on egfr / ras / mapk pathway or by targeting zeb1 and zeb2 . in a study by peng et al . , both mir-143 and mir-145 expressions were significantly decreased in pca and were negatively associated with metastasis . based on all these observations , circulating mirnas profiling offers the potential to improve the diagnosis of cancer and might predict outcome for cancer patients . nevertheless , further studies are required to better understand the function of these potential biomarkers and their relation with the development , progression , and spread of pca . exosomes are membrane - bound nanoparticles ( 30150 nm ) normally released from cells in the body that contain molecules such as proteins , mrna , and mirna . these microvesicles are generated from internalized parts of the cellular membrane and subsequently secreted into bodily fluids such as blood , urine , or semen . increased level of exosomes was detected in the serum from prostate cancer patients compared to men with no disease , and elevated levels of exosomes may also correlate with disease aggressiveness . they may act as messengers and may play a crucial role in cell - cell interaction both in vicinity and at distance . . such vesicles may be a useful noninvasive source of markers for prostate cancer since they often carry genetic components that come directly from tumors . likewise , some recent studies have also reported the presence of pca3 and tmprss2-erg fusion , two known prostate cancer biomarkers , in exosomes from urine samples of prostate cancer patients [ 106 , 107 ] . cancer phenotypes have a complex and heterogeneous character , which can not be explained by genetic defects alone . several groups have shown the crucial role of epigenetic modifications in the manifestation of various cancer types [ 109112 ] . epigenetic modifications are defined as heritable changes in the expression and regulation of gene expression without altering the dna sequencing . feinberg and vogelstein first reported aberrant dna methylation as an epigenetic event to be associated with cancer as a consequence of the alteration it causes in normal gene regulation . many investigators have identified the role of dna methylation in the development and progression of pca [ 115 , 116 ] . hypermethylation refers to gain of methylation at specific sites , which under normal conditions are unmethylated . this happens mainly at promoter cpg islands ( cgis ) , which are defined as a dna sequence ( > 2k base pairs ) with a gc content greater than 50% and an observed : expected ratio of more than 0.6 [ 117 , 118 ] . the promoter cgi hypermethylation in turn is associated with stabilization of transcriptional repression and loss of gene function and mostly occurs in tumor suppressor genes [ 119 , 120 ] . hypermethylation of glutathione s - transferase - pi gene ( gstp1 ) promoter has been reported to be the most frequent epigenetic modification in pca and is present in 70% of high - grade prostatic intraepithelial neoplasia ( high - grade pin ) lesions and 90% of cancerous tissue samples when compared to normal or benign hyperplastic epithelium . gstp1 methylation patterns can also be detected in serum and urine making the procedure less invasive and the circulating biomarker a potential candidate for clinical use . it has a high specificity ( 86.8100% ) but low sensitivity both in urine ( 18.838.9% ) and serum / plasma ( 13.072.5% ) [ 122124 ] . to improve upon the utilization of this biomarker rouprt et al . ( 2007 ) showed that the promoter methylation pattern of four genes , gstp1 , rassf1a , rarbeta2 , and apc , was able to differentiate malignant from nonmalignant cases with 86% sensitivity and 89% specificity . similarly in 2005 , hoque et al . had examined promoter methylation patterns of nine genes in urine sediment to differentiate pca patients from normal . results from urine samples correlated with methylation patterns reported from corresponding primary tumor tissues . out of the 9 genes , just the four - gene combination ( p16 , arf , mgmt , and gstp1 ) was able to detect prostate cancer with 87% sensitivity and 100% specificity . ( 2009 ) utilized serum samples for methylation status using another 4-gene combination ( gstp1 , ptgs2 , rprm , and tig ) that provided slightly higher specificity ( auc = 0.699 ) when serum samples from pca patients were compared with bph patients . a recent review article on methylation markers for pca concludes that evidence on the prognostic utility is still inconclusive and recommends further research with larger sample sizes , and adequate follow - up data and to include patients from other races / ethnicities as well as those who have received treatment other than radical prostatectomy . they have been at the center of intense scientific investigation since they circulate in blood and are postulated to mediate hematogenous metastasis . they may potentially provide beneficial information for risk stratification , to gauge therapy response for better clinical management of cancer patients , predict disease recurrence , and provide new insights for an individual cancer treatment strategy . in addition , ctcs have been shown to manifest bidirectional flow and are reported to colonize their tumors of origin . this behavior is known as tumor self - seeding and is considered to accelerate primary tumor growth , angiogenesis , and stromal recruitment . these cells may also be a source of molecular information , such as tmprss2-erg , ar , and pten copy number status . some studies have reported that the increased number of ctcs in the blood of castration - resistant prostate cancer ( crpc ) patients predicts a less favorable survival outcome [ 132 , 133 ] . despite these promising findings , detecting ctcs and extracting their molecular information are both labor - intensive and expensive . in addition , these cells may evade the detection through a phenotypic switching mechanism such as emt - like process . ongoing clinical trials may be proven to be helpful in establishing ctcs as potential surrogate markers for this disease in the near future . a recent study by suades et al . has revealed that platelet - derived microparticles ( pmps ) enhance platelet deposition and thrombus formation in atherosclerotic arteries as well as in normal blood conditions . they also report that these microparticles have functional effects on cardiovascular atherothrombotic disease . in 2010 , kerr et al . described that murine platelets sequestered functionally active molecules like monocyte chemotactic protein-1 ( mcp-1 ) and tumor necrosis factor- ( tnf- ) in blood collected from a xenograft model injected with human prostate cancer cells . the author also reported preferential localization of tumor - derived mcp-1 , matrix metalloproteinase-2 ( mmp-2 ) , receptor activator of nf - kappab ( rank ) , receptor activator of nf - kappab ligand ( rankl ) , and tissue inhibitor of matrix metalloproteinase-1 ( timp-1 ) and host - derived tnf- and thrombopoietin ( tpo ) within host platelets . similarly , nilsson et al . demonstrated that ( mutant ) rna from tumor cells could be transferred into blood platelets both in vitro and in vivo . they also showed that the cancer associated rna biomarker pca3 was preferentially sequestered in the circulating blood platelets of pca patients . these findings suggest that protein and/or genetic elements sequestered within host platelets act as messengers for tumor cells and may be potential biomarkers for pca diagnosis and its progression . nearly fifteen years ago lin et al . reported increased in vitro proliferation due to decreased apoptosis and increased cell attachment of skeletal metastatic prostate cell lines ( pc-3 and c4 - 2b ) in the presence of elevated serum calcium ( ca ) . the proliferative effect of elevated serum calcium was associated with higher expression of the calcium - sensing receptor , which is a membrane - bound , heterotrimeric g - protein - coupled receptor that transduces signals involved in serum calcium regulation . recently , schwartz reported that prostate cancer patients with increased serum calcium levels ( total and/or ionized ) or any factor that leads to it ( such as high serum parathyroid hormone ) carry an increased risk of mortality . these results were derived from the national health and nutrition examination surveys iii ( nhanes ) and reaffirmed findings from their 2007 study where a greater than 2.5-fold increased risk amongst men was found in the highest tertile of serum calcium . another group tried to determine a serum calcium level association with biochemical recurrence ( bcr ) following salvage radiation therapy ; however , no evidence of a linear association between serum calcium and bcr was identified . these findings suggest that serum calcium ( possibly in combination with other biomarkers ) may be useful as a prognostic tool to identify patients with higher risk of mortality from pca rather than serving as diagnostic tool . further molecular and epidemiological investigations are required to better understand the significance of serum calcium levels as a promising prospective biomarker for pca . it is a template - free process carried out by various enzymes like transferases and endoglycosidases . it involves attachment of various glycan moieties ( fucose , mannose , sialic acid , etc . ) to different proteins and lipids before undergoing further intricate pruning and addition of several monosaccharides . aberrant glycosylation has been associated with many diseases including multiple types of cancers [ 141143 ] . some studies have suggested correlations between glycan structures and cancer prognosis [ 144 , 145 ] . there are three distinct types of protein glycosylations : n - glycans , o - glycans , and glycosaminoglycans . the same protein may possess different glycan structures , referred to as glycoforms . in 2007 , kyselova et al . utilized matrix - assisted laser desorption / ionization mass spectrometry ( maldi - ms ) profiles derived from sera of pca patients ( n = 24 ) and disease - free group ( n = 10 ) . they demonstrated that when these samples from pca patients were compared to disease - free group out of the fifty n - glycan structures that were observed ten were significantly more and two were significantly less present and the differences were statistically significant ( anova scores < 0.001 ) . similarly , in 2008 de leoz et al . profiled n - glycan in human sera from twenty pca patients ( ten under active surveillance and ten after radical prostatectomy ) and in immortalized prns prostate epithelial cell lines ( prns ) that express wild type or mutant androgen receptors . while data from ex vivo experiments was not conclusive , the one from human sera reported that fourteen glycans were downregulated and ten were upregulated in the active surveillance group when compared to post - radical - prostatectomy group . various groups have also studied glycosylated psa as a biomarker for pca . when pca patients ' sera were compared to bph patient 's sera , an increased core fucosylation and an increased expression of 2 - 3 linked sialic acid in pca serum glycomes were observed . similarly , decreased sialylation was observed in seminal fluid samples from pca patients when compared to control group and bph group . major advancements in mass spectrometry and separation have tremendously helped characterize glycan changes brought about by different disease processes . this has helped us better understand these changes and their role in carcinogenesis and progression . still , more studies are needed to validate these findings and to help us appreciate their precise role in diagnostics . since 1994 psa testing in prostate cancer has been the primary biomarker used in aggressive screening , early diagnosis , and treatment . however concerns that its high false positive results may create confusion for patients and clinicians like in deciding who and when to treat have motivated a search for more sensitive and highly specific biomarkers . our current pca diagnosis and management protocols need significant update , to better address some of the pitfalls left unaddressed by singularly deploying psa testing . when used in the right context , some of these potential prostate cancer biomarkers could avoid unnecessary biopsies , reduce the number of radical prostatectomies and the requirement for other treatment modalities like radiotherapy , stratify organ - confined tumors ( curable by surgery ) , monitor progression during watchful waiting , and/or lower overall mortality from the disease . a more rational approach to biomarker discovery , combined with modern molecular science and bioinformatics , will eventually allow clinicians to better diagnose and target treatment for those patients who are most likely to benefit .

prostate cancer ( pca ) is a major health concern in current times . ever since prostate specific antigen ( psa ) was introduced in clinical practice almost three decades ago , the diagnosis and management of pca have been revolutionized . with time , concerns arose as to the inherent shortcomings of this biomarker and alternatives were actively sought . over the past decade new pca biomarkers have been identified in tissue , blood , urine , and other body fluids that offer improved specificity and supplement our knowledge of disease progression . this review focuses on superiority of circulating biomarkers over tissue biomarkers due to the advantages of being more readily accessible , minimally invasive ( blood ) or noninvasive ( urine ) , accessible for sampling on regular intervals , and easily utilized for follow - up after surgery or other treatment modalities . some of the circulating biomarkers like pca3 , il-6 , and tmprss2-erg are now detectable by commercially available kits while others like micrornas ( mir-21 , -221 , -141 ) and exosomes hold potential to become available as multiplexed assays . in this paper , we will review some of these potential candidate circulating biomarkers that either individually or in combination , once validated with large - scale trials , may eventually get utilized clinically for improved diagnosis , risk stratification , and treatment .

the large hadron collider ( lhc ) has started running . with its unprecedented center of mass energy , there is a high hope that it will discover new physics which revolutionizes high energy physics . however , lhc is a complicated machine with very high luminosities . in order to find new physics , we need to know what signals the new physics may give rise to , and how to search for them with the enormous standard model ( sm ) backgrounds . a major motivation for new physics at the tev scale is the hierarchy problem the stability of the electroweak scale under radiative corrections . many models for tev - scale new physics are invented to address this problem , _ e.g. , _ supersymmetry ( susy ) , technicolor models , large and warped extra dimensions , little higgs models , etc . a lot of collider phenomenology studies have been devoted to these models . however , these models certainly do not cover all possible new physics that may appear at the lhc . there is no theorem that at the tev scale we should only see the minimal models which just address the hierarchy problem . from the experimental point of view , the collider searches should be signal - based . even though there are experimental studies targeted for some specific models , generic searches for new particles such as new gauge bosons , new quarks and leptons apply to a wide range of models . as the lhc is starting , the recent model - building efforts have shifted from `` solving problems of the standard model '' to studying models which can give rise to `` unexpected signals '' ( _ e.g. , _ hidden valleys @xcite , quirks @xcite , unparticles @xcite , etc . ) irrespective of whether they are related to any particular problem of the standard model . it is possible that the tev - scale physics includes some of these extra sectors in additional to the standard scenario . the presence of the extra sector may obscure the experimental signals of the standard scenario if there is mixing between them , so it is imperative to study these possibilities and their experimental consequences . in this talk , consider such a case with a ( super)conformal sector softly broken at the tev scale and mixed with the supersymmetric standard model . as we will see , the mixings can make the superpartners of the sm particles have continuum spectra , and hence make their experimental consequences quite different from the standard susy scenario . this presentation is based on the work done in collaboration with haiying cai , anibal medina , and john terning @xcite . we first give a brief introduction to unparticles . in ref . georgi:2007ek georgi considered the possibility that a hidden conformal field theory ( cft ) sector coupled to the sm through higher - dimensional operators , @xmath0 where @xmath1 is the scale where the interaction is induced , @xmath2 is the scale where the hidden sector becomes conformal , @xmath3 , and @xmath4 is the scaling dimension of the operator @xmath5 . there is no `` particle '' in a cft . one can only talk about operators with some scaling dimensions . the spectral densities are continuous and hence georgi called them `` unparticles . '' the phase space of an unparticle looks like a fractional number of particles . for a scalar unparticle , @xmath6 where @xmath7 is a normalization constant . in the limit @xmath8 , it becomes the phase space of a single massless particle , @xmath9 . for @xmath10 , the spectral density is continuous . because the unparticle spectral density is continuous down to zero , many phenomenological consequences and constraints are similar to other scenarios with very light ( or massless ) degrees of freedom , _ e.g. , _ large extra dimensions proposed by arkani - hamed , dimopoulos , and dvali @xcite . a list of things to be considered contains * invisible decays , _ e.g. , _ from @xmath11 , heavy mesons , quarkonia , neutrinos , @xcite , * missing energy in high energy collisions @xcite , * higher - dimensional operators induced by unparticles @xcite , * astrophysics : star ( sn1987a ) cooling @xcite , * cosmology : big bang nucleosynthesis ( bbn ) @xcite , * long - range forces induced by unparticles @xcite . in particular , unparticles can not carry sm charges if the spectral density continues down to zero without any gap . otherwise they would have been copiously produced and observed . however , as pointed by fox , rajaraman , and shirman @xcite , coupling to the higgs sector will break the conformal invariance of the unparticles in the infrared ( ir ) , which will induce a gap in general . above the gap , there are two possibilities : * if the theory confines , then it would produce qcd - like resonances . * if the theory does not confine , one then expect that the spectral density is still continuous above the mass gap . a simple ansatz to describe it is to introduce an ir cutoff @xmath12 @xcite , @xmath13 such a spectral density arises when a massive particle couples to massless degrees of freedom . for example , quark jets can be considered as unparticles @xcite . with a mass gap , many low - energy phenomenological constraints which result from new light degrees of freedom no longer apply . in particular , with a mass gap , one can consider the possibility that unparticles carry sm charges @xcite ( if the gap is larger than @xmath14 gev ) , which can be more interesting phenomenologically . this is the scenario that will be discussed in this talk . a useful tool to study the ( large @xmath15 ) conformal field theory is the ads / cft correspondence @xcite . the metric of a 5d anti de sitter ( ads@xmath16 ) space in conformal coordinates is given by @xmath17 where @xmath18 is the curvature radius and @xmath19 is the coordinate in the extra dimension . using the ads / cft correspondence , georgi s unparticle scenario can be described by the randall - sundrum ii ( rs2 ) @xcite setup . the 5-dimensional ( 5d ) bulk fields correspond to the 4-dimensional ( 4d ) cft operators , and the 5d bulk mass of a bulk field is related to the scaling dimension of the corresponding cft operator . in rs2 , the space is cut off by a uv brane ( located at @xmath20 ) but there is no ir brane which means that the conformal invariance is good down to zero energy . the momentum in the extra dimension of a bulk field is not quantized . from the 4d point of view , the momentum in the extra dimension becomes the mass in 4d , so the 4d mass spectrum is continuous . sm fields are localized on the uv brane . they can interact with the bulk fields ( cft operators ) through higher - dimensional interactions . such a representation allows us to perform calculations involving unparticles using the ordinary ( 5d ) field theory @xcite . in this talk we are interested in unparticles carrying sm charges with mass gaps . some modifications of the rs2 setup are necessary . in particular , sm fields have to propagate in the extra dimension as well and a soft wall is needed to produce the gap in the ir . before going to these discussions , we first describe how to formulate susy in the ads bulk . it is convenient to describe a 5d supersymmetric theory using the 4d @xmath21 superspace formalism @xcite . the 5d @xmath21 susy corresponds to @xmath22 susy in 4d . a 5d @xmath21 hypermultiplet contains two chiral multiplets in 4d , @xmath23 . the action of the 5d @xmath21 hypermultiplet is given by @xcite @xmath24 + \right.\nonumber\\ & & \left.+ \int d^2 \theta\ , \left ( \frac{r}{z } \right)^3 \left [ \frac{1}{2}\ ; \phi_c\ , \partial_z \phi - \frac{1}{2}\ ; \partial_z \phi_c\ , \phi + m \frac{r}{z}\ ; \phi_c\ , \phi \right ] + h.c . \right\}\ , , \label{5daction } \end{aligned}\ ] ] it is convenient to define a dimensionless bulk mass @xmath25 . it is related to the dimension of the corresponding operator in the 4d cft picture @xcite . for a left - handed cft operator @xmath26 ( which corresponds to the 5d bulk field @xmath27 ) , we have @xmath28 , @xmath29 for @xmath30 , where @xmath31 and @xmath32 are the scaling dimensions of the scalar and fermion operators respectively . for @xmath33 ( @xmath34 ) , the correlator diverges as we take the uv brane to the ads boundary ( @xmath35 ) . a counter term is needed on the uv brane to cancel the divergence , which implies uv sensitivity . on the other hand , for @xmath36 the cft becomes a free field theory with @xmath37 , @xmath38 . we will focus on the most interesting range @xmath39 ( @xmath40 ) . for the right - handed cft operator , we have the similar interpretations but with @xmath41 . in solving the equations of motion ( eoms ) , we include a @xmath19-dependent mass @xmath42 which represents the soft wall . the eoms for the fermions and the @xmath43-terms are @xmath44 @xmath45 using the @xmath43-term equations we can find the second order eom for the scalars : @xmath46 we can decompose the 5d field into a product of the 4d field and a profile in the extra dimensions @xmath47 where @xmath48 represents the 4d momentum . then we find the profiles in the extra dimension @xmath49 satisfy the schrdinger - like equations with the potential determined by the mass term . for a constant mass , the potential scales as @xmath50 for large @xmath19 , so there is a continuum of solutions starting from zero energy ( 4d mass ) . we can get different behaviors if @xmath51 for large @xmath19 : * for @xmath52 , the potential still goes to zero for large @xmath19 , so we have continuum solutions without gap . * for @xmath53 , the potential grows without bounds at large @xmath19 , so we get discrete solutions @xcite . * for @xmath54 , the potential approaches a positive constant for large @xmath19 , so we have a continuum with a gap @xcite . we are interested in the last possibility so we consider the case @xmath55 . in the uv ( small @xmath19 ) , @xmath56 , we have the usual cft interpretation . at large @xmath19 , @xmath57 , the conformal invariance in broken in the ir and a mass gap is developed . we can easily obtain the zero mode solutions for @xmath55 : @xmath58 one can see that only one of them has a normalizable zero mode . for definiteness we choose @xmath59 , then only the left - handed field has a zero mode , which is identified as the sm fermion . the nonzero modes satisfy the schrdinger - like equations , @xmath60 they have the same form as the radial wave equation of the hydrogen atom , @xmath61 except that @xmath62 is in general a fractional number instead of an integer . we can immediately see the pattern of the solutions from our knowledge of the hydrogen atom . for @xmath63 which corresponds to a repulsive coulomb potential , we have continuum solutions above the gap , @xmath64 . for @xmath65 on the other hand , we get discrete hydrogen - like spectrum below the gap in addition to the continuum above the gap . one can derive the unparticle propagator by probing the cft with a boundary source field @xmath66 . the holographic boundary action can be obtained by integrating out the bulk using the bulk eoms with the boundary condition @xmath67 @xcite,@xmath68\label{holoaction}\end{aligned}\ ] ] where @xmath69 from the cft point of view , the right - handed superfield @xmath66 is a source of the left - handed cft operator which correspond to @xmath27 . since @xmath70 is the source for the scalar component , the propagator for the scalar cft operator is @xmath71 with @xmath72 where @xmath73 is the whittaker function of the second kind . the fermionic and the @xmath43-component cft correlators are simply @xmath74 and @xmath75 by susy relations . we are interested in the conformal limit @xmath35 , so we expand @xmath76 for small @xmath77 and focus on the range @xmath78 . after properly rescaling the correlator by a power of @xmath77 to account for the correct dimension of the correlator , we find @xmath79 the first term vanishes in the conformal limit for @xmath78 . we can see that there is a pole at @xmath80 which represents the zero mode , and a branch cut for @xmath81 which represents the continuum in the propagator . for @xmath82 , there are addition poles below the gap @xmath83 which correspond to the hydrogen - like bound states discussed in the previous subsection . now we introduce susy breaking on the uv boundary by a scalar mass term , @xmath84 the scalar propagator is modified due to the modified boundary conditions , @xmath85 one can repeat the analysis of the previous subsection and finds for @xmath78 in the limit @xmath35 , @xmath86 for small @xmath87 , the pole which was at zero mass is shifted to @xmath88 the shift is smaller for smaller ( more negative ) @xmath62 ( fig . [ logm2 ] ) , because the zero mode wave function is localized farther away from the uv brane ( @xmath89 ) . for @xmath90 , as we increase @xmath87 , the pole eventually merge into the continuum and only a continuum superpartner is left ( fig . [ merge ] ) . the continuum parts of the spectral functions for several choices of @xmath87 are shown in fig . [ continuum3 ] . for @xmath91 , the discrete poles below the gap move towards the gap as @xmath87 increase ( fig . [ susybreaking ] however , they do not merge into the continuum for arbitrarily large @xmath87 . a 5d @xmath21 vector supermultiplet can be decomposed into a 4d @xmath21 vector supermultiplet @xmath92 and a chiral supermultiplet @xmath93 . we can not proceed as before by introducing a bulk mass term for the gauge field because of the gauge invariance . the same effect can be obtained with a dilaton profile @xmath94 coupling to the gauge kinetic term , which softly breaks the conformal symmetry in the ir @xcite . the action for the 5d @xmath21 vector supermultiplet can be written as @xmath95 we can obtain the bulk action in components after rescaling the fields , @xmath96 , @xmath97 , and @xmath98 . we find a @xmath19-dependent bulk gaugino mass @xmath99 induced by the dilaton profile . it leads to a continuum with a mass gap as we found for the matter fields , and @xmath62 is fixed to be equal to @xmath100 in this case because the 4d gauge field must have dimension one by gauge invariance . adding a susy - breaking gaugino mass term on the uv brane will lift the gaugino zero mode . for small majorana gaugino mass @xmath12 on the uv brane , the zero mode pole is shifted to @xmath101 for large gaugino mass the zero mode will merge into the continuum just as what we saw for the scalar superpartners of matter fields with @xmath102 . we discussed a novel possibility for the supersymmetric extension of the standard model , where there are continuum excitations of the sm particles and their superpartners arising from conformal dynamics . the properties of the superpartners can be quite different in this type of models . the superpartner of a standard model particle can be either a discrete mode below a continuum , or the first of a series of discrete modes , or just a continuum . the continuum superpartners will be quite challenging experimentally . it would be difficult to reconstruct any peak or edge because of the additional smearing of the mass by the continuous spectrum . at a high energy collider , if the superpartners are produced well above the threshold of the continuum , there is a possibility of extended decay chains as shown in fig . [ chain ] . these events are expected to have large multiplicities and more spherical shapes as a reflection of the underlying conformal theory @xcite . the experimental searches and verifications of this scenario will be very challenging . it is a topic under current investigation . the lhc will be the only high energy collider in the foreseeable future . we need to be prepared for any surprises and challenges that new physics may present to us at the lhc . i would like to thank the organizers for inviting me to give a talk at the scgt 09 workshop . this work is supported in part by the department of energy grant de - fg02 - 91er40674 . m. j. strassler and k. m. zurek , phys . b * 651 * , 374 ( 2007 ) [ arxiv : hep - ph/0604261 ] ; m. j. strassler , arxiv : hep - ph/0607160 ; t. han , z. si , k. m. zurek and m. j. strassler , jhep * 0807 * , 008 ( 2008 ) [ arxiv:0712.2041 [ hep - ph ] ] . j. kang and m. a. luty , jhep * 0911 * , 065 ( 2009 ) [ arxiv:0805.4642 [ hep - ph ] ] . h. georgi , phys . lett . * 98 * , 221601 ( 2007 ) [ arxiv : hep - ph/0703260 ] . h. cai , h. c. cheng , a. d. medina and j. terning , phys . d * 80 * , 115009 ( 2009 ) [ arxiv:0910.3925 [ hep - ph ] ] . n. arkani - hamed , s. dimopoulos and g. r. dvali , phys . b * 429 * , 263 ( 1998 ) [ arxiv : hep - ph/9803315 ] ; n. arkani - hamed , s. dimopoulos and g. r. dvali , phys . d * 59 * , 086004 ( 1999 ) [ arxiv : hep - ph/9807344 ] . t. m. aliev , a. s. cornell and n. gaur , jhep * 0707 * , 072 ( 2007 ) [ arxiv:0705.4542 [ hep - ph ] ] . k. cheung , w. y. keung and t. c. yuan , phys . lett . * 99 * , 051803 ( 2007 ) [ arxiv:0704.2588 [ hep - ph ] ] ; k. cheung , w. y. keung and t. c. yuan , phys . d * 76 * , 055003 ( 2007 ) [ arxiv:0706.3155 [ hep - ph ] ] . h. georgi , phys . b * 650 * , 275 ( 2007 ) [ arxiv:0704.2457 [ hep - ph ] ] . m. luo and g. zhu , phys . b * 659 * , 341 ( 2008 ) [ arxiv:0704.3532 [ hep - ph ] ] . h. davoudiasl , phys . lett . * 99 * , 141301 ( 2007 ) [ arxiv:0705.3636 [ hep - ph ] ] . s. hannestad , g. raffelt and y. y. y. wong , phys . d * 76 * , 121701 ( 2007 ) [ arxiv:0708.1404 [ hep - ph ] ] . j. mcdonald , jcap * 0903 * , 019 ( 2009 ) [ arxiv:0709.2350 [ hep - ph ] ] . y. liao and j. y. liu , phys . * 99 * , 191804 ( 2007 ) [ arxiv:0706.1284 [ hep - ph ] ] . h. goldberg and p. nath , phys . lett . * 100 * , 031803 ( 2008 ) [ arxiv:0706.3898 [ hep - ph ] ] . n. g. deshpande , s. d. h. hsu and j. jiang , phys . b * 659 * , 888 ( 2008 ) [ arxiv:0708.2735 [ hep - ph ] ] . p. j. fox , a. rajaraman and y. shirman , phys . d * 76 * , 075004 ( 2007 ) [ arxiv:0705.3092 [ hep - ph ] ] . g. cacciapaglia , g. marandella and j. terning , jhep * 0801 * , 070 ( 2008 ) [ arxiv:0708.0005 [ hep - ph ] ] . m. neubert , phys . b * 660 * , 592 ( 2008 ) [ arxiv:0708.0036 [ hep - ph ] ] . j. m. maldacena , adv . * 2 * , 231 ( 1998 ) [ int . j. theor . * 38 * , 1113 ( 1999 ) ] [ arxiv : hep - th/9711200 ] ; s. s. gubser , i. r. klebanov and a. m. polyakov , phys . b * 428 * , 105 ( 1998 ) [ arxiv : hep - th/9802109 ] ; e. witten , adv . * 2 * , 253 ( 1998 ) [ arxiv : hep - th/9802150 ] . l. randall and r. sundrum , phys . lett . * 83 * , 4690 ( 1999 ) [ arxiv : hep - th/9906064 ] . g. cacciapaglia , g. marandella and j. terning , jhep * 0902 * , 049 ( 2009 ) [ arxiv:0804.0424 [ hep - ph ] ] . a. falkowski and m. perez - victoria , phys . d * 79 * , 035005 ( 2009 ) [ arxiv:0810.4940 [ hep - ph ] ] . a. friedland , m. giannotti and m. graesser , phys . b * 678 * , 149 ( 2009 ) [ arxiv:0902.3676 [ hep - th ] ] . o. aharony , s. s. gubser , j. m. maldacena , h. ooguri and y. oz , phys . rept . * 323 * , 183 ( 2000 ) [ arxiv : hep - th/9905111 ] . r. contino and a. pomarol , jhep * 0411 * , 058 ( 2004 ) [ arxiv : hep - th/0406257 ] . g. cacciapaglia , g. marandella and j. terning , jhep * 0906 * , 027 ( 2009 ) [ arxiv:0802.2946 [ hep - th ] ] . a. karch , e. katz , d. t. son and m. a. stephanov , phys . d * 74 * , 015005 ( 2006 ) [ arxiv : hep - ph/0602229 ] . j. polchinski and m. j. strassler , jhep * 0305 * , 012 ( 2003 ) [ arxiv : hep - th/0209211 ] ; m. j. strassler , arxiv:0801.0629 [ hep - ph ] . d. m. hofman and j. maldacena , jhep * 0805 * , 012 ( 2008 ) [ arxiv:0803.1467 [ hep - th ] ] . y. hatta , e. iancu and a. h. mueller , jhep * 0805 * , 037 ( 2008 ) [ arxiv:0803.2481 [ hep - th ] ] . c. csaki , m. reece and j. terning , jhep * 0905 * , 067 ( 2009 ) [ arxiv:0811.3001 [ hep - ph ] ] .

in an exact conformal theory there is no particle . the excitations have continuum spectra and are called `` unparticles '' by georgi . we consider supersymmetric extensions of the standard model with approximate conformal sectors . the conformal symmetry is softly broken in the infrared which generates a gap . however , the spectrum can still have a continuum above the gap if there is no confinement . using the ads / cft correspondence this can be achieved with a soft wall in the warped extra dimension . when supersymmetry is broken the superpartners of the standard model particles may simply be a continuum above gap . the collider signals can be quite different from the standard supersymmetric scenarios and the experimental searches for the continuum superpartners can be very challenging . _ talk presented at 2009 nagoya global coe workshop strong coupling gauge theories in lhc era ( scgt09 ) , 811 december , 2009 _

als is a fatal neurodegenerative disease of motor neurons , has various subtypes , and shows a markedly heterogeneous clinical presentation and course . despite a uniformly fatal outcome , patients with als display a wide range of survival times from a few months to several decades . in addition , phenotypic variation is evident through different sites of onset and variable disease progression . the 3 main clinical als categories are classic limb onset als , progressive bulbar palsy ( bulbar onset als ; pbp ) , and a lower motor neuron dominant variant termed progressive muscular atrophy ( pma ) . bulbar onset als tends to have a worse prognosis than limb onset , and both forms have worse prognosis than pma . however , these 3 phenotypic categories do not fully capture the spectrum of clinical heterogeneity in als , which may contribute to diagnostic error . furthermore , there are no definitive diagnostic tests or well defined biomarkers for als at present , leaving neurologists to rely on only clinical history , physical examination , and neurophysiological evidence of lower motor neuron ( lmn ) involvement . apart from the 3 main als subtypes , other forms have been recognized but relatively inadequately studied . fas , also known as brachial amyotrophic diplegia or man - in - a - barrel syndrome , is characterized by progressive , predominantly proximal , symmetric weakness and wasting of the upper limbs , with no significant lower limb or bulbar muscle involvement [ 4 , 5 , 6 ] . recent studies have indicated that fas was associated with a significantly better prognosis than typical als or pma . the male to female ratio was 4~10 to 1 , in contrast to the reported ratio of 1.5 to 1 for the als population as a whole . in the initial stages of the disease , a substantial proportion of patient with als could be noted only upper limb weakness without bulbar or lower limb weakness , aside from those with pbp who account for approximately 20% of als patients . almost all progressed to lower limb , bulbar , or respiratory muscle weakness and consequently had a fatal prognosis . when clinicians encounter a patient with symptoms restricted to the upper limbs , they should consider that the possible diagnoses include classic als with upper limb onset ( ul - als ) or fas . it may be difficult to differentiate between these 2 phenotypes , however , the distinction is significant importance , as they differ considerably in their prognosis . studies investigating the clinical features and electromyographic ( emg ) findings from patients with fas are still lacking . the aim of the current study was to compare the clinical and emg findings of patients diagnosed with fas with those of patients diagnosed with ul - als . to accomplish this , a retrospective review of patients who were diagnosed with motor neuron disease and presented with progressive and symmetric weakness of the upper limbs , with no lower limb or bulbar muscle involvement , was conducted . the seoul national university hospital als center is located in downtown seoul and serves a diverse community of patients from the metropolitan area . all patients diagnosed with ' motor neuron disease ' in our als center from 2006~2011 who had initial complaints of bilateral upper limb weakness were selected for study inclusion . emg and nerve conduction studies ( ncs ) were performed on this patients at the initial visit only . the simultaneous presence of spontaneous denervation potential ( fibrillations and positive sharp waves ) and enlarged motor unit potentials ( mups ) on emg was considered as evidence of lmn involvement . the time of disease onset was set as the date when patients first noticed their symptoms . during the follow - up visits , we established the progression to als when they had evidence of bulbar or respiratory muscle involvement or lower limb weakness . fas was defined in patients with symmetric weakness of both upper limbs , with sparing of the lower limbs and bulbar and respiratory muscles for at least 12 months after their first visit . we also included patients who had a pattern of wasting typical for flail arm , but also had pathological deep tendon reflex or hoffman sign in the upper limbs at some point during the disease . patients with distal upper limb weakness or wasting without proximal involvement at presentation were excluded from this category . ul - als was defined in patients with limited upper limb weakness at their initial visit that spread to bulbar , respiratory , or lower limb muscles during the observation period . those with unexplained sensory signs or symptoms , abnormal nerve conduction studies , weakness in the distribution of individual motor nerves , or any abnormality on cervical mri suggestive of an alternate diagnosis such as spinal stenosis or cervical myelopathy were not included in the study . patients diagnosed with conditions such as spinal muscular atrophy , kennedy syndrome , monomelic amyotrophy , hirayama syndrome , or multifocal motor neuropathy , which are not considered as part of the als spectrum , were excluded from the study . baseline demographics , time to hospital visit after symptom onset , the medical research council ( mrc ) scale of the weakest muscle , the predominantly affected site between proximal and distal muscles , upper motor neuron ( umn ) signs ( jaw jerk , glabella reflex , snout reflex , brisk deep tendon reflexes , hoffman sign , extensor plantar response ) at initial visit , and emg findings were specifically noted . the fas and ul - als groups were compared by data analysis using the spss ( ver . bivariate data analysis was conducted to assess factors associated with fas and ul - als , and categorical variables were analyzed using chi - square and fisher 's exact tests . eighteen ( 19% ) patients were diagnosed with fas , and 56 ( 58% ) with ul - als . of the remaining 22 patients , 5 had brachial plexitis , 4 had cervical radiculopathy , 2 had charcot - marie - tooth disease ( cmt1a ) , and 11 were classified as having disease of unknown origin . all fas and ul - als patients underwent brain mri and cervical mri to exclude the possibility of cervical myelopathy , synringomyelia , and cervical root lesions . the baseline demographic and clinical characteristics of the patients studied are reported in table 1 . the mean age at symptom onset was 59 years ( range 48~76 ) in the fas group and 57 years ( range 39~76 ) in the ul - als group . the male - to - female ratio was 5:1 in the fas group and 1.8:1 in the ul - als group . the fas group showed a male predominance , however , this trend was not statistically significant ( p=0.129 ) . the mean observation period was 24 months in the fas group ( range 13~50 ) and 25 months ( range 17~51 ) in the ul - als group . the weakness predominantly affecting the proximal muscles was observed in 70% ( 7/10 ) of those in the fas group and 18% ( 6/34 ) of those in the ul - als group , while the weakness predominantly affecting distal muscles was observed in 30% ( 3/10 ) of those in the fas group and 82% ( 28/34 ) of those in the ul - als group ( p=0.003 ) . mrc scale of the weakest muscle was significantly lower in the fas group compared to the ul - als group ( 2.8 vs. 3.4 p=0.047 ) . the rate of presence of fasciculation was 70% ( 39/56 ) in those with ul - als and 17% ( 3/18 ) in those with fas ( p=0.001 ) . the proportion of umn signs in bulbar , cervical , lumbar , and 2 or more of these 3 regions , did not differ significantly between the 2 groups . emg studies of all 4 regions including bulbar , cervical , thoracic , and lumbar spinal segments , were performed in 12 patients with fas and 52 patients with ulals . between the 2 groups , there were no statistically significant differences in lmn signs on emg . although fas has been described in several reports , the current study was the first to compare fas and ul - als regarding clinical features including emg findings . in the current study , significant between - group differences were observed in the rate of fasciculation , the pattern of predominantly affected muscles , and the mrc grade of the weakest muscle . fasciculation was noted in 17% of patients with fas and 70% of patients with ul - als . although the reasons underlying this difference are not clear , a potential explanation may be that lmn degeneration in patients with fas was limited to the upper limbs , but had spread to 2 or more regions in those with classic als . ul - als patients may have a greater chance of feeling fasciculation than fas patients . the results of the current study are in line with the results of earlier studies which reported that fas most often involved proximal muscles , while als usually involved distal muscles . in a sense , this result is not surprising . when we initially defined fas , the patients with distal upper limb weakness without proximal involvement were excluded . our results indicate that the mrc grades of the weakest muscles were significantly lower in the fas group than in the ul - als group , and that this is a reliable way to discriminate between these groups diagnostically . among 7 fas patients who had proximal dominant weakness , 6 were classified as having mrc grade 2 at shoulder abduction , and 1 as mrc grade 3 . meanwhile , among 6 ul - als patients who had proximal dominant weakness , 3 were classified as having mrc grade 3 at shoulder abduction , 2 as mrc grade 2 , and 1 as mrc grade 4 . in conclusion , in case of proximal muscle weakness , fas patients are more severely affected than ul - als patients . the median age and time to hospital visit did not differ between the 2 groups . patients with fas showed a male predominance pattern as compared to patients with ul - als ( 5:1 vs. 1.8:1 , p=0.129 ) . these results are consistent with those reported in previous studies [ 3 , 8 , 9 ] ; however , the small sample size of the current study may have impacted our ability to observe a statistically significant difference . although umn signs tend to be more frequent in ul - als than in fas , many fas patients also had umn signs . at time of initial diagnosis , 8 ( 44% ) fas patients showed at least one umn sign . the previous study , which tested 20 patients with fas , 50% met the el escorial criteria for probable als . fas is considered a lower motor neuron disease , but about half of fas patients may have at least one umn sign . in addition , when the fas group was categorized according to the revised el escorial criteria , 8 patients were classified as clinically probable - laboratory supported als and 3 as possible als . , 36 patients were classified as clinically probable - laboratory supported als , and 3 as possible als . before the study began , we expected that lmn involvement evidenced through emg would be more wide - spread to other regions including the brainstem and thoracic and lumbar spine in patients with ul - als compared to those with fas . many patients with fas had electrophysiological evidence suggestive of lmn involvement of 2 or 3 segments ( 81% and 56% , respectively ) . since the mean age of patients with fas was 59 years , these findings may have been attributable to patient age , as the elderly are known to have higher prevalence rates of lumbar or thoracic radiculopathy . the lmn involvement in their emgs may have been caused not by anterior horn cell degeneration from motor neuron disease , but rather from lumbar or thoracic radiculopathy associated with degenerative changes . in fact , only 1 patient with fas had emg lmn involvement in the bulbar region . although the difference lacked statistical significance in our study , more patients with ul - als had lmn involvement of other segments , especially the bulbar region . mean survival time in our population was higher than in other studies [ 1 , 3 ] . this might be related to a selection bias , as patients managed in als centers tend to survive longer . this in turn may be related to greater use of non - invasive positive pressure ventilation , percutaneous endoscopic gastrostomy placement , and riluzole . first , the number of patients was insufficient for reliable data analysis . in the future , clinical and electrophysiological studies on fas we could not evaluate the whole information because of the lack or missing of some clinical data such as checking upper motor neuron signs . third , as mentioned above , the mrc grade of the weakest muscle was significantly lower in the fas group than in the ul - als group . the comparison of mrc grades of different muscles between the two groups has obvious limitations . fourth , we have not paid sufficient attention to fasciculation potentials in the emg study . the lack of information on fasciculation potentials in the emg study prevented comparison to clinical fasciculation . it is important to recognize fas because the natural history differs from that of classic als . it is difficult to differentiate between progression to the lower limb , bulbar , or respiratory muscles characteristic of classic als and restriction to the upper limb muscles observed in fas . the results of the current study may help in discriminating between the 2 groups , but are not sufficient to do so with certainty . future studies will be required to find factors ( genetic , laboratory , radiographic ) that further distinguish between fas and ul - als .

flail arm syndrome ( fas ) , an atypical presentation of amyotrophic lateral sclerosis ( als ) , is characterized by progressive , predominantly proximal , weakness of upper limbs , without involvement of the lower limb , bulbar , or respiratory muscles . when encountering a patient who presents with this symptomatic profile , possible diagnoses include upper limb onset als ( ul - als ) , and fas . the lack of information regarding fas may make differential diagnosis between fas and ul - als difficult in clinical settings . the aim of this study was to compare clinical and electromyographic findings from patients diagnosed with fas with those from patients diagnosed with ul - als . to accomplish this , 18 patients with fas and 56 patients with ul - als were examined . significant differences were observed between the 2 groups pertaining to the rate of fasciculation , patterns of predominantly affected muscles , and the medical research council scale of the weakest muscle . the presence of upper motor neuron signs and lower motor neuron involvement evidenced through electromyography showed no significant between - group differences .

( * b * ) superimposed fluorescence pictures of a dilute ensemble of rollers ( @xmath0 , @xmath1 ) . the colloids propel only inside a circular disc of radius @xmath2 and follow persistent random walks . [ fig1 ] ] * experiments . * the experimental setup is fully described in the _ methods _ section and in figs . [ fig1]a and [ fig1]b . briefly , we use colloidal rollers powered by the quincke electrorotation mechanism as thoroughly explained in @xcite . an electric field @xmath3 is applied to insulating colloidal beads immersed in a conducting fluid . above a critical field amplitude @xmath4 , the symmetry of the electric charge distribution at the bead surface is spontaneously broken . as a result , a net electric torque acts on the beads causing them to rotate at a constant rate around a random axis transverse to the electric field @xcite . when the colloids sediment , or are electrophoretically driven , onto one of the two electrodes , rotation is converted into a net rolling motion along a random direction . here , we use pmma spheres of radius @xmath5 immersed in a hexadecane solution . as sketched in fig . [ fig1]a , the colloids are handled and observed in a microfluidic device made of double - sided scotch tape and of two ito - coated glass slides . the ito layers are used to apply a uniform dc field @xmath6 in the @xmath7-direction , with @xmath8 ( @xmath9 ) . importantly , the electric current is nonzero solely in a disc - shaped chamber at the center of the main channel . as exemplified by the trajectories shown in fig . [ fig1]b and in _ supplementary movie 1 _ , quincke rotation is hence restrained to this circular region in which the rollers are trapped . we henceforth characterize the collective dynamics of the roller population for increasing values of the colloid packing fraction @xmath10 . + * individual self - propulsion . * for area fractions smaller than @xmath11 , the ensemble of rollers uniformly explores the circular confinement as illustrated by the flat profile of the local packing fraction averaged along the azimuthal direction @xmath12 in fig . the rollers undergo uncorrelated persistent random walks as demonstrated in figs . [ fig2]b and [ fig2]c . the probability distribution of the roller velocities is isotropic and sharply peaked on the typical speed @xmath13 . in addition , the velocity autocorrelation function decays exponentially at short time as expected from a simple model of self - propelled particles having a constant speed @xmath14 and undergoing rotational diffusion with a rotational diffusivity @xmath15 that hardly depends on the area fraction ( see _ supplementary discussion 1 _ ) . these quantities correspond to a persistence length of @xmath16 that is about a decade smaller than the confinement radius @xmath17 used in our experiments : @xmath18 . at long time , due to the collisions on the disc boundary , the velocity autocorrelation function sharply drops to 0 as seen in fig . [ fig2]c . unlike swimming cells @xcite , self - propelled grains @xcite or autophoretic colloids @xcite , dilute ensembles of rollers do not accumulate at the boundary . instead , they bounce off the walls of this virtual box as shown in a close - up of a typical roller trajectory in fig . [ fig2]d , and in the _ supplementary movie 1_. as a result , the outer region of the circular chamber is depleted , and the local packing fraction vanishes as @xmath19 goes to @xmath17 , fig . the repulsion from the edges of the circular hole in the microchannel stems from another electrohydrodynamic phenomenon @xcite . when an electric field is applied , a toroidal flow sketched in fig . [ fig1]a is osmotically induced by the transport of the electric charges at the surface of the insulating adhesive films . consequently , a net inward flow sets in at the vicinity of the bottom electrode . as the colloidal rollers are prone to reorient in the direction of the local fluid velocity @xcite , this vortical flow repels the rollers at a distance typically set by the channel height @xmath20 while leaving unchanged the colloid trajectories in the center of the disc . this electrokinetic flow will be thoroughly characterized elsewhere . + * collective motion in confinement . * as the area fraction is increased above @xmath21 , collective motion emerges spontaneously at the entire population level . when the electric field is applied , large groups of rollers akin to the band - shaped swarms reported in @xcite form and collide . however , unlike what was observed in periodic geometries , the colloidal swarms are merely transient and ultimately self - organize into a single vortex pattern spanning the entire confining disc as shown in fig . [ fig3]a and _ supplementary movie 2_. once formed , the vortex is very robust , rotates steadily and retains an axisymmetric shape . in order to go beyond this qualitative picture , we measured the local colloid velocity field @xmath22 and use it to define the polarization field @xmath23 , which quantifies local orientational ordering . the spatial average of @xmath24 vanishes when a coherent vortex forms , therefore we use its projection @xmath25 along the azimuthal direction as a macroscopic order parameter to probe the transition from an isotropic gas to a polar - vortex state . as illustrated in fig . [ fig3]b , @xmath26 displays a sharp bifurcation from an isotropic state with @xmath27 to a globally ordered state with equal probability for left- and right - handed vortices above @xmath28 . furthermore , fig . [ fig3]b demonstrates that this bifurcation curve does not depend on the confinement radius @xmath17 . the vortex pattern is spatially heterogeneous . the order parameter and density fields averaged over time are displayed in figs . [ fig3]c and [ fig3]d , respectively . at first glance , the system looks phase - separated : a dense and ordered polar - liquid ring where all the colloids cruise along the azimuthal direction encloses a dilute and weakly ordered core at the center of the disc . we shall also stress that regardless of the average packing fraction , the packing fraction in the vortex core is measured to be very close to @xmath21 , the average concentration below which the population is in a gaseous state , see fig . this phase - separation picture is consistent with the variations of the area occupied by the ordered outer ring , @xmath29 , for different confinement radii @xmath17 , as shown in fig . we define @xmath29 as the area of the region where the order parameter exceeds 0.5 , and none of the results reported below depend on this arbitrary choice for the definition of the outer - ring region . @xmath29 also bifurcates as @xmath10 exceeds @xmath21 , and increases with @xmath17 . remarkably , all the bifurcation curves collapse on a single master curve when @xmath29 is rescaled by the overall confinement area @xmath30 , fig . [ fig3]f . in other words , the strongly polarized outer ring always occupies the same area fraction irrespective of the system size , as would a molecular liquid coexisting with a vapor phase at equilibrium . however , if the system were genuinely phase - separated , one should be able to define an interface between the dense outer ring and the dilute inner core , and this interface should have a constant width . this requirement is not borne out by our measurements . the shape of the radial density profiles of the rollers in fig . [ fig3]g indeed makes it difficult to unambiguously define two homogeneous phases separated by a clear interface . repeating the same experiments in discs of increasing radii , we found that the density profiles are self - similar , fig . the width of the region separating the strongly polarized outer ring from the inner core scales with the system size , which is the only characteristic scale of the vortex patterns . the colloidal vortices therefore correspond to a monophasic yet spatially heterogeneous liquid state . in order to elucidate the physical mechanisms responsible for this intriguing structure , we now introduce a theoretical model that we solve both numerically and analytically . + * numerical simulations . * the quincke rollers are electrically powered and move in a viscous fluid , and hence interact at a distance both hydrodynamically and electrostatically . in @xcite , starting from the stokes and maxwell equations , we established the equations of motion of a dilute ensemble of quincke rollers within a pairwise additive approximation . when isolated , the @xmath31th roller located at @xmath32 moves at a speed @xmath14 along the direction @xmath33 opposite to the in - plane component of the electrostatic dipole responsible for quincke rotation @xcite . when interacting via contact and electrostatic repulsive forces , the roller velocity and orientation are related by : @xmath34 inertia is obviously ignored , and for the sake of simplicity we model all the central forces acting on the colloids as an effective hard - disc exclusion @xmath35 of range @xmath36 . in addition , @xmath37 follows an overdamped dynamics in an effective angular potential capturing both the electrostatic and hydrodynamic torques acting on the colloids @xcite : @xmath38 the @xmath39 s account for rotational diffusion of the rollers . they are uncorrelated white noise variables with zero mean and variance @xmath40 . the effective potential in eq . * [ eq2 ] * is composed of three terms with clear physical interpretations : @xmath41 where @xmath42 . the symmetry of these interactions is not specific to colloidal rollers and could have been anticipated phenomenologically exploiting both the translational invariance and the polar symmetry of the surface - charge distribution of the colloids @xcite . the first term promotes alignment and is such that the effective potential is minimized when interacting rollers propel along the same direction . @xmath43 is positive , decays exponentially with @xmath44 , and results both from hydrodynamic and electrostatic interactions . the second term gives rise to repulsive _ torques _ , and is minimized when the roller orientation points away from its interacting neighbor . @xmath45 also decays exponentially with @xmath44 but solely stems from electrostatics . the third term has a less intuitive meaning , and promotes the alignment of @xmath46 along a dipolar field oriented along @xmath47 . this term is a combination of hydrodynamic and electrostatic interactions , and includes a long - ranged contribution . the functions @xmath43 , @xmath45 , and @xmath48 are provided in the _ supplementary discussion 2_. as it turns out , all the physical parameters ( roller velocity , field amplitude , fluid viscosity , etc . ) that are needed to compute their exact expressions have been measured , or estimated up to logarithmic corrections , see _ supplementary discussion 2_. we are then left with a model having a single free parameter that is the range , @xmath36 , of the repulsive _ forces _ between colloids . we numerically solved this model in circular simulation boxes of radius @xmath17 with reflecting boundary conditions using an explicit euler scheme with adaptive time - stepping . all the numerical results are discussed using the same units as in the experiments to facilitate quantitative comparisons . the simulations revealed a richer phenomenology than the experiments , as captured by the phase diagram in fig . [ fig4]a corresponding to @xmath49 . by systematically varying the range of the repulsive forces and the particle concentration , we found that the @xmath50 plane is typically divided into three regions . at small packing fractions , the particles hardly interact and form an isotropic gaseous phase . at high fractions , after transient dynamics strikingly similar to that observed in the experiments , the rollers self - organize into a macroscopic vortex pattern , fig . [ fig4]b and _ supplementary movie 3_. however , at intermediate densities , we found that collective motion emerges in the form of a macroscopic swarm cruising around the circular box through an ensemble of randomly moving particles , fig . [ fig4]c and _ supplementary movie 4_. these swarms are akin to the band patterns consistently reported for polar active particles at the onset of collective motion in periodic domains @xcite . this seeming conflict between our experimental and numerical findings is solved by looking at the variations of the swarm length @xmath51 with the confinement radius @xmath17 in fig . we define @xmath51 as the correlation length of the density fluctuations in the azimuthal direction . the angular extension of the swarms @xmath52 increases linearly with the box radius . therefore , for a given value of the interaction parameters , there exists a critical box size above which the population undergoes a direct transition from a gaseous to an axisymmetric vortex state . for @xmath53 , which was measured to be the typical interparticle distance in the polar liquid state @xcite , this critical confinement is @xmath2 . this value is close to the smallest radius accessible in our experiments where localized swarms were never observed , thereby solving the apparent discrepancy with the experimental phenomenology . more quantitatively , we systematically compare our numerical and experimental measurements in figs . [ fig3]b and [ fig3]c for @xmath2 . even though a number of simplifications were needed to establish eqs . * [ eq1 ] * , * [ eq2 ] * and * [ eq3 ] * @xcite , the simulations account very well for the sharp bifurcation yielding the vortex patterns as well as their self - similar structure . this last point is proven quantitatively in fig . [ fig3]h , which demonstrates that the concentration increases away from the vortex core , where @xmath54 , over a scale that is solely set by the confinement radius . we shall note however that the numerical simulations underestimate the critical packing fraction @xmath21 at which collective motion occurs , which is not really surprising given the number of approximations required to establish the interaction parameters in the equations of motion eq . we unambiguously conclude from this set of results that eqs . * 1 * , * 2 * and * 3 * include all the physical ingredients that chiefly dictate the collective dynamics of the colloidal rollers . we now exploit the opportunity offered by the numerics to turn on and off the four roller - roller interactions one at a time , namely the alignment torque , @xmath55 , the repulsion torque @xmath56 and force @xmath36 , and the dipolar coupling @xmath57 . snapshots of the resulting particle distributions are reported in fig . none of these four interactions alone yields a coherent macroscopic vortex . we stress that when the particles solely interact via pairwise - additive alignment torques , @xmath58 , the population condenses into a single compact polarized swarm . potential velocity - alignment interactions are _ not _ sufficient to yield macroscopic vortical motion . we evidence in fig . [ fig4]e ( top - right and bottom - left panels ) that the combination of alignment ( @xmath59 ) and of repulsive interactions ( @xmath60 and/or @xmath61 ) is necessary and sufficient to observe spontaneously flowing vortices . + * analytical theory . * having identified the very ingredients necessary to account for our observations , we can now gain more detailed physical insight into the spatial structure of the vortices by constructing a minimal hydrodynamic theory . we start from eqs . * 1 * , * 2 * and * 3 * , ignoring the @xmath57 term in eq . * 3*. the model can be further simplified by inspecting the experimental variations of the individual roller velocity with the local packing fraction , see _ supplementary figure 1_. the roller speed only displays variations of 10@xmath62 as @xmath63 increases from @xmath64 to @xmath65 . these minute variations suggest ignoring the contributions of the repulsive forces in eq . * 1 * , and solely considering the interplay between the alignment and repulsion torques on the orientational dynamics of eq . * 2*. these simplified equations of motion are coarse - grained following a conventional kinetic - theory framework reviewed in @xcite to establish the equivalent to the navier - stokes equations for this two - dimensional active fluid . in a nutshell , the two observables we need to describe are the local area fraction @xmath66 and the local momentum field @xmath67 . they are related to the first two angular moments of the one - particle distribution function @xmath68 , which evolves according to a fokker - plank equation derived from the conservation of @xmath69 and eqs . * [ eq1 ] * and * [ eq2]*. this equation is then recast into an infinite hierarchy of equations for the angular moments of @xmath69 . the two first equations of this hierarchy , corresponding to the mass conservation equation and to the momentum dynamics , are akin to the continuous theory first introduced phenomenologically by toner and tu @xcite : @xmath70 where @xmath71 is the usual nematic order parameter . the meaning of the first equation is straightforward , while the second calls for some clarifications . the divergence term on the left - hand side of eq . * [ eq5 ] * is a convective kinematic term associated with the self - propulsion of the particles . the force field @xmath72 on the right - hand side would vanish for non - interacting particles . here , at first order in a gradient expansion , @xmath72 is given by : @xmath73 this force field has a clear physical interpretation . the first term reflects the damping of the polarization by the rotational diffusion of the rollers . the second term , defined by the time rate @xmath74 , echoes the alignment rule at the microscopic level and promotes a nonzero local polarization . the third term , involving @xmath75 , is an anisotropic pressure reflecting the repulsive interactions between rollers at the microscopic level . eqs . * [ eq4 ] * and * [ eq5 ] * are usually complemented by a dynamical equation for @xmath76 and a closure relation . this additional approximation , however , is not needed to demonstrate the existence of vortex patterns and to rationalize their spatial structure . looking for axisymmetric steady states , it readily follows from mass conservation , eq . * [ eq4 ] * , that the local fields must take the simple forms : @xmath77 , @xmath78 and @xmath79 , where @xmath80 . we also infer the relation @xmath81\phi \pi_\varphi=0 $ ] from the projection of the momentum equation , eq . * [ eq5 ] * , on the azimuthal direction . this relation tells us that the competition between rotational diffusion and local alignment results in a mean - field transition from an isotropic state with @xmath27 to a polarized vortex state with @xmath82 and @xmath83 . this transition occurs when @xmath66 exceeds @xmath84 , the ratio of the rotational diffusivity to the alignment strength at the hydrodynamic level . in addition , the projection of eq . * [ eq5 ] * on the radial direction sets the spatial structure of the ordered phase : @xmath85 with again @xmath86 in the ordered polar phase . this equation has a clear physical meaning and expresses the balance between the centrifugal force arising from the advection of momentum along a circular trajectory and the anisotropic pressure induced by the repulsive interactions between rollers . it has an implicit solution given by @xmath87 . \label{eq8}\ ] ] @xmath12 is therefore parametrized by the dimensionless number @xmath88 reflecting the interplay between self - propulsion and repulsive interactions . given the experimental values of the microscopic parameters , @xmath89 is much smaller that unity ( @xmath90 ) . an asymptotic analysis reveals that @xmath91 is the typical core radius of the vortex . for @xmath92 , the density increases slowly as @xmath93 $ ] for all @xmath10 and @xmath17 . as @xmath19 reaches @xmath91 , it increases significantly and then growths logarithmically as @xmath94 away from the vortex core . however , @xmath91 is an integration constant which is solely defined via the mass conservation relation : @xmath95 and therefore only depends on @xmath10 and @xmath17 . @xmath91 does not provide any intrinsic structural scale , and the vortex patterns formed in different confinements are predicted to be self - similar in agreement with our experiments and simulations despite the simplification made in the model , fig . in addition , eq . * [ eq8 ] * implies that the rollers self - organize by reducing their density at the center of the vortex down to @xmath96 , the mean area fraction at the onset of collective motion , again in excellent agreement with our measurements in fig . [ fig3]e . in order to characterize the orientational structure of the vortices , an additional closure relation is now required . the simplest possible choice consists in neglecting correlations of the orientational fluctuations , and therefore assuming @xmath97 . this choice implies that @xmath98 eqs . * [ eq8 ] * and * [ eq9 ] * provide a very nice fit of the experimental polarization curve as shown in fig . [ fig3]b , and therefore capture both the pitchfork bifurcation scenario at the onset of collective motion and the saturation of the polarization at high packing fractions . the best fit is obtained for values of @xmath21 and @xmath99 respectively five and two times larger than those deduced from the microscopic parameters . given the number of simplifications needed to establish both the microscopic and hydrodynamic models , the agreement is very convincing . we are then left with a hydrodynamic theory with no free fitting parameter , which we use to compute the area fraction of the outer polarized ring where @xmath100 . the comparison with the experimental data in fig . [ fig3]f is excellent . furthermore , eqs . * [ eq8 ] * and * [ eq9 ] * predict that the rollers are on the verge of a phase separation . if the roller fraction in the vortex core were smaller ( @xmath101 ) , orientational order could not be supported and an isotropic bubble would nucleate in a polar liquid . this phase separation is avoided by the self - regulation of @xmath102 at @xmath21 . altogether our theoretical results confirm that the vortex patterns stem from the interplay between self - propulsion , alignment , repulsion and confinement . self - propulsion and alignment interactions promote a global azimuthal flow . the repulsive interactions prevent condensation of the population on the geometrical boundary and allow for extended vortex patterns . if the rollers were not confined , the population would evaporate as self - propulsion induces a centrifugal force despite the absence of inertia . we close this discussion by stressing on the generality of this scenario . firstly , the vortex patterns do not rely on the perfect rotational symmetry of the boundaries . as illustrated in _ supplementary figure 2 _ the same spatial organization is observed for a variety of convex polygonal geometries . however , strongly anisotropic , and/or strongly non - convex confinements can yield other self - organized states such as vortex arrays which we will characterize elsewhere . secondly , neither the nature of the repulsive couplings nor the symmetry of the interactions yielding collective motion are crucial , thereby making the above results relevant to a much broader class of experimental systems . for instance , self - propelled particles endowed with nematic alignment rules are expected to display the same large - scale phenomenology . the existence of a centrifugal force does not rely on the direction of the individual trajectories . shaken rods , concentrated suspensions of bacteria , or motile biofilaments , among other possible realizations , are expected to have a similar phase behavior . quantitative local analysis of their spatial patterns @xcite would make it possible to further test and elaborate our understanding of the structure of confined active matter . for instance , the polar order found in confined bacteria is destroyed upon increasing the size of the confinement . the analysis of the spacial distribution of the bacteria could be used to gain insight on the symmetries and the magnitude of the additional interactions mediated by the host fluid which are responsible for the emergence of bacterial turbulence @xcite . in conclusion , we take advantage of a model experimental system where ensembles of self - propelled colloids with well - established interactions self - organize into macrosopic vortices when confined by circular geometric boundaries . we identify the physical mechanism that chiefly dictates this emergent behavior . thanks to a combination of numerical simulations and analytical theory , we demonstrate that orientational couplings alone can not account for collective circular motion . repulsion between the motile individuals is necessary to balance the centrifugal flow intrinsic to any ordered active fluid and to stabilize heterogeneous yet monophasic states in a broad class of active fluids . a natural challenge is to extend this description to the compact vortices observed in the wild , e. g. in shoals of fish . in the absence of confining boundaries , the centrifugal force has to be balanced by additional density - regulation mechanisms @xcite . a structural investigation akin to the one introduced here for roller vortices could be a powerful tool to shed light on density regulation in natural flocks which remains to be elucidated . * experiments . * we use fluorescent pmma colloids ( thermo scientific g0500 , 2.4@xmath103 m radius ) , dispersed in a 0.15 mol.l@xmath104 aot / hexadecane solution . the suspension is injected in a wide microfluidic chamber made of double - sided scotch tapes . the tape is sandwiched between two ito - coated glass slides ( solems , itosol30 , 80 nm thick ) . an additional layer of scotch tape including a hole having the desired confinement geometry is added to the upper ito - coated slide . the holes are made with a precision plotting cutter ( graphtec robo ce 6000 ) . the gap between the two ito electrodes is constant over the entire chamber @xmath105 . the electric field is applied by means of a voltage amplifier ( stanford research systems , ps350/5000v-25w ) . all the measurements were performed 5 minutes after the beginning of the rolling motion , when a steady state was reached for all the observables . the colloids are observed with a 4x microscope objective for particle tracking , piv and number - density measurements . high - speed movies are recorded with a cmos camera ( basler ace ) at a frame rate of 190fps . all images are 2000@xmath1062000 8-bit pictures . the particles are detected to sub - pixel accuracy and the particle trajectories are reconstructed using a matlab version of a conventional tracking code @xcite . the piv analysis was performed with the mpiv matlab code . a block size of @xmath107 m was used . * numerical simulations . * the simulations are performed by numerically integrating the equations of motion eqs . * 1 * and * 2*. particle positions and rolling directions are initialized randomly inside a circular domain . integration is done using an euler scheme with an adaptive time step @xmath108 , and the diffusive term in the equation for the rotational dynamics is modeled as a gaussian variable with zero mean and with variance @xmath109 . steric exclusion between particles is captured by correcting particle positions after each time step so as to prevent overlaps . bouncing off of particles at the confining boundary is captured using a phenomenological torque that reorients the particles towards the center of the disc ; the form of the torque was chosen so at the reproduce the bouncing trajectories observed in the experiments . keber , f. c. , loiseau , e. , sanchez , t. , decamp , s. j. , giomi , l. , bowick , m. j. , marchetti , m. c. , dogic , z. & bausch , a. r. topology and dynamics of active nematic vesicles . _ science _ * 345 * , 11351139 ( 2014 ) . vladescu , i. d. , marsden , e. j. , schwarz - linek , j. , martinez , v. a. , arlt , j. , morozov , a. n. , marenduzzo , d. , cates , m. e. & poon , w. c. k. filling an emulsion drop with motile bacteria . _ * 113 * , 268101 ( 2014 ) . * acknowledgments * we benefited from valuable discussions with hugues chat , nicolas desreumaux , olivier dauchot , cristina marchetti , julien tailleur and john toner . this work was partly funded by the anr program mitra , and institut universitaire de france . d.s . acknowledges partial support from the donors of the american chemical society petroleum research fund and from nsf career grant no . k.s . was supported by the jsps core - to - core program `` non - equilibrium dynamics of soft matter and information '' . * author contributions * a.b . and v.c . carried out the experiments and processed the data . f.p . , and d.s . carried out the the numerical simulations . j .- , k.s . and d.b . established the analytical model . all the authors discussed and interpreted results . , j .- b.c . and d.s . wrote the manuscript . conceived the project . a.b . and j .- b.c . have equally contributed to this work . . the self organization of the population is robust to the shape of the confinement . these pictures show that the same heterogeneous vortex pattern emerge in polygonal confinements which do not have a perfect rotational symmetry . the center of the vortex is dilute and less ordered that the outer region where polar order is pronounced . the shape of the polygonal geometries is reflected by the velocity and density profiles yet the salient features of the vortex is preserved . ] * supplementary discussion 1 @xmath115 dynamics of a single roller * + at low packing fraction , @xmath116 , the colloids behave as non - interacting persistent random walkers . their motion is described by : @xmath117 where @xmath39 is a white noise with zero mean and variance @xmath118 . the velocity autocorrelation function decays exponentially as @xmath119 and the mean - squared displacement is given by : @xmath120 ^ 2 \rangle & = 2 \frac{v_0 ^ 2}{d^2 } \left ( d t - 1 + \mathrm e^{-d t } \right ) . \end{aligned}\ ] ] the later expressions are used to fit the experimental data , fig . 2e ( main text ) and supplementary figure 3 below , and provide the following values for the particle speed and diffusivity : @xmath121 + * supplementary discussion 2 @xmath115 population of interacting rollers * + * microscopic model . * in @xcite , we have theoretically described the microscopic dynamics of a population of colloids rolling on a conducting surface . we briefly summarize this model . a colloid powered by the quincke mechanism , when rotating close to a wall , exchanges momentum with this solid surface and translates at a speed given by @xmath122 @xmath123 is the critical electric field below which the particle does not rotate . the maxwell - wagner time @xmath124 characterizes the dynamics of the electric charges at the colloid surface , which are responsible for the quincke instability . @xmath125 and @xmath126 are mobility coefficients accounting for the viscous drag exerted by the liquid in the vicinity of solid wall that depend logarithmically on the distance to the solid wall @xcite . in order to account for the roller - roller interactions at long distances , we have computed the electrostatic and hydrodynamic fields induced by the motion of a colloid . assuming pairwise additive interactions , we have shown that these fields promote the alignement of the velocity of neighboring particles . within this framework , the speed of the colloids is taken to be a constant as it relaxes to @xmath14 much faster than the typical timescale of the orientation dynamics . in addition to these far - field couplings , we model the short - distance repulsion between colloids by an effective hard - core potential . the resulting equations of motion are given by eqs . [ 1][3 ] in the main text , where the functions @xmath43 , @xmath45 , @xmath48 are given by : @xmath127 + c_2\left(\frac{a}{r}\right)^5\theta(r ) .\end{aligned}\ ] ] these electrostatic and hydrodynamic couplings are exponentially screened over a distance set by the channel height @xmath20 ( see fig . 1a , main text ) . for sake of simplicity , we approximate the screening function @xmath128 by the step function @xmath129 if @xmath130 and @xmath131 otherwise . in addition , the coefficients of the above functional forms are given by : @xmath132 , \\ & c_1 = a_1 , \\ & c_2 = \frac{5}{3 } a_2.\end{aligned}\ ] ] @xmath125 and @xmath133 are mobility coefficients which only depend on the viscosity of the liquid and the gap @xmath134 between the colloid and the surface . @xmath135 depends on the dielectric permittivities @xmath136 and @xmath137 of the liquid and of the particles : @xmath138 the derivation of this model is provided in the supplementary informations of @xcite . + * estimation of the simulation parameters . * in order to perform numerical simulations relevant to our experimental conditions , we have estimated the coefficients of the equations of motion as follows . the speed @xmath14 and the rotational diffusivity @xmath139 have been deduced from the single - particle dynamics , eqs . and . the threshold electric field @xmath123 is measured experimentally as the critical value at which the colloids start moving . we use typical values for the dielectric permittivities of hexadecane ( @xmath140 ) and pmma colloids ( @xmath141 ) @xcite to evaluate @xmath142 . the mobility coefficients are estimated . we assume the distance between a particle and the surface to be @xmath143 . although this parameter is not controlled precisely , it only yields small corrections to the mobility coefficients in the limit @xmath144 , and weakly impacts the particle dynamics . using the expressions derived in @xcite , we find @xmath145 , @xmath146 and @xmath147 . finally , the maxwell - wagner time @xmath124 was calculated from eq . : @xmath148 . as a result , we obtain the following values for the microscopic coefficients : @xmath149 , @xmath150 , and @xmath151 . +

coherent vortical motion has been reported in a wide variety of populations including living organisms ( bacteria , fishes , human crowds ) and synthetic active matter ( shaken grains , mixtures of biopolymers ) , yet a unified description of the formation and structure of this pattern remains lacking . here we report the self - organization of motile colloids into a macroscopic steadily rotating vortex . combining physical experiments and numerical simulations , we elucidate this collective behavior . we demonstrate that the emergent - vortex structure lives on the verge of a phase separation , and single out the very constituents responsible for this state of polar active matter . building on this observation , we establish a continuum theory and lay out a strong foundation for the description of vortical collective motion in a broad class of motile populations constrained by geometrical boundaries . building upon the pioneering work of vicsek et al . @xcite , physicists , mathematicians and biologists have contemplated the self - organization of living - organism groups into flocks as an emergent process stemming from simple interaction rules at the individual level @xcite . this idea has been supported by quantitative trajectory analysis in animal groups @xcite , together with a vast number of numerical and theoretical models @xcite , and more recently by the observations of flocking behavior in ensembles of non - living motile particles such as shaken grains , active colloids , and mixtures of biofilaments and molecular motors @xcite . from a physicist s perspective , these various systems are considered as different instances of polar active matter , which encompasses any ensemble of motile bodies endowed with local velocity - alignment interactions . the current paradigm for flocking physics is the following . active particles are persistent random walkers , which when dilute form a homogeneous isotropic gas . upon increasing density , collective motion emerges in the form of spatially localized swarms that may cruise in a sea of randomly moving particles ; further increasing density , a homogeneous polar liquid forms and spontaneously flows along a well - defined direction @xcite . this picture is the outcome of experiments , simulations and theories mostly performed in unbounded or periodic domains . beyond this picture , significant attention has been devoted over the last five years to confined active matter @xcite . confined active particles have consistently , yet not systematically , been reported to self - organize into vortex - like structures . however , unlike for our understanding of flocking , we are still lacking a unified picture to account for the emergence and structure of such vortex patterns . this situation is mostly due to the extreme diversity in the nature and symmetries of the interactions between the active particles that have been hitherto considered . do active vortices exist only in finite - size systems as in the case of bacterial suspensions @xcite , which lose this beautiful order and display intermittent turbulent dynamics @xcite when unconfined ? what are the necessary interactions required to observe and/or engineer bona fide stationary swirling states of active matter ? in this paper , we answer these questions by considering the impact of geometrical boundaries on the collective behavior of motile particles endowed with velocity - alignment interactions . combining quantitative experiments on motile colloids , numerical simulations and analytical theory , we elucidate the phase behavior of _ polar _ active matter restrained by geometrical boundaries . we use colloidal rollers which , unlike most of the available biological self - propelled bodies , interact via well established dynamical interactions @xcite . we first exploit this unique model system to show that above a critical concentration populations of motile colloids undergo a non - equilibrium phase transition from an isotropic gaseous state to a novel ordered state where the entire population self - organizes into a single heterogeneous steadily rotating vortex . this self - organization is _ not _ the consequence of the finite system size . rather , this emergent vortex is a genuine state of polar active matter lying on the verge of a macroscopic phase separation . this novel state is the only ordered phase found when unidirectional directed motion is hindered by convex isotropic boundaries . we then demonstrate theoretically that a competition between alignment , repulsive interactions and confinement is necessary to yield large - scale vortical motion in ensembles of motile particles interacting via alignment interactions , thereby extending the relevance of our findings to a broad class of active materials .

Donald Trump’s tweet was a tacit attack on House Speaker Paul Ryan. | Getty Trump: 'It is so nice that the shackles have been taken off me' Donald Trump celebrated his freedom from the Republican establishment Tuesday, boasting that it’s “so nice” to be unchained. Trump’s tweet was a tacit attack on House Speaker Paul Ryan, whom the Republican nominee has continued to lash out at since the top elected Republican on Monday told his conference he would no longer defend Trump. Story Continued Below “It is so nice that the shackles have been taken off me and I can now fight for America the way I want to,” Trump tweeted. The real estate mogul also highlighted the chasm in the Republican Party, conceding that Democrats are “far more loyal” than the GOP. More than two dozen Republicans have either said they will no longer support their nominee or called on him to step aside from the top of the ticket since a tape emerged Friday showing Trump speaking in incredibly lewd terms about sexually assaulting women. “With the exception of cheating Bernie out of the nom the Dems have always proven to be far more loyal to each other than the Republicans!” Trump wrote. Trump began blasting Ryan on Twitter at about 8 a.m., when he posted a tweet criticizing the GOP leader for not supporting him and followed up by calling him “weak and ineffective.” ||||| Tweet with a location You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| Tweet with a location You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more

– In a Twitter storm on Tuesday, Donald Trump implied he'd been chained to the Republican Party for too long. But in the wake of recent denouncements from dozens of Republicans, including Paul Ryan, "the shackles have been taken off me and I can now fight for America the way I want to," he said, per Politico. In what is widely viewed as evidence of a widening rift in the Republican Party, Trump went on to bash Ryan as a "very weak and ineffective leader" and label Democrats—"with the exception of cheating Bernie"—as "far more loyal to each other" than Republicans. "Despite winning the second debate in a landslide (every poll), it is hard to do well when Paul Ryan and others give zero support!" he continued, adding, Republicans "are far more difficult than Crooked Hillary." Bustle's take: Trump's "going rogue and it could get scary." In response, a rep says Ryan "is focusing the next month on defeating Democrats, and all Republicans running for office should probably do the same," per USA Today. Despite several GOP members calling on Trump to remove himself from the presidential race, the nominee vowed Tuesday to teach Republicans "how to win."

sarcoidosis is a multisystem disorder characterized by the presence of noncaseating granulomas in affected tissues . the most commonly affected organs are the lungs and lymph nodes , followed by the liver , although several other organs can also be involved , including the liver , skin , eyes , heart , and brain . previous reports have documented evident liver involvement in approximately 5080% of cases by biopsy and approximately 70% by autopsy . however , the diagnosis of hepatic sarcoidosis is difficult because liver dysfunction is often mild and the condition is clinically silent in most cases . furthermore , hepatic sarcoidosis rarely causes severe complications such as jaundice , liver failure , cirrhosis , and portal hypertension , and the symptoms of cirrhosis or portal hypertension are reportedly present in 1% of the cases . granulomas may lead to chronic intrahepatic cholestasis with the loss of interlobular bile ducts , and these conditions may sequentially lead to the development of periportal fibrosis or micronodular cirrhosis . in addition , the association of hepatic sarcoidosis with hepatocellular carcinoma ( hcc ) is thought to be considerably rare . here we report a rare case of a 75-year - old male who was diagnosed with hcc associated with sarcoidosis and was treated by subsegmentectomy of the liver and cholecystectomy . a 75-year - old male was referred to our hospital for an abnormal liver mass detected on ultrasonography during a periodic medical checkup . he had no symptoms , although he had a medical history of arterial hypertension and type 2 diabetes mellitus that was controlled by an oral hypoglycemic agent for several years . his preoperative laboratory data were as follows : platelet count , 193 10/l ( normal , 120330 103/l ) ; albumin , 3.3 g / dl ( normal , 4.05.0 g / dl ) ; total bilirubin , 0.3 mg / dl ( normal , 0.21.0 mg / dl ) ; aspartate aminotransferase , 53 iu / l ( normal , 1128 iu / l ) ; alanine aminotransferase , 49 iu / l ( normal , 630 iu / l ) ; blood urea nitrogen , 24.2 mg / dl ( normal , 8.021.0 mg / dl ) ; creatinine , 1.60 mg / dl ( normal , 0.631.05 mg / dl ) ; prothrombin time international normalized ratio , 0.98 ; and indocyanine green retension rate at 15 min , 6.6% . high serum levels of blood urea nitrogen and creatinine were evident , but urinary output was preserved and serum potassium level was not elevated . in addition , proteinuria ( 2.5 g / day ) and hypoalbuminemia were observed . judging from his medical history , diabetic nephropathy was thought to be responsible for these abnormal findings , although a renal biopsy for definitive diagnosis was not performed . moreover , the elevation of the tumor markers such as serum alpha - fetoprotein ( 88.0 ng / ml ; normal , 0.010.0 ng / ml ) and des - gamma - carboxy prothrombin ( 76 mau / ml ; normal , 0.039.9 mau / ml ) was detected ; however , test results for serum hepatitis b virus surface antigen , hepatitis b virus core antibodies , and hepatitis c virus antibodies were negative . abdominal computed tomography ( ct ) revealed a 3 2 cm hypervascular tumor with washout of contrast - medium located in the right posterior section of the liver ( fig . the tumor showed no gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid ( gd - eob - dtpa ) uptake and demonstrated hypointensity on hepatocyte - phase images obtained by gd - eob - dtpa magnetic resonance imaging ( fig . subsequently , subsegmentectomy ( segment vi ) of the liver and cholecystectomy were performed for the diagnosis of hcc . the resected solid encapsulated tumor measured 2.6 2.3 cm , and contained a septum that was evident on macroscopic examination ( fig . 2a ) . a histopathological examination of the resected specimen revealed tumor cells that resembled hepatocytes and grew in cords of variable thicknesses with bile plugs . small non - necrotizing granulomas with a tendency to coalesce were scattered in ( fig . no evidence of liver cirrhosis was found , but a slight degree of fibrosis was observed around the portal areas ( fig . in addition , vascular invasion and intrahepatic metastases were not apparent , and no features of steatohepatitis or any other liver diseases were observed . on the basis of these findings , bilateral hilar lymphadenopathy with uptake of 18f - fluorodeoxyglucose was observed on positron emission tomography / ct ( fig . the diagnosis of hepatic sarcoidosis is difficult , because liver dysfunction is usually mild and the condition is clinically silent in most cases . cirrhosis or portal hypertension has been reported in 1% of all sarcoidosis cases . in other reports , 13% fo the patients with hepatic sarcoidosis exhibit liver involvement without lung disease and approximately 3540% have abnormal liver function test results , which are most commonly indicated by alkaline phosphatase levels . less frequently , multiple , tiny , low - density nodules are detected on abdominal ct and liver enlargement is observed in approximately 50% of patients with nodular hepatosplenic sarcoidosis . however , the lymph nodes and lungs are most commonly involved , followed by the liver , and hepatic sarcoidosis rarely causes severe complications such as jaundice , liver failure , cirrhosis , or portal hypertension . in addition , the association of hepatic sarcoidosis with hcc is thought to be considerably rare . cirrhosis is an obvious risk factor for the development of hcc , but the mechanisms by which cirrhosis predisposes to carcinogenesis are poorly understood . numerous studies have shown that chronic inflammation and oxidative stress increase the risk of carcinogenesis , and several recent studies have demonstrated that oxidative stress can enhance the malignant potential of hcc through telomerase activation . chronic inflammation and oxidative stress because of sarcoidosis may be associated with an increased risk of the development of hcc . our patient suffered from type 2 diabetes mellitus which is reportedly a potential risk factor for hcc ; therefore , additive or synergistic adverse effects to the liver because of both sarcoidosis and diabetes mellitus may promote the development of hcc . previous studies have demonstrated an increased risk of hcc in patients with sarcoidosis ; however , this result is thought to be controversial because there was no mention of hepatitis b or c infection , alcohol addiction , or autoimmune status of the patients . on the other hand , a direct causal link between hcc and sarcoidosis was not detected by reviewing this case . although the coincidence of these two diseases may be possible , this potential comorbidity can not be predicted by case series . by reviewing previous cases , we found only five ( four males and one female ) that described patients diagnosed with hcc associated with sarcoidosis ( table 1 ) . the mean age of the patients , including our patient , was 57.0 12.5 years . case 1 presented with incidental manifestation of sarcoidosis and hcc - associated liver cirrhosis , which terminated in a rupture into the peritoneal cavity . cardiac involvement was considered as a cause of complete a - v block before death in this patient . case 2 also developed tumor rupture , and cases 3 and 4 were inoperable because of large tumor size . in contrast , radical hepatectomy was performed at an earlier stage of disease in case 5 and our patient , and both of these patients have remained healthy with no recurrences or metastases at the latest follow - up visit . these findings suggest that the outcomes of patients with hcc associated with sarcoidosis can be improved if surgery is performed at an earlier stage of disease . periodic checkups of the liver should be conducted in patients with systemic sarcoidosis , regardless of the presence of liver cirrhosis . written consent was obtained from the patient and a copy of the written consent is available for review by the editor - in - chief of this journal on request . conception and design , takuma arai and shiro miwa ; collection and assembly of data , masahiro sakon , shingo akita , taishi fujii , haruki tanaka , and keiko ishii ; data analysis and interpretation , takuma arai ; manuscript writing , takuma arai ; final approval of manuscript , takuma arai , masahiro sakon , shingo akita , taishi fujii , haruki tanaka , keiko ishii , and shiro miwa .

introductionthe association of hepatic sarcoidosis with hepatocellular carcinoma ( hcc ) is considerably rare . here we report a rare case of hcc associated with sarcoidosis.presentation of casea 75-year - old male with no history of alcohol addiction or viral hepatitis was referred to our hospital because of an abnormal liver mass . subsegmentectomy of the liver was performed for the diagnosis of hcc . a histopathological examination revealed small non - necrotizing granulomas with a tendency to coalesce that were scattered in and around the carcinoma . no features of cirrhosis , steatohepatitis , and any other liver diseases were observed . furthermore , swelling of the bilateral lung hilar lymph nodes with uptake of 18f - fluorodeoxyglucose was found on positron emission tomography / computed tomography and the tuberculin reaction test results were negative . on the basis of these findings , the final diagnosis of hcc associated with sarcoidosis was confirmed.discussionby reviewing previous cases , we found only five cases that described patients diagnosed with hcc associated with sarcoidosis . of these , four patients died within two years after diagnosis because of ruptures or inoperable huge tumors . in contrast , radical hepatectomy was performed at an earlier stage of disease in two patients , including ours , and both these patients have remained healthy with no recurrences or metastases at the latest follow - up visit.conclusionperiodic checkups of the liver should be conducted for patients with systemic sarcoidosis , regardless of the presence of liver cirrhosis .

comprehensive understanding of the nature and origin of gas flows in the very central regions of agns is elusive despite decades of intensive investigation . presence of outflows with very large velocities ( @xmath220000 km s@xmath3 ) is revealed by the broad as well as narrow absorption lines ( bals and nals ) observed in the spectrum of agns . it has been suggested for long that the momentum transfered through resonance absorption lines could play an important role in driving these flows as it does in the case of o star winds ( castor , abbott & klein 1975 ; arav , li , & begelman 1994 ) . however , signatures of acceleration , though claimed to be noted in nearby seyfert galaxy ngc 3515 ( hutchings et al . 2001 ) , are not generic . a possible way to reveal line - driven acceleration is the presence of absorption features with velocity separation similar to doublet and/or multiplet splittings ( a consequence of the so - called `` line - locking '' effect ) . such a structure in absorption is achieved when there is a reduction in the flux that drives the far away gas element due to line absorption produced by the gas closer to the qso ( scargle 1973 ; braun & milgrom 1989 ) . for higher efficiency , the gas from different elements of the flow must cover the same region of the background source . since the gas producing intrinsic absorption is known to cover the background source only partially ( petitjean et al . 1994 ; hamann 1997 ; barlow & sargent 1997 ) , line - locking can be achieve in this case if the flow is somehow collimated . this may be one of the reasons why tentative evidences for line - locking ( foltz et al . 1987 ; srianand 2000 ; srianand & petitjean 2001 ; vilkoviskiji & irwin 2001 ) as well as double trough ( the so - called lyman - alpha ghost ) seen in the mean profile of bals ( weymann et al . 1991 ; korista et al . 1993 ; arav , li & begelman 1994 ) are not completely convincing . in this paper we present clear evidence for a flow that is highly structured through radiative pressure modulated by absorption in different resonance lines . cclc & & & + @xmath4 & 2.8186 & c iv & [email protected] + @xmath6 & 2.8398 & c iv & [email protected] + @xmath7 & 2.8523 & ly @xmath8 & [email protected] + & & ly series & [email protected] + & & c iv & [email protected] + & & si iv & [email protected] + & & n v@xmath10&[email protected] + @xmath11 & 2.8607 & ly @xmath12 & @xmath13 + & & ly series & [email protected] + & & al iii&[email protected] + & & c iv & @xmath14 + & & si iv & @xmath15 + @xmath16 & 2.8641 & c iv & [email protected] + & & n v & [email protected] + @xmath17(blue ) & 2.8908 & ly @xmath18 & @xmath19 + & & c iv & @xmath20 + & & si iv & [email protected] + & & n v & [email protected] + @xmath17(red ) & 2.8934 & ly @xmath18 & @xmath19 + & & c iv & @xmath20 + & & si iv & [email protected] + & & n v & [email protected] + [ tab1 ] we have used the ultra - violet and visible echelle spectrograph uves ( dodorico et al . 2000 ) mounted on the eso kueyen 8.2 m telescope at the paranal observatory on april 4 - 7 2000 to obtain a high - spectral resolution spectrum of the @xmath21 = 2.878 and @xmath22 = 17 quasar q 1511 + 091 . two standard dichroic settings have been used to observe with both arms of the spectrograph at the same time . the final wavelength range is 3260@xmath910,000 . the slit width was 1 arcsec resulting in a resolution of @xmath245000 . the total exposure time was 10 hours in seeing conditions better than 0.8 arcsec full width at half maximum . the data were reduced using the uves pipeline , a set of procedures implemented in a dedicated context of midas , the eso data reduction package . the main characteristics of the pipeline is to perform a precise inter - order background subtraction for science frames and master flat - fields , and to allow for an optimal extraction of the object signal rejecting cosmic ray impacts and performing sky - subtraction at the same time . the reduction is checked step by step . wavelengths were corrected to vacuum - heliocentric values and individual 1d spectra were combined together . this resulted in a s / n ratio per pixel of 25 at @xmath23600 and 80 at @xmath26000 . typical errors in the wavelength calibration are less than @xmath20.5 km s@xmath3 . the uves spectrum of q 1511 + 091 over the c iv and si iv emission line wavelength ranges is shown in the left - hand side panels of fig . [ fig1 ] together with the fit to the effective continuum ( i.e. , quasar continuum plus broad emission lines ) we used to normalize the spectrum . partial coverage of the absorbing gas implies some residual at the bottom of absorption lines even if they are heavily saturated . partial coverage is apparent when the two resolved lines of a doublet , with different oscillator strengths , have the same apparent residuals without going to zero . this is obviously the case for most of the components in the c iv flow toward q 1511 + 091 . the two absorption lines of the c iv doublet corresponding to components * a * , * c * , * d * and * f * have exactly the same apparent depths over their profiles . it can be seen on right panels of fig . [ fig1 ] that when the spectrum is shifted by the velocity separation of the two lines of the c iv doublet , the profiles coincide nearly perfectly for most of the wavelength range . using the method described in srianand & shankaranarayanan ( 1999 ) we estimated the covering factor for different species in individual components . the results are given in table . [ tab1 ] . it is possible to say that different part of the flow cover the same background region . indeed , it can be noted that when of one component , say component 1 , overlaps with of another component , say component 2 , the resultant optical depth , although smaller than 0.5 is not the sum of the optical depths of the two absorption lines . this is particularly striking for of component * e * and of component * d * or for of component * g * and of component * e*. this can be understood if one of the saturated components , say component 1 , is shielding the other component , say component 2 in such a way that the flux supposed to reach component 2 in is absorbed completely by component 1 in c iv@xmath231550 . this explains why , although blending is apparent , the profile matches so closely the same profile shifted by the velocity splitting between the two lines ( see fig . [ fig2 ] ) . this shows that at least part of the flow is collimated and covers the same part of the emitting region . .velocity splitting among distinct components [ cols="^,^,^,^ " , ] [ tab2 ] the most striking observation in this flow is that the velocity differences between distinct components coincide with various doublet velocity splittings ( see fig [ fig2 ] and table . [ tab2 ] ) . the most apparent coincidences are seen for the doublet splitting . both the lines of components * c * and * d * match very closely . not only the velocity difference between the centroids of the two components is very close to the doublet splitting but also the residual intensities and the widths of the components ( @xmath24 @xmath2 300 km s@xmath3 ) are nearly identical . very good matchings are also seen for one of the lines of * e * and * h * and * d * and * f*. in addition to this we notice that components * h * ( defined by weak albeit broad and absorptions ) and * j * are separated by the doublet splitting ( see fig . [ fig2 ] ) . for the splitting , coincidences are seen for components * a * and * c * , * c * and * e * ( with similar residuals ) . this is complemented by coincidences with splitting between * b * and * c * but mostly between * e * and * g * and between component * i * and diffuse absorption component * j*. in a spectral range where crowding of absorption lines is so important , chance coincidences are possible . in order to consider the probability that such coincidences occur by chance , we randomly populated the observed velocity range with 10 components . using 10@xmath25 realizations we find a probability of 6@xmath26 for the occurrence of , at least two coincidences , each with the velocity splittings of the , or doublets with a matching uncertainty of @xmath520 . if we introduce the additional condition that at least two coincidences occur between three components in splitting ( like the one seen among * a*-*c * and * c*-*e * ) the probability becomes @xmath27 for a wavelength matching uncertainty of @xmath520 . this low probability for mere velocity coincidence together with tight matching of some of the profiles and consistent covering factors clearly confirms the line - locking situation in this system . it must be noted that , although the corresponding wavelength range is crowded by intervening lines , additional coincidences are apparent between the corresponding absorptions . in addition , the velocity separation between components * a * and the red component of * i * ( @xmath28 km s@xmath3 ) is very close to the to velocity splitting . therefore , all components are connected by a complex set of coincidences . under the assumption that line - locking is structuring the flow , it is expected that components with larger covering factors be located closer to the source . this would imply in that case that the flow is an accelerating wind . the physical conditions in part of the flow can be investigated from the very peculiar component * e * at = 2.8606 ( @xmath91350 km s@xmath3 in fig . [ fig2 ] ) . absorption lines from h i lyman series lines as well as excited levels of singly ionized species and are present ( see fig . [ fig3 ] and from c ii to p v. however , none of the lyman series absorption lines are dark . lyman-@xmath18 is not even seen as a distinct component when it should be conspicuous . similar situation was observed by telfer et al . ( 1998 ) toward qso sbs 1542 + 531 . from the flat bottom of the lyman-@xmath29 line , it is apparent that the cloud does not cover the background source completely . higher lyman series lines are well fitted with a covering factor of the order of 0.4 . it must be noted that the emission lines for the corresponding transitions are negligible compared to the continuum . in addition , such a low covering factor can not be accommodated by scattered light ( ogle et al . therefore , it can be concluded that _ the cloud covers only about 40% of the central source of continuum _ whose radius is of the order of 10@xmath30 pc . all neutral hydrogen lines can be fitted consistently ( see fig . [ fig3 ] ) with @xmath31 and log @xmath32(h i ) @xmath2 16.30 . a consistent model for all other absorption lines is found with this covering factor ( see fig . [ fig4 ] ) and using the al iii and si iii profiles as templates for , respectively , the singly - ionized and high - ionization species . the difference between the two profiles is mainly due to an extra component in the red wing that is seen in si iii and other higher ionization lines . note that although the centroids of the lines are the same , the width of the lines increases with ionization . it is striking to note that with this covering factor , the ratios c ii@xmath33/c ii and si ii@xmath33/si ii are found to be both of the order of two which is the value expected in case of thermal equilibrium . given the ionization state of the gas ( see below ) , the temperature is most probably larger than 10@xmath34 k , and from the thermal equilibrium between populations of si ii levels we can derive the electronic density @xmath3510@xmath36 @xmath37 cm@xmath30 ( t@xmath39 is the temperature in the units of 10@xmath34 k ) . for a mathews & ferland ( 1987 ) qso ionizing spectrum , and using the constraints from observed ion ratios , the ratio of the ionizing photon density to the hydrogen particle density ( the so - called ionization parameter , u ) can be shown to be in the range @xmath92.0 @xmath40 log @xmath41 @xmath40 @xmath90.6 . the metallicities are most probably larger than solar . this is somewhat consistent with the typical values obtained for the broad line region , @xmath91.0 @xmath40 log @xmath41 @xmath40 @xmath90.0 and @xmath42 @xmath43 cm@xmath30 , although the density is probably smaller in the cloud ( see below ) . assuming a typical luminosity density at the lyman limit of @xmath44 , and a spectral index of @xmath45 the maximum distance of the absorbing gas from the source is @xmath46 . the lower limit on @xmath47 derived above suggests the gas has to be at a distance less than a few kpc from the ionizing source . from the absence of absorption due to c iii@xmath48 originating from an excited metastable level , we derive an upper limit on the density of 8@xmath49 cm@xmath30 . this gives a minimum distance of a few 10@xmath3 pc . thus the observations are consistent with the absorbing gas being inside or close to the blr . for a spherical absorbing cloud the particle density is @xmath50(h)/@xmath51 , where @xmath52 and @xmath32(h ) are the radius of the continuum emitting region and the total hydrogen column density of the absorbing gas ( in the range , @xmath53 @xmath32(h)@xmath54 @xmath55 , from the models ) respectively . for the lower limit on density we get , @xmath56pc . the largest blue - shift observed in the c iv profile is much smaller than the typical terminal velocities of bal flows . this probably means that the gas could be further accelerated . indeed , for physical conditions similar to those observed in different components of the q 1511 + 091 outflow , the line - radiation force is much larger than gravity even in the close proximity of the black - hole ( de kool & begelman 1995 ) . most of the hydrodynamical radiatively driven wind models predict the gas to reach terminal velocity at a distance of a few pc from the ionizing source ( arav et al . lack of acceleration in components with velocity much lower than the terminal velocity could be accounted for if either our line of sight probes a small portion of a non - radial flow ( arav 1996 ) or the extra drag forces are at play in reducing the effective acceleration of the gas . in the case of q 1511 + 091 , the absorption lines are seen at redshift very close to or slightly higher than the systemic redshift . in addition , nearly perfect velocity matching with doublet splittings suggests that the direction of the flow is very close to our line of sight . disk winds have been suggested as the natural origin for ejected material from quasars giving rise to bal systems ( de kool & begelman 1995 ; murray et al . 1995 ; proga et al . 2000 ) . in these models , a cylindrically symmetric disk wind is ejected away from the surface of the disk and is radiatively accelerated radially once exposed to the strong continuum source . line - driven instabilities could lead to the formation of distinct velocity components seen in the flow ( feldmeier et al . our observations illustrated in fig . [ fig5 ] support the basic mechanism at work in these models . it would be very interesting to constrain the acceleration over a large time - scale for our understanding of the nature of drag forces and in general the nature of the flow . we thank the referee , dr . n. arav , for useful comments . we gratefully acknowledge support from the indo - french centre for the promotion of advanced research ( centre franco - indien pour la promotion de la recherche avance ) under contract no . this work was supported in part by the european communities rtn network `` the physics of the intergalactic medium '' . rs thanks the institute of astronomy in cambridge and the institut dastrophysique de paris and ppj thanks iucaa for hospitality during the time part of this work was completed . arav n. , 1996 , apj , 465 , 617 arav n. & begelman m. , 1994 , apj , 434 , 479 arav n. , li z. , begelman m. , 1994 , apj , 432 , 62 barlow t. a. & sargent w. l. w. , 1997 , aj , 113 , 136 braun e. & milgrom m. , 1989 , apj , 342 , 100 castor j. i. , abbott d. c. , klein r. i. , 1975 , apj , 195 , 157 . de kool m. & begelman m. c , 1995 , apj , 455 , 448 dodorico s. , et al . , 2000 , spie , 4005,1 feldmeier a. , norman c. , pauldrach a. , owocki s. , puls j. , kaper , l. , 1997 , in mass ejection from active galactic nuclei , asp conference series , vol , 128 , p258 . foltz c. b. , weymann r. j. , morris s. l. , turnshek d. a. , 1987 , apj , 317 , 450 hamann f. , 1997 , apjs , 109 , 279 hutchings j. b. , et al . , 2001 , apj , 559 , 173 korista t. k. , voit g. m. , morris s. l. , weymann r. j. , 1993 , apjs , 88 , 357 mathews w. g. & ferland g. j. , 1987 , apj , 323,456 murray n. , chiang j. , grossman a. , voit m. , 1995 , apj . 441 , 498 ogle p. m. , cohen m. h. , mill j. s. , tran h. d. , goodrich r. w. , martel a. r. , 1999 , apjs , 125 , 1 petitjean p. , rauch m. , carswell r. f. , 1994 , a&a , 291,29 proga d. , stone j. m. , kallman t. r. , 2000 , apj , 543 , 686 sargent , w. l. w. , steidel , c. c. , & boksenberg , a. 1988 , apjs , 68 , 539 scargle j. d. , 1973 , apj , 179 , 705 srianand r. , 2000 , apj , 528 , 617 srianand r. & petitjean p. , 2001 , a&a , 357 , 414 srianand r. & shankaranarayanan , 1999 , apj , 518 , 672 telfer r. c. , kriss g. a. , zheng w. , davidsen a. f. , green r. f. , 1998 , apj , 509 , 132 vilkoviskiji e. y. & irwin m. j. , 2001 , mnras , 321 , 4 weymann r. j. , morris s. l. , foltz c. b. , hewett p. c. , 1991 , apj , 373 , 25

high velocity outflows from quasars are revealed by the absorption signatures they produce in the spectrum of the quasar . clues on the nature and origin of these flows are important for our understanding of the dynamics of gas in the central regions of the active galactic nucleus ( agns ) but also of the metal enrichment of the intergalactic space . line radiation pressure has often been suggested to be an important process in driving these outflows , however no convincing evidence has been given so far . here we report observation of a highly structured flow , toward q 1511 + 091 , where the velocity separations between distinct components are similar to o vi , n v and c iv doublet splittings with some of the profiles matching perfectly . this strongly favors the idea that the absorbing clumps originate at similar physical location and are driven by radiative acceleration due to resonance lines . the complex absorption can be understood if the flow is highly collimated so that the different optically thick clouds are aligned and cover the same region of the background source . one component shows saturated h i lyman series lines together with absorptions from excited levels from c ii and si ii but covers only 40% of the source of continuum . the fact that clouds cover only part of the small continuum source implies that the flow is located very close to it . -0.3 cm 2h@xmath0 _ quasars : _ absorption lines _ quasars : _ individual : q1511@xmath1091

SECTION 1. SHORT TITLE. This Act may be cited as the ``Brown Tree Snake Control and Eradication Act of 2004''. SEC. 2. DEFINITIONS. In this Act: (1) Brown tree snake.--The term ``brown tree snake'' means the species of the snake Boiga irregularis. (2) Compact of free association.--The term ``Compact of Free Association'' means the Compacts of Free Association entered into between the United States and the governments of the Federated States of Micronesia and the Republic of the Marshall Islands, as approved by and contained in Public Law 108-188 (117 Stat. 2720; 48 U.S.C. 1921 et seq.), and the Compact of Free Association entered into between the United States and the government of the Republic of Palau, as approved by and contained in Public Law 99-658 (100 Stat. 3673; 48 U.S.C. 1931 et seq.). (3) Freely associated states.--The term ``Freely Associated States'' means the Republic of Palau, the Federated States of Micronesia, and the Republic of the Marshall Islands. (4) Introduction.--The terms ``introduce'' and ``introduction'' refer to the expansion of the brown tree snake outside of the range where this species is endemic. (5) Secretary.--The term ``Secretary concerned'' means-- (A) the Secretary of the Interior, with respect to matters under the jurisdiction of the Department of the Interior; and (B) the Secretary of Agriculture, with respect to matters under the jurisdiction of the Department of Agriculture. (6) Secretaries.--The term ``Secretaries'' means both the Secretary of the Interior and the Secretary of Agriculture. (7) Technical working group.--The term ``Technical Working Group'' means Brown Tree Snake Technical Working Group established under the authority of section 1209 of the Nonindigenous Aquatic Nuisance Prevention and Control Act of 1990 (16 U.S.C. 4728). (8) Territorial.--The term ``territorial'', when used to refer to a government, means the Government of Guam, the Government of American Samoa, and the Government of the Commonwealth of the Northern Mariana Islands, as well as autonomous agencies and instrumentalities of such a government. (9) United states.--The term ``United States'', when used in the geographic sense, means the several States, the District of Colombia, American Samoa, Guam, the Commonwealth of the Northern Mariana Islands, the Commonwealth of Puerto Rico, the United States Virgin Islands, any other possession of the United States, and any waters within the jurisdiction of the United States. SEC. 3. SENSE OF CONGRESS REGARDING NEED FOR IMPROVED AND BETTER COORDINATED FEDERAL POLICY FOR BROWN TREE SNAKE INTRODUCTION, CONTROL, AND ERADICATION. It is the sense of Congress that there exists a need for improved and better coordinated control, interdiction, research, and eradication of the brown tree snake on the part of the United States and other interested parties. SEC. 4. BROWN TREE SNAKE CONTROL, INTERDICTION, RESEARCH AND ERADICATION. (a) Funding Authority.--Subject to the availability of appropriations to carry out this section, the Secretaries shall provide funds to support brown tree snake control, interdiction, research, and eradication efforts carried out by the Department of the Interior and the Department of Agriculture, other Federal agencies, States, territorial governments, local governments, and private sector entities. Funds may be provided through grants, contracts, reimbursable agreements, or other legal mechanisms available to the Secretaries for the transfer of Federal funds. (b) Authorized Activities.--Brown tree snake control, interdiction, research, and eradication efforts authorized by this section shall include at a minimum the following: (1) Expansion of science-based eradication and control programs in Guam to reduce the undesirable impact of the brown tree snake in Guam and reduce the risk of the introduction or spread of any brown tree snake to areas in the United States and the Freely Associated States in which the brown tree snake is not established. (2) Expansion of interagency and intergovernmental rapid response teams in Guam, the Commonwealth of the Northern Mariana Islands, Hawaii, and the Freely Associated States to assist the governments of such areas with detecting the brown tree snake and incipient brown tree snake populations. (3) Expansion of efforts to protect and restore native wildlife in Guam or elsewhere in the United States damaged by the brown tree snake. (4) Establishment and sustained funding for an Animal Plant and Health Inspection Service, Wildlife Services, Operations Program State Office located in Hawaii dedicated to vertebrate pest management in Hawaii and United States Pacific territories and possessions. Concurrently, the Animal Plant and Health Inspection Service, Wildlife Services Operations Program shall establish and sustain funding for a District Office in Guam dedicated to brown tree snake control and managed by the Hawaii State Office. (5) Continuation, expansion, and provision of sustained research funding related to the brown tree snake, including research conducted at institutions located in areas affected by the brown tree snake. (6) Continuation, expansion, and provision of sustained research funding for the Animal Plant and Health Inspection Service, Wildlife Services, National Wildlife Research Center of the Department of Agriculture related to the brown tree snake, including the establishment of a field station in Guam related to the control and eradication of the brown tree snake. (7) Continuation, expansion, and provision of sustained research funding for the Fort Collins Science Center of the United States Geological Survey related to the brown tree snake, including the establishment of a field station in Guam related to the control and eradication of the brown tree snake. (8) Expansion of long-term research into chemical, biological, and other control techniques that could lead to large-scale reduction of brown tree snake populations in Guam or other areas where the brown tree snake might become established. (9) Expansion of short, medium, and long-term research, funded by all Federal agencies interested in or affected by the brown tree snake, into interdiction, detection, and early control of the brown tree snake. (10) Provision of planning assistance for the construction or renovation of centralized multi-agency facilities in Guam to support Federal, State, and territorial brown tree snake control, interdiction, research and eradication efforts, including office space, laboratory space, animal holding facilities, and snake detector dog kennels. (11) Provision of technical assistance to the Freely Associated States on matters related to the brown tree snake through the mechanisms contained within a Compact of Free Association dealing with environmental, quarantine, economic, and human health issues. (c) Authorization of Appropriations.--There is authorized to be appropriated to the Secretaries to carry out this section (other than subsection (b)(10)) the following amounts: (1) For activities conducted through the Animal and Plant Health Inspection Service, Wildlife Services, Operations, not more than $2,600,000 for each of the fiscal years 2006 through 2010. (2) For activities conducted through the Animal and Plant Health Inspection Service, Wildlife Services, National Wildlife Research Center, Methods Development, not more than $1,500,000 for each of the fiscal years 2006 through 2010. (3) For activities conducted through the Office of Insular Affairs, not more than $3,000,000 for each of the fiscal years 2006 through 2010. (4) For activities conducted through the Fish and Wildlife Service, not more than $2,000,000 for each of the fiscal years 2006 through 2010. (5) For activities conducted through the United States Geological Survey, Biological Resources, not more than $1,500,000 for each of the fiscal years 2006 through 2010. (d) Planning Assistance.--There is authorized to be appropriated to the Secretary of Agriculture and the Secretary of the Interior such amounts as may be required to carry out subsection (b)(10). SEC. 5. ESTABLISHMENT OF QUARANTINE PROTOCOLS TO CONTROL THE INTRODUCTION AND SPREAD OF THE BROWN TREE SNAKE. (a) Establishment of Quarantine Protocols.--Not later than two years after the date of the enactment of this Act, but subject to the memorandum of agreement required by subsection (b) with respect to Guam, the Secretaries shall establish and cause to be operated at Federal expense a system of pre-departure quarantine protocols for cargo and other items being shipped from Guam and any other United States location where the brown tree snake may become established to prevent the introduction or spread of the brown tree snake. The Secretaries shall establish the quarantine protocols system by regulation. Under the quarantine protocols system, Federal quarantine, natural resource, conservation, and law enforcement officers and inspectors may enforce State and territorial laws regarding the transportation, possession, or introduction of any brown tree snake. (b) Cooperation and Consultation.--The activities of the Secretaries under subsection (a) shall be carried out in cooperation with other Federal agencies and the appropriate State and territorial quarantine, natural resource, conservation, and law enforcement officers. In the case of Guam, as a precondition on the establishment of the system of pre-departure quarantine protocols under such subsection, the Secretaries shall enter into a memorandum of agreement with the Government of Guam to obtain the assistance and cooperation of the Government of Guam in establishing the system of pre-departure quarantine protocols. (c) Implementation.--The system of pre-departure quarantine protocols to be established under subsection (a) shall not be implemented until funds are specifically appropriated for that purpose. (d) Authorization of Appropriations.--There is authorized to be appropriated to carry out this section the following amounts: (1) To the Secretary of Agriculture, not more than $3,000,000 for each of the fiscal years 2006 through 2010. (2) To the Secretary of the Interior, not more than $1,000,000 for each of the fiscal years 2006 through 2010. SEC. 6. TREATMENT OF BROWN TREE SNAKES AS NONMAILABLE MATTER. A brown tree snake constitutes nonmailable matter under section 3015 of title 39, United States Code. SEC. 7. ROLE OF BROWN TREE SNAKE TECHNICAL WORKING GROUP. (a) Purpose.--The Technical Working Group shall ensure that Federal, State, territorial, and local agency efforts concerning the brown tree snake are coordinated, effective, complementary, and cost- effective. (b) Specific Duties and Activities.--The Technical Working Group shall be responsible for the following: (1) The evaluation of Federal, State, and territorial activities, programs and policies that are likely to cause or promote the introduction or spread of the brown tree snake in the United States or the Freely Associated States and the preparation of recommendations for governmental actions to minimize the risk of introduction or further spread of the brown tree snake. (2) The preparation of recommendations for activities, programs, and policies to reduce and eventually eradicate the brown tree snake in Guam or other areas within the United States where the snake may be established and the monitoring of the implementation of those activities, programs, and policies. (3) Any revision of the Brown Tree Snake Control Plan, originally published in June 1996, which was prepared to coordinate Federal, State, territorial, and local government efforts to control, interdict, eradicate or conduct research on the brown tree snake. (c) Reporting Requirement.-- (1) Report.--Subject to the availability of appropriations for this purpose, the Technical Working Group shall prepare a report describing-- (A) the progress made toward a large-scale population reduction or eradication of the brown tree snake in Guam or other sites that are infested by the brown tree snake; (B) the interdiction and other activities required to reduce the risk of introduction of the brown tree snake or other nonindigenous snake species in Guam, the Commonwealth of the Northern Mariana Islands, Hawaii, American Samoa, and the Freely Associated States; (C) the applied and basic research activities that will lead to improved brown tree snake control, interdiction and eradication efforts conducted by Federal, State, territorial, and local governments; and (D) the programs and activities for brown tree snake control, interdiction, research and eradication that have been funded, implemented, and planned by Federal, State, territorial, and local governments. (2) Priorities.--The Technical Working Group shall include in the report a list of priorities, ranked in high, medium, and low categories, of Federal, State, territorial, and local efforts and programs in the following areas: (A) Control. (B) Interdiction. (C) Research. (D) Eradication. (3) Assessments.--Technical Working Group shall include in the report the following assessments: (A) An assessment of current funding shortfalls and future funding needs to support Federal, State, territorial, and local government efforts to control, interdict, eradicate, or conduct research on the brown tree snake. (B) An assessment of regulatory limitations that hinder Federal, State, territorial, and local government efforts to control, interdict, eradicate or conduct research on the brown tree snake. (4) Submission.--Subject to the availability of appropriations for this purpose, the Technical Working Group shall submit the report to Congress not later than one year after the date of the enactment of this Act. (d) Meetings.--The Technical Working Group shall meet at least annually. (e) Inclusion of Guam.--The Secretaries shall ensure that adequate representation is afforded to the government of Guam in the Technical Working Group. (f) Support.--To the maximum extent practicable, the Secretaries shall make adequate resources available to the Technical Working Group to ensure its efficient and effective operation. The Secretaries may provide staff to assist the Technical Working Group in carrying out its duties and functions. (g) Authorization of Appropriations.--There is authorized to be appropriated to each of the Secretaries not more than $450,000 for each of the fiscal years 2006 through 2010 to carry out this section. SEC. 8. MISCELLANEOUS MATTERS. (a) Availability of Appropriated Funds.--Amounts appropriated under this Act shall remain available until expended. (b) Administrative Expenses.--Of the amounts appropriated to carry out this Act for a fiscal year, the Secretaries may expend not more than five percent to cover the administrative expenses necessary to carry out this Act. Speaker of the House of Representatives. Vice President of the United States and President of the Senate.

Brown Tree Snake Control and Eradication Act of 2004 - (Sec. 3) Expresses the sense of Congress that there is a need for better coordinated control, interdiction, research, and eradication of the brown tree snake. (Sec. 4) Directs the Secretaries of the Interior and Agriculture to fund brown tree snake control, interdiction, research, and eradication efforts carried out by the Department of the Interior and the Department of Agriculture, other Federal agencies, States, territorial governments, local governments, and private sector entities. Includes among such activities: (1) expansion of eradication and control programs in Guam, including facilities construction; (2) expansion of interagency and intergovernmental rapid response teams in Guam, the Commonwealth of the Northern Mariana Islands, the Freely Associated States (Palau, Micronesia, Marshall islands), and Hawaii; (3) expansion of efforts to protect and restore native wildlife damaged by such snake; (4) research funding related to brown tree snakes; (5) research funding for the Fort Collins Science Center of the U.S. Geological Survey; and (6) related technical assistance to the Freely Associated States. Authorizes related FY 2006 through 2010 appropriations for: (1) the Animal and Plant Health Inspection Service, Wildlife Services, Operations; (2) the Animal and Plant Health Inspection Service, Wildlife Services, National Wildlife Research Center, Methods Development; (3) the Office of Insular Affairs; (4) the Fish and Wildlife Service; (5) the United States Geological Survey, Biological Resources; and (6) planning assistance to each of the Secretaries. (Sec. 5) Directs the Secretaries to establish quarantine protocols for baggage, cargo, and other items being shipped from Guam and other U.S. locations in order to prevent such snake's spread. Authorizes FY 2006 through 2010 appropriations. (Sec. 6) Designates the brown tree snake as non-mailable matter. (Sec. 7) States that the Brown Tree Snake Technical Working Group shall: (1) ensure coordinated brown tree snake efforts among Federal, State, territorial, and local agencies; (2) develop a list of control, research, interdiction, and eradication priorities; and (3) report to Congress. Authorizes FY 2006 through 2010 appropriations. (Sec. 8) Limits administrative expenditures to not more than five percent of fiscal year appropriations.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Saddleback Mountain-Arizona Settlement Act of 1995''. SEC. 2. FINDINGS AND PURPOSES. (a) Findings.--Congress finds that-- (1) the Salt River Pima-Maricopa Indian Community and the city of Scottsdale, Arizona, have a longstanding interest in a 701-acre tract of land known as the ``Saddleback Property'', that lies within the boundaries of the City and abuts the north boundary of the Salt River Pima-Maricopa Indian Reservation; (2) the Saddleback Property includes Saddleback Mountain and scenic hilly terrain along the Shea Boulevard corridor in Scottsdale, Arizona, that-- (A) has significant conservation value; and (B) is of historic and cultural significance to the Community; (3) in 1989, the Resolution Trust Corporation acquired the Saddleback Property as a receiver for the Sun City Savings and Loan Association; (4) after the Saddleback Property was noticed for sale by the Resolution Trust Corporation, a dispute between the Community and the City arose concerning the future ownership, use, and development of the Saddleback Property; (5) the Community and the City each filed litigation with respect to that dispute, but in lieu of pursuing that litigation, the Community and the City negotiated a Settlement Agreement that-- (A) addresses the concerns of each of those parties with respect to the future use and development of the Saddleback Property; and (B) provides for the dismissal of the litigation; (6) under the Settlement Agreement, subject to detailed use and development agreements-- (A) the Community will purchase a portion of the Saddleback Property; and (B) the City will purchase the remaining portion of that property; and (7) the Community and the City agree that the enactment of legislation by Congress to ratify the Settlement Agreement is necessary in order for-- (A) the Settlement Agreement to become effective; and (B) the United States to take into trust the property referred to in paragraph (6)(A) and make that property a part of the Reservation. (b) Purposes.--The purposes of this Act are-- (1) to approve and confirm the Settlement, Release, and Property Conveyance Agreement executed by the Community, the City, and the Resolution Trust Corporation; (2) to ensure that the Settlement Agreement (including the Development Agreement, the Use Agreement, and all other associated ancillary agreements and exhibits)-- (A) is carried out; and (B) is fully enforceable in accordance with its terms, including judicial remedies and binding arbitration provisions; and (3) to provide for the taking into trust by the United States of the portion of the Saddleback Property purchased by the Community in order to make that portion a part of the Reservation. SEC. 3. DEFINITIONS. For the purposes of this Act, the following definitions shall apply: (1) City.--The term ``City'' means the city of Scottsdale, Arizona, which is a municipal corporation in the State of Arizona. (2) Community.--The term ``Community'' means the Salt River Pima-Maricopa Indian Community, which is a federally recognized Indian tribe. (3) Dedication property.--The term ``Dedication Property'' means a portion of the Saddleback Property, consisting of approximately 27 acres of such property, that the City will acquire in accordance with the Settlement Agreement. (4) Development agreement.--The term ``Development Agreement'' means the agreement between the City and the Community, executed on September 11, 1995, that sets forth conditions and restrictions that-- (A) are supplemental to the Settlement, Release and Property Conveyance Agreement referred to in paragraph (11)(A); and (B) apply to the future use and development of the Development Property. (5) Development property.--The term ``Development Property'' means a portion of the Saddleback Property, consisting of approximately 211 acres, that the Community will acquire in accordance with the Settlement Agreement. (6) Mountain property.--The term ``Mountain Property'' means a portion of the Saddleback Property, consisting of approximately 365 acres, that the Community will acquire in accordance with the Settlement Agreement. (7) Preservation property.--The term ``Preservation Property'' means a portion of the Saddleback Property, consisting of approximately 98 acres, that the City will acquire in accordance with the Settlement Agreement. (8) Reservation.--The term ``Reservation'' means the Salt River Pima-Maricopa Indian Reservation. (9) Saddleback property.--The term ``Saddleback Property'' means a tract of land that-- (A) consists of approximately 701 acres within the city of Scottsdale, Arizona; and (B) includes the Dedication Property, the Development Property, the Mountain Property, and the Preservation Property. (10) Secretary.--The term ``Secretary'' means the Secretary of the Interior. (11) Settlement agreement.--The term ``Settlement Agreement''-- (A) means the Settlement, Release and Property Conveyance Agreement executed on September 11, 1995, by the Community, the City, and the Resolution Trust Corporation (in its capacity as the Receiver for the Sun State Savings and Loan Association, F.S.A.); and (B) includes the Development Agreement, the Use Agreement, and all other associated ancillary agreements and exhibits. (12) Use agreement.--The term ``Use Agreement'' means the agreement between the City and the Community, executed on September 11, 1995, that sets forth conditions and restrictions that-- (A) are supplemental to the Settlement, Release and Property Conveyance Agreement referred to in paragraph (11)(A); and (B) apply to the future use and development of the Mountain Property. SEC. 4. APPROVAL OF AGREEMENT. The Settlement Agreement is hereby approved and ratified and shall be fully enforceable in accordance with its terms and the provisions of this Act. SEC. 5. TRANSFER OF PROPERTIES. (a) In General.--Upon satisfaction of all conditions to closing set forth in the Settlement Agreement, the Resolution Trust Corporation shall transfer, pursuant to the terms of the Settlement Agreement-- (1) to the Secretary, the Mountain Property and the Development Property purchased by the Community from the Resolution Trust Corporation; and (2) to the City, the Preservation Property and the Dedication Property purchased by the City from the Resolution Trust Corporation. (b) Trust Status.--The Mountain Property and the Development Property transferred pursuant to subsection (a)(1) shall, subject to sections 6 and 7-- (1) be held in trust by the United States for the Community; and (2) become part of the Reservation. (c) Limitation on Liability.--Notwithstanding any other provision of law, the United States shall not incur any liability for conditions, existing prior to the transfer, on the parcels of land referred to in subsection (b) to be transferred to the United States in trust for the Salt River Pima-Maricopa Indian Community. (d) Records.--Upon the satisfaction of all of the conditions of closing set forth in the Settlement Agreement, the Secretary shall file a plat of survey depicting the Saddleback Property (that includes a depiction of the Dedication Property, the Development Property, the Mountain Property, and the Preservation Property) with-- (1) the office of the Recorder of Maricopa County, Arizona; and (2) the Titles and Records Center of the Bureau of Indian Affairs, located in Albuquerque, New Mexico. SEC. 6. LIMITATIONS ON USE AND DEVELOPMENT. Upon the satisfaction of all of the conditions of closing set forth in the Settlement Agreement, the properties transferred pursuant to paragraphs (1) and (2) of section 5(a) shall be subject to the following limitations and conditions on use and development: (1) Preservation property.-- (A) In general.--Except as provided in subparagraph (B), the Preservation Property shall be forever preserved in its natural state for use only as a public park or recreation area that shall-- (i) be utilized and maintained for the purposes set forth in section 4(C) of the Settlement Agreement; and (ii) be subject to the restrictions set forth in section 4(C) of the Settlement Agreement. (B) Shea boulevard.--At the sole discretion of the City, a portion of the Preservation Property may be used to widen, reconfigure, repair, or reengineer Shea Boulevard in accordance with section 4(D) of the Settlement Agreement. (2) Dedication property.--The Dedication Property shall be used to widen, reconfigure, repair, or reengineer Shea Boulevard and 136th Street, in accordance with sections 4(D) and 7 of the Settlement Agreement. (3) Mountain property.--Except for the areas in the Mountain Property referred to as Special Cultural Land in section 5(C) of the Settlement Agreement, the Mountain Property shall be forever preserved in its natural state for use only as a public park or recreation area that shall-- (A) be utilized and maintained for the purposes set forth in section 5(C) of the Settlement Agreement; and (B) be subject to the restrictions set forth in section 5(C) of the Settlement Agreement. (4) Development property.--The Development Property shall be used and developed for the economic benefit of the Community in accordance with the provisions of the Settlement Agreement and the Development Agreement. SEC. 7. AMENDMENTS TO THE SETTLEMENT AGREEMENT. No amendment made to the Settlement Agreement (including any deviation from an approved plan described in section 9(B) of the Settlement Agreement) shall become effective, unless the amendment-- (1) is made in accordance with the applicable requirements relating to the form and approval of the amendment under sections 9(B) and 34 of the Settlement Agreement; and (2) is consistent with the provisions of this Act. Speaker of the House of Representatives. Vice President of the United States and President of the Senate.

Saddleback Mountain-Arizona Settlement Act of 1995 - Approves and ratifies the Settlement Agreement providing for the transfer of certain lands by the Resolution Trust Corporation to the Salt River Pima-Maricopa Indian Community (to be held in trust by the Department of the Interior) and the City of Scottsdale, Arizona. Directs the Corporation to make such land transfer. Declares that the United States shall not be liable for any preexisting conditions on the land to be held (by the United States) in trust for the Community. Sets forth land use limitations (public use and development property).

let @xmath7 be a finite connected graph without loops , but with multiple edges allowed . the _ adjacency matrix _ of @xmath0 , denoted by @xmath8 , is given by @xmath9 , where @xmath10 is the number of the edges between @xmath11 and @xmath12 in @xmath13 . the _ laplacian matrix _ of @xmath0 is the matrix @xmath14 where @xmath15 and @xmath16 is the degree of the vertex @xmath11 in @xmath0 . if @xmath1 is a vertex of @xmath0 , the _ reduced laplacian matrix _ , denoted by @xmath17 , is the matrix obtained from @xmath18 by removing the row and column @xmath1 . critical group _ of @xmath0 , denoted by @xmath19 , is the cokernel of @xmath17 , @xmath20 where @xmath21 . the critical group is an abelian group that is isomorphic to the sandpile group introduced by dhar in @xcite , which generalizes the case of a grid from @xcite . the critical group has been studied by several authors , see for instance @xcite . the concept of critical group can be generalized easily to an arbitrary commutative ring with identity @xmath22 . more precisely , if @xmath23 , then the _ critical module _ of @xmath24 , denoted by @xmath25 , is defined as : @xmath26 given @xmath27 and @xmath28 , we say that @xmath29 are _ @xmath30-equivalent _ , denoted by @xmath31 , if there exist @xmath32 and @xmath33 such that @xmath34 . when @xmath35 and @xmath36 , then we simply say that @xmath24 and @xmath37 are _ unitary equivalent _ and will be denoted by @xmath38 . also , if @xmath39 and @xmath40 are the subgroups generated by the elementary matrices , we simply say that @xmath24 and @xmath37 are _ elementary equivalent _ and will be denoted by @xmath41 . finally , if @xmath42 and @xmath42 , then we simply say that @xmath24 and @xmath37 are equivalent and will be denoted by @xmath43 or @xmath44 if the ring @xmath22 is clear from the context . usually the critical group of a graph can be described in terms of a diagonal matrix called the smith normal form of @xmath18 . moreover , is not difficult to see that if @xmath24 and @xmath37 are equivalent , then @xmath45 when the base ring @xmath22 is principal ideal domain ( pid ) , another description of the critical group of a matrix @xmath24 is given by @xmath46 where @xmath47 is the greatest common divisor of all the @xmath48 minors of @xmath24 . this article is divided in two sections : in the first section , we find diagonal matrices over an arbitrary commutative ring with identity that are equivalent to some matrices that generalize the laplacian matrices of the path , the cycle , and the complete graph . in the second section we apply the results obtained in the first section in the case when the base ring is the ring of integers and some subrings of matrices . in particular we are able to calculate the critical group of the @xmath4-cones of the @xmath5-duplications of the path , the cycle , the complete graph , the bipartite complete graph with @xmath4 vertices in each partition , the bipartite complete graph with @xmath6 vertices minus a matching , etc . in the following , every multigraph will be connected and will have a distinguished vertex @xmath49 , called the _ sink _ of @xmath50 . sometimes we will simply write @xmath1 instead of @xmath51 . in @xcite it can be seen any unexplained term of graph theory . in this section we will find diagonal matrices that are equivalent to some matrices that generalize the laplacian matrices of the path , the cycle , and the complete graphs . after that , we will apply these results in order to calculate the critical group for several families of graphs . for all @xmath52 and @xmath53 , let @xmath54 , @xmath55 , @xmath56 , and @xmath57 where @xmath58 is the identity matrix on order @xmath59 . since the critical module of a matrix is invariant under equivalency classes , then in order to determine the critical module of a matrix , it is enough to find an equivalent diagonal matrix . [ prin ] let @xmath53 such that the equation @xmath60 has solution in @xmath22 and @xmath61 polynomials in @xmath62 $ ] that satisfy the recurrence relation @xmath63 with initial values @xmath64 and @xmath65 . then ( i ) : : @xmath66 for all @xmath52 , ( ii ) : : @xmath67 for all @xmath52 , ( iii ) : : @xmath68 for all @xmath52 , and ( iv ) : : @xmath69 for all @xmath70 , where @xmath71 @xmath72 for all @xmath73 and @xmath74 , let @xmath75 where @xmath76 for all @xmath77 and @xmath78 is the matrix with all the entries equal to @xmath79 . note that @xmath80 now we will prove the following statement : [ reduction1 ] for all @xmath73 and @xmath74 @xmath81 let @xmath82 be a solution of the equation @xmath60 moreover , for all @xmath83 , let @xmath84 that is , @xmath85 and @xmath86 are a solution of the equation @xmath87 . since @xmath88 and @xmath89 , then @xmath90 . applying claim [ reduction1 ] , we get that @xmath91 . @xmath92 for all @xmath93 , @xmath94 , let @xmath95 also , let @xmath96 that is , @xmath85 and @xmath86 are a solution of the equation @xmath97 . since @xmath98 for all @xmath73 and @xmath99 , then @xmath100 for all @xmath73 . thus @xmath101 therefore , @xmath102 because @xmath103 @xmath104 we begin proving the following statement : [ claimk ] if @xmath52 , then @xmath105 . it turns out because @xmath106 where @xmath107 are elementary matrices . on the other hand , @xmath108 because @xmath109 and @xmath110 . @xmath111 for all @xmath112 and @xmath83 , let @xmath113 and @xmath114 also , let @xmath115 since @xmath116 for all @xmath117 , @xmath118 for all @xmath119 , and @xmath120 , then @xmath121 moreover , since @xmath122 , then @xmath123 finally , using similar reductions we get that @xmath124 and @xmath125 in ( * ? ? ? 44 ) , a simpler proof of theorem [ prin ] ( iii ) when @xmath22 is a principal ideal domain can be found . the next lemma give us some useful properties of the polynomials @xmath61 . if @xmath126 , then ( i ) : : @xmath127 , ( ii ) : : @xmath128 , ( iii ) : : @xmath129 , ( iv ) : : @xmath130 . it follows using induction on @xmath59 . note that , @xmath131 . if @xmath22 is a principal ideal domain and @xmath132 , then the equation @xmath60 has a solution if and only if @xmath133 . [ prinpid ] let @xmath22 be a principal ideal domain , @xmath132 with @xmath134 , @xmath135 , and @xmath136 . then ( i ) : : @xmath137 for all @xmath52 , ( ii ) : : @xmath138 for all @xmath52 , ( iii ) : : @xmath139 for all @xmath52 , and ( iv ) : : @xmath140 for all @xmath70 , where @xmath141 let @xmath142 be either one of the matrices @xmath143 , @xmath144 , @xmath145 , or @xmath146 , then @xmath147 . on the other hand , since @xmath134 if and only if @xmath148 if and only if the equation @xmath149 has solution in @xmath22 . then , we get the result applying theorem [ prin ] to @xmath150 . in this section we will apply the equivalences of the matrices @xmath145 , @xmath146 , @xmath144 and @xmath143 obtained in the previous section to the cases when @xmath151 and @xmath152 are in the ring of integers and in the subring of matrices of the form @xmath145 where @xmath153 are in a commutative ring with identity @xmath22 . at this point we need to introduce some definitions . given a simple graph @xmath0 and a natural number @xmath154 , the @xmath5-duplication of @xmath0 , denoted by @xmath155 , is the multigraph obtained from @xmath0 when we replace every edge of @xmath0 by @xmath5 parallel edges . note that @xmath156 for any graph @xmath0 . = [ inner sep=0pt , minimum width=4.5pt ] ( 0,0 ) + ( 45:1 ) node[draw , circle , fill = gray ] ( v1 ) + ( 135:1 ) node[draw , circle , fill = gray ] ( v2 ) + ( 225:1 ) node[draw , circle , fill = gray ] ( v3 ) + ( 315:1 ) node[draw , circle , fill = gray ] ( v4 ) ( v1 ) to ( v2 ) to ( v3 ) to ( v4 ) to ( v1 ) ( v1)+(0,0.25 ) node @xmath157 ( v2)+(0,0.25 ) node @xmath158 ( v3)+(0,-0.3 ) node @xmath159 ( v4)+(0,-0.3 ) node @xmath160 ( 0,0 ) node @xmath161 ; ( 5,0 ) + ( 45:1 ) node[draw , circle , fill = gray ] ( v1 ) + ( 135:1 ) node[draw , circle , fill = gray ] ( v2 ) + ( 225:1 ) node[draw , circle , fill = gray ] ( v3 ) + ( 315:1 ) node[draw , circle , fill = gray ] ( v4 ) ( v1 ) .. controls + ( 150:0.5 ) and + ( 30:0.5 ) .. ( v2 ) ( v1 ) .. controls + ( 210:0.5 ) and + ( -30:0.5 ) .. ( v2 ) ( v2 ) .. controls + ( 240:0.5 ) and + ( 120:0.5 ) .. ( v3 ) ( v2 ) .. controls + ( 300:0.5 ) and + ( 60:0.5 ) .. ( v3 ) ( v4 ) .. controls + ( 150:0.5 ) and + ( 30:0.5 ) .. ( v3 ) ( v4 ) .. controls + ( 210:0.5 ) and + ( -30:0.5 ) .. ( v3 ) ( v1 ) .. controls + ( 240:0.5 ) and + ( 120:0.5 ) .. ( v4 ) ( v1 ) .. controls + ( 300:0.5 ) and + ( 60:0.5 ) .. ( v4 ) ( v1)+(0,0.25 ) node @xmath157 ( v2)+(0,0.25 ) node @xmath158 ( v3)+(0,-0.3 ) node @xmath159 ( v4)+(0,-0.3 ) node @xmath160 + ( -0.7,0.7 ) node @xmath162 ; given a graph @xmath0 and a natural number @xmath163 , the @xmath163-cone of @xmath0 , denoted by @xmath164 , is the multigraph obtained from @xmath0 by adding a new vertex @xmath1 and adding @xmath163 parallel edges between @xmath1 and all the vertices of @xmath0 . note that @xmath165 for any graph @xmath0 . = [ inner sep=0pt , minimum width=4.5pt ] ( 0,0 ) + ( 45:1 ) node[draw , circle , fill = gray ] ( v1 ) + ( 135:1 ) node[draw , circle , fill = gray ] ( v2 ) + ( 225:1 ) node[draw , circle , fill = gray ] ( v3 ) + ( 315:1 ) node[draw , circle , fill = gray ] ( v4 ) ( v1 ) to ( v2 ) to ( v3 ) to ( v4 ) to ( v1 ) ( v1)+(0,0.25 ) node @xmath157 ( v2)+(0,0.25 ) node @xmath158 ( v3)+(0,-0.3 ) node @xmath159 ( v4)+(0,-0.3 ) node @xmath160 + ( -0.7,-0.5 ) node @xmath161 ; ( 5,0 ) + ( 45:1 ) node[draw , circle , fill = gray ] ( v1 ) + ( 135:1 ) node[draw , circle , fill = gray ] ( v2 ) + ( 225:1 ) node[draw , circle , fill = gray ] ( v3 ) + ( 315:1 ) node[draw , circle , fill = gray ] ( v4 ) + ( 0:0 ) node[draw , circle , fill = gray ] ( s ) ( v1 ) to ( v2 ) to ( v3 ) to ( v4 ) to ( v1 ) ( v1 ) to ( v3 ) ( v2 ) to ( v4 ) ( s)+(0,0.2 ) node @xmath1 ( v1)+(0,0.25 ) node @xmath157 ( v2)+(0,0.25 ) node @xmath158 ( v3)+(0,-0.3 ) node @xmath159 ( v4)+(0,-0.3 ) node @xmath160 + ( -0.7,-0.5 ) node @xmath166 ; the most direct application of the results obtained in the first section is when the base ring @xmath22 is the ring of integers and the matrices are the reduced laplacian matrix of the @xmath59-cone of the thick path , the thick cycle and the thick complete graph . ( 0,0 ) + ( 0,0 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( s ) + ( -1.8,-1.5 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v1 ) + ( -0.9,-1.5 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v2 ) + ( 0.9,-1.5 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v3 ) + ( 1.8,-1.5 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v4 ) + ( -0.3,-1.5 ) node[draw , circle , fill = black , inner sep=0pt , minimum width=1.6pt ] + ( 0,-1.5 ) node[draw , circle , fill = black , inner sep=0pt , minimum width=1.6pt ] + ( 0.3,-1.5 ) node[draw , circle , fill = black , inner sep=0pt , minimum width=1.6pt ] ( s ) to ( v1 ) ( s ) to ( v2 ) ( s ) to ( v3 ) ( s ) to ( v4 ) ( v1 ) to ( v2 ) ( v3 ) to ( v4 ) ( s)+(0,+0.3 ) node @xmath1 ( v1)+(0,-0.3 ) node @xmath157 ( v2)+(0,-0.3 ) node @xmath158 ( v3)+(0,-0.3 ) node @xmath168 ( v4)+(0.1,-0.3 ) node @xmath169 ( v1)+(0.65,0.8 ) node @xmath4 ( v1)+(1.55,0.6 ) node @xmath4 ( v1)+(2.1,0.6 ) node @xmath4 ( v1)+(2.95,0.8 ) node @xmath4 ( v1)+(0.6,0.2 ) node @xmath5 ( v3)+(0.4,0.2 ) node @xmath5 ; ( 0,0 ) + ( 0,0 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( s ) + ( 60:1.4 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v1 ) + ( 0:1.4 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v2 ) + ( -60:1.4 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v3 ) + ( -120:1.4 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v4 ) + ( -180:1.4 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v5 ) + ( -240:1.4 ) node[draw , circle , fill = gray , inner sep=0pt , minimum width=4pt ] ( v6 ) + ( 80:1.4 ) node[draw , circle , fill = black , inner sep=0pt , minimum width=1.6pt ] + ( 90:1.4 ) node[draw , circle , fill = black , inner sep=0pt , minimum width=1.6pt ] + ( 100:1.4 ) node[draw , circle , fill = black , inner sep=0pt , minimum width=1.6pt ] ( s ) to ( v1 ) ( s ) to ( v2 ) ( s ) to ( v3 ) ( s ) to ( v4 ) ( s ) to ( v5 ) ( s ) to ( v6 ) ( v1 ) to ( v2 ) to ( v3 ) to ( v4 ) to ( v5 ) to ( v6 ) ( s)+(0,0.3 ) node @xmath1 ( v1)+(0.2,0.2 ) node @xmath159 ( v2)+(0.3,0 ) node @xmath158 ( v3)+(0,-0.3 ) node @xmath176 ( v4)+(0.1,-0.3 ) node @xmath177 ( v5)+(-0.3,-0.2 ) node @xmath168 ( v6)+(-0.2,0.2 ) node @xmath178 ( s)+(40:0.7 ) node @xmath4 ( s)+(-15:0.7 ) node @xmath4 ( s)+(-80:0.7 ) node @xmath4 ( s)+(-140:0.7 ) node @xmath4 ( s)+(-195:0.7 ) node @xmath4 ( s)+(-260:0.7 ) node @xmath4 ( s)+(30:1.4 ) node @xmath5 ( s)+(-30:1.4 ) node @xmath5 ( s)+(-90:1.4 ) node @xmath5 ( s)+(-150:1.4 ) node @xmath5 ( s)+(-210:1.4 ) node @xmath5 ; [ completagorda ] for all @xmath167 , @xmath154 , and @xmath70 , let @xmath188 be the @xmath4-cone of the thick complete graph where all the edges have multiplicity equal to @xmath5 . then @xmath189 where @xmath172 . note that @xmath193 is a commutative ring with identity because @xmath210 for all @xmath211 . on the other hand , since @xmath212 , then @xmath193 is not a principal ideal domain because it has zero divisors . now , we will apply theorem [ prin ] @xmath104 when the base ring is the subring of matrices with entries in @xmath193 to obtain a theorem that will be a powerful tool to calculate the critical group of several graphs . given @xmath216 and @xmath217 , let @xmath218 let @xmath221 and @xmath222 be as in claim [ claimk ] , then @xmath223 are elementary matrices and @xmath224 \oplus \left ( \begin{array}{cc } a&b\\ 0 & a+mb \end{array } \right),\end{aligned}\ ] ] where @xmath225 . in the last part of this paper , we will use theorem [ completamatrices ] to find the critical group of some graphs whose laplacian matrix is given by @xmath219 for @xmath226 . the simplest case is when @xmath227 . if @xmath219 for @xmath228 is the laplacian matrix of a graph , then the vertex set of the graph can be partitioned in two sets and the incidence structure between these sets is given by a matrix in @xmath229 . in this sense , we will define the following families of graphs : note that @xmath238 is the bipartite complete graph with @xmath4 vertices in each partition and @xmath239 is the bipartite complete graph with @xmath6 vertices minus a matching . the laplacian matrix of all these graphs can be represented by @xmath219 for some two by two matrices @xmath240 and @xmath241 . ( 0,-0.8 ) ( 0,0.8 ) arc ( 0:180:0.3 ) ( -0.6,-0.8 ) arc ( 180:360:0.3 ) ; ( 0,0 ) + ( 0,-0.8 ) ( 0,0.8 ) arc ( 0:180:0.3 ) ( -0.6,-0.8 ) arc ( 180:360:0.3 ) + ( -0.3,1.6 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v1 ) + ( -0.3,1.2 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v2 ) + ( -0.3,0.95 ) node[inner sep=0pt , minimum width=1pt , draw , circle , fill = black ] ( ) + ( -0.3,0.8 ) node[inner sep=0pt , minimum width=1pt , draw , circle , fill = black ] ( ) + ( -0.3,0.65 ) node[inner sep=0pt , minimum width=1pt , draw , circle , fill = black ] ( ) + ( -0.3,0.4 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v3 ) + ( -0.3,0 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v4 ) + ( 1.5,1.6 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v5 ) + ( 1.5,1.2 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v6 ) + ( 1.5,0.4 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v7 ) + ( 1.5,0 ) node[inner sep=0pt , minimum width=3.5pt , draw , circle , fill = gray ] ( v8 ) ( v2 ) .. controls + ( 252:0.4 ) and + ( 108:0.4 ) .. ( v3 ) ( v1 ) .. controls + ( 246:0.6 ) and + ( 114:0.6 ) .. ( v3 ) ( v2 ) .. controls + ( 246:0.6 ) and + ( 114:0.6 ) .. ( v4 ) ( v1 ) to ( v2 ) ( v3 ) to ( v4 ) ( v1 ) to ( v5 ) ( v2 ) to ( v6 ) ( v3 ) to ( v7 ) ( v4 ) to ( v8 ) + ( -2.4,0.8 ) node @xmath243 + ( -0.8,0.9 ) node @xmath244 + ( -2.3,-0.1 ) node @xmath245 + ( 0.3,0 ) ( 1.8,0.8 ) arc ( 0:180:0.3 ) ( 1.2,-0.8 ) arc ( 180:360:0.3 ) + ( 0.2,-0.1 ) node @xmath236 + ( -5,0 ) node ; ( 3.07,0 ) node ; before using theorem [ completamatrices ] in order to calculate the critical group of the @xmath59-cones of graphs @xmath246 , we will introduce a theorem that gives an equivalent matrix of @xmath246 when the base ring is a general commutative ring with identity . @xmath72 since @xmath252 for @xmath253 and @xmath254 , then by theorem [ completamatrices ] @xmath255 \oplus \left ( \begin{array}{cccc } a & 0 & 0&b\\ 0 & a & b&0\\ 0 & 0 & a&mb\\ 0 & 0 & mb&a \end{array } \right).\ ] ] moreover , since @xmath256 and @xmath257 then @xmath258 hence @xmath259 @xmath92 since @xmath260 for @xmath261 and @xmath254 , then by theorem [ completamatrices ] @xmath262 \oplus \left ( \begin{array}{cccc } a & -b & 0&b\\ -b & a & b&0\\ 0 & 0 & a&(m-1)b\\ 0 & 0 & ( m-1)b&a \end{array } \right).\ ] ] moreover , since @xmath263 @xmath264 @xmath265 and @xmath266 then @xmath267 @xmath104 since @xmath268 for @xmath269 and @xmath270 , then by theorem [ completamatrices ] @xmath271 \oplus \left ( \begin{array}{cccc } a - b & -b & b&b\\ -b & a - b & b&b\\ 0 & 0 & a+(m-1)b&(m-1)b\\ 0 & 0 & ( m-1)b&a+(m-1)b \end{array } \right).\ ] ] moreover , since @xmath272 @xmath273 and @xmath274 then the result is followed . @xmath111 since @xmath275 for @xmath276 and @xmath277 , then by theorem [ completamatrices ] @xmath278 \oplus \left ( \begin{array}{cccc } a - b & b & b&0\\ b & a - b & 0&b\\ 0 & 0 & a+(m-1)b&b\\ 0 & 0 & b&a+(m-1)b \end{array } \right).\ ] ] moreover , since @xmath279 and @xmath280 then the result is followed . when a graph @xmath0 is not regular , then there is not a straightforward way to define their matrix @xmath284 . thus , we will define @xmath285 as @xmath286 , @xmath287 as @xmath288 , and @xmath289 as @xmath290 . now , we have the following equivalent matrices of @xmath285 , @xmath287 , and @xmath289 . @xmath72 since @xmath294 for @xmath295 and @xmath296 , then by theorem [ completamatrices ] @xmath297 \oplus \left ( \begin{array}{cccc } a&0&0&b\\ 0&2a&b&b\\ 0&0&a&mb\\ 0&0&mb&2a+mb \end{array } \right).\ ] ] moreover , @xmath298 and @xmath299 @xmath92 since @xmath300 for @xmath301 and @xmath302 , then by theorem [ completamatrices ] @xmath303 \oplus \left ( \begin{array}{cccc } a&b&0&0\\ b&(m+1)a&0&b\\ 0&0&a&b\\ 0&0&b&(m+1)a+mb \end{array } \right)\ ] ] moreover , @xmath304 and @xmath305 @xmath104 since @xmath306 for @xmath307 and @xmath296 , then by theorem [ completamatrices ] @xmath308 \oplus \left(\begin{array}{cccc}a&-b&0&b\\-b&2a&b&b\\0&0&a&(m-1)b \\0&0&(m-1)b&2a+mb \end{array}\right).\ ] ] moreover , @xmath309 @xmath310 and @xmath311 since @xmath316 and @xmath317 with @xmath318 , then applying corollary [ bipartitacompleta ] @xmath72 to @xmath319 we get that @xmath320 on the other hand , @xmath321 where @xmath315 and we get the result . note that @xmath238 is the complete bipartite graph with @xmath4 vertices in each partition . lorenzini in @xcite calculated that @xmath322 which agrees with the corollary [ bipartitacompletag1 ] for @xmath323 and @xmath324 . also note that @xmath325 has @xmath326 invariant factors different to @xmath327 . on the other hand , it is not difficult to see that @xmath360/r % \end{array } % \right ) % = \left ( \begin{array}{cc } st / r&-l^2(n+t)/r^2\\ 0 & n(n+2l)/r \end{array } \right ) \sim_u u \oplus stn(n+2l)/ur^2,\ ] ] where @xmath351 and @xmath352 . note that @xmath370 is the graph @xmath371 . in general the expression for @xmath372 given in corollary [ bipartitacompletag5 ] does not give us the invariant factors of @xmath372 . also note that @xmath373 has @xmath326 invariant factors different to @xmath327 .

given a graph @xmath0 with a distinguished vertex @xmath1 , the critical group of @xmath2 is the cokernel of their reduced laplacian matrix @xmath3 . in this article we generalize the concept of the critical group to the cokernel of any matrix with entries in a commutative ring with identity . in this article we find diagonal matrices that are equivalent to some matrices that generalize the reduced laplacian matrix of the path , the cycle , and the complete graph over an arbitrary commutative ring with identity . we are mainly interested in those cases when the base ring is the ring of integers and some subrings of matrices . using these equivalent diagonal matrices we calculate the critical group of the @xmath4-cones of the @xmath5-duplications of the path , the cycle , and the complete graph . also , as byproduct , we calculate the critical group of another matrices , as the @xmath4-cones of the @xmath5-duplication of the bipartite complete graph with @xmath4 vertices in each partition , the bipartite complete graph with @xmath6 vertices minus a matching .

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. ||||| Salvation Army volunteer Dyane Welt, left, pulls several bottles of water from an ice cooler to give to Michael Martinez, right, at a hydration station in an effort to beat the rising temperatures expected... (Associated Press) Salvation Army volunteer Dyane Welt, left, pulls several bottles of water from an ice cooler to give to Michael Martinez, right, at a hydration station in an effort to beat the rising temperatures expected to hit 115-degrees, Monday, June 20, 2016, in Phoenix. The National Weather Service is expecting... (Associated Press) PHOENIX (AP) — The Latest on the extreme heat baking the Southwest (all times local): 8:00 p.m. A severe heat wave has set new record highs for several cities in Southern California. The National Weather Service says the thermometer hit 112 degrees in Lancaster, breaking the old record of 110 degrees set for the same day in 1961. The service says a record high temperature was set at the Bob Hope Airport in Burbank with 111 degrees. That breaks the old record of 106 degrees set for this date in 2008. Forecasters expect Monday to be the peak of the heat wave. Officials say about 20,000 customers were without electricity when outages were at their worst Monday. ___ 6:45 p.m. Arizona cities saw more record-setting high temperatures, including the hottest day on record in Prescott. The National Weather Service says Monday's mark of 105 degrees in Prescott was the highest recorded in the city's history. Weather records go back as far as 1898. Phoenix hit 116 degrees Monday, topping the previous record for June 20 of 115, set in 1968. It was 112 degrees in Tucson, two degrees hotter than the mark set in 2005 for that date. Portions of Arizona and southeast California are getting scorched by a high pressure ridge lifting out of Mexico. ___ 5:50 p.m. Authorities say a man who died and another who is missing after going for a hike in Arizona were from Germany and were in the state for a conference at a resort. The men were in a group of three who went hiking Sunday on a trail outside the Tucson resort. One of the men is recovering, while 57-year-old Stefan Guenster was found dead. The third man, 33-year-old Marcus Turowski, was still missing Monday. Authorities didn't release their hometowns. The Pima County Sheriff's Department says it likely would end its search at sundown Monday and resume Tuesday. Tucson hit a record high of 115 degrees Sunday as a heatwave took over parts of the Southwest. ___ 5:05 p.m. Las Vegas has sizzled to 115 degrees and topped a record high temperature of 113 for the date set just a year ago. National Weather Service meteorologist Nathan Foster said Monday it's possible Sin City could reach another record Tuesday, when the predicted high of 113 would eclipse the record 111 in 1954. Summer arrived Monday amid an excessive heat warning through Wednesday in southern Nevada, northwest Arizona and much of Southern California. Foster says Las Vegas temperatures will ease through the week to a predicted 107 on Saturday. Clark County officials have opened several recreation centers and other public buildings as air-conditioned cooling stations for people to beat the heat. ___ 4:30 p.m. Authorities say another woman has died as a result of the heatwave in the Southwest. The Pima County Sheriff's Department said Monday a 54-year-old woman died on Sunday night in Tucson walking along a loop trail. It brought the death toll to five in Arizona, where temperatures have exceeded 114 degrees. The Pima County Sheriff's Department reported three heat deaths on Sunday. In addition, a Phoenix man hiking in the Superstition Mountains died from exposure to extreme heat. Pinal County Sheriff's officials say 25-year-old Anthony Quatela III and a male friend ran out of water. A 28-year-old woman who was mountain biking with two friends also died after running out of water and struggling to breath. Fire officials say the personal trainer was taken to a hospital, where she later died. ___ 2 p.m. Southern California is in the grip of a severe heat wave that has sent temperatures surging. Numerous places across Los Angeles and neighboring counties passed 100 degrees well before noon Monday. The National Weather Service says the thermometer hit 121 degrees in Palm Springs by 1 p.m. Forecasters expect Monday to be the peak of the heat wave. The state's power grid operator has called on residents to conserve electricity to avoid outages. ___ 9:40 a.m. Southern California is in for another day of dangerously high temperatures resulting from high pressure over the Four Corners region of the Southwest. Forecasters say Monday will be the peak of the heat wave, with highs in the lower deserts to be near 120 degrees. The National Weather Service reported 17 daily heat records broken on Sunday, most of them for readings well over 100 degrees. The aptly named desert town of Thermal about 25 miles southeast of Palm Springs topped the list with a high of 119 degrees. The Woodland Hills area of Los Angeles was 109, tying the record set in 2008. Burbank was a record 109, breaking the old mark of 104. The temperature reached 96 in downtown Los Angeles. ___ 9:20 a.m. Two deaths related to extreme heat are being reported by search and rescue crews in southern Arizona. Pima County sheriff's Deputy Ryan Inglett on Monday confirmed the deaths of hikers in two separate incidents the previous day. A 18-year-old woman suffering from heat-related illness died northeast of Tucson. The sheriff's department says she and a companion had run out of drinking water. On Sunday afternoon, search crews responded to a report of dehydrated hikers and found one man dead on another trail in the same area. Another hiker from that party is missing. This item has been corrected to show the victim's age was 18, not 19. The original information was provided by the sheriff's department. ___ 8:40 a.m. Extreme heat forced a Phoenix-bound flight to return to Houston. United Airlines says the hot weather led the plane to return to Texas on Sunday evening and that passengers will be accommodated with an added flight Monday morning. The National Weather Service says the mercury hit 118 on Sunday, breaking a record of 115 set nearly 50 years ago. Forecasters expect the same excessively high temperatures Monday in portions of Arizona and southeast California. ___ 7:55 a.m. The National Weather Service is expecting another day of triple-digit temperatures in Phoenix and across much of the Southwest. National Weather Service meteorologist Biana Hernandez said Monday that temperatures in Phoenix are expected to peak at between 115 and 120 degrees, with the highest regional temperatures anticipated in Southern California. The agency issued excessive heat warnings for Tucson and Yuma as well as recreation spots such as the Grand Canyon and Lake Havasu. On Sunday, the mercury ascended to 118, breaking a record of 115 set nearly 50 years ago. Portions of Arizona and southeast California are getting scorched by a high pressure ridge lifting out of Mexico. The heat played a role in the deaths of mountain biker in Phoenix and a hiker in Pinal County over the weekend. ||||| Floyd E. Roberts III, reported missing from the Grand Canyon National Park Saturday. (Photo: National Park Service) The National Park Service is searching for a 52-year-old Florida man who went missing while hiking the Grand Canyon, according to a park statement Monday. The Grand Canyon Regional Communication Center got a call reporting Floyd E. Roberts III missing from the extreme western portion of the park at about 3 p.m. Saturday. The call was made by a member of Roberts' hiking group on the first day of a scheduled multiday backpacking trip through the Grand Canyon, the statement said. Roberts was last seen near Kelly Tanks in Grand Canyon-Parashant National Monument. He is described as 5 feet 11 inches tall, 170 pounds, with gray hair. He was last seen wearing a red long-sleeve shirt, blue jeans, multicolored Nike sneakers, a blue Lowe Alpine backpack and white-rimmed sunglasses with orange lenses. Authorities ask anyone with information about Roberts' whereabouts to call the National Park Service information line at 928-638-7300. Read or Share this story: http://azc.cc/28KM1fD

– One German man is dead and another is missing after going hiking during the heat wave that's scorching the Southwest. Stefan Guenster, 57, died after becoming dehydrated while hiking the Ventana Canyon Trail on Sunday, when temperatures hit 115, a record for the date, reports the Arizona Daily Star. Marcus Turowski, 33, is missing. A third member of the party who went to seek help survived. Two other hikers died in the area on the same day, including a 19-year-old woman who called for help after becoming lost and died before rescuers reached the scene. Her male companion was hospitalized. Heat records for June 20 were set in parts of California and Nevada as well, where other heat-related deaths over the weekend included a 25-year-old Phoenix man overcome by extreme heat while hiking in the Superstition Mountains and a 28-year-old woman who died while mountain biking, reports the AP. The Arizona Republic reports that the search is ongoing for Floyd Roberts, a 52-year-old Florida man who disappeared while hiking in the Grand Canyon on Saturday afternoon.

one of the major uncertainties in modern astrophysics is the issue of whether the stellar initial mass function ( imf ) is universal or , alternatively , determined by environmental effects . galactic globular clusters and rich , compact magellanic cloud star clusters are ideal laboratories for providing strong constraints on the universality of the imf , in particular because they are essentially single age , single metallicity systems for which statistically significant samples of individual stars over a range of masses can easily be resolved . although the standard picture , in which stars in dense clusters evolve rapidly towards a state of energy equipartition through stellar encounters with the corresponding mass segregation is generally accepted , observations of various degrees of mass segregation in very young star clusters ( e.g. , de grijs et al . 2002a , b and references therein ) suggest that at least some of this effect is related to the process of star and star cluster formation itself . the effects of mass segregation in star clusters , with the more massive stars being more centrally concentrated than the lower - mass stars , clearly complicates the interpretation of an observed luminosity function ( lf ) at a given position within a star cluster in terms of its imf . without reliable corrections for the effects of mass segregation , hence for the structure and dynamical evolution of the cluster , it is impossible to obtain a realistic global cluster lf . quantifying the degree of actual mass segregation is thus crucial for the interpretation of observational luminosity and mass functions ( mfs ) in terms of the imf , even for very young star clusters . the time - scale for the onset of significant dynamical mass segregation is comparable to the cluster s dynamical relaxation time ( spitzer & shull 1975 , inagaki & saslaw 1985 , bonnell & davies 1998 , elson et al . a cluster s characteristic time - scale may be taken to be its half - mass ( or median ) relaxation time , i.e. , the relaxation time at the mean density for the inner half of the cluster mass for cluster stars with stellar velocity dispersions characteristic for the cluster as a whole ( spitzer & hart 1971 , lightman & shapiro 1978 , meylan 1987 , malumuth & heap 1994 , brandl et al . 1996 ) , and can be written as ( meylan 1987 ) : @xmath1 where @xmath2 is the half - mass ( median ) radius ( in pc ) , @xmath3 the total cluster mass , and @xmath4 the typical mass of a cluster star ( both masses in @xmath5 ) . although the half - mass relaxation time characterises the dynamical evolution of a cluster as a whole , significant differences are expected locally within the cluster . from eq . ( [ trelax.eq ] ) it follows immediately that the relaxation time - scale will be shorter for higher - mass stars ( greater @xmath4 ) than for their lower - mass companions . from this argument it follows that dynamical mass segregation will also be most rapid where the local relaxation time is shortest , i.e. , near the cluster centre ( cf . fischer et al . 1998 , hillenbrand & hartmann 1998 ) . the relaxation time in the core can be written as ( meylan 1987 ) : @xmath6 where @xmath7 is the cluster core radius ( in pc ) , @xmath8 ( km s@xmath9 ) the velocity scale , and @xmath10 the mean mass ( in @xmath5 ) of all particles in thermal equilibrium . it should be kept in mind , however , that even the concept of a `` local relaxation time '' is only a general approximation , as dynamical evolution is a continuing process . the time - scale for a cluster to lose all traces of its initial conditions also depends on the smoothness of its gravitational potential , i.e. the number of stars ( bonnell & davies 1998 ) , the degree of equipartition reached ( e.g. , hunter et al . 1995 ) , and the slope of the mf ( e.g. , lightman & shapiro 1978 , inagaki & saslaw 1985 , pryor et al . 1986 , sosin 1997 ) , among others . in addition , as the more massive stars move inwards towards the cluster centre , their dynamical evolution will speed up . this process will be accelerated if there is no ( full ) equipartition ( cf . inagaki & saslaw 1985 ) , thus producing high - density cores very rapidly , where stellar encounters occur very frequently and binary formation is thought to be very effective ( cf . inagaki & saslaw 1985 , elson et al . 1987 ) . this may accelerate the mass segregation even more significantly ( e.g. , nemec & harris 1987 , de marchi & paresce 1996 , bonnell & davies 1998 , elson et al . this process will act on similar ( or slightly shorter ) time - scales as the conventional dynamical mass segregation ( cf . nemec & harris 1987 , bonnell & davies 1998 , elson et al . 1998 ) . we obtained f555w and f814w _ hst / wfpc2 _ imaging observations of two young compact lmc clusters , ngc 1805 ( @xmath11 myr ) and ngc 1818 ( @xmath12 myr ) , covering a large range of radii ( see de grijs et al . 2002a for observational details ) . the radial dependence of the lf and mf slopes indicate clear mass segregation in both clusters at radii @xmath13 ( de grijs et al . 2002a , b ) . in fig . 1a we show the dependence of the cluster core radius on the adopted magnitude ( mass ) range . for both clusters we clearly detect the effects of mass segregation for stars with masses @xmath14 ( @xmath15 ) . stars with masses @xmath16 show a similar concentration , while a trend of increasing core radius with decreasing mass ( increasing magnitude ) is apparent for lower masses . elson et al . ( 1987 ) estimated the central velocity dispersion in ngc 1818 to be in the range @xmath17 km s@xmath9 . combining this central velocity dispersion , the core radius of @xmath18 pc ( de grijs et al . 2002a , b ) , and the cluster age of @xmath19 myr , we estimate that the cluster core is between @xmath20 and @xmath21 crossing times old , so that dynamical mass segregation in the core should be well under way . although we do not have velocity dispersion information for ngc 1805 , it is particularly interesting to extend this analysis to this younger ( @xmath11 myr ) cluster . we know that its core radius is roughly half that of ngc 1818 ( de grijs et al . 2002a , b ) , and its mass is a factor of @xmath11 smaller . simple scaling of eq . ( [ trelax.eq ] ) shows then that the half - mass relaxation time of ngc 1805 is @xmath22 as short as that of ngc 1818 ; if we substitute the scaling laws into eq . ( [ tcore.eq ] ) , we estimate that the central velocity dispersion in ngc 1805 is @xmath23 smaller than that in ngc 1818 . from this argument it follows that the cluster core of ngc 1805 is @xmath24 crossing times old . however , since strong mass segregation is observed out to @xmath25 and @xmath26 in ngc 1805 and ngc 1818 , respectively , for stellar masses in excess of @xmath27 , it is most likely that significant primordial mass segregation was present in both clusters , particularly in ngc 1805 ( cf . fig . 1b ) . within the uncertainties , we can not claim that the slopes of the outer mfs in ngc 1805 and ngc 1818 are significantly different , which therefore implies that these clusters must have had very similar imfs . in fact , in de grijs et al . ( 2002c ) we extended our study of mass segregation in clusters of various ages to a sample of six rich lmc clusters , selected to include three pairs of clusters of similar age ( roughly @xmath28 and @xmath29 yr old ) , metallicity , and distance from the lmc centre , and exhibiting a large spread in core radii between the clusters in each pair . the large spread in core radii in any given cluster pair was chosen because the core radius distribution of rich lmc clusters systematically increases in both upper limit and spread with increasing cluster age ( e.g. , mackey & gilmore 2002 and references therein ) . all clusters show clear evidence of mass segregation : ( i ) their luminosity function slopes steepen with increasing cluster radius , and ( ii ) the brighter stars are characterized by smaller core radii . _ for all sample clusters _ , both the slope of the luminosity function in the cluster centres and the degree of mass segregation are similar to each other , within observational errors of a few tenths of power - law slope fits to the data . this implies that their _ initial _ mass functions must have been very similar , down to @xmath30 ( cf . de grijs et al .

we present the detailed analysis of _ hubble space telescope _ observations of the spatial distributions of different stellar species in two young compact star clusters in the large magellanic cloud ( lmc ) , ngc 1805 and ngc 1818 . based on a comparison of the characteristic relaxation times in their cores and at their half - mass radii with the observed degree of mass segregation , it is most likely that significant primordial mass segregation was present in both clusters , particularly in ngc 1805 . both clusters were likely formed with very similar initial mass functions ( imfs ) . in fact , we provide strong support for the universality of the imf in lmc clusters for stellar masses @xmath0 .

effects in superconductors in the microwave regime have been the subject of a large number of intensive studies in recent years . most of the attention is focused on studying one or more of the following issues : investigating the origins of nonlinear effects in superconductors @xcite,@xcite , introducing theoretical models that explain nonlinear behavior @xcite,@xcite , identifying the dominant factors that manifest these effects @xcite,@xcite , find ways to control and minimize nonlinear effects @xcite,@xcite such as , harmonic generation and intermodulation distortions , which degrade the performance of promising superconducting microwave applications mainly in the telecommunication area @xcite . among the nonlinear effects reported in the literature associated with resonance curves , one can find the commonly known duffing nonlinearity which is characterized by skewed resonance curves above certain power level , appearance of infinite slope in the resonance lineshape , pronounced shift of the resonance frequency and hysteretic behavior @xcite,@xcite,@xcite . to account for this effect , associated with the rise of kinetic inductance of superconductors , both thermal @xcite , and weak link @xcite explanations have been successfully applied . other nonlinear effects were reported by portis _ @xcite , where they observed notches that develop on both sides of the frequency response of their hts microstrip patch antenna , accompanied with hysteresis and frequency shift , as they have driven their antenna into the nonlinear regime . similar results were reported also by hedges _ @xcite , in their ybco stripline resonator , and by @xcite in their ybco thin film dielectric cavity . all three studies attributed the observed nonlinear behavior to abrupt changes in the resistive loss of weak links , thermal quenching and weak link switching to normal state . in this study , being interested in the behavior of nonlinear resonances , we have fabricated different nbn superconducting microwave resonators exhibiting some unusual nonlinear effects , which to the best of our knowledge , have not been reported before in the literature . we study the dependence of these resonators on the injected input power level , and examine the resonance curve behavior under different scan directions showing interesting features . to account for our results , we consider briefly some possible physical mechanisms that may be responsible for the observed effects . c | c | c | c * process parameter & * b1 & * b2 & * b3 + * partial flow ratios ( ar , n2 ) & ( 87.5%,12.5% ) & ( 75%,25% ) & ( 70%,30% ) + * base temperature & @xmath0 & @xmath1 & @xmath2 + * total pressure & @xmath3 torr & @xmath4 torr & @xmath5 torr + * discharge current & @xmath6 & @xmath7 & @xmath6 + * discharge voltage & @xmath8 & @xmath9 & @xmath10 + * discharge power & @xmath11 & @xmath12 & @xmath13 + * deposition rate & @xmath14 & @xmath15 & @xmath16 + * thickness ( t ) & @xmath17 & @xmath18 & @xmath19 + * base pressure & @xmath20 torr & @xmath21 torr & @xmath22 torr + * target - substrate distance & @xmath23 & @xmath24 & @xmath25 + * * * * * * * * * * * * * * the resonators were designed in the standard stripline geometry , which consists of five layers as shown in the cross section illustration depicted in fig . [ stripline_geometry ] . [ ptb ] stripline.eps the superconducting resonator was dc - magnetron sputtered on one of the sapphire substrates , whereas the superconducting ground planes were sputtered on the inner covers of a gold plated oxygen free high conductivity ( ofhc ) cupper faraday package that was employed to house the resonators . the dimensions of the sapphire substrates were @xmath26 @xmath27 @xmath28 @xmath29 @xmath30 the resonator geometries implemented , which we will refer to them , for simplicity , by the names b1 , b2 , b3 , are presented in the insets of figs . [ b1_s11_jumps ] , [ s11_4.39 ] , [ s11 two jumps ] respectively . the width of the feedlines and the thin part of the resonators was set to @xmath31 to obtain characteristic impedance of @xmath32 . the gap between the feedline and the resonators was set to @xmath31 in the b1 , b3 cases , and to @xmath33 in b2 case . the frequency modes of b1 , b2 , b3 resonators were theoretically calculated using a simple transmission line model , presented in appendix a , and were also experimentally measured using vector network analyzer ( na ) . the theoretical calculation was generally found to be in good agreement with the measurement results , as discussed in appendix a. * * * * the sputtering of the nbn films was done using a dc - magnetron sputtering system . all of the resonators reported here were deposited near room temperature @xcite,@xcite,@xcite , where no external heating was applied . the system was usually pumped down prior to sputtering to @xmath34 base pressure ( achieved overnight ) . the sputtering was done in ar / n@xmath35 atmosphere under current stabilization condition @xcite . the relative flow ratio of the two gases into the chamber and the total pressure of the mixture were controlled by mass flow meters . the sputtering usually started with a two minute pre - sputtering in the selected ambient before removal of the shutter and deposition on the substrate . the sputtering parameters of the three resonators are summarized in table 1 . following the nbn deposition , the resonator features were patterned using standard photolithography process , whereas the nbn etching was done using ar ion - milling . the fabricated resonators were characterized by relatively low @xmath36 for nbn and relatively high normal resistivity @xmath37 that is in good agreement with ref . @xmath36 measured for b1 , b2 and b3 was @xmath38 @xmath39 @xmath40 @xmath41 $ ] respectively , whereas @xmath42 measured for b2 and b3 was @xmath43 and @xmath44 @xmath45 $ ] respectively . to obtain resonators with reproducible physical properties we have used the sputtering method discussed in @xcite , where it was claimed that reproducible parameters of films are assured , by keeping the difference between the discharge voltage in a gas mixture , and in pure argon , constant , for the same discharge current . in fig . [ knee_temp ] we show one of the characterization measurements applied to our dc - magnetron sputtering system , exhibiting a knee - shape graph of discharge current as a function of discharge voltage . the knee - shape graph was obtained for different ar / n@xmath35 mixtures at room temperature as shown in the figure . the discharge voltage difference measured in the presence of n@xmath35 gas relative to the value measured in pure argon at the same discharge current , is also pointed out in the figure , corresponding to different currents and n@xmath35 percentages . [ ptb ] process.eps all measurements presented in this paper have been conducted at liquid helium temperature . the resonance response of the resonators was measured using the reflection parameter @xmath46of a vector na . the resonance response obtained for the third mode of b1 resonator @xmath478.26@xmath48 at low input powers , between @xmath49 dbm and @xmath50 dbm in steps of @xmath51 dbm@xmath52 is shown in fig . [ b1_s11_jumps ] . a small offset was applied between the sequential graphs , corresponding to different input powers , for clarity , and to emphasize the nonlinear evolution of the resonance response as the input power is increased . the interesting characteristics of this nonlinear evolution could be summarized as follows : [ ptb ] b1res.eps \1 ) in the power range between @xmath53 dbm and @xmath54 dbm , the resonance is symmetrical and broad . \2 ) at input power level of @xmath54 dbm , a sudden jump of about @xmath55 db occurs in the resonance curve at the minima where the slope of the resonance response is small . \3 ) as the input power is increased in steps of @xmath51 dbm the resonance becomes asymmetrical , and the left jump shifts towards the lower frequencies gradually . \4 ) as we continue to increase the input power , the jumps decrease their height but the resonance curve following the jumps becomes more symmetrical and deeper , and at certain input power level we even witness a critical coupling phenomenon where @xmath56 at resonance is almost zero , no power reflection is present . \5 ) the resonance becomes symmetrical again and broader and the bifurcations disappear . \6 ) all previously listed effects occur within a frequency span of 10@xmath57 , power range of about 5 dbm , and power step of @xmath51 dbm . moreover , in order to estimate how narrow this resonance could be in the vicinity of critical coupling , a separate @xmath46 measurement has been applied near critical coupling power , using 1601 measurement points and frequency span of 2 @xmath57 . the bandwidth of the resonance curves measured , according to the + 3 db method , was about @xmath58 whereas the ratio @xmath59 similar behavior to that exhibited by the nonlinear third mode of resonator b1 can be clearly seen in fig . [ s11_4.39 ] and fig . [ s11 two jumps ] , which show the nonlinear dynamic evolution of the second mode of resonator b2 and the first of b3 respectively . the main differences between the figures are : \1 ) the power levels at which these nonlinear effects take place . whereas in b1 case they happen between @xmath49 dbm and @xmath50 dbm , in b2 case they happen between @xmath60 dbm and @xmath61 dbm and in b3 case they happen around @xmath62 dbm . \2 ) in fig . [ s11 two jumps ] corresponding to b3 resonator we witness two apparent bifurcations within the resonance band as indicated by circles on the figure , a feature that we did not encounter in figs . [ b1_s11_jumps ] and [ s11_4.39 ] . [ ptb ] b2res.eps [ ptb ] b3res.eps in order to verify that the bifurcation feature , previously measured using na @xmath46 parameter , is not a measurement artifact , we applied a different measurement configuration , shown in fig . [ verify_diode ] , where we scanned the frequency axis with cw mode of an agilent synthesizer and measured the reflected power from the resonator by a power diode and voltage meter . the load that appears in fig . [ verify_diode ] following the diode is an agilent load used in order to extend the linear regime of the power diode . the results of this measurement configuration are shown in fig . [ verify_diode_meas ] . the frequency scan around the resonance was done using 201 points in each direction ( forward and backward ) . a small hysteresis loop can be seen around the two bifurcations . [ ptb ] diode.eps [ ptb ] dioderesults.eps in attempt to find out whether the resonance curve of these nonlinear resonances changes its form along two or more frequency points , further measurements where carried out using na , where we scanned the frequency axis in the vicinity of the jump with high frequency resolution . the measurement results corresponding to frequency step of @xmath47600 @xmath63 and @xmath472.5 @xmath64 are presented in fig . [ 8001pointcw ] plot ( a ) and ( b ) respectively , indicating abrupt transition between two bistable states . [ ptb ] highfreqres.eps applying forward and backward frequency sweeps to these resonators , reveals a very interesting hysteretic behavior . in fig . [ hysteresis_behavior_b2 ] we show a representative frequency scan of b2 second mode , applied in both directions , featuring the following nonlinear dynamic behavior : \1 ) at low input powers @xmath65 dbm and @xmath66 dbm , the resonance is symmetrical and there is no hysteresis . \2 ) as the power is increased by 0.01 dbm to @xmath67 dbm , two bifurcations occur at both sides of the resonance response and hysteresis loops form at the bistable regions . \3 ) as we continue to increase the input power gradually , the hysteresis loop , associated with the right bifurcation , changes direction . at first it circulates counterclockwise between @xmath67 dbm and @xmath68 dbm , at @xmath69 dbm the two opposed bifurcations , at the right side , meet and no hysteresis is detected , as we increase the power further the right hysteresis loop appears again , circulating , this time , in the opposite direction , clockwise . furthermore , it is worth mentioning that the hysteresis loops changing direction are not unique to this resonator , or to the bifurcation occurring on the right side of the resonance . it appears also in the modes of b1 , and it occurs at the left side bifurcation as well , but at different power level . [ ptb ] hysteresis.eps frequency sweep applied to b3 first resonance in both directions , exhibits yet another feature , in addition to the two bifurcations at the sides of the resonance curve , which we have seen earlier , there are another two smaller bifurcations accompanied with hysteresis within the resonance lineshape , adding up to 4 bifurcations in each scan direction , as can be seen in fig . [ 2000point_four_jump ] . this feature may have a special significance in explaining the physical origin of these nonlinearities . [ ptb ] b3hys.eps this unusual dynamic behavior of our nbn films , demonstrated earlier , highly suggest built - in josephson junctions , forming at the boundaries of the granular nbn columnar structure @xcite,@xcite , as the underlying physical mechanism responsible for the observed nonlinearities @xcite . another physical mechanism that may be considered as a strong candidate for explaining the effects , is the local heating mechanism which was hypothesized as the source of notches and switching effects observed in hts films @xcite,@xcite,@xcite . nevertheless recent measurements done on squid ring containing a single josephson junction inductively coupled to a radio frequency resonant circuit @xcite , @xcite , @xcite exhibiting opposed bifurcations , hammerhead resonance lineshape and similar effects , suggest similar physical mechanism and further support the former hypothesis . in the course of this experimental work we have fabricated several stripline nbn resonators dc - magnetron sputtered on sapphire substrates at room temperature implementing different geometries . the resonators have exhibited similar and unusual nonlinear effects in their resonance response curves . the onset of the nonlinear effects in these nbn resonators varied between the different resonators , but usually occurred at relatively low powers , typically 2 - 3 orders of magnitude lower than nb for example . among the nonlinear effects observed : abrupt and multiple bifurcations in the resonance curve , power dependent resonance frequency shift , hysteresis loops in the vicinity of the bifurcations , hysteresis loops changing direction , and critical coupling phenomenon . weak links forming in the nbn films are hypothesized as the source of the nonlinearities . further study of these effects under other modes of operation and measurement conditions would be carried in the future , in order to substantiate our understanding of these extraordinary effects . the calculation process of the resonance frequencies of b1 and b2 makes use of opposite traveling voltage - current waves method @xcite . for this purpose we model b1 and b2 resonators as a straight transmission line extending in the z - direction with two characteristic impedance regions @xmath70 and @xmath71 as shown in fig . [ resonator general model ] . [ ptb ] model.eps the equivalent voltage along the resonator transmission line would be given , in general , by a standing waves expression in the form : @xmath72{cc}a_{+}\cos\beta\left ( z - a\right ) + b_{+}\sin\beta\left ( z - a\right ) & z\epsilon(a , b)\\ a\cos\beta z+b\sin\beta z & z\epsilon(-a , a)\\ a_{-}\cos\beta\left ( z+a\right ) + b_{-}\sin\beta\left ( z+a\right ) & z\epsilon(-b ,- a ) \end{array } \right.\ ] ] where @xmath73 @xmath74 is the propagation constant along the transmission line , and @xmath75 are constants that can be determined using boundary conditions and applied power amplitude . however due to the symmetry of the problem @xmath76 we expect the solutions to have defined parity , where @xmath77 for symmetric solution and @xmath78 for antisymmetric solution . thus by taking advantage of this property and demanding that @xmath79 be continuous at @xmath80 and @xmath81 , one gets : [ c]l@xmath82{cc}\begin{array } [ c]{c}\cos\beta a\cos\beta\left ( z - a\right ) \\ + b_{s}\sin\beta\left ( z - a\right ) \end{array } & z\epsilon(a , b)\\ \cos\beta z & z\epsilon(-a , a)\\\begin{array } [ c]{c}\cos\beta a\cos\beta\left ( z+a\right ) \\ -b_{s}\sin\beta\left ( z+a\right ) \end{array } & z\epsilon(-b ,- a ) \end{array } \right . $ ] + @xmath83{cc}\begin{array } [ c]{c}\sin\beta a\cos\beta\left ( z - a\right ) \\ + b_{a}\sin\beta\left ( z - a\right ) \end{array } & z\epsilon(a , b)\\ \sin\beta z & z\epsilon(-a , a)\\\begin{array } [ c]{c}-\sin\beta a\cos\beta\left ( z+a\right ) \\ + b_{a}\sin\beta\left ( z+a\right ) \end{array } & z\epsilon(-b ,- a ) \end{array } \right . $ ] where @xmath84 stands for the symmetric solution whereas @xmath85 for the antisymmetric solution . to calculate the value of the new constants @xmath86 , we require that the equivalent current @xmath87 along the transmission line , which is given by @xmath88 where @xmath89 is the characteristic impedance of the line , be continuous at @xmath80 and @xmath90 following this requirement one gets @xmath91 and @xmath92 , where @xmath93 . the symmetric and antisymmetric solutions of @xmath79 and @xmath87 are given by : [ c]l@xmath82{cc}\begin{array } [ c]{c}\cos\beta a\cos\beta\left ( z - a\right ) \\ -\eta\sin\beta a\sin\beta\left ( z - a\right ) \end{array } & z\epsilon(a , b)\\ \cos\beta z & z\epsilon(-a , a)\\\begin{array } [ c]{c}\cos\beta a\cos\beta\left ( z+a\right ) \\ + \eta\sin\beta a\sin\beta\left ( z+a\right ) \end{array } & z\epsilon(-b ,- a ) \end{array } \right . $ ] + @xmath83{cc}\begin{array } [ c]{c}\sin\beta a\cos\beta\left ( z - a\right ) \\ + \eta\cos\beta a\sin\beta\left ( z - a\right ) \end{array } & z\epsilon(a , b)\\ \sin\left ( \beta z\right ) & z\epsilon(-a , a)\\\begin{array } [ c]{c}-\sin\left ( \beta a\right ) \cos\beta\left ( z+a\right ) \\ + \eta\cos\left ( \beta a\right ) \sin\beta\left ( z+a\right ) \end{array } & z\epsilon(-b ,- a ) \end{array } \right . $ ] [ c]l@xmath94{cc}\begin{array } [ c]{c}(\frac{-i\cos\beta a\sin\beta\left ( z - a\right ) } { z_{2}}\\ -\frac{i\eta\sin\beta a\cos\beta\left ( z - a\right ) } { z_{2 } } ) \end{array } & z\epsilon(a , b)\\ -\frac{i\sin\left ( \beta z\right ) } { z_{1 } } & z\epsilon(-a , a)\\\begin{array } [ c]{c}(\frac{-i\cos\beta a\sin\beta\left ( z+a\right ) } { z_{2}}\\ + \frac{i\eta\sin\beta a\cos\beta\left ( z+a\right ) } { z_{2 } } ) \end{array } & z\epsilon(-b ,- a ) \end{array } \right . $ ] + @xmath95{cc}\begin{array } [ c]{c}(\frac{-i\sin\beta a\sin\beta\left ( z - a\right ) } { z_{2}}\\ + \frac{i\eta\cos\beta a\cos\beta\left ( z - a\right ) } { z_{2 } } ) \end{array } & z\epsilon(a , b)\\ \frac{i\cos\beta z}{z_{1 } } & z\epsilon(-a , a)\\\begin{array } [ c]{c}(\frac{i\sin\beta a\sin\beta\left ( z+a\right ) } { z_{2}}\\ + \frac{i\eta\cos\beta a\cos\beta\left ( z+a\right ) } { z_{2 } } ) \end{array } & z\epsilon(-b ,- a ) \end{array } \right . $ ] since the resonator ends are shorted we demand @xmath96 the symmetric case : in this case we either have maximum or minimum at @xmath97 thus we get @xmath98 yielding the following condition on the resonance frequencies@xmath99 @xmath100 the antisymmetric case : from the antisymmetric @xmath101 and the continuity @xmath102 conditions , we get @xmath103 which yields : @xmath104 substituting the following numerical values @xmath105 into the above resonance frequency conditions and solving for frequencies below @xmath106 , yields the following solutions ( @xmath107 @xmath108 @xmath109 ) to the symmetric case , and ( @xmath110 @xmath111 @xmath112 ) to the antisymmetric case , with doubly degenerate mode at @xmath112 . by comparing these calculated resonances to the directly measured resonances of b1 resonator , obtained using a broadband @xmath46 measurement ( @xmath113)@xmath52 we find that the excited resonances correspond to the symmetrical case only . the antisymmetric modes do not get excited because they have a voltage node at the feeding line position . since the resonator ends are open - circuited we demand @xmath114 the symmetric case : we require that the current associated with the symmetric voltage , vanishes : @xmath115 + \eta\sin\left ( \beta a\right ) \cos\left [ \beta\left ( b - a\right ) \right ] = 0\ ] ] the antisymmetric case : we require that the current associated with the antisymmetric voltage , vanishes : @xmath116 substituting the following numerical values @xmath117 into the above resonance frequency conditions and solving for frequencies below @xmath106 , yields the following solutions ( @xmath118 @xmath119 @xmath120 ) to the symmetric case , and ( @xmath121 @xmath122 @xmath123 @xmath124 ) to the antisymmetric case . by comparing these calculated resonances to the directly measured resonances of b2 resonator , obtained using a broadband @xmath46 measurement ( @xmath125 @xmath126 @xmath127 @xmath128)@xmath52 we find a good agreement between the two results . the missing resonances do not get excited apparently because of the coupling location of the feedline relative to the resonator . b3 resonator , in contrast , showed some larger discrepancy between the measured value for the first mode @xmath129 @xmath48 ( seen in fig . [ s11 two jumps ] ) and the theoretical value @xmath130 @xmath48 calculated according to the approximated equation : @xmath131 where @xmath132 is the mode number , @xmath133 is the light velocity , @xmath134 is the open - circuited line length ( @xmath135 and @xmath136 is the relative dielectric coefficient of the sapphire ( @xmath137 e.b . would especially like to thank michael l. roukes for supporting the early stage of this research and for many helpful conversations and invaluable suggestions . very helpful conversations with gad eisenstein , oded gottlieb , gad koren , emil polturak , and bernard yurke are also gratefully acknowledged . j. wosik , l .- m . xie , j. mazierska , and r. grabovickic , `` influence of columnar defects on surface resistance of ybacuo superconducting thin films ; nonlinear effects , '' _ appl . _ , vol . 75 , p. 1781 , september 1999 . d.e oates , m. a. hein , p. j. hirst , r. g. humphreys , g. koren , and e. polturak , `` nonlinear microwave surface impedance of ybco films : latest results and present understanding , '' _ physica c _ , 372 - 376 , p. 462 , 2002 . s. m. anlage , w. hu , c. p. vlahacos , d. steinhauer , b. j. feenstra , s. k. dutta , a. thanawalla , and f. c. wellstood , `` microwave nonlinearities in high - t@xmath138 superconductors : the truth is out there , '' _ j. supercond . _ , vol . 12 , p. 353 , 1999 . d. e. oates , s .- h . park , m. a. hein , p. j. hirst , and r. g. humphreys , `` intermodulation distortion and third - harmonic generation in ybco films of varying oxygen content , '' _ ieee trans . _ , vol . 13 , p. 311 , june 2003 . t. dahm , and d. j. scalapino , `` analysis and optimization of intermodulation in high t@xmath138 superconducting microwave filter design , '' _ ieee trans . _ , vol . 8 , p. 149 , december 1998 . c. c. chen , d. e. oates , g. dresselhaus , and m. s. dresselhaus , `` nonlinear electrodynamics of superconducting nbn and nb thin films at microwave frequencies , '' _ phys b. , _ vol . 45 , p. 4788 , march 1992 . j. wosik , l .- m . xie , j. h. miller , jr . , s. a. long , and k. nesteruk , `` thermally - induced nonlinearities in the surface impedance of superconducting ybco thin films , '' _ ieee trans . _ , vol . 7 , p. 1470 , june 1997 . b. a. willemsen , j. s. derov , j. h. silva , and s. sridhar , `` nonlinear response of suspended high temperature superconducting thin film microwave resonators , '' _ ieee trans . _ , vol . 5 , p. 1753 , june 1995 . l. f. cohen , a. l. cowie , a. purnell , n. a. lindop , s. thiess , and j c gallop , `` thermally induced nonlinear behavior of hts films at high microwave power , '' _ supercond . sci . and technol . 15 , p.559 , 2002 . j. wosik , l .- m . xie , r. grabovickic , t. hogan , and s. a. long , `` microwave power handling capability of hts superconducting thin films : weak links and thermal effects induced limitation , '' _ _ ieee trans . supercond . , _ _ vol . 9 , p. 2456 , june 1999 . z. wang , a. kawakami , y. uzawa , and b. komiyama , `` superconducting properties and crystal structures of single - crystal niobium nitride thin films deposited at ambient substrate temperature , '' _ j. appl 79 , p. 7837 , february 1996 . d. d. bacon , a.t . english , s. nakahara , f. g. peters , h. schreiber , w. r. sinclair , and r. b. van dover , `` properties of nbn thin films deposited on ambient temperature substrates , '' _ j. appl 54 , p. 6509 , july 1983 . p. yagoubov , g. goltsman , b. voronov , l. seidman , v. siomash , s. cherednichenko , and e. gershenzon , `` the bandwidth of heb mixers employing ultrathin nbn films on sapphire substrate , '' seventh international symposium on space terahertz technology , charlottesville , p. 290 , march 1996 . r. whiteman , j. diggins , v. schollmann , t. d. clark , r. j. prance , h. prance , and j. f. ralph , `` opposed ( hammerhead ) bifuractions in the resonant lineshape of a strongly driven squid ring - tank circuit system , '' _ phys . 234 , p. 205 , september 1997 . r. j. prance , r. whiteman , t. d. clark , h. prance , v. schollmann , j. f. ralph , s. al - khawaja , and m. everitt , `` nonlinear multilevel dynamics of a coupled squid ring - resonator system in the hysteretic regime , '' _ phys . 82 , p. 5401 , june 1999 . h. prance , t. d. clark , r. whiteman , r. j. prance , m. everitt , p. stiffel , and j. f. ralph , `` pinch resonances in a radio frequency driven squid ring - resonator system , '' _ arxiv : cond - mat/0411139 _ , novemeber 2004 . baleegh abdo ( s2002 ) was born in haifa , israel in 1979 . he received the b.sc . degree in computer engineering , in 2002 , and the m.sc . degree in electrical engineering in 2004 , both from the technion israel institute of technology , haifa , israel . currently he is pursuing the ph.d . degree in electrical engineering at the technion . his graduate research interests are nonlinear effects in superconducting resonators in the microwave regime , resonator coupling and quantum computation . eran segev - arbel was born in haifa , israel in 1975 . he received the b.sc . degree in electrical engineering from the technion israel institute of technology , haifa , israel , in 2002 . he is currentely working toward the ms.c . in electrical engineering at the technion . his research is focused on parametric gain in superconducting microwave resonators . oleg shtempluck * * * * was born in moldova in 1949 . he received the m.sc . degree in electronic engineering from the physical department of chernovtsy state university , soviet union , in 1978 . his research concerned semiconducters and dielectrics . from 1983 to 1992 , he was a team leader in the division of design engineering in electronmash factory , and from 1992 to 1999 he worked as stamp and mould design engineer in ikar company , both in ukraine . currently he is working as a laboratory engineer in microelectronics research center , technion- israel institute of technology , haifa , israel . eyal buks received the b.sc . degree in mathematics and physics from the tel - aviv university , tel - aviv , israel , in 1991 and the m.sc . and ph.d . degrees in physics from the weizmann institute of science , israel , in 1994 and 1998 , respectively . his graduate work concentrated on interference and dephasing in mesoscopic systems . from 1998 to 2002 , he worked at the california institute of technology ( caltech ) , pasadena , as a postdoctoral scholar studying experimentally nanomachining devices . he is currently a senior lecturer at the technion israel institute of technology , haifa . his current research is focused on nanomachining and mesoscopic physics .

in this paper we report some extraordinary nonlinear dynamics measured in the resonance curve of nbn superconducting stripline microwave resonators . among the nonlinearities observed : aburpt bifurcations in the resonance response at relatively low input powers , asymmetric resonances , multiple jumps within the resonance band , resonance frequency drift , frequency hysteresis , hysteresis loops changing direction and critical coupling phenomenon . weak links in the nbn grain structure are hypothesized as the source of the nonlinearities . bifurcations , nonlinear effects , hysteresis , nbn , microwave resonators .

a graph ( digraph ) @xmath0 with a distinguished subset @xmath3 of nodes is said to be _ inner eulerian _ if each node @xmath12 has even degree ( resp . the indegree and outdegree of @xmath2 are equal ) . the nodes in @xmath3 and in @xmath13 are called _ terminals _ and _ inner _ nodes , respectively . a simple path in @xmath4 is called a @xmath3-_path _ if its ends are distinct terminals and the other nodes are inner . there is a nice max - min relation established by cherkassky @xcite and lovsz @xcite for graphs , and by lomonosov @xcite for digraphs : if @xmath14 is inner eulerian , then the maximum number @xmath15 of pairwise edge - disjoint @xmath3-paths is equal to @xmath16 . [ eq : cll ] here and later on , for a subset @xmath17 of nodes , @xmath18 denotes the set of edges with one end in @xmath17 and the other in @xmath19 , called the _ cut _ induced by @xmath17 . for @xmath20 , we refer to a subset @xmath21 with @xmath22 as an @xmath7-_set_. then @xmath23 is defined to be the minimum cardinality @xmath24 among the @xmath7-sets @xmath17 . the above max - min relation has an obvious extension to the capacitated case . given a nonnegative integer function @xmath25 of edge _ capacities _ , let us say that the triple ( _ network _ ) @xmath26 is _ inner eulerian _ if for each inner node @xmath2 , the total capacity of edges incident with @xmath2 is even when @xmath4 is a graph , and the total capacity of edges entering @xmath2 is equal to that of edges leaving @xmath2 when @xmath4 is a digraph . then ( [ eq : cll ] ) yields the following relation for an inner eulerian @xmath26 : @xmath27 where @xmath28 denotes the minimum cut capacity @xmath29 among the @xmath7-sets @xmath17 , the maximum is taken over all collections @xmath30 of @xmath3-paths @xmath31 along with nonnegative _ integer _ weights @xmath32 that satisfy the packing condition @xmath33 and @xmath34 denotes the _ total value _ of @xmath30 , defined to be @xmath35 ) was stated for fractional multiflows @xmath30 in @xcite , with a flaw in the proof . ] . ( hereinafter for a function @xmath36 and a subset @xmath37 , @xmath38 stands for @xmath39 . ) a collection @xmath30 consisting of @xmath3-paths @xmath40 with real weights @xmath41 that obeys ( [ eq : pack ] ) is called a _ free multiflow _ ( the adjective `` free '' is used to emphasize that any pair of distinct terminals is allowed to be connected by a path , i.e. , the commodity graph in the multiflow maximization problem is complete ) . a multiflow achieving the equality in ( [ eq : mm ] ) is called _ maximum_. thus , whenever @xmath26 is inner eulerian , there exists an _ integer _ maximum free multiflow ( i.e. , having the weights of all paths integral ) . cherkassky @xcite showed that such a multiflow in an inner eulerian undirected network can be found in strongly polynomial time . subsequently much faster algorithms both for graphs and digraphs have been developed . they apply a `` divide - and - conquer '' approach in which a current network @xmath26 with @xmath42 is recursively replaced by two networks @xmath43 and @xmath44 such that @xmath45 . originally , such an approach was applied in @xcite to find , in @xmath46 time , a _ half - integer _ maximum multiflow in a graph @xmath4 with integer edge capacities ( but not guaranteeing integrality in the inner eulerian case ) . hereinafter , in notation involving functions of numerical arguments or time bounds , we indicate sets for their cardinalities , and @xmath47 stands for the complexity of an algorithm for finding a maximum flow in a network with @xmath48 nodes and @xmath49 edges . this algorithm was improved and extended in @xcite so as to find an integer maximum free multiflow in an inner eulerian undirected network in the same time @xmath46 , and in an inner eulerian directed network in @xmath50 time . * remark 1 . * the inner eulerianness condition is important . withdrawing it makes the undirected problem more difficult , though still polynomially solvable in the noncapacitated case ( a max - min relation is due to mader @xcite and an original polynomial algorithm is due to lovsz @xcite ) , and makes the directed noncapacitated problem np - hard already for two terminals @xcite . the purpose of this paper is to extend the above theoretical and algorithmic results to bidirected graphs . ( this sort of nonstandard graphs was introduced by edmonds and johnson @xcite in connection with one important class of integer linear programs generalizing problems on flows and matchings ; for a survey , see also @xcite . ) recall that in a _ bidirected _ graph @xmath0 three types of edges are allowed : ( i ) a usual directed edge , or an _ arc _ , that leaves one node and enters another one ; ( ii ) an edge _ from both _ of its ends ; or ( iii ) an edge _ to both _ of its ends . when @xmath51 , the edge becomes a loop ; in what follows we admit only loops of types ( ii ) and ( iii ) ( as loops of type ( i ) do not affect our problem and can be excluded from consideration ) . a nonloop edge entering a node @xmath2 contributes one unit to the indegree @xmath52 of @xmath2 , while a loop of type ( iii ) at @xmath2 contributes two units to @xmath52 ; the outdegree @xmath53 of @xmath2 is specified in a similar way . edges @xmath54 connecting nodes @xmath55 are called _ parallel _ if @xmath56 enters @xmath57 if and only if @xmath58 does so , and similarly for @xmath2 . if @xmath4 has no parallel edges , then @xmath59 . an instance of bidirected graphs is drawn in fig . [ fig : bidir ] . the notion of inner eulerianness for a bidirected graph @xmath4 with a set @xmath3 of terminals is analogous to that for usual digraphs : @xmath60 for all inner nodes @xmath2 . inner eulerian triples @xmath26 , where @xmath25 , are those that turn into inner eulerian pairs @xmath61 when each edge @xmath56 is replaced by @xmath62 parallel edges . in order to be able to extend the above results to bidirected graphs , we need to admit @xmath3-paths with restricted self - intersections . ( in undirected or directed graphs , when one node is reachable from another one by a path , then it is reachable by a simple path as well , but this need not hold in a bidirected graph . ) a _ walk _ in a bidirected graph @xmath4 is an alternating sequence @xmath63 of nodes and edges such that each edge @xmath64 connects nodes @xmath65 and @xmath66 , and for @xmath67 , the edges @xmath68 form a _ transit pair _ at @xmath66 , which means that one of @xmath68 enters and the other leaves @xmath66 . note that @xmath69 may enter @xmath7 and @xmath70 may leave @xmath71 ; nevertheless , we refer to @xmath72 as a walk from @xmath7 to @xmath71 , or an @xmath7@xmath71 _ walk_. @xmath72 is a _ cycle _ if @xmath73 and the pair @xmath74 is transit at @xmath75 ; a cycle is usually considered up to cyclically shifting . observe that an @xmath7@xmath7 walk is not necessarily a cycle . by a _ path _ in a bidirected graph @xmath4 we mean an _ edge - simple _ walk @xmath72 , i.e. , a walk with all edges different . similar to usual graphs / digraphs , a @xmath3-path ( a @xmath3-walk ) is meant to be a path ( resp . walk ) whose ends are distinct terminals and the other nodes are inner . define the number @xmath23 for @xmath20 as before . we show the following [ tm : main ] property ( [ eq : cll ] ) remains valid for a bidirected graph @xmath4 and the set of @xmath3-paths in it . * remark 2 . * in this theorem it suffices to consider only minimal @xmath3-paths , where a path ( edge - simple cycle ) @xmath76 is called _ minimal _ if no part of @xmath72 from @xmath66 to @xmath77 with @xmath78 ( resp . @xmath79 ) forms a cycle . ( a minimal path / cycle need not be simple but it passes any node of @xmath4 at most twice . ) moreover , one can consider only those @xmath3-paths whose induced bidirected graphs contain no cycle . ( in the underlying undirected graph of such a path , each edge belongs to at most one circuit . ) a usual digraph is a special case of bidirected graphs and theorem [ tm : main ] generalizes the above - mentioned result in @xcite . also there is a natural correspondence between the @xmath3-paths in an undirected graph @xmath4 and the minimal @xmath3-paths in the bidirected graph @xmath80 formed from @xmath4 as follows : direct each edge of @xmath4 from both of its ends , and for each inner node @xmath2 , assign @xmath81 loops entering ( twice ) @xmath2 . then a @xmath3-path @xmath72 in @xmath4 is turned into a @xmath3-path in @xmath80 by adding one loop to each intermediate node of @xmath72 . moreover , @xmath61 is inner eulerian if @xmath14 is such . due to this correspondence , theorem [ tm : main ] generalizes the above - mentioned cherkassky lovsz result for undirected graphs as well . like the pure graph and digraph cases , one can reformulate theorem [ tm : main ] in capacitated terms : relation ( [ eq : mm ] ) concerning integer free multiflows @xmath30 remains valid when @xmath4 is bidirected and @xmath26 is inner eulerian . in this case one should consider @xmath3-walks , rather than @xmath3-paths , and refine the packing condition ( [ eq : pack ] ) as @xmath82 where @xmath83 is the number of occurrences of an edge @xmath56 in a walk @xmath40 . thus , the above problem for undirected and directed networks is generalized as : * _ given an inner eulerian network @xmath26 , where @xmath4 is bidirected , find a collection ( free multiflow ) @xmath30 of @xmath3-walks @xmath31 with weights @xmath84 that satisfies ( [ eq : packbd ] ) and maximizes the value @xmath85 . _ * remark 3 . * let @xmath17 be an arbitrary subset of nodes of @xmath4 . one can modify @xmath4 as follows : for each node @xmath86 and each edge @xmath56 incident with @xmath2 , reverse the direction of @xmath56 at @xmath2 . also for an arbitrary arc @xmath56 incident with a terminal @xmath7 , one can reverse the direction of @xmath56 at @xmath7 . both transformations preserve the inner euleriannes of @xmath26 and the set of @xmath3-walks . therefore , problem ( p ) remains equivalent under such transformations . another appealing class of nonstandard graphs was introduced by tutte @xcite who originated a mini - theory , parallel to @xcite in a sense , aiming to unify and generalize flow and matching problems . these are so - called _ skew - symmetric graphs _ ( or anti - symmetrical digraphs , in tutte s terminology ) , digraphs with involutions on the nodes and on the arcs which reverse the orientation of each arc ( a precise definition is given in section [ sec : skew ] ) . his and other researchers study of structural and optimization problems on skew - symmetric graphs has resulted in a number of interesting theorems , methods and applications . there is a close relationship between skew - symmetric and bidirected graphs , and typically results on the former can be reformulated for the latter , and vice versa . so is for the problem of our study , too . we take advantage from both representations . the language of bidirected graphs is more preferable for us to work in the non - capacitated case ; we prove theorem [ tm : main ] directly and obtain its analog for skew - symmetric graphs as a corollary . on the other hand , we prefer to deal with skew - symmetric graphs in algorithmic design for the capacitated case . ( a serious reason is that a flow in a bidirected network is defined as a packing of @xmath3-paths and we do not see reasonable alternative settings for it , while a flow in a skew - symmetric network can be given in a more compact form , via a function on the arc set . ) some facts about skew - symmetric flows and technical tools elaborated for them help us to devise a fast algorithm for the skew - symmetric analog of problem ( p ) concerning _ integer skew - symmetric free multiflows _ in an inner eulerian skew - symmetric network . this yields a fast algorithm for ( p ) as well . the paper is organized as follows . in section [ sec : proof ] we prove theorem [ tm : main ] ( which is relatively simple ) relying on the fact that an inner eulerian bidirected graph can be decomposed into cycles and paths with both ends in @xmath3 . section [ sec : skew ] explains the correspondence between bidirected and skew - symmetric graphs , reviews some known results about the latter ( in particular , tutte s result on symmetric decompositions of skew - symmetric flows ) and gives a skew - symmetric analog of theorem [ tm : main ] . section [ sec : alg ] develops an algorithm for finding a maximum integer skew - symmetric free multiflow in an inner eulerian skew - symmetric network . it relies on a general approach in @xcite and some ingredients from @xcite and attracts additional combinatorial ideas and techniques . as a consequence , problem ( p ) is solved in time @xmath10 ( if the @xmath87-algorithm of goldberg and tarjan @xcite is applied for finding a maximum flow in a directed network with @xmath48 nodes and @xmath49 arcs ) . this improves the bound in @xcite for digraphs . to achieve this bound , we use a faster procedure for the particular flow decomposition problem : given an integer flow @xmath88 with @xmath11 sources and sinks in a digraph with @xmath48 nodes and @xmath49 arcs , decompose @xmath88 into the sum of integer flows , each connecting one source to one sink . the procedure developed in section [ sec : decom ] solves this problem in @xmath89 time . in the concluding section [ sec : sdecom ] , this procedure is extended to symmetric flows in skew - symmetric graphs ( it is not used in the algorithm for ( p ) but may be of interest for other applications ) . let @xmath0 be an inner eulerian bidirected graph with a terminal set @xmath3 . one may assume that @xmath4 has no loops incident with terminals . since @xmath14 is inner eulerian , for each inner node @xmath2 , one can choose a set @xmath90 of transit pairs at @xmath2 so that each non - loop edge incident with @xmath2 occurs in exactly one pair and each loop at @xmath2 ( if any ) occurs in two pairs . the collection @xmath91 determines a decomposition of ( the edge - set of ) @xmath4 into a collection @xmath92 of edge - simple cycles and a collection @xmath93 of paths with both ends at @xmath3 . more precisely , each edge @xmath94 belongs to exactly one member @xmath72 of @xmath95 and satisfies the following condition : for each end @xmath2 of @xmath56 , if @xmath12 and @xmath96 , then either @xmath97 or @xmath98 are three consecutive elements in @xmath72 , while if @xmath99 , then @xmath72 begins with @xmath100 or ends with @xmath101 . note that all nodes of any cycle in @xmath92 and all intermediate nodes of any path in @xmath93 are inner . so each path in @xmath93 is a @xmath3-path unless it connects equal terminals . when needed , we may reverse some paths in @xmath93 . for @xmath20 , let @xmath102 ( @xmath103 ) denote the set of paths in @xmath93 with exactly one end ( resp . with both ends ) at @xmath7 . since @xmath104 ( where @xmath105 is the full degree @xmath106 of @xmath2 ) , the theorem becomes trivial when all sets @xmath103 are empty . in a general case , we try to transform the decomposition so as to increase the `` useful value '' @xmath107 , by applying a certain augmenting approach . consider @xmath20 and assume , w.l.o.g . , that all paths in @xmath102 begin at @xmath7 . let @xmath108 be a sequence of distinct nodes such that either @xmath109 , or @xmath110 belongs to a path in @xmath103 , and for @xmath111 , the nodes @xmath112 occur in a cycle in @xmath92 or occur in _ this order _ in a path in @xmath102 . [ eq : aug ] we say that @xmath113 is augmenting if @xmath114 belongs to a path in @xmath93 having both ends in @xmath8 . consider two cases . . there is no augmenting sequence for @xmath7 . let @xmath115 be the set of all nodes occurring in sequences @xmath113 as in ( [ eq : aug ] ) . clearly @xmath116 . consider an edge @xmath56 of the cut @xmath117 ; let @xmath55 be the ends of @xmath56 in @xmath115 and @xmath118 , respectively . observe that @xmath56 belongs to neither a cycle in @xmath92 nor a path in @xmath119 . also ( by ( [ eq : aug ] ) ) if @xmath56 belongs to a path @xmath120 , then all nodes of @xmath72 from @xmath7 to ( the last occurrence of ) @xmath57 are contained in @xmath115 , i.e. , @xmath72 traverses the cut @xmath117 exactly once . this implies @xmath121 . hence , if none of terminals admits an augmenting sequence as above , then the number of @xmath3-paths in @xmath93 is at least @xmath16 , as required . an augmenting sequence @xmath108 for @xmath7 exists . let @xmath113 be chosen so that no proper subsequence in it is augmenting . then : any cycle in @xmath92 meets at most two nodes in @xmath113 and these nodes are consecutive in @xmath113 ; [ eq : intc ] if a path @xmath120 contains a node @xmath122 , then the part of @xmath72 from @xmath7 to ( the last occurrence of ) @xmath122 can contain at most one node @xmath123 with @xmath124 ; moreover , if such an @xmath123 exists then @xmath125 . [ eq : intp ] we transform @xmath126 along @xmath113 , step by step , as follows . choose a @xmath127 containing @xmath110 . at the first step , if ( a ) @xmath128 belong to a cycle @xmath129 , then we combine @xmath130 and @xmath131 into one @xmath7@xmath7 path . and if ( b ) @xmath128 belong to a path @xmath120 from @xmath7 to @xmath71 , say , and if @xmath132 occurs in @xmath72 earlier than @xmath110 , then we replace @xmath130 by the concatenation of the part @xmath133 of @xmath72 from @xmath7 to ( the last occurrence of ) @xmath110 and the part @xmath134 of @xmath130 from @xmath110 to @xmath7 , and replace @xmath72 by the concatenation of the rest of @xmath130 ( from @xmath7 to @xmath110 ) and the rest of @xmath72 ( from @xmath110 to @xmath71 ) . ( we assume , w.l.o.g . , that the last edge of @xmath133 and the first edge of @xmath134 form a transit pair at @xmath110 ; otherwise reverse @xmath130 . ) as a result , we obtain an @xmath7@xmath7 path , denoted by @xmath130 as before , that contains @xmath132 . in case ( a ) , the cycle @xmath131 vanishes , and in case ( b ) , the new path @xmath72 goes from @xmath7 to @xmath71 as before , and its part from @xmath110 to @xmath71 preserves . this together with ( [ eq : intc ] ) and ( [ eq : intp ] ) implies validity of ( [ eq : aug ] ) for the remaining sequence @xmath135 ; moreover , ( [ eq : intc ] ) and ( [ eq : intp ] ) are maintained as well . at the second step , we consider the pair @xmath136 and act in a similar way , and so on . eventually , after @xmath137 steps , the current @xmath7@xmath7 path @xmath130 contains the node @xmath114 . since @xmath113 is augmenting , @xmath114 also belongs to some @xmath71@xmath138 path @xmath139 with @xmath140 ( possibly @xmath141 ) . now splitting @xmath142 at @xmath114 and concatenating the arising four pieces in another way , we obtain two @xmath3-paths , one connecting @xmath7 and @xmath138 and the other connecting @xmath7 and @xmath71 . this gives a new decomposition @xmath126 of @xmath4 having a larger value of @xmath143 , and the theorem follows . in fact , the above proof is constructive and prompts a polynomial algorithm for finding a maximum number of pairwise edge - disjoint @xmath3-paths in an inner eulerian bidirected graph . a more efficient and more general algorithm ( dealing with the capacitated case ) is described in section [ sec : alg ] . this section contains terminology and some basic facts concerning skew - symmetric graphs and explains the correspondence between these and bidirected graphs . for a more detailed survey on skew - symmetric graphs , see , e.g. , @xcite . a _ skew - symmetric graph _ is a digraph @xmath0 endowed with two bijections @xmath144 such that : @xmath145 is an involution on the nodes ( i.e. , @xmath146 and @xmath147 for each @xmath148 ) , @xmath149 is an involution on the arcs , and for each arc @xmath56 from @xmath57 to @xmath2 , @xmath150 is an arc from @xmath151 to @xmath152 . for brevity , we combine the mappings @xmath144 into one mapping @xmath153 on @xmath154 and call @xmath153 the _ symmetry _ ( rather than skew - symmetry ) of @xmath4 . for a node ( arc ) @xmath155 , its symmetric node ( arc ) @xmath156 is also called the _ mate _ of @xmath155 , and we will often use notation with primes for mates , denoting @xmath156 by @xmath157 . obviously , @xmath158 for each @xmath148 . we admit parallel arcs , but not loops , in @xmath4 . observe that if @xmath4 contains an arc @xmath56 from a node @xmath2 to its mate @xmath159 , then @xmath58 is also an arc from @xmath2 to @xmath159 ( so the number of arcs of @xmath4 from @xmath2 to @xmath159 is even and these parallel arcs are partitioned into pairs of mates ) . by a path ( circuit ) in @xmath4 we mean a simple directed path ( cycle ) , unless explicitly stated otherwise . the symmetry @xmath153 is extended in a natural way to paths , subgraphs , and other objects in @xmath4 . in particular , two paths or circuits are symmetric to each other if the elements of one of them are symmetric to those of the other and go in the reverse order : for a path ( circuit ) @xmath76 , the symmetric path ( circuit ) @xmath160 is @xmath161 . one easily shows that @xmath4 can not contain self - symmetric circuits ( cf . @xcite ) . following terminology in @xcite , a path or circuit in @xmath4 is called _ regular _ if it contains no pair of symmetric arcs ( while symmetric nodes in it are allowed ) . for a function @xmath162 on @xmath163 , its symmetric function @xmath164 is defined by @xmath165 , @xmath94 , and @xmath162 is called ( self-)_symmetric _ if @xmath166 . for a function @xmath167 and a node @xmath148 , define @xmath168 ( the _ divergency _ of @xmath88 at @xmath2 ) , where @xmath169 ( @xmath170 ) denotes the set of arcs of @xmath4 leaving ( resp . entering ) @xmath2 . let @xmath88 be nonnegative , integer - valued and symmetric , and let @xmath171 be a subset of nodes not intersecting @xmath172 . when @xmath173 is nonnegative at each @xmath174 and zero at each @xmath175 , @xmath88 is said to be an _ is - flow _ ( integer symmetric flow ) from @xmath171 to @xmath176 . the _ value _ @xmath177 of @xmath88 is @xmath178 . by a multiterminal version of a theorem due to tutte @xcite , an is - flow @xmath88 from @xmath171 to @xmath176 has an _ integer symmetric decomposition_. this means that @xmath88 is representable as @xmath179 , where for @xmath180 , @xmath40 is a path from @xmath171 to @xmath176 or a circuit , @xmath181 is the path ( also going from @xmath171 to @xmath176 ) or circuit symmetric to @xmath40 , and @xmath182 . [ eq : sdecom ] here @xmath183 denotes the incidence vector of the arc - set of a path / circuit @xmath72 , i.e. , for @xmath94 , @xmath184 if @xmath56 belongs to @xmath72 , and 0 otherwise . note that paths / circuits in ( [ eq : sdecom ] ) need not be regular . considering @xmath185 as the weight of @xmath40 and of @xmath181 , observe that the total weight of paths from @xmath171 to @xmath176 is equal to @xmath177 . similar to flow decomposition in usual digraphs , an integer symmetric decomposition of an is - flow @xmath88 can be found in @xmath186 time . let @xmath14 be inner eulerian , where the terminal set @xmath3 is ( self-)symmetric . take a partition @xmath187 of @xmath3 such that @xmath188 for all @xmath189 . since the all - unit function @xmath88 on @xmath163 represents an is - slow from @xmath171 to @xmath176 , ( [ eq : sdecom ] ) implies that there exists a symmetric collection @xmath93 of circuits and paths from @xmath171 to @xmath176 in @xmath4 such that the members of @xmath93 are pairwise arc - disjoint and cover @xmath163 , and each terminal @xmath189 is the beginning of exactly @xmath190 paths in @xmath93 . [ eq : decomp ] moreover , the members of @xmath93 are regular ( for if some @xmath191 contains mates @xmath192 , then @xmath54 are in @xmath160 as well , which is impossible ) . next we explain the correspondence between skew - symmetric and bidirected graphs ( cf . 2 ) ) . for sets @xmath193 , we may use notation @xmath194 when @xmath195 and @xmath196 . given a skew - symmetric graph @xmath0 , choose an arbitrary partition @xmath197 of @xmath198 such that @xmath199 is symmetric to @xmath200 . then @xmath201 determine bidirected graph @xmath202 with node set @xmath200 whose edges correspond to the pairs of symmetric arcs in @xmath4 . more precisely , arc mates @xmath203 of @xmath4 generate one edge @xmath56 of @xmath202 connecting nodes @xmath204 such that : ( i ) @xmath56 goes from @xmath57 to @xmath2 if one of @xmath203 goes from @xmath57 to @xmath2 ( and the other goes from @xmath159 to @xmath205 in @xmath199 ) ; ( ii ) @xmath56 leaves both @xmath55 if one of @xmath203 goes from @xmath57 to @xmath159 ( and the other from @xmath2 to @xmath205 ) ; ( iii ) @xmath56 enters both @xmath55 if one of @xmath203 goes from @xmath205 to @xmath2 ( and the other from @xmath159 to @xmath57 ) . in particular , @xmath56 is a loop if @xmath203 connect a pair of symmetric nodes . conversely , a bidirected graph @xmath202 with node set @xmath200 , say , determines skew - symmetric graph @xmath0 with symmetry @xmath153 as follows . take a copy @xmath206 of each element @xmath2 of @xmath200 , forming the sets @xmath207 and @xmath208 . for each edge @xmath56 of @xmath202 connecting nodes @xmath57 and @xmath2 , assign two `` symmetric '' arcs @xmath203 in @xmath4 so as to satisfy ( i)-(iii ) above ( where @xmath209 and @xmath210 ) . an example is depicted in fig . [ fig : sk - bi ] . * remark 4 . * a bidirected graph generates one skew - symmetric graph , while a skew - symmetric graph generates a number of bidirected ones , depending on the partition @xmath211 of @xmath198 that we choose in the first construction . the latter bidirected graphs are produced from each other by the edge reversing transformation with respect to a subset of nodes as indicated in remark 3 in the introduction , so they are equivalent for us . a terminal set @xmath171 in @xmath202 generates the symmetric terminal set @xmath212 in @xmath4 , and vice versa . one easily checks that @xmath213 is inner eulerian if and only if @xmath14 is such . also there is a correspondence between the @xmath171-paths in @xmath202 and certain @xmath3-paths in @xmath4 . more precisely , let @xmath214 be the natural mapping of @xmath154 to @xmath215 ( where @xmath216 is the edge set of @xmath202 ) . each walk ( cycle ) @xmath217 in @xmath4 induces the sequence @xmath218 of nodes and edges in @xmath202 . conversely , for a walk ( cycle ) @xmath219 in @xmath202 , form the sequence @xmath220 of nodes and arcs in @xmath4 by the following rule : * @xmath221 if @xmath69 leaves @xmath222 , and @xmath223 if @xmath69 enters @xmath222 ; and for @xmath180 : ( a ) if @xmath64 leaves @xmath224 , then @xmath225 is the arc in @xmath226 that leaves @xmath224 , and @xmath66 is the head of @xmath225 ; ( b ) if @xmath64 enters @xmath224 , then @xmath225 is the arc in @xmath226 that leaves @xmath227 , and @xmath66 is the head of @xmath225 . ( when @xmath64 is a loop , the arcs in @xmath226 are parallel , and the arc @xmath225 in this set is chosen arbitrarily . ) it is not difficult to conclude that ( r ) provides : for a walk ( cycle ) @xmath130 in @xmath202 , * @xmath228 is a walk ( cycle ) in @xmath4 and @xmath229 ; * if @xmath130 is edge - simple and minimal ( see remark 2 in the introduction ) , then @xmath228 is a regular path ( circuit ) . [ eq : corresp ] also the walk ( cycle ) reverse to @xmath130 determines the walk ( cycle ) in @xmath4 symmetric to @xmath228 ( up to the choice of arcs @xmath225 for loops @xmath64 ) . the corresponding converse properties to those in ( [ eq : corresp ] ) also take place . let us say that a @xmath3-walk @xmath72 from @xmath7 to @xmath71 in @xmath4 is _ essential _ if @xmath71 is different from @xmath230 . thus , we have a natural bijection between the essential regular @xmath3-paths in @xmath4 ( considered up to parallel arc mates ) and the minimal @xmath171-paths in @xmath202 . this gives @xmath231 where @xmath232 is the maximum cardinality of a symmetric collection of pairwise arc - disjoint essential @xmath3-paths in @xmath4 . note also that for a terminal @xmath189 and an @xmath7-set @xmath17 in @xmath202 , each edge of the cut @xmath233 generates two arc mates in the symmetric cut @xmath234 in @xmath4 . therefore , @xmath235 where @xmath236 is the minimum cardinality of a symmetric cut in @xmath4 separating @xmath237 and @xmath238 . in view of relations ( [ eq : twice1 ] ) and ( [ eq : twice2 ] ) , theorem [ tm : main ] is equivalent to the following [ cor : skew ] for a skew - symmetric graph @xmath0 with a symmetric set @xmath3 of terminals , if @xmath14 is inner eulerian , then @xmath239 . in the capacitated case , we are given a symmetric function @xmath25 of arc capacities in a skew - symmetric graph @xmath0 with a symmetric set @xmath240 of terminals . by an integer symmetric free multiflow ( or , briefly , an is-_multiflow _ ) in the network @xmath26 we mean a collection @xmath241 of integer flows @xmath242 for the ordered pairs @xmath243 of distinct terminals in @xmath171 such that : ( a ) @xmath244 is a flow from @xmath237 to @xmath245 ( i.e. , @xmath173 is nonnegative for @xmath246 , nonpositive for @xmath247 , and 0 otherwise ) ; ( b ) each @xmath242 is symmetric to @xmath248 ; and ( c ) @xmath241 is @xmath249-_admissible _ , i.e. , @xmath250 the ( total ) _ value _ @xmath251 of @xmath241 is @xmath252 . the problem is : * _ given an inner eulerian network @xmath26 , where @xmath4 is a skew - symmetric graph and @xmath3 and @xmath249 are symmetric , find a _ maximum is - multiflow _ , i.e. , an is - multiflow @xmath241 maximizing @xmath251 . _ to see how this problem is related to ( p ) , let @xmath14 correspond to @xmath213 , where @xmath202 is bidirected . let @xmath253 be the corresponding capacity function in @xmath202 , i.e. , @xmath254 for an edge @xmath255 and its images @xmath203 in @xmath4 . the inner eulerianness of @xmath26 implies that of @xmath256 , and vice versa . given an is - multiflow @xmath241 in @xmath26 , represent each flow @xmath242 in the path packing form : @xmath257 , where @xmath258 and @xmath40 is a circuit or a ( simple ) path from @xmath237 to @xmath245 . [ eq : fst ] we assume that the representation of each flow @xmath242 is symmetric to that of @xmath248 . then the set @xmath93 of ( essential ) @xmath3-paths in these representations is symmetric , with @xmath259 for each @xmath191 , and we have @xmath260 . now each pair @xmath261 of path mates determines an @xmath171-walk @xmath262 in @xmath202 ( considered up to reversing ) , and taking together these paths @xmath262 with weights @xmath263 , we obtain a multiflow @xmath30 in @xmath256 satisfying @xmath264 . conversely , let @xmath265 be an integer multiflow in @xmath256 , where @xmath266 consists of @xmath171-walks . one may assume that for each edge @xmath56 of @xmath202 , no path @xmath267 traverses @xmath56 twice in the same direction ( for otherwise one can remove a cycle from @xmath262 ) . then each @xmath7@xmath71 walk @xmath262 determines an arc - simple directed walk @xmath72 from @xmath237 to @xmath245 and its mate @xmath133 from @xmath245 to @xmath237 in @xmath4 . assign @xmath268 . let @xmath242 be the sum of functions @xmath269 over the obtained walks @xmath72 from @xmath237 to @xmath245 . then @xmath248 is symmetric to @xmath242 . these flows form an is - multiflow @xmath241 in @xmath26 satisfying @xmath270 . thus , problems ( ps ) and ( p ) ( regarding @xmath271 ) are reduced to each other . in the next section we devise an efficient algorithm for finding an optimal solution to ( ps ) and then explain that it can be transformed into an optimal solution to the corresponding instance of ( p ) without increasing the time bound . in this section we describe an algorithm to solve problem ( ps ) and estimate its complexity . we use terminology and facts from the previous section . let @xmath272 be an inner eulerian skew - symmetric network . as before , we represent the terminal set @xmath3 as @xmath273 and associate with @xmath26 the corresponding bidirected network @xmath256 . one may assume that no arc in @xmath4 connects a pair of terminal mates . also if @xmath4 has an arc entering a terminal @xmath189 , then replacing its head @xmath7 by @xmath274 and symmetrically replacing the tail @xmath274 of the symmetric arc @xmath58 by @xmath7 does not affect the problem in essence . so we may assume that @xmath275 for each terminal @xmath189 in @xmath4 . then any flow from @xmath237 to @xmath245 , where @xmath276 , is essentially a flow from @xmath7 to @xmath277 , and its symmetric flow is a flow from @xmath71 to @xmath274 ; this property will simplify technical details in our construction . in terms of @xmath202 , the latter assumption says that each edge incident with a terminal @xmath7 in @xmath202 leaves @xmath7 ( cf . remark 3 in section [ sec : intr ] ) . the algorithm uses a recursion analogous to that in @xcite , and the case @xmath278 is the base in it . we first consider this special case ( which generalizes the case @xmath279 ) . the algorithm for this case uses one auxiliary skew - symmetric graph @xmath280 . it is obtained from @xmath4 by adding , for each pair @xmath281 of inner node mates , four _ auxiliary arcs _ connecting @xmath2 and @xmath159 : two arc mates @xmath282 going from @xmath2 to @xmath159 and two arc mates @xmath283 from @xmath159 to @xmath2 , regardless of the existence of such arcs in @xmath4 . this @xmath284 corresponds to the bidirected graph @xmath285 obtained from @xmath202 by adding two auxiliary loops at each inner node @xmath2 , one leaving @xmath2 ( twice ) and the other entering @xmath2 . the algorithm consists of three stages . let @xmath286 . at _ stage 1 _ , we apply the algorithm for inner eulerian graphs from @xcite to find a maximum integer free multiflow in the underlying undirected graph @xmath287 for @xmath202 having the same set @xmath171 of terminals and the same capacities @xmath253 . it runs in @xmath288 time ( since @xmath289 ) and outputs ( simple ) @xmath171-paths @xmath290 in @xmath287 and weights @xmath84 satisfying the packing condition w.r.t . ( recall that @xmath291 is a bound for the applied max flow algorithm ; we assume @xmath292 ) . it also outputs pairwise disjoint @xmath293-sets @xmath294 , @xmath295 , such that for each @xmath296 , the sum of weights @xmath297 of paths @xmath298 connecting @xmath293 and @xmath299 is equal to @xmath300 . however , some pairs of consecutive edges in @xmath298 may be non - transit in @xmath202 , i.e. , @xmath298 is not necessarily a path in @xmath202 . at _ stage 2 _ , we transform @xmath290 into paths in the auxiliary bidirected graph @xmath285 . more precisely , for each @xmath301 and for each non - transit pair @xmath302 in it , if both edges @xmath302 enter ( leave ) @xmath77 , then the element @xmath77 of @xmath303 is replaced by the string @xmath304 , where @xmath305 is the auxiliary loop leaving ( resp . entering ) @xmath77 . this results in minimal @xmath171-paths @xmath306 in @xmath285 . and its images in the graphs @xmath285 and @xmath284,title="fig : " ] and its images in the graphs @xmath285 and @xmath284,title="fig : " ] and its images in the graphs @xmath285 and @xmath284,title="fig : " ] each path @xmath307 and its reverse one are then lifted to @xmath284 ( by the method explained in section [ sec : skew ] ) , giving regular @xmath3-paths @xmath308 symmetric to each other . ( figure [ fig : pi ] illustrates paths @xmath309 . ) for each pair @xmath310 ( @xmath311 ) , the functions @xmath312 or @xmath313 for the paths from @xmath314 to @xmath315 are added up , forming @xmath314@xmath315 flow @xmath316 . this gives a symmetric collection of six integer flows in @xmath284 ; see figure [ fig:3term ] . the @xmath253-admissibility of the above multiflow in @xmath287 and the fact that each path @xmath40 is regular imply that the total flow though each arc @xmath56 of @xmath4 does not exceed @xmath62 . also the fact that the cuts @xmath317 are saturated implies that for @xmath295 , the arcs in @xmath318 are saturated by @xmath319 , and symmetrically , the arcs in @xmath320 are saturated by @xmath321 , [ eq : satur ] where @xmath322 and the indices are taken modulo 3 . so the is - multiflow consisting of these six flows has maximum value . in @xmath284 ] at _ stage 3 _ , we improve the above flows @xmath324 in @xmath284 by reducing their values on the auxiliary arcs to zero , eventually obtaining the desired multiflow in @xmath4 . in view of ( [ eq : satur ] ) , for @xmath295 , one may assume that @xmath325 and @xmath326 take zero values on all arcs of the subgraph @xmath327 of @xmath284 induced by @xmath328 . take the residual capacities @xmath329 of arcs @xmath94 . the divergency of @xmath249 ( w.r.t . @xmath163 ) and of each @xmath324 ( w.r.t . @xmath330 ) at any inner node is zero , therefore , @xmath331 where @xmath332 denotes @xmath333 ( recall that @xmath334 are the auxiliary arcs from @xmath2 to @xmath159 ) . the function @xmath335 on @xmath163 is nonnegative , integer - valued and symmetric . also ( [ eq : divdelta ] ) and @xmath336 imply that @xmath337 is even for each @xmath12 . hence we can extend @xmath335 to the auxiliary arcs so as to obtain an is - flow in @xmath338 . ( the extended @xmath335 satisfies @xmath339 for each @xmath12 . ) notice that @xmath340 for each arc @xmath56 in the cut @xmath341 , @xmath295 , by ( [ eq : satur ] ) . therefore , the restriction @xmath342 of @xmath335 to the set @xmath343 of arcs of the subgraph @xmath344 is an is - flow from @xmath293 to @xmath345 . in its turn , the restriction @xmath346 of @xmath335 to the set @xmath347 of arcs with both ends in @xmath348 is an integer symmetric circulation in the subgraph @xmath349 . ( recall that the sets @xmath350 are pairwise disjoint . ) we start with getting rid of nonzero arc values of the above flows on the auxiliary arcs within the subgraph @xmath351 . to this aim , apply the integer symmetric decomposition procedure to @xmath352 ( cf . ( [ eq : sdecom ] ) ) to represent it as the sum of integer @xmath353@xmath354-flows @xmath355 , where @xmath164 is symmetric to @xmath162 . combine @xmath356 and @xmath357 ( where @xmath355 are formally extended by zeros on @xmath358 ) . then @xmath359 is an integer flow from @xmath353 to @xmath176 , and @xmath360 is the flow from @xmath171 to @xmath354 symmetric to @xmath359 . also @xmath361 in view of @xmath362 , @xmath363 and @xmath364 for all @xmath365 . so we can reduce @xmath366 to zero on all auxiliary arcs in @xmath367 . now using standard flow decomposition , we represent the new flow @xmath359 as the sum of three integer flows @xmath368 , from @xmath353 to @xmath354 , from @xmath353 to @xmath369 , and from @xmath353 to @xmath370 , respectively . note that @xmath371 for each @xmath372 implies that @xmath373 is zero on all arcs of the cut @xmath374 . update @xmath375 and @xmath376 ; the flows @xmath377 and @xmath378 are updated symmetrically . then the resulting four flows together with the remaining flows @xmath379 satisfy ( [ eq : satur ] ) as before ( thus forming a maximum is - multiflow ) and take zero values on the auxiliary arcs in @xmath351 , as required . do similarly for @xmath380 and @xmath381 . the task of improving the flows within the subgraph @xmath382 is a bit more involved . first of all we modify @xmath383 ( and @xmath377 ) so as to get @xmath384 ( this situation is technically simpler ) . this is done by decomposing the above - mentioned symmetric circulation @xmath346 in @xmath385 into the sum of an integer circulation @xmath386 and its symmetric circulation @xmath387 and then by updating @xmath388 and @xmath389 ( with @xmath390 extended by zeros to @xmath391 ) . then the equality @xmath363 provides ( [ eq : zero ] ) . the process of improving the flows within @xmath385 consists of @xmath392 iterations ( the idea is borrowed from the algorithm for digraphs in @xcite ) . at a current iteration , we choose a node @xmath393 where some @xmath394 is nonzero . w.l.o.g , one may assume that @xmath395 and @xmath396 . let @xmath397 and @xmath398 ) . let @xmath399 be the set of ( four ) auxiliary arcs connecting @xmath2 and @xmath159 . first of all we represent @xmath383 as the sum of two integer @xmath353@xmath400 flows @xmath401 such that @xmath402 and @xmath403 . to do so , replace @xmath399 by new terminals @xmath404 and arcs @xmath405 , @xmath406 and @xmath407 , and add an arc @xmath408 from @xmath400 to @xmath353 . define @xmath409 , @xmath410 , @xmath411 , @xmath412 and @xmath413 for the remaining arcs @xmath56 this turns @xmath162 into a flow from @xmath71 to @xmath414 , and we decompose it into the sum of integer flows @xmath415 , from @xmath71 to @xmath416 and from @xmath71 to @xmath417 , respectively . these @xmath415 determine the desired @xmath401 in a natural way . combine @xmath418 . then @xmath419 . update @xmath420 for each @xmath421 and decompose the updated @xmath353@xmath422 flow @xmath88 into the sum of integer flows @xmath423 , from @xmath353 to @xmath400 and from @xmath353 to @xmath424 , respectively . then @xmath425 and @xmath426 . doing similarly for the flow @xmath427 and the flow @xmath428 symmetric to @xmath429 ( which have the source @xmath430 in common ) , we obtain corresponding @xmath430@xmath424 flow @xmath431 and @xmath430@xmath354 flow @xmath432 . finally , update @xmath433 ( where @xmath373 is symmetric to @xmath432 ) , @xmath434 and @xmath435 . the updated flows @xmath324 together with their symmetric ones satisfy @xmath436 for each arc @xmath421 . then we choose a next pair of node mates in @xmath437 , and so on . upon termination of the process , the resulting flows @xmath324 take zero values on all auxiliary arcs , and it is easily seen from the construction that @xmath438 preserves for all pairs @xmath439 . so their restrictions to @xmath163 form a maximum is - multiflow in @xmath26 , as required . the above algorithm runs in @xmath288 time plus the time needed to perform @xmath392 , or @xmath440 , flow decompositions during the iterative process at stage 3 ( the other operations including those in @xmath11 symmetric decompositions take @xmath186 time ) . each of these decompositions is applied to a flow with @xmath11 sources and sinks , and we use the procedure in section [ sec : decom ] to implement it in @xmath441 time . this gives the bound @xmath442 for the six ( or four ) terminal case . we now describe the algorithm for an arbitrary @xmath443 . it is based on a recursive network partition approach . for a _ current _ inner eulerian skew - symmetric network @xmath444 , with @xmath240 , the _ network partition procedure _ partitions @xmath171 into two sets @xmath445 such that @xmath446 and @xmath447 and finds a symmetric subset @xmath21 with @xmath448 whose induced cut @xmath449 has minimum capacity @xmath29 . this is done by finding a minimum capacity cut @xmath450 with @xmath451 in the underlying undirected network for @xmath452 , and by making the symmetrization @xmath453 ( relying on @xmath454 ) . next we shrink the subgraph @xmath455 of @xmath4 into two new ( _ extra _ ) terminals @xmath456 , making each arc in @xmath457 enter @xmath458 , and each arc in @xmath459 leave @xmath417 . similarly , @xmath460 is shrunk into extra terminals @xmath461 , each arc in @xmath459 becomes entering @xmath462 and each arc in @xmath457 becomes leaving @xmath463 . this produces two smaller inner eulerian networks @xmath464 with @xmath465 , @xmath466 , satisfying @xmath467 ( since @xmath468 when @xmath469 ) . also for @xmath470 , the cut @xmath341 of @xmath471 has minimum capacity among the cuts separating @xmath472 and @xmath473 . one application of the network partition procedure , to a current @xmath474 , takes one minimum cut computation , so it runs in @xmath288 time . let @xmath475 be a ( recursively found ) maximum free is - multiflow in @xmath476 . the _ aggregation procedure _ transforms @xmath477 into a maximum free is - multiflow @xmath241 in @xmath474 . the flows in @xmath475 going from @xmath478 to @xmath479 are combined into one ( multisource ) flow @xmath480 from @xmath478 to @xmath479 , and symmetrically , the flows from @xmath481 to @xmath482 are combined into one flow @xmath483 . by the maximality of @xmath475 and the minimality of @xmath484 , @xmath480 saturates @xmath320 and @xmath483 saturates @xmath318 . we glue together ( the images of ) @xmath373 and @xmath485 , obtaining @xmath486@xmath487 flow @xmath88 in @xmath474 , and do symmetrically for @xmath488 , obtaining @xmath489 . these @xmath490 are decomposed symmetrically into a symmetric collection of integer one - source - one - sink flows . then the flows formed from @xmath490 together with the remaining flows in @xmath477 connecting pairs of terminals in @xmath491 or in @xmath492 give the desired @xmath241 . ( the maximality of @xmath241 follows from the fact that for each @xmath493 , the total value of flows in @xmath494 leaving @xmath7 or entering @xmath274 is equal to the minimum capacity of a cut in @xmath495 separating @xmath237 and @xmath496 , and similarly for @xmath497 . the above construction maintains such an equality for @xmath241 and each @xmath189 . ) at the bottom level ( @xmath278 ) , we apply the algorithm described in [ ssec : three ] . one application of the aggregation procedure , to current @xmath498 , takes @xmath499 time to create the flows @xmath500 as above plus @xmath186 time to decompose @xmath88 , or @xmath186 time in total ( in view of ( [ eq : tve ] ) ) . it remains to explain that the resulting multiflow @xmath241 in the initial network @xmath474 can be efficiently transformed into a maximum integer free multiflow in the corresponding bidirected network @xmath256 . we show that @xmath501 time is sufficient to create from @xmath241 a corresponding symmetric collection @xmath502 of weighted @xmath3-paths in @xmath474 ; these paths determine weighted @xmath3-walks in @xmath202 forming an optimal solution to problem ( p ) with @xmath256 , by the relationship explained in section [ sec : skew ] . we assume that each flow @xmath88 in @xmath241 is explicitly given only within its support @xmath503 . let @xmath504 be the binary rooted tree formed by all networks arising during the recursion , with the natural ordering on them . the height of @xmath504 ( or the depth of the recursion ) is @xmath9 , in view of the first inequality in ( [ eq : tve ] ) . for a network @xmath505 in @xmath504 , let @xmath506 be the set of terminals from the initial @xmath3 that are contained in @xmath505 , and @xmath507 the set of flows in @xmath241 with both terminals in @xmath508 . we use the fact that for incomparable @xmath509 in @xmath504 , the supports of flows in @xmath510 are disjoint from those in @xmath511 . ( indeed , for the closest common predecessor @xmath505 of @xmath509 , the minimum cut found by the network partition procedure for @xmath505 separates @xmath512 and @xmath513 and is saturated by the flows not in @xmath514 . ) we proceed as follows . for each non - leaf network @xmath505 with children @xmath498 , combine the flows in @xmath241 with the source in @xmath515 and the sink in @xmath516 into one multiterminal flow @xmath517 ( in the initial network ) , and then decompose @xmath517 into a set @xmath518 of weighted paths from @xmath515 to @xmath516 ( the circuits appeared in the decomposition are removed ) . this takes @xmath519 time . taken together , the sets @xmath518 , their symmetric sets and corresponding paths appeared by decomposing the flows in @xmath241 having both terminals in one leaf network , constitute the desired symmetric collection @xmath502 . to estimate the complexity , consider the networks @xmath505 at height @xmath296 in @xmath504 . they are incomparable , so the supports of flows @xmath517 as above in them are pairwise disjoint . hence to form the sets @xmath518 for these @xmath505 takes @xmath186 time in total . this gives the bound @xmath501 for the whole procedure , as declared . we show that the above algorithm runs in @xmath520 time , where @xmath521 , assuming @xmath522 ( as in goldberg tarjan s max flow algorithm ) . we use induction on the height @xmath523 of the binary tree @xmath504 ( it depends only on @xmath524 ) . when @xmath525 ( i.e. @xmath526 ) , the required time bound was shown in [ ssec : three ] . let @xmath527 and let @xmath498 be the children of @xmath474 in @xmath504 . for @xmath466 , we have @xmath528 , and by induction the time @xmath529 of the algorithm to solve the problem for @xmath476 is bounded from above as @xmath530 for some appropriately chosen constant @xmath531 ( specified later ) . here @xmath532 and @xmath533 , keeping notation from [ ssec : gen ] . the network partition and aggregation procedures applied to @xmath474 take time @xmath534 and @xmath535 , respectively , or @xmath536 time together , where @xmath537 is some constant @xmath538 , @xmath539 and @xmath540 . therefore , the time @xmath214 to solve the problem for @xmath474 is estimated as @xmath541 we have @xmath542 ( since @xmath543 ) and @xmath544 ( this follows from @xmath545 and from @xmath546 for @xmath547 and @xmath548 ) . also @xmath549 and @xmath550 , by ( [ eq : tve ] ) . then ( [ eq : time1 ] ) implies @xmath551 since @xmath552 and @xmath553 grows faster than @xmath554 , one can choose constants @xmath555 and @xmath131 ( depending on @xmath537 ) such that the right hand side value in ( [ eq : time2 ] ) becomes smaller than @xmath556 for any @xmath557 . ( for the networks with @xmath558 , the problem is solved in @xmath559 time . ) this yields the desired time bound . [ tm : time ] a maximum is - multiflow ( resp . a maximum integer free multiflow ) in an inner eulerian skew - symmetric ( resp . bidirected ) network @xmath272 can be found in @xmath10 time . for a fixed @xmath560 , we consider the problem : * _ given a flow ( integer flow ) @xmath88 from @xmath171 to @xmath3 , with @xmath561 , in a digraph @xmath0 , find a decomposition @xmath562 , where each @xmath242 is a flow ( resp . integer flow ) from @xmath7 to @xmath71 , _ and show the following ( allowing parallel arcs in @xmath4 and assuming @xmath563 ) . [ tm : decom ] ( d ) can be solved in @xmath441 time . note that when @xmath4 is acyclic , a decomposition ( into one - source - one - sink flows or into weighted paths ) of any flow in @xmath4 is carried out in @xmath559 time by using a topological sorting of the nodes . sleator and tarjan @xcite showed that any flow @xmath88 in an arbitrary digraph can be decomposed , in @xmath564 time , into a circulation and a flow whose support induces an acyclic subgraph of @xmath4 ( so a decomposition of @xmath88 into one - source - one - sink flows can be found with the same complexity @xmath564 ) . the algorithm in @xcite uses sophisticated computational tools , so - called dynamic trees . our approach to solve ( d ) is based on a node splitting technique and uses only simple data structures . let @xmath565 be the set of pairs @xmath566 with @xmath189 and @xmath567 . in the beginning of the algorithm , we delete from @xmath4 the arcs @xmath56 with @xmath568 . also we sort the nodes @xmath2 by increasing their degrees @xmath105 . ( this takes @xmath559 time . ) the algorithm applies @xmath569 iterations . at each iteration , we choose a node @xmath2 with @xmath105 minimum in the current graph @xmath0 . first of all we scan the arcs incident with @xmath2 to select parallel arcs among them . each tuple of parallel arcs is merged into one arc ( and the flows on these are added up ) . the node degrees and the ordering on @xmath198 are updated accordingly . ( this preliminary stage is performed in @xmath570 time . as a result , the degree of @xmath2 becomes less than @xmath571 . ) then we make at most @xmath105 splittings at @xmath2 . more precisely , at a current step of the iteration , we choose an arc entering @xmath2 and an arc leaving @xmath2 , say , @xmath572 and @xmath573 . if @xmath56 or @xmath58 is a loop , we simply delete it from @xmath4 . otherwise define @xmath574 . the _ splitting - off operation _ applied to @xmath575 creates a new arc @xmath576 from @xmath57 to @xmath577 , assigns @xmath578 , updates @xmath579 and @xmath580 , and deletes from @xmath4 the arc ( or arcs ) for which the new value becomes zero ; it takes @xmath11 time . the ordering on @xmath198 is updated accordingly ( in @xmath11 time ) . clearly the operation maintains both the divergency at each node and the flow integrality ( when the original flow is integer ) . also @xmath581 decreases and the number of all arcs does not increase . at the next step of the iteration , the operation is applied to another pair of arcs , one entering and the other leaving @xmath2 , and so on until such pairs no longer exist . after that , if @xmath582 , then @xmath2 is removed from @xmath4 ( as @xmath583 implies @xmath584 ) . at the next iteration , we again choose a vertex where the current degree is minimum , and so on . one can see that after @xmath569 iterations , each arc of the resulting graph @xmath585 goes from a source @xmath189 to a sink @xmath567 . the decomposition @xmath586 for the resulting @xmath88 in @xmath585 is trivial : @xmath587 and @xmath588 for @xmath589 ( letting @xmath590 if the arc @xmath243 does not exist in @xmath585 ) . now going in the reverse order and applying the corresponding _ restoration procedure _ reverse to the splitting - off one , we transform @xmath591 into the desired decomposition of the initial flow . more precisely , consider a current graph @xmath4 and the arcs @xmath572 , @xmath573 , @xmath592 as above , and let @xmath242 , @xmath593 , be the flows already obtained for the graph @xmath80 formed from @xmath4 by the splitting - off operation w.r.t . @xmath575 . for each @xmath593 , add @xmath594 to @xmath595 and to @xmath596 and then delete @xmath576 . ( the backward iteration concerning @xmath2 finishes with restoring the corresponding tuples of parallel arcs incident with @xmath2 and assigning , in a due way , the flows @xmath242 on these arcs . ) eventually , we obtain the desired decomposition @xmath597 of the initial @xmath88 . ( strictly speaking , we have @xmath598 and @xmath599 for all @xmath148 ; so one should add the circulation @xmath600 to one of the flows @xmath242 . ) next we estimate complexity of the above algorithm . let @xmath601 be the sequence of nodes in the splitting - off process . since @xmath602 , the restoration process is only @xmath11 times slower than the splitting - off one . ( this is just where we essentially use the condition that @xmath88 has @xmath11 terminals . ) using this fact , one can conclude that the algorithm runs in @xmath603 time for the initial @xmath163 , where @xmath604 and @xmath605 denotes the degree of @xmath2 at the beginning of splitting at @xmath2 . each iteration @xmath296 in the former process does not increase the number of arcs of the current graph and decreases the number of nodes by one , unless @xmath606 . so @xmath607 is at most @xmath608 . summing up the latter numbers over @xmath296 , we obtain @xmath609 , which is worse than the time bound in theorem [ tm : decom ] . however , we can estimate @xmath335 more carefully , by using the inequality @xmath610 ( provided by merging parallel arcs incident with @xmath66 ) . for any integer @xmath611 , apply the first bound on @xmath612 for @xmath613 , and the second bound for @xmath614 . this gives @xmath615 or @xmath616 . now taking @xmath617 , we obtain @xmath618 , and the theorem follows . in this section theorem [ tm : decom ] is extended to ( skew-)symmetric flows . for a fixed @xmath560 , we consider the problem : * _ given an integer symmetric flow @xmath88 from @xmath619 to @xmath172 in a skew - symmetric graph @xmath0 , find a decomposition of @xmath88 of the form @xmath620 where each @xmath621 is an integer flow from @xmath293 to @xmath622 and @xmath623 is symmetric to @xmath621 . _ note that @xmath623 is a flow from @xmath314 to @xmath624 . so in the above decomposition , for @xmath625 , @xmath293 and @xmath622 are connected by the only flow @xmath621 if @xmath78 , by only @xmath626 if @xmath627 , and by the two flows @xmath628 and @xmath629 if @xmath630 . we show the following this generalizes theorem [ tm : decom ] for integer flows because a digraph @xmath537 with an integer @xmath171@xmath3 flow @xmath359 is turned into a skew - symmetric graph with an integer symmetric @xmath631@xmath632 flow by adding a disjoint copy of the reverse to @xmath537 with the flow reverse to @xmath359 in it . [ lm : lem ] let @xmath359 be a ( not necessarily symmetric ) half - integer flow from @xmath171 to @xmath3 in a skew - symmetric graph @xmath0 such that @xmath633 is an integer for each @xmath148 . let @xmath634 be integer . then there exists , and can be found in @xmath559 time , an integer flow @xmath162 in @xmath4 such that @xmath635 and @xmath636 for all @xmath148 . let @xmath637 be the set of arcs @xmath56 with @xmath638 . the integrality of @xmath634 implies @xmath639 , so the subgraph @xmath640 induced by @xmath637 is skew - symmetric . also the half - integrality of @xmath359 and the integrality of @xmath641 imply that each node is incident with an even number of arcs in @xmath637 . so the underlying undirected graph @xmath202 of @xmath642 is eulerian . we grow a ( simple ) path @xmath72 in @xmath642 such that @xmath643 , starting with an arbitrary node @xmath75 and allowing backward arcs in @xmath72 . let @xmath2 be the last node of the current @xmath72 , and choose an arc @xmath644 incident with @xmath2 and different from the last arc of @xmath72 ( @xmath56 exists as @xmath202 is eulerian ) . let @xmath57 be the end of @xmath56 different from @xmath2 . three cases are possible . ( i ) if both @xmath645 are not in @xmath72 , we increase @xmath72 by adding @xmath646 , and continue the process . ( ii ) if @xmath647 , we remove the part of @xmath72 from @xmath57 to @xmath2 , obtaining the new current path from @xmath75 to @xmath57 , and add @xmath56 to the removed part , forming circuit @xmath131 ( with possible backward arcs ) . ( iii ) if @xmath648 , we remove the part @xmath130 of @xmath72 from @xmath205 to @xmath2 , obtaining the new current path , and add @xmath649 and @xmath58 to @xmath130 , forming circuit @xmath131 ( which is reverse to @xmath650 ) . in case ( ii ) , we update @xmath359 by pushing half - unit along @xmath131 ( i.e. , by setting @xmath651 for the forward arcs @xmath652 in @xmath131 , and @xmath653 for the backward arcs @xmath652 ) and by pushing half - unit along the circuit reverse to @xmath650 . accordingly , we update @xmath360 by pushing half - unit along @xmath650 and along the circuit reverse to @xmath131 . and in case ( iii ) , @xmath359 ( @xmath360 ) is updated by pushing half - unit along @xmath131 ( resp . @xmath650 ) . in both cases , the new @xmath360 is symmetric to the new @xmath359 and each of the functions @xmath634 and @xmath641 preserves . also @xmath637 decreases by the set of arcs occurring in @xmath654 , and the new @xmath202 is eulerian . we continue the process with the new @xmath72 . return to problem ( ds ) . add to @xmath4 new nodes @xmath655 and arcs @xmath656 and @xmath657 , forming skew - symmetric graph @xmath284 , and extend @xmath88 to an is - flow from @xmath71 to @xmath277 in @xmath284 in a natural way . the fact that @xmath88 is integer and symmetric implies that @xmath658 is even . so we can apply lemma [ lm : lem ] to the flows @xmath659 , obtaining corresponding integer flows @xmath355 . the restriction @xmath660 of @xmath162 to @xmath163 is an integer flow from @xmath171 to @xmath176 , and we apply the @xmath441-algorithm from section [ sec : decom ] to decompose it as @xmath661 where @xmath662 is an integer flow from @xmath293 to @xmath622 . then the flows @xmath663 for @xmath180 , and @xmath664 for @xmath665 are as required , and theorem [ tm : sdecom ] follows . [ cor : cor ] let @xmath88 be an is - flow from @xmath171 to @xmath176 in a skew - symmetric graph @xmath666 ( where @xmath667 is not fixed ) , and let @xmath173 be even for all @xmath148 . then there exists , and can be found in @xmath559 time , an integer flow @xmath359 from @xmath171 to @xmath176 such that @xmath668 and @xmath669 for all @xmath148 .

a graph ( digraph ) @xmath0 with a set @xmath1 of terminals is called _ inner eulerian _ if each nonterminal node @xmath2 has even degree ( resp . the numbers of edges entering and leaving @xmath2 are equal ) . cherkassky @xcite and lovsz @xcite showed that the maximum number of pairwise edge - disjoint @xmath3-paths in an inner eulerian graph @xmath4 is equal to @xmath5 , where @xmath6 is the minimum number of edges whose removal disconnects @xmath7 and @xmath8 . a similar relation for inner eulerian digraphs was established by lomonosov @xcite . considering undirected and directed networks with `` inner eulerian '' edge capacities , ibaraki , karzanov , and nagamochi @xcite showed that the problem of finding a maximum integer multiflow ( where partial flows connect arbitrary pairs of distinct terminals ) is reduced to @xmath9 maximum flow computations and to a number of flow decompositions . in this paper we extend the above max - min relation to inner eulerian _ bidirected _ and _ skew - symmetric _ graphs and develop an algorithm of complexity @xmath10 for the corresponding capacitated cases . in particular , this improves the bound in @xcite for digraphs . our algorithm uses a fast procedure for decomposing a flow with @xmath11 sources and sinks in a digraph into the sum of one - source - one - sink flows . _ keywords _ : bidirected graph , skew - symmetric graph , edge - disjoint paths , multiflow . _ ams subject classification _ : 90c27 , 90b10

nasopalatine duct cyst ( ndc ) is a benign non - odontogenic lesion arising from the nasopalatine duct , which probably originates from the epithelial remnants of the nasopalatine duct stimulated to proliferate by trauma , infection , or mucous retention . ndc , also known as incisor canal cyst , nasopalatine canal cyst , nasopalatine cyst or median palate cyst , is the most common non - odontogenic cyst in the maxilla , occurs in 1% of the population , and is most common in middle age . since ndc is not a tumor , simple marsupialization to the nasal cavity is another treatment option . we treated a 29-year - old male with ndc by endoscopic endonasal marsupialization from the bilateral nasal cavities . a 29-year - old male with pain in the palate was referred to our department . he had no history of maxillofacial trauma , or genetic disorders . computed tomography showed an eggshaped round radiolucent area on the midline of the maxilla ( figure 1a - c ) . sagittal t2-weighted magnetic resonance imaging showed a high intensity area in the nasopalatine duct ( figure 1d ) . bulging of the corner of the nasal septum and nasal floor was seen only on the right side ( figure 2a , b ) . the mucoperiosteal flap was elevated and the bone exposed ( figure 2c , d ) . the cyst wall facing the nasal cavity was resected whereas the cyst wall facing palate was preserved . although the pain had disappeared postoperatively , the patient noticed paresthesia of the upper incisor area . recently , three cases of ndc were treated with endoscopic endonasal marsupialization but had no paresthesia after endoscopic surgery . previously , ndc was treated with external incision so that some paresthesia was considered to be a common postoperative sequela and was not a matter of concern . the nasopalatine duct contains the nasopalatine nerve and the terminal branch of the descending palatine artery . the nasopalatine nerve is a branch of the maxillary division of the trigeminal nerve , which passes through the pterygopalatine ganglion , enters the sphenopalatine foramen , and passes medially across the roof of the nose to the upper part of the posterior border of the nasal septum , then passes forward in the mucous membrane of the nasal septum , slopes down to and passes through the incisor canal to reach the hard palate ( figure 3 ) . the upper incisor area is co - innervated with the nasopalatine nerve and anterior palatine nerve . blocking of the anterior palatine nerve did not change either light touch or pinprick threshold . our patient treated with endoscopic endonasal surgery suffered from long - lasting paresthesia of the upper incisor region . the previous three cases treated by endoscopic endonasal marsupialization were apparently fenestrated from only one side . to reduce the possibility of stenosis of fenestration , we chose bilateral fenestration to open the ndc as far as possible . the orifices of two lateral canals are present on the nasal floor side , which descend and merge to form the main canal that opens on the hard palate as a single nasopalatine foramen ( figure 3 ) . unilateral damage of nasopalatine nerve may not cause any sensory abnormality but damage of both nerves may result in paresthesia . since the sensory innervation of the upper incisor region is not exclusively served by the nasopalatine nerve but also by the anterior palatine nerve , complete loss of sensation may not occur . this single case report does not establish how the likelihood of paresthesia after bilateral marsupialization of ndc , but this complication is possible after damage to the bilateral nasopalatine nerves . in conclusion , endoscopic endonasal fenestration of ndc is a simple and less invasive treatment . however , bilateral fenestration of the ndc carries the risk of injury to the bilateral nasopalatine nerves on the surface of the ndc , resulting in paresthesia of the upper incisor region . we recommend thorough investigation of the surface of the cyst wall and preservation of nerve fibers during this procedure .

nasopalatine duct cysts are the most common non - odontogenic cysts in the maxilla , and are conventionally treated through a sublabial or palatine approach . recently , the endoscopic approach has been used , but experience is extremely limited . we treated a 29-year - old male with nasopalatine duct cyst by endoscopic marsupialization , but paresthesia of the incisor region occurred after surgery . this paresthesia gradually remitted within 6 months . the nasopalatine nerve , which innervates the upper incisor region , enters two lateral canals separately at the nasal floor and exits the central main canal at the palate . damage to the bilateral nasopalatine nerves might lead to paresthesia , so we recommend careful examination for nerve fibers during endoscopic surgery , especially if fenestration is performed on both sides .

glucokinase ( gk ) ( ec 2.7.1.1 ) is expressed in glucosensitive cells of the pancreas , liver , hypothalamus , anterior pituitary gland , and enteroendocrine k and l cells [ 13 ] . gk has a prominent role as a glucose sensor because of its specific kinetic properties , including an affinity for glucose that is within the physiological plasma concentration range ( half - saturation level for glucose [ s0.5 ] of ~8 mmol / l ) , positive cooperativity , and lack of inhibition by glucose-6-phosphate . in liver and brain , gk is controlled by an endogenous inhibitor , the glucokinase regulatory protein ( gkrp ) [ 4 , 5 ] . during starvation , the enzyme after refeeding , glucose mediates the dissociation of the gk - gkrp complex and gk translocates to the cytoplasm . also , several naturally occurring activating mutations have been described that induce a conformational change in gk , which results in higher affinity for glucose , and reduce the interaction between gk and gkrp [ 6 , 7 ] . similarly , synthetic gk activators ( gkas ) enhance gk activity and induce its translocation to the cytosol . there is evidence that a defect in gkrp regulation of gk , resulting in increased liver gk activity probably as a result of increased cytosolic translocation , has consequences on glucose and triglyceride homeostasis in humans , even though these patients have reduced risk to type 2 diabetes [ 13 , 14 ] . we aimed to study the metabolic consequences of gk - gkrp deregulation by overexpressing a gk activating mutant ( gka456v ) in the liver of insulin - deficient mice ( lacking endogenous gk ) . transfected gk456v is maintained in the cytosol of hepatocytes in vivo leading to improved glycemia in the absence of dyslipidemia . these data provide novel insights into the consequences of gk - gkrp derangement and widen the scope for gka research in the liver . site - directed mutagenesis to generate gk - a456v cdna was performed using the quickchange site - directed mutagenesis kit ( strategene ) , and specific primers containing the desired mutation ( 3ctggtctctgcggcggcctgcaagaag5 and 5gaccagagacgccgccggtgcaagaacg3 ) from dharmacon . the cdnas for gk and gk - a456v were cloned into ecori - bglii of a pcaggs vector which contains the cag ( cytomegalovirus immediate - early enhancer - chicken -actin hybrid ) promoter . the resulting plasmids pgk and pgka456v were amplified in e. coli jm109 cells and extracted using nucleobond pc 2000 ef mega prep kit ( macherey - nagel ) . dna for animal injection was digested with sali and hindiii which cut on both sides of the expression cassette [ 16 , 17 ] in order to extend expression in vivo . expression plasmids were transfected in huh7 cells for kinetic analysis ( supplementary figure 1 available at doi : 10.1155/2011/707928 ) . male icr mice purchased from harlan interfarma iberica s.l were maintained in a constant 12-hour light - dark cycle and fed standard rodent chow and water ad libitum . all animal protocols were approved by the ethics committee at the university of barcelona . to obtain diabetic animals , mice weighing approximately 22 g were injected i.p . with a single dose of streptozotocin ( stz ) ( 200 mg / kg ) dissolved in 100 mm citric / citrate buffer , ph 4.5 . digested plasmid dna was introduced into murine livers using a hydrodynamic - based gene transfer technique via rapid injection of a large volume of dna solution through the tail vein . briefly , 60 g / mouse dna was diluted in 2.0 to 2.5 ml of apyrogenic ringer - lactate solution ( fresenius kabi ) ( 0.1 ml / g body weight ) and injected into the tail vein using a 27-gauge needle and syringe within 5 to 10 seconds . typically , the mice recovered from the injection within 2 to 10 min . at the end of the experiment , animals were sacrificed under xylazine / ketamine anesthesia . blood samples were taken by inferior cava vein puncture and serum was obtained by centrifugation at 700 g at 4c for 15 min . liver was dissected , snap frozen in liquid nitrogen , and subsequently stored at 80c until analysis . for gk immunodetection , livers from 5-hour fasted animals were fixed in a 4% pfa solution and frozen in oct compound . 7 m cryosections were obtained in a cryostat and immunostained with a 1 : 50 dilution of gk antibody ( ap7901c , abgen ) followed by an anti - rabbit antibody alexa fluor 488 ( molecular probes ) . blood glucose levels were measured using a glucocard memory 2 apparatus ( menarini ) from a blood drop collected from the tail tip . the veterinarian clinical biochemistry service from the veterinary hospital of the universitat autnoma de barcelona , bellaterra , spain , measured serum metabolites . cdna synthesis was performed using ready - to - go you - prime first strand beads ( amersham biosciences ) with random hexamers . mrna levels of the transgenic rat gk ( r - gk ) were quantified with specie - specific primers ( applied biosystems ) and normalized using -2-microglobulin as an internal control in an ht7700 real time - pcr system ( applied biosystems ) . mrna levels of selected genes of interest were measured running a low density array ( applied biosystems ) in an ht7900 real time - pcr system ( applied biosystems ) . frozen liver samples were homogenized in ice - cold homogenization buffer ( hepes 50 mm ph 7.4 , kcl 100 mm , edta 1 mm , mgcl2 5 mm , dtt 2.5 mm ) using a polytron pt 3000 and centrifuged at 100,000 g for 1 hour at 4c . supernatants were used for the determination of gk activity following the spectrophotometric method described by davidson and arion . briefly , the assays were carried out in a solution containing hepes 50 mm ph 7.4 , kcl 100 mm , mgcl2 7.5 mm , nad 1 mm , atp 5 mm , bsa 1% and indicated amounts of glucose . the reactions were initiated by adding 5 u / ml of glucose-6-phosphate dehydrogenase ( g6pdh ) from leuconostoc mesenteroides ( roche ) and the rate of increase in absorbance at 340 nm was measured . the gk activity was calculated as the difference between the kinase activities measured at different glucose concentrations and 0.5 mm glucose ( hexokinase activity ) , and was expressed as munits / mg liver . frozen liver samples were homogenized in ice - cold buffer , which contained hepes 50 mm ph 7.4 , kcl 100 mm , edta 1 mm , mgcl2 5 mm , dtt 2.5 mm , and 1% pluronic f-127 ( calbiochem ) , and centrifuged at 20,000 g for 20 min at 4c . g6pdh activity was assayed by measuring the rate of nadph production from nadp 0.5 mm and glucose-6-phosphate 2 mm , at ph 7.6 . frozen tissue was homogenized in radioimmunoprecipitation assay buffer ( ripa ) supplemented with protease and phosphatase inhibitors and centrifuged at 15,000 g for 15 min at 4c . 30 g of tissue extract was resolved by sds - page ( 812% gel ) and electrotransferred onto a hybond - p membrane ( amersham biosciences ) . / fructose-2,6-biphosphatase ( ub - pfk2 ) and l - pyruvate kinase ( l - pk ) ( gifts from ramon bartrons , barcelona university ) , and carbohydrate response element binding protein ( chrebp ) ( novus biologicals ) . acc and acc - p ser-79 ( upstate ) were used at 1/2000 . sheep anti - pepck - c antiserum ( a gift from daryl granner , vandervilt university , usa ) was used at 1 : 20,000 dilution . all membranes were normalized using monoclonal anti--tubulin ( sigma ) at 1 : 10,000 dilution . horseradish peroxidase activity linked to secondary antibody was detected with ecl substrate ( pierce ) in a fujifilm las 300 intelligent dark box iv imaging system . densitometry was performed using multi gauge software . to measure hepatic free glucose , glucose-6-phosphate ( g6p ) , and lactate briefly , perchloric acid 10% was added to frozen pieces of liver ( 5 : 1 v : w ) and the mixture was homogenized in a potter elvehjem apparatus at 1,500 rpm . the homogenate was then centrifuged at 20,000 g for 10 min at 4c . the supernatant was brought to ph 7 with k2co3 4 n and centrifuged again to remove the kclo4 formed during neutralization . g6p was measured following the spectrofluorometric method described by lang & michal , which is based in the reaction catalyzed by g6pdh . briefly , the assay solution contained triethanolamine 0.2 m ph 7.6 , nadp 0.2 m , mgcl2 5 mm , and g6pdh 0.17 u / ml . lactate was determined by a spectrophotometric method based on the reaction catalyzed by lactate dehydrogenase , following gutmann & wahlefeld . briefly , the reaction cuvette contained hydrazine / glycine buffer 0.25 m/0.7 m , ph 9.3 , edta 0.15 mm , nad 2 mm , and 35 u / ml of lactate dehydrogenase . for fructose-2,6-bisphosphatase ( f2,6bp ) determination , frozen livers were homogenized in 0.1 m naoh , heated to 80c for 15 min , and centrifuged at 12,000 g for 5 min . f2,6bp was determined in supernatants by its ability to activate pyrophosphate - dependent 6-phosphofructo-1-kinase from potato tubers , as described by van schaftingen et al . . the hepatic triacylglyceride ( tag ) content was measured in 3 m koh , 65% ethanol extracts using a tag kit ( sigma ) , based on the method of salmon and flatt for liver saponification . a solution of u - c - glucose and glucose was intraperitoneally injected into 5-hour fasted stz - diabetic mice ( 0.2 mg glucose , 10 ci per animal ) . blood , liver , brain , and muscle were obtained 30 minutes after injection and dissolved into solvable ( perkin elmer ) . blood samples were bleached with edta 0.1 m and h2o2 ( 30% ) , and liver and brain samples were bleached with h2o2 ( 30% ) alone . radioactivity was quantified by adding scintillation liquid ( ecoscint h ) and counted in a wallac 1409 - 001 counter . pgka456v , wild - type gk ( pgk ) and an empty vector ( pcontrol ) , were introduced into the liver of streptozotocin ( stz- ) treated mice . hydrodynamic - based delivery of plasmid dna led to specific transfection of hepatocytes around the central vein [ 23 , 24 ] , reproducing the physiologic distribution of gk in the liver acinus . this technique induces a transient release of liver enzymes that returns to control values by the second day after injection . consistently , transaminase levels were low at the end - point of analysis , and similar in all treatment groups ( pcontrol 207.5 29.88 u / l , pgk 121.0 48.43 u / l , pgka456v 117.5 40.35 u / l ; n = 49 ) . at the time of injection mice were hyperglycemic ( > 350 mg / dl ) and their insulin level was undetectable ( < 0.1 forty - eight hours postinjection the expression of transfected rat gk and gka456v was detected by rt - pcr ( data not shown ) . further confirmation of gk overexpression was obtained by western blot from liver extracts ( figure 1(a ) ) and gk activity assay ( figure 1(b ) ) . gk activity was undetectable in pcontrol transfected livers irrespective of glucose concentration , as expected in long - term stz diabetic animals . in contrast , both pgk and pgka456v transfected groups had similar gk activity at 100 mm glucose ( mu / g fresh ) , demonstrating that both treatment groups had similar amounts of gk protein . consistent with the s0.5 for glucose of gka456v , liver extracts from pgka456v - injected animals had twice the gk activity of livers from pgk - injected animals at physiological glucose concentrations ( 5 mm ) ( figure 1(b ) ) . gkrp retains gk in the nucleus at low glucose concentrations and releases gk when insulin , high glucose , or fructose-1p are present [ 26 , 27 ] . different studies have suggested that the a456v mutation impairs gkrp regulation in vitro [ 6 , 28 ] . therefore , we assessed gkrp - dependent nuclear sequestration in primary hepatocytes from stz - treated rats transfected with pgk and pgka456v , in the presence or absence of pgkrp . densitometry analysis of western blots from nuclear and cytosolic fractions showed that cellular gka456v distribution was not affected by the presence of gkrp ( data not shown ) . pgk - treated mice showed gk immunoreactivity throughout the liver , especially in nuclei ( figure 2 ) . these data demonstrates , that impaired gkrp binding to gka456v changes its compartmentalization in vivo . the impact of both gk enzymes on glucose metabolism was first evaluated in fed animals . both gk and gka456v slightly reduced glycemia ( figure 3(a ) ) . to explore the fate of glucose in the liver fed pgk - treated mice showed significantly higher f2,6bp and glycogen contents ( figure 4(a ) ) , together with a rise in lactate , indicating a higher glycolytic flux . gka456v - expressing livers also showed higher hepatic free glucose than both control and gk groups , even though the content of g6p was similar in all three groups . glycogen content was significantly higher than control but similar to pgk - treated group ( figure 4(a ) ) . pgka456v - treated animals showed a marked reduction of glycemia after a 5-hour fast ( figure 3(a ) ) . lactate was only increased after pgk treatment ( pcontrol , 7.296 0.772 mm ; pgka456v , 8.778 0.649 mm ; pgk , 10.62 0.608 mm hepatic free glucose content was low in the pgka456v treatment group ( table 1 ) . g6p levels were reduced to the same extent in control and gka456v groups , whereas gk - expressing animals showed similar g6p and atp concentrations to well - fed animals . glycogen content in gk - expressing animals was significantly higher than control and gka456v - expressing groups . fed - to - fast transition produced a marked reduction of glycogen stores in pgka456v - treated animals as compared to pcontrol and pgk , suggesting an increased rate of glycogenolysis in gka456v - expressing animals ( figure 4(b ) ) . in order to clarify whether glucose distribution in vivo favored the liver , we quantitated c radioactivity derived from uptake and metabolism of uc - glucose in various tissues 30 minutes after injection . c label was increased exclusively in the liver of both pgk and pgka456v treatment groups ( control , 100 7.88% ; gk , 138.73 14.63% ; gka456v 144.1 8.99% ; p = 0.037 gk versus control and p = 0.003 pgka456v versus control ) . to assess whether pgka456v expression would affect glucose clearance in healthy mice , we performed a glucose tolerance test 1 week after transfection ( figure 3(b ) ) . consistently , our data demonstrates a significant increase in serum tag ( pcontrol 33.5 7.72 mg / dl , pgka456v 38.13 7.66 mg / dl , pgk 74.00 14.76 mg / dl , p < 0.05 versus pcontrol and pgka456v ) and nefa ( pcontrol 0.325 0.09 mm , pgka456v 0.4013 0.05 mm , pgk 0.66 0.10 mm p < 0.05 versus pcontrol ) only in the postabsorptive state . besides , gk overexpressing mice showed a tendency to increase hepatic tag content , which is consistent with the literature [ 30 , 31 ] . in contrast , gka456v overexpression did not promote dislipemia , as evidenced by maintained levels of circulating nefa and tag . there was a significant increase in -hydroxybutyrate levels in the pgka456v group ( pcontrol , 0.18 0.03 mm ; pgka456v , 0.27 0.03 mm in order to elucidate the mechanism responsible for the metabolic profile observed , we analyzed protein and mrna levels for key enzymes and transcription factors . both gk and gka456v treatments were accompanied by increases in l - pk protein ( figures 5(a ) and 5(b ) ) . pgk - treatment resulted in higher levels of ubiquitous pfk2 ( pfkfb3 ) protein ( figures 5(a ) and 5(b ) ) , but not mrna ( table 2 ) , consistent with elevated f2,6bp observed in this treatment group ( table 1 ) . also , endogenous , mouse gk mrna expression was induced in the livers of pgk - injected mice , as detected by species - specific qrt - pcr . correlating with the induction of the expression of endogenous gk , cmyc mrna was only increased in pgk - treated animals . other regulatory factors implicated in the regulation of endogenous gk expression , such as srebp and lxr , were not affected by treatment with pgk and pgka456v ( table 2 ) . as an increment in gk expression in the liver is commonly associated with increased lipogenesis [ 32 , 33 ] , enzymes and transcription factors involved in de novo lipogenesis were analyzed . gk- and pgka456v - expressing groups presented increased mrna content for fasn and mod1 that were more pronounced in pgk - treated animals . also , acc1 and chrebp were more induced by the overexpression of gk than by gka456v . gk , through the production of xylulose-5p , mediates the inhibition of gluconeogenesis by glucose [ 34 , 35 ] . f2,6bp has also been associated with the inhibitory effect of glucose metabolism on gluconeogenesis . consistently , we observed a reduction of pepck at the protein level in both pgk- and pgka456v - treated mice . similarly , pgc-1 and hnf4 mrnas were reduced in pgk - injected mice , whereas gka456v - overexpressing livers only showed reduced pgc-1 mrna . in contrast , the level of mrna for the catalytic subunit of glucose-6-phosphatase ( glc6pase ) were strikingly higher in gka456v - overexpressing animals , consistent with more glycogen breakdown observed after a 5-hour fast . similar results were observed in healthy mice overexpressing pgka456v after a short fast ( data not shown ) . to evaluate the consequences of gk activation and deregulation by gkrp in the liver , we hydrodynamically injected pgka456v in the liver of stz - diabetic mice . this strategy allowed us to obtain a mouse model where the effects of exogenous gks are isolated from those of endogenous gk ( undetectable levels of mouse gk mrna and activity in pcontrol - treated animals ) and insulin action ( insulin levels in addition , the use of hydrodynamic gene transfer provides proper zonal expression of gk and gka456v in perivenous hepatocytes [ 23 , 25 ] . therefore , only animals that were positive for exogenous expression of gk as determined by qrt - pcr ( 3x sd of controls ) were selected for further analysis ( data not shown ) . after selection , both gk - overexpressing groups had identical protein levels and maximal activity ( 100 mm glucose ) figures 1(a)1(b ) . these results are not in agreement with the reported instability of liver gk protein in a phhi - gka456v transgenic mouse and the gkrp knock - out model [ 37 , 38 ] , probably because of the lack of endogenous transcriptional control in pgka456v . also , gka456v activity at 5 mm glucose was higher in liver extracts , as expected from the kinetic changes associated with the mutation . the gka456v mutation resides on a hinge of the enzyme responsible for the conformational changes associated with gkrp interaction and allosteric activation . gkrp regulates gk action in hepatocytes by retaining the enzyme in the nucleus at low glucose concentrations and liberating gk when insulin , high glucose levels , or fructose-1p is present [ 26 , 27 ] . we show here that gka456v is predominantly cytosolic in the liver of transfected animals , contrary to the expected nuclear compartmentalization of wild - type gk . in addition , gka456v was not appropriately translocated to the nucleus of diabetic primary hepatocytes in the presence of excess gkrp ( data not shown ) . lack of gkrp binding to gka456v has been shown by heredia et al . in vitro and inferred from the structural characterization of gk bound to synthetic activators [ 12 , 39 ] . recent reports on the p446l mutation in gkrp also suggest that a decrease in gk inhibition results in increased gk activity , suggesting that gk localizes to the cytosol . an analysis of gk and gka456v overexpression in well - fed animals demonstrated small but significant changes in glycemia , together with increased hepatic glucose metabolism , as suggested by higher f2,6bp and glycogen content , in the absence of alterations to lipid serum metabolites . no changes were observed in enzymes or regulatory proteins involved in gluconeogenesis in fed animals ( data not shown ) . [ 31 , 33 , 40 ] , who used a low dose of gk - expressing adenovirus ( expressed largely in periportal hepatocytes , [ 41 , 42 ] ) but differ from those obtained using high doses of adenovirus , indicating that dose and/or zonal expression of gk influences the metabolic impact of gk overexpression . when animals were examined after a short fast ( postabsorptive ) , marked differences were observed among groups . ( 1 ) gk overexpression reduced glycemia ~15% , consistent with enhanced glucose metabolism in the liver , as shown by increased g6p , f2,6bp , glycogen content , and glycolytic and lipogenic enzymes together with higher serum lactate , nefa and tag concentrations . have shown that a fed - to - fast transition in stz - diabetic mice results in increased gluconeogenic potential and fatty acid oxidation in the liver , consistent with results obtained in pcontrol - treated animals in the present study . conversely , pgk treatment resulted in reduced pepck and pgc1 mrna , supporting the view that gk overexpression indirectly inhibits gluconeogenesis and fatty - acid oxidation . consistently , we measured higher nefa and tag serum levels in the postabsorptive state although no changes in -hydroxybutyrate were observed . these results indicate that enhanced glucose metabolism resulting from gk overexpression had a small effect on glycemia , possibly because pgk dose was low . ( 2 ) gka456v overexpression led to a significant reduction of serum glucose of ~60% that was consistent with higher glucose clearance on a glucose tolerance test in fasting , healthy mice . fasting hypoglycemia is also observed in human carriers of the p446l gkrp mutation [ 14 , 44 ] . gka456v overexpression did not impact the concentration of serum lipids whereas -hydroxybutyrate was increased , contrary to the dyslipidemia observed in gk overexpressing animals in this and earlier studies , including human carriers of the p446l gkrp mutation [ 14 , 44 ] . hepatic levels of f2,6bp and l - pk protein were increased but other indicators ( g6p , fasn mrna , chrebp protein , and mrna and glycogen content ) of glucose utilization were lower than in gk - expressing livers . importantly , glycogen balance ( fed - to - fast ) was significantly lower in gka456v - expressing animals , indicating an important net loss of glycogen . g6pase expression was also higher in this group of animals , providing an explanation for increased glycogen loss observed in gka456v - containing livers . the involvement of g6pase in the positive regulation of glycogenolysis has been shown in several animal models overexpressing p36 or p46 components of the g6pase system , resulting in decreased glycogen levels in the hepatocyte [ 4548 ] . moreover , a lack of g6pase system activity observed in glycogen storage disease type 1a , or in a g6pase ko promotes glycogen accumulation . activation of the nonoxidative branch of the pentose phosphate pathway , as a result of high exogenous glucose , transiently upmodulates g6pase mrna levels and stability in an insulin - independent manner [ 34 , 35 ] . gka456v - expressing livers showed higher g6pdh activity and gsh / gssg ratio during the fed - to - fast transition than control or gk groups ( figures 4(c)-4(d ) and table 1 ) . increased g6pase mrna and protein in the presence of gka456v would suggest an induction of glucose cycling . it is , however , clear that this counter regulation shall have consequential effects on glucose homeostasis if persistent , as occurs in the gka456v model . all in all , the present data confirms that pgk overexpression in the liver results in relatively small changes in glycemia but overt dislypidemia . the present model represents the first attempt to overexpress pgk in perivenous hepatocytes , and confirms previous observations using adenovirus . in contrast to the work of scott et al . and morral et al . , gk overexpression in perivenous hepatocytes does not significantly affect glc6pase expression , suggesting that zonation is an important experimental variable not sufficiently addressed to date in the field . in addition , we have demonstrated that gka456v overexpression reduces blood glucose to a great extent , probably due to its capacity to induce glc6pase . we conclude that impaired gkrp regulation and gka456v altered kinetics greatly influence liver metabolism , in line with results obtained in humans with a mutant gkrp . besides , it suggests that activating gk exclusively in the liver could be a feasible strategy for diabetes , widening the scope for gka research . similar conclusions , based on its potent induction of glucose clearance by the liver , have been obtained after liver - specific gk activation in chicken in a recent study by rideau et al . . studies on animal models of type 2 diabetes are under way in our laboratory in order to evaluate the metabolic impact in the context of insulin resistance and obesity .

recent reports point out the importance of the complex gk - gkrp in controlling glucose and lipid homeostasis . several gk mutations affect gkrp binding , resulting in permanent activation of the enzyme . we hypothesize that hepatic overexpression of a mutated form of gk , gka456v , described in a patient with persistent hyperinsulinemic hypoglycemia of infancy ( phhi ) and could provide a model to study the consequences of gk - gkrp deregulation in vivo . gka456v was overexpressed in the liver of streptozotocin diabetic mice . metabolite profiling in serum and liver extracts , together with changes in key components of glucose and lipid homeostasis , were analyzed and compared to gk wild - type transfected livers . cell compartmentalization of the mutant but not the wild - type gk was clearly affected in vivo , demonstrating impaired gkrp regulation . gka456v overexpression markedly reduced blood glucose in the absence of dyslipidemia , in contrast to wild - type gk - overexpressing mice . evidence in glucose utilization did not correlate with increased glycogen nor lactate levels in the liver . pepck mrna was not affected , whereas the mrna for the catalytic subunit of glucose-6-phosphatase was upregulated ~4 folds in the liver of gka456v - treated animals , suggesting that glucose cycling was stimulated . our results provide new insights into the complex gk regulatory network and validate liver - specific gk activation as a strategy for diabetes therapy .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Alcohol Abuse Prevention and Treatment Trust Fund Act of 1999''. SEC. 2. ALCOHOL ABUSE PREVENTION AND TREATMENT TRUST FUND. (a) General Rule.--Subchapter A of chapter 98 of the Internal Revenue Code of 1986 (relating to establishment of trust funds) is amended by adding at the end the following: ``SEC. 9511. ALCOHOL ABUSE PREVENTION AND TREATMENT 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 `Alcohol Abuse Prevention and Treatment Trust Fund' (in this section referred to as `Trust Fund'), consisting of such amounts as may be appropriated or credited to the Trust Fund as provided in this section or section 9602(b). ``(b) Transfers to Trust Fund.--There are hereby appropriated to the Trust Fund amounts equivalent to the additional taxes received in the Treasury under chapter 51 by reason of the amendments made by section 3 of the Alcohol Abuse Prevention and Treatment Trust Fund Act of 1999 and the additional taxes received in the Treasury by reason of section 3(d) of such Act. ``(c) Expenditures From Trust Fund.--Amounts in the Trust Fund shall be available, as provided in appropriation Acts, for appropriation to the National Institute of Alcohol Abuse and Alcoholism and to the Substance Abuse and Mental Health Services Administration for programs for the prevention and treatment of alcoholism and for research on the causes, consequences, prevention, and treatment of the health problems related to alcohol use, including high blood pressure, stroke, heart disease, cancer (including breast cancer), and birth defects.'' (b) Conforming Amendment.--The table of sections for subchapter A of chapter 98 of the Internal Revenue Code of 1986 is amended by adding at the end the following: ``Sec. 9511. Alcohol Abuse Prevention and Treatment Trust Fund.'' SEC. 3. INCREASE IN EXCISE TAXES ON WINE TO ALCOHOLIC EQUIVALENT OF TAXES ON DISTILLED SPIRITS. (a) In General.-- (1) Wines containing not more than 14 percent alcohol.-- Paragraph (1) of section 5041(b) of the Internal Revenue Code of 1986 (relating to rates of tax on wines) is amended by striking ``$1.07'' and inserting ``$2.97''. (2) Wines containing more than 14 (but not more than 21) percent alcohol.--Paragraph (2) of section 5041(b) of such Code is amended by striking ``$1.57'' and inserting ``$4.86''. (3) Wines containing more than 21 (but not more than 24) percent alcohol.--Paragraph (3) of section 5041(b) of such Code is amended by striking ``$3.15'' and inserting ``$6.08''. (b) Effective Date.--The amendments made by this section shall take effect on October 1, 1999. (c) Floor Stocks Taxes.-- (1) Imposition of tax.-- (A) In general.--In the case of any tax-increased article-- (i) on which tax was determined under part I of subchapter A of chapter 51 of the Internal Revenue Code of 1986 or section 7652 of such Code before October 1, 1999, and (ii) which is held on such date for sale by any person, there shall be imposed a tax at the applicable rate on each such article. (B) Applicable rate.--For purposes of clause (i), the applicable rate is-- (i) $1.90 per wine gallon in the case of wine described in paragraph (1) of section 5041(b) of such Code, (ii) $3.29 per wine gallon in the case of wine described in paragraph (2) of section 5041(b) of such Code, and (iii) $2.93 per wine gallon in the case of wine described in paragraph (3) of section 5041(b) of such Code. In the case of a fraction of a gallon, the tax imposed by subparagraph (A) shall be the same fraction of the amount of such tax imposed on a whole gallon. (C) Tax-increased article.--For purposes of this subsection, the term ``tax-increased article'' means wine described in paragraph (1), (2), or (3) of section 5041(b) of such Code. (2) Exception for certain small wholesale or retail dealers.--No tax shall be imposed by paragraph (1) on tax- increased articles held on October 1, 1999, by any dealer if-- (A) the aggregate liquid volume of tax-increased articles held by such dealer on such date does not exceed 500 wine gallons, and (B) such dealer submits to the Secretary (at the time and in the manner required by the Secretary) such information as the Secretary shall require for purposes of this subparagraph. (3) Liability for tax and method of payment.-- (A) Liability for tax.--A person holding any tax- increased article on October 1, 1999, to which the 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 shall prescribe by regulations. (C) Time for payment.--The tax imposed by paragraph (1) shall be paid on or before March 31, 2000. (4) Controlled groups.-- (A) Corporations.--In the case of a controlled group of corporations, the 500 wine gallon amount specified in paragraph (2) shall be apportioned among the dealers who are component members of such group in such manner as the Secretary shall by regulations prescribe. For purposes of the preceding sentence, the term ``controlled group of corporations'' has the meaning given to such term by subsection (a) of section 1563 of such Code; except that for such purposes the phrase ``more than 50 percent'' shall be substituted for the phrase ``at least 80 percent'' each place it appears in such subsection. (B) Nonincorporated dealers under common control.-- Under regulations prescribed by the Secretary, principles similar to the principles of subparagraph (A) shall apply to a group of dealers under common control where 1 or more of such dealers is not a corporation. (5) Other laws applicable.--All provisions of law, including penalties, applicable to the tax imposed by section 5041 of such Code with respect to any tax-increased article shall, insofar as applicable and not inconsistent with the provisions of this section, apply to the floor stocks taxes imposed by paragraph (1) to the same extent as if such taxes were imposed by such section 5041. (6) Definitions.--For purposes of this subsection-- (A) In general.--Terms used in this paragraph which are also used in subchapter A of chapter 51 of such Code shall have the respective meanings such terms have in such subchapter. (B) Person.--The term ``person'' includes any State or political subdivision thereof, or any agency or instrumentality of a State or political subdivision thereof. (C) Secretary.--The term ``Secretary'' means the Secretary of the Treasury or his delegate.

Alcohol Abuse Prevention and Treatment Trust Fund Act of 1999 - Amends the Internal Revenue Code to establish the Alcohol Abuse Prevention and Treatment Trust Fund from which funds shall be made available for programs for the prevention and treatment of alcoholism and for research on the causes, consequences, prevention, and treatment of the health problems related to alcohol use, including high blood pressure, stroke, heart disease, cancer (including breast cancer), and birth defects. Increases the excise taxes on wine and appropriates the increased revenue to the Alcohol Abuse Prevention and Treatment Trust Fund.

Mr. Partilla, then a 42-year-old triathlete and a president of media sales at Time Warner, recognized a kindred dynamo. “She’s such a force,” he said. “She rocks back and forth on her feet as if she can’t contain her energy as she’s talking to you.” Advertisement Continue reading the main story The connection was immediate, but platonic. In fact, as they became friends so did their spouses. There were dinners, Christmas parties and even family vacations together. So Ms. Riddell was surprised to find herself eagerly looking for Mr. Partilla at school events — and missing him when he wasn’t there. “I didn’t admit to anyone how I felt,” she said. “To even think about it was disruptive and disloyal.” What she didn’t know was that he was experiencing similar emotions. “First I tried to deny it,” Mr. Partilla said. “Then I tried to ignore it.” But it was hard to ignore their easy rapport. They got each other’s jokes and finished each other’s sentences. They shared a similar rhythm in the way they talked and moved. The very things one hopes to find in another person, but not when you’re married to someone else. Ms. Riddell said she remembered crying in the shower, asking: “Why am I being punished? Why did someone throw him in my path when I can’t have him?” In May 2008, Mr. Partilla invited her for a drink at O’Connell’s, a neighborhood bar. She said she knew something was up, because they had never met on their own before. “I’ve fallen in love with you,” he recalled saying to her. She jumped up, knocking a glass of beer into his lap, and rushed out of the bar. Five minutes later, he said, she returned and told him, “I feel exactly the same way.” Then she left again. As Mr. Partilla saw it, their options were either to act on their feelings and break up their marriages or to deny their feelings and live dishonestly. “Pain or more pain,” was how he summarized it. Photo “The part that’s hard for people to believe is we didn’t have an affair,” Ms. Riddell said. “I didn’t want to sneak around and sleep with him on the side. I wanted to get up in the morning and read the paper with him.” Advertisement Continue reading the main story With that goal in mind, they told their spouses. “I did a terrible thing as honorably as I could,” said Mr. Partilla, who moved out of his home, reluctantly leaving his three children. But he returned only days later. Then he boomeranged back and forth for six months. The pain he had predicted pervaded both of their lives as they faced distraught children and devastated spouses, while the grapevine buzzed and neighbors ostracized them. 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 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. “He said, ‘Remind me every day that the kids will be O.K.,’ ” Ms. Riddell recalled. “I would say the kids are going to be great, and we’ll spend the rest of our lives making it so.” The problem was she could not guarantee that. All they had were their feelings, which Ms. Riddell described as “unconditional and all-encompassing.” “I came to realize it wasn’t a punishment, it was a gift,” she said. “But I had to earn it. Were we brave enough to hold hands and jump?” They did jump. Both officially separated from their spouses by late 2008, though they waited until July 2009 before moving in together. “I didn’t believe in the word soul mate before, but now I do,” said Mr. Partilla, who is 46 and in January is to become a chief operating officer of Dentsu, a Japanese advertising agency. They finalized their divorces this year. “I will always feel terribly about the pain I caused my ex-husband,” said Ms. Riddell, 44 and working freelance. “It was not what I ever would have wished on him.” Or on her children. Advertisement Continue reading the main story “My kids are going to look at me and know that I am flawed and not perfect, but also deeply in love,” she said. “We’re going to have a big, noisy, rich life, with more love and more people in it.” On Nov. 15, the couple were legally wed at the Marriage Bureau in New York by Blanca Martinez of the City Clerk’s office. Then on Dec. 11, Ms. Riddell donned a Nicole Miller strapless gown for a small ceremony in the presidential suite of the Mandarin Oriental New York hotel. As if on cue, the hotel room phone rang as she began to recite her vows. Mr. Partilla’s 10-year-old daughter answered. “We’re in the middle of a wedding,” she informed the caller, while her younger two siblings and two soon-to-be step-siblings spun off like small planets freed from the pull of gravity. “This is life,” said the bride, embracing the messiness of the moment along with her bridegroom. “This is how it goes.” ||||| vows Times No Longer Even Euphemizing Spouse-Dumping ShareThis Counter Email Only one year ago, we noted the Times' gross habit of including people in the "Vows" column who very clearly cheated on and abandoned a former spouse or lover before getting hitched to the current one, then went on to revel in it in the Times, so their exes can relive that period in all its painful glory. But that practice seems practically innocent compared to today's "Vows:" See, time was, the Times would say a couple "faced many obstacles to romance," or "the road to love was bumpy," when what they meant was that there were other human lives involved. In 2009, affairs and spouse-dumping would still pop out at you in the column - abruptly, perhaps, but rarely with unmitigated pride. But now, with print media facing its struggles and competing with saucier online writing, the spouse-dumping goes right in the lede: What happens when love comes at the wrong time? Carol Anne Riddell and John Partilla met in 2006 in a pre-kindergarten classroom. They both had children attending the same Upper West Side school. They also both had spouses. Part “Brady Bunch” and part “The Scarlet Letter,” their story has played out as fodder for neighborhood gossip. But from their perspective, the drama was as unlikely as it was unstoppable. Once a subject of shame, this affair is made to sound like a veritable harlequin novel. Except, in reality, it was clearly still awkward and sort of sad: The connection was immediate, but platonic. In fact, as they became friends so did their spouses. There were dinners, Christmas parties and even family vacations together. The couple claims that they didn't have a sexual affair, but they did have an encounter that their spouses couldn't have been too happy about: "I’ve fallen in love with you,” he recalled saying to her. She jumped up, knocking a glass of beer into his lap, and rushed out of the bar. Five minutes later, he said, she returned and told him, “I feel exactly the same way.” Then she left again. You sort of expect this "Vows" to hook right at some point; for the former spouses to be quoted saying that they've accepted things, they're all friends now, the kids are okay. Because, you know, Carol Ann Riddell and John Partilla opted to have this tale put in print. We don't doubt that these things just happen, but we do question the decision to celebrate it in the face of your exes and children, right in the New York Times. Especially when the "Brady Bunch" part turned out to be pretty shaky. Because it sounds like they're by no means all friends: “He said, ‘Remind me every day that the kids will be O.K.,’ ” Ms. Riddell recalled. “I would say the kids are going to be great, and we’ll spend the rest of our lives making it so.”The problem was she could not guarantee that. All they had were their feelings, which Ms. Riddell described as “unconditional and all-encompassing.” “My kids are going to look at me and know that I am flawed and not perfect, but also deeply in love,” she said. “We’re going to have a big, noisy, rich life, with more love and more people in it.” ||||| Wedding announcements in The New York Times often elicit a certain amount of resentment and schadenfreude, but the reaction to yesterday’s “Vows” column was of a whole different order of magnitude. That column told the story of TV reporter Carol Anne Riddell and advertising executive John Partilla, who divorced their longtime spouses and split up their families in order to be with each other. In addition to strong condemnation from numerous bloggers and many of the paper’s own commenters, the article, as a first of sorts for the Times, invited a number of questions. Why were the ex-spouses of the newlyweds not mentioned by name in the story? Did the reporter call them for comment, as basic journalistic practice would dictate? Why did the Times open up the comment board when most Vows stories are off-limits? And above all, what were the couple thinking in telling their story in a space normally reserved for feel-good, soft-focus meet-cute tales? “We did this because we just wanted one honest account of how this happened for our sakes and for our kids’ sakes,” Riddell told me. “We are really proud of our family and proud of the way we’ve handled this situation over the past year. There was nothing in the story we were ashamed of.” Riddell says the backlash is “sort of surprising to me. I think people are focusing a lot on the negative, but there was a lot of positive.” But, she notes, “we’ve had a lot of people say to us how brave we are to do this, how commendable it was that we were as honest as we were.” Indeed, while most Times commenters expressed disapproval, there were also some like the one who wrote “Thank you Carol and John for the honest reflection…I wish them a long and happy marriage.” Riddell declines to say whether she or her husband asked for their exes’ consent to tell their story in the Times, or at least notified them that it was in the works. “I really don’t want to wade into this any further than we already have,” she says. “It’s not helpful to anybody.” She says, however, that she and her groom did not ask the paper not to interview the exes or negotiate any other preconditions: “They made their own decisions on that front.” So did the story’s author, Devan Sipher, seek comment from the exes? “I would assume not, but I don’t really know,” says Riddell. Asked that same question, a Times spokeswoman says, “We do not comment on the process of editing and reporting including who was and was not contacted for interviews related to a specific story. The Vows/Wedding column adheres to the standards of the Times.” The paper’s Weddings/Celebrations editor, Robert Woletz, did not return a message; nor did the exes, who, like their former spouses, both have high-level jobs in the media industry. (In both cases, the first marriage was also written up in the Times.) That leaves the question of why this story, unlike most “Vows” columns, was opened for reader comments. “We open up comments on articles that are engaging to readers,” says the Times spokeswoman. “This is a very interesting story.” That is undoubtedly true — though it would be even more true had the exes been interviewed as well. ||||| iStockphoto/Crisma Turns out godless left-wing urban sodomites can get morally uppity too. With its genteel, Jane Austen-like formula, the New York Times' "Vows" section is the nation's most reliable weekly comedy of manners, a tale in which sexual chemistry and inevitable misunderstandings lead to showers of rice instead of restraining orders and inflammatory Facebook status updates. The usual narrative goes as follows: Unlikely yet well-heeled duo (vegetarian/hunter, conservative/liberal, city slicker/country mouse) meets cute. Duo encounters obstacles -- distance, job demands, a history of meth abuse -- amusingly related in wry, illuminating anecdotes from friends and family. Couple overcomes said obstacles and winds up at the altar -- usually with their kids or a dog in tow, and pledges to be each other's "force field of awesome." New York Times readers feel mixture of romantic hopefulness and oddly satisfying, "Jesus Christ, who are these pretentious tools?" disdain while polishing off their morning Lavazzas. But while previous "Vows" columns have skirted with drama, controversy and even a hint of the verboten, Sunday's column really took the proverbial fondant-enrobed, lemon curd-filled, multi-tiered cake. From the first sentence -- "What happens when love comes at the wrong time?" -- readers knew this was to be a story full of intrigue, ripe for finger wagging. The celebratory couple, former local news reporter Carol Anne Riddell and media executive John Partilla, met in 2006 in their children's classroom -- while they were both married to other people. A friendship blossomed between the two families, and all that closeness soon kindled a feeling more than platonic between Riddell and Partilla. They fell in love, and though Riddell says, "We didn’t have an affair," they did begin a long, emotionally grueling courtship that eventually led to much social ostracism, two divorces, a small, private ceremony last month, and then, you know, a splashy story in the New York Times on Sunday. It didn't take long for the gasps of outrage to rise up. As New York magazine noted, "We do question the decision to celebrate it in the face of your exes and children, right in the New York Times" while Gawker facetiously noted the "Homewrecking Couple's Scandalous New York Times Wedding Announcement." And Slate's film critic Dana Stevens minced no words, calling it "staggeringly monstrous." But though Gothamist says that "Vows" isn't "usually a place where you reel in disgust," that's almost always an appropriate response to its "We're so wacky and unconventional, in our Fortune 500 way!" weekly litany of dynasty-making. The novelty this time is the openness of the narrative -- one that does not follow a more conventionally appropriate form. And there is undeniably something deeply unsettling about a father saying of his brand-new second wife, "I didn’t believe in the word soul mate before, but now I do." Finding a "soul mate" is wonderful, but divorce is crappy, especially when offspring are involved. The reality that Mom and Dad do not love each other -- and that they've likely been pretending otherwise for a while -- is a cruel blow for anyone, whether the child is 2 or 42. To have that sting instigated at least in part by the arrival of another person on the scene, and to have that relationship then become the subject of croissant-nibbling conversation at breakfast tables across the land -- yow, that's got to hurt. Nearly 200 comments later, many Times readers agree. The National Review unsurprisingly called the tale "heartbreaking," tut-tutting, "Make sure you have the kind of lovingly rigorous support system -- faith, friends, family -- that will remind you that there might be another choice other than succumbing to feelings vs. dishonesty." There might be. Then again, there might not. Because love, as the "Vows" column proves, is not always neat, wise or even good. And what this particular story leaves out, surely for the sake of the spurned exes, is the state of Riddell and Partilla's respective prior unions. The drama of a pair of home-wreckers mangling up each other's families is certainly juicy, but who's to judge whatever loneliness or pain already existed in both their lives before they found each other? Who's to say that sticking with something that may no longer be happy or fulfilling or even healthy is for the ultimate best? And who's to say that everybody isn't exponentially better off now? The real head-scratcher isn't that the couple found each other; marriages bust up and people pair off anew every day. It's the fact that they chose to go so public with their joyous new union, and that the Times leapt so eagerly on a story so guaranteed to turn off plenty of readers, that's perplexing. Is it all just narcissism combined with whopping insensitivity? Can't rule it out, but maybe it's something else. As many of us have learned through hard-won experience, the great beauty of the modern era is that we now have the world's most efficient mechanism for the ripping off of Band-Aids at our fingertips. We can tweet about cancer. We can announce that we just had a miscarriage in a Facebook update. And we can tell friends and neighbors, "My mate and I fell in love while we were married to other people." People don't have to like it, and don't have to approve, but at least they can know, so they don't have to whisper when we run run into them at Fairway. It must be easier to give a public version of events than to repeat it forever to every curious friend. Would being ashamed make Riddell and Partilla any less married right now -- or would being quiet about it just make other people a little more comfortable? While the "Vows" column will no doubt continue to inspire shudders of revulsion on a reliable, seven-day cycle, I can't take particular umbrage with a story of two people who did not heroically triumph over illness or age or prior heartbreak, who were instead flawed and mistake-prone and know what it feels like to hurt their families and lose friends. Because as romantic and frothy as the "Vows" section often is, a wedding is not always simply a happy ending. Sometimes it's just a messed-up true story.

– The New York Times’ normally genteel “Vows” column hit a nerve on Sunday, with its tale of John Partilla and Carol Riddell—who each left spouses to get hitched. It’s “part Brady Bunch, part The Scarlet Letter,” the paper cooed. Bloggers and commenters tore the paper a new one. “These things happen,” says New York magazine, “but we do question the decision to celebrate it in the face of your exes and children.” Now Partilla tells the New York Post he regrets the whole thing. “We can't control other people's judgments,” he says, but if they’d known the reaction they’d get, “we obviously would not have shared our life in any way publicly.” So why did they do it at all? “We just wanted one honest account of how this happened,” Riddell tells Forbes. Heck, Mary Elizabeth Williams of Salon doesn’t see why this is worse than typical vomit-inducing Vows column. “A wedding is not always simply a happy ending,” she writes. “Sometimes it’s just a messed-up true story.”

the motivation is to develop fast solver schemes to solve stochastic hamiltonians in solitary waves and collisions . the idea is based on almost asymptotic symplecticity for stochastic hamiltonian partial differential equations , such underlying algorithms are applied to develop stochastic symplectic methods for solving a stochastic schroedinger equations , see @xcite . it is shown that the noval schemes preserve the symplectic structure in an asymptotic regime , which means it is @xmath0 away from a symplectic scheme with @xmath1 . we consider a hamiltonian system , while @xmath2 and we write : @xmath3 where @xmath4 and @xmath5 and @xmath6 is the d - dimensional identity matrix , @xmath7 is the gradient with respect to @xmath8 . we assume that @xmath9 is the solution operator with @xmath10 , where @xmath11 isthe time step and we have the following definition about the symplecticity : * @xmath9 preserves the symplecticness of the system ( [ sympl_1 ] ) , if : @xmath12 * @xmath9 preserves the almost ( or asymptotic ) symplecticness of the system ( [ sympl_1 ] ) , if : @xmath13 is a constant with @xmath14 and @xmath15 is a function of @xmath16 , which is given from the solution method . the idea of almost symplecticity has the origin of modifying the definition of symplecticity . for example , if one assume that @xmath17 depends on @xmath8 , then one can proof , that we have an almost poisson structure and we preserve the poisson structure up to the second order , see @xcite . such ideas are also used in the development in pseudo - symplectic methods , see @xcite . in the following , we deal with the stochastic nonlinear schrdinger equation with multiplicative noise , which is given by @xmath18 where @xmath19 is the complex - valued solution and @xmath20 denotes @xmath21 is defined as a real - valued white noise which is delta correlated in time and either smooth or delta correlated in space . the deterministic nonlinear schroedinger equation is given by @xmath22 which is well - known in the literature @xcite . we can rewrite this to a hamiltonian system by @xmath23 , where @xmath24 and @xmath25 are real - valued functions and we can separate it into the following form and we obtain a multi - symplectic system : @xmath26 where we have the symplectic structure @xmath27 . the system is given by @xmath28 where the matrices are given by the semi - discretization of the original system ( [ orig_1 ] ) . the iterative splitting scheme is almost symplectic . for the hamiltonian system @xmath29 we apply the successive approximation method : @xmath30 where we apply the linearised scheme : @xmath31 further , the contraction mapping is given by @xmath32 where @xmath33 and @xmath34 and @xmath35 . in the following , we discuss the linearised equation in the algorithm . we have the fixed - splitting discretisation step - size @xmath11 , on the time - interval @xmath36 $ ] , and the stochastic time step @xmath37 ( wiener process ) , where @xmath38 is a gaussian distributed random variable with @xmath39 and @xmath40 , see @xcite . we solve the following sub - problems consecutively for @xmath41 . @xcite ) : @xmath42 where @xmath43 is the known successive approximation at the time - level @xmath44 . the split approximation at the time - level @xmath45 is defined by @xmath46 . we can rewrite this into the following ode form : @xmath47 where @xmath48 . [ th1 ] we are given @xmath49 linear bounded operators ( e.g. , due to the linearisation ) and we consider the abstract cauchy problem @xmath50 then the problem ( [ eq : acp ] ) has a unique solution ; the iterations ( [ kap3_iter_1 ] ) over @xmath51 are convergent with order @xmath52 . the problem ( [ eq : acp ] ) has a unique solution @xmath53 . for the local error function @xmath54 , we have the relations @xmath55 , \\ \noalign{\vskip 1ex } { \displaystyle e_i(t^n)=0}. \end{array } \label{eq : err1}\ ] ] applying the method of variation of constants , the solution of the abstract cauchy problem can be written as @xmath56 . } \end{array } \label{eq : errsol}\ ] ] furthermore , we have @xmath57 . \end{array}\ ] ] based on our assumption that @xmath58 is bounded , we have @xmath59 . \end{array } \label{eq : err3}\ ] ] where @xmath60 . the estimations ( [ eq : err3 ] ) result in @xmath61 which proves our statement . furthermore , the almost asymptotic symplecticity of the scheme ( [ kap3_iter_1 ] ) is given as : [ th2 ] consider the algorithm ( [ kap3_iter_1 ] ) and let @xmath62 be the solver step of the algorithm . then for any @xmath63 , there exists @xmath64 , where @xmath65 and the time - step @xmath66 , where @xmath67 is the number of iterative steps , and we have @xmath68 where @xmath69 is a constant . the algorithm ( [ kap3_iter_1 ] ) has the following solution : @xmath70 furthermore , we have @xmath71 and the recursion is given by @xmath72 when the estimations result in @xmath73 and @xmath64 , which proves our statement . in the following , we treat the different numerical methods . the underlying equation is given as @xmath74 where the initial values are given as @xmath75 , @xmath76 and @xmath77 is a wiener process . we apply a semi - discretisation via finite difference schemes and obtain the ode problem @xmath78 where the operators are given by @xmath79 , \\ b(u ) = 2 |u|^{2 \sigma } \\ c = \epsilon u , \end{aligned}\ ] ] where we apply the different splitting schemes . we consider the following linearised stochastic schroedinger equation : @xmath80 \times [ 0 , 1 ] , \\ & & u(x , 0 ) = u_0(x ) , x \in [ 0,1 ] , \\ & & u(0 , t ) = u(1 , t ) , t \in [ 0 , 1 ] , \end{aligned}\ ] ] where @xmath81 . + we assume periodic boundary conditions @xmath82 , + where @xmath83 $ ] , e.g. @xmath84 , @xmath85 and @xmath86 is small . we employ the following transformation and change of variables : @xmath87 + @xmath88 we apply a finite difference discretisation and the matrices are given as @xmath89 , \\ & & a_2(t , x , \eta , \xi ) = \left ( v(x ) + 2 ( \eta^2 + \xi^2 ) \right ) \ ; [ 0 \ ; 1 \ ; 0 ] , \\ & & a_3(t , x ) = \epsilon \delta w \ ; [ 0 \ ; 1 \ ; 0 ] .\end{aligned}\ ] ] @xmath90 where we have @xmath91 , @xmath92 , @xmath93 . we apply the operator splitting schemes : @xmath94 where @xmath95 , the random variable @xmath96 is based on a wiener process with @xmath97 , and @xmath38 is a gaussian distributed random variable with @xmath98 and @xmath40 . this means we have @xmath99 . the splitting operators are @xmath100 we present the different convergent time - steps results for @xmath101 . the analytical solution is we apply the operator splitting schemes as follows : @xmath102 where @xmath95 , the random variable @xmath96 is based on a wiener process with @xmath97 , and @xmath38 is a gaussian distributed random variable with @xmath98 and @xmath40 . this means we have @xmath99 . the solution is given by @xmath103 and the errors are @xmath104 in the following figures , we present the results for the error of the iterative splitting schemes , see fig . [ error_1 ] . in the following figures , we present the results for the different splitting schemes , see fig . [ experiment_2_1 ] . with more iterative steps , we see an improvement in the numerical results . with two to three iterative steps , we obtain nearly the analytical solution . here , we could see the almost asymptotic behaviour of the scheme . we consider the following equation : @xmath105 where @xmath106 , @xmath107 . we employ the following transformation and change of variables : @xmath87 + @xmath108 , \\ & & a_2(t , x , \eta , \xi ) = \left ( \frac{1}{1 + \sin^2(x ) } + \lambda ( \eta^2 + \xi^2 ) \right ) \ ; [ 0 \ ; 1 \ ; 0 ] .\end{aligned}\ ] ] the underlying discretised matrices for the splitting schemes are given as : @xmath109 in the next list of schemes we discuss different splitting scheme . the first splitting scheme is known as an a - b splitting or lie - trotter splitting scheme , see @xcite , while we apply multiplicative the different separated operators . the second splitting scheme is known as an iterative splitting scheme , see @xcite . such a scheme apply iteratively the separated operators based on a fix - point approximation , see @xcite . we will employ the following splitting schemes : * a b splitting @xmath110 * strang splitting scheme @xmath111 * weighted iterative splitting 1 : we define a relaxed iterative splitting method based on the critical value @xmath112 : @xmath113 and @xmath114 , @xmath115 and @xmath116 . + the algorithm is @xmath117 and is solved as : @xmath118 ds \ ; , \nonumber \\ & & c_2(t ) = c_1(t ) + c_1(t ) \ ; [ \hat{a}_2 , \phi_1(t \hat{a}_1 ) ] , \\ & & c_3(t ) = c_2(t ) + c_1(t ) \ ; \int_0^t [ \hat{a}_2 , \exp(s \hat{a}_1 ) ] [ \hat{a}_2 , \phi_1(s \hat{a}_1 ) ] ds \ ; , \nonumber \\ & & c_3(t ) = c_2(t ) + c_1(t ) \;\left ( [ \hat{a}_2 , \exp(t \hat{a}_1 ) ] [ \hat{a}_2 , \phi_2(t \hat{a}_1 ) ] \right . \\ & & \left . + [ \hat{a}_2 , \hat{a}_1 \exp(t \hat{a}_1 ) ] [ \hat{a}_2 , \phi_3(t \hat{a}_1 ) ] \right ) + o(t^3 ) \ ; , \nonumber \\ & & \cdots \nonumber\end{aligned}\ ] ] where the given @xmath119 is defined as : @xmath120 * weighted iterative splitting 2 : we define a relaxed iterative splitting method based on the critical value @xmath112 : @xmath121 where @xmath122 is the known split approximation at the time level @xmath44 . the split approximation at the time level @xmath45 is defined as @xmath123 . the parameter @xmath124 $ ] . for @xmath125 , we have the sequential splitting method , and for @xmath126 we have the iterative splitting method . the following figures present the results for the different splitting schemes , see fig . [ experiment_1 ] . here , we have compared the standard splitting scheme with our iterative splitting approach . based on the resolution of the analytical solution , we obtain the same results as for the standard schemes . we consider the equation @xmath127 with @xmath128 and @xmath129 . we choose the initial condition : @xmath130 then the exact single - soliton solution is @xmath131 we employ the following transformation and change of variables : @xmath87 + @xmath132 , \\ & & a_2(t , x , \eta , \xi ) = \left ( 2 ( \eta^2 + \xi^2)^{\sigma } \right ) \ ; [ 0 \ ; 1 \ ; 0 ] .\end{aligned}\ ] ] the underlying discretised matrices for the splitting schemes are @xmath133 we consider the following splitting schemes : * a b splitting @xmath110 * strang splitting scheme @xmath111 * weighted iterative splitting 1 : we define a relaxed iterative splitting method based on the critical value @xmath112 : @xmath113 and @xmath114 , @xmath115 and @xmath116 . + the algorithm is @xmath117 and is solved as @xmath118 ds \ ; , \nonumber \\ & & c_2(t ) \approx c_1(t ) + c_1(t ) \ ; t [ \hat{a}_2 , \exp(t \hat{a}_1 ) ] , \end{aligned}\ ] ] the following figures present the results for the different splitting schemes , see fig . [ experiment_2 ] . we apply @xmath103 for each solution and obtain the following errors : @xmath104 the following figures present the results for the errors of the iterative splitting schemes , see fig . [ error_3 ] . in both resolution in time and space the iterative splitting method is more accurate than the standard a b and strang splitting schemes . here , we see an improvement based on the successive approximation idea and obtain a more accurate linearisation than for the standard schemes . we consider the equation @xmath127 with @xmath128 and @xmath129 . we choose the initial condition @xmath130 for the reference solution , we apply a fine resolution strang splitting . we employ the following transformation and change of variables : @xmath87 + @xmath134 , \\ & & a_2(t , x , \eta , \xi ) = \left ( 2 ( \eta^2 + \xi^2)^{\sigma } \right ) \ ; [ 0 \ ; 1 \ ; 0 ] , \\ & & a_3(t , x ) = \epsilon \ ; \delta w \ ; [ 0 \ ; 1 \ ; 0 ] , \\\end{aligned}\ ] ] the underlying discretised matrices for the splitting schemes are @xmath135 and @xmath136 * a b splitting we apply the operator splitting schemes as : @xmath137 where @xmath95 , the random variable @xmath96 is based on a wiener process with @xmath97 , and @xmath38 is a gaussian distributed random variable with @xmath98 and @xmath40 . this means we have @xmath99 . * iterative splitting scheme : + first iterative step @xmath138 second iterative step @xmath139 , \quad t \in ( t^n , t^{n+1 } ] , \nonumber \\ & & x_{2,n}(t ) = x_{1,n}(t ) + x_{1,n}(t ) [ \tilde{a}_3 , c_1(t ) ] , \quad t \in ( t^n , t^{n+1 } ] , \nonumber \label{eq : err1}\end{aligned}\ ] ] the stochastic integral is computed as a stratonovich integral : @xmath140 we apply @xmath103 for each solution and deal with the following errors : @xmath141 the following figures present the results for the error of the iterative splitting schemes , see fig . [ error_4 ] . in both resolution in time and space the iterative splitting method is more accurate than the standard a b and strang splitting schemes . here , we obtain an improvement based on the successive approximation scheme . we discuss the problems of using novel iterative splitting schemes to solve stochastic nonlinear schroedinger equations . we could prove the almost asymptotic symplectic behaviour of the novel scheme . the improvement with more iterative steps allows resolving the nonlinearity and obtaining an improved symplectic scheme . while standard splitting schemes have drawbacks as regards linearisation and symplecticity , we could derive a combination of both higher accuracy and conservation of the symplecticity . in the future , we will take into account larger equation systems for a realistic application .

in this paper we present splitting methods which are based on iterative schemes and applied to stochastic nonlinear schrdinger equation . we will design stochastic integrators which almost conserve the symplectic structure . the idea is based on rewriting an iterative splitting approach as a successive approximation method based on a contraction mapping principle and that we have an almost symplectic scheme , see @xcite and @xcite . we apply a stochastic differential equation , that we can decouple into a deterministic and stochatic part , while each part can be solved analytically . such decompositions allow accelerating the methods and preserving , under suitable conditions , the symplecticity of the schemes . a numerical analysis and application to the stochastic schrdunger equation are presented . * keywords * : splitting methods , stochastic differential equations , iterative splitting schemes , stochastic schrdinger equation . + * ams subject classifications . * 35k25 , 35k20 , 74s10 , 70g65 .

the magnetization process of strongly correlated electron systems has received a lot of attention , because it may involve at low enough temperatures intermediate plateaus as a profound manifestation of peculiar quantum ground states @xcite . an existence of the intermediate magnetization plateaus , which refer to regions with a constant magnetization spread over a finite range of the magnetic fields , has been convincingly evidenced in a variety of one - dimensional quantum systems including spin chains , ladders and other related systems @xcite . it is well established that the magnetization plateaus of quantum spin chains do occur just at rational fractions of the saturation magnetization , whereas their position is subject to a quantization condition @xcite derived by generalizing lieb - schultz - mattis theorem @xcite . a special mechanism leading to intermediate magnetization plateaus controlled by doping has been studied within integrable spin-@xmath0 chains doped with spin-1/2 mobile carriers @xcite . it has been evidenced that the doping within a relatively large range of carrier concentrations leads to the magnetization plateaus at a tunable fraction of the saturation magnetization in the high - field region @xcite . however , the doping may also allow a continuous variation of the magnetization plateaus even in the low - field region as exemplified by rigorous analytical and numerical calculations for the modulated hubbard chains @xcite and ladders @xcite . in the present work we will propose and exactly solve a correlated spin - electron chain , which involves the localized ising spins situated at nodal lattice sites and mobile electrons delocalized over the pairs of decorating sites placed at each its bond . our main goal is to examine the low - temperature magnetization process of this system as a function of the electron density with the aim to bring insight into doping - dependent magnetization plateaus . the outline of this paper is as follows . in section [ sec : model ] , the model under investigation will be defined and the method used for its exact solution will be briefly described . the ground - state phase diagram and respective spin arrangement realized within particular ground states will be discussed in section [ sec : results ] along with the magnetization process and magnetocaloric effect . finally , the most significant findings will be summarized in section [ sec : conclusions ] . let us define a coupled spin - electron chain in an external magnetic field , which involves localized ising spins situated on its nodal sites and mobile electrons delocalized over the pairs of decorating sites as schematically shown in fig . [ fig1 ] . ) .,width=377 ] for further convenience , the total hamiltonian of the investigated spin - electron model can be written as a sum over the bond hamiltonians @xmath1 whereas each bond hamiltonian @xmath2 contains all interaction terms involving the mobile electrons from the @xmath3-th bond ( see fig . [ fig1 ] ) @xmath4/2 \nonumber \\ & - & h_{\rm e } [ ( \hat{n}_{ai,\uparrow } - \hat{n}_{ai,\downarrow } ) + ( \hat{n}_{bi,\uparrow } - \hat{n}_{bi,\downarrow})]/2 - h_{\rm i } ( \sigma_i^z + \sigma_{i+1}^z)/2 . \label{hi}\end{aligned}\ ] ] here , the symbols @xmath5 and @xmath6 denote standard creation and annihilation fermionic operators for the mobile electrons occupying the decorating sites @xmath7 with the spin orientation @xmath8 and @xmath9 represents the respective number operator with eigenvalues @xmath10 . the symbol @xmath11 corresponds to the ising spin situated at @xmath3-th nodal lattice site . the parameter @xmath12 thus represents the hopping term accounting for the kinetic energy of the mobile electrons and the parameter @xmath13 describes the ising - type interaction between the nearest - neighbour localized spins and mobile electrons . for the purpose of the future calculations , we have distinguished between the magnetic field @xmath14 acting on the localized ising spins and the magnetic field @xmath15 acting on the mobile electrons though both magnetic fields will be finally set equal to each other @xmath16 at the end of the calculation . the crucial step in finding of the exact solution of the correlated spin - electron chain is to calculate the grand - canonical partition function @xmath17 where @xmath18 , @xmath19 is boltzmann s constant , @xmath20 stands for the absolute temperature , @xmath21 denotes a summation over all possible configurations of the ising spins and the symbol @xmath22 stands for a trace over degrees of freedom of all mobile electrons . furthermore , the number operator @xmath23 corresponds to the total number of the mobile electrons on @xmath3-th bond and @xmath24 is the respective chemical potential , which allows to tune the electron density . due to the commuting character of different bond hamiltonians @xmath25 = 0 $ ] ( @xmath26 ) , the grand - canonical partition function @xmath27 can be partially factorized into the product @xmath28 where the symbol @xmath29 is used to denote a partial trace over degrees of freedom of the mobile electrons from the @xmath3-th bond . an explicit form of the grand - canonical partition function @xmath27 can be found with the use of the standard transfer - matrix approach @xcite . all subsequent steps of the further calculation are quite analogous to the ones reported in our preceding work for the zero - field case @xcite and hence , we will only discuss them briefly here . the bond hamiltonian @xmath2 commutes with the @xmath30-component of the total spin operator @xmath31 of the mobile electrons from the @xmath3-th bond , i.e. @xmath32 = 0 $ ] . owing to this fact , the eigenvalues of the bond hamiltonian @xmath2 for the coupled spin - electron chain in an external magnetic field can be simply obtained by shifting the respective eigenvalues of the zero - field model @xcite by the appropriate zeeman s terms . using this procedure , one obtains the following energy spectrum @xmath33 , \nonumber \\ \fl e_{i4,i5 } = e_{i14,i15 } = - \frac{h_{\rm i}}{2 } ( \sigma_i^z + \sigma_{i+1}^z ) + \frac{1}{2 } \left [ h_{\rm e } + ( h_i + h_{i+1 } ) \pm \sqrt{(h_i - h_{i+1})^2 + 4t^2 } \right ] , \nonumber \\ \fl e_{i6,i7 } = - \frac{h_{\rm i}}{2 } ( \sigma_i^z + \sigma_{i+1}^z ) \pm [ h_{\rm e } + ( h_i + h_{i+1 } ) ] , \nonumber \\ \fl e_{i10,i11 } = - \frac{h_{\rm i}}{2 } ( \sigma_i^z + \sigma_{i+1}^z ) \pm \frac{1}{2 } \sqrt{(h_i - h_{i+1})^2 + 4t^2}. \label{es } \end{aligned}\ ] ] here , we have introduced the following notation @xmath34 in order to write the relevant eigenvalues in a more abbreviated form , whereas the notation for lower indices follows from ref . @xcite ( it determines the sectors with different number of the mobile electrons per unit cell ) . at this stage , the eigenvalues ( [ es ] ) of the bond hamiltonian ( [ hi ] ) can be employed for a calculation of the expression entering the right - hand - side of the factorized form ( [ gcpf ] ) of the grand - canonical partition function @xmath35 \bigl\ { 1 + 2z^2 + z^4 + 2 z^2 \cosh [ \beta ( h_e + h_i + h_{i+1 } ) ] \bigr . \nonumber \\ \fl & + & 4 \left(z + z^3\right ) \cosh \left[\frac{\beta}{2 } \sqrt{(h_i - h_{i+1})^2 + 4t^2}\right ] \cosh \bigl[\beta \left(h_e + h_i + h_{i+1}\right ) \bigr ] \nonumber \\ \fl & + & \left . 2 z^2 \cosh \left [ \frac{\beta}{2}\sqrt{(h_i - h_{i+1})^2 + 4t^2}\right ] \right\}. \label{tmd}\end{aligned}\ ] ] the parameter @xmath36 denotes the fugacity of the mobile electrons . after substituting eq . ( [ tmd ] ) into eq . ( [ gcpf2 ] ) and performing successive summation over spin degrees of freedom of individual ising spins one obtains @xmath37 since the expression @xmath38 can be identified as the usual transfer matrix @xcite @xmath39 the transfer - matrix elements are explicitely given by @xmath40 \cosh(\beta t ) \right . \nonumber \\ & + & \left . 2 z^2 \cosh \left[\frac{\beta}{2 } ( 2 h_{\rm e } + j)\right ] + 2 z^2 \cosh(2 \beta t ) \right\ } , \nonumber \\ v_2 & = & \exp \left(-\frac{\beta h_{\rm i}}{2}\right ) \left\ { 1 + 2z^2 + z^4 + 4 ( z + z^3 ) \cosh \left[\frac{\beta}{4 } ( 2 h_{\rm e } - j)\right ] \cosh(\beta t ) \right . \nonumber \\ & + & \left . 2 z^2 \cosh \left[\frac{\beta}{2 } ( 2 h_{\rm e } - j)\right ] + 2 z^2 \cosh(2 \beta t ) \right \ } , \nonumber \\ v_3 & = & 1 + 2 z^2 + z^4 + 4 ( z + z^3 ) \cosh(\beta h_{\rm e}/2 ) \cosh(\beta p/4 ) \nonumber \\ & + & 2 z^2 \cosh(\beta h_{\rm e } ) + 2 z^2 \cosh(\beta p/2 ) , \label{v123}\end{aligned}\ ] ] where the parameter @xmath41 . in the thermodynamic limit ( @xmath42 ) , the grand potential ( per elementary unit cell ) associated to the grand - canonical partition function ( [ gcpf3 ] ) will take a simple form @xmath43 whereas the larger eigenvalue @xmath44 of the transfer matrix ( [ tm ] ) is given by @xmath45 . \label{lmax}\end{aligned}\ ] ] the exact result ( [ grandpotr ] ) for the grand potential can be subsequently employed in order to determine the electron density per one couple of the decorating sites @xmath46 which reflects the doping of the coupled spin - electron chain with the mobile electrons . our particular interest will be successively focused on a magnetization process , so let us calculate separate contributions of the localized ising spins and the mobile electrons to the total magnetization . the sublattice magnetization @xmath47 of the localized ising spins and the sublattice magnetization @xmath48 of the mobile electrons per elementary unit cell can be obtained from the following relations @xmath49 the final exact expressions for the sublattice magnetizations @xmath47 and @xmath48 are listed below @xmath50 the latter expression involves the new parameters @xmath51 , @xmath52 and @xmath53 defined as @xmath54/2 + 2 z^2 \sinh [ \beta ( 2 h_{\rm e } \pm j)/2 ] . \nonumber \end{aligned}\ ] ] it is worth recalling that the sublattice magnetization @xmath48 actually gives the overall magnetization of the mobile electrons per one couple of the decorating sites . the total magnetization @xmath55 of the coupled spin - electron chain per unit cell is then given by @xmath56 and the total magnetization normalized with respect to its saturation value @xmath57 follows from @xmath58 last but not least , we have exactly calculated the entropy of the studied spin - electron chain according to the basic thermodynamic relation @xmath59 @xcite , but the final expression is too cumbersome to write it down here explicitly . this section will be devoted to a discussion of the most interesting results obtained for the coupled spin - electron linear chain with the ferromagnetic interaction between the localized ising spins and mobile electrons , which will hereafter serve as the energy unit ( i.e. @xmath60 ) . for the sake of simplicity , the boltzmann s constant is set to unity ( i.e. @xmath61 ) and the local magnetic fields acting on the localized ising spins and mobile electrons are set equal to each other @xmath62 to avoid overparametrization . plane for three different values of the hopping term @xmath63 , @xmath64 and @xmath65.,title="fig:",width=377 ] plane for three different values of the hopping term @xmath63 , @xmath64 and @xmath65.,title="fig:",width=377 ] plane for three different values of the hopping term @xmath63 , @xmath64 and @xmath65.,title="fig:",width=377 ] let us begin with a detailed analysis of the ground - state phase diagram , which is depicted in fig . [ fig2 ] in the magnetic field versus chemical potential ( @xmath66 ) plane for three different values of the hopping term @xmath67 and @xmath65 . as one can see , there are seven different ground states of the studied spin - electron system enumerated as @xmath68 - @xmath69 . the constructed ground - state phase diagrams are symmetric with respect to @xmath70 axis due to the particle - hole symmetry , which connects the phases @xmath71 and @xmath72 , as well as , the phases @xmath73 and @xmath74 . owing to a commuting character of different bond hamiltonians , the ground state of the full spin - electron chain can be written as a tensor product over the lowest - energy eigenstate ( [ es ] ) of the bond hamiltonian ( [ hi ] ) . in the following , we will specify eigenvectors of all individual ground states along with their respective eigenenergies per elementary unit cell . the phase @xmath71 with the character of disordered paramagnetic phase becomes the ground state for sufficiently low values of the chemical potential @xmath75 where the former ( latter ) ket vector specifies the spin orientation of the localized ising spin ( mobile electrons ) from the @xmath3-th elementary unit . the paramagnetic state @xmath68 emerges due to absence of the mobile electrons on the decorating sites , which splits the investigated spin - electron chain into a set of non - interacting ising spins separated from each other by the empty decorating sites . the alignment of localized ising spins solely comes from a presence of the external magnetic field . a more interesting spin arrangement can be found in the phase @xmath73 @xmath76 which is characterized by a single hopping electron on each couple of decorating sites coupled ferromagnetically to its neighbouring ising spins . another intriguing spin arrangement can be detected in the phase @xmath77 @xmath78 { |0,0\rangle}_{2i-1 } \nonumber \\ \ \fl & \otimes & { \bigl|-\frac{1}{2 } \bigr\rangle}_{\!\sigma_{2i } } \!\!\ ! \otimes \biggl[- r_{- } \hat{a}_{2i,\uparrow}^{\dagger } \hat{b}_{2i,\downarrow}^{\dagger } + r_{+ } \hat{a}_{2i,\downarrow}^{\dagger } \hat{b}_{2i,\uparrow}^{\dagger } + \frac{2t}{p } \left ( \hat{a}_{2i,\uparrow}^{\dagger } \hat{a}_{2i,\downarrow}^{\dagger } + \hat{b}_{2i,\uparrow}^{\dagger } \hat{b}_{2i,\downarrow}^{\dagger } \right ) \biggr ] { |0,0\rangle}_{2i } , \nonumber \\ \fl e_{\rm iii } \!\!\!&=&\!\!\ ! -2 \mu - \frac{p}{2 } , \label{gsiii}\end{aligned}\ ] ] whereas @xmath79 . each pair of the decorating sites is occupied in the phase @xmath80 by two mobile electrons , which underlie due to a hopping process a quantum superposition of two antiferromagnetic states ( @xmath81 ) and two non - magnetic ionic states ( @xmath82 ) . it is quite evident that the hopping process of the mobile electrons gives rise to an antiferromagnetic order of the localized ising spins and consequently , the phase @xmath80 has translationally broken symmetry . owing to the particle - hole symmetry , the ground state of the studied spin - electron chain may also form the phase @xmath83 with three mobile electrons per unit cell @xmath84 which represents a mirror image of the phase @xmath85 under assumption that the hopping process of one electron is replaced by a virtual hopping process of one hole . the phase @xmath86 with fully occupied decorating sites can be characterized by the following state vector @xmath87 both decorating sites are fully occupied in the phase @xmath86 and hence , the mobile electrons transmit zero effective interaction between the localized ising spins quite similarly as in the phase @xmath68 . the phase @xmath88 is totally absent in the ground - state phase diagram at small enough hopping terms ( c.f . the upper panel in fig . [ fig2 ] with the central and lower panels ) , but it may become the relevant ground state on assumption that the hopping term is sufficiently large , the chemical potential is small enough and the external magnetic field is of moderate strength @xmath89 the phase @xmath90 is very similar to the phase @xmath80 except that all localized ising spins are fully polarized into the magnetic field and consequently , the mobile electrons underlie a symmetric quantum superposition of two antiferromagnetic and two ionic states with four equal probability amplitudes . finally , the phase @xmath69 becomes the ground state of the investigated spin - electron chain at sufficiently high magnetic fields @xmath91 the phase @xmath69 involves two mobile electrons per each couple of the decorating sites , which align their spins into the external magnetic field quite similarly as the localized ising spins . for completeness , analytical expressions for the first - order phase boundaries between the respective ground states are listed below @xmath92 next , let us proceed to a discussion of the low - temperature magnetization process of the investigated spin - electron chain . for this purpose , we have plotted in fig . [ magnetization ] the total magnetization @xmath55 per elementary unit against the electron density @xmath93 and the magnetic field @xmath94 for three different values of the hopping term @xmath67 and @xmath65 at relatively low temperature @xmath95 . at sufficiently small electron densities @xmath96 the total magnetization starts from zero and abruptly reaches its saturated value with increasing of the magnetic field , because all localized ising spins as well as mobile electrons are aligned into the magnetic - field direction . contrary to this , the magnetization scenario is much more complex at higher values of the doping parameter @xmath93 , where the shape of magnetization curve basically depends on a relative strength of the kinetic term @xmath12 . per unit cell as a function of the electron density @xmath93 and the magnetic field @xmath94 at low enough temperature @xmath95 for three particular values of the hopping term @xmath97 and @xmath65.,title="fig:",width=377 ] per unit cell as a function of the electron density @xmath93 and the magnetic field @xmath94 at low enough temperature @xmath95 for three particular values of the hopping term @xmath97 and @xmath65.,title="fig:",width=377 ] per unit cell as a function of the electron density @xmath93 and the magnetic field @xmath94 at low enough temperature @xmath95 for three particular values of the hopping term @xmath97 and @xmath65.,title="fig:",width=377 ] for sufficiently low values of the hopping term ( e.g. @xmath63 in the upper panel of fig . [ magnetization ] ) one generally observes just one intermediate plateau before the total magnetization reaches the saturated value upon strengthening of the external magnetic field . to get an insight into the ground state corresponding to the particular magnetization plateau , let us take a closer look at two limiting cases with the electron density @xmath98 and @xmath99 corresponding to a quarter and a half filling of the decorating sites . the observed plateau at a quarter filling ( @xmath98 ) is consistent with the ferromagnetic phase @xmath85 involving a single hopping electron per elementary unit , while the zero magnetization plateau at a half filling ( @xmath100 ) appears due to the quantum antiferromagnetic phase @xmath80 with two hopping electrons per unit cell . it could be thus concluded that a doping with the mobile electrons gradually increases the number of the effective antiferromagnetic bonds occupied by two hopping electrons at the expense of the effective ferromagnetic bonds mediated by a single hopping electron . in this way , the height of doping - dependent magnetization plateau can be tuned continuously . even more striking low - temperature magnetization curves with two intermediate plateaus can be detected at higher values of the hopping term ( e.g. @xmath101 and @xmath65 in the central and lower panel of fig . [ magnetization ] ) . the first magnetization plateau at lower magnetic fields is of the same origin as described previously , i.e. the doping with the mobile electrons causes a gradual onset of the antiferromagnetic spin order of the localized ising spins due to the effective antiferromagnetic coupling mediated by the bonds occupied with two hopping electrons with an opposite spins . on the other hand , the additional intermediate plateau observed at moderate magnetic fields emerges owing to a mutual competition between the magnetic field and the quantum - mechanical hopping process . the magnetic field of the moderate strength is strong enough to polarize all localized ising spins towards the magnetic - field direction , but simultaneously it does not suffice to break the antiferromagnetic alignment on the bonds occupied with two hopping electrons of opposite spins . as a matter of fact , the one - third magnetization plateau existing at a half filling of the decorating sites ( @xmath100 ) is consistent with the ferrimagnetic ground state @xmath90 given by eq . ( [ gsvi ] ) . in accordance with this statement , the second magnetization plateau extends over a wider range of the magnetic fields upon strengthening of the hopping term @xmath12 , which makes an opposite spin alignment of two mobile electrons more favourable . to summarize this part , we have verified that the doping of decorating sites of the spin-1/2 ising chain with the mobile electrons allows one to control the height of the fractional plateaus in the low - temperature magnetization curve even if the mobile electrons are delocalized only over the pairs of decorating sites . last but not least , let us investigate in detail an adiabatic change of the temperature with the external magnetic field as the most significant characteristics of the magnetocaloric effect . [ entropy ] displays typical isentropic dependences of temperature on the magnetic field for the hopping term @xmath102 and three different electron densities @xmath103 and @xmath104 . as one can see , the most abrupt drop ( rise ) of the temperature upon decreasing of the magnetic field can be found for all three electron densities above ( below ) the critical fields @xmath105 and @xmath64 , which perfectly coincide with the field - driven magnetization jumps between the individual magnetization plateaus . a vigorous drop of the temperature upon the adiabatic demagnetization observable slightly above zero magnetic field implies an intriguing refrigeration potential of the studied spin - electron system , which is capable of reaching ultra - low temperatures down to the absolute zero temperature . the main difference between the displayed cases with three different electron densities lies in the temperature range , over which the fast cooling effect can be achieved by the adiabatic demagnetization . it turns out that the annealed bond disorder generally enhances the refrigeration capability in comparison to the special cases without the annealed bond disorder . and three different values of the electron density @xmath103 and @xmath104.,title="fig:",width=377 ] and three different values of the electron density @xmath103 and @xmath104.,title="fig:",width=377 ] and three different values of the electron density @xmath103 and @xmath104.,title="fig:",width=377 ] in the present work , the coupled spin - electron chain consisting of localized ising spins and mobile electrons has been exactly solved in an external magnetic field within the transfer - matrix method . it has been shown that the ground - state phase diagram involves seven different phases , which differ by the number of mobile electrons per unit cell and respective spin arrangements . in particular , we have rigorously studied how the low - temperature magnetization curves depend on the electron doping and magnetic field . it has been demonstrated that the magnetization curves may involve one or two intermediate magnetization plateaus , whose height may be continuously tuned by the electron doping . besides , we have exactly examined the adiabatic change of temperature upon varying of the external magnetic field . the enhanced magnetocaloric effect has been detected close to all field - driven phase transitions , whereas the annealed bond disorder turns out to enhance the fast cooling down to the absolute zero temperature . although we are currently not aware of any magnetic material that would afford an experimental realization of the considered spin - electron chain , the targeted design achieved by a chemical reduction of binuclear dicopper core of the polymeric coordination compound mncu@xmath106(bapo)(h@xmath106o)@xmath107.2h@xmath106o [ bapo = n , n-bis(oxamato-1,3-propylene)oxamide ] @xcite could represent an intriguing possibility for an experimental testing of doping - dependent magnetization plateaus . this work was financially supported by the grant of the ministry of education , science , research and sport of the slovak republic under the contract no . vega 1/0043/16 and by the grant of the slovak research and development agency provided under contract no . apvv-0097 - 12 . 100 schollwck u , richter j , farnell d j j , bishop r f 2004 _ quantum magnetism _ ( berlin : springer , lecture notes in physics ) honecker a , schulenburg j , richter j 2004 _ j. phys . : condens . matter _ * 16 * s749 tsvelik a , oshikawa m 2001 new _ theoretical approaches to strongly correlated systems _ ( berlin : springer , nato science series ) , hu h p , cheng ch , luo h g , chen s 2015 _ sci . rep . _ * 5 * 8433 hida k 1994 _ j. phys . soc . japan _ * 63 * 2359 totsuka k 1997 _ phys . rev . b _ * 57 * 3454 cabra d c , honecker a , pujol p 1998 _ phys . rev . b _ * 58 * 6241 sakai t , takahashi m 1998 _ phys . rev . b _ * 57 * r3201 . momoi t , sakamoto h , kubo k 1999 _ phys . b _ * 59 * 9491 oshikawa m , yamanaka m , affleck i 1997 _ phys . _ * 78 * 1984 lieb e h , schultz t d , mattis d c 1961 _ ann . phys . ( n. y. ) _ * 16 * 407 frahm h , sobiella c 1999 _ phys lett . _ * 83 * 5579 lamas c a , capponi s , pujol p 2011 _ phys . b _ * 84 * 115125 cabra d c , de martino a , honecker a , pujol p , simon p 2000 _ phys . lett . a _ * 268 * 418 cabra d c , de martino a , honecker a , pujol p , simon p 2001 _ phys . rev . b _ * 63 * 094406 cabra d c , de martino a , pujol p , simon p 2002 _ europhys . lett . _ * 57 * 402 roux g , white s , capponi s , poilblanc d 2006 _ phys . lett . _ * 97 * 087207 roux g , orignac e , pujol p , poilblanc d 2007 _ phys . rev . b _ * 75 * 245119 baxter r j 1982 _ exactly solved models in statistical mechanics _ , ( london : academic press ) isrov j , streka j 2014 _ phys . a _ * 378 * 2801 huang k 1963 _ statistical mechanics _ ( new york : wiley ) pei y , kahn o , sletten j 1986 _ j. am . soc . _ * 108 * 3143 georges r , kahn o 1989 _ mol . cryst . _ * 176 * 473

a coupled spin - electron chain composed of localized ising spins and mobile electrons is exactly solved in an external magnetic field within the transfer - matrix method . the ground - state phase diagram involves in total seven different ground states , which differ in the number of mobile electrons per unit cell and the respective spin arrangements . a rigorous analysis of the low - temperature magnetization process reveals doping - dependent magnetization plateaus , which may be tuned through the density of mobile electrons . it is demonstrated that the fractional value of the electron density is responsible for an enhanced magnetocaloric effect due to an annealed bond disorder of the mobile electrons . _ keywords _ : coupled spin - electron chain , localized spins , mobile electrons , magnetization plateaus , doping

Unintentional Injury Death Data Trends for Years 2000-2010 DS 13-13000 Background Unintentional injuries are a subset of a larger category that represents all injuries referred to as “external causes of injury” based on the International Classification of Disease, Tenth Edition codes (ICD-10). The external ICD-10 codes are two-dimensional resulting in codes that indicate both the injury intent (such as unintentional, assault/homicide, intentional/self-harm) and the mechanism or cause (e.g. fall, burn, poison) of injury. Other subset categories within “external causes of injury” include assault (homicide), intentional self-harm (suicide), undetermined, legal intervention or operation of war.1 In 2010, unintentional injury deaths represented 62.3 percent of all injuries deaths in California followed by intentional self-harm (suicide) 23.6 percent, assault (homicide) 11.7 percent, undetermined intent 1.8 percent, and other less than 1.0 percent.2 This report examines unintentional injury deaths from 2000 through 2010. Unintentional injury deaths result from a variety of causes such as motor vehicle traffic crashes, falls, firearms, drownings, suffocations, bites, stings, sports/recreational activities, natural disasters, fires or burns, and poisonings. From 2000 to 2010, California’s top three fatal unintentional injuries include motor vehicle traffic crashes (36.2 percent), poisoning and exposure to noxious substances (including drugs and other substances) (26.7 percent), and falls (16.2 percent). These three causes totaled 79.1 percent of all unintentional injury deaths. Unintentional injury deaths have consistently ranked among the leading causes of death for the United States and California. In 2010, unintentional injuries ranked fifth nationally and sixth in California.2,3 During the same time period, unintentional injuries ranked first nationally as the leading cause of death for those 1 to 44 years old.4 Regardless of age, race, or economic status, unintentional injuries affects everyone, although differences do exist.5 Males account for more unintentional injury deaths than females. California’s 2010 data was used to identify the differences between unintentional injury causes by age groups. Drowning was the most common unintentional injury cause of death for those aged 1 to 4. Motor vehicle traffic crashes were the most frequent unintentional injury deaths for those aged 5 to 24. Poisonings (including drugs and other substances) were the most common unintentional injury death for people aged 25 to 64. Falls were the most prevalent unintentional injury cause of death for individuals over 65.2 Most unintentional injuries are preventable and predictable -- they are not “accidents.” 6 The word accident implies the events are inevitable and unavoidable.7 Like diseases, injuries are preventable if preventative strategies are in place. Preventative strategies such as minimum age drinking requirements, seatbelt and helmet laws, smoke alarms, tai chi and other exercise programs for older adults, and other safety awareness campaigns have saved lives.5 Due to the prevalence of unintentional injury deaths in this country, the U.S. Department of Health and Human Services (HHS) has established Healthy People 2020 objectives that pertain to all injuries. HHS has established Healthy People 2020 Objective IVP—11 to reduce unintentional injuries age-adjusted death rate to no more than 36.0 per 100,000 population.8 The definition of unintentional injuries used for the Healthy People Objective IVP—11 and the report’s content was based on the ICD-10 codes V01-X59, Y85-Y86. ||||| Deaths in America caused by accidental overdoses to prescription medications have quadrupled since 1999. CVS wants to do something about that. The company said Thursday it's putting an opioid antidote on its shelves in 12 states. The drug, Naloxone, reverses opioid overdoses and is already available without a prescription at CVS's in Rhode Island and Massachusetts. The following states will now have access as well: Arkansas, California, Minnesota, Mississippi, Montana, New Jersey, North Dakota, Pennsylvania, South Carolina, Tennessee, Utah and Wisconsin. Opioids include heroin and legal prescription pain medications such as oxycodone (Vicodin), which are addictive and commonly abused. "Over 44,000 people die from accidental drug overdoses every year in the United States," CVS vice president Tom Davis said in a statement Thursday. "By providing access to this medication in our pharmacies without a prescription in more states, we can help save lives." He added that the company is looking into ways to make Naloxone available in even more states. Company spokesperson Michael DeAngelis said states must set up programs allowing the medication to be dispensed without a prescription, which "is typically done through a state's department of health or board of pharmacy." Naloxone has been carried for years by emergency response teams and police departments, and can be administered via a shot or nasally. The antidote expansion is one of several unique initiatives by the retailer. Last year CVS said it would stop selling cigarettes. It also works with the Partnership for Drug-Free Kids to provide a unit to police departments where the community can safely dispose of drugs. ||||| WOONSOCKET, R.I., Sept. 23, 2015 /PRNewswire/ -- CVS/pharmacy, the retail division of CVS Health (NYSE: CVS), is reinforcing its longstanding commitment in the fight against the nationwide epidemic of prescription drug abuse with a number of efforts launching this month. CVS/pharmacy has expanded the availability of the opioid overdose reversal medicine, naloxone, in several states. The medication was already available at CVS/pharmacy without a prescription in Rhode Island and Massachusetts. Naloxone is now available without a prescription at CVS/pharmacy locations in 12 additional states: Arkansas, California, Minnesota, Mississippi, Montana, New Jersey, North Dakota, Pennsylvania, South Carolina, Tennessee, Utah and Wisconsin. "Over 44,000 people die from accidental drug overdoses every year in the United States and most of those deaths are from opioids, including controlled substance pain medication and illegal drugs such as heroin. Naloxone is a safe and effective antidote to opioid overdoses and by providing access to this medication in our pharmacies without a prescription in more states, we can help save lives," said Tom Davis, RPh, Vice President of Pharmacy Professional Practices at CVS/pharmacy. "While all 7,800 CVS/pharmacy stores nationwide can continue to order and dispense naloxone when a prescription is presented, we support expanding naloxone availability without a prescription and are reviewing opportunities to do so in other states." In addition, CVS Health is currently participating in a research project with Boston Medical Center and Rhode Island Hospital to support a demonstration project of pharmacy-based naloxone rescue kits to help reduce opioid addiction and overdose deaths. CVS/pharmacy has also renewed its Medication Disposal for Safer Communities Program, in which it has teamed up with the Partnership for Drug-Free Kids to donate drug collection units to police departments around the country to help their communities safely dispose of unwanted medications, including controlled substances. "Our Safer Communities program has donated more than 400 drug collection units to local law enforcement around the country since last year, resulting in almost seven tons of unused medication being collected in our communities," said Davis. "We are pleased to continue this program with the Partnership for Drug-Free Kids and provide a permanent drug disposal solution at local police departments." Police departments interested in receiving a drug collection unit can apply at www.cvs.com/safercommunities. Also, the Drug Enforcement Administration (DEA) will hold National Prescription Drug Take-Back Day on Saturday, September 26. On that day, hundreds of CVS/pharmacy locations around the country will host local law enforcement collection events in store parking lots from 10:00 AM to 2:00 PM. To locate a participating collection site, visit http://www.deadiversion.usdoj.gov/drug_disposal/takeback/. Other on-going initiatives at CVS/pharmacy to combat prescription drug abuse include: Availability of postage-paid Environmental Return System envelopes at all of its pharmacies with which customers can send their unwanted medications for secure and environmentally-safe disposal. Identification of physicians who exhibit extreme patterns of prescribing high risk drugs such as pain medications and suspension of dispensing their controlled substance prescriptions. Advocating at the federal and state levels to implement policy changes to curb prescription drug abuse, such as mandatory electronic prescribing of controlled substances and improved prescription drug monitoring programs. About CVS/pharmacy CVS/pharmacy, the retail division of CVS Health (NYSE: CVS), is America's leading retail pharmacy with over 7,800 locations. It is the first national pharmacy to end the sale of tobacco and the first pharmacy in the nation to receive the Community Pharmacy accreditation from URAC, the leading health care accreditation organization that establishes quality standards for the health care industry. CVS/pharmacy is reinventing pharmacy to help people on their path to better health by providing the most accessible and personalized expertise, both in its stores and online at CVS.com. General information about CVS/pharmacy and CVS Health is available at www.cvshealth.com. MEDIA CONTACT: Mike DeAngelis [email protected] 401-770-2645 Logo - http://photos.prnewswire.com/prnh/20100816/NE50800LOGO SOURCE CVS/pharmacy Related Links http://www.cvs.com ||||| Naloxone injection comes as a solution (liquid) to be injected intravenously (into a vein), intramuscularly (into a muscle), or subcutaneously (just under the skin). It also comes as a prefilled auto-injection device containing a solution to be injected intramuscularly or subcutaneously. It is usually given as needed to treat opiate overdoses. You will probably be unable to treat yourself if you experience an opiate overdose. You should make sure that your family members, caregivers, or the people who spend time with you know how to tell if you are experiencing an overdose, how to use naloxone injection, and what to do until emergency medical help arrives. Your doctor or pharmacist will show you and your family members how to use the medication. You and anyone who may need to give the medication should read the instructions that come with the nasal injection. Ask your pharmacist for the instructions or visit the manufacturer's website to get the instructions. Naloxone injection may not reverse the effects of certain opiates such as buprenorphine (Belbuca, Buprenex, Butrans) and pentazocine (Talwin) and may require additional naloxone doses. You will probably be unable to treat yourself if you experience an opiate overdose. You should make sure that your family members, caregivers, or the people who spend time with you know how to tell if you are experiencing an overdose, how to inject naloxone, and what to do until emergency medical help arrives. Your doctor or pharmacist will show you and your family members how to administer the medication. You and anyone who may need to administer the medication should read the instructions that come with the device and practice with the training device provided with the medication. Ask your pharmacist for the instructions or visit the manufacturer's website. In case of emergency, even a person who has not been trained to inject naloxone should still try to inject the medication. If you have been given an automatic injection device, you should keep the device available at all times in case you experience an opioid overdose. Be aware of the expiration date on your device and replace the device when this date passes. Look at the solution in the device from time to time. If the solution is discolored or contains particles, call your doctor to get a new injection device. The automatic injection device has an electronic voice system that provides step by step directions for use in an emergency. The person who is injecting naloxone for you can follow these directions, but he or she should know that it is not necessary to wait for the voice system to finish one direction before beginning the next step. Also, at times the voice system may not work and the person may not hear the directions. However, the device will still work and will inject the medication even if the voice system is not working. Symptoms of an opioid overdose include excessive sleepiness; not awakening when spoken to in a loud voice or when the middle of your chest is rubbed firmly; shallow or stopped breathing; or small pupils (black circles in the center of the eyes). If someone sees that you are experiencing these symptoms, he or she should give you your first dose of naloxone into the muscle or under the skin of your thigh. The medication may be injected through your clothing if necessary in an emergency. After injecting naloxone, the person should call 911 immediately and then stay with you and watch you closely until emergency medical help arrives. Your symptoms may return within a few minutes after you receive a naloxone injection. If your symptoms return, the person should use a new automatic injection device to give you another dose of naloxone. Additional injections may be given every 2-3 minutes if symptoms return before medical help arrives. Each prefilled automatic injection device should be used only once and then should be discarded. Do not try to replace the red safety guard on the auto-injection device after you remove it, even if you did not inject the medication. Instead, replace the used device in the outer case before discarding. Ask your doctor or pharmacist how to safely dispose of used injection devices. ||||| What is this medicine? NALOXONE (nal OX one) is a narcotic blocker. It is used to treat narcotic (opioid) drug overdose. It is used to temporarily reverse the effects of opioid medicines. This medicine has no effect in people who are not taking opioid medicines. Similar Brand Name Drugs : Narcan: Solution for injection | EVZIO: Solution for injection What should I tell my health care provider before I take this medicine? Open They need to know if you have any of these conditions: -drug abuse or addiction -heart disease -an unusual or allergic reaction to naloxone, other medicines, foods, dyes, or preservatives -pregnant or trying to get pregnantbreast-feeding How should I use this medicine? Open This medicine may be administered in a hospital, clinic, or can be used by the public to give aid to a person who has overdosed until emergency medical help is available. This medicine is for injection into the outer thigh. It can be injected through clothing if needed. Get emergency medical help right away after giving the first dose of this medicine, even if the person wakes up. You should be familiar with how to recognize the signs and symptoms of a narcotic overdose. Administer according to the printed instructions on the device label or the electronic voice instructions. You should practice using the Trainer injector before this medicine is needed. Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for children as young as newborn for selected conditions, precautions do apply. For infants less than 1 year of age, pinch the thigh muscle while administering. What if I miss a dose? Open This does not apply. What may interact with this medicine? Open This medicine is only used during an emergency. No interactions are expected during emergency use. What should I watch for while using this medicine? Open Keep this medicine ready for use in the case of a narcotic overdose. Make sure that you have the phone number of your doctor or health care professional and local hospital ready. You may need to have additional doses of this medicine. Each injector contains a single dose. Some emergencies may require additional doses. After use, bring the treated person to the nearest hospital or call 911. Make sure the treating health care professional knows that the person has received an injection of this medicine. You will receive additional instructions on what to do during and after use of this medicine before an emergency occurs. What side effects may I notice from receiving this medicine? Open ||||| SAN FRANCISCO— The Drug Policy Alliance is applauding CVS/pharmacy for being the first chain pharmacy in California to stock and sell the opiate overdose reversal drug naloxone without a prescription. More than 50 CVS/pharmacy stores in California will make the lifesaving drug available to friends and family members of people at risk of an opiate overdose. This new program is a direct result of the passage of Assemblymember Richard Bloom’s AB 1535, which was co-sponsored by the Drug Policy Alliance and the California Pharmacists Association. The bill was signed into law by Governor Jerry Brown in 2014. The full list of participating pharmacies can be found at www.naloxoneCA.org. Some overdose prevention advocates are cheering how quickly California medical and pharmacy professionals, as well as CVS/pharmacy, worked to fully implement the law. “The fact that just one year ago the bill was signed, and now today we’re seeing CVS stores all across California beginning to sell naloxone without a prescription is a testament to how hard many, many people worked behind the scenes to make this happen so fast,” said Laura Thomas, California deputy director of the Drug Policy Alliance. “It can sometimes take years for laws to be fully implemented due to myriad levels of bureaucracy, but in the case of pharmacy naloxone, everyone worked together from the very beginning with cooperation and excitement to do something great for California families,” she added. “Expanding access to naloxone without a prescription is an important way that pharmacies can help save lives while also combating the nationwide epidemic of drug abuse, and we are committed to partnering with states such as California to make this possible,” said Tom Davis, RPh, Vice President of Pharmacy Professional Practices at CVS Health. “We are pleased to expand the availability of non-prescription naloxone in our California pharmacies. We want to thank the Drug Policy Alliance, the California Pharmacists Association and other state health advocates for their hard work to make this possible.” Accidental drug overdose continues to be the leading cause of accidental death in California, causing more deaths than motor vehicle accidents. Over 44,000 people die of accidental drug overdose every year in the United States and the number of deaths has doubled since 1999. Most of those deaths are from opiates, including prescription pain medications and illicit opiates such as heroin. Naloxone is a very safe and effective antidote to opiate overdose. Advocates such as the Drug Policy Alliance are working to ensure that people who use drugs and their family members have access to naloxone to reverse potential overdoses. “We’ve been waiting for this day for years,” said Denise Cullen, an Orange County mom who lost her son Jeff to a heroin overdose. “Dozens of moms and dads who lost kids to overdose worked to get the pharmacy naloxone bill passed. We know better than anyone that having access to that important drug can literally be the difference between life and death for our kids. This is a hugely significant day for all of us. We hope many more chain pharmacies will now come on board and make naloxone available to even more parents across the state,” said Cullen. ||||| Good Morning, Mr. Chairman and Members of the Subcommittee. Thank you for inviting the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH), to participate in this important hearing and contribute what I believe will be useful insights into the growing and intertwined problems of prescription pain relievers and heroin abuse in this country. Background The abuse of and addiction to opioids such as heroin, morphine, and prescription pain relievers is a serious global problem that affects the health, social, and economic welfare of all societies. It is estimated that between 26.4 million and 36 million people abuse opioids worldwide,[1] with an estimated 2.1 million people in the United States suffering from substance use disorders related to prescription opioid pain relievers in 2012 and an estimated 467,000 addicted to heroin.[2] The consequences of this abuse have been devastating and are on the rise. For example, the number of unintentional overdose deaths from prescription pain relievers has soared in the United States, more than quadrupling since 1999. There is also growing evidence to suggest a relationship between increased non-medical use of opioid analgesics and heroin abuse in the United States.[3] To address the complex problem of prescription opioid and heroin abuse in this country, we must recognize and consider the special character of this phenomenon, for we are asked not only to confront the negative and growing impact of opioid abuse on health and mortality, but also to preserve the fundamental role played by prescription opioid pain relievers in healing and reducing human suffering. That is, scientific insight must strike the right balance between providing maximum relief from suffering while minimizing associated risks and adverse effects. Abuse of Prescription Opioids: Scope and Impact Prescription opioids are one of the three main broad categories of medications that present abuse liability, the other two being stimulants and central nervous system (CNS) depressants. Several factors are likely to have contributed to the severity of the current prescription drug abuse problem. They include drastic increases in the number of prescriptions written and dispensed, greater social acceptability for using medications for different purposes, and aggressive marketing by pharmaceutical companies. These factors together have helped create the broad “environmental availability” of prescription medications in general and opioid analgesics in particular. To illustrate this point, the total number of opioid pain relievers prescribed in the United States has skyrocketed in the past 25 years (Fig. 1).[4] The number of prescriptions for opioids(like hydrocodone and oxycodone products) have escalated from around 76 million in 1991 to nearly 207 million in 2013, with the United States their biggest consumer globally, accounting for almost 100 percent of the world total for hydrocodone (e.g., Vicodin) and 81 percent for oxycodone (e.g., Percocet).[5] Figure 1. Opioid Prescriptions Dispensed by US Retail Pharmacies. IMS Health, Vector One: National, Years 1991-1996, Data Extracted 201. IMS Health, National Prescription Audit, Years 1997-2013, Data Extracted 2014. IMS Health, Vector One: National, Years 1991-1996, Data Extracted 201. IMS Health, National Prescription Audit, Years 1997-2013, Data Extracted 2014. This greater availability of opioid (and other) prescribed drugs has been accompanied by alarming increases in the negative consequences related to their abuse.[6] For example, the estimated number of emergency department visits involving nonmedical use of opioid analgesics increased from 144,600 in 2004 to 305,900 in 2008;[7] treatment admissions for primary abuse of opiates other than heroin increased from one percent of all admissions in 1997 to five percent in 2007[8]; and overdose deaths due to prescription opioid pain relievers have more than tripled in the past 20 years, escalating to 16,651 deaths in the United States in 2010.[9] In terms of abuse and mortality, opioids account for the greatest proportion of the prescription drug abuse problem. Deaths related to prescription opioids began rising in the early part of the 21st century. By 2002, death certificates listed opioid analgesic poisoning as a cause of death more commonly than heroin or cocaine.[10] Figure 2. Chemical similarity between Opioid Prescriptions and Heroin Chemical similarity between Opioid Prescriptions and Heroin Because prescription opioids are similar to, and act on the same brain systems affected by, heroin and morphine (Fig.2), they present an intrinsic abuse and addiction liability, particularly if they are used for non-medical purposes. They are most dangerous and addictive when taken via methods that increase their euphoric effects (the “high”), such as crushing pills and then snorting or injecting the powder, or combining the pills with alcohol or other drugs. Also, some people taking them for their intended purpose risk dangerous adverse reactions by not taking them exactly as prescribed (e.g., taking more pills at once, or taking them more frequently or combining them with medications for which they are not being properly controlled); and it is possible for a small number of people to become addicted even when they take them as prescribed, but the extent to which this happens currently is not known. It is estimated that more than 100 million people suffer from chronic pain in this country,[11] and for some of them, opioid therapy may be appropriate. The bulk of American patients who need relief from persistent, moderate-to-severe non-cancer pain have back pain conditions (approximately 38 million) or osteoarthritis (approximately 17 million).[12] Even if a small percentage of this group develops substance use disorders (a subset of those already vulnerable to developing tolerance and/or clinically manageable physical dependence[13]), a large number of people could be affected. Scientists debate the appropriateness of chronic opioid use for these conditions in light of the fact that long-term studies demonstrating that the benefits outweigh the risks have not been conducted. In June 2012, NIH and FDA held a joint meeting on this topic,[14] and now FDA is requiring companies who manufacture long-acting and extended-release opioid formulations to conduct post-marketing research on their safety.[15] The Effects of Opioid Abuse on the Brain and Body. Opioids include drugs such as OxyContin and Vicodin that are mostly prescribed for the treatment of moderate to severe pain. They act by attaching to specific proteins called opioid receptors, which are found on nerve cells in the brain, spinal cord, gastrointestinal tract, and other organs in the body. When these drugs attach to their receptors, they reduce the perception of pain and can produce a sense of well-being; however, they can also produce drowsiness, mental confusion, nausea, and constipation.[16] The effects of opioids are typically mediated by specific subtypes of opioid receptors (mu, delta, and kappa) that are activated by the body’s own (endogenous) opioid chemicals (endorphins, encephalins). With repeated administration of opioid drugs (prescription or heroin), the production of endogenous opioids is inhibited, which accounts in part for the discomfort that ensues when the drugs are discontinued (i.e., withdrawal). Adaptations of the opioid receptors’ signaling mechanism have also been shown to contribute to withdrawal symptoms. Opioid medications can produce a sense of well-being and pleasure because these drugs affect brain regions involved in reward. People who abuse opioids may seek to intensify their experience by taking the drug in ways other than those prescribed. For example, extended-release oxycodone is designed to release slowly and steadily into the bloodstream after being taken orally in a pill; this minimizes the euphoric effects. People who abuse pills may crush them to snort or inject which not only increases the euphoria but also increases the risk for serious medical complications, such as respiratory arrest, coma, and addiction. When people tamper with long-acting or extended-release medicines, which typically contain higher doses because they are intended for release over long periods, the results can be particularly dangerous, as all of the medicine can be released at one time. Tampering with extended release and using by nasal, smoked, or intravenous routes produces risk both from the higher dose and from the quicker onset. Opioid pain relievers are sometimes diverted for nonmedical use by patients or their friends, or sold in the street. In 2012, over five percent of the U.S. population aged 12 years or older used opioid pain relievers non-medically.[17] The public health consequences of opioid pain reliever abuse are broad and disturbing. For example, abuse of prescription pain relievers by pregnant women can result in a number of problems in newborns, referred to as neonatal abstinence syndrome (NAS), which increased by almost 300 percent in the United States between 2000 and 2009.[18] This increase is driven in part by the high rate of opioid prescriptions being given to pregnant women. In the United States, an estimated 14.4 percent of pregnant women are prescribed an opioid during their pregnancy.[19] Prescription opioid abuse is not only costly in economic terms (it has been estimated that the nonmedical use of opioid pain relievers costs insurance companies up to $72.5 billion annually in health-care costs[20]) but may also be partly responsible for the steady upward trend in poisoning mortality. In 2010, there were 13,652 unintentional deaths from opioid pain reliever (82.8 percent of the 16,490 unintentional deaths from all prescription drugs),[21] and there was a five-fold increase in treatment admissions for prescription pain relievers between 2001 and 2011 (from 35,648 to 180,708, respectively).[22] In the same decade, there was a tripling of the prevalence of positive opioid tests among drivers who died within one hour of a crash.[23] A property of opioid drugs is their tendency, when used repeatedly over time, to induce tolerance. Tolerance occurs when the person no longer responds to the drug as strongly as he or she did at first, thus necessitating a higher dose to achieve the same effect. The establishment of tolerance hinges on the ability of abused opioids (e.g., OxyContin, morphine) to desensitize the brain’s own natural opioid system, making it less responsive over time.[24] This tolerance contributes to the high risk of overdose during a relapse to opioid use after a period in recovery; users who do not realize they may have lost their tolerance during a period of abstinence may initially take the high dosage that they previously had used before quitting, a dosage that produces an overdose in the person who no longer has tolerance.[25] Another contributing factor to the risk of opioid-related morbidity and mortality is the combined use of benzodiazepines (BZDs) and/or other CNS depressants, even if these agents are used appropriately. Thus, patients with chronic pain who use opioid analgesics along with BZDs (and/or alcohol) are at higher risk for overdose. Unfortunately, there are few available practice guidelines for the combined use of CNS depressants and opioid analgesics; such cases warrant much closer scrutiny and monitoring.[26] Finally, it must be noted in this context that, although more men die from drug overdoses than women, the percentage increase in deaths seen since 1999 is greater among women: Deaths from opioid pain relievers increased five-fold between 1999 and 2010 for women versus 3.6 times among men.[27] Relationship between Prescription Opioids and Heroin Abuse The recent trend of a switch from prescription opioids to heroin seen in some communities in our country alerts us to the complex issues surrounding opioid addiction and the intrinsic difficulties in addressing it through any single measure such as enhanced diversion control (Fig.3). Of particular concern has been the rise in new populations of heroin users, particularly young people. Figure 3. Growing evidence suggests that abusers of prescription opioids are shifting to heroin as prescription drugs become less available or harder to abuse. For example, a recent increase in heroin use accompanied a downward trend in Oxycontin abuse following the introduction of an abuse-deterrent formulation of that medication (dashed vertical line). For example, a recent increase in heroin use accompanied a downward trend in Oxycontin abuse following the introduction of an abuse-deterrent formulation of that medication (dashed vertical line). 3 The emergence of chemical tolerance toward prescribed opioids, perhaps combined in a smaller number of cases with an increasing difficulty in obtaining these medications illegally[28], may in some instances explain the transition to abuse of heroin, which is cheaper and in some communities easier to obtain than prescription opioids. The number of past-year heroin users in the United States nearly doubled between 2005 and 2012, from 380,000 to 670,000 (Fig. 4).[29] Heroin abuse, like prescription opioid abuse, is dangerous both because of the drug’s addictiveness and because of the high risk for overdosing. In the case of heroin, this danger is compounded by the lack of control over the purity of the drug injected and its possible contamination with other drugs (such as fentanyl, a very potent prescription opioid that is also abused by itself).[30] All of these factors increase the risk for overdosing, since the user can never be sure of the amount of the active drug(or drugs) being taken. In 2010, there were 2,789 fatal heroin overdoses, approximately a 50 percent increase over the relatively constant level seen during the early 2000s.[31] What was once almost exclusively an urban problem is spreading to small towns and suburbs. In addition, the abuse of an opioid like heroin, which is typically injected intravenously, is also linked to the transmission of human immunodeficiency virus (HIV), hepatitis (especially Hepatitis C), sexually-transmitted infections, and other blood-borne diseases, mostly through the sharing of contaminated drug paraphernalia but also through the risky sexual behavior that drug abuse may engender. Figure 4. Trend in prevalence of heroin use and heroin related overdose death in the US (1999-2012) NIDA Activities to Stem the Tide of Prescription Opioid and Heroin Abuse NIDA first launched its prescription drug abuse public health initiative in 2001. Our evidence-based strategy calls for a comprehensive three-pronged approach consisting of (1) enhancing our understanding of pain and its management; (2) preventing overdose deaths; and (3) effectively treating opioid addiction. Research on Pain and Next Generation Analgesics. Although opioid medications effectively treat acute pain and help relieve chronic pain for some patients,[32] their addiction risk presents a dilemma for healthcare providers who seek to relieve suffering while preventing drug abuse and addiction. Little is yet known about the risk for addiction among those being treated for chronic pain or about how basic pain mechanisms interact with prescription opioids to influence addiction potential. To better understand this, NIDA launched a research initiative on "Prescription Opioid Use and Abuse in the Treatment of Pain." This initiative encourages a multidisciplinary approach using both human and animal studies to examine factors (including pain itself) that predispose or protect against opioid abuse and addiction. Funded grants cover clinical neurobiology, genetics, molecular biology, prevention, treatment, and services research. This type of information will help develop screening and diagnostic tools that physicians can use to assess the potential for prescription drug abuse in their patients. Because opioid medications are prescribed for all ages and populations, NIDA is also encouraging research that assesses the effects of prescription opioid abuse by pregnant women, children, and adolescents, and how such abuse in these vulnerable populations might increase the lifetime risk of substance abuse and addiction. Another important initiative pertains to the development of new approaches to treat pain. This includes research to identify new pain relievers with reduced abuse, tolerance, and dependence risk, as well as devising alternative delivery systems and formulations for existing drugs that minimize diversion and abuse (e.g., by preventing tampering and/or releasing the drug over a longer period of time) and reduce the risk of overdose deaths. New compounds are being developed that exhibit novel properties as a result of their combined activity on two different opioid receptors (i.e., mu and delta). Preclinical studies show that these compounds can induce strong analgesia but fail to produce tolerance or dependence. Researchers are also getting closer to developing a new generation of non–opioid-based medications for severe pain that would circumvent the brain reward pathways, thereby greatly reducing abuse potential. This includes compounds that work through a type of cannabinoid receptor found primarily in the peripheral nervous system. NIDA is also exploring the use of non-medication strategies for managing pain. An example is the use of “neurofeedback,” a novel modality of the general biofeedback approach, in which patients learn to regulate specific regions in their brains by getting feedback from real-time brain images. This technique has shown promising results for altering the perception of pain in healthy adults and chronic pain patients and could even evolve into a powerful psychotherapeutic intervention capable of rescuing the circuits and behaviors impaired by addiction. Developing More Effective Means for Preventing Overdose Deaths. The opioid overdose antidote naloxone has reversed more than 10,000 overdose cases between 1996 and 2010, according to CDC. [33] For many years, naloxone was available only in an injectable formulation and was generally only carried by medical emergency personnel. However, FDA has recently approved a new hand-held auto-injector of naloxone to reverse opioid overdose that is specifically designed to be given by family members or caregivers. In order to expand the options for effectively and rapidly counteracting the effects of an overdose, NIDA is also supporting the development of a naloxone nasal spray—a needle-free, unit-dose, ready-to-use opioid overdose antidote that can easily be used by an overdose victim, a companion, or a wider range of first responders (e.g., police) in the event of an emergency.[34] Research on the Treatment of Opioid Addiction. Drug abuse treatment must address the brain changes mentioned earlier, both in the short and long term. When people addicted to opioids first quit, they undergo withdrawal symptoms, which may be severe (pain, diarrhea, nausea, vomiting, hypertension, tachycardia, seizures). Medications can be helpful in this detoxification stage, easing craving and other physical symptoms that can often trigger a relapse episode. However, this is just the first step in treatment. Medications have also become an essential component of an ongoing treatment plan, enabling opioid-addicted persons to regain control of their health and their lives. Agonist medications developed to treat opioid addiction work through the same receptors as the addictive drug but are safer and less likely to produce the harmful behaviors that characterize addiction, because the rate at which they enter and leave the brain is slower. The three classes that have been developed to date include (1) agonists, e.g., methadone (Dolophine or Methadose), which activate opioid receptors; (2) partial agonists, e.g., buprenorphine (Subutex, Suboxone), which also activate opioid receptors but produce a diminished response; and (3) antagonists, e.g., naltrexone (Depade, Revia, Vivitrol), which block the receptor and interfere with the rewarding effects of opioids. Physicians can select from these options on the basis of a patient’s specific medical needs and other factors. Research has shown methadone- and buprenorphine-containing medicines, when administered in the context of an addiction treatment program, can effectively maintain abstinence from other opioids and reduce harmful behaviors; we believe their gradual onset and long duration contribute to this ability to “stabilize” patient behavior. Scientific research has established that medication-assisted treatment of opioid addiction is associated with decreases in the number of overdoses from heroin abuse,[35] increases retention of patients in treatment and decreases drug use, infectious disease transmission, and criminal activity. For example, studies among criminal offenders, many of whom enter the prison system with drug abuse problems, showed that methadone treatment begun in prison and continued in the community upon release extended the time parolees remained in treatment, reduced further drug use, and produced a three-fold reduction in criminal activity (Fig. 5). Investment in medication-assisted treatment of opioid addiction also makes good economic sense. According to a 2005 published analysis that tracked methadone patients from age 18 to 60 and included such variables as heroin use, treatment for heroin use, criminal behavior, employment, and healthcare utilization, every dollar spent on methadone treatment yields $38 in related economic benefits—seven times more than previously thought.[36] Figure 5. Methaone Treatment Pre-and Post Release Increases Treatment Retention and Reduces drug use (Findings at 12 months Post-Release) Buprenorphine is worth highlighting in this context for its pioneering contributions to addiction treatment. NIDA-supported basic and clinical research led to the development of this compound, which rigorous studies have shown to be effective, either alone or in combination with naloxone, in significantly reducing opiate drug abuse and cravings. The arrival of buprenorphine represented a significant health services delivery innovation. FDA approved Subutex® (buprenorphine) and Suboxone® tablets (buprenorphine/naloxone formulation) in October 2002, making them the first medications to be eligible for prescribing under the Drug Addiction Treatment Act of 2000. Subutex contains only buprenorphine hydrochloride. This formulation was developed as the initial product. The second medication, Suboxone, contains naloxone to guard against misuse (by initiating withdrawal if the formulation is injected). Subutex and Suboxone are less tightly controlled than methadone because they have a lower potential for abuse and are less dangerous in an overdose. As patients progress in their therapy, their doctor may write a prescription for a take-home supply of the medication. To date, of the nearly 872,615 potential providers registered with the Drug Enforcement Administration (DEA), 25,021 registered physicians are authorized to prescribe these two medications. The development of buprenorphine and its authorized use in physicians' offices gives opioid-addicted patients more medical options and extends the reach of addiction medication to remote populations. Medication-assisted treatments remain grossly underutilized in many addiction treatment settings, where stigma and negative attitudes (based on the misconception that buprenorphine or methadone “substitute a new addiction for an old one”) persist among clinic staff and administrators. This leads to insufficient dosing or limitations on the duration of use of these medications (when they are used at all), which often leads to treatment failure and the perception that the drugs are ineffective, further reinforcing the negative attitudes toward their use.[37] Policy and regulatory barriers also can present obstacles. Integrating Drug Treatment into Healthcare Settings Medication-assisted treatment will be most effective when offered within the larger context of a high-quality delivery system that addresses opioid addiction not only with medication but also with behavioral interventions to support treatment participation and progress, infectious disease identification and treatment (especially HIV and HCV), screening and treatment of co-morbid psychiatric diseases, and overdose protection (naloxone). NIDA’s research over the last two decades has provided us with evidence that a high quality treatment system to address opioid addiction must include all these components, yet there are currently very few systems in the United States that provide this bundle of effective services.[38] Health care reform—with a focus on both expanding access to treatment and improving the quality of care—offers hope that we may be better able to integrate drug treatment into healthcare settings and offer comprehensive treatment services for opioid addiction. We also are examining ways to use health care reform and the focus on health promotion and wellness to pay for and deliver prevention interventions targeted at children, adolescents, young adults, and high-risk adult populations like those with chronic pain or returning veterans. Prevention, Education, and Outreach Figure 6. Medscape's Test-and-Teach is one example of NIDA's multiplatform approached to enhance a physician's ability to properly manage pain while preventing the abuse of prescription opioids. Medscape's Test-and-Teach is one example of NIDA's multiplatform approached to enhance a physician's ability to properly manage pain while preventing the abuse of prescription opioids. Because prescription drugs are safe and effective when used properly and are broadly marketed to the public, the notion that they are also harmful and addictive when abused can be a difficult one to convey. Thus, we need focused research to discover targeted communication strategies that effectively address this problem. Reaching this goal may be significantly more complex and nuanced than developing and deploying effective programs for the prevention of abuse of illegal drugs, but good prevention messages based on scientific evidence will be difficult to ignore.[39] Education is a critical component of any effort to curb the abuse of prescription medications and must target every segment of society, including doctors (Fig.6). NIDA is advancing addiction awareness, prevention, and treatment in primary care practices, including the diagnosis of prescription drug abuse, having established four Centers of Excellence for Physician Information. Intended to serve as national models, these Centers target physicians-in-training, including medical students and resident physicians in primary care specialties (e.g., internal medicine, family practice, and pediatrics). NIDA has also developed, in partnership with the Office of National Drug Control Policy (ONDCP), two online continuing medical education courses on safe prescribing for pain and managing patients who abuse prescription opioids. To date, combined, these courses have been completed over 80,000 times. Additionally, NIDA is directly reaching out to teens with its PEERx initiative, an online education program that aims to discourage prescription drug abuse among teens,[40] by providing factual information about the harmful effects of prescription drug abuse on the brain and body. NIDA will also continue its close collaborations with ONDCP, the Substance Abuse and Mental Health Services Administration (SAMHSA), and other Federal Agencies. It will also continue to work with professional associations with a strong interest in preserving public health. For example, NIDA recently sponsored a two-day meeting in conjunction with the American Medical Association and NIH Pain Consortium, where more than 500 medical professionals, scientific researchers, and interested members of the public had a chance to dialogue about the problems of prescription opioid abuse and to learn about new areas of research. In another important collaborative effort, NIDA, CDC, SAMHSA, and the Office of the National Coordinator for Health Information Technology reviewed eight clinical practice guidelines on the use of opioids to treat pain and developed a common set of provider actions and associated recommendations.[41] Conclusion We are seeing an increase in the number of people who are dying from overdoses, predominantly after abuse of prescribed opioid analgesics. This disturbing trend appears to be associated with a growing number of prescriptions in and diversion from the legal market. We commend the Subcommittee for recognizing the serious and growing challenge posed by the abuse of prescription and non-prescription opioids in this country, a problem that is exceedingly complex. Indeed, prescription opioids, like other prescribed medications, do present health risks but they are also powerful clinical allies. Therefore, it is imperative that we strive to achieve a balanced approach to ensure that people suffering from chronic pain can get the relief they need while minimizing the potential for negative consequences. We support the development and implementation of multipronged, evidence-based strategies that minimize the intrinsic risks of opioid medications and make effective, long term treatments available. References

– People in 14 states can now walk into a CVS and pick up an opioid-overdose antidote without a prescription, the company announced yesterday. Naloxone was already available in stores in Rhode Island and Massachusetts, but now Arkansas, California, Minnesota, Mississippi, Montana, New Jersey, North Dakota, Pennsylvania, South Carolina, Tennessee, Utah, and Wisconsin join that list, CNNMoney reports. Opioids such as heroin and prescription meds such as oxycodone are habit-forming and often abused, the site notes, and have led to four times the number of unintentional ODs on prescription meds since 1999, per the National Institute on Drug Abuse. "By providing access to this medication in our pharmacies without a prescription in more states, we can help save lives," CVS exec Tom Davis says in a statement. All 7,800 CVS stores around the country can dispense naloxone—which can be injected or administered nasally—with a prescription, Davis says in a press release, but the company wants to bump up the number of states that can do so without one (it's looking to get the OK in even more states). The nonprofit Drug Policy Alliance applauds CVS' initiative, especially in California, where poisonings that include drugs and other substances are the leading cause of accidental death. "We've been waiting for this day for years," an OC mom who lost her son to a heroin overdose says in a press release. (Last year, the pharmacy chain dumped cigarettes from all of its stores.)

terpenes are omnipresent natural products mainly found as constituents of plant oils , and have long held importance as flavours and fragrances , and as poisons and medicines . isolation , structural elucidation and synthetic studies on this vast family of natural products were already being conducted over 100 years ago , providing constant challenges to chemists and thus resulting in a continuous development of the field . taxol ( 1 ) , a successful anti - cancer drug , is one example of societal and scientific merit , being one of the most famous terpenes from a medicinal standpoint and one of the most densely functionalised and complex molecules from a structural standpoint . its unique mechanism of action involving the stabilisation of microtubules has been fascinating biologists as well , and thus extensive research efforts have been carried out around the globe by chemists and biologists alike . taxol ( 1 ) is a potent anticancer drug originally used as a treatment for ovarian and breast cancer , but its versatile effects now extend to treatments of lung , liver and other types of cancer . initially isolated from the bark of the yew tree , substantial work in the 1980s and 1990s allowed for a semisynthetic route to taxol ( 1 ) that reduced the accompanying detrimental effects to the yew tree population , and currently , its commercial supply relies on cell - culture production ( taxol is currently manufactured with plant cell - culture technology through a collaboration of bristol - myers squibb and phyton biotech , inc . , a dfb pharmaceuticals company ) . this diterpene is one of few natural products that continues to engender worldwide attention , and tremendous efforts have already culminated in seven total syntheses and one formal synthesis . however , the inventory of man - made taxol ( 1 ) produced by total synthesis is still less than 30 mg , even when including the most recent approach by takahashi wherein an automated synthesis was employed for the majority of their synthetic steps . in contrast , the current industrial output of 1 through the use of biological machinery is of ton - scale ( 10 mg ) , clearly indicating the magnitudes of difference in chemical versus biological scale and efficiency . closing this huge gap is not simply a matter of engineering , but rather a learning objective with which to guide chemical innovation , in the tactics , strategies , and methods of synthesis(for a discussion of the terms strategy versus tactics , see reference 21 ) . up until the pioneering bioengineering work of stephanopoulos in 2010 , there was no access to large quantities of the less - oxidised taxane members such as taxadiene ( 7 ) . although not necessarily as a means of supplanting its current ton - scale production , a reexamination of taxol ( 1 ) over 15 years after its first total syntheses could be of academic and medicinal merit . in this article , we present the first scalable synthetic entry to the taxane family , setting the stage for rapid access to minimally oxidised taxane analogs and a scalable laboratory preparation of taxol ( 1 ) itself . inspired by nature s efficiency in creating vast numbers of complex terpene natural products , a research program was initiated in 2007 to mimic the essence of the two - phase biosynthesis of terpenes . in the first biogenetic phase ( the cyclase phase ) , linear hydrocarbon building blocks are brought together and cyclised efficiently , and in the second phase ( the oxidase phase ) , c = c and c the taxanes represent a large family of terpenes comprising over 350 natural products , for which this two - phase terpene synthesis strategy , if realised in a laboratory setting , could target not only taxol ( 1 ) but also related taxanes that differ in oxidation levels ( figure 1 ) . as such the goal is to divergently access all pre - taxol compounds ( both natural and unnatural ) and to unveil new insights to chemical reactivity during an oxidative ascent of the taxane pyramid . this article outlines the completion of our artificial cyclase phase for the taxane terpene family , as a prelude to a total synthesis of taxol ( 1 ) . thus , the logic ( including strategic and tactical concerns ) and execution of a concise and scalable synthesis of minimally oxidised taxanes , including nature s putative cyclase phase endpoint , taxadiene ( 7 ) , are reported . structurally , taxol ( 1 ) is a highly oxygenated diterpene adorned with acetyl and benzoyl groups , as well as a signature taxol side chain at the c13 oxygen atom ( see carbon numbering on 1 , figure 1a ) . for retrosynthetic discussion purposes , 1 is treated as if it were devoid of acyl groups , and this target is substituted with oxygenated hydrocarbon 2 . placing 2 at the apex of an oxidase phase pyramid , the number of c o bonds decreases as one moves down the pyramid , with taxanes 3 , 4 and 5 corresponding to the oxidation pattern of 2-acetoxybrevifoliol , taxinines e and j , and yunnanxane , respectively ( figure 1b ) . these highly oxidised taxanes all feature a c2-hydroxyl group and can be further simplified to taxa-4(5),11(12)-dien-2-one ( 6 ) , dubbed taxadienone , which represents a benchmark intermediate for a comprehensive access to the taxane family . furthermore , if taxadiene ( 7 ) were to be desired , one could simply deoxygenate 6 to generate the least oxidised natural product in the taxane family ( figure 1c ) . a full scholarly analysis of the taxane pyramid has been previously described , along with the merits in choosing a c2-oxidised taxane such as 6 . strategic disconnections of 6 were built upon the landmark syntheses of 1 and the many studies geared toward the taxane framework . out of the many possible disconnections of the 6 - 8 - 6 tricyclic backbone , one was chosen such that : 1 ) the forward synthesis would be short , convergent , and scalable ; and 2 ) its asymmetric synthesis would only rely on one enantioselective reaction , after which the resulting stereochemical information could be propagated to set all other stereocentres diastereoselectively . a vicinal difunctionalisation / diels alder strategy to forge the taxane ab ring system ( see ring numbering in 2 , figure 1 ) seemed to adhere most to the above criteria . the diels alder strategy was previously utilised in the context of taxane synthesis by shea , jenkins , williams and others , and in fact , williams has reported the only total synthesis of ( )-taxadiene ( 7 ) , in 26 steps , back in 1995 . furthermore , the decision to implement a vicinal difunctionalisation strategy was underpinned by recent developments in the asymmetric formation of all - carbon quaternary centres . thus , a concise , enantioselective strategy was conceived , allowing for a gram - scale access to 6 in only seven steps , as well as a gram - scale synthesis of ( + ) -taxadiene ( 7 ) . in the forward direction , known compounds 10 ( made from 8 in a modified one - pot procedure ; see supplementary information ) and 11 ( made from 9 using a known one - step procedure ) were combined to generate enone 12 by means of a lewis acid - modified organocopper 1,6-addition ( figure 2 ) . this convergent synthesis of 12 is operationally simple and provides decagram quantities per reaction batch ( 86% ; over 50 grams of this material has been synthesised to date ) . this enone was deemed to be a suitable substrate for alexakis enantioselective conjugate addition to establish the quaternary centre ( c8 ) . however , this strategy was contingent upon the feasibility of trapping the resulting aluminum enolate by tmscl . although alexakis noted that isolation of such silyl enol ethers is difficult due to facile desilylation , a modified quenching procedure involving dilution with thf , addition of tmscl , followed by addition onto florisil in 1:10 et3n / hexanes , allowed the isolation of tms enol ether 14 in 89% yield and in 93% ee ( 1.0 g scale ; enantioselectivity was measured for desilylated ketone 15 on chiral hplc ; see supplementary information ) . only 2 mol% of cutc and 4 mol% of chiral phosphoramidite ligand 13 were required , and this asymmetric reaction was routinely conducted on gram scale ( over 20 grams of this material has been synthesised to date ) . tms enol ether 14 was indeed quite prone to desilylation , and formation of undesired ketone 15 was often the sole reaction pathway when attempting mukaiyama aldol reactions with commonly used lewis acids ( such as ticl4 , sncl4 , sn(otf)2 , sc(otf)3 , bf3oet2 , tmsotf , zncl2 , or mgbr2oet2 ) or other catalysts ( such as liclo4 , zr(obu)4 , bi(otf)3 , agotf , or sicl4 ) , even when performed under strictly anhydrous conditions . surprisingly , water was found to be the enabling additive that allowed for an aldol reaction with acrolein . gratifyingly , kobayashi conditions with gd(otf)3 in 1:10:4 h2o / etoh / phme generated the corresponding aldol product smoothly as a 2:1 mixture of diastereomers that are isomeric at c3 . this aldol product was then oxidised in the same reaction pot with jones reagent to generate keto - enone 16 in 85% over two steps ( 3.2 g scale , 2:1 ratio of diastereomers at c3 ; this inseparable mixture of stereoisomers was carried onward for the ensuing step ) . a diels alder reaction to generate the 6 - 8 - 6 tricyclic skeleton has been previously demonstrated on similar systems , and the mixture 16 reacted predictably with bf3oet2 to furnish tricyclic compound 17 ( 2.3 g scale ) . the desired diketone 17 was obtained in 47% yield , along with its diastereomer ( see supplementary information ) in 29% yield , with complete diastereoselectivity at c1 . these cyclised diketones displayed very different polarities and were thus easily separated by silica gel chromatography at this stage . only one more carbon remained to be installed to complete the taxane framework : this was achieved via enol triflate formation followed by negishi coupling to generate taxadienone ( 6 ) in 84% over two steps ( 2.4 g scale ) . this material solidified quite readily , and a single - crystal x - ray analysis confirmed both the absolute and relative stereochemistry of the synthesised abc ring system . this lowly oxidised core is the key intermediate for our future research efforts to elaborate the taxane pyramid . in summary , the total synthesis of ( + ) -taxadienone ( 6 ) was achieved in a total of 8 steps , with a longest linear sequence of 7 steps . a few grams of taxadienone ( 6 ) could be synthesised by one chemist over the course of 7 days , with an overall yield of 18% from 8 or 20% from 9 . with the key taxane 6 secured in gram quantities , taxadiene ( 7 ) was then targeted , primarily as a means of spectroscopic comparison to previously reported data , but also to demonstrate the feasibility of a large - scale laboratory production of enantioenriched 7 . furthermore , taxadiene ( 7 ) is produced in negligible amounts in nature ( less than 1 mg can be obtained from 750 kg of tree bark from t. brevifolia ) and therefore its optical rotation has never been recorded . to this end , a three - step deoxygenation sequence was performed in 52% yield overall on gram - scale , to generate ( + ) -7 , which was spectroscopically indistinguishable from that of natural 7 , previously synthesised ( )-7 , and bioengineered ( + ) -7 . the optical rotation of [ ] ( chcl3 ) = + 165 ( c = 1.0 ) is reported herein for the first time and is comparable to that obtained for a bioengineered sample of ( + ) -7 ( see supplementary information ) . in retrospect , the forward synthesis of ( + ) -taxadienone ( 6 ) appears to be rather simple and perhaps intuitive , however , in practice , this optimised approach required many rounds of strategic and tactical revision . strategically , the retrosynthesis designed in figure 1c was one of many that were considered at the outset . a small snapshot of the many evaluated blueprints is illustrated in figure 4 . for example , the known difficulties in forming the 6 - 8 - 6 tricyclic framework of taxanes led us to first consider a ring - closing metathesis strategy to close the central 8-membered ring ( disconnection a ) . however , the realisation that the required substrate 18 would take many steps to build , and the fact that the stereocentres at c1 and c8 would have to be formed with two separate enantioselective reactions , dissuaded us from pursuing this route . an aldol route was then conceived , partly due to the facile formation of 19 via ketone 15 ( disconnection b ) . although installation of the stereocentres at c1 and c8 might still require two independent enantioselective transformations , the hope was that the reaction conditions used for the aldol cyclisation would concomitantly epimerise the c1 stereocentre into the desired configuration however , despite a plethora of attempted experiments , the desired cyclisation from 19 did not proceed . thereafter , strategies involving closure of the ab ring by a diels alder reaction were envisioned . one attempt involved the formation of ketone 20 by a sequence involving a coupling of the enolate of 2,6-dimethylcyclohexanone and a primary alkyl bromide , a shapiro reaction onto acrolein , oxidation , and diels alder ( disconnection c ) , much akin to the transformation from 14 to 17 ( figure 2 ) . however , ketone 20 already required many steps to construct , and the stereocentre at c8 was challenging to control , despite existing methods in asymmetric enolate alkylation . lastly , enones 21 were considered as viable intermediates toward the formation of 6 ( disconnection d ) , due to our initial difficulties in forging the c2c3 bond by mukaiyama aldol reaction ( vide supra ) . although enones 21 were formed in short order and already contained all but one carbon of the taxane framework , they did not undergo [ 4 + 2 ] cyclisation , likely due to the rigidity of the sp carbons at c3 and c8 . furthermore , a methyl 1,4-addition at c8 was not possible , since reaction first occurred at the less hindered c14 , even when a large tert - butyldiphenylsilyl group was appended at c14 . after many more strategic revisions and the success in forming the required c2c3 bond from tms enol ether 14 using gd(otf)3 , the final synthetic strategy depicted in figure 2 was realised . tactically , although quite efficient at present , most steps shown in figure 2 were initially difficult to scale and suffered from low and inconsistent yields . even the first transformation from 8 to 10 ( figure 2 ) was not trivial , despite it being a known two - step transformation . modifying the reaction stoichiometry and reaction times was necessary to coax this process into giving good yields consistently on a decagram - scale , with eventual success as a one - pot operation . the second transformation , a merging of the two similar - sized fragments 10 and 11 , can be conducted in good yields ( 86% ) on a decagram - scale , but initially , this reaction was plagued with inconsistent yields due to side product formation : the original reaction conditions of tert - butyllithium , bf3oet2 and cui resulted in 1,6-addition of tert - butyllithium ( whereas sec - butyllithium is not a very competent nucleophile for this reaction ) , iodination of 12 ( whereas the use of cubrsme2 circumvents this problem ) , and deconjugation of 12 to give a ,-substituted ketone ( this problem was rectified by optimising the work - up procedure ; see supplementary information ) . the third , asymmetry - inducing step from 12 to 14 was straightforward when run on a small scale ( < 100 mg ) and delivered high enantioselectivity with 0.5 mol% cutc and 1 mol% ligand loading . however , upon increasing the reaction scale to gram - scale , the reaction conversion suffered significantly . eventually , a higher catalyst loading ( 2 mol% cutc and 4 mol% ligand ) and precise temperature control allowed this reaction to give reliable yields and consistent enantioselectivity on gram - scale . also worth mentioning is a modified quenching procedure that was developed to address the troublesome tms trapping of the aluminum enolate ( videsupra ) . the fourth and the most difficult reaction was the aldol reaction of 14 and acrolein , which only returned desilylated ketone 15 under most reaction conditions . a variety of lewis acid - mediated reactions ( vide supra ) , as well as anionic silicon - metal exchange reactions , never led to the desired product . this aldol reaction only proceeded when lanthanide triflates such as yb(otf)3 or gd(otf)3 and very specific solvent systems were used . the final challenge was a scalable diels alder reaction from 16 to 17 , which has been known to proceed in moderate yields on similar substrates . although efficient on a small scale , the yield decreased when the reaction was conducted on gram - scale , possibly due to formation of oligomers and polymers . 0.01 m ) and through slow addition of substrate 16 to the lewis acid solution ( see supplementary information ) . developing a scalable route to the taxane core involved the study and modification of fundamental aspects of the described chemistry , rather than a mere exercise in scale - up . the conciseness of the synthetic route is a direct result of trying to achieve a scalable synthesis , and the reliability of the yields attests to the small variability of reactions ran on a larger scale . despite the efficiency of the described approach , there are two obvious limitations in the synthesis of taxadienone ( 6 ) : 1 ) the single functional group manipulation from cyclised diketone 17 to the corresponding enol triflate ( rendering the route 85% rather than 100% ideal ) ; and 2 ) the 2:1 diastereoselectivity in the aldol reaction of 14 and acrolein . these issues are currently being addressed by : 1 ) developing a scalable , one - step enol triflation / methyl coupling reaction ; and 2 ) generating creative acrolein equivalents and/or reaction conditions with various additives to increase to diastereoselectivity of the aldol step . in summary , a scalable , enantioselective entry to the taxane family of natural products was achieved in only seven steps from commercially available starting material ( 1820% overall yield ) . this triply convergent approach to taxa-4(5),11(12)-dien-2-one ( 6 ) allowed for a minimisation of concession steps , wherein six out of seven steps formed skeletal ( c c ) bonds . every one of these steps was performed on a gram - scale , attesting to the scalability and robustness of the sequence . furthermore , ( + ) -taxadiene ( 7 ) was synthesised , enabling further structural confirmation , as well as the first optical rotation determination of this natural product . the simple chemical route to ( + ) -7 nicely complements the recent pioneering studies of stephanopoulos and co - workers , whose bioengineering strategy also delivers gram - scale quantities of ( + ) -7 , albeit as a 9:1 mixture of olefin isomers ( taxa-4(5),11(12)-diene ( 7 ) and taxa-4(20),11(12)-diene ) ( see supplementary information ) . studies are currently underway to utilise the existing functional group handles in 6 to oxidise various sites on the taxane skeleton , in order to create a pyramid - like library of unnatural and natural taxanes en route to taxol ( 1 ) .

taxanes are a large family of terpenes comprising over 350 members , the most famous of which is taxol ( paclitaxel ) a billion - dollar anticancer drug . here , we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of ( + ) -taxa-4(5),11(12)-dien-2-one , which possesses a suitable functional handle to access more oxidised members of its family . this route enabled a gram - scale preparation of the parent taxane , taxadiene , representing the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form . the taxane family s characteristic 6 - 8 - 6 tricyclic system containing a bridgehead alkene is forged via a vicinal difunctionalisation / diels alder strategy . asymmetry is introduced by means of an enantioselective conjugate addition that forms an all - carbon quaternary centre , from which all other stereocentres are fixed via substrate control . this study lays a critical foundation for a planned access to minimally oxidised taxane analogs and a scalable laboratory preparation of taxol itself .

the earth orientation is generally considered as ( i ) earth rotation axis movements in space ( precession - nutation ) , ( ii ) earth rotation axis movements in the earth ( polar motion ) , or ( iii ) earth rotation speed variations ( exces in the length of the day ) . these movements come from earth inside masses distributions . the earth gravity field can give us information about this distribution of masses because nowadays we can determine the variations of the earth gravity field by space geodetic techniques . hence , there is a link between the variations of the earth gravity field and the variations of the earth orientation parameters . and the high accuracy now reached in the vlbi ( very long baseline interferometry ) earth orientation parameters ( eop ) determination requires looking further at the various geophysical contributions to variations in eop . so we investigate here if this variable gravity field can be valuable for the improving the modelisation of the earth rotation . the fundamental equations for the rotation of the earth in an inertial frame are euler s dynamical equations , based on the conservation of the angular momentum @xmath0 of the earth under an external torque @xmath1 ( lambeck 1980 ) : @xmath2 for a non - rigid earth , these equations in a rotating frame become : @xmath3 + \vec \omega \wedge \left [ i(t)~\vec \omega + \vec h(t)\right ] = \vec l\ ] ] where the inertia tensor @xmath4 is time dependent , as well as the relative angular momentum @xmath5 , and @xmath6 is the earth instantaneous rotation vector which direction is the one of the rotation axis and which norm is the rotation speed . it depends on the earth orientation parameters ( eop ) . the inertia tensor , which is symetric , can be written as : @xmath7 = \left [ \begin{array}{ccc } a+c_{11 } & c_{12 } & c_{13 } \\ c_{12 } & b+c_{22 } & c_{23 } \\ c_{13 } & c_{23 } & c+c_{33 } \end{array } \right]\ ] ] with @xmath8 the constant part and @xmath9 ( @xmath10 ) the variable part of the inertia tensor . the earth gravity field of the earth devived from the external gravitational potential @xmath11 which is expressed in a spherical harmonic expansion as ( lambeck 1980 ) : @xmath12\ ] ] where @xmath13 is the geocentric distance , @xmath14 the latitude and @xmath15 the longitude of the point at which @xmath11 is detremined . @xmath16 is the gravitational constant , @xmath17 and @xmath18 are the mass and the equatorial radius of the earth , respectively . @xmath19 and @xmath20 are the stokes coefficients of degree @xmath21 and order @xmath22 , and @xmath23 are the legendre polynomials . hence the second - degree stokes coefficients can be directely related to the inertia tensor components ( lambeck , 1988 ) : @xmath24 we just have shown that the earth rotation ( with @xmath6 and the eop ) could be related to the earth gravity field ( with the degree 2 stokes coefficients ) . then , we investigate now how we can link each eop with these coefficients . the exces in the length of the day @xmath25 ( with respect to a mean lod ) can be related to ( i ) the third component @xmath26 of the variable part of the inertia tensor and ( ii ) the third component @xmath27 of the relative angular momentum of the earth , ignoring the external torques : @xmath28 moreover , with the help of eq . ( [ eq : coeffs_c_inertie ] ) , we can write : @xmath29 where @xmath30 is the variation in time of the sum of the diagonal elements of the inertia tensor . we can consider that it is equal to zero ( rochester & smylie 1974 ) . then , we can obtain : @xmath31 where the coefficient @xmath32 accounts for the loading effects and @xmath33 is the third moment of inertia of the earth s mantle ( barnes et al . then we have compared the @xmath25 obtained with eq . ( [ eq : lod_fin ] ) and the @xmath34 data in fig . [ fig : bourda_fig2 ] with the one usually used but corrected from zonal tides , atmopheric wind effects ( @xmath27 ) and long terms ( see fig . [ fig : bourda_fig1 ] ) . the study of the earth precession nutation angles variations influenced by the temporal variations of the @xmath35 coefficients of the geopotential is developped in the article of bourda & capitaine ( 2004 ) . it is based on the works of williams ( 1994 ) and capitaine et al . ( 2003 ) which considered secular terms for the @xmath35 variations , whereas we consider also annual and semi - annual ones . the polar motion @xmath36 , where @xmath37 and @xmath38 are the components of the rotation axis in space can be theoretically related to the degree 2 and order 1 coefficients of the earth gravity field : @xmath39 where @xmath40 is related to @xmath41 and @xmath42 with eq . ( [ eq : coeffs_c_inertie ] ) , and @xmath43 . the part of the length of the day obtained with the @xmath34 data corresponds to gravitational terms . then we have compared @xmath25 corrected from the movements terms ( as atmospheric ones ) , the zonal tides and the decadal terms ( from magnetic effects in the core - mantle boundary ) . but the residual term has an amplitude of the order of @xmath44 @xmath45s , whereas the better precision on these lod data is of the order of @xmath46 @xmath45s . barnes , r. t. h. , hide , r. , white , a. a. , & wilson , c. a. 1983 , proc . lond . , a 387 , 31 bourda , g. , & capitaine , n. 2004 , a&a , in press capitaine , n. , wallace , p. t. , & chapront , j. 2003 , a & a , 412 , 567 lambeck , k. 1980 , the earth s variable rotation ( cambridge : cambridge univ . press ) lambeck , k. 1988 , geophysical geodesy : the slow deformations of the earth ( oxford : oxford science publications ) rochester , m. g. , & smylie , d. e. 1974 , j. geophys . res . , 79 , 4948 williams , j. g. 1994 , astron . j. , 108(2 ) , 711

the determination of the earth gravity field from space geodetic techniques now allows us to obtain the temporal variations of the low degree coefficients of the geopotential , combining the orbitography of several satellites ( e.g. lageos1 , lageos2 , starlette ) . these temporal variations of the earth gravity field can be related to the earth orientation parameters ( eop ) through the inertia tensor . this paper shows these relations and discusses how such geodetic data can contribute to the understanding of the variations in eop .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Improving Opportunities for Service- Disabled Veteran-Owned Small Businesses Act of 2014''. SEC. 2. SMALL BUSINESS DEFINITION OF SMALL BUSINESS CONCERN CONSOLIDATED. Section 3(q) of the Small Business Act (15 U.S.C. 632(q)) is amended-- (1) by amending paragraph (2) to read as follows: ``(2) Small business concern owned and controlled by service-disabled veterans.--The term `small business concern owned and controlled by service-disabled veterans' means a small business concern-- ``(A)(i) not less than 51 percent of which is owned by one or more service-disabled veterans or, in the case of any publicly owned business, not less than 51 percent of the stock of which is owned by one or more service-disabled veterans; and ``(ii) the management and daily business operations of which are controlled by one or more service-disabled veterans or, in the case of a veteran with permanent and severe disability, the spouse or permanent caregiver of such veteran; or ``(B) not less than 51 percent of which is owned by one or more veterans with service-connected disabilities that are permanent and total who are unable to manage the daily business operations of such concern or, in the case of a publicly owned business, not less than 51 percent of the stock of which is owned by one or more such veterans.''; and (2) by adding at the end the following: ``(6) Treatment of businesses after death of veteran- owner.-- ``(A) In general.--If the death of a service- disabled veteran causes a small business concern to be less than 51 percent owned by one or more such veterans, the surviving spouse of such veteran who acquires ownership rights in such small business concern shall, for the period described in subparagraph (B), be treated as if the surviving spouse were that veteran for the purpose of maintaining the status of the small business concern as a small business concern owned and controlled by service-disabled veterans. ``(B) Period described.--The period referred to in subparagraph (A) is the period beginning on the date on which the service-disabled veteran dies and ending on the earliest of the following dates: ``(i) The date on which the surviving spouse remarries. ``(ii) The date on which the surviving spouse relinquishes an ownership interest in the small business concern. ``(iii) The date that-- ``(I) in the case of a surviving spouse of a veteran with a service- connected disability rated as 100 percent disabling or who dies as a result of a service-connected disability, is 10 years after the date of the veteran's death; or ``(II) in the case of a surviving spouse of a veteran with a service- connected disability rated as less than 100 percent disabling who does not die as a result of a service-connected disability, is three years after the date of the veteran's death.''. SEC. 3. VETERANS AFFAIRS DEFINITION OF SMALL BUSINESS CONCERN CONSOLIDATED. Section 8127 of title 38, United States Code, is amended-- (1) by striking subsection (h); and (2) in subsection (l)(2), by striking ``means'' and all that follows through the period at the end and inserting the following: ``has the meaning given that term under section 3(q) of the Small Business Act (15 U.S.C. 632(q)).''. SEC. 4. GAO REPORT ON VERIFICATION OF STATUS. Not later than 270 days after the date of enactment of this Act, the Comptroller General of the United States shall submit to the Committee on Veterans' Affairs and the Committee on Small Business and Entrepreneurship of the Senate and the Committee on Veterans' Affairs and the Committee on Small Business of the House of Representatives a report-- (1) evaluating whether it is practicable for the Administrator of the Small Business Administration or the Secretary of Veterans Affairs to have Government-wide responsibility for verifying whether a business concern purporting to be a small business concern owned and controlled by service-disabled veterans (as defined under section 3(q) of the Small Business Act (15 U.S.C. 632(q)), as amended by this Act) qualifies as a small business concern owned and controlled by service-disabled veterans; and (2) making recommendations on the advisability of the Administrator of the Small Business Administration or the Secretary of Veterans Affairs having such Government-wide responsibility.

Improving Opportunities for Service-Disabled Veteran-Owned Small Businesses Act of 2014 - Amends the Small Business Act to expand the definition of "small business concern owned and controlled by service-disabled veterans" for purposes of federal agencies awarding&nbsp;small business contracts pursuant to Small Business Administration (SBA) programs to&nbsp;include: (1) a small business concern not less than 51% of which is owned by one or more veterans with service-connected disabilities that are permanent and total who are unable to manage the daily business operations of such concern; or (2) in the case of a publicly owned business, a small business concern not less than 51% of the stock of which is owned by one or more such veterans. (Currently, such veterans with permanent and total disabilities are provided for in a separate small business program under veterans' benefits laws&nbsp;carried out by the&nbsp;Department of Veterans Affairs [VA].) Revises the VA definition of "small business concern owned and controlled by veterans" to be the same as the SBA definition of such term, thereby making the eligibility requirements for participation in veteran-owned small business contracting programs consistent for both SBA programs and VA programs. Provides that if the death of a service-disabled veteran causes a small business concern to be less than 51% owned by one or more such veterans, the surviving spouse of such veteran who acquires ownership rights in such small business concern shall be treated as if the surviving spouse were that veteran for the purpose of maintaining the business's eligibility for such contracting programs&nbsp;until the earliest of the following dates: (1) the date on which the surviving spouse either remarries or relinquishes the ownership interest, (2) 10 years after the veteran's death in the case of a surviving spouse of a veteran with a service-connected disability rated as 100% disabling or who dies as a result of a service-connected disability, or (3) 3 years after the veteran's death in the case of a surviving spouse of a veteran with a service-connected disability rated as less than 100% disabling who does not die as a result of a service-connected disability. (Currently, the SBA program does not provide such treatment&nbsp;for surviving spouses while the VA program provides such treatment only until remarriage, ownership relinquishment, or for 10 years&nbsp;with respect to&nbsp;surviving spouses of veterans with a 100% disabling service-connected disability or who die as a result of a service-connected disability.) Requires&nbsp;a Comptroller General (GAO) report on the advisability of the SBA or the VA having government-wide responsibility for verifying businesses purporting to be small business concerns owned and controlled by service-disabled veterans.

BEIJING — China is investigating four possible cases of human-to-human transmission of a deadly bird flu that has killed 17 people, but so far there has been “no sustained” evidence of transmission between people, the World Health Organization said Thursday. Three families in Shanghai and two young children in Beijing were being examined as possible examples of human-to-human transmission, Gregory Hartl, the spokesman for W.H.O. in Geneva, said in a telephone interview. “Even if two family members are positive, it is not necessarily the case they got it from each other,” Mr. Hartl said. “They may have gotten it from the same bird.” As investigators looked at the possibility of human-to-human transmission, there was mounting concern that the new virus, known as H7N9, may not originate in poultry but in other animals, he said. To that end, a team of international influenza experts from the agency’s headquarters in Geneva and a regional office in Manila, as well as scientists from the United States Centers for Disease Control and Prevention who were invited by China to help investigate the virus, arrived in Beijing on Thursday. The experts would be looking at possible sources for the virus other than birds, Mr. Hartl said. A Chinese expert on the disease, Feng Zijian, the director of the health emergency center at the Chinese Center for Disease Control and Prevention, said Wednesday that an estimated 40 percent of people infected with the virus said they never had contact with poultry. Mr. Hartl concurred with Mr. Feng about that statistic. “It is not clear all cases so far have had contact with poultry,” Mr. Hartl said. Because it seemed possible that the virus originated in animals other than poultry, the international investigating team would be casting a wide net for possible sources, Mr. Hartl said. Seventeen people have died since China told the W.H.O. in March of the bird flu outbreak, according to China’s state-run news agency, Xinhua. There were 83 cases of infection, the news agency said. Even as the international investigators would be seeking other sources of infection, China’s agricultural authorities were insisting the H7N9 virus was still confined to live poultry markets. The news agency said that 47,801 samples had been collected from 1,000 poultry markets, habitats and farms from across China, and that agricultural authorities said that 39 tested positive for H7N9. Mr. Hartl noted that the percentage of positives was very low. Early suspicions that pigs might be the carrier of the virus have not been confirmed, Mr. Hartl said. Pigs were tested soon after the outbreak was announced, he said, and there were no positive results. The Chinese authorities had informed the W.H.O. about three families in Shanghai where more than one person was infected with the virus, Mr. Hartl said. In two, two people were infected, he said, and in the other, three were infected. In that case, an 87-year-old man and his 55-year-old son died, and his other son, 69, was sick, Mr. Hartl said. The two children infected in Beijing, a boy and a girl, were neighbors and often played together, Mr. Hartl said. It is possible, he said, that they may have picked up the virus from the same infected bird. In a news conference on Wednesday, Mr. Feng played down the possibility of “effective” human-to-human transmission. “Effective human-to-human transmission is the case when a disease becomes a human flu virus, as seen in the case of H1N1, where groups of people would be infected at once, such as in schools and communities,” Mr. Feng said. “Effective human-to-human transmission means one patient could infect many and the virus continues to pass on to first, second and third patients. Effective human-to-human transmission has a clear chain of infection.” The H1N1 virus was a new flu virus strain that caused a worldwide pandemic in humans from June 2009 to August 2010. There was “currently no evidence showing that H7N9 carries continuous infecting power,” Mr. Feng said. Mia Li contributed research. ||||| Chickens are seen at a poultry farm on the outskirts of Shanghai April 16, 2013. Dead chickens are seen at a poultry farm on the outskirts of Shanghai April 16, 2013. Chickens are seen at a poultry farm on the outskirts of Shanghai April 16, 2013. An employee works at a poultry farm on the outskirts of Shanghai April 16, 2013. GENEVA/BEIJING (Reuters) - The World Health Organization said on Wednesday that a number of people who have tested positive for a new strain of bird flu in China appear to have had no contact with poultry, adding to the mystery about a virus that has killed 17 people to date. Chinese authorities have slaughtered thousands of birds and closed some live poultry markets to try to slow the rate of human infection, but many questions remain unsolved, including whether the H7N9 strain is being transmitted between people. WHO spokesman Gregory Hartl confirmed that "there are people who have no history of contact with poultry", after a top Chinese scientist was quoted as saying this applied to about 40 percent of those infected. "This is one of the puzzles still (to) be solved and therefore argues for a wide investigation net," Hartl said in emailed comments. Hartl an international team of experts going to China soon would include in their investigation the possibility that the virus can be spread between people, although there was "no evidence of sustained human-to-human transmission". "It might be because of dust at the wet markets, it could be another animal source beside poultry, it could also be human-to-human transmission," he said by telephone. Wendy Barclay, an influenza expert at Imperial College London, said it could be hard to reveal or rule out exposure to poultry - or to wild birds, which could also be a possible source of infection: "The incubation time might be quite long, so visiting a market even 14 days before might have resulted in infection." Hartl said two new suspected cases of possible human-to-human transmission were being investigated. The first is a couple in Shanghai who tested positive, Hartl said, adding that the wife had died and husband was still sick. A seven-year-old girl in Beijing was the first case in the capital at the weekend and the boy next door has also tested positive, but is not showing symptoms, he said. NUMBERS TO RISE The WHO had previously reported two suspected family "clusters", but the first turned out to be a false alarm and the second was inconclusive. China has warned that the number of infections, 82 so far, could rise. Most of the cases and 11 of the deaths have been in the commercial capital Shanghai. China reported three new outbreaks to the World Animal Health Organization (OIE) this week, bringing the total number of locations to 11, the OIE said. Poultry markets remain the focus of investigation by China and the U.N.'s Food and Agriculture Organization. But Zeng Guang, chief scientist in charge of epidemiology at the China Disease Prevention and Control Centre (CDPCC), said about 40 percent of human victims had no clear history of poultry exposure, the Beijing News reported. The centre declined to comment on state media reports saying only 10 of the 77 cases known by Tuesday had had contact with poultry. A study published last week showed the H7N9 strain was a so-called "triple reassortant" virus with a mixture of genes from three other flu strains found in birds in Asia. One of those three strains is thought to have come from a brambling, a type of small wild bird. "We can't rule out that this ... has passed through poultry but then been reintroduced to a wild bird population from which some spread to humans might be occurring," Barclay said. China's poultry sector has recorded losses of more than $1.6 billion since reports of the strain emerged two weeks ago. (Reporting by Stephanie Nebehay in Geneva, Sui-Lee Wee, Michael Martina and Huang Yan in Beijing, Kate Kelland in London and Sybille de La Hamaide in Paris; Editing by Jon Hemming)

– H7N9 is growing no less mysterious: Roughly 40% of those infected in China's bird flu outbreak have never actually come in contact with poultry, according to a leading Chinese scientist, and the World Health Organization yesterday backed up that claim. WHO spokesman Gregory Hartl acknowledged "there are people who have no history of contact with poultry. ... This is one of the puzzles still (to) be solved," he tells Reuters. "It might be because of dust at the wet markets, it could be another animal source besides poultry, it could also be human-to-human transmission," though he added that there was still "no sustained evidence" of the latter. Officials are keeping a watchful eye on three Shanghai families and two boys in Beijing that they suspect may have infected each other, Hartl tells the New York Times, but he cautioned that even if members of the same family tested positive, it wouldn't be conclusive. The Times reports there's also growing concern that the virus may not have originated in birds, but in another animal. But China maintains that live poultry markets are the source; it's collected 47,801 samples from 1,000 such markets and farms to prove it. But only 39 tested positive, a number that Hartl notes is low.

New Orleans Saints running back Reggie Bush isn't waiting on the Heisman Trophy Trust to rule on whether it will take back the award he won in 2005 as a member of the USC football team. In a statement released by the Saints on Tuesday afternoon, Bush said he plans on giving back the Heisman Trophy. Here is his statement: "One of the greatest honors of my life was winning the Heisman Trophy in 2005. For me, it was a dream come true. But I know that the Heisman is not mine alone. Far from it. I know that my victory was made possible by the discipline and hard work of my teammates, the steady guidance of my coaches, the inspiration of the fans, and the unconditional love of my family and friends. And I know that any young man fortunate enough to win the Heisman enters into a family of sorts. Each individual carries the legacy of the award and each one is entrusted with its good name. It is for these reasons that I have made the difficult decision to forfeit my title as Heisman winner of 2005. The persistent media speculation regarding allegations dating back to my years at USC has been both painful and distracting. In no way should the storm around these allegations reflect in any way on the dignity of this award, nor on any other institutions or individuals. Nor should it distract from outstanding performances and hard-earned achievements either in the past, present or future. For the rest of my days, I will continue to strive to demonstrate through my actions and words that I was deserving of the confidence placed in me by the Heisman Trophy Trust. I would like to begin in this effort by turning a negative situation into a positive one by working with the Trustees to establish an educational program which will assist student-athletes and their families avoid some of the mistakes that I made. I am determined to view this event as an opportunity to help others and to advance the values and mission of the Heisman Trophy Trust. I will forever appreciate the honor bestowed upon me as a winner of the Heisman. While this decision is heart-breaking, I find solace in knowing that the award was made possible by the support and love of so many. Those are gifts that can never be taken away." ||||| FILE - In this Dec. 10, 2005, file photo, Southern California tailback back Reggie Bush pauses while giving his acceptance speech as the winner of the Heisman Trophy award in New York. Yahoo! sports is... (Associated Press) The New Orleans Saints' running back released a statement Tuesday saying he would give back the award that he won in 2005 while he was at Southern California. It's the first time college football's top award was returned by a recipient. "While this decision is heart-breaking, I find solace in knowing that the award was made possible by the support and love of so many," Bush said. "Those are gifts that can never be taken away." USC was hit with heavy sanctions by the NCAA this summer after it determined Bush had received improper benefits. The NCAA ruled that Bush was ineligible for the 2005 season, which opened the possibility that the Heisman Trophy Trust would take back the award. One of the few guidelines given to Heisman Trophy voters is that a player must be in compliance with NCAA rules to be eligible for the trophy. The eight-member Heisman Trophy Trust, based in New York, had said it would have to consider what to do about Bush, who won in a landslide vote over Texas quarterback Vince Young. There was no immediate word from the Heisman Trust if the award would be vacated or given to Young.

– Reggie Bush says he will give back his 2005 Heisman Trophy over allegations that he received improper benefits while playing for USC. "While this decision is heart-breaking, I find solace in knowing that the award was made possible by the support and love of so many," said the New Orleans Saints running back in a statement. "Those are gifts that can never be taken away." The Times-Picayune has the statement here. Bush becomes the first player to return the award, and he did so before Heisman officials decided whether to strip him of the honor. "The persistent media speculation regarding allegations dating back to my years at USC has been both painful and distracting," says Bush. "In no way should the storm around these allegations reflect in any way on the dignity of this award." Vince Young finished second in Heisman voting that year, notes AP, but there's no word on whether he will get it belatedly.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Fair Insurance Premiums for Disabled Veterans Act''. SEC. 2. REDUCTION IN SERVICE-DISABLED VETERANS INSURANCE PREMIUMS. (a) In General.--Section 1922(a) of title 38, United States Code, is amended-- (1) by inserting ``(1)'' after ``(a)''; and (2) by striking the fourth sentence and all that follows and inserting the following: ``(2) Insurance granted under this section shall be issued upon the same terms and conditions as are contained in the standard policies of National Service Life Insurance, except that-- ``(A) the premium rates for such insurance-- ``(i) for premiums for months beginning before the date of the enactment of the Fair Insurance Premiums for Disabled Veterans Act shall be based on the Commissioners 1941 Standard Ordinary Table of Mortality and interest at the rate of 2\1/4\ percent per year; and ``(ii) for premiums for months beginning on or after that date shall be based upon the 2001 Commissioners Standard Ordinary Table of Mortality and interest at the rate of 4.5 percent per year; ``(B) all cash, loan, paid-up, and extended values-- ``(i) for a policy issued under this section before the date of the enactment of the Fair Insurance Premiums for Disabled Veterans Act shall be based upon the Commissioners 1941 Standard Ordinary Table of Mortality and interest at the rate of 2\1/4\ percent per year; and ``(ii) for a policy issued under this section on or after that date shall be based upon the 2001 Commissioners Standard Ordinary Table of Mortality and interest at the rate of 4.5 percent per year; ``(C) all settlements on policies involving annuities shall be calculated on the basis of the Annuity Table for 1949, and interest at the rate of 2\1/4\ percent per year; ``(D) insurance granted under this section shall be on a nonparticipating basis; ``(E) all premiums and other collections for insurance under this section shall be credited directly to a revolving fund in the Treasury of the United States; and ``(F) any payments on such insurance shall be made directly from such fund. ``(3) Appropriations to the fund referred to in subparagraphs (E) and (F) of paragraph (2) are hereby authorized. ``(4) As to insurance issued under this section, waiver of premiums pursuant to section 602(n) of the National Service Life Insurance Act of 1940 and section 1912 of this title shall not be denied on the ground that the service-connected disability became total before the effective date of such insurance. ``(5) Administrative costs to the Government for the costs of the program of insurance under this section shall be paid from amounts credited to the fund under subparagraph (E) of paragraph (2), and payments for claims against the fund for amounts in excess of amounts credited to the fund under that subparagraph (after such administrative costs have been paid) shall be paid from appropriations to the fund.''. (b) Conforming Amendment.--Section 1982 of such title is amended by inserting ``1922(a)(5),'' after ``1920(c),''. SEC. 3. INCREASE IN MAXIMUM COVERAGE UNDER VETERANS' MORTGAGE LIFE INSURANCE PROGRAM TO $200,000. (a) Increase.--Subsection (b) of section 2106 of title 38, United States Code, is amended-- (1) by inserting ``(1)'' after ``(b)''; (2) by designating the second, third, and fourth sentences as paragraphs (2), (3), and (4), respectively; (3) in paragraph (1), as designated by paragraph (1) of this subsection, by striking ``may not exceed'' and all that follows through ``on the housing unit.'' and inserting ``shall be the amount of the loan outstanding on the housing unit, except that-- ``(A) coverage may not exceed $200,000; and ``(B) a veteran may elect, in writing, to be covered for less than the maximum coverage available.''; and (4) in paragraph (2), as designated by paragraph (2) of this subsection, by striking ``of such insurance'' and inserting ``of insurance provided a veteran under this section''. (b) Conforming Amendment.--Subsection (g) of such section is amended by striking ``of this section or'' and inserting ``or an election under that subsection or by''. (c) Effective Date.--The amendments made by subsection (a) shall take effect at the end of the 120-day period beginning on the date of the enactment of this Act.

Fair Insurance Premiums for Disabled Veterans Act - Amends Federal provisions concerning service-disabled veterans' life insurance to state that the premium rates for such insurance: (1) for months beginning before the date of enactment of this Act shall be based upon the Commissioners 1941 Standard Ordinary Table of Mortality and interest at the rate of 2 and one-fourth percent per year; and (2) for months beginning on or after the date of enactment of this Act shall be based upon the 2001 Commissioners Standard Ordinary Table of Mortality at a four and one-half percent interest rate. Makes the same changes with respect to all policy cash, loan, paid-up, and extended values. Increases from $90,000 to $200,000 the maximum amount of veterans' mortgage life insurance coverage.

ironically , the dramatic increase in the prevalence of type 2 diabetes can be attributed to the rapid economic development and correlated to changes in lifestyle within the last 50 years . up to 90% of the patients in the us with type 2 diabetes are either overweight or obese ( 2,3 ) . it seems likely that the readily available high calorie food and a sedentary life style are major causes for obesity . reducing obesity and stopping weight gain constitutes a way to slow down the rate of occurrence of type 2 diabetes . type 2 diabetes is caused by insulin resistance , which is defined as defective insulin signaling and a decreased insulin efficiency to induce glucose transport from the blood into key target cells such as muscle and fat ( adipocyte ) cells ( 3 ) . in general , obesity leads to hyperglycemia , which in turn leads to and exacerbates insulin resistance . insulin resistance , if not treated , results in hyperinsulinemia and eventually leads to full blown type 2 diabetes ( 3,4 ) . obesity or excessive adiposity , particularly visceral adiposity , contributes to and worsens insulin resistance ( 2,5 ) . . however , most of these drugs are , to different extents , weight gain promoting ( adipogenic ) ( 6,7 ) . thus , these drugs treat one of the key symptoms of type 2 diabetes , hyperglycemia , but exacerbate the condition of being overweight or obese , one of the leading causes of type 2 diabetes . therefore , while these drugs are beneficial over the short term , they are not optimal for long term health of type 2 diabetic patient . the most desirable situation would be the development of new types of antidiabetic drugs that are either hypoglycemic or anti - hyperglycemic without the side effect of promoting weight gain ( adiposity ) . herbal medicines known to be useful in diabetes treatment may be able to lead to compounds with such a combination of ideal therapeutic properties ( 813 ) . 1 ) , also called banaba in the tagalog language of the philippines , is a tropical plant found in many parts of southeast asia including the philippines , vietnam , malaysia and southern china . it is a tree that can grow as tall as 20 m. despite growing in several countries , only in the philippines are the dried and shredded banaba leaves known to be used as a treatment for diabetes and kidney disease . it is not clear if banaba plants grown in different countries are equally effective in the treatment of diabetes . garcia published the first research on banaba 's insulin - like , hypoglycemic effect as early as 1940 ( 1418 ) . later , the popular use of banaba in the philippines was noticed and led to its introduction in japan . however , it was not until 50 years after garcia 's first publication that scientific interest in banaba 's potential for the treatment of diabetes resurfaced . scientists from countries including japan , the philippines , korea and the united states are currently studying banaba . lagerstroemia speciosa ( banaba ) has become relatively popular in the form of health - promoting tea products in eastern asia and the united states . in 1996 , kakuda et al . ( 19 ) studied banaba 's antidiabetic activity by preparing water and methanol extracts of the plant . after feeding the extracts to hereditary type 2 diabetic kk - ay / ta jcl mice , they found that food containing either 5% of water extract ( be ) or 3% of methanol extract was effective in reducing blood glucose and insulin levels ( p < 0.05 ) ( 19 ) . it is interesting to note that the total cholesterol in treated mice was also significantly reduced , but the plasma triglyceride level remained unchanged ( 19 ) . in a second study by kakuda 's research group , food containing 5% banaba water extract was used to feed female obese kk - ay / ta jcl mice . obese mice treated with banaba extract had a significantly reduced body weight ( 10% ) compared with control mice fed with a regular diet ( 20 ) . interestingly , it was also discovered that liver triglyceride content was reduced by more than 40% in the banaba extract - treated mice . in addition , the parametrial adipose tissue was 10% lighter ( p < 0.01 ) ( 20 ) . however , as in the previous antidiabetic activity study of be in animals ( 19 ) , both the identity of the effective component(s ) and the mechanism for the activity were not studied . nevertheless , these two studies clearly demonstrated the in vivo antidiabetic and anti - weight gaining efficacy of the extract . in 1993 , a group of scientists from hiroshima university used an ehrlich ascites tumor cell line coupled with a bioassay guided fractionation to screen compounds isolated by hplc from banaba extract in order to identify the effective antidiabetic component ( 21 ) . corosolic acid ( 2-hydroxyursoloic acid ) was identified as the effective compound in the methanol extract of banaba leaves in a glucose uptake assay ( fig . however , this result should be considered with caution since the tumor cell line used in this study is a very unusual and unconventional cell line for diabetes studies or antidiabetic compound screening . furthermore , the result could not explain the discrepancy that both the banaba water extract and the methanol extract were active in antidiabetic and anti - obesity animal studies since corosolic acid only exists in the methanol extract ( 1921 ) . corosolic acid ( a ) is a triterpenoid ( 21 ) , not a tannin . corosolic acid ( a ) is a triterpenoid ( 21 ) , not a tannin . lagerstroemin ( b ) is an ellagitannin ( 22 ) . realizing the potential problems associated with the cell line selection and assay method , the researchers acknowledged in a later publication that corosolic acid could not represent the whole activity of the banaba extract ( 22 ) . consequently , the researchers switched their cell model from the original tumor cells to a natural cell target of insulin , adipocytes , in order to allow for the isolation and the identification of more active compounds using the improved methodology ( 22 ) . after hplc purification , ellagitannins were identified in the water extract of banaba as the activators of glucose transport in fat cells with a glucose uptake assay ( 22 ) . in a recent study , the same group reported the activation of the insulin receptor ( ir ) by lagerstroemin ( fig . 2 , 23 ) . in this study , lagerstroemin was able to induce phosphorylation of the -subunit of ir at 150 m ( 23 ) but the mechanism responsible for ir activation was not found . the researchers speculated that lagerstroemin could act intracellularly or bind to the insulin receptor ( ir ) extracellularly . in 2004 , a separate group of researchers from several universities found that glucose transporter 4 ( glut4 ) translocation from the intracellular microsomal membrane to the plasma membrane was significantly increased in the muscle cells of mice treated orally with corosolic acid ( p < 0.05 , 24 ) . glut4 is the major glucose transporter protein in both muscle and adipocytes and glut4 is insulin - responsive ( 4,25 ) . however , since corosolic acid does not possess insulin - like glucose transport stimulatory activity , the process that leads to glut4 translocation is not known . the glut4 membrane translocation mechanism initiated by corosolic acid as described ( 24 ) must be independent of the ir mediated signaling pathway since corosolic acid does not use this pathway for its activity . in 2006 , the same group of researchers found that corosolic acid significantly reduces blood glucose levels and plasma insulin levels in kk - ay diabetic mice ( 26 ) . additionally , this group of researchers published another article in 2006 in which they showed that corosolic acid significantly lowered blood glucose levels at the 90 min mark in an oral glucose tolerance test done on type 2 diabetic patients ( 27 ) . however , no statistical difference between the treated group and the control group was found for any other time point during the test ( 27 ) . our interest in the isolation and identification of antidiabetic compounds from natural sources initiated our investigation of banaba extracts with 3t3-l1 adipocytes as a cell model and a radioactive glucose uptake assay as a screening method for the identification of potential antidiabetic compounds . in our study , we confirmed that the water and methanol extracts of banaba leaves exhibit glucose transport stimulatory activity ( 28 ) . in addition , we showed that the activity induced by the extract had a concentration - activity profile similar to that of insulin , suggesting that the activity of banaba extract ( be ) might be triggered via an insulin - like mechanism ( 28 ) . furthermore , we demonstrated that the same be also inhibits adipocyte differentiation ( 28 ) . 3t3-l1 preadipocytes treated with methylisobutylxanthine , dexamethasone , and insulin ( mdi ) and be did not differentiate into adipocytes as they normally do under the sole influence of mdi . unlike the glucose transport stimulation , the anti - differentiation activity is anti - insulin like , since insulin plays an important role in adipocyte differentiation and is a component of mdi ( i in mdi stands for insulin ) . thus , be differs from insulin in that it is anti - adipogenic whereas insulin is adipogenic , which is considered to be a negative side effect of insulin . in order to identify the component(s ) in be responsible for the antidiabetic activity , our first goal was to confirm that corosolic acid was responsible for the glucose transport stimulatory activity . since tannins comprise up to 40% of the material in the extract , we were interested in separating it from corosolic acid first . to our surprise , after removing tannins by either gelatin or bovine serum albumin tannin precipitations ( 29 ) , the remaining extract was not able to induce glucose transport . we concluded that the glucose transport activity was caused by the tannin component of the extract , and not corosolic acid ( 29 ) . furthermore , we tested pure corosolic acid and found that it was not able to stimulate glucose transport in our cell model ( fig . although we can not exclude the possibility that corosolic acid may have some antidiabetic activity , we can eliminate corosolic acid from having the insulin - like glucose transport stimulatory activity found in adipocytes . it should be noted that banaba extracts prepared from banaba leaves from different sources may have different chemical compositions , which in turn may lead to different experimental results ( our lab used dried banaba leaves from the philippines ) . pure corosolic acid in aqueous solution was added to 3t3-l1 adipocytes grown in wells of 6-well cell culture plates to induce glucose transport by a commonly used procedure ( 28,29 ) . cells treated with either 1 m insulin or 30 m penta - galloyl - glucose ( pgg ) were used as positive controls . samples were in triplicate in the experiment , and the experiment was repeated three times . no difference was found by a one - way anova statistical analysis between the negative ( vehicle ) control and corosolic acid samples at any concentration . pure corosolic acid in aqueous solution was added to 3t3-l1 adipocytes grown in wells of 6-well cell culture plates to induce glucose transport by a commonly used procedure ( 28,29 ) . cells treated with either 1 m insulin or 30 m penta - galloyl - glucose ( pgg ) were used as positive controls . samples were in triplicate in the experiment , and the experiment was repeated three times . no difference was found by a one - way anova statistical analysis between the negative ( vehicle ) control and corosolic acid samples at any concentration . after testing corosolic acid , we also tested the corosolic acid - based banaba extract product glucosol ( 30 ) . 4 ) . however , since corosolic acid itself does not have any insulin receptor mediated glucose transport activity , the effect of glucosol is likely to originate from other chemical compounds in the banaba extract and not from corosolic acid . figure 4.glucose transport stimulatory activity of glucosol as compared with banana extract . the result of the assays was analyzed with a one - way anova . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 . the result of the assays was analyzed with a one - way anova . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 . our search for the active components in the tannin fraction of be was made much easier after we discovered that commercially available tannic acid ( ta ) shows similar glucose transport stimulatory activity to be ( 29 ) . the main components of ta are gallotannins , a subclass of the tannins usually consisting of a glucose core connected to a variable number of galloyl groups via ester bonds ( fig . figure 5.chemical structures of gallotannins ( tannic acid , a ) and pgg ( b ) . chemical structures of gallotannins ( tannic acid , a ) and pgg ( b ) . ta is known to exhibit various health - beneficial activities ( 3336 ) . as a constituent of red wine , it has been shown to effectively reduce blood glucose levels in type 2 diabetes patients ( 37 ) and the production of endothelin-1 ( 38 ) , a key protein factor intimately involved in the development of cardiovascular disease ( 38 ) . in our study , ta was found to be much more potent and efficacious than the ellagitannin lagerstroemin ( 29 ) . therefore , ta was chosen as the focus of our research for isolating active compounds from the tannin fraction of be . components of ta were separated by hplc , and active fractions were identified with a glucose uptake assay in 3t3-l1 adipocytes ( 29 ) . the study led to the discovery of penta - o - galloyl - d - glucopyranose ( pgg ) as the most effective compound in ta ( fig . 5 , 39 ) . the -anomer was found to be slightly more active than the -form in its glucose transport stimulatory activity ( 39 ) . in the ellagitannin study mentioned earlier , lagerstroemin exhibits glucose transport stimulation at 40 m with an ec50 of 80 m ( 22 ) . in comparison , - and -pgg exhibit activity at a concentration as low as 10 m with ec50 of 17 and 18 m ( 39 ) . in other words , - and -pgg are about five times more potent than lagerstroemin in stimulating glucose transport . we would like to emphasize that both - and -pgg possess the adipogenesis inhibitory activity exhibited by the banaba extract ( 28 ) and by ta ( 29 ) . it also indicates the functional differences between insulin ( glucose transport inducing and adipogenic ) and pgg ( glucose transport inducing but anti - adipogenic ) . both compounds may have the potential to reduce hyperglycemia without increasing adiposity , a very desirable combination of properties that insulin lacks . the lagerstroemin study also showed that its glucose transport inducing activity is about 54% of that of insulin ( 22 ) . in comparison , - and -pgg showed 6070% of insulin 's glucose transport inducing activity ( 39 ) . thus , - and -pgg are at least 30% more effective than lagerstroemin ( table 1 ) . it is interesting that pgg possesses many other health - beneficial bioactivities , such as anticancer ( 41,42 ) , anti - inflammation ( 43,44 ) , anti - virus ( anti - hiv , 45 ; anti - sars , 46 ) and antioxidant activity ( 47,48 ) . table 1.comparison of potency and efficacy of the glucose transport stimulatory activity of different compounds isolated from lagerstroemia speciosacompoundglucose transport activity ( ec50 = potency)relative transport activityreferencetannin - based be+70(28)-pgg ( mw = 940)18 m100*(39)lagerstroemin ( mw > 1200)80 m70(22)corosolic acid0(21)insulin1 nm156*activity of -pgg was arbitrarily assigned as 100 . comparison of potency and efficacy of the glucose transport stimulatory activity of different compounds isolated from lagerstroemia speciosa * activity of -pgg was arbitrarily assigned as 100 . 1 ) , also called banaba in the tagalog language of the philippines , is a tropical plant found in many parts of southeast asia including the philippines , vietnam , malaysia and southern china . it is a tree that can grow as tall as 20 m. despite growing in several countries , only in the philippines are the dried and shredded banaba leaves known to be used as a treatment for diabetes and kidney disease . it is not clear if banaba plants grown in different countries are equally effective in the treatment of diabetes . garcia published the first research on banaba 's insulin - like , hypoglycemic effect as early as 1940 ( 1418 ) . later , the popular use of banaba in the philippines was noticed and led to its introduction in japan . however , it was not until 50 years after garcia 's first publication that scientific interest in banaba 's potential for the treatment of diabetes resurfaced . scientists from countries including japan , the philippines , korea and the united states are currently studying banaba . lagerstroemia speciosa ( banaba ) has become relatively popular in the form of health - promoting tea products in eastern asia and the united states . in 1996 , kakuda et al . ( 19 ) studied banaba 's antidiabetic activity by preparing water and methanol extracts of the plant . after feeding the extracts to hereditary type 2 diabetic kk - ay / ta jcl mice , they found that food containing either 5% of water extract ( be ) or 3% of methanol extract was effective in reducing blood glucose and insulin levels ( p < 0.05 ) ( 19 ) . it is interesting to note that the total cholesterol in treated mice was also significantly reduced , but the plasma triglyceride level remained unchanged ( 19 ) . in a second study by kakuda 's research group , food containing 5% banaba water extract was used to feed female obese kk - ay / ta jcl mice . obese mice treated with banaba extract had a significantly reduced body weight ( 10% ) compared with control mice fed with a regular diet ( 20 ) . interestingly , it was also discovered that liver triglyceride content was reduced by more than 40% in the banaba extract - treated mice . in addition , the parametrial adipose tissue was 10% lighter ( p < 0.01 ) ( 20 ) . however , as in the previous antidiabetic activity study of be in animals ( 19 ) , both the identity of the effective component(s ) and the mechanism for the activity were not studied . nevertheless , these two studies clearly demonstrated the in vivo antidiabetic and anti - weight gaining efficacy of the extract . in 1993 , a group of scientists from hiroshima university used an ehrlich ascites tumor cell line coupled with a bioassay guided fractionation to screen compounds isolated by hplc from banaba extract in order to identify the effective antidiabetic component ( 21 ) . corosolic acid ( 2-hydroxyursoloic acid ) was identified as the effective compound in the methanol extract of banaba leaves in a glucose uptake assay ( fig . however , this result should be considered with caution since the tumor cell line used in this study is a very unusual and unconventional cell line for diabetes studies or antidiabetic compound screening . furthermore , the result could not explain the discrepancy that both the banaba water extract and the methanol extract were active in antidiabetic and anti - obesity animal studies since corosolic acid only exists in the methanol extract ( 1921 ) . corosolic acid ( a ) is a triterpenoid ( 21 ) , not a tannin . corosolic acid ( a ) is a triterpenoid ( 21 ) , not a tannin . realizing the potential problems associated with the cell line selection and assay method , the researchers acknowledged in a later publication that corosolic acid could not represent the whole activity of the banaba extract ( 22 ) . consequently , the researchers switched their cell model from the original tumor cells to a natural cell target of insulin , adipocytes , in order to allow for the isolation and the identification of more active compounds using the improved methodology ( 22 ) . after hplc purification , ellagitannins were identified in the water extract of banaba as the activators of glucose transport in fat cells with a glucose uptake assay ( 22 ) . in a recent study , the same group reported the activation of the insulin receptor ( ir ) by lagerstroemin ( fig . 2 , 23 ) . in this study , lagerstroemin was able to induce phosphorylation of the -subunit of ir at 150 m ( 23 ) but the mechanism responsible for ir activation was not found . the researchers speculated that lagerstroemin could act intracellularly or bind to the insulin receptor ( ir ) extracellularly . in 2004 , a separate group of researchers from several universities found that glucose transporter 4 ( glut4 ) translocation from the intracellular microsomal membrane to the plasma membrane was significantly increased in the muscle cells of mice treated orally with corosolic acid ( p < 0.05 , 24 ) . glut4 is the major glucose transporter protein in both muscle and adipocytes and glut4 is insulin - responsive ( 4,25 ) . however , since corosolic acid does not possess insulin - like glucose transport stimulatory activity , the process that leads to glut4 translocation is not known . the glut4 membrane translocation mechanism initiated by corosolic acid as described ( 24 ) must be independent of the ir mediated signaling pathway since corosolic acid does not use this pathway for its activity . in 2006 , the same group of researchers found that corosolic acid significantly reduces blood glucose levels and plasma insulin levels in kk - ay diabetic mice ( 26 ) . additionally , this group of researchers published another article in 2006 in which they showed that corosolic acid significantly lowered blood glucose levels at the 90 min mark in an oral glucose tolerance test done on type 2 diabetic patients ( 27 ) . however , no statistical difference between the treated group and the control group was found for any other time point during the test ( 27 ) . our interest in the isolation and identification of antidiabetic compounds from natural sources initiated our investigation of banaba extracts with 3t3-l1 adipocytes as a cell model and a radioactive glucose uptake assay as a screening method for the identification of potential antidiabetic compounds . in our study , we confirmed that the water and methanol extracts of banaba leaves exhibit glucose transport stimulatory activity ( 28 ) . in addition , we showed that the activity induced by the extract had a concentration - activity profile similar to that of insulin , suggesting that the activity of banaba extract ( be ) might be triggered via an insulin - like mechanism ( 28 ) . furthermore , we demonstrated that the same be also inhibits adipocyte differentiation ( 28 ) . 3t3-l1 preadipocytes treated with methylisobutylxanthine , dexamethasone , and insulin ( mdi ) and be did not differentiate into adipocytes as they normally do under the sole influence of mdi . unlike the glucose transport stimulation , the anti - differentiation activity is anti - insulin like , since insulin plays an important role in adipocyte differentiation and is a component of mdi ( i in mdi stands for insulin ) . thus , be differs from insulin in that it is anti - adipogenic whereas insulin is adipogenic , which is considered to be a negative side effect of insulin . in order to identify the component(s ) in be responsible for the antidiabetic activity , our first goal was to confirm that corosolic acid was responsible for the glucose transport stimulatory activity . since tannins comprise up to 40% of the material in the extract , we were interested in separating it from corosolic acid first . to our surprise , after removing tannins by either gelatin or bovine serum albumin tannin precipitations ( 29 ) , the remaining extract was not able to induce glucose transport . we concluded that the glucose transport activity was caused by the tannin component of the extract , and not corosolic acid ( 29 ) . furthermore , we tested pure corosolic acid and found that it was not able to stimulate glucose transport in our cell model ( fig . although we can not exclude the possibility that corosolic acid may have some antidiabetic activity , we can eliminate corosolic acid from having the insulin - like glucose transport stimulatory activity found in adipocytes . it should be noted that banaba extracts prepared from banaba leaves from different sources may have different chemical compositions , which in turn may lead to different experimental results ( our lab used dried banaba leaves from the philippines ) . pure corosolic acid in aqueous solution was added to 3t3-l1 adipocytes grown in wells of 6-well cell culture plates to induce glucose transport by a commonly used procedure ( 28,29 ) . cells treated with either 1 m insulin or 30 m penta - galloyl - glucose ( pgg ) were used as positive controls . samples were in triplicate in the experiment , and the experiment was repeated three times . no difference was found by a one - way anova statistical analysis between the negative ( vehicle ) control and corosolic acid samples at any concentration . pure corosolic acid in aqueous solution was added to 3t3-l1 adipocytes grown in wells of 6-well cell culture plates to induce glucose transport by a commonly used procedure ( 28,29 ) . cells treated with either 1 m insulin or 30 m penta - galloyl - glucose ( pgg ) were used as positive controls . samples were in triplicate in the experiment , and the experiment was repeated three times . no difference was found by a one - way anova statistical analysis between the negative ( vehicle ) control and corosolic acid samples at any concentration . after testing corosolic acid , we also tested the corosolic acid - based banaba extract product glucosol ( 30 ) . 4 ) . however , since corosolic acid itself does not have any insulin receptor mediated glucose transport activity , the effect of glucosol is likely to originate from other chemical compounds in the banaba extract and not from corosolic acid . figure 4.glucose transport stimulatory activity of glucosol as compared with banana extract . the result of the assays was analyzed with a one - way anova . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 . the result of the assays was analyzed with a one - way anova . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 . our search for the active components in the tannin fraction of be was made much easier after we discovered that commercially available tannic acid ( ta ) shows similar glucose transport stimulatory activity to be ( 29 ) . the main components of ta are gallotannins , a subclass of the tannins usually consisting of a glucose core connected to a variable number of galloyl groups via ester bonds ( fig . 5 ) . figure 5.chemical structures of gallotannins ( tannic acid , a ) and pgg ( b ) . chemical structures of gallotannins ( tannic acid , a ) and pgg ( b ) . ta is known to exhibit various health - beneficial activities ( 3336 ) . as a constituent of red wine , it has been shown to effectively reduce blood glucose levels in type 2 diabetes patients ( 37 ) and the production of endothelin-1 ( 38 ) , a key protein factor intimately involved in the development of cardiovascular disease ( 38 ) . in our study , ta was found to be much more potent and efficacious than the ellagitannin lagerstroemin ( 29 ) . therefore , ta was chosen as the focus of our research for isolating active compounds from the tannin fraction of be . components of ta were separated by hplc , and active fractions were identified with a glucose uptake assay in 3t3-l1 adipocytes ( 29 ) . the study led to the discovery of penta - o - galloyl - d - glucopyranose ( pgg ) as the most effective compound in ta ( fig . 5 , 39 ) . the -anomer was found to be slightly more active than the -form in its glucose transport stimulatory activity ( 39 ) . in the ellagitannin study mentioned earlier , lagerstroemin exhibits glucose transport stimulation at 40 m with an ec50 of 80 m ( 22 ) . in comparison , - and -pgg exhibit activity at a concentration as low as 10 m with ec50 of 17 and 18 m ( 39 ) . in other words , - and -pgg are about five times more potent than lagerstroemin in stimulating glucose transport . we would like to emphasize that both - and -pgg possess the adipogenesis inhibitory activity exhibited by the banaba extract ( 28 ) and by ta ( 29 ) . it also indicates the functional differences between insulin ( glucose transport inducing and adipogenic ) and pgg ( glucose transport inducing but anti - adipogenic ) . both compounds may have the potential to reduce hyperglycemia without increasing adiposity , a very desirable combination of properties that insulin lacks . the lagerstroemin study also showed that its glucose transport inducing activity is about 54% of that of insulin ( 22 ) . in comparison , - and -pgg showed 6070% of insulin 's glucose transport inducing activity ( 39 ) . thus , - and -pgg are at least 30% more effective than lagerstroemin ( table 1 ) . it is interesting that pgg possesses many other health - beneficial bioactivities , such as anticancer ( 41,42 ) , anti - inflammation ( 43,44 ) , anti - virus ( anti - hiv , 45 ; anti - sars , 46 ) and antioxidant activity ( 47,48 ) . table 1.comparison of potency and efficacy of the glucose transport stimulatory activity of different compounds isolated from lagerstroemia speciosacompoundglucose transport activity ( ec50 = potency)relative transport activityreferencetannin - based be+70(28)-pgg ( mw = 940)18 m100*(39)lagerstroemin ( mw > 1200)80 m70(22)corosolic acid0(21)insulin1 nm156*activity of -pgg was arbitrarily assigned as 100 . comparison of potency and efficacy of the glucose transport stimulatory activity of different compounds isolated from lagerstroemia speciosa * activity of -pgg was arbitrarily assigned as 100 . from the known studies , we conclude that tannin molecules are responsible for the insulin - like glucose transport stimulatory activity of the banaba extract . gallotannins such as pgg appear to be more potent and efficacious than ellagitanins such as lagerstroemin in ir binding , ir activation and glucose transport induction . corosolic acid does not possess any insulin - like glucose transport stimulatory activity . if its antidiabetic activity can be confirmed , it is likely to be induced via a non - insulin like , indirect mechanism . although tannins were identified as the effective component for the insulin like glucose transport inducing activity in banaba extract , the most effective tannin molecule in the extract has not been identified . a well designed bioassay ( glucose uptake assay ) guided other studies regarding banaba extracts or chemicals derived from banaba extracts were reported ( 4952 ) . these studies indicate that banaba extracts contain interesting biomedical substances that have attracted significant scientific attention . more detailed studies at molecular and cellular levels as well as in animal models are required to elucidate banaba extract 's antidiabetic activity and other health beneficial activities such as its anti - adipogenesis activity .

the leaves of lagerstroemia speciosa ( lythraceae ) , a southeast asian tree more commonly known as banaba , have been traditionally consumed in various forms by philippinos for treatment of diabetes and kidney related diseases . in the 1990s , the popularity of this herbal medicine began to attract the attention of scientists worldwide . since then , researchers have conducted numerous in vitro and in vivo studies that consistently confirmed the antidiabetic activity of banaba . scientists have identified different components of banaba to be responsible for its activity . using tumor cells as a cell model , corosolic acid was isolated from the methanol extract of banaba and shown to be an active compound . more recently , a different cell model and the focus on the water soluble fraction of the extract led to the discovery of other compounds . the ellagitannin lagerstroemin was identified as an effective component of the banaba extract responsible for the activity . in a different approach , using 3t3-l1 adipocytes as a cell model and a glucose uptake assay as the functional screening method , chen et al . showed that the banaba water extract exhibited an insulin - like glucose transport inducing activity . coupling hplc fractionation with a glucose uptake assay , gallotannins were identified in the banaba extract as components responsible for the activity , not corosolic acid . penta - o - galloyl - glucopyranose ( pgg ) was identified as the most potent gallotannin . a comparison of published data with results obtained for pgg indicates that pgg has a significantly higher glucose transport stimulatory activity than lagerstroemin . chen et al . have also shown that pgg exhibits anti - adipogenic properties in addition to stimulating the glucose uptake in adipocytes . the combination of glucose uptake and anti - adipogenesis activity is not found in the current insulin mimetic drugs and may indicate a great therapeutic potential of pgg .

reliable and accurate prediction of precipitation is of great importance in agriculture , tourism , aviation and in some other fields of economy as well . in order to represent the uncertainties of forecasts based on observational data and numerical weather prediction ( nwp ) models one can run these models with different initial conditions or change model physics , resulting in a forecast ensemble @xcite . in the last two decades this approach has became a routinely used technique all over the world and recently all major weather prediction centres have their own operational ensemble prediction systems ( eps ) , e.g. the consortium for small - scale modelling ( cosmo - de ) eps of the german meteorological service ( dwd ; * ? ? ? * ; * ? ? ? * ) , the prvision densemble arpege ( pearp ) eps of mteo france @xcite or the eps of the independent intergovernmental european centre for medium - range weather forecasts @xcite . with the help of a forecast ensemble one can estimate the distribution of the predictable weather quantity which opens up the door for probabilistic forecasting @xcite . by post - processing the raw ensemble the most sophisticated probabilistic methods result in full predictive cumulative distribution functions ( cdf ) and correct the possible bias and underdispersion of the original forecasts . the underdispersive character of the ensemble has been observed with several ensemble prediction systems @xcite and this property also leads to the lack of calibration . using predictive cdfs one can easily get consistent estimators of probabilities of various meteorological events or calculate different prediction intervals . recently , probably the most widely used ensemble post - processing methods leading to full predictive distributions ( for an overview see e.g. * ? ? ? * ; * ? ? ? * ) are the bayesian model averaging ( bma ; * ? ? ? * ) and the non - homogeneous regression or ensemble model output statistics ( emos ; * ? ? ? * ) , as they are partially implemented in the ensemblebma and ensemblemos packages of r @xcite . the bma predictive probability density function ( pdf ) of the future weather quantity is the mixture of individual pdfs corresponding to the ensemble members with mixture weights determined by the relative performance of the ensemble members during a given training period . to model temperature or sea level pressure a normal mixture seems to be appropriate @xcite , wind speed requires non - negative and skewed component pdfs such as gamma @xcite or truncated normal @xcite distributions , whereas for surface wind direction a von mises distribution @xcite is suggested . however , in some situations bma post - processing might result , for instance , in model overfitting @xcite or over - weighting climatology @xcite . in contrast to bma , the emos technique uses a single parametric pdf with parameters depending on the ensemble members . again , for temperature and sea level pressure the emos predictive pdf is normal @xcite , whereas for wind speed truncated normal @xcite , generalized extreme value ( gev ; * ? ? ? * ) , censored logistic @xcite , truncated logistic , gamma @xcite and log - normal @xcite distributions are suggested . however , statistical calibration of ensemble forecasts of precipitation is far more difficult than the post - processing of the above quantities . as pointed out by @xcite , precipitation has a discrete - continuous nature with a positive probability of being zero and larger expected precipitation amount results in larger forecast uncertainty . @xcite introduced a bma model where each individual predictive pdf consists of a discrete component at zero and a gamma distribution modelling the case of positive precipitation amounts . @xcite uses extends logistic regression to provide full probability distribution forecasts , whereas @xcite suggests an emos model based on a censored gev distribution . finally , @xcite propose a more complex three step approach where they first fit a censored and shifted gamma ( csg ) distribution model to the climatological distribution of observations , then after adjusting the forecasts to match this climatology derive three ensemble statistics , and with the help of a nonhomogeneus regression model connect these statistics to the csg model . based on the idea of @xcite we introduce a new emos approach which directly models the distribution of precipitation accumulation with a censored and shifted gamma predictive pdf . the novel emos approach is applied to 24 hour precipitation accumulation forecasts of the eight - member university of washington mesoscale ensemble ( uwme ; * ? ? ? * ) and the 11 member operational eps of the hungarian meteorological service ( hms ) called aire limite adaptation dynamique dvelopment international - hungary eps ( aladin - huneps ; * ? ? ? * ; * ? ? ? * ) . in these case studies the performance of the proposed emos model is compared to the forecast skills of the gev emos method of @xcite and to the gamma bma approach of @xcite serving as benchmark models . as mentioned in the introduction , the emos predictive pdf of a future weather quantity is a single parametric distribution with parameters depending on the ensemble members . due to the special discrete - continuous nature of precipitation one should think only of non - negative predictive distributions assigning positive mass to the event of zero precipitation . mixing a point mass at zero and a separate non - negative distribution does the job ( see e.g. the bma model of * ? ? ? * ) , but left censoring of an appropriate continuous distribution at zero can also be a reasonable choice . the advantage of the latter approach is that the probability of zero precipitation can directly be derived from the corresponding original ( uncensored ) cumulative distribution function ( cdf ) , so the cases of zero and positive precipitation can be treated together . the emos model of @xcite utilizes a censored gev distribution with shape parameter ensuring a positive skew and finite mean , whereas our emos approach is based on a csg distribution appearing in the more complex model of @xcite . consider a gamma distribution @xmath0 with shape @xmath1 and scale @xmath2 having pdf @xmath3 where @xmath4 denotes value of the gamma function at @xmath5 . a gamma distribution can also be parametrized by its mean @xmath6 and standard deviation @xmath7 using expressions @xmath8 now , let @xmath9 and denote by @xmath10 the cdf of the @xmath0 distribution . then the shifted gamma distribution left censored at zero ( csg ) @xmath11 with shape @xmath5 , scale @xmath12 and shift @xmath13 can be defined with cdf @xmath14 this distribution assigns mass @xmath15 to the origin and has generalized pdf @xmath16 where @xmath17 denotes the indicator function of the set @xmath18 . short calculation shows that the mean @xmath19 of @xmath11 equals @xmath20 whereas the @xmath21-quantile @xmath22 ( @xmath23 ) of equals @xmath24 if @xmath25 , and the solution of @xmath26 , otherwise . now , denote by @xmath27 the ensemble of distinguishable forecasts of precipitation accumulation for a given location and time . this means that each ensemble member can be identified and tracked , which holds for example for the uwme ( see section [ subs : subs3.1 ] ) or for the cosmo - de eps of the dwd . in the proposed csg emos model the ensemble members are linked to the mean @xmath28 and variance @xmath29 of the underlying gamma distribution via equations @xmath30 where @xmath31 denotes the ensemble mean . mean parameters @xmath32 and variance parameters @xmath33 of model can be estimated from the training data , consisting of ensemble members and verifying observations from the preceding @xmath34 days , by optimizing an appropriate verification score ( see section [ subs : subs2.2 ] ) . however , most of the currently used epss produce ensembles containing groups of statistically indistinguishable ensemble members which are obtained with the help of random perturbations of the initial conditions . this is the case for the aladin - huneps ensemble described in section [ subs : subs3.2 ] or for the 51 member ecmwf ensemble . the existence of several exchangeable groups is also a natural property of some multi - model epss such as the the thorpex interactive grand global ensemble @xcite or the glameps ensemble @xcite . suppose we have @xmath35 ensemble members divided into @xmath36 exchangeable groups , where the @xmath5th group contains @xmath37 ensemble members , such that @xmath38 . further , we denote by @xmath39 the @xmath40th member of the @xmath5th group . in this situation ensemble members within a given group should share the same parameters @xcite resulting in the exchangeable version @xmath41 of model . note , that the expression of the mean ( or location ) as an affine function of the ensemble is general in emos post - processing ( see e.g. * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) , whereas the dependence of the variance parameter on the ensemble mean is similar to the expression of the variance in the gamma bma model of @xcite , and it is in line with the relation of forecast uncertainty to the expected precipitation amount mentioned in the introduction . moreover , practical tests show that , at least for the uwme and aladin - huneps ensemble considered in the case studies of section [ sec : sec5 ] , models and , respectively , significantly outperform the corresponding csg emos models with variance parameters @xmath42 where @xmath43 are the ensemble variance and the more robust ensemble mean difference @xcite , respectively . further , compared to the proposed models , natural modifications @xmath44 in the csg emos variance structure do not result in improved forecasts skills . the main aim of probabilistic forecasting is to access the maximal sharpness of the predictive distribution subject to calibration @xcite . the latter means a statistical consistency between the predictive distributions and the validating observations , whereas the former refers to the concentration of the predictive distribution . this goal can be addressed with the help of scoring rules which measure the predictive performance by numerical values assigned to pairs of probabilistic forecasts and observations @xcite . in atmospheric sciences the most popular scoring rules for evaluating predictive distributions are the logarithmic score , i.e. the negative logarithm of the predictive pdf evaluated at the verifying observation @xcite , and the continuous ranked probability score ( crps ; * ? ? ? * ; * ? ? ? for a predictive cdf @xmath45 and an observation @xmath46 the crps is defined as @xmath47 where @xmath48 denotes the indicator of a set @xmath49 , while @xmath50 and @xmath51 are independent random variables with cdf @xmath52 and finite first moment . the crps can be expressed in the same units as the observation and one should also note that both scoring rules are proper @xcite and negatively oriented , that is the smaller the better . for a csg distribution defined by the crps can be expressed in a closed form , @xcite showed that @xmath53 following the ideas of @xcite and @xcite , the parameters of models ( and as well ) are estimated by minimizing the mean crps of predictive distributions and validating observations corresponding to forecast cases of the training period . we remark that optimization with respect to the mean logarithmic score , that is , maximum likelihood ( ml ) estimation of parameters , has also been investigated . obviously , in terms of crps this model can not outperform the one fit via crps minimization , however , in our test cases the ml method results in a reduction of the predictive skill of the csg emos model in terms of almost all verification scores considered , so the corresponding values are not reported . the eight - member uwme covers the pacific northwest region of north america and operates on a 12 km grid . the ensemble members are obtained from different runs of the fifth generation pennsylvania state university national center for atmospheric research mesoscale model ( psu - ncar mm5 ; * ? ? ? * ) with initial and boundary conditions from various weather centres . we consider 48 h forecasts and corresponding validating observations of 24 h precipitation accumulation for 152 stations in the automated surface observing network @xcite in five us states . the forecasts are initialized at 0 utc ( 5 pm local time when daylight saving time ( dst ) is in use and 4 pm otherwise ) and we investigate data for calendar year 2008 with additional forecasts and observations from the last three months of 2007 used for parameter estimation . after removing days and locations with missing data 83 stations remain resulting in 20522 forecast cases for 2008 . to 9 cma ) b ) figure [ fig : fig1]a shows the verification rank histogram of the raw ensemble , that is the histogram of ranks of validating observations with respect to the corresponding ensemble forecasts computed for all forecast cases ( see e.g. * ? ? ? * section 7.7.2 ) , where zero observations are randomized among all zero forecasts . this histogram is far from the desired uniform distribution as in many cases the ensemble members overestimate the validating observation . the ensemble range contains the observed precipitation accumulation in @xmath54 of the cases , whereas the nominal coverage of the ensemble equals @xmath55 , i.e @xmath56 . hence , the uwme is uncalibrated , and would require statistical post - processing to yield an improved forecast probability density function . the ensemble forecasts produced by the operational aladin - huneps system of the hms are obtained with dynamical downscaling of the global pearp system of mto france by the aladin limited area model with an 8 km horizontal resolution . the eps covers a large part of continental europe and has 11 ensemble members , 10 exchangeable forecasts from perturbed initial conditions and one control member from the unperturbed analysis @xcite . the data base at hand contains ensembles of 42 h forecasts ( initialized at 18 utc , i.e. 8 pm local time when dst operates and 7 pm otherwise ) for 24 h precipitation accumulation for 10 major cities in hungary ( miskolc , sopron , szombathely , gyr , budapest , debrecen , nyregyhza , nagykanizsa , pcs , szeged ) together with the corresponding validating observations for the period between 1 october 2010 and 25 march 2011 . the data set is fairly complete since there are only two dates when three ensemble members are missing for all sites . these dates are excluded from the analysis . the verification rank histogram of the raw ensemble , displayed in figure [ fig : fig1]b , shows far better calibration , than that of the uwme . the coverage of the aladin - huneps ensemble equals @xmath57 , which is very close to the nominal value of @xmath58 ( @xmath59 ) . as mentioned earlier , the predictive performance of the csg emos model is tested on ensemble forecasts produced by the uwme and aladin - huneps epss , and the results are compared with the fits of the gev emos and gamma bma models investigated by @xcite and @xcite , respectively , and the verification scores of the raw ensemble . we remark that according to the suggestions of @xcite for estimating the parameters of the gev emos model for a given day , the estimates for the preceding day serve as initial conditions for the box constrained broyden - fletcher - goldfarb - shanno @xcite optimization algorithm . compared with the case of fixed initial conditions this approach results in a slight increase of the forecast skills of the gev emos model , whereas for the csg emos method , at least in our case studies , fixed initial conditions are preferred . further , we consider regional ( or global ) emos approach ( see e.g. * ? ? ? * ) which is based on ensemble forecasts and validating observations from all available stations during the rolling training period and consequently results in a single universal set of parameters across the entire ensemble domain . to get the first insight about the calibration of emos and bma post - processed forecasts we consider probability integral transform ( pit ) histograms generally , the pit is the value of the predictive cdf evaluated at the verifying observation @xcite , however , for our discrete - continuous models in the case of zero observed precipitation a random value is chosen uniformly from the interval between zero and the probability of no precipitation @xcite . obviously , the closer the histogram to the uniform distribution , the better the calibration . in this way the pit histogram is the continuous counterpart of the verification rank histogram of the raw ensemble and provides a good measure about the possible improvements in calibration . the predictive performance of probabilistic forecasts is quantified with the help of the mean crps over all forecast cases , where for the raw ensemble the predictive cdf is replaced by the empirical one . further , as suggested by @xcite , diebold - mariano ( dm ; * ? ? ? * ) tests are applied for investigating the significance of the differences in scores corresponding to the various post - processing methods . the dm test takes into account the dependence in the forecasts errors and for this reason it is widely used in econometrics . besides the crps we also consider brier scores ( bs ; * ? ? ? * section 8.4.2 ) for the dichotomous event that the observed precipitation amount @xmath46 exceeds a given threshold @xmath60 . for a predictive cdf @xmath45 the probability of this event is @xmath61 , and the corresponding brier score is given by @xmath62 see e.g. @xcite . obviously , the bs is negatively oriented and the crps is the integral of the bss over all possible thresholds . in our case studies we consider 0 mm precipitation , 5 , 15 , 25 , 30 mm and 1 , 5 , 7 , 9 mm threshold values for the uwme and aladin - huneps ensemble , respectively , corresponding approximately to the 45th , 75th , 85th and 90th percentiles of the observed non - zero precipitation accumulations , and compare the mean bss of the pairs of predictive cdfs and verifying observations over all forecast cases . .5 truecm .@xmath21-values of kolmogorov - smirnov tests for uniformity of pit values for the uwme . means of @xmath63 random samples of sizes @xmath64 each . [ cols="<,^,^,^",options="header " , ] concerning the two emos approaches , the verification scores of table [ tab : tab6 ] together with the results of the corresponding dm tests for equal predictive performance ( see table [ tab : tab7 ] ) display similar behavior as in the case of the uwme . there is no significant difference between the mae values of the csg and gev emos methods and the former results in the lowest crps and the sharpest @xmath58 central prediction interval . further , the emos models significantly outperform both the raw ensemble and the gamma bma approach , despite the raw ensemble is rather well calibrated and has far better predictive skill than the bma calibrated forecast . note that the large mean crps and coverage of the bma predictive distribution is totally in line with the shape of the corresponding pit histogram of figure [ fig : fig4 ] . 2 mm 2 mm 2 mm the good predictive performance of the aladin - huneps ensemble can also be observed on the large amount of negative skill scores reported in table [ tab : tab8 ] and on the reliability diagrams of figure [ fig : fig5 ] . similar to the case of the uwme , for 0 mm threshold the gamma bma model has good predictive performance , whereas for higher threshold values it underperforms the csg and gev emos models and the raw ensemble . however , in connection with the reliability diagrams one should also note that the hectic behavior of the graphs ( compared to the rather smooth diagrams of figure [ fig : fig3 ] ) is a consequence of the shortage of data , as the verification period contains only 394 observations of positive precipitation , which is around one third of the forecast cases . taking into account both the uniformity of the pit values and the verification scores in tables [ tab : tab6 ] and [ tab : tab8 ] it can be said that the proposed csg emos model has the best overall performance in calibration of the raw aladin - huneps ensemble forecasts of precipitation accumulation . a new emos model for calibrating ensemble forecasts of precipitation accumulation is proposed where the predictive distribution follows a censored and shifted gamma distribution , with mean and variance of the underlying gamma law being affine functions of the raw ensemble and the ensemble mean , respectively . the csg emos method is tested on ensemble forecasts of 24 h precipitation accumulation of the eight - member university of washington mesoscale ensemble and on the 11 member aladin - huneps ensemble of the hungarian meteorological service . these ensemble prediction systems differ both in the climate of the covered area and in the generation of the ensemble members . by investigating the uniformity of the pit values of predictive distributions , the mean crps of probabilistic forecasts , the brier scores and reliability diagrams for various thresholds , the mae of median forecasts and the average width and coverage of central prediction intervals corresponding to the nominal coverage , the predictive skill of the new approach is compared with that of the gev emos method @xcite , the gamma bma model @xcite and the raw ensemble . from the results of the presented case studies one can conclude that in terms of calibration of probabilistic and accuracy of point forecasts the proposed csg emos model significantly outperforms both the raw ensemble and the bma model and shows slightly better forecast skill than the gev emos approach . * acknowledgments . * sndor baran is supported by the jnos bolyai research scholarship of the hungarian academy of sciences . dra nemoda partially carried out her research in the framework of the center of excellence of mechatronics and logistics at the university of miskolc . the authors are indebted to michael scheuerer for his useful suggestions and remarks and for providing the r code for the gev emos model . the authors further thank the university of washington muri group for providing the uwme data and mihly szcs from the hms for the aladin - huneps data . 99 bao l , gneiting t , raftery ae , grimit ep , guttorp p. 2010 . bias correction and bayesian model averaging for ensemble forecasts of surface wind direction . _ monthly weather review _ * 138*:18111821 , doi : 10.1175/2009mwr3138.1 . baran s. 2014 . probabilistic wind speed forecasting using bayesian model averaging with truncated normal components . _ computational statistics and data analysis _ * 75*:227238 , doi : 10.1016/j.csda.2014.02.013 . baran s , lerch s. 2015 . log - normal distribution based emos models for probabilistic wind speed forecasting . _ quarterly journal of the royal meteorological society _ * 141*:22892299 , doi : 10.1002/qj.2521 . baran s , sikolya k , veress l. 2013 . estimating the risk of a down s syndrome term pregnancy using age and serum markers : comparison of various methods . _ communications in statistics simulation and computation _ * 42*:16541672 , doi : 10.1080/03610918.2012.674596 . buizza r , houtekamer pl , toth z , pellerin g , wei m , zhu y. 2005 . a comparison of the ecmwf , msc , and ncep global ensemble prediction systems . _ monthly weather review _ * 133*:10761097 , doi : 10.1175/mwr2905.1 . descamps l , labadie c , joly a , bazile e , arbogast p , cbron p. 2014 . pearp , the mto - france short - range ensemble prediction system . _ quarterly journal of the royal meteorological society _ * 141*:16711685 , doi : 10.1002/qj.2469 . fraley c , raftery ae , gneiting t. 2010 . calibrating multimodel forecast ensembles with exchangeable and missing members using bayesian model averaging . _ monthly weather review _ * 138*:190202 , doi : 10.1175/2009mwr3046.1 . friederichs p , thorarinsdottir tl . forecast verification for extreme value distributions with an application to probabilistic peak wind prediction . _ environmetrics _ * 23*:579594 , doi : 10.1002/env.2176 . gebhardt c , theis se , paulat m , bouallgue zb . uncertainties in cosmo - de precipitation forecasts introduced by model perturbations and variation of lateral boundaries . _ atmospheric research _ * 100*:168177 , doi : 10.1016/j.atmosres.2010.12.008 . gneiting t. 2014 . calibration of medium - range weather forecasts . _ ecmwf technical memorandum _ no . 719 . ( available from : http://old.ecmwf.int/publications/library/ecpublications/_pdf/tm/701-800/tm719.pdf . ) [ accessed on 24 november 2015 ] gneiting t , balabdaoui f , raftery ae . probabilistic forecasts , calibration and sharpness . _ journal of the royal statistical society : series b _ * 69*:243268 , doi : 10.1111/j.1467 - 9868.2007.00587.x . gneiting t , raftery ae , westveld ah , goldman t. 2005 . calibrated probabilistic forecasting using ensemble model output statistics and minimum crps estimation . _ monthly weather review _ * 133*:10981118 , doi : 10.1175/mwr2904.1 . grell ga , dudhia j , stauffer dr . 1995 . a description of the fifth - generation penn state / ncar mesoscale model ( mm5 ) . technical note ncar / tn-398+str . national center for atmospheric research , boulder . ( available from : http://www2.mmm.ucar.edu/mm5/documents/mm5-desc-doc.html ) [ accessed on 24 november 2015 ] hamill tm . 2007 . comments on `` calibrated surface temperature forecasts from the canadian ensemble prediction system using bayesian model averaging . '' _ monthly weather review _ * 135*:42264230 , doi : 10.1175/2007mwr1963.1 . hodyss d , satterfield e , mclay j , hamill tm , scheuerer m. 2015 . inaccuracies with multi - model post - processing methods involving weighted , regression - corrected forecasts . _ monthly weather review _ doi : 10.1175/mwr - d-15 - 0204.1 . iversen t , deckmin a , santos c , sattler k , bremnes jb , feddersen h , frogner i - l . 2011 . evaluation of glameps a proposed multimodel eps for short range forecasting . _ tellus a _ * 63*:513530 , doi : 10.1111/j.1600 - 0870.2010.00507.x . messner jw , mayr gj , zeileis a , wilks ds . heteroscedastic extended logistic regression for postprocessing of ensemble guidance . _ monthly weather review _ * 142*:448456 , doi : 10.1175/mwr - d-13 - 00271.1 . scheuerer m. 2014 . probabilistic quantitative precipitation forecasting using ensemble model output statistics . _ quarterly journal of the royal meteorological society _ * 149*:10861096 , doi : 10.1002/qj.2183 . scheuerer m , hamill tm . statistical post - processing of ensemble precipitation forecasts by fitting censored , shifted gamma distributions _ monthly weather review _ * 143*:45784596 , doi : 10.1175/mwr - d-15 - 0061.1 . sloughter jm , gneiting t , raftery ae . probabilistic wind speed forecasting using ensembles and bayesian model averaging . _ journal of the american statistical association _ * 105*:2537 , doi : 10.1198/jasa.2009.ap08615 . sloughter jm , raftery ae , gneiting t , fraley c. 2007 . probabilistic quantitative precipitation forecasting using bayesian model averaging . _ monthly weather review _ * 135*:32093220 , doi : 10.1175/mwr3441.1 . swinbank r , kyouda m , buchanan p , froude l , hamill tm , hewson td , keller jh , matsueda m , methven j , pappenberger f , scheuerer m , titley ha , wilson l , yamaguchi m. 2015 . the tigge project and its achievements . _ bulletin of the american meteorological society _ , doi : 10.1175/bams - d-13 - 00191.1 . thorarinsdottir tl , gneiting t. 2010 . probabilistic forecasts of wind speed : ensemble model output statistics by using heteroscedastic censored regression . _ journal of the royal statistical society : series a _ * 173*:371388 , doi : 10.1111/j.1467 - 985x.2009.00616.x . williams rm , ferro cat , kwasniok f. 2014 . a comparison of ensemble post - processing methods for extreme events . _ quarterly journal of the royal meteorological society _ * 140*:11121120 , doi : 10.1002/qj.2198 .

recently all major weather prediction centres provide forecast ensembles of different weather quantities which are obtained from multiple runs of numerical weather prediction models with various initial conditions and model parametrizations . however , ensemble forecasts often show an underdispersive character and may also be biased , so that some post - processing is needed to account for these deficiencies . probably the most popular modern post - processing techniques are the ensemble model output statistics ( emos ) and the bayesian model averaging ( bma ) which provide estimates of the density of the predictable weather quantity . in the present work an emos method for calibrating ensemble forecasts of precipitation accumulation is proposed , where the predictive distribution follows a censored and shifted gamma ( csg ) law with parameters depending on the ensemble members . the csg emos model is tested on ensemble forecasts of 24 h precipitation accumulation of the eight - member university of washington mesoscale ensemble and on the 11 member ensemble produced by the operational limited area model ensemble prediction system of the hungarian meteorological service . the predictive performance of the new emos approach is compared with the fit of the raw ensemble , the generalized extreme value ( gev ) distribution based emos model and the gamma bma method . according to the results , the proposed csg emos model slightly outperforms the gev emos approach in terms of calibration of probabilistic and accuracy of point forecasts and shows significantly better predictive skill that the raw ensemble and the bma model . _ key words : _ continuous ranked probability score , ensemble calibration , ensemble model output statistics , gamma distribution , left censoring .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Supportive Communities Helping Offer Opportunities for Learning Act of 2005'' or as the ``SCHOOL Act of 2005''. SEC. 2. ESTABLISHMENT OF SUPPORTIVE COMMUNITIES HELPING OFFER OPPORTUNITIES FOR LEARNING PROGRAM. (a) In General.--The Secretary of Education shall establish a program to be known as the ``Supportive Communities Helping Offer Opportunities for Learning Program'' or as the ``SCHOOL Program''. (b) Certification of Scholarship Granting Organizations.-- (1) In general.--The Secretary of Education may certify an organization as a scholarship granting organization participating in the SCHOOL Program if such organization meets all of the following requirements: (A) Notifies the Secretary of its intent to provide educational scholarships for eligible students attending qualified schools. (B) Demonstrates to the Secretary that it is described in section 501(c)(3) of the Internal Revenue Code of 1986 and exempt from tax under section 501(a) of such Code. (C) Provides a receipt to taxpayers for contributions made to the organization. (D) Ensures that at least 90 percent of its annual receipts are spent on educational scholarships, and that all receipts from interest or investments is spent on educational scholarships. (E) Spends each year a portion of its expenditures on scholarships for low-income eligible students equal to the percentage of low-income eligible students in the county where the organization expends the majority of its scholarships. (F) Ensures that at least 30 percent of first time recipients of educational scholarships were not continuously enrolled in a private elementary or secondary school during the previous year. (G) Distributes periodic scholarship payments as checks made out to a student's parent or guardian and mailed to the qualified school where the student is enrolled. (H) Cooperates with the Secretary in conducting criminal background checks on all of its employees and board members and excluding from employment or governance any individual that might reasonably pose a risk to the appropriate use of contributed funds. (I) Ensures that scholarships are portable during the school year and can be used at any qualified school that accepts the student according to a parent's wishes. (J) Ensures that if a student moves to a new qualified school during a school year, the scholarship amount may be prorated. (K) Demonstrates its financial accountability by-- (i) submitting a financial information report for the organization that complies with uniform financial accounting standards established by the Secretary and that has been conducted by a certified public accountant; and (ii) having an auditor certify that the report is free of material misstatements. (L) Demonstrates its financial viability, if the organization is to receive donations of $50,000 or more during any school year (as determined by the Secretary), by-- (i) filing with the Secretary prior to the start of the school year a surety bond payable to the Federal Government in an amount equal to the aggregate amount of contributions expected to be received during the school year; or (ii) filing with the Secretary prior to the start of the school year financial information that demonstrates the financial viability of the organization. (M) Ensures that qualified schools that accept its scholarship students will-- (i) comply with all health and safety laws or codes that apply to the school; (ii) hold a valid occupancy permit if required by their municipality; (iii) certify that they will not discriminate in admissions on the basis of race, color, national origin, religion or disability; and (iv) provide academic accountability to parents of the students in the program by regularly reporting to the parent on the student's progress. (N) Does not provide educational scholarships for students to attend any school with paid staff or board members, or relatives thereof, in common with the organization. (O) Publicly reports to the Secretary by June 1 of each year the following information prepared by a certified public accountant for the previous calendar year-- (i) the name and address of the organization; (ii) the total number and total dollar amount of contributions received during the previous calendar year; (iii) the total number and total dollar amount of educational scholarships awarded during the previous calendar year; (iv) the total number and total dollar amount of educational scholarships awarded during the previous year to low-income eligible students; and (v) the percentage of first time recipients of educational scholarships who were continuously enrolled in a public elementary or secondary school during the previous year. (2) Definitions.--For purposes of this subsection-- (A) Educational scholarships.--The term ``educational scholarships'' means grants for eligible students to cover all or part of-- (i) in the case of a private or religious school which charges tuition or fees, the tuition and fees of such school, (ii) in the case of a public school, the cost of transportation to such school, and (iii) in the case of any other school or program, such expenses as the Secretary of Education may provide. (B) Qualified school.--The term ``qualified school'' means any public, private, religious, or other school or program which provides elementary or secondary education (as determined under State law). (C) Eligible student.--The term ``eligible student'' means any student who-- (i) has not-- (I) attained age 21, or (II) been graduated from high school, and (ii) as of the time that such student first receives assistance under the SCHOOL Program, is a member of a household whose total annual income during the year before receipt of such assistance does not exceed an amount equal to 2.5 times the highest amount of income which qualifies for a reduced price lunch under section 9(b)(1) of the Richard B. Russell National School Lunch Act. (D) Low-income eligible student.--The term ``low- income eligible student'' means a student who meets the requirements of paragraph (3)(A) and who qualifies for a free or reduced price lunch under section 9(b)(1) of the Richard B. Russell National School Lunch Act. (E) Parent.--The term ``parent'' includes a guardian, custodian, or other person with authority to act on behalf of the child. (c) Duties of the Secretary of Education.--The Secretary of Education shall-- (1) adopt such rules and procedures as are necessary or appropriate to implement the SCHOOL Program; and (2) provide a standardized format for certified organizations to report the information described in subsection (b)(1)(O). SEC. 3. EDUCATIONAL IMPROVEMENT CONTRIBUTIONS CREDIT. (a) In General.--Subpart B of part IV of subchapter A of chapter 1 of the Internal Revenue Code of 1986 (relating to other credits) is amended by adding at the end the following new section: ``SEC. 30B. EDUCATIONAL IMPROVEMENT CONTRIBUTIONS CREDIT. ``(a) In General.--There shall be allowed as a credit against the tax imposed by this chapter for the taxable year an amount equal to the aggregate amount of the qualified contributions made by the taxpayer to qualified scholarship granting organizations during the taxable year. ``(b) Limitation.-- ``(1) Individuals.--In the case of an individual, the amount of the credit determined under this section for any taxable year shall not exceed $3,000 ($6,000 in the case of a joint return). ``(2) Corporations.--In the case of a corporation, the amount of the credit determined under this section for any taxable year shall not exceed the lesser of-- ``(A) 5 percent of the taxpayer's regular tax liability for the taxable year, or ``(B) $20,000. ``(c) Qualified Scholarship Granting Organization.--For purposes of this section, the term `qualified scholarship granting organization' means any organization which-- ``(1) is described in section 501(c)(3) and exempt from tax under section 501(a), and ``(2) has in effect a certification from the Secretary of Education that such organization is a scholarship granting organization participating in the SCHOOL Program (within the meaning of section 2 of the SCHOOL Act of 2005). ``(d) Qualified Contributions.--For purposes of this section, the term `qualified contribution' means any cash contribution which the taxpayer elects (at such time and in such form and manner as the Secretary may prescribe) to treat as a qualified contribution. ``(e) Coordination With Other Credits; Carryover of Unused Credit.-- ``(1) In general.--If the credit allowable under subsection (a) for a taxable year exceeds the limitation imposed by paragraph (2) for such taxable year, such excess shall be carried over to the succeeding taxable year and added to the credit allowable under subsection (a) for such succeeding taxable year. No credit may be carried forward under this subsection to any taxable year following the third taxable year after the taxable year in which the credit arose. For purposes of the preceding sentence, credits shall be treated as used on a first-in first-out basis. ``(2) Application with other credits.--The credit allowed by subsection (a) for any taxable year shall not exceed the excess (if any) of-- ``(A) the regular tax liability for the taxable year reduced by the sum of the credits allowed by this part (other than this section), over ``(B) the tentative minimum tax for the taxable year. ``(f) Special Rules.-- ``(1) Substantiation.--No credit shall be allowed under subsection (a) with respect to any contribution to a qualified scholarship granting organization unless the taxpayer attaches to the taxpayer's return for the taxable year a receipt from such organization which meets such requirements as the Secretary may establish. ``(2) Controlled groups.--Rules similar to the rules of paragraphs (1) and (2) of section 41(f) shall apply for purposes of this section. ``(3) Denial of double benefit.--No deduction or credit shall be allowed under this subtitle for any contribution which is taken into account under this section. ``(g) Regulations.--The Secretary may prescribe such regulations as may be necessary or appropriate to carry out the purposes of this section.''. (b) Coordination With Limitations on Charitable Deductions.-- Subsection (c) of section 170 of such Code is amended by adding at the end the following: ``Such term shall not include any contribution taken into account under section 30B.'' (c) Clerical Amendment.--The table of sections for subpart B of part IV of subchapter A of chapter 1 of such Code is amended by adding at the end the following new item: ``Sec. 30B. Educational improvement contributions credit.''. (d) Effective Date.--The amendments made by this section shall apply to contributions made during taxable years beginning after the date of the enactment of this Act.

Supportive Communities Helping Offer Opportunities for Learning Act of 2005 - SCHOOL ACT of 2005 - Directs the Secretary of Education to establish the Supportive Communities Helping Offer Opportunities for Learning (SCHOOL) Program. Allows educational scholarships under the SCHOOL Program to be grants to eligible low-income elementary or secondary school students to cover all or part of: (1) private or religious school tuition and fees; (2) the cost of transportation to a public school; or (3) any other school or educational program expenses as the Secretary may determine. Authorizes the Secretary to certify scholarship granting organizations participating in the SCHOOL Program if they meet specified requirements. Amends the Internal Revenue Code to allow an income tax credit for individuals and corporations for their contributions to qualified scholarship granting organizations certified as SCHOOL Program participants.

a 6-year - old , 19 kg , child was admitted to our hospital with symptoms of proximal muscle weakness and a one - month history of difficulty climbing steps . preoperative laboratory tests were abnormal : aspartate transaminase ( ast ) 560 iu / l , alanine transaminase ( alt ) 773 iu / l , alkaline phosphatase 352 iu / l , lactate dehydrogenase ( ldh ) 4,280 iu / l , creatinine phosphokinase ( cpk ) preoperative echocardiography and pulmonary function test were considered to be unnecessary by the attending pediatrician . the patient received no premedication . upon arrival in the operating room , standard monitoring , including ekg , pulse oximetry , end - tidal capnography , transesophageal temperature probe , bispectral index ( bis vista , aspect medical systems , the netherlands ) and train - of - four monitor ( tof watch , organon , ireland ) were applied . anesthesia was induced with intravenous midazolam 1 mg , fentanyl 25 g , and continuous infusion of propofol . bis 40 - 65 was maintained and 30 ma at 2 hz tof was monitored during anesthesia . anesthesia was maintained with nitrous oxide 50% in oxygen and end - tidal co2 was maintained at 30 - 35 mmhg . intraoperative vital signs were as follows : blood pressure : 92 - 115/50 - 60 mmhg , heart rate : 100 - 107 bpm , oxygen saturation : 100% , and temperature : 36.3. propofol was stopped at the end of surgery . following recovery of tof to 90% , neuromuscular blockade was reversed with pyridostigmine 4 mg and glycopyrrolate 0.16 mg . the patient opened his eyes spontaneously , responded to verbal command , and was able to lift his head . muscular tone was re - evaluated but we did not check the tof . biopsy result confirmed duchenne muscular dystrophy . the disease is characterized by severe proximal muscle weakness , progressive degeneration , and fatty infiltration of the muscles . progressive and severe muscle atrophy and weakness cause loss of ability to ambulate by the teenager . dmd affects the muscles of respiration and is associated with dilated cardiomyopathy , which often leads to death secondary to cardiopulmonary causes . patients with dmd are vulnerable to the adverse physiologic effects of general anesthesia and procedural sedation . they are at increased risk of rhabdomyolysis , life - threatening hyperkalemia , malignant hyperthermia - like reaction and heart failure when they are exposed to inhalational anesthetics and succinylcholine . intravenous anesthetics such as propofol , ketamine and dexmedetomidine are reasonable alternatives and commonly used at variable doses [ 1 - 3 ] . however , there is no risk - free choice and a lack of prospective clinical studies to determine the safest anesthetic technique for dmd patients . in order to decrease risks such as rhabdomyolysis the responsiveness of dmd patients administered with standard dosage of nondepolarizing neuromuscular blocking agent differs from that in normal patients . delayed onset of blockade in dmd following administration of standard dose rocuronium , and the prolonged recovery from rocuronium - induced blockade necessitate the need for careful assessment of neuromuscular function . if rocuronium is administered in dmd , assessment of complete neuromuscular recovery ( tof ratio = 0.9 ) by quantitative measurement , such as acceleromyography , is mandatory . however , use of reduced electrical current for pediatric tof monitoring may be necessary [ 4 - 6 ] . using succinylcholine for the setup and stabilization of neuromuscular monitoring in children has been reported . however , this method is not appropriate for dmd . tof was not established for the child in the recovery room , and we monitored the muscle strength clinically . anesthetic induction dosage of propofol decreases with increasing patient age . as such , bolus dose used for children are much higher than that of adult . according to the pharmacokinetics of child , initial loading dose and maintenance dose target - controlled infusion ( tci ) system of propofol ( diprifusor , fresenius vial sa , france ) is based on adult pharmacokinetic model , and usage in children is limited . the limitation of age and body weight for the tci is 16 years - old and 30 kg respectively , and it is difficult to use in younger children . bispectral index monitoring has been developed as a tool for measuring the depth of anesthesia in adults , but the use of bis has generated several curious findings in children . the nervous system is functionally immature at birth , myelination is rapid during the first 2 years and completed by 7 years of age . but some studies showed the validity of bis in children older than 2 years [ 13 - 15 ] . monitoring with bis , bis is the most valid monitor to measuring the depth of anesthesia to date . in conclusion , we recommend anesthetists to pay close attention to the neurophysiologic and neuromuscular monitoring for patients with duchenne muscular dystrophic .

duchenne muscular dystrophy is a hereditary disorder characterized by progressive muscle weakness and contracture , and special care during anesthesia is needed in these patients . because inhalational anesthetics and succinylcholine can cause fatal results , intravenous anesthetics are commonly used . however , monitorings for the pediatric population are not otherwise specified . we report our experience of a 6 year - old boy that underwent muscle biopsy suspicious of muscle dystrophy under general anesthesia . the patient received midazolam , fentanyl , propofol and a small dose of rocuronium . he was monitored with bispectral index ( bis ) , acceleromyography ( tof ) . at the end of surgery , recovery of tof ratio to 90% was evaluated , followed by injection of pyridostigmine and glycopyrrolate . when reversal of neuromuscular block was confirmed quantitatively and clinically , the patient was extubated and he experienced no complication .

quantum heat engines(qhe ) have twin purposes to act as highly efficient heat engine enabled by quantum principles and also to act as a conduit for excess heat @xcite , therein lies their appeal . in this work we probe the thermo - electric properties of an open strained graphene system and show its action as a very efficient quantum heat engine(qhe ) @xcite . earlier , a closed strained graphene system has been shown to operate as a qhe@xcite . a closed system differs from an open system in that no transport of heat or charge current is involved in the operation of such a closed heat engine @xcite . closed heat engines operate on the principle that the outside environment is almost decoupled from the system . in the quantum regime most of these closed qhe operate in the single particle regime , meaning these are more of theoretical constructs than with wide experimental applicability . open system qhe on the other hand are enabled due to charge and heat transport , thus these are actively coupled to the environment and thereby with more experimental and possible commercial applications . + and @xmath0 and temperatures @xmath1 and @xmath2 . bottom : an incident electron at the interface between normal and strained regions is transmitted or reflected with a finite probability . @xmath3 is the incident angle and @xmath4 is the refracted angle into strained region.,title="fig:",scaledwidth=50.0% ] + and @xmath0 and temperatures @xmath1 and @xmath2 . bottom : an incident electron at the interface between normal and strained regions is transmitted or reflected with a finite probability . @xmath3 is the incident angle and @xmath4 is the refracted angle into strained region.,title="fig:",scaledwidth=50.0% ] our aim in this work is to design an extremely efficient qhe which operates at full power using a strained graphene system . to do this we calculate the thermoelectric properties of our system in the linear transport regime , wherein electric and heat currents are linearly proportional to the applied biases be it electric or thermal . in a thermoelectric system temperature difference @xmath5 and applied electric bias @xmath6 across it work in tandem to operationalise it . the linear dependencies can be expressed as follows @xcite- @xmath7 where @xmath8 and @xmath9 are the electric and heat currents respectively , @xmath10 with i , j @xmath11 1,2 represents onsager coefficients for a two terminal thermo - electric system . the seeback coefficient is defined as the electric response due to the finite temperature difference @xmath5 across the system . on the other hand , the peltier coefficient @xmath12 is defined as the heat current generated due to the applied bias voltage @xmath6 across the system . they are expressed as follows- @xmath13 the onsager co - efficient matrix in eq . [ [ current ] ] , which relates the electric and heat currents to the temperature differences and applied electric bias , can be rewritten as follows @xcite- @xmath14 wherein , @xmath15 here @xmath16 , @xmath17 is conductance of system with sample width @xmath18 @xcite , @xmath3 is the angle at which the electron is incident , @xmath19 is the energy of the electron , @xmath20 is the fermi - dirac distribution , @xmath21 is the fermi energy and @xmath22 is the transmission probability for electrons through strained graphene . to calculate the onsager coefficients @xmath23 in eq . ( [ current ] ) , we need the transmission probability @xmath22 . after calculating the onsager coefficients @xmath23 in eq . ( [ current ] ) , maximal efficiency and power can be determined , as follows . the output power @xcite , defined as - @xmath24 is maximized by @xmath25 , at @xmath26 , which gives maximum power as- @xmath27 the efficiency at maximum power is defined as the ratio of maximum power to the heat current transported and is derived to be- @xmath28 at @xmath29 , which is the condition for maximum power , and @xmath30 is the thermal conductance , defined as- @xmath31 similarly , efficiency @xmath32 becomes@xcite- @xmath33 to calculate maximal efficiency we need to find the relation between @xmath6 and @xmath5 , substituting @xmath34 in eq . ( [ eta ] ) , with the condition @xmath35 , gives- @xmath36 wherein @xmath37 is the carnot efficiency defined by @xmath38 and @xmath39 is the figure of merit , a dimensionless quantity , defined as- @xmath40 graphene is a 2d carbon allotrope with honeycomb lattice structure which consists of two triangular sublattices a and b. to design our system we apply an uniaxial mechanical strain @xcite to the monolayer graphene sheet lying in the @xmath41 plane between @xmath42 and @xmath43 . a potential bias is applied at contact 1 with a finite temperature difference between the two contacts 1 and 2 . the corresponding set up is shown in fig . 1 . in fig . 1 , a general two terminal thermodynamic model is shown to operate between two temperatures @xmath44 and a bias @xmath45 . at steady state , a steady heat and electric current , @xmath9 and @xmath8 flow between these two reservoirs . if @xmath35 and output ( as defined in eq.([power ] ) ) @xmath46 then it is a qhe and if @xmath47 and output @xmath48 then it acts as a refrigerator . in landau gauge , the strain can be expressed as a pseudo magnetic vector potential @xmath49 , where ` + ' and ` - ' signs are for @xmath50 and @xmath51 valley respectively @xcite . this system is described by the hamiltonian , which is given for @xmath50 and @xmath51 valleys as- @xmath52 here @xmath53 $ ] is the strain , @xmath54 are the pauli matrices operating on the sublattices a and b with @xmath55 being the complex conjugate , @xmath56 is the 2d wave vector , @xmath57 being the step function and @xmath58 the fermi velocity . solving the hamiltonian in eq . ( [ ham ] ) we can write the wave equation for @xmath50 valley as- @xmath59 in the next subsection we will solve the ( [ wav ] ) to calculate the transmission @xmath22 for ballistic transport in monolayer graphene with uniaxial strain . let us consider an electron with energy @xmath19 incident on the interface between region 1 and 2 with angle @xmath3 , which can reflect or transmit depending on it s energy and angle of incidence . here , we have three well defined regions - normal graphene @xmath60 , strained graphene between @xmath42 and @xmath43 and again normal graphene for @xmath61 . the wave functions for the three regions for a and b sublattices in @xmath50 valley are given below . + for , @xmath60- @xmath62=\left[\begin{array}{c } ( e^{ik_xx}+r e^{-ik_xx } ) \\(e^{ik_xx+i\phi}-r e^{-ik_xx - i\phi})\end{array}\right]e^{ik_yy}\end{aligned}\ ] ] + in region @xmath63- @xmath64=\left[\begin{array}{c } ( a e^{iq_xx}+b e^{-iq_xx } ) \\ ( a e^{iq_xx+i\theta}-b e^{-iq_xx - i\theta } ) \end{array}\right]e^{ik_yy}\end{aligned}\ ] ] and for @xmath61- @xmath65=\left[\begin{array}{c } t e^{ik_xx } \\t e^{ik_xx+i\phi } \end{array}\right]e^{ik_yy}\end{aligned}\ ] ] + where @xmath66 is the @xmath67 component of momentum wave vector inside the strained region . in the normal regions @xmath68 is replaced with @xmath69 and @xmath70 wherein @xmath71 and @xmath72 . in the strained region @xmath73 and @xmath74 , @xmath4 being the refraction angle in the strained region as shown in fig . 1(bottom ) and also satisfies @xmath75 . to solve eq . ( [ wav ] ) for the wave functions in eqs . ( [ a]-[c ] ) we impose following boundary conditions- + at @xmath42- @xmath76 and at @xmath43- @xmath77 solving eqs . ( [ ba]-[bb ] ) we get the transmission probablity for @xmath50 valley as- @xmath78+\sin^2[q_xl](\frac{1-\sin[\theta]\sin[\phi]}{\cos[\theta]\cos[\phi]})^2}\end{aligned}\ ] ] finally from the hamiltonian for @xmath51 valley as in eq . ( [ ham ] ) and imposing boundary conditions similar to that for @xmath50 valley and then replacing @xmath79 , @xmath80 we get the transmission probability for @xmath51 valley . the total conduction then is sum of both k and @xmath51 valley conductances . it so turns out that although transmission @xmath81 differs in @xmath50 and @xmath51 valley , when integrated over @xmath82 this differences disappear . thus total conductance @xmath83 is the twice that of @xmath50 valley conductance . our aim as defined in the introduction was to design an efficient qhe operating at maximum power via strained graphene . the generated power should be comparable to or better than other qhe s based on quantum hall effect@xcite , chaotic cavities@xcite , etc . to generate maximum power the system should have a large seeback coefficient ( @xmath84 ) with a large electrical conductance ( @xmath83 ) , as power is proportional to the @xmath85 , see eq . ( [ pmax ] ) . increasing strain reduces the electrical conductance , see fig . 2 , but increases the seeback coefficient , as in fig . 3 . as strain increases the transmittance of electrons through strained graphene decreases , thus reducing the electrical conductance . from fig . 2 , we see that increasing strain opens a gap in the conduction , not a band gap , it is due to the shift of the dirac cones by the strain in the brillouin zone . a real energy band gap opens for a strain beyond 20 percent ( 540 mev ) in pristine graphene @xcite , so we will restrict ourselves only to a maximum of 15 percent strain ( 400 mev ) . a sign change seen in fig . 3 , for the seeback co - efficient near the charge neutrality point ( cnp ) , is due to switching between hole and electron carriers . the first peak , close to the cnp , is due to the imbalance between electron and hole contributions to the thermo - electric co - efficient @xmath86 , and is present even at zero strain . this peak dies at a distance from the cnp . the origin of the second peak in the seeback co - efficient ( blue line in fig . 3 ) is due to the applied strain . as a result of this strain , transmission becomes a function of the fermi energy and gives rise to a large seeback co - efficient , which leads to large power with finite efficiency . at lower levels of strain ( @xmath87 mev ) our proposed qhe can exhibit maximum power , i.e. , 0.2 @xmath88 pico watt at 30 k for 40 nm strained region , with @xmath89 , see figs . 4 and 5 . this is more than what is seen in two and three terminal quantum hall heat engines operating at maximum power@xcite . the efficiency at maximum power @xmath90 is @xmath91 , which is also good enough as compared to the other qhe s , see fig . 6 . efficiency at maximum power can also be raised to more than 0.4 @xmath37 , as in fig . 7 , but then maximum power @xmath92 reduces to less than 0.03 @xmath93 . this is because maximum power generated in the qhe depends on both seeback co - efficient and electrical conductance , see eq . ( [ pmax ] ) , and these two factors so conspire to reduce the maximum power . however , the overall efficiency at maximum power again though dependent on seeback co - efficient ( @xmath84 ) , conductance @xmath83 and thermal conductane @xmath30 , effectively increases with increasing strain , see fig . 7 . individually , seeback co - efficient increases with increasing strain , while for @xmath83 and @xmath30 it is the opposite . although , the maximum efficiency @xmath90 and maximum power @xmath92 generated for this system are better than comparable qhe s proposed , the dimension of the considered heat engines , as in the figs . 2 - 7 , is large ( @xmath94 @xmath95 ) . an effective qhe should deliver high power with high efficiency and its dimensions should be as small as possible , so that in less area more number of nano heat engines can be fabricated , and thus total generated power would be large . from fig . 8(a ) , we see that with increasing strain(150mev ) but decreasing the length ( @xmath96 ) of the strained region , massive power can be generated at high efficiency . the performance of the heat engine can be increased further by tuning one more variable , the fermi velocity @xmath58 . we have considered the fermi velocity of dirac electrons to be equal to @xmath97 m/s , but increasing strain reduces@xcite the fermi velocity to around @xmath98 m/s , the performance of the qhe can thus increase further , such that the maximum power as well as efficiency at maximum power both are enhanced to values as high as 0.28 @xmath93 and 0.1@xmath37 respectively , see fig . this can be understood better , if a 1@xmath99 area is occupied by our proposed nanoscale qhe s in parallel , then 0.06 watts total power can be generated with an efficiency of 0.1 @xmath37 , which is better than quantum hall heat engines , see table 1 . increasing temperature , seeback coefficient and electrical conductance both can be increased to a large value with a maximum power more than 0.2@xmath93 ( at @xmath100 m / s ) and efficiency at maximum power also more than @xmath91 . but then the phonon contribution to the thermal conductivity comes into play and that increases the thermal conductivity , implying a reduction in zt , thermodynamic figure of merit . this in turn reduces the efficiency at maximum power , though it does not affect the power of the qhe . we do not consider the phonon contribution , hence in our calculations and figures plotted have restricted ourselves to an upper limit for temperature of 30k , at which the phonon contribution can be safely neglected @xcite . .how does the strained graphene qhe compare with related proposals ? [ cols="^,<,<,<",options="header " , ] finally we discuss the use of our model as a quantum refrigerator . as in our model external magnetic field is absent , so time - reversal symmetry ( tr ) is not broken . the co - efficient of performance of the refrigerator is defined by the ratio of heat current extracted from the hot reservoir to the electrical power @xmath101 , such as - @xmath102 which is maximum , considering @xmath47 and @xmath103 , for - @xmath104 where @xmath105 is the efficiency of an ideal refrigerator . for the systems with broken tr symmetry , the upper bound of the refrigerator efficiency @xmath106 is always less than @xmath107 . for systems with conserved tr symmetry , the asymmetric parameter @xmath108 becomes unity , and the upper bound of the corresponding maximum efficiency @xcite @xmath106 equals @xmath107 . this is the advantage of systems with conserved tr symmetry , that it can work as both heat engine as well as a refrigerator , but for systems with broken tr symmetry , they can only work as a heat engine . we show here that strain acting solely can act as a qhe with better performance characteristics like high efficiency than most other qhe like quantum hall heat engine , chaotic cavity qhe , etc . it has some advantage over magnetically driven qhe . application of magnetic field breaks the tr symmetry , which in turn reduces the performance of the system as a refrigerator . on the other hand , strain does not break tr symmetry , so our system can act as both heat engine as well as refrigerator @xcite . in table 1 we compare efficiency @xmath90 , power @xmath92 and total power generated for some configured open qhe s . we see that our model system has excellent characteristics compared to other qhe s . this raises a question that perhaps large power and efficiency can also be found with different kind of strain patterns in multi - terminal graphene system , for which further investigations are needed . muttalib and selman hershfield , nonlinear thermoelectricity in disordered nanowires , phys . rev . applied 3 , 054003 ( 2015 ) . https://en.wikipedia.org/wiki/quantum_heat_engines_and + _ refrigerators . t. prosen , revisiting thermodynamic efficiency , physics 6 , 16 ( 2013 ) . f. j. pena , e. munoz , magnetostrain - driven quantum engine on a graphene flake , phys . rev . b 91 , 052152 ( 2015 ) . m. c. nguyen , et . al . , enhanced seebeck effect in graphene devices by strain and doping engineering , physica e. 73 , 207 ( 2015 ) . babak zare rameshti and ali g. moghaddam , spin - dependent seebeck effect and spin caloritronics in magnetic graphene , phys . rev . b 91 , 155407 ( 2015 ) . g. benenti , k. saito , g. casati , thermodynamics bounds on efficiency for systems with broken time - reversal symmetry , prl 106 , 230602 ( 2011 ) . v. m. pereira and a. h. castro neto , strain engineering of graphene s electronic structure , prl 103 , 046801 ( 2009 ) . b. sothmann , r. sanchez , a. n. jordan , and m. buttiker , phys . rev . b 85 , 205301 ( 2012 ) . patrick p. hofer and bjorn sothmann , quantum heat engines based on electronic mach - zehnder interferometers , phys . rev . b 91 , 195406 ( 2015 ) . a. n. jordan , b. sothmann , r. sanchez , and m. buttiker , phys . b 87 , 075312 ( 2013 ) . e. munoz , f. j. pena , megneticlly driven quanum heat engine , phys rev b 89 , 052107 ( 2014 ) . harihar behera and gautam mukhopadhyay , fermi velocity modulation in graphene by strain engineering , aip conference proceedings , 1512 , 1 ( 2013 ) . f. mazzamuto , et . al . , enhanced thermoelectric properties in graphene nanoribbons by resonant tunneling of electrons , phys b 83 , 235426 ( 2011 ) . kay brandner , et . , strong bounds on onsager coefficients and efficiency for three - terminal thermoelectric transport in a magnetic field , phys . 110 , 070603 ( 2013 ) . v. m. pereira and a. h. castro neto , tight - binding approach to uniaxial strain in graphene , phys . b. 80 , 045401 ( 2009 ) .

a strained graphene monolayer is shown to operate as a highly efficient quantum heat engine delivering maximum power . the efficiency and power of the proposed device exceeds that of recent proposals . the reason for these excellent characteristics is that strain enables complete valley separation in transmittance through the device , implying that increasing strain leads to very high seeback coefficient as well as lower conductance . in addition , since time - reversal symmetry is unbroken in our system , the proposed strained graphene quantum heat engine can also act as a high performance refrigerator .

although its incidence is decreasing , coronary stent dislodgement continues to occur in this modern era of percutaneous coronary interventions ( pci ) . it is often associated with significant morbidity , including systemic or coronary embolizations , acute myocardial infarctions ( mi ) , emergency coronary artery bypass graft surgeries ( cabg ) , and even death.1 ) several factors are associated with stent dislodgement , including heavy vessel calcification , pronounced vessel tortuosity , diffuse disease , and an attempt to deliver a stent to a distal lesion through a previously implanted proximal stent.2 ) unfortunately , coronary stents can not be extracted or repositioned after deployment . extraction of a fully deployed stent may cause endothelial injury , dissection , or perforation of coronary arteries . while many reports have previously described retrieval of a dislodged stent , reports on cases of fully deployed stent are rare . we report a case of extraction of a fully deployed coronary stent during retrieval of another dislodged stent . a 65-year - old male patient visited a local hospital complaining of chest pain , but did not present with any cardiovascular risk factors . coronary angiography ( cag ) at a local hospital revealed severe three vessel disease . the patient was found to have 90% stenosis in the proximal segment of the left anterior descending artery ( lad ) , 90% stenosis at the proximal segment , total occlusion at the distal segment in the left circumflex artery ( lcx ) , and the right coronary artery ( rca ) showed diffuse , tortuous , and up to 90% stenosis at the proximal to mid segment with near total occlusion at the distal segment ( fig . 1a ) . a 2.7526 mm drug eluting stent ( des ) was implanted in the proximal lad and two dess of 2.7538 mm , and 2.7522 mm ( xience xpedition , abbott vascular , santa clara , ca , usa ) were implanted in the proximal and mid segments of the rca , respectively ( fig . 1b ) . on the next day , staged pci for distal rca was attempted via the right femoral artery . after pre - dilation with a 2.520 mm balloon at the distal rca , the operator made several attempts to deliver a 2.538 mm des ( promus premier , boston scientific , mn , usa ) through a previous stent with no success . while pulling the undeployed stent back into the guiding catheter , it became entrapped by the fully deployed proximal rca des ( xience xpedition , abbott vascular , santa clara , ca , usa ) . after several retrieval attempts , the undeployed stent was totally detached from the stent balloon . fluorography revealed that part of the dislodged stent was almost located out of the rca ostium , and flail motion of the stent , which was still entangled with a previous stent at the proximal rca , was noted in the ascending aorta ( fig . the patient complained of chest pain and his electrocardiogram revealed st segment elevation in leads ii , iii , and avf . the patient was subsequently transferred to our hospital . through an 8 fr guiding catheter ( jr 4.0 , cordis , bridgewater , nj , usa ) , a snare catheter ( 6 fr , 15 mm , multi - snare , pfm medical , carlsbad , ca , usa ) was positioned to capture the stent . after several attempts in the ascending aorta , we were able to seize the middle part of the undeployed stent and pushed and pulled the captured snare system several times with the aim of detaching it from the deployed des ( fig . , the deployed des at the proximal rca had gradually elongated into the aorta ( fig . thus , we decided to extract the two stents ( dislodged and fully deployed elongated stent ) as a last resort . after tugging with adequate manual force , the captured dislodged stent was bent in half and , successfully retrieved into the guiding catheter ( fig . subsequently , both the undeployed and elongated deployed stents were successfully withdrawn into the guiding catheter under maximal manual retraction ( fig . after removal of the guiding catheter including the snare catheter and two stents , a follow - up cag revealed dissection at the proximal rca , without any remnant part of the two stents . two des ( 3.534 mm at proximal rca , 3.038 mm at d - rca , resolute integrity , medtronic , santa rosa , ca , usa ) were successfully implanted under intravascular ultrasonography ( ivus , opticross , boston scientific , natick , ma , usa ) guidance . 2f ) and the patient was free of angina and subsequently discharged two days after the procedure . coronary stent dislodgement is a catastrophic complication of pci and is associated with arterial thrombosis , embolism due to retained stent fragments , and major adverse cardiovascular events ( including myocardial infarction , stroke , and death).3 ) successful retrieval is important as it is associated with a good prognosis.1 ) there are two retrieval methods available , either surgical or percutaneous . percutaneous retrieval can be a good therapeutic option when the clinical situation and the patient 's vital signs are stable . several percutaneous retrieval techniques using a snare,4 ) wire,5 ) and balloon6 ) have previously been established and a number of unique cases have been reported.7)8 ) in our case , the part of dislodged stent almost protruding into the ascending aorta and the distal remnant part was tightly entangled with the fully deployed stent in the proximal rca . as we know , this is a situation that is rarely encountered and as such , common retrieval methods have several limitations . our solution in this case was to first capture the middle portion of the undeployed dislodged stent using a multi - snare catheter in order to maximize the force of retraction , a unique point in our case . the dislodged stent was bent in half and safely and fully retrieved into the guiding catheter . next , under normal manual retraction force , the proximal rca deployed stent was gradually elongated . it was , however , not separated from the undeployed dislodged stent as the two were tightly entangled with each other . as we had no other option , we were forced to pull back on the two stents , finally extracting the fully deployed stent together with the dislodged stent without any major complications . the successful extraction of a fully deployed stent in this case can be attributed to several factors . first , we performed ivus of the rca after both stents were removed and this showed that the vessel diameter of the proximal rca was considerably larger ( 3.7 mm ) than the previously deployed proximal rca stent diameter ( 2.75 mm ) . ivus also showed large amounts of remnant plaque burden , which suggests severe insufficient plaque modification . these findings suggest underexpansion and incomplete apposition of the stent , and paradoxically , would have facilitated stent extraction . second , we attempted to remove the stent just one day after the first procedure had been performed . the proximal rca fully deployed stent was not disconnected but rather elongated . to elucidate the mechanism of this phenomenon our results showed that a stent with 3 connectors ( xience xpedition , abbott vascular , santa clara , ca , usa ) was not disconnected , while a stent with 2 connectors ( promus premier , boston scientific , mn , usa ) was fractured into four segments ( fig . we believe that the number of stent connectors is therefore critical when attempting this procedure . if the deployed stents were comprised of 2 connectors ( for example , a promus stent ) , we would have alternatively considered surgical removal . a small - sized stent when compared to the reference diameter under insufficient plaque modification , and protrusion of the stent into the aorta are the main reasons for successful retrieval in this case . however , they are also the cause of complication . we have frequently encountered difficulties when attempting to deliver a stent to a distal lesion through a previously implanted proximal stent . to avoid a stent trapping while passing through a previous stent , sufficient plaque modification should be performed at the site of the lesion prior to implantation to ensure that the stent is appropriate for the luminal area . implantation of the distal stent first , and the proximal stent last , is a more reasonable and recommended method . in conclusion , extra care should be given to avoid stent dislodgement when the lesion itself has many risk factors . should an event occur such as that described in our case , extraction of a fully deployed stent may be carefully executed , provided there is a thorough understanding of the surrounding circumstances .

coronary stent dislodgement is a rare and serious complication of percutaneous coronary intervention and is associated with major adverse cardiac events . successful retrieval of the stent is recommended in this situation because it is important for the prognosis . recently , a patient was referred to our hospital with a dislodged coronary stent . when attempting to percutaneously extract the dislodged stent , a challenging situation was encountered , as the stent was entrapped and tightly entangled with another fully deployed coronary stent . extraction of a fully deployed stent is generally prohibited as it may result in severe complications . nevertheless , we extracted both the dislodged stent and the fully deployed stent , as a last resort . herein , we report about this case . our case highlights if the operator had a thorough understanding of the surrounding circumstances regarding the fully deployed coronary stent , successful extraction of the fully deployed coronary stent without any complications could be possible .

the cast metal core is a component frequently used to restore endodontically treated teeth with extensive coronal destruction [ 1 , 2 ] . post retention in the root canal is fundamental for the longevity and success of treatment . length , shape , diameter , and post surface , as well as the type of cement used , are factors that may affect core retention and stability . a prefabricated retainer must adapt adequately to the prepared root canal ; otherwise , a cast post and core should be the treatment option . there is no consensus with regard to the choice of a luting agent for cast metal cores ; therefore , the choice of cement must take into consideration its biological and functional properties [ 4 , 5 ] . an ideal luting agent must be sufficiently fluid to flow , provide adequate working and setting time to allow the part to seat , permit easy removal of excess material , and allow adjustments to be made to the part without losing retention . cements can retain the core in the root canal mechanically , chemically , or by other means . mechanical bonding is not always effective for retention , and a cement with the potential to chemically bond to tooth surfaces and prosthesis may be indicated . in addition to being the material most frequently used for this purpose , zinc phosphate cement is the oldest of the luting agents ; therefore , it serves as a standard for comparison with new systems [ 79 ] . it has high resistance and forms a thin film ; it can support elastic deformations even when it is used as a luting agent for restorations subject to high masticatory stresses . more recently , resin cements have become an alternative to zinc phosphate cement , particularly because they are practically insoluble in the oral medium and have adhesive properties [ 1 , 9 , 11 , 12 ] . dual - activated cements provide long working time until they are exposed to light activation , and , due to the chemical polymerization process , their bond strength continues to increase over time . however , after posts have been cemented with resin agents , stresses produced by polymerization shrinkage may harm the integrity of the bond between the resin cement and the root canal walls . the use of sodium hypochlorite as an irrigant solution during endodontic treatment , as well as filling cements containing eugenol in their formulae , may also influence retention of posts cemented with resin cement [ 1416 ] . some studies have concluded that cores cemented with zinc phosphate cement have retention values higher than or similar to those cemented with resin cements [ 1720 ] . however , other studies have shown better performance of resin cements when compared with zinc phosphate cement . amongst the various reasons for failure in teeth restored with a core , detachment , displacement , and root fracture occlusal forces and predominantly functional and occasionally parafunctional forces tend to make cemented posts unstable in teeth that need coronal reconstruction . coronal preparation of the cast metal core after cementation may contribute to reducing its retention . studies have proved the capacity of ultrasound vibration in facilitating removal of cemented posts in endodontically treated teeth [ 21 , 23 ] . high - speed rotary instruments cause similar vibrations , which suggests that the layer of cement formed between the tooth and post may be fractured , thus compromising core retention . the aim of this study was to investigate the effect of post - cementation waiting time for coronal preparation of core and the different types of cement had on cast metal core retention in root canals . in this study , 60 extracted human canines of approximately the same size were collected and stored in aqueous 0.1% thymol . each tooth was sectioned perpendicularly to its long axis 16 mm from the root apex , using a double - faced diamond disk number 7020 ( kg sorensen ind . ltda , barueri , sp , brazil ) coupled to a straight handpiece at low speed , leaving a flat surface . the largest vestibular - lingual ( vl ) and mesiodistal ( md ) diameters of the flat surfaces of the roots were recorded with a digital pachymeter ( mitutoyo sul amrica ltda . , suzano , sp , brazil ) . these measurements were statistically compared to certify that the difference between the areas was not significant , and the discrepant teeth were eliminated . the root canals were debrided conventionally with the k - type files up to number 45 ( maillefer instruments , ballaigues , switzerland ) , irrigated with 5 ml of 2.5% sodium hypochlorite over 5 minutes , and filled using the lateral condensation technique with gutta - percha and a calcium hydroxide - based and eugenol - free endodontic cement ( sealer 26 , dentsply materiais odontolgicos , rio de janeiro , rj , brazil ) . , rio de janeiro , rj , brazil ) and stored in distilled water in an oven at 37c for 7 days . to prepare the cores , 10 mm of root filling was removed with a peeso bur ( number 4 maillefer instruments , ballaigues , switzerland ) at low speed controlled with a cursor . the root canals were cylindrical with 10 mm length and 1,3 mm diameter ; they had the peeso bur number 4 dimensions . to complete the preparation , a small channel was made on the internal vestibular wall of the root canal with a spherical carbide bur number 4 ( kg sorensen ind . ltda , barueri , sp , brazil ) to guide the insertion of the cast core and prevent it from rotating . the root canals and coronal surfaces were isolated with lubricant gel ( ky , johnson & johnson industrial ltda , so jos dos campos , sp , brazil ) to mold the cores . co. , usa ) with the aid of prefabricated plastic posts ( pinjet , angelus , londrina , pr , brazil ) for use in the 60 prepared teeth . in order to standardize the coronal portion of the cores , hollow crowns were used ( provjet - angelus - londrina , paran , brazil ) . all the cores were made 1 mm short from the external margin of the flat coronal face of the tooth . the cores were cast in ni - cr alloy ( talladium do brasil , curitiba , pr , brazil ) and tested in the respective root canals to verify adaptation and were then subjected to airborne abrasion with 50 m aluminum oxide particles . a diamond tip was used to make scratches on the external root surface , perpendicular to the long axis , to provide additional retention of the root during tensile tenting . each tooth was fixed on the rod of a delineator ( bio art , art equipamentos ltda , so carlos , sp , brazil ) with the aid of a number 4 peeso reamer ( maillefer instruments , ballaigues , switzerland ) fitted to the canal so that the roots were perpendicular to the ground . proper devices were developed for the embedded specimens so that they would fit into the adaptor of the universal testing machine . the teeth were cleaned with detergent ( tergensol , inodon laboratrio , porto alegre , rs , brazil ) and the cast metal cores were also washed with detergent ( limpol , bombril s / a , abreu e lima , pe , brazil ) . the cast metal cores in the first group were cemented with zinc phosphate cement ( ss white artigos dentrios ltda , rio de janeiro , rj , brazil ) using the technique described in table 1 , and in the second group they were cemented with resin cement ( panavia f , kuraray co. , osaka , japan ) . the zinc phosphate cement was placed on the post and also inserted into the canal with the aid of a lentulo spiral ( maillefer instruments , ballaigues , switzerland ) . after cementation , all the specimens were placed in a manual press and submitted to a 5 kgf pressure for 10 minutes to assure complete adaptation of the cast metal cores in the respective roots . the excess zinc phosphate cement was removed immediately after setting ( 10 minutes ) . in order to remove the excess resin cement , it was light activated for 10 seconds on the incisal margin of the core in the direction of the root . each face of the tooth was then light activated for another 20 seconds with the light facing the core - tooth interface . to light activate the resin cement , a halogen light - curing appliance ( optilight ld max , gnatus , ribeiro preto , sp , brazil ) with an irradiance of 450 mw / cm was used . each group of 30 teeth was subdivided into the following three groups ( n = 10 ) : group 1 ( control ) , time delay after setting ; group 2 , coronal portion of post space prepared 15 minutes after cementation ; and group 3 , coronal portion of post space prepared 7 days after cementation . the teeth were stored in a 100% humidity environment heated to 37c during the storage time . figure 1 shows a diagram illustration presenting the experimental design of the tensile strength test . the test specimens were fixed to a lathe and the metal cores were prepared by the same operator , using a tapered round trunk diamond tip ( number 2135 , kg sorensen ind . the coronal portion of the cores was prepared for 4 minutes : 3 minutes of axial preparation and 1 minute of incisal preparation . for the axial preparation , the diamond tip was placed so that it touched only the core in the direction of the long axis of the tooth , simulating preparation for a metal - ceramic crown . the diamond tip remained in contact with the core and the operator sought to exert constant pressure , going over all the faces of the core . for the incisal preparation , the diamond tip was placed forming an angle of 45 with the base . tensile strength tests were performed in a testing machine ( emic , so jos dos pinhais , pr , brazil ) at speed of 0.5 mm / min with a load cell of 2000 kgf . the samples were placed and fastened to an adaptor at the base of the machine . a device on the active part of the machine was placed on the coronal portion of the cast metal core so that tensile force would be applied in the direction of the long axis of the tooth . as soon as the core was displaced , the test was interrupted and the displacement force value was recorded in the program . table 2 shows the results of the tensile strength test ( mean and standard deviation ) and the results of the tukey test . the tensile strength values of the samples cemented with zinc phosphate cement were statistically higher than those of the samples cemented with panavia f resin cement . none of the samples in either group were influenced by the post - cementation time interval waiting for coronal preparation of the core . intraradicular posts are widely used to restore endodontically treated teeth that have insufficient coronal tooth structure to retain a definitive restoration [ 25 , 26 ] . the use of prefabricated posts has become commonplace due to the satisfactory results , the reduction in clinical attendance time , and its quick application , which allows enhanced preservation of the tooth structure . however , a prefabricated retainer must adequately adapt to the prepared root canal ; otherwise a cast post and core may be the treatment option . traditionally , zinc phosphate cement has been used to cement intraradicular retainers , although they have the disadvantage of lacking a bond both to the retainer and to the tooth structure . in this regard in addition to showing good results in retention tests , zinc phosphate cement has shown satisfactory performance in flexural tests and resistance to rotational forces [ 3 , 6 , 8 , 10 , 24 ] . on the other hand , resin cements have also been indicated for cementation of intraradicular retainers . this type of cement could favor the retention of cast metal cores and prefabricated posts . using resin cements was suggested mainly to strengthen the remainder of the tooth , due to the advancement of adhesive systems with properties of bonding to metals [ 18 , 19 , 23 ] . when comparing the means obtained by the resin luting agent and zinc phosphate cement in this experiment , it was observed that the latter showed better performance , corroborating other studies that also showed better results for zinc phosphate in comparison with resin composite used as luting agent in cast metal posts [ 9 , 17 , 20 ] . the hardening of zinc phosphate cement does not involve any reaction with the surrounding mineralized tissue or other restorative materials . therefore , the main bond occurs by mechanical interlocking at the interfaces and not by chemical interactions . due to this method of bonding , it may be inferred that the original adaptation of retainers before cementation and their irregularities may increase the retention of metal cores cemented with zinc phosphate cement . perfect adaptation of cast metal cores to the prepared canal results from the formation of a very thin film of cement . zinc phosphate cement forms a thinner film than the resin cement , which may have contributed to the former 's better performance observed in the present study . due to frictional mechanical retention of the parts involved [ 6 , 9 ] , fracture of this thin film is made more difficult when there is a demand by traction . the manufacturer of panavia f does not recommend inserting the cement into the root canal with the aid of a lentulo spiral because the cement setting may be altered due to the movement of particles , accelerating its setting time . this occurs due to the mixture of cement with the catalyzer ( ed primer ) . however , the use of a lentulo spiral to take the cement into the root canal when cementing cast posts , in addition to the cement applied on the post , prevents the presence of empty spaces inside the canal . in this study , this technique was used for zinc phosphate cement , but not resin cement , which may have contributed to the more favorable result of the former than that obtained with the latter . on the other hand , sodium hypochlorite , traditionally used as a chemical irrigant in endodontic treatment , may remove organic components from dentin , especially collagen , influencing the resin cement bonds to dentin . this might increase penetration of monomers into the demineralized dentinal structure ; however , sodium hypochlorite dissociates into sodium chloride and oxygen . the oxygen present at the tooth - resin cement interface could inhibit cement polymerization and interfere in resin penetration into the dentinal tubules [ 14 , 15 ] . in this regard , the use of sodium hypochlorite as an irrigant of canals another factor relative to endodontic treatment that might interfere with polymerization and resin cement bonding is the use of filling cements containing eugenol in their composition . in order to avoid this interference , calcium hydroxide - based and eugenol - free filling cement the importance of adhesive systems in contemporary dentistry is unquestionable [ 1 , 3 , 6 , 9 ] . the introduction of resin cements in dentistry has provided a significant improvement in the success rates of restorations retained by intraradicular retainers . thus , the good performance of resin cements in comparison with zinc phosphate cement has also been reported in the cementation of cast metal cores , prefabricated posts , indirect restorations , and fixed dentures [ 3 , 5 , 6 , 21 , 25 , 28 ] . there are studies that have compared the retention of cast titanium cores cemented with zinc phosphate cement and resin cement and found no difference between the two types of cements [ 18 , 19 ] . it should be pointed out that resin cements have some disadvantages ; such as it is critical to use the correct technique , it is difficult to remove excess material when cementing , and it has a high cost . some studies have suggested that the lower values shown by resin cements in comparison with zinc phosphate cement are due to stress generated during polymerization shrinkage of resin cement , which causes its displacement from the dentinal surface as well as incomplete bonding . the high cavity factor ( i.e. , c factor ) of a root canal and the impossibility of light from the light - curing unit penetrating deep enough into the canal may interfere and lead to the low tensile strength values [ 1 , 15 ] . the use of a primer containing coinitiators , such as panavia f ed primer , is essential for the polymerization of resin cement when it is not exposed to light activation . despite the capacity of the acid resin monomer present in panavia f ed primer to produce bonding between the resin composites and metal , the bond strength shown by panavia some studies indicate that immature cement that is disturbed during setting time due to the preparation of the core may cause loss of cementation and , consequently , displacement of the post and it is suggested that the use of high - speed rotary instruments during the core repreparation is capable of causing vibration , damaging the cement film between the post and the root canal surface . therefore , it is recommended that this type of preparation should not be performed immediately after cementation of intraradicular retainers [ 24 , 29 ] . however , this study showed that the preparation of metal cores had no influence on the retention values obtained by tensile test . the differences in the results of these studies can be attributed to the variations in the study model that affect their clinical performance , particularly with regard to resin cements , technique sensitivity , and the difficulties with manipulation . one of the relevant physical properties of the cement for retaining fixed dentures is its mechanical properties . although zinc phosphate cement shows relatively low solubility in water , it is very resistant and capable of supporting elastic deformations even when it is used as a luting agent for restorations subject to high masticatory stresses . in this study , the retention values of the zinc phosphate cement were much higher than those for the resin cement . there are some factors that may justify the results found , such as the methods of inserting the cement into the root canals , difficulty of polymerizing resin cement , cement film thickness , and the use of sodium hypochlorite to irrigate the root canals . zinc phosphate cement is less sensitive to technique and is more retentive in the cementation of cast metal cores than resin cement and , therefore , it is recommended over resin cement . coronal preparation of the core performed immediately after cementation did not diminish its retention , which favors the use of this clinical procedure due to its reduction in working time . it may be concluded that cast metal cores cemented with zinc phosphate cement showed higher tensile strength values in comparison with resin cement . the preparation time of metal cores did not influence retention values obtained by the tensile test .

this study aimed to assess the effect of post - cementation waiting time for core preparation of cemented cast posts and cores had on retention in the root canal , using two different luting materials . sixty extracted human canines were sectioned 16 mm from the root apex . after cast nickel - chromium metal posts and cores were fabricated and luted with zinc phosphate ( zp ) cement or resin cement ( rc ) , the specimens were divided into 3 groups ( n = 10 ) according to the waiting time for core preparation : no preparation ( control ) , 15 minutes , or 1 week after the core cementation . at the appropriate time , the specimens were subjected to a tensile load test ( 0.5 mm / min ) until failure . two - way anova ( time versus cement ) and the tukey tests ( p < 0.05 ) showed significantly higher ( p < 0.05 ) tensile strength values for the zp cement groups than for the rc groups . core preparation and post - cementation waiting time for core recontouring did not influence the retention strength . zp was the best material for intraradicular metal post cementation .

“I would not feel so alone,” sang Bob Dylan back in 1966, “everybody must get stoned.” It would seem lots of people have obliged: cannabis is now far and away the world’s favourite illicit drug, with approximately 180 million people having taken it in the past year. In England and Wales about 13.5% of 16 to 24 years olds have used cannabis in the past year, and almost one in three people will try it at least once during their lifetime. Of the 6.4% of adults aged 16-59 who reported using cannabis in the past year, over 40% said they used it at least once a month. Given that a significant chunk of the population are consuming the stuff, it is perhaps not surprising that most people believe the risks involved in getting stoned are more or less equivalent to the risks from getting drunk. US president Barack Obama seems to be one of them: “I smoked pot as a kid, and I view it as a bad habit and a vice, not very different from the cigarettes that I smoked as a young person up through a big chunk of my adult life," he explained to the New Yorker. "I don't think it is more dangerous than alcohol." Certainly many people use cannabis without adverse effects, and indeed with plenty of very pleasant ones. Moreover, there is evidence that cannabis can bring real medical benefits, for example in alleviating chronic pain. But there is also known to be a link between cannabis and paranoid thoughts. “Paranoid” in this context means the unfounded or excessive fear that other people are trying to harm us. It’s a feeling that is far more common than previously thought. That is understandable given that we are all constantly compelled to interpret social situations, weighing up the attitudes and intentions of the people we meet. Because it is impossible to know for sure what other people are thinking, there is ample scope for our anxiety to get the better of us. Like most psychological experiences, there is a spectrum of paranoia within the population: many people have a few, relatively mild paranoid thoughts, while for a few people those thoughts are numerous, persistent, and profoundly unsettling. Cannabis users are more likely to be at the problematic end of that spectrum. For instance, our study of the population of England found that the belief that people are deliberately trying to harm you is three times as common among cannabis users as it is among non-users. The belief that people are trying to cause you serious injury or harm is five times as common among cannabis users. However, what we see here is an association between cannabis and paranoia. Experts generally agree that regular use of cannabis starting from an early age is an accurate predictor of later severe mental health problems, but what hasn’t been established is whether the drug causes paranoid thoughts. Maybe people suffering from paranoia are more likely to start taking cannabis; or perhaps the drug use and the suspicious thoughts are independent consequences of another factor entirely. This question of the tangled interrelationship of paranoia and cannabis use was at the heart of a study we conducted with colleagues from the University of Oxford, the Institute of Psychiatry at King's College London, and the University of Manchester, published on Wednesday in Schizophrenia Bulletin. Why did we focus on paranoia rather than mental health in general? Other studies tend to lump all such problems together under the heading of “psychosis” or “schizophrenia”, but as we’ve argued previously on this blog such experiences frequently occur independently: having paranoid thoughts doesn’t mean, for example, that someone will also hear imaginary voices. To discover whether cannabis really does cause paranoia in vulnerable individuals, we carried out the largest ever study of the effects of THC (∆9-tetrahydrocannabinol, the drug’s principal psychoactive ingredient). We recruited 121 volunteers, all of whom had taken cannabis at least once before, and all of whom reported having experienced paranoid thoughts in the previous month (which is typical of half the population). None had been diagnosed with a mental illness. The volunteers were randomly chosen to receive an intravenous 1.5mg dose of either THC (the equivalent of a strong joint) or a placebo (saline). To track the effects of these substances, we used the most extensive form of assessment yet deployed to test paranoia, including a virtual-reality scenario, a real-life social situation, self-administered questionnaires, and expert interviewer assessments. The results were clear: THC caused paranoid thoughts. Half of those given THC experienced paranoia, compared with 30% of the placebo group: that is, one in five had an increase in paranoia that was directly attributable to the THC. (Interestingly, the placebo produced extraordinary effects in certain individuals. They were convinced they were stoned, and acted accordingly. Because at the time we didn’t know who had been given the drug, we assumed they were high too.) THC also produced other unsettling psychological effects, such as anxiety, worry, lowered mood, and negative thoughts about the self. Short-term memory was impaired. And the THC sparked a range of what psychologists call “anomalous experiences”: sounds seemed louder than usual and colours brighter; thoughts appeared to echo in the individuals’ minds; and time seemed to be distorted. Why is cannabis such a potent trigger for paranoia? Our statistical analysis showed that in our experiment the culprits were THC’s negative effects on the individual’s mood and view of the self, and the anomalous sensory experiences it can produce. Negative emotions leave us feeling down and vulnerable. Worry leads us to the worst conclusions. So when we try to make sense of the anomalous experiences – when we try, in other words, to understand what’s happening to us – the world can appear a weird, frightening and hostile place. Hence the paranoia. Our analysis suggests that the impairments in short-term memory did not increase the paranoia. Clearly cannabis doesn’t cause these problems for everyone. And the suspiciousness wore off as the drug left the bloodstream. But the study does show that paranoia isn’t tenuously linked to THC: for a significant number of people, it’s a direct result. Perhaps most importantly, the research shines a light on the psychological processes underlying paranoia in general. When we worry, think negatively about ourselves and experience perceptual disturbances, it’s much more likely that we will feel needlessly suspicious of others. Follow @ProfDFreeman and @JasonFreeman100 on Twitter ||||| In what is deemed the largest and most in-depth study of the effects of the main ingredient in marijuana, researchers say they have identified the psychological factors that can lead to feelings of paranoia among users of the drug. The research team, led by Prof. Daniel Freeman of the University of Oxford in the UK, recently published their findings in the journal Schizophrenia Bulletin. Marijuana, also known as cannabis, is a drug that is produced from the plants Cannabis sativa or Cannabis indica. The main active ingredient in marijuana is delta-9-tetrahydrocannabinol (THC), which is responsible for the majority of the drug's psychological effects, such as hallucinations and delusions. Researchers suggest that THC - the main active ingredient in marijuana - causes certain negative feelings and changes perceptions that induce paranoid feelings among users of the drug. Researchers suggest that THC - the main active ingredient in marijuana - causes certain negative feelings and changes perceptions that induce paranoid feelings among users of the drug. Past research has indicated that marijuana use can induce paranoia - which Prof. Freeman describes as "excessive thinking that other people are trying to harm us." "It's very common because in our day-to-day lives we have to weigh up whether to trust or mistrust, and when we get it wrong - that's paranoia," he explains." Many people have a few paranoid thoughts, and a few people have many paranoid thoughts." For the study, Prof. Freeman and colleagues tested the effects of THC on 121 participants ages 21-50 in order to see whether the compound triggers paranoid feelings and how it does this. All participants had used cannabis at least once previously and had no history of mental health conditions. Two thirds of participants were injected with THC at a dose equivalent to a strong joint, while a third of participants were injected with a placebo. The researchers note that they chose to inject the participants with the compound as it ensured they all had similar levels of THC in their bloodstream. The researchers report that the effects of THC on participants lasted for 90 minutes. THC causes 'negative feelings and changes in perception that induce paranoia' Results of the study revealed that among participants who were injected with THC, around 50% reported paranoid thoughts, compared with 30% of participants who received the placebo. The researchers note that as the compound left the bloodstream, feelings of paranoia reduced. The team found that THC also induced anxiety, worry, reduced mood, negative thoughts about oneself, changes in perception - including the report of louder noises and clouds being brighter - and altered their perception of time. Using a statistical analysis, the researchers found that it may be these negative feelings and changes in perception that cause paranoid feelings among marijuana users. The team says their findings not only "very convincingly" show that cannabis can cause short-term paranoia in some users, but they may also explain how our mind encourages paranoid feelings. "Paranoia is likely to occur when we are worried, think negatively about ourselves, and experience unsettling changes in our perceptions," says Prof. Freeman, adding: "The study identifies a number of highly plausible ways in which our mind promotes paranoid fears. Worry skews our view of the world and makes us focus on perceived threat. Thinking we are inferior means we feel vulnerable to harm. Just small differences in our perception can make us feel that something strange and even frightening is going on." He notes that although the study - funded by the UK's Medical Research Council - provides more information about the immediate effects marijuana can have, it does not look at the effects of cannabis addiction and therefore "does not necessarily hold implications for policing, the criminal justice system or legislation." "The implication is that reducing time spent ruminating, being more confident in ourselves, and not catastrophizing when unusual perceptual disturbances occur will in all likelihood lessen paranoia," adds Prof. Freeman. This research is the latest in a line of studies that reveal potential negative implications of marijuana use. Earlier this year, Medical News Today reported on a study suggesting that marijuana use may increase the likelihood of sleep problems, while another study published in the Journal of the American Heart Association links cannabis use to cardiovascular complications and death.

– There has long been a known association between marijuana and paranoia, but UK researchers wanted to find out if cannabis actually causes paranoia in some people—and the answer is a resounding yes, write researchers Daniel Freeman and Jason Freeman in the Guardian. They studied 121 people who had taken cannabis at least once, reported paranoid thoughts sometime during the past month, and had not been diagnosed with a mental illness. Then, in a random and blind test, two-thirds received an intravenous dose of THC (equivalent to a "strong joint," Medical News Today notes) while the rest got a placebo. Then paranoia was comprehensively tracked, and half of the subjects who'd received THC experienced it, compared to 30% of those who got the placebo. "That is, one in five had an increase in paranoia that was directly attributable to the THC," the researchers write. The study shows that "paranoia isn’t tenuously linked to THC: For a significant number of people, it’s a direct result." The researchers also found that the THC produced other negative mental health effects, including anxiety, negative thoughts, and lowered mood. Oh, and it also caused "anomalous experiences" like echoing thoughts and a distorted sense of time, sounds, and colors. Trying to make sense of those experiences while already in a vulnerable state (thanks to the lowered mood) could lead to the paranoia, the researchers suggest. The good news? Subjects' paranoia decreased as the drug left their bloodstream. (Cannabis is also genetically linked to schizophrenia.)

A 40-year-old Army veteran and suspected white supremacist who gunned down six inside a Milwaukee-area Sikh temple shot the responding officer eight to nine times before he was killed by police, authorities said Monday. Officials said the gunman, whom they identified as Wade Michael Page, walked into the Sikh Temple of Wisconsin on Sunday and opened fire with a 9mm semi-automatic handgun as several dozen people prepared for morning services. The victims ranged in age from 39 to 84, authorities said. Three others were wounded and remain in critical condition, including 51-year-old veteran police officer Brian Murphy. Authorities said during a Monday press conference that there is no reason to believe anyone other than Page was involved in the shooting in the Milwaukee suburb of Oak Creek. The FBI had shown a photo of a person wanted for questioning, but after talking with the man, he was not found to be tied to the shooting. FBI Special Agent in Charge, Teresa Carlson, said a motive is still under investigation, and noted that authorities are looking at Page's "ties to white supremacist groups." Carlson said the shooting is being investigated as a "possible act of terrorism." She said the suspect "had contact with law enforcement in the past," but said there was no reason to believe he was capable of such violence. "Nobody knew that this guy was a threat," Carlson said. Oak Creek Police Chief John Edwards said police received a distress call at 10:25 a.m. from inside the temple. He said the shooting suspect ambushed and opened fire on Murphy, a 20-year veteran of the police force, after he showed up on scene and tried to help a victim outside. Murphy was shot by the suspect eight to nine times, Edwards said. Other officers responding to the scene exchanged rounds of gunfire with the suspect before "putting the individual down," Edwards said. Four people were found dead inside the temple, while three, including the suspected shooter, were found dead outside. The victims were identified Monday as Sita Singh, 41, Ranjit Singh, 49, Satwant Singh Kaleka, 65, Prakash Singh, 39, Paramjit Kaur, 41, and Suveg Singh, 84. Sources close to the investigation told Fox News that Page was at one time attached to the Fort Bragg Army installation in North Carolina. Authorities said Page enlisted in April 1992 and was discharged from the Army in 1998 "under honorable conditions," which is less than honorable discharge. While not as negative as a dishonorable discharge, such a release would preclude one from reenlisting or entering another military service, sources explained to Fox News. Reuters reported that the discharge was for "patterns of misconduct," including being drunk on duty. Page served at Fort Bliss, Texas, in the psychological operations unit in 1994, and was last stationed at Fort Bragg, N.C., attached to the psychological operations unit. He was an E4 psychological operations specialist, but was never deployed. He was awarded the Army Commendation Medal, Army Achievement Medal, Army Good Conduct award, the National Defense Service Medal, Humanitarian Service Medal and Parachutist Badge. The shooting left the local Sikh community devastated. Sikhism, a monotheistic faith founded in South Asia more than 500 years ago, has roughly 27 million followers worldwide. Most are in India, though there are an estimated 500,000 in the U.S. Many Sikhs in the U.S. worship on Sundays at a temple, or gurdwara, and a typical service consists of meditation and singing in a prayer room where worshippers remove their shoes and sit on the floor. Worshippers gather afterward for a meal that is open to the entire community. The Sikh Temple of Wisconsin started in 1997 with about 25 families who gathered in community halls in Milwaukee. Construction on the current temple in Oak Creek began in 2006, according to the temple's website. Sikh rights groups have reported a rise in bias attacks since the Sept. 11, 2001, terrorist attacks. The Washington-based Sikh Coalition has reported more than 700 incidents in the U.S. since 9/11, which advocates blame on anti-Islamic sentiment. Sikhs are not Muslims, but their long beards and turbans often cause them to be mistaken for Muslims, advocates say. Satwant Singh Kaleka, president of the temple, was one of those killed. Sources told Fox News he attempted to tackle the suspect as he sprayed gunfire inside the temple. A woman who says she was a neighbor of the suspect tells FoxNews.com that last week she heard yelling coming from the apartment she believes is the same one the FBI is now searching. The neighbor says, as she understood it, the suspect had lived in the apartment with his girlfriend until their recent break-up. The suspect had then moved into another apartment nearby two weeks ago. She says he had returned to the old apartment and was banging on the door of his old apartment, demanding to be let in. The neighbor also said she believed the suspect had a 9-11 tattoo. Another local resident Kurt Weins told the Journal Sentinel he rented out the upper flat of the duplex to a man in his 40s. "I had him checked out and he definitely checked out," Weins told the newspaper. "The cops told me they don't want me to say nothing right now." Click for more from the Journal Sentinel. Click for more from Fox6Now.com. Fox News' Justin Fishel, Mike Levine, Jana Winter and the Associated Press contributed to this report. ||||| NBC's John Yang reports from Oak Creek, Wisc., where a white, male Army veteran is the suspected gunman in a deadly shooting at a Sikh temple which claimed the lives of seven people. Updated at 7:53 a.m. ET: The alleged gunman in Sunday’s killing rampage at a Sikh temple in southern Wisconsin is Wade Michael Page, authorities told NBC’s Pete Williams Monday. Page, who served in the Army from April 1992 through October 1998, allegedly killed six people at the temple and wounded three before he was shot and killed. According to the Southern Poverty Law Center, Page is the former leader of a neo-Nazi music group called End Apathy. Police say Page, 40, purchased the pistol used in the shooting within the past 10 days near his home. A police officer called to the scene shot Page dead before he could fire on more worshippers as they prepared for Sunday services at the temple in the suburb of Oak Creek, south of Milwaukee. Police searched Page’s apartment for clues early on Monday. The FBI said on Sunday that it had not determined a motive for the Sunday morning shooting. Authorities said they were treating the attack as an act of domestic terrorism. The names of the victims were not made public pending notification of relatives, although members said the president of the congregation and a priest were among the victims. Authorities said Page had used a 9mm semi-automatic handgun, which was recovered at the scene. Amardeep Kaleka tells TODAY's Matt Lauer that his community is at a "breaking point" after a gunman opened fire and killed his father and five other faithful inside a Sikh temple in Wisconsin. Wisconsin has some of the most permissive gun laws in the country and had passed a law in 2011 allowing citizens to carry a concealed weapon. Jagjit Singh Kaleka, the brother of the president of the temple, who was among the six Sikhs killed, said he had no idea what the motive was for the attack. "But we know the more assault weapons we distribute the more situations like this we will have," he said. The U.S. had a ban on certain assault weapons but it expired in 2004. Gunman opens fire at Sikh temple in Wisconsin; 7 dead Early on Monday, police were searching an apartment at a duplex in the Cudahy neighborhood near Milwaukee, presumed to be the residence of the gunman. Generators and floodlights were set up along the street and a bomb squad was on the scene. The attack came just over two weeks after a gunman killed 12 people at a theater in Aurora, Colorado, where they were watching a screening of new Batman movie "The Dark Knight Rises." In January 2011, a gunman killed six people in an attack on an event by then Congresswoman Gabrielle Giffords in Tucson, Arizona. Giffords was shot in the head but survived. Slideshow: Gunman opens fire at Sikh temple in Wisconsin Jeffrey Phelps / AP A gunman opened fire Sunday morning at a Sikh temple outside of Milwaukee, killing six people and wounding at least three others, including a police officer, before being shot to death, authorities said. Launch slideshow American Sikhs said they have often been singled out for harassment, and occasionally violent attack, since the September 11, 2001 attacks because of their colorful turbans and beards. 9/11 tattoo? The 2001 attacks were carried out by Muslims linked to the al-Qaida militant group led by Osama bin Laden. Sikhs are not Muslim but many Americans do not know the difference, members of the Sikh community said. Tight-knight Sikh community shocked by shooting Some witnesses to the Wisconsin shooting said the suspect had a tattoo marking the September 11, 2001 attacks. Authorities confirmed he had tattoos but said they were not sure exactly what the tattoos illustrated. There are 500,000 or more Sikhs in the United States but the community in Wisconsin is small, about 2,500 to 3,000 families, said local Sikhs. Police officials says that they are treating the shooting by a gunman that left 7 people dead, including the gunman, and 3 others injured, as a 'domestic terrorist incident.' The Sikh faith is the fifth-largest in the world, with more than 30 million followers. It includes belief in one God and that the goal of life is to lead an exemplary existence. The temple in Oak Creek was founded in October 1997 and has a congregation of 350 to 400 people. "These people were going to church. Two weeks ago, it was people going to a movie. When is it going to end?" said Ray Zirkle, who came from Racine, Wisconsin with his wife to light votive candles near the site of the shooting. A mass shooting at a Sikh temple in Oak Creek, Wisc., leaves seven dead, including the suspected gunman, and three wounded, including an ambushed police officer. NBC's John Yang reports. On Sunday evening, hundreds gathered in downtown Milwaukee to hold a vigil of for the victims of the shootings, The Milwaukee Journal Sentinel reported. Participants stood in a circle, prayed and lit candles at the event held at Cathedral Square, and one-by-one people made unscripted statements to the group, according to the newspaper. Tom Lynn / Reuters People gather in downtown Milwaukee at a vigil for the victims of Sunday's shooting in a Sikh temple in nearby Oak Creek, Wis. One man recited "The Lord's Prayer." "This isn't about the city of Oak Creek, we are all responsible," another said, while a third declared: "I'm an atheist and I stand behind every peace loving religion," the newspaper reported. Members of the Sikh community attended the vigil, the Journal reported. "It was same as 9/11," Manpreet Kaur, who attended the vigil with her husband and two daughters, told the newspaper. "My mother-in-law and father-in-law thought that it's not safe for you to go in your turban today." Reuters contributed to this report. More content from NBCNews.com: Follow US News from NBCNews.com on Twitter and Facebook ||||| Jhalman Singh of Oak Creek (second from right) hides tears as he listens during a news conference Monday to a moving story about the president of the Sikh Temple who died trying to stave off the gunman. Many at the news conference at the Oak Creek Salvation Army office offered their perspectives on their faith and shared stories about members of the temple who died in the shooting. Credit: Rick Wood By of the He wore his beliefs on his arm, along with his hate. He called non-whites "dirt people," and sent roses to his grandmother. He talked about accomplishing positive results in society, then killed six people and tried to gun down a cop (hitting him at least eight times) who was helping the wounded. Wade Michael Page, dead himself in the wake of his mass-slaying rampage at the Sikh temple in Oak Creek Sunday, appears to have been many things - Army veteran of a special unit, fired truck driver, devoted grandson, hard-metal musician, white supremacist. But to psychiatric nurse Jennifer Dunn, the 40-year-old with the shaved head was merely the "creepy quiet" neighbor who moved into her Cudahy building three weeks ago, toting his belongings in two black plastic garbage bags. He rarely left his one-bedroom upper, where he lived alone. His only visitor, Dunn said, was a pizza delivery guy who stopped by a couple of times. She didn't think twice about Page's numerous tattoos - one, it turns out, was an obscure reference to white supremacist doctrine - but his manner was strange. "He made no eye contact," she said. "That's an abnormal thing. He wasn't rude, but he was not wanting to be engaged." Late last week, Dunn said, Page's behavior became odder still. On Friday and Saturday, he blasted aggressive music from his stereo. "He really had the tunes cranked up," said Dunn, who lives downstairs with her two daughters. Then, on Saturday, Page carried what appeared to be the same "two bags full of crap" to his red SUV parked in the alley. He also carried out a large cardboard box. "He paced around the truck for about 10 minutes" and then sat behind the wheel for a long time "staring off into space," Dunn said. One of her daughters came inside and told her mother, "the dude is acting strange." A day later, with police SWAT teams surrounding their home and Page and six innocent victims shot dead in and around the temple, she'd find out how strange he was. But it didn't start that way. 'We have no idea' Sobbing Tuesday as she spoke by telephone from her home in Denver, Colo., Page's stepmother said he grew up as a "precious child" in a normal, loving family. "Where he changed and where this came from, we have no idea," said Laura Page, who was married to Wade Michael Page's father for about two decades. The boy was 10 when the couple married. Three years later, his birth mother died, from lupus. Like any child losing a parent, "he was devastated," Laura Page said. Yet, she said, her stepson was mostly happy and liked to do "normal little boy stuff" - play with his dog, fish, camp. He loved music and played his guitar often, she said. "He was kind and gentle and loving," she said. "He was normal in every way that I can think of." She and Page's father moved to Texas when the boy was a teenager, but he stayed in Colorado, splitting time between an aunt and his grandmother, with whom he was very close. He rejoined his parents in Texas after graduating from high school, took a job at a convenience store and eventually joined the Army. "He said it was one of the best things he ever did - it gave him focus, a direction," Laura Page said. She divorced Page's father in 2001, but talked with him after Sunday's killings. The father said he had tried calling his son about three weeks ago, but never got a call back. 'Exclusive' unit Page may have thought he found direction in the Army, but it appears that by then he was already pointed down the road that would lead to the mass shooting in Oak Creek. He served approximately from 1992 to 1998, and was assigned to psychological operations - the specialists who analyze, develop and distribute intelligence used for information and psychological effect. "That is very exclusive," said John Liebert, a psychiatrist who performs fitness examinations for the military and is an expert on suicidal mass murderers. "It's like going from the lobby to the 20th floor." But Page's beliefs were starting to show. Fred Allen Lucas, a Bloomington, Ind., man who served with Page at Fort Bragg, N.C., in a psychological operations battalion, recalled that he spoke of the need for securing a homeland for white people and referred to all non-whites as "dirt people." "It didn't matter if they were black, Indian, Native American, Latin - he hated them all," Lucas said. Lucas said he met Page in 1995, the same year that the killings of a black couple in Fayetteville by two members of the 82nd Airborne Division at Fort Bragg revealed the presence of a white-supremacist movement among soldiers on the base. At the time, Lucas said, Page was covered with tattoos, including one that made a reference to the "14 words," a phrase used by white supremacists: "We must secure the existence of our people and a future for white children." "He criticized me for my attraction to (Latina) women," Lucas said. "He'd call me a 'race-traitor.' He said I should change my ways because I was a blond-haired, blue-eyed white guy, and I shouldn't be wasting myself on that." Page left the Army in 1998 with a general discharge, a cut below honorable. He was ineligible for re-enlistment, Oak Creek Police Chief John Edwards said Monday. Two skinhead bands By 2000, according to an interview Page gave two years ago, he was circulating in what the Southern Poverty Law Center called the white-power music scene. The center said Page was a member of two racist skinhead bands -- End Apathy and Definite Hate. End Apathy was Page's project, started in 2005. In the interview two years ago with a website, he said he launched the band "to figure out what it would take to actually accomplish positive results in society and what is holding us back. "A lot of what I realized at the time was that if we could figure out how to end people's apathetic ways it would be the start toward moving forward," Page is quoted as saying. "Of course after that it requires discipline, strict discipline, to stay the course in our sick society." Photos on the band's MySpace page, which was taken down Monday, show Page playing a guitar with a stars-and-bars strap, and the "14" tattoo prominent on his shoulder. In a picture of a band practice, a Nazi flag hangs behind the drummer. The Southern Poverty Law Center said that in 2010 Page played at a racist music festival in Baltimore called Independent Artist Uprise. For part of the last decade, Page lived in North Carolina. According to the Fayetteville Observer, he worked at a Harley-Davidson dealership as a parts coordinator, but was fired after a series of clashes - one involving his displeasure at taking orders from a female co-worker. The newspaper quoted general manager John Tew as saying that, after Page was fired, he found an application for joining the Ku Klux Klan on Page's desk. "I threw that in the trash can," Tew was quoted as saying. "He came back looking for it. And I told him I discarded that. He got all chapped again." Move to Wisconsin Page worked as a truck driver for about five years, but was dismissed from that job as well, in 2010. Last year, he lost a house, too. He had purchased a $165,000 home in the Fayetteville, N.C., area in September 2009, using a Veterans Administration loan. Last August, with the house already vacant, Wells Fargo foreclosed. The bank took over the property in February. By then, Page was in Wisconsin. He moved into a South Milwaukee apartment in late 2011, joining his girlfriend, who had been living there for about two years. Neighbors described him as a grumpy loner who occasionally pumped high-volume music through the building, worked third shift at a south side factory and disappeared on weekends, with a couple of guitars and his girlfriend in tow to play gigs with his band. "If you were lucky, he would just say 'hi,' otherwise he would just shrug," said Dave Brown, who lived downstairs. "The less I had to do with him the better." Page stayed in South Milwaukee only for a few months, moving out in June and getting his own place in Cudahy. He appears to have lost his job around then. Neighbors near his Cudahy apartment said he didn't appear to be working. Page has had minor scuffles with the law, most notably a drunken driving conviction - he pleaded guilty - in Colorado in 1999. But while he had no police record of violence, Liebert, the psychiatrist who does examinations for the military, sees in Page's past warning signs of potential trouble. The fact that the Army essentially dropped Page after he had been selected for psychological operations team seems significant, said Liebert, who practices in Arizona and, for a time, worked at St. Francis Hospital here. "I would want to know what happened to cause him to leave suddenly," he said. Liebert wonders now, given Sunday's carnage, whether Page was mentally ill, and what could possibly have been going through his mind. "He had to know that he was going to be killed," Liebert said. *** This story was written by Rick Romell with additional reports from James B. Nelson, Karen Herzog, Don Walker, Mike Johnson, Sharif Durhams, John Diedrich, Annysa Johnson, Meg Kissinger, Raquel Rutledge, Cary Spivak, Ellen Gabler, Piet Levy, Georgia Pabst, Jesse Garza and Mark Johnson.

– The man suspected of killing six at a Sikh temple in Wisconsin yesterday before being shot dead by a cop has been identified as Wade Michael Page, sources tell Fox News. And more details on Page are trickling in, by way of NBC and the Milwaukee Journal Sentinel: The 40-year-old was an Army vet with ties to Fort Bragg in North Carolina; he reportedly served from April 1992 through October 1998. While in the Army, he was assigned to psychological operations. According to military sources, he was discharged for "patterns of misconduct." He had previously lived in Colorado as well as North Carolina, before moving to Wisconsin. The Southern Poverty Law Center reports that Page was the former frontman of neo-Nazi music group End Apathy. Police say the gun he used in the shooting was bought sometime in the last 10 days, in Wisconsin. It was reportedly a 9mm semi-automatic handgun, and police have recovered it.

The American Civil Liberties Union is suing county officials in Alabama who told a Christian woman to remove her headscarf for her driver's license photo. Yvonne Allen of Tuskeegee says the clerk insisted that only Muslim women are allowed to cover their hair. The ACLU's suit filed Tuesday in Montgomery federal court says Lee County Clerk Becky Frayer and her supervisor, Probate Judge Bill English, are violating her religious freedom rights under the U.S. and state constitutions by refusing her repeated requests to take a new picture with her hair covered. English did not immediately return a message seeking comment. ||||| Yvonne Allen says she wears a headscarf because she believes her Christian faith requires it. But the Tuskegee woman says she was ordered by Lee County officials to take the headscarf off when she went to get her drivers' license renewed in December, according to a federal lawsuit filed Tuesday by the American Civil Liberties Union and the ACLU of Alabama on Allen's behalf. Lee County officials told Allen there are religious exemptions for head coverings but claimed it only applied to Muslims, the lawsuit states. She was also "ridiculed" by the probate staff for her belief, the lawsuit claims. "I was devastated when they forced me to remove my headscarf to take my driver license photo," Allen stated in an ACLU press statement. "Revealing my hair to others is disobedient to God. I should have the same right as people of other faiths to be accommodated for my religious beliefs." Alabama Law Enforcement Agency rules provide a religious accommodation for such headgear to be worn in driver license photos as long as it does not cover the face. The lawsuit asks a federal judge to order Lee County officials to allow Allen to retake her driver license photo with her headscarf and to award Allen damages and attorneys' fees. The lawsuit names Lee County Probate Judge Bill English and Chief Clerk Becky Frayer as defendants. Frayer declined comment Tuesday and English had not responded to a request for comment prior to publication of this story. Lee County's refusal to grant Allen a religious accommodation is in violation of the First Amendment to the U.S. Constitution and the Alabama Religious Freedom Amendment to the state constitution, according to the lawsuit. "The county's interpretation of state rules blatantly violates the First Amendment," said Susan Watson, executive director of the ACLU of Alabama. "The government cannot discriminate between faiths in granting religious accommodations." Allen v English Filing ||||| NOTE - August 30, 2016: This post originally ran in April 2016. Today the ACLU and ACLU of Alabama filed a federal lawsuit on Ms. Allen’s behalf, arguing that Lee County’s refusal to provide a religious accommodation to Ms. Allen violates her rights under the Alabama Constitution and the First Amendment to the U.S. Constitution. The lawsuit asks the court to order Lee County officials to allow Ms. Allen to retake her driver license photo with her headscarf. I have always been a spiritual being. Even as a young child I would spend countless hours delving into the tattered pages of my Bible. Though I often have failed, I have tried to remain obedient to God and his Word. But last December, at the Alabama Department of Motor Vehicles, my faith was tested in a way that was humiliating and demeaning. In accordance with my Christian faith, I cover my hair with a headscarf, but the DMV refused to take my driver license photo unless I removed it. The DMV officials said only Muslims were allowed to keep their headscarves on for photos. I didn’t know what to do. Without question, I believe that Muslim women should not have to violate their faith just to take a driver license photo, but neither should Christian women. I couldn’t believe that DMV officials could discriminate against me in this way, and it turns out, they can’t. On Friday, the ACLU and ACLU of Alabama sent the state a letter, informing officials that what the DMV did was wrong and unconstitutional. The government can’t provide a religious accommodation to members of one faith while denying the same right to those of other faiths. Wearing a headscarf is an integral part of my Christian beliefs. In 2011, I moved with my children to Alabama after the end of a 12-year relationship with their father. I was lost, confused, hurt, and broken. But I turned to God and spent hours in prayer and study. During that time, it became clear to me that, to be obedient to God’s Word and show my submission to him, I had to cover my hair on a daily basis. In 1 Corinthians 11, Paul speaks very clearly without ambiguity about this. I have followed this command every day since and believe that removing my headscarf in public is extremely shameful and dishonors God. Yet on that December day at the Lee County DMV office, I was forced into doing just that — or else officials said they would not renew my driver license, which was set to expire. As I posed for the photo, the clerk told me that I would have to remove my head covering and eyeglasses. I replied, “No ma’am, I don’t uncover my hair.” She asked me, “Is it for religious purposes?” I smiled, “Yes, ma’am.” She then asked, “Are you Muslim?” I responded, “No, Ma’am, I am Christian.” She abruptly stated, “No, then you need to uncover your hair. Only Muslim women have the right to cover their hair in their driver license photos.” I was horrified. A friend who had accompanied me saw the look on my face and quickly explained, “Ma’am she doesn’t uncover her hair ever.” The clerk, in a smug and condescending tone, replied, “You are not a Muslim, and Christian women don’t cover their hair.” I raised the issue with the clerk’s supervisor, but she too claimed that the rule was policy, adding that she was a Christian and does not cover her hair. I told the supervisor that while she is entitled to her interpretation of the Bible, so am I. She would not relent. With no other choice — I could not be without a valid driver license — I agreed to remove my headscarf for the photo. I first politely asked whether the clerk could close the door while my hair was uncovered. She refused. With tears in my eyes and utter disgust in my belly, I took the picture. As I have aged, life has handed me many challenges, prompting me to seek solace and guidance in the Bible and my faith. That did not change with the incident at the DMV. But I also knew that I could not stop there; I could not allow the DMV to discriminate against me or others, and that’s why I contacted the American Civil Liberties Union to help me vindicate my right to assert my religious beliefs and have them respected by the government. I hope that the DMV officials will do the right thing without the need for litigation by allowing me to retake my photo with my headscarf and putting in place policies that ensure that no else endures the same treatment I did.

– The ACLU filed a lawsuit this week alleging that an Alabama county clerk and her supervisor violated a Christian woman's religious freedom rights under both federal and state constitutions when they required that the woman remove her head scarf for her driver's license photo in spite of repeated requests that she be allowed to keep her hair covered, reports Fox News. Yvonne Allen wrote about the ordeal on an ACLU blog in April, saying her faith "was tested in a way that was humiliating and demeaning." Wearing a headscarf on a daily basis is, Allen writes, an "integral" part of her Christian faith; she says that in 1 Corinthians 11 Paul "speaks very clearly without ambiguity" on the matter. Allen says that when she explained to DMV staff last December that she is Christian, she was told that the religious exemption only applies to Muslims and was later "ridiculed" by the probate staff, reports Al.com. Allen decided to take action because, as an ACLU executive director puts it, "The government cannot discriminate between faiths in granting religious accommodations." The state's law enforcement agency allows for religious accommodation for headgear in driver's license photos so long as the face is not hidden. The lawsuit asks a federal judge to allow the photo to be retaken with the headscarf on, and to grant Allen damages and attorneys' fees. (This Christian professor was suspended for wearing a hijab.)

growth arrest - specific 6 ( gas6 ) was identified in 1988 and was further characterized in mouse embryonic nih 3t3 fibroblasts in 1993 [ 1 , 2 ] . it is considered a growth arrest protein involved in regulation of the cell cycle . to date , gas6 has been reported to be involved in the processes of proliferation , differentiation , and inflammation in various cell types ( adipocytes , endothelial cells , vascular smooth muscle cells , bone marrow cells , etc . ) and tissues ( ovary , heart , kidney , etc . ) [ 24 ] . it is worth mentioning that the role of gas6 signaling in inflammation remains controversial nowadays . in dendritic cells and macrophages , it negatively regulates inflammation , but it promotes phagocytosis of apoptotic cells and also positively participates in the maturation of natural killer cells . gas6 is a member of the vitamin k - dependent protein family , and it contains 678-amino acids . gas6 shares approximately 42% similarity with protein s , a nonenzymatic cofactor for activated protein c and its downstream cascades leading to the inhibition of coagulation . although the gas6 protein shares structural homology with protein s , their functions are dissimilar . the functions of gas6 are limited to binding with tam ( tyro3 , axl , and mer ) receptors , particularly with axl . gas6 shows the highest affinity to bind to axl , followed by tyro3 and lastly to mer . gas6 interacts with tam receptors through its shbg - domain to activate downstream signaling pathways , such as plc , pi3k , erk , and nf-b to regulate cell survival , proliferation , migration , differentiation , adhesion , and apoptosis [ 8 , 9 ] . analysis of gas6 and tam receptors signaling is likely to be fundamental to improve the understanding of disease progression and development of therapeutics . obesity has been shown to be a predominant risk factor in the progression of chronic cardiometabolic disorders , such as diabetes , chronic renal failure , cardiovascular disease , and hypertension . however , only a few reports have been published regarding the link between gas6 signaling and the pathogenesis of obesity . this paper summarizes the relevant clinical and basic researches published to date and attempts to pinpoint the potential role of gas6 signaling molecules in the development of obesity and associated inflammation . the recent studies focusing on gas6 signaling and the development of obesity in various studies from clinical and basic researches are summarized in tables 1 and 2 . for instance , a recent clinical study conducted in taiwan teenagers from our research team showed that levels of circulating gas6 ( 12.3 versus 13.9 ng / ml ) and soluble axl ( 3.8 versus 4.7 ng / ml ) were significantly increased in overweight and obese adolescents and were positively correlated with bmi ( 19.5 versus 27.8 kg / m ) and body fat mass ( table 2 ) . furthermore , we also analyzed genetic polymorphisms among taiwan adolescents and the result further showed an increased bmi and waist circumference significantly correlated with the gg genotype of gas6 ( rs8191974 ) . this genotyping of gas6 might be suitable for predicting the future progress of obesity and its related complications . consistently , gas6 expression was increased in subcutaneous fat of high - fat fed mice , compared to those fed a standard fat diet ( 363 versus 976 copy number ) ( table 1 ) . in addition , gas6-deficient mice exhibited significantly less fat accumulation in the subcutaneous and gonadal fat pads than wild - type mice when fed a high - fat diet ( table 1 ) . from mechanistic aspect , the in vitro study showed that gas6 was highly expressed at growth arrest and participated in cell proliferation and differentiation [ 2 , 14 ] . in addition , studies showed that gas6 receptor - axl might have a role in the development of obesity . a report demonstrated that mice overexpressing axl showed an increase in body weight gain and may subsequently cause the development of obesity ( table 1 ) . in addition , antagonizing the axl receptor with the administration of r428 by oral gavage impaired adipose tissue development through inhibition of preadipocyte differentiation into mature adipocytes that resulted from reduced lipid uptake in mice . the r428 treatment significantly reduced body weight gain and also subcutaneous ( 831 versus 421 mg ) and gonadal ( 123 versus 685 mg ) fat mass after high - fat diet feeding compared to controls ( table 1 ) . the expression levels of gas6 ( 3.11 versus 2.58 ( ct ) ) and mer ( 6.74 versus 6.17 ( ct ) ) showed a significant decrease in gonadal fat but not in subcutaneous fat in r428-treated mice ( table 1 ) . collectively , these observations implicate that gas6 may participate in adipogenesis by regulating cell proliferation and differentiation through tam receptors and may subsequently affect the development of obesity . nevertheless , the clinical study conducted with elderly patients with type 2 diabetes showed that plasma gas6 level ( 14.3 versus 11.5 ng / ml ) was negatively correlated with bmi ( 23.9 versus 26 kg / m ) and blood glucose level , compared to healthy individuals ( table 2 ) [ 17 , 18 ] , implying that aging and hyperglycemia might be the significant cofounding factors that affect circulating gas6 levels . moreover , as shown in table 2 , the plasma gas6 level did not differ between overweight males and females . however , plasma gas6 levels were significantly lowered in postmenopausal than in premenopausal overweight females , implying a potential effect of estrogen on gas6 expression . these observations implicate that the gas6 expression level is accounted not only for obesity but also for other factors such as ages , sex hormones , and hyperglycemia . on the other hand , there was a contradictory result from the animal study suggesting that axl deficiency had no significant effect on adipogenesis . they found that deficiency of axl in mouse embryonic fibroblasts did not affect their differentiation and lipid uptake . furthermore , the body weight gain , subcutaneous and gonadal fat mass , and gas6 signaling molecules showed no significant differences between axl - deficient or wild - type mice fed on either a standard diet or a high - fat diet ( table 1 ) . however , compared to standard fat diet feeding , axl - deficient mice fed a high - fat diet showed a dramatic increase in the mrna expression levels of mer ( 74 versus 147 copy number ) and tyro3 ( 5.1 versus 13 copy number ) in subcutaneous adipose tissues ( table 1 ) . this compensatory enhancement of genes expression caused by high - fat diet feeding was not observed in wild - type mice . based on this finding , the authors speculated that the other two tam receptors ( mer and tyro3 ) compensate for the effect of axl deficiency in gas6 signaling . since axl - deficient mice show that their axl mrna levels were increased in mice fed a high - fat diet compared to a standard fat diet ( 102 versus 371 copy number ) and a similar trend was observed in the wild - type group in subcutaneous adipose tissues ( 420 versus 1127 copy number ) ( table 1 ) , the authors speculated that the axl mrna levels detected in axl - deficient mice might be the incomplete fragments with no function to transduce signaling . however , it still has another possibility that axl did not knockout completely in their mouse model , and its low expression levels still can transduce gas6 signaling . taken together , gas6 signaling is important for the development of obesity , but the underlying mechanism remains to be elucidated . plasma and adipose tissue levels of inflammatory cytokines such as il-6 and tnf- have been reported to increase along with the progression of obesity [ 21 , 22 ] . in a clinical study , circulating gas6 and soluble axl levels were found to be positively correlated with plasma tnf- , il-6 , and c reactive protein ( crp ) levels in overweight and obese adolescents ( table 4 ) . furthermore , the crp level was significantly elevated in boys carrying the gg polymorphism of the gas6 rs8191974 genotype . these observations imply that circulating gas6 and soluble axl levels are positively correlated with obesity - induced inflammation in adolescents , especially in boys . in addition , females show a lower correlation between gas6 expression and systemic inflammation indicated by the increase in plasma crp levels , which might be attributed to the effect of estrogen in the link between gas6 expression and inflammation and it requires further investigation . on the other hand , a previous study showed that elderly patients with type 2 diabetes exhibited a significantly decreased gas6 level but a significantly increased inflammatory marker - plasma crp level compared to healthy individuals [ 17 , 18 ] , suggesting that the relationship between circulating gas6 level and obesity - induced inflammation could be significantly affected by ageing and hyperglycemia . furthermore , axl , an important receptor of gas6 , originally characterized as a transforming gene in human myeloid leukemia cells , has been shown to play a role in regulating inflammation . the axl transgenic mice exhibited phenotypes of obesity and type 2 diabetes , such as hyperglycemia , hyperinsulinemia , and insulin resistance , and showed elevated plasma tnf- level ( table 3 ) . collectively , these findings indicate that the correlation between gas6 and systemic inflammation could be significantly affected by ageing , gender , and hyperglycemia . the axl receptor - mediated pathway may play a substantial role in gas6-mediated inflammatory signaling in states of obesity and associated type 2 diabetes . the normal plasma concentration of gas6 is in the range of 2050 ng / ml , and patients with cancer or inflammation showed higher concentrations . in addition , gas6 signaling has been demonstrated to be associated with various chronic cardiometabolic disorders , including thrombosis , diabetes , chronic renal failure , cardiovascular disease , and cancer [ 6 , 2427 ] . in addition , gas6-deficient mice exhibited significantly less fat accumulation in the subcutaneous and gonadal fat . the level of circulating gas6 was positively correlated with bmi and inflammatory cytokines in adolescents . these observations suggest that gas6 might be casually correlated with the obesity and associated inflammation . furthermore , gas6 is the only ligand known to induce axl downstream cascades among tam receptors . like gas6 , the level of plasma axl was positively correlated with bmi and inflammatory cytokines in adolescents . administration of r428 reduced lipid uptake resulting in decreasing subcutaneous and gonadal fat mass and also body weight gain in mice . it is implicated that gas6 receptor axl might be a top priority for the development of therapeutic strategies in obesity and related complications . of about 650 papers on growth arrest - specific genes were published since gas6 was first cloned in 1988 , more than 400 have focused on gas6 signaling . several recent clinical studies have shown that gas6 signaling significantly contributes to the development of obesity and associated inflammation . in particular , gas6/axl signaling is important in the mechanism underlying inflammation that resulted from obesity and associated complications . however , the causal relationship between gas6 and obesity - related cardiometabolic abnormalities remains controversial . from a clinical perspective , clarifying the role of gas6 signaling from bench to clinic will provide great benefit in development of strategies for the prevention and treatment of obesity and its related complications .

growth arrest - specific 6 ( gas6 ) , a vitamin k - dependent protein , plays a role in the survival , proliferation , migration , differentiation , adhesion , and apoptosis of cells . gas6 is highly expressed during growth arrest , followed by a sharp decrease during differentiation in adipocytes . the functions of gas6 signaling are limited to tam ( tyro3 , axl , and mer ) receptors and are dependent on the cell type . while many studies have focused on the role of gas6 in inflammation and cancer , only few studies focused on its roles of gas6 in obesity . accordingly , the participation of gas6 in the progression of obesity remains controversial . in this review , we summarize the results of current studies from clinical and basic research to elucidate the possible role of gas6 signaling in obesity and associated disorders . in addition , this summary may offer a direction to develop clinical therapeutic strategies for the prevention and treatment of obesity and related complications .

American woman and partner attending family wedding in Pakistan murdered in suspected honour killing Couple about to start new life together in the U.S. Sources suggest the groom's relatives had been happy with the marriage, but it had caused upset among the bride's family A Scottish businessman and his American wife were gunned down in the street in a suspected honour killing while on holiday in Pakistan. Glasgow-based Saif Rehman, 31, and Uzma Naurin from New York, 30, were shot dead when their car was ambushed in the north-eastern city of Gujrat following a shopping trip. The couple had been about to start a new life together in the U.S. after their trip to Pakistan for Mr Rehman’s brother’s wedding. Tragic: The couple were murdered in Pakistan during an ambush on their taxi It is understood the couple were accompanied by a driver, Mr Rehman’s sister and her two-year-old daughter, but the other passengers were unharmed. The group of four gunmen stopped the car, opened fire and killed Mr Rehman before bundling his wife into their vehicle and killing her at a spot nearby – then dumping her body by the roadside. Pakistani police are probing claims that there had been tension between the couple’s in-laws over their marriage three years ago. They were married in Manchester but another, fuller ceremony involving both sides of the family took place in Glasgow in June, when it appeared that the differences might have been resolved. The couple pictured here at a celebration. A group of four gunmen stopped the car, opened fire and killed Mr Rehman before bundling his wife into their vehicle and killing her at a spot nearby - then dumping her body by the roadside Sources close to the dispute last night suggested Mr Rehman’s relatives had been happy with the marriage, but it had caused upset among some of his bride’s relatives. Saif Ali, 30, of Cumbernauld, Dunbartonshire, who runs a mobile phone repair company, met Mr Rehman – who ran a similar firm called GSM Communications in Glasgow – three years ago. He said: ‘It was a long-distance relationship between Saif and Uzma but they made it work really well. Saif had just got a visa to go to the U.S., so they were on the brink of a new life together when this happened. Committed: The couple had been in a long-distance relationship, but had made it work ‘I found out from Saif’s brother when the killings happened on November 1 and couldn’t believe it – I was shocked, angry and devastated because we were very close. Saif had been in Glasgow for six years and met Uzma at a friend’s wedding four or five years ago.’ Describing their murder, Mr Ali added: ‘They were going back home and basically, all of a sudden, their driver just stopped the car. ‘Four people were in a different car which stopped in front of them. They pulled Saif, his sister, her daughter and his wife out of the car and, as soon as he was pulled out of the car, they shot him without saying anything.’ Mr Ali said that ‘no words were exchanged’ between Mr Rehman and any of the people who shot him. He added: ‘Five minutes up the road they basically killed her (Uzma Naurin) as well. She wasn’t found until quite a bit of time later. ‘Probably about three or four hours later, she was found, as they had basically put her in the shrubs somewhere, just on the side of the road.’ Mr Ali said Uzma Naurin worked in sales for Costa Coffee and was based in New Jersey. Her father, a taxi driver in New York, had relatives in Gujrat and the driver of the car the couple were in when they were shot is said to have been employed by his Pakistani relatives. The Foreign Office cannot become involved as Mr Rehman was a Pakistani national and his wife was a U.S. citizen. ||||| Saif and Uzma Rehman murders treated as 'honour killing' Pakistani police are investigating the deaths of Uzma Naurin and Saif Rehman Continue reading the main story Related Stories Police in Pakistan have confirmed they are treating the murder of a couple from Glasgow as an honour killing. Saif Rehman, 31, and his wife Uzma Naurin, 30, were shot after their car was ambushed in Gujrat on 1 November. It is understood Mr Rehman was shot dead by a group of men at the scene and his wife was driven away and killed. Pakistan police said Uzma's father, Musafar Hussain, went to his home in the US after the murder and they may seek to extradite him. Mr Rehman had lived in Glasgow for six years and met his wife Uzma at a friend's wedding. They were married in Glasgow in February. The Foreign Office cannot become involved in the murder as Mr Rehman was a Pakistani national and his wife was a US citizen.

– Pakistani police now believe that the killing of an American woman and her husband in Gujrat, Pakistan, earlier this month may have been an honor killing. New Yorker Uzma Naurin, 30, was in Pakistan for a family wedding with her husband, Scottish businessman Saif Rehman, 31, when gunmen accosted and killed them. Sources tell the Daily Mail that while Rehman’s family was happy with the marriage, Naurin’s was not. Naurin’s father, a New York taxi driver, returned to the US after the killings, and Pakistani police are now considering trying to have him extradited, the BBC reports. According to a friend, the couple was returning from a shopping trip when their driver suddenly stopped their car. Gunmen then pulled them out, shot Rehman on the spot, and made off with Naurin, killing her further down the road. The driver was reportedly employed by Naurin’s Pakistani relatives.

predicting a protein three dimensional structure from its sequence is equivalent to reproducing a three dimensional structure from one dimensional information encoded in its sequence . from such a viewpoint , there are many studies that try to reconstruct three dimensional structures from one dimensional information such as contact numbers and the principal eigenvector of a contact matrix @xcite . an important question is not only what kind of one dimensional information is needed to reconstruct protein structures but also why such information is critical to reconstruct protein structures . let us think about a distance matrix each element of which is equal to distance between atoms or residues specified by its column and row . information contained in the distance matrix is equivalent with the specification of three - dimensional coordinates of each atom / residue , except that a mirror image of the native structure can not be excluded in distance information . reconstructing a distance matrix from one - dimensional vectors requires in principle the specification of all eigenvectors as well as eigenvalues . in other words , for an @xmath2 matrix , @xmath3 @xmath3-dimensional vectors are required . however , protein s particular characteristics may allow the reconstruction of a distance matrix with fewer one - dimensional vectors . a contact matrix whose element is equal to one for contacting atom / residue pairs or zero for no - contacting atom / residue pairs or more generally a value between one and zero representing the degree of contact is a simplification of a distance matrix with two categories , contact or non - contact for the distance of atom / residue pairs , but keeps almost all information needed to reconstruct three - dimensional structures of proteins . in the case of a contact matrix consisting of discrete values , one and zero , for residues , porto et al . @xcite showed that the contact map of the native structure of globular proteins can be reconstructed starting from the sole knowledge of the contact map s principal eigenvector , and the reconstructed contact map allow in turn for the accurate reconstruction of the three - dimensional structure . a vector of contact numbers , which is defined as the number of atoms or residues in contact with each atom / residue in a protein , is another type of one - dimensional vector that is often used as a one - dimensional representation of proteins structures @xcite , and may be similar to but not the same as the principal eigenvector of a contact matrix . kabakiolu et al . @xcite suggested that the number of feasible protein conformations that satisfy the constraint of a contact number for each residue is very limited . a question is why the principal eigenvector of a contact matrix and a contact number vector contain significant information of protein structures . here , we consider what properties of contact matrices are induced by pairwise contact interactions for native proteins to be the lowest energy conformations . for simplicity , a total conformational energy is assumed to consist of pairwise interactions over all atom or residue pairs . it is further assumed that the pairwise interaction can be expressed as a product of a conformation - dependent ( @xmath0-dependent ) factor and a sequence - dependent ( @xmath4-dependent ) factor ; the @xmath4-dependent factor corresponds to an energy parameter specific to a given pair of atom / residues . here we call a matrix of @xmath0-dependent factor a generalized contact matrix or even simply a contact matrix ( @xmath0-matrix ) , and call a matrix of @xmath4-dependent factor a generalized contact energy matrix or even simply contact energy matrix ( @xmath1-matrix ) . a simple linear algebra indicates that such a total energy function is bounded by the lowest value corresponding to the total energy for a @xmath0-matrix in which all pairs with lower contact energies than a certain threshold are in contact . such a lower bound is achieved if and only if proteins are ideal to have the so - called go - like potential @xcite . the go - like potential is defined as one in which interaction energies between native contacts are always lower than those between non - native contacts . real pairwise interactions in proteins could nt be the go - like potential . in other words , real proteins could not achieve this lowest bound of a pairwise potential because of atom / residue connectivities and steric hindrance that are not included in this type of total energy function . how should they approach to the lowest bound as closely as possible ? the lowest bound can be approached by making the singular vectors of @xmath0-matrix parallel to the corresponding singular vectors of @xmath1-matrix with the same value of the singular values . also , in the lowest bound a contact number vector tends to be parallel to the principal eigenvectors of @xmath0-matrix and of @xmath1-matrix . the most effective way would be to first make the principal singular vector of @xmath0-matrix parallel to that of @xmath1-matrix . a similar strategy was used to recognize protein structures by three - dimensional threading of protein sequences @xcite . bastolla et al . @xcite pointed out that the principal eigenvector of a contact matrix must be correlated with that of a contact energy matrix , if the free energy of a conformation folded into a contact map is approximated by a pairwise contact potential . it was shown that the correlation coefficients of these two principal eigenvectors are actually statistically significant in protein folds . however , unlike their analyses the lowest bound of the total energy indicates the @xmath1-matrix to be singular - decomposed with a constant term that corresponds to the threshold energy to separate native contacts from non - native ones . the eigenvectors of @xmath1-matrix may depend on the value of the additional constant . based on the indication above , we have analyzed the relationships between the principal eigenvectors of @xmath0-matrix and of @xmath1-matrix and contact number vector by examining the inner product of the two vectors . a statistical contact potential @xcite estimated from protein crystal structures is used to evaluate pairwise residue - residue interactions in proteins . 182 representatives of single domain proteins from each family in the scop version 1.69 database @xcite are used to analyze the relationship between the principal eigenvectors of native @xmath0- and of @xmath1-matrices and the contact number vector . results show that the inner product of both the principal eigenvectors has a maximum at a certain value of the threshold energy for contacts , and that there are parallel tendencies between both the principal eigenvectors and contact number vector . it is worth noting that the principal eigenvector of native @xmath0-matrix corresponds to the lower frequency normal modes of the native structure of protein . in addition , the spectral representation of the contact and contact energy matrices reveals that pairwise residue - residue interactions , which depends only on the types of interacting amino acids but not on other residues in a protein , are insufficient and other interactions including residue connectivities and steric hindrance are needed to make native structures the unique lowest energy conformations . * basic assumptions and conventions * we first assume that the total conformational energy of a protein with conformation @xmath0 and amino acid sequence @xmath4 of @xmath3 units can be approximated as the sum of pairwise interaction energies between the units . here a single unit may consist of an atom or a residue , although in most cases we treat a residue as a unit . we further assume that each pairwise interaction term can be expressed as a product of a @xmath0-dependent factor and a @xmath4-dependent factor . the @xmath0-dependent factor represents the degree to which a pair of units are in contact , while the @xmath4-dependent factor represents an interaction energy for a contacting pair of units . in other words , the total conformational energy is assumed to be approximated as @xmath5 where @xmath6 and @xmath7 are the @xmath4-dependent term and @xmath0-dependent term for the pairwise interaction energy between the @xmath8 and @xmath9th units , respectively . @xmath10 is the total number of contacts between units and defined as @xmath11 where the generalized contact number @xmath12 that is the total number of units contacting with @xmath8th unit is defined as @xmath13 each @xmath7 is a function of coordinates of @xmath8th and @xmath9th units , and assume values between 0 and 1 , with the diagonal elements always defined to be equal to 0 . the @xmath4-dependent term @xmath6 can include not only two - body interactions but multi - body effects as a mean - field , that is , not only depends on the type of a unit pair but on the entire protein sequence . we call the matrix @xmath14 as a generalized contact matrix or @xmath0-matrix for short . similarly , we call the matrix @xmath15 as a generalized contact energy matrix or @xmath1-matrix for short . each element of the energy function of eq . ( [ eq : total - contact - energy - a ] ) can represent either attractive or repulsive interactions but not both . in the next sections , we consider mathematical lower limits of the total contact energy ignoring atomic details of proteins such as atom / residue connectivities and steric hindrance . the volume exclusions between atoms are assumed to be satisfied and are not included in the total energy function . to minimally reflect the effects of steric hindrance , the total number of contacts @xmath16 is explicitly treated in the evaluation of the total energy , eq . ( [ eq : total - contact - energy - b ] ) , by introducing a constant @xmath17 in eq . ( [ eq : def - varepsilon ] ) . the expression of eq . ( [ eq : total - contact - energy ] ) can be regarded as a special case of eq . ( [ eq : total - contact - energy - b ] ) in which @xmath17 is equal to zero . * lower bounds of the total contact energy * let us consider lower bounds of the total contact energy represented by eq . ( [ eq : total - contact - energy ] ) under a condition that each element of @xmath0-matrix can independently take any value within @xmath18 irrespective of whether or not they can be reached in real protein conformations ; in other words , atom / residue connectivities and steric hindrance are completely ignored . if one regards @xmath19 and @xmath20 as the elements of vectors @xmath21 and @xmath22 in @xmath23-dimensional euclidean space , it will be obvious that the first term of eq . ( [ eq : total - contact - energy - b ] ) can be bounded by a product of the norms of those two vectors : @xmath24 where @xmath25 means a euclidian norm . obviously the equality of eq . ( [ eq : unreachable - lowest - bound - a ] ) is achieved if and only if those vectors are anti - parallel to each other : @xmath26 where @xmath27 is a negative constant . in addition , there is a simple mathematical limit for the total energy of eq . ( [ eq : total - contact - energy ] ) for which @xmath0-matrix is equal to @xmath28 : @xmath29 where @xmath30 is the heaviside step function that takes one for @xmath31 and zero for otherwise . @xmath32 is the lowest energy conformation with a constraint on the total contact number @xmath16 , although it is not necessarily reached due to atom and residue connectivity , and steric hindrance . if each @xmath20 is allowed to take either 0 or 1 only , and also each @xmath33 takes either one of two real values only to be able to satisfy eq . ( [ eq : go - type-1 ] ) , both the lower bounds of eq . ( [ eq : unreachable - lowest - bound - a ] ) and eq . ( [ eq : unreachable - lowest - bound - b ] ) are equal to each other . otherwise , the lower bound of eq . ( [ eq : unreachable - lowest - bound - a ] ) is further bounded by the lower bound of eq . ( [ eq : unreachable - lowest - bound - b ] ) , or the equality in eq . ( [ eq : unreachable - lowest - bound - a ] ) can not be achieved with @xmath18 , but eq . ( [ eq : unreachable - lowest - bound - b ] ) is always satisfied . if the total number of contacts @xmath16 is constrained to be equal to @xmath34 , then @xmath17 must be properly chosen as a non - positive value so that eq . ( [ eq : def - total - number - of - contacts ] ) is satisfied . otherwise , @xmath17 should be taken to be equal to zero to obtain the lower bound of eq . ( [ eq : unreachable - lowest - bound ] ) . eq . ( [ eq : unreachable - lowest - bound ] ) describes the lowest bound without any constraint on the number of contacts and corresponds to the energy of the conformation @xmath32 for @xmath35 . the potentials that satisfies eq . ( [ eq : go - type-1 ] ) and eq . ( [ eq : go - type-2 ] ) are just a go - like potential @xcite , in which interactions between native contact pairs are always more attractive than those between non - native pairs . let us call proteins with a go - like potential as ideal proteins . there are multiple levels of nativelikeliness in the go - like potential . the most nativelike potential of the present go - like potentials is one in which all interactions between native contacts are attractive and other interactions are all repulsive . in other words , @xmath36 is negative for native contacts and positive for non - native contacts . in such a go - like potential , the native conformation can attain the lowest bound of eq . ( [ eq : unreachable - lowest - bound - c ] ) , which is equivalent to eq . ( [ eq : unreachable - lowest - bound - b ] ) with @xmath35 . a less nativelike potential is one in which interactions between non - native contact pairs can be attractive but always less attractive than those between native contact pairs . an ideal protein with such a potential can attain eq . ( [ eq : unreachable - lowest - bound - b ] ) with a proper value of @xmath17 , which is the threshold energy for native and non - native contacts . in real protein , we should define @xmath17 as a threshold of contact energy under which unit pairs tend to be in contact in native conformations . in ideal proteins , the lowest energy conformation must be one for which the contact potential looks like a go - like potential , and inversely the potential must be a go - like potential for the lowest energy conformation . in real proteins , it would be impossible that contact potentials for native structures are exactly like a go - like potential such as eq . ( [ eq : go - type-1 ] ) and eq . ( [ eq : go - type-2 ] ) , even though the contact potential considered here may be an effective one that includes not only actual pairwise interactions but also the effects of higher order interactions near native structures . in other words , the lowest bound of eq . ( [ eq : unreachable - lowest - bound - b ] ) could not be achieved for real pairwise potentials , because of atom / residue connectivities and steric hindrance . however , it is desirable to reduce frustrations among interactions so that an effective pairwise potential in native structures must approach the go - like potential . then , a question is how native contact energies approach the mathematical lowest limit . in the following , we will show tips of how the @xmath0-matrix should be designed to decrease the total energy towards the theoretical lowest limit . it should be noted here that the lowest energy conformation , @xmath0-matrix , is considered for a given potential , @xmath1-matrix , but not its inverse problem , which is to consider an optimum potential or an optimum sequence for a given conformation , that is , an optimum @xmath1-matrix for a given @xmath0-matrix . in the inverse problem , the total partition function varies depending on each sequence , and it must be taken into account to evaluate the stability of the given @xmath0-matrix in relative to the other conformations @xcite . the z - score of the energy gap between the given @xmath0-matrix and other compact conformations may be used to evaluate the optimality of each sequence @xcite . * spectral relationship between @xmath0- and @xmath1-matrices * we apply singular value decomposition to both @xmath0-matrix ( generalized contact matrix ) and @xmath1-matrix ( generalized contact energy matrix ) . @xmath0-matrix is decomposed as @xmath37 is the eigenvalue of @xmath38 , and its absolute value , @xmath39 , is the @xmath40th non - negative singular value of @xmath38 arranged in the decreasing order , and @xmath41 and @xmath42 are the corresponding left and right singular vectors ; both @xmath43 and @xmath44 are orthonormal matrices . note that the singular values for a symmetric matrix such as a contact matrix is equal to the absolute value of its eigenvalue . we choose the eigenvector corresponding to the eigenvalue @xmath45 as a right singular vector @xmath46 and if @xmath47 , @xmath48 and otherwise @xmath49 . likewise , @xmath1-matrix , @xmath15 , is decomposed as @xmath50 , and @xmath51 and @xmath52 are the @xmath53th singular value , left and right singular vector of the matrix @xmath54 , respectively . we choose the eigenvector corresponding to the eigenvalue @xmath55 as a right singular vector @xmath56 and if @xmath57 , @xmath58 and otherwise @xmath59 . we then substitute eq . ( [ eq : eigen - equation - for - contact - matrix ] ) and eq . ( [ eq : eigen - equation - for - e - matrix ] ) into the definition of the total energy , eq . ( [ eq : total - contact - energy ] ) , and obtain @xmath60 where @xmath61 because the first term in eq . ( [ eq : total - contact - energy-2 ] ) is simply the trace of the product of two matrices , @xmath62 , neumann s trace theorem @xcite leads to the following inequality : @xmath63 the equality in eq . ( [ eq : lowest - bound - of - energy - eigenvector - c ] ) is achieved if and only if @xmath64 that is , all the corresponding left and right singular vectors of the @xmath0- and @xmath1-matrices are exactly parallel / anti - parallel to each other . then , regarding the singular values as the elements of a vector , i.e. , @xmath65 and @xmath66 , the sum of the products of the eigenvalues of @xmath1- and @xmath0-matrices in eq . ( [ eq : lowest - bound - of - energy - eigenvector - d ] ) can be bounded by the product of the norms of those two vectors , which is equal to the product of the norms of the vectors consisting of @xmath1- or @xmath0-matrix elements . as a result , we obtain the lower bound corresponding to eq . ( [ eq : unreachable - lowest - bound - a ] ) already derived in the previous section : @xmath67 where @xmath68 means the norm in the subspace of @xmath69 . the equality of eq . ( [ eq : lowest - bound - of - energy - eigenvector - e ] ) is achieved if and only if the values of the eigenvalues of @xmath0-matrix are proportional to those of @xmath1-matrix ; @xmath70 note that @xmath27 is a negative constant due to eq . ( [ eq : best - optimum - singular - vectors ] ) . this condition with eq . ( [ eq : best - optimum - singular - vectors ] ) corresponds to eq . ( [ eq : go - type-1a ] ) , but the spectral representation of @xmath0- and @xmath1-matrices reveals that the relation of eq . ( [ eq : go - type-1b ] ) is required only for the eigenspaces of @xmath69 . * is a pairwise residue - residue potential sufficient to make native structures the unique lowest energy conformations ? * if there exists @xmath71 such that @xmath72 , and the @xmath0-matrices for two conformations @xmath0 and @xmath73 satisfy @xmath74 for @xmath75 and @xmath76 , those two conformations have the same conformational energy , because the total contact energy can be represented as @xmath77 if the contact interactions are genuine two - body between residues , @xmath6 and @xmath78 will depend only on the residue type of @xmath8th and @xmath9th units and therefore @xmath79 will be less than or equal to the number of amino acid types in a protein ; therefore , @xmath80 . thus , in the case of genuine two - body interactions between residues , there must exist @xmath71 such that @xmath72 for any chain longer than 20 residues , that is , multiple @xmath0-matrices with the same energy . in other words , other interactions than pairwise interactions are needed to make native structures the unique lowest energy conformations . a certain success @xcite of statistical potentials of genuine two body in identifying native structures as the unique lowest energy conformations indicates that most of the eigenspaces of @xmath72 , especially in orientation - dependent potentials , may be significantly reduced or even disallowed for short proteins by atom / residue connectivities and steric hindrance . it may be worthy of note that the number of possible @xmath0-matrices is the order of @xmath81 but the conformational entropy of self - avoiding chains is proportional to at most @xmath3 , where @xmath3 is chain length ; that is , vast conformational space becomes disallowed by chain connectivity and steric hindrance . however , it would be not surprising even if a two - body contact potential is insufficient to make all the native structures be the unique lowest energy conformations , especially for long amino acid sequences . actually it was reported@xcite that it is impossible to optimize a pairwise potential to identify all native structures . multi - body interactions @xcite may be required as a mean - field or even explicitly together with the two - body interactions , as well as other interactions such as secondary structure potentials @xcite . * relationship between a contact number vector @xmath82 and the eigenvectors of @xmath0-matrix * eq . ( [ eq : lowest - bound - of - energy - eigenvector - d ] ) indicates that the larger the principal eigenvalue is , the lower the lower bound of the total contact energy is . the eigenvalue @xmath83 satisfies @xmath84 where @xmath85 is the cosine of the angle between the contact number vector @xmath82 and eigenvector @xmath86 , and @xmath87 is one between the eigenvector @xmath86 and the vector @xmath88 whose elements are all equal to one . @xmath89 represents the second moment of contact numbers over all units . we can say that the eigenvalue @xmath90 is equal to the weighted average of contact number @xmath12 with each component of the eigenvector , @xmath91 , and also that it is roughly proportional to the square root of the second moment of contact numbers . the principal eigenvalue has a value within the range of @xmath92 @xcite . the larger the ratio , @xmath93 , of the cosine is , the larger the eigenvalue @xmath90 becomes . * relationship between a contact number vector @xmath82 and the eigenvectors of @xmath1-matrix * a contact number vector is @xmath0-matrix summed over a row or a column . thus , to obtain a relationship between the contact number vector , @xmath82 , and the principal eigenvector of @xmath1-matrix , an averaging of @xmath1-matrix over a row or a column is needed . we approximate the total contact energy as follows by replacing @xmath19 by its average over index @xmath9 , @xmath94 , and then obtain an approximate expression for the lower bound of the total contact energy : @xmath95 \delta_{ij}(c ) + \varepsilon_0 n_{{{\mbox{\scriptsize c}}}}(c ) \label{eq : approx_total_contact_energy-0 } \\ & = & \frac{1}{2 } \ ; ^t\delta \vec{\mathcal{e}}_{\bullet}(s ) { { \bf n}}(c ) + \varepsilon_0 n_{{{\mbox{\scriptsize c}}}}(c ) \label{eq : approx_total_contact_energy } \\ & \geq & - \ ; \frac{1}{2 } \| \delta \vec{\mathcal{e}}_{\bullet}(s ) \| \| { { \bf n}}(c)\| + \varepsilon_0 n_{{{\mbox{\scriptsize c}}}}(c ) { { , } } \label{eq : mean - contact - energy - vs - contact - number-1}\end{aligned}\ ] ] where the mean contact energy vector @xmath96 is defined as @xmath97 . the equality in eq . ( [ eq : mean - contact - energy - vs - contact - number-1 ] ) holds if and only if the two vectors @xmath96 and @xmath82 are anti - parallel : @xmath98 eq . ( [ eq : mean - contact - energy - vs - contact - number ] ) above is equivalent to the following relation between the contact number vector and the eigenvector of @xmath1-matrix : @xmath99 if @xmath1-matrix can be well approximated by a primary eigenvector term only , then this condition leads to the parallel orientation between @xmath82 and the primary eigenvector of @xmath1-matrix , that is , @xmath100 . it has been reported that the contact number vector is highly correlated with the principal eigenvector of the @xmath0-matrix @xcite . if the conformation for the lower bound of the total energy is also the lower - bound conformation even for this averaging over @xmath1-matrix , eq . ( [ eq : mean - contact - energy - vs - contact - number ] ) or eq . ( [ eq : eigenvector - vs - contact - number ] ) above together with eq . ( [ eq : best - optimum - eigenvectors ] ) , eq . ( [ eq : eigenvalue - vs - contact - number ] ) , @xmath101 and @xmath102 leads to eq . ( [ eq : go - type-1b ] ) between the eigenvalues of @xmath0- and @xmath1-matrices as follows : @xmath103 where @xmath104 is a constant taking any negative value . eq . ( [ eq : lowest - bound - of - energy - eigenvector - d ] ) indicates that with an optimum value for @xmath17 the spectral relationship of eq . ( [ eq : best - optimum - singular - vectors ] ) between @xmath1- and @xmath0-matrices tend to be satisfied in the lowest energy conformations . here we will examine it by crudely evaluating pairwise interactions with a contact potential between amino acids , which was estimated as a statistical potential from contact frequencies between amino acids observed in protein crystal structures . * a pairwise contact potential used * a contact potential used is a statistical estimate @xcite of contact energies with a correction @xcite for the bethe approximation @xcite . the contact energy between amino acids of type @xmath105 and @xmath106 was estimated as @xmath107 { { . } } \label{eq : contact_potential_b}\end{aligned}\ ] ] @xmath108 is part of contact energies irrespective of residue types and is called a collapse energy , which is essential for a protein to fold by cancelling out the large conformational entropy of extended conformations but can not be estimated explicitly from contact frequencies between amino acids in protein structures . @xmath109 and @xmath110 are the values of @xmath111 and @xmath112 evaluated by the bethe approximation from the observed numbers of contacts between amino acids . @xmath113 is a partition energy or hydrophobic energy for a residue of type @xmath105 . @xmath112 is an intrinsic contact energy for a contact between residues of type @xmath105 and @xmath106 ; refer to @xcite for those exact definitions . the proportional constants for correction was estimated as @xmath114 and @xmath115 @xcite . here energy is measured in @xmath116 t units ; @xmath116 is the boltzmann constant and t is temperature . with the spectral expansion of the second term of eq . ( [ eq : contact_potential_b ] ) , the contact energies can be represented by @xmath117 { { , } } \label{eq : eigen_system_for_contact_energy}\end{aligned}\ ] ] where @xmath118 and @xmath119 are eigenvalues and eigenvectors for the second term of eq . ( [ eq : contact_potential_b ] ) with a constant @xmath120 . @xcite showed that the contact potential @xcite corresponding to @xmath121 between residues can be well approximated by the principal eigenvector term together with a constant term . then , the following relationship is derived for the eigenvalues and eigenvectors between @xmath1-matrix @xmath122 and the contact energy matrix @xmath123 : @xmath124 where @xmath125 is the amino acid type of @xmath8th residue , and @xmath3 is protein length . it should be noted here that the eigenvectors @xmath126 do not depend on the value of @xmath127 . @xmath0-matrix , @xmath38 , is defined in such a way that non - diagonal elements take a value one for residues that are completely in contact , the value zero for residues that are too far from each other , and values between one and zero for residues whose distance is intermediate between those two extremes . contacts between neighboring residues are completely ignored , that is @xmath128 for @xmath129 . the geometric center of side chain heavy atoms or @xmath130 atom for glycine is used to represent each residue . previously , this function was defined as a step function for simplicity . here , it is defined as a switching function as follows ; in the equation below to define residue contacts , @xmath131 means the position vector of a geometric center of side chain heavy atoms or the @xmath132 atom for glycine : @xmath133 \\ \hspace*{1em } \times \ [ 3(b^2 - a^2 ) - 2 ( b^2 - x^2 ) ] \\ \ \hspace*{2em } \mbox { for $ a < x < b$ } { { , } } \\ 0 \hspace*{2em } \mbox { for $ b \le x$ } \end{array } \right . \label{eq : def_sw}\end{aligned}\ ] ] where @xmath134 is a switching function that sharply changes its value from one to zero between the lower distance @xmath135 and the upper distance @xmath136 . those critical distances @xmath135 and @xmath136 are taken here as @xmath137 and @xmath138 , respectively . * protein structures analyzed * proteins each of which is a single - domain protein representing a different family of protein folds were collected . in the case of multi - domain proteins in which contacts between domains are significantly less that those within domains , a contact matrix could be approximated by a direct sum of subspaces corresponding to each domain . this characteristic of multi - domain proteins has been used for domain decomposition @xcite and for identification of side - chain clusters in a protein @xcite . thus , only single - domain proteins are used here . release 1.69 of the scop database @xcite was used for the classification of protein folds . we have assumed that proteins whose domain specifications in the scop database consist of protein i d only , are single - domain proteins . representatives of families are the first entries in the protein lists for each family in scop ; if these first proteins in the lists are not appropriate ( see below ) to use , for the present purpose , then the second ones are chosen . these species are all those belonging to the protein classes 1 to 4 ; that is , classes of all @xmath139 , all @xmath140 , @xmath141 , and @xmath142 proteins . classes of multi - domain , membrane and cell surface proteins , small proteins , peptides and designed proteins are not used . proteins whose structures @xcite were determined by nmr or having stated resolutions worse than 2.0 are removed to assure that the quality of proteins used is high . also , proteins whose coordinate sets consist either of only @xmath143 atoms , or include many unknown residues , or lack many atoms or residues , are removed . in addition , proteins shorter than 50 residues are also removed . as a result , the set of family representatives includes 182 protein domains . the spectral relationship between @xmath0-matrix and @xmath1-matrix is analyzed for single domain proteins that are representatives from each family of class 1 to 4 in the scop database of version 1.69 . the statistical potential used is crude , so that the following analyses are limited only to relationships between the principal eigenvectors of @xmath0-matrix and of @xmath1-matrix and contact number vector . it should be noted here that the crude evaluation of the pairwise interactions may make their relationships unclear . the ratio of @xmath144 to @xmath145 is shown for each of 182 proteins , which are representatives of single domain protein from each family of class 1 to 4 in the scop version 1.69 . @xmath146 and @xmath82 are the principal eigenvector and the contact number vector of the native @xmath0-matrix , respectively . the dotted lines indicate the iso - value lines for @xmath144 , whose values are shown in the figure . , width=302 ] eq . ( [ eq : eigenvalue - vs - contact - number ] ) indicates that the eigenvalues of @xmath0-matrix are proportional to the square root of the second moment of contact numbers . the proportional constant for the principal eigenvalue of @xmath0-matrix , that is , @xmath147 , is plotted for each protein in fig . [ fig : cos_cpe_cn_vs_sqrt_n_ave_cpei ] . the dotted lines are iso - cosine lines for the angle between the principal eigenvector of @xmath0-matrix and the contact number vector , whose values are written in the figure . the ratios are scattered between 1.2 and 1.6 , although the value of the ratio depends on the value of the abscissa , @xmath145 . cosine of angle is upper bounded by the value of one , and therefore the value of the ratio of the cosines becomes correlated with the value of the denominator of the ratio , i.e. , @xmath145 . the important fact is that the ratio takes values larger than one , making the principal eigenvalue larger . here , it should be noted that the lower bound of conformational energy linearly depends on the principal eigenvalue of @xmath0-matrix ; see eq . ( [ eq : lowest - bound - of - energy - eigenvector - d ] ) . thus , the larger the principal eigenvalue is , the lower the conformational energy becomes . in practice , this condition seems to yield the high correlation between the principal eigenvector and the contact number vector ; the most values of the @xmath144 , are greater than 0.7 . the mean of @xmath148 over 182 proteins is plotted with plus marks against @xmath120 . these proteins are representatives of single domain protein from each family of class 1 to 4 in the scop version 1.69 . @xmath146 is the principal eigenvector of the native @xmath0-matrix . @xmath149 is the principal eigenvector for @xmath1-matrix with the value of @xmath120 specified on the abscissa . , width=302 ] now let us think about the relationship between the @xmath0-matrix and the pairwise interactions . pairwise interactions between residues are evaluated by using a statistical estimate @xcite of contact energies with a correction @xcite for the bethe approximation . figure [ fig : mean_cos_cpe_epe_vs_e0_scc7.0_22 ] shows the average of @xmath150 over all proteins for each value of @xmath120 . the average @xmath151 takes the maximum value @xmath152 at @xmath153 , although its decrements according to the increase of @xmath120 are not large . in the following , @xmath153 is used to calculate the eigenvectors of @xmath1-matrices . the value of @xmath148 is plotted against @xmath154 for each of 182 proteins , which are representatives of single domain protein from each family of class 1 to 4 in the scop version 1.69 . @xmath146 is the principal eigenvector of the native @xmath0-matrix . @xmath149 is the principal eigenvector for @xmath1-matrix with @xmath153 . the dotted line shows the line of equal values between the ordinate and abscissa . , height=302 ] the value of @xmath150 for each protein is plotted against the value of @xmath155 in fig . [ fig : cos_cpe_epe_vs_sqrt_n_ave_cpei_scc70_22 ] . the value of @xmath150 is larger for most of the proteins than that of @xmath155 . if the direction of @xmath156 is randomly distributed in the domain of @xmath157 , the probability that @xmath150 is larger than @xmath155 must be smaller than @xmath158 . then , in such a random distribution , a probability to observe fig . [ fig : cos_cpe_epe_vs_sqrt_n_ave_cpei_scc70_22 ] , in which 175 of 182 proteins fall into the region of @xmath159 , must be smaller than @xmath160 . also t - test is performed for a correlation coefficient between @xmath156 and @xmath161 for each protein . the geometric mean of probabilities for significance over 182 proteins examined here is equal to @xmath162 . thus , it is statistically significant that the direction of the vector @xmath156 is closer to @xmath161 rather than @xmath88 whose elements do not depend on residues in proteins , this fact indicates again that the parallel orientation between the principal eigenvectors of @xmath0-matrix and of @xmath1-matrix is favored . the value of @xmath163 is plotted against @xmath164 for each of 182 proteins , which are representatives of single domain protein from each family of class 1 to 4 in the scop version 1.69 . @xmath153 is used for the @xmath1-matrix . the dotted line shows the line of equal values between the ordinate and abscissa . , width=302 ] eq . ( [ eq : mean - contact - energy - vs - contact - number ] ) indicates that the the mean contact energy vector @xmath165 being anti - parallel to the contact number vector is favorable to decrease the conformational energy . figure [ fig : cos_ave_e_cn_vs_cos_ave_e_1 ] does not show strong but statistically significant tendency that the value of @xmath166 tends to be larger than @xmath167 ; in t - tests for correlation coefficients between @xmath96 and @xmath82 , the geometric mean of probabilities for significance over 182 proteins is equal to @xmath168 . if the @xmath1-matrix can be approximated by the primary eigenvector term , this fact indicates that the contact number vector tends to be parallel to the principal eigenvector of @xmath1-matrix . actually this is the case for the present estimate of contact energies ; the figure of @xmath169 versus @xmath170 is not shown . in t - tests for correlation coefficients between @xmath161 and @xmath82 , the geometric mean of probabilities for significance is equal to @xmath171 . the norms of @xmath0-matrix eigenvectors , @xmath86 , projected on the subspace consisting of the @xmath172 lowest normal modes of a kirchihoff matrix corresponding to the @xmath0-matrix , are plotted against @xmath172 . @xmath173 means a projection operator on the @xmath172 lowest normal modes of the kirchhoff matrix . plus marks indicate the norm of the principal eigenvector of the @xmath0-matrix of each of 182 proteins projected on each subspace consisting of the @xmath172 lowest normal modes indicated on the abscissa . the solid curves with cross marks indicate those norms averaged over all proteins ; their curves from the left to the right show those values for the first , the second , and the third principal eigenvectors of @xmath0-matrix , respectively . , width=302 ] here , we have shown that the principal eigenvector among other eigenvectors of @xmath0-matrix seems to be a main contributor to minimize conformation energy . it is important to take notice that the principal eigenvector of @xmath0-matrix corresponds to the lower frequency normal modes of protein motion . let us think about a kirchhoff matrix that is defined as @xmath174 where @xmath175 is a kronecker s delta . the eigenvalue of the kirchhoff matrix are equal to the square of normal mode angular frequency in a system in which @xmath8 and @xmath9th units are connected to each other by a spring with a spring constant equal to @xmath20 . if contact number @xmath12 is equal to a constant @xmath176 irrespective of unit @xmath8 , then the eigenvalue of the kirchhoff matrix is equal to @xmath177 . in other words , in this case the principal eigenvector of @xmath0-matrix corresponding to the largest eigenvalue is equal to the eigenvector of the kirchhoff matrix corresponding to the smallest eigenvalue , that is , the lowest frequency normal mode corresponding to a motion that leads to the large conformational change @xcite . in actual proteins , contact number @xmath12 depends on unit @xmath8 , and then the correspondence between the eigenvectors of @xmath0-matrix and the kirchhoff matrix would become vague , but it will be expected that the principal eigenvector of @xmath0-matrix belongs to a subspace consisting of lower frequency normal modes . in fig . [ fig : proj_of_cpe_on_normal_modes ] , plus marks indicate the norm of the principal eigenvector of @xmath0-matrix of each of 182 proteins projected on each subspace consisting of the @xmath172 lowest normal modes indicated on the abscissa . in most of the proteins , the principal eigenvector of @xmath0-matrix corresponds to the lower frequency modes of the kirchhoff matrix . the solid curves with cross marks indicate those norms averaged over all proteins ; their curves from the left to the right show those values for the first , the second , and the third principal eigenvectors of @xmath0-matrix , respectively . the solid curve for the principal eigenvector shows that about 70% of the principal eigen vector of the @xmath0-matrix can be explained by only @xmath178 lower frequency modes . thus , the principal eigenvector of @xmath0-matrix is not only an important contributor to minimize conformation energy , but also corresponds to the lower frequency normal modes of protein motion . the lower bounds of the total contact energy lead to the relationship between @xmath1- and @xmath0-matrices such that the contact potential looks like a go - like potential . such a relationship may be realized only for ideal proteins , but in real proteins , atom- and residue - connectivity and steric hindrance not included in the contact energy can significantly reduce conformational space ; the number of possible @xmath0-matrices is the order of @xmath81 but the conformational entropy of self - avoiding chains is proportional to at most @xmath3 , where @xmath3 is chain length . as a result , eq . ( [ eq : best - optimum - eigenvectors ] ) is expected to be approximately satisfied only for some singular spaces , probably for singular values taking relatively large values , but at least for the primary singular space . it was confirmed in the representative proteins that the inner products of the principal eigenvectors of @xmath1- and @xmath0-matrices are significantly biased toward the value , one , at a certain value of the threshold energy @xmath17 for contacts , where their average over all proteins has a maximum ; see fig . [ fig : cos_cpe_epe_vs_sqrt_n_ave_cpei_scc70_22 ] . parallel relationships were also indicated and confirmed between the primary eigenvector @xmath146 and the contact number vector @xmath82 of @xmath0-matrix , and between the mean contact energy vector @xmath96 and the contact number vector @xmath82 ; see fig . [ fig : cos_cpe_cn_vs_sqrt_n_ave_cpei ] and fig . [ fig : cos_ave_e_cn_vs_cos_ave_e_1 ] . in these analyses , a statistical potential was used to evaluate contact energies between residues , and the coarse grain of the evaluations limits the present analysis to a relationship between the primary eigenvectors of @xmath1- and @xmath0-matrices , and also can make the relationship between these matrices vague . however , the results clarify significance of the principal eigenvectors of @xmath1- and @xmath0-matrices and the contact number vector in protein structures . here , it may be worthy of note that the primary eigenvector of @xmath0-matrix corresponds to the lower frequency normal modes of protein structures . the condition for the lowest bound of energy , eq . ( [ eq : go - type-2 ] ) , indicate that @xmath17 in real proteins corresponds to a threshold of contact energy for a unit pair to tend to be in contact in the native structures . in principle , such a threshold for contact energy depends on the size of protein and protein architecture ; it should be noted that many types of interactions in real proteins are missed in representing interactions by contact potentials . the estimate of @xmath120 shown in fig . [ fig : mean_cos_cpe_epe_vs_e0_scc7.0_22 ] is an estimate only for the present specific type of a contact potential . the important things are that the total contact energy is bounded by eq . ( [ eq : unreachable - lowest - bound - b ] ) with a constant term , and that the spectral relationships of eq . ( [ eq : best - optimum - singular - vectors ] ) and eq . ( [ eq : go - type-1b ] ) between @xmath1- and @xmath0-matrices are expected for the conformations of the lower bounds if @xmath1-matrix is decomposed with a constant term as shown in eq . ( [ eq : eigen - equation - for - e - matrix ] ) . besides that , the spectral representation of @xmath0- and @xmath1-matrices reveals that pairwise residue - residue interactions , which depends only on the types of interacting amino acids but not on other residues in a protein , are insufficient and other interactions including residue connectivities and steric hindrance are needed to make native structures the unique lowest energy conformations .

properties of contact matrices ( @xmath0-matrices ) for native proteins to be the lowest energy conformations are considered in relation with a contact energy matrix ( @xmath1-matrix ) under an assumption that the total conformational energy of a protein can be approximated by a sum of pairwise interaction energies represented as a product of corresponding elements of these matrices each of which corresponds to a conformation - dependent function and an sequence - dependent energy parameter . such pairwise interactions in proteins force native @xmath0-matrices to be in a relationship as if the interactions are a go - like potential @xcite for the native @xmath0-matrix , because the lowest bound of the total energy function is equal to the total energy of the native conformation interacting in a go - like pairwise potential . this relationship between @xmath0- and @xmath1-matrices corresponds to 1 ) a parallel relationship between the eigenvectors of @xmath0-matrix and those of @xmath1-matrix and a linear relationship between their eigenvalues , 2 ) a parallel relationship between a contact number vector and the principal eigenvectors of @xmath0-matrix and of @xmath1-matrix , where @xmath1-matrix is expanded in a series of eigenspaces with an additional constant term . the additional constant term in the spectral expansion of @xmath1-matrix is indicated by the lowest bound of the total energy function to correspond to a threshold of contact energy that approximately separates native contacts from non - naive contacts . inner products between the principal eigenvector of @xmath0-matrix , that of @xmath1-matrix , and a contact number vector have been examined for 182 proteins each of which is a representative from each family of the scop database , and the results indicate the parallel tendencies between those vectors . a statistical contact potential @xcite estimated from protein crystal structures was used to evaluate pairwise residue - residue interactions in proteins . in addition , the spectral representation of @xmath0- and @xmath1-matrices reveals that pairwise residue - residue interactions , which depends only on the types of interacting amino acids but not on other residues in a protein , are insufficient and other interactions including residue connectivities and steric hindrance are needed to make native structures the unique lowest energy conformations .

photons , due to its nature of low interaction with the environment , is the most popular candidate of an information carrier for secure quantum communication . the technology of light transmission has been well developed , which raises its popularity . however , because a photon is not well suited for local manipulation , a photonic state must be converted to a stationary state of a solid system for storage and information processing @xcite . in fact , various methods for such a state conversion have been studied @xcite . in particular , the electromagnetic induced transparency ( eit ) effect can be employed to switch the couplings between the metastable states of atoms and an optical field to preserve the state once the photon has been absorbed into the atoms @xcite . we refer to refs . @xcite for reviewing the recent progress of optical quantum memory . now let us consider the general configuration of a quantum memory system . as illustrated in fig . [ fig : quantummemory ] , it consists of two subsystems : the buffer subsystem and the memory subsystem . the buffer subsystem is coupled to both the external field and the memory subsystem , while the memory subsystem is only coupled to the buffer subsystem . the interaction between the two subsystems can be controlled by an on / off switching signal @xmath1 so that the quantum state is preserved inside the memory subsystem once all the state is fed into it . given a physical system having the above configuration , then the problem is how to design an efficient or even optimal transfer , storage , and retrieval processes . for instance , for an atomic quantum memory incorporating the eit effect , we find some methods that compute a time - varying control signal @xmath1 achieving optimal state transfer , based on the information gained from the leaking output @xcite . also , for a wide class of open quantum systems , i.e. , _ passive linear quantum systems _ such as a large atomic ensemble and an opto - mechanical crystal array @xcite , the general procedure for achieving a _ perfect _ state transfer was developed @xcite ; in particular , it was found that the pulse shape of an input photon , @xmath2 , must be the generalized _ rising - exponential _ function to accomplish the perfect state transfer if the on signal takes a constant value . however , it is often the case that a generalized rising - exponential function has a complicated form , and experimental implementation of such a complex pulse shaping of a single photon field is a challenging task . in fact , even in the case of generating a simple rising exponential such as @xmath3 , we need to elaborate a sophisticated photon generator based on a cold atomic media @xcite or an asymmetric optical parametric oscillator @xcite . extension of these schemes to the general multi - mode setup must be more involved and challenging . of a single - photon field and the control signal @xmath1 are properly designed so that the single photon is effectively transferred to the memory subsystem . ] the contribution of this paper is to solve the above mentioned issue ; that is , for a general passive linear quantum system having the configuration shown in fig . [ fig : quantummemory ] , we develop an optimal control theory for computing a low - complexity pulse function @xmath2 of an input single - photon that can be perfectly absorbed into the memory subsystem , by employing a time - varying control signal @xmath1 . this idea is based on the fact that , in contrast to the difficulty for shaping a complex pulse function of a single - photon field in an experiment , there are many setups where even a complicated and fast control signal can be easily implemented using a laser pulse shaping ; this fact has been demonstrated in the field of quantum ( open - loop ) optimal control @xcite . that is , our method can be used to make the perfect state transfer protocol more feasible , by converting the complexity of @xmath2 ( hard to implement ) to that of @xmath1 ( easy to implement compared to @xmath2 ) . note that a similar approach , but for a concrete example , was developed in @xcite ; a remarkable difference of these works to our approach is that in their setup the input pulse function @xmath2 is _ given _ and then the optimal control _ maximizing _ the storage efficiency is computed ; note thus that , in this setup , the state transfer is in general not perfect . meanwhile , in our case , both the optimal pulse function and the optimal control signal can be found out of many combinations of those , in such a way that the perfect state transfer is guaranteed . this paper is organized as follows . section [ sec : preliminaries ] presents the general model analyzed throughout the paper and introduces the dynamical equations for the single - photon pulse function . in section [ sec : model ] , we derive the general condition for the pulse function and the control signal to achieve the perfect state transfer . section [ sec : optimalcontrol ] begins with the formulation of optimal control problem and then presents two examples , @xmath0-type atomic media and a networked atomic ensembles system . a concrete algorithm for solving the optimal control problem is given in appendix b. * notations : * for a matrix @xmath4 , the symbols @xmath5 , @xmath6 , and @xmath7 represent its hermitian conjugate , transpose , and complex conjugation in elements of @xmath8 , respectively ; i.e. , @xmath9 , @xmath10 , and @xmath11 . for a matrix of operators we use the same notation , in which case @xmath12 denotes the adjoint to @xmath13 . for a time - dependent variable @xmath14 , we denote @xmath15 . in this work , we follow the same model presented in @xcite , the general _ passive linear quantum system _ @xcite . this is an open quantum system composed of @xmath16 harmonic oscillators represented by a vector of annihilation operators @xmath17^t$ ] , satisfying the commutation relation @xmath18 . the system interacts with a single external optical field , whose annihilation process is denoted by the operator @xmath19 , satisfying @xmath20 . the system has a time - varying hamiltonian of the form @xmath21 , where @xmath22 is an @xmath23 hermitian matrix . further , the system - field instantaneous coupling is represented by @xmath24 $ ] , where @xmath25 is a @xmath16-dimensional complex row vector . then from the input - output formalism @xcite , the heisenberg dynamics of the system variable , @xmath26^t$ ] with @xmath27 the joint unitary evolution of the system and the field , together with the change of the field operator , is given by : @xmath28 where @xmath29 and @xmath30 is the annihilation process operator of the output field . note that the vector @xmath25 can be time - varying , but in this paper it is assumed to be time - invariant . the annihilation operator for the continuous - mode single - photon state is defined by @xmath31 where @xmath2 is a @xmath32-valued pulse shape function satisfying the normalization condition @xmath33 ( thus @xmath34 have the meaning of a probability distribution ) . a single photon field state is defined as @xmath35 where @xmath36 denotes the field vacuum state . as expected , the operator @xmath19 annihilates the photon ; @xmath37 . note that the method proposed in this paper also functions for the case when the input is given by a pulsed coherent field state . however , for a coherent field state , even a complex wave packet can be effectively generated by an electro - optic modulator , and thus our method may not need to be applied in this case . in this paper , the input field state for the system is given by the single photon field state . the system s initial state , at time @xmath38 , is assumed to be the ground state @xmath39 . thus , the initial state of the whole system is @xmath40 . then , due to the passivity property , the system s output state on the field @xmath41 is also a single photon state ; let @xmath42 be the pulse function of this output single photon state . in this setup , the input pulse shape @xmath2 and the output pulse shape @xmath42 are connected by the following classical differential equation having the same form as that of eq . @xcite : @xmath43 the derivation of this equation is given in appendix a ; in particular , the definition of the @xmath44-valued vector @xmath45 is given in eq . . at time @xmath46 when the perfect state transfer is achieved , @xmath47 coincides with the superposition coefficients of the system state ( see appendix a ) ; this will be used as a terminal condition of the optimization problem formulated in section 4 . note that , if the input is a coherent field state with amplitude @xmath2 , we have the same input - output relationship as above , in which case @xmath45 stands for the vector of means of the system coherent state . next let us define the correlation matrix as @xmath48 , whose diagonal terms represent the mean photon number in each mode . the dynamics of @xmath49 is given by @xmath50 where @xmath45 obeys eq . . throughout this paper , we consider a particular class of passive linear quantum systems which has the ability for transfer , storage , and retrieval of a quantum state . we let the system to have three components @xmath51^t$ ] , where @xmath52 is a single annihilation operator , and @xmath53 and @xmath54 are vectors of @xmath55 and @xmath56 annihilation operators , respectively . then the hamiltonian matrix @xmath22 is given by @xmath57 , where @xmath58,~~ g=\left[\begin{array}{ccc } 0 & \bm{0}^t & \bm{0}^t\\ \bm{0 } & g_{11 } & g_{12}\\ \bm{0 } & g_{12}^{\dagger } & g_{22 } \end{array}\right ] , \nonumber\end{aligned}\ ] ] are time - invariant matrices and @xmath59 is a control signal which modulates the hamiltonian . the size of the matrices @xmath60 and @xmath61 is @xmath62 , where we have defined @xmath63 . we also define @xmath64 $ ] with @xmath65 . hence , eq . is now given by @xmath66 & = \left[\begin{array}{ccc } -\frac{1}{2}|c|^2-if_{00 } & -if_{01 } & \bm{0}^t\\ -if_{01}^{\dagger } & -if_{11}-ig_{11}u(t ) & -ig_{12}u(t)\\ \bm{0 } & -ig_{12}^{\dagger}u(t ) & -ig_{22}u(t ) \end{array}\right ] \left[\begin{array}{c } a_0\\ \bm{a}_1\\ \bm{a}_2 \end{array}\right ] -\left[\begin{array}{c } c^*\\ \bm{0}\\ \bm{0 } \end{array}\right]b , \nonumber \\ & \hspace{-0.2 cm } \tilde{b}=ca_0+b . \label{eqn : arg}\end{aligned}\ ] ] it is immediate to see that , during @xmath67 , the second mode @xmath54 entirely decouples from the input field and the other system modes . therefore , @xmath54 functions as a memory subsystem , because once the photon is transferred into the state of @xmath54 , that state can be preserved for a long time by tuning @xmath67 . the other modes @xmath52 and @xmath53 are the buffer subsystems , which mediate the state transfer from the optical field to the memory subsystem . the relation of the three groups of modes is illustrated in fig . [ fig : toy ] . finally note that the input and output pulse functions @xmath2 and @xmath42 are connected by eq . , which is now @xmath68 & = \left[\begin{array}{ccc } -\frac{1}{2}|c|^2-if_{00 } & -if_{01 } & \bm{0}^t\\ -if_{01}^{\dagger } & -if_{11}-ig_{11}u(t ) & -ig_{12}u(t)\\ \bm{0 } & -ig_{12}^{\dagger}u(t ) & -ig_{22}u(t ) \end{array}\right ] \left[\begin{array}{c } \eta_0\\ \bm{\eta}_1\\ \bm{\eta}_2 \end{array}\right ] -\left[\begin{array}{c } c^*\\ \bm{0}\\ \bm{0 } \end{array}\right]\xi , \nonumber \\ & \hspace{-0.2 cm } \tilde{\xi}=c\eta_0+\xi.\end{aligned}\ ] ] the relation between the three groups of modes ; @xmath69 denotes the buffer subsystem and @xmath54 does the memory subsystem . the arrow represents the input and the output fields . the solid line represents the regular interaction , and the dotted line represents the tunable interaction with strength @xmath1 . ] for the perfect transfer of a photonic state , the output pulse function must always be zero during the state transfer process ; this is the idea of zero - dynamics principle for perfect state transfer @xcite . thus , from eq . , the condition we desire is @xmath70 . the time derivative of the output pulse is then calculated as @xmath71 which is also zero since the output must be constantly zero . substituting the zero - output condition @xmath72 for the above equation , we have @xmath73=\left [ \begin{array}{ccc } \frac{1}{2}|c|^2-if_{00 } & if_{01}c & \bm{0}^t\\ if_{01}^{\dagger}/c & -if_{11}-ig_{11}u(t ) & -ig_{12}u(t)\\ \bm{0 } & -ig_{12}^{\dagger}u(t ) & -ig_{22}u(t ) \end{array } \right]\left [ \begin{array}{c } \xi(t)\\ \bm{\eta}_1(t)\\ \bm{\eta}_2(t ) \end{array } \right].\ ] ] this equation can be simply represented as @xmath74 where @xmath75^t$ ] and @xmath76 are fixed matrices . let us next derive the boundary condition from the system s final state when the state transfer is accomplished at time @xmath77 . first , since @xmath47 coincides with the terminal superposition coefficients of @xmath78 , we have @xmath79 and @xmath80 for the perfect state transfer into the memory subsystem . also from @xmath81 , the input pulse must satisfy @xmath82 . in total , @xmath83^t$ ] . the dynamics or with this boundary condition is called the zero - dynamics , and it can be uniquely solved backwards in time starting from @xmath77 once @xmath1 is specified . in other words , this dynamics is the condition imposed on @xmath1 and @xmath2 for achieving the perfect state transfer . let us consider the special case when the control signal @xmath1 is constant . in this case , letting @xmath84 in eq . readily yields @xmath85 where @xmath86 is a heaviside step function taking @xmath87 for @xmath88 and @xmath89 for @xmath90 . note of course that eq . is the solution of eq . when @xmath1 is constant . to see explicitly a feature of the function , let us consider a single - mode system specified by @xmath91 and @xmath92 ; the dynamical equation of the system annihilation operator @xmath93 is given by @xmath94 typically , this system can be implemented as an optical cavity coupled to an external field , where @xmath95 is proportional to the transmissivity of the coupling mirror . in this case , eq . is given by @xmath96 , where @xmath97 is assumed for simplicity . that is , the pulse function is of the rising exponential form . has to be a controllable time - varying parameter ; that is , @xmath95 must be changed to zero immediately after the state transfer is finished . ] based on this observation , we call eq . the generalized rising exponential function , for systems with the number of modes more than or equal to two . in fact , in terms of the eigenvalues of @xmath8 , @xmath98 , eq . can be represented as @xmath99 with @xmath100 the constant coefficients ; hence , under the assumption that @xmath101 , which is required to achieve the perfect state transfer @xcite , eq . is indeed the sum of rising exponential functions . note again that a single - photon field state over the pulse function is perfectly absorbed into the corresponding multi - mode passive linear system . also we remark that eq . is the time - reversed version of the system s output field @xcite , as in the single - mode case @xcite . however , as we refer in the examples in the next section , a generalized rising exponential function has a complicated form in general ; thus realization of a single - photon field state with such a complex pulse function is still a challenging task , while , as mentioned in section 1 , a simple rising exponential of a single - photon field state is possible to experimentally generate , using current technology . the main purpose for considering the variation of the control signal @xmath1 is to reduce the complexity of the pulse function , while maintaining the perfect state transfer . the problem is that , as implied by eq . , there are infinitely many combinations of @xmath2 and @xmath1 that satisfy the condition for perfect state transfer . in this section , we present an optimal - control formulation for determining the optimal pair of low - complexity pulse function and the corresponding control signal , and then show two examples . as mentioned above , the general rising - exponential pulse function of a single - photon is often of a very complicated form , which would be hard to generate . on the other hand , a single - photon field traveling with a simple rising exponential pulse function such as @xmath96 shown above can be experimentally generated @xcite , although such a simple function can not perfectly transfer the photon into the memory subsystem . is @xmath102 . thus , the simple rising exponential function does not transfer the state into the memory subsystem perfectly , except the case where the system is a single - mode system ; see the footnote in page 6 . ] therefore , as a compromise , we consider a unimodal function ; that is , here we formulate an optimal control problem such that the cost function is minimized when the pulse function takes a unimodal form . this policy is supported by the fact that a source system generating a single photon with unimodal pulse function has been experimentally implemented in several setups , such as cavity qed @xcite , ion trap @xcite , circuit qed @xcite , and cold atoms @xcite . actually , by properly modulating the source system during the photon emission process , we can flexibly tailor the pulse shape so that the desired unimodal pulse function is realized . for instance , it was demonstrated in the ion - trap setup in @xcite that the duration of the gaussian - shaped pulse of the emitted single photon can be controlled by tuning the intensity of the driving field for the ion ; also , the circuit - qed - based scheme developed in @xcite generates a single photon with various @xmath103-shaped form , by a proper modulation of the driving microwave signal that effectively changes the qubit - resonator coupling . ( represented by the solid black line ) , @xmath104 ( the red dotted line ) , and @xmath105 ( the blue dashed line ) . , scaledwidth=62.0% ] according to the above - described policy , we define a cost function so that @xmath34 would monotonically increase until it meets its single extremum and decrease after the pulse reaches that extremum . let @xmath106 be the time of this extremum ; hence @xmath107 . then , the cost function should impose a penalty when the pulse function is not increasing until @xmath106 and not decreasing after @xmath106 . a simple optimal control problem satisfying this policy can be defined as @xmath108 where @xmath109 for a dimensionless constant @xmath110 . actually this cost function takes a smaller value if @xmath111 for @xmath112 and @xmath113 for @xmath114 ; fig . [ fig : pulsecost ] illustrates the relation between @xmath34 , @xmath104 , and @xmath105 in this desired case . note that @xmath106 is a decision variable . also the constraint of this optimization problem is given by eq . , which together with the boundary condition is @xmath115^t . \label{eqn : subjectsimple}\end{aligned}\ ] ] the above optimal control problem can be generalized to @xmath116 where @xmath117 is an increasing function introduced to enhance the penalty . in particular , we set @xmath118 . moreover , the cost over the control sequence and the boundary condition should be also taken into account . thus , the overall cost function is given by @xmath119 = \int_{t_0}^{t_1 } \left[\alpha \ , { \rm exp}\left(h(s)\frac{d}{ds}|\xi(s)|^2\right ) + \beta u^2(s)\right]ds + \gamma \|\bm{x}(t_0)\|^2.\ ] ] here , @xmath120 are dimensionless positive constants that change the weight of each cost . summarizing , the optimal control problem is to find @xmath1 that minimizes the cost under the constraint . because the variable is fixed at the terminal time @xmath77 , this optimization problem is solved backwards in time ; the initial time @xmath121 is chosen so that the initial system state is enough close to the ground state , or equivalently that the initial variable @xmath122 is enough close to zero . the detailed procedure for calculating the optimal pair of @xmath2 and @xmath1 is given in appendix b. -type atom . ( b ) relation of the modes ; @xmath123 is the buffer subsystem and @xmath124 is the memory subsystem . ] ; the generalized rising exponential corresponding to the constant control ( dashed blue line ) and the optimized unimodal function corresponding to the time - varying control ( solid red line ) . ( b ) the constant control signal @xmath158 ( dashed blue line ) , and the optimized time - varying control signal ( solid red line ) . ] now the objective is to transfer a single - photon to the spin - wave mode @xmath124 , implying that the final state is set to @xmath159^t$ ] . the pair of optimal low - complexity input pulse function @xmath2 and the corresponding control signal @xmath1 , which achieves the perfect state transfer , can be computed by solving the optimal control problem developed in the previous subsection ; more precisely , as described in appendix b , the gradient method @xcite combined with the euler - lagrange equations , , and subject to the dynamics and the cost function yields the optimal solution . the system parameters are chosen so that @xmath160 . also the dimensionless weighting parameters are set to @xmath161 ; the reason of choosing a large value of @xmath95 is to strongly impose the initial variable @xmath122 to be close to zero . figure [ fig : pulseshape ] ( a ) shows the absolute value of pulse function ( probability density ) , i.e. , @xmath34 with @xmath162 and @xmath97 . the dashed blue line represents the generalized rising exponential function corresponding to the constant control @xmath158 , and the solid red line shows the optimized pulse function corresponding to the optimal time - varying control signal @xmath1 ; these control signals are illustrated in fig . [ fig : pulseshape ] ( b ) . a remarkable fact is that , in contrast to the complicated pulse shape realized with the constant control , the optimized pulse function has a simple unimodal shape with extremum point @xmath163 , thanks to the aid of optimal time - varying control signal . as discussed in section 4.1 , implementing this unimodal pulse of a single photon may be feasible with current technology . also , the phase of the single - photon pulse is fixed to @xmath164 for all @xmath165 , implying that the phase modulation of the single - photon field is unnecessary . note that this time - varying signal @xmath1 looks complicated as well , but the external optical field with this level of frequency envelope is feasible to implement , as shown in the experiment @xcite ; recall that , on the other hand , implementing the complex pulse shape @xmath2 corresponding to the constant control @xmath158 may be a challenging task . finally let us confirm that the perfect state transfer is achieved . figure [ fig : statfigure ] shows the time evolution of the mean photon numbers inside the atomic medium , i.e. , @xmath166 , which can be calculated using eq . . we then actually observe that the photon has been transferred into the memory subsystem mode @xmath151 at the final time @xmath97 , while the buffer subsystem @xmath150 is excited during the time - evolution but finally decays to the ground states . , the single photon is completely transferred into the memory subsystem mode @xmath151 ( yellow dotted line ) . ] first of all , let us remember the fact that the optimization problem formulated in section 4.1 does not necessarily yields a unimodal pulse function @xmath2 as the optimal solution . hence , it should be worth investigating to see if a unimodal input pulse function could be obtained for a more complicated system than the previous @xmath0-type atomic media where actually the optimal solution is given by a unimodal function . in this subsection , we study a networked system composed of large atomic ensembles and an optical cavity field , provided in @xcite ; in fact , as will be shown later , this system forms a target memory subsystem in a nontrivial way , unlike the previous example . is the buffer subsystem and @xmath167 is the memory subsystem . ] ; the generalized rising exponential corresponding to the constant control ( dashed blue line ) and the optimized unimodal function corresponding to the time - varying control ( solid red line ) . ( b ) the constant control signal @xmath158 ( dashed blue line ) , and the optimized time - varying control signal ( solid red line ) . ] here we set the goal to transfer a single - photon into the mode @xmath191 , implying that the terminal condition is given by @xmath192^t$ ] . the parameters are chosen so that @xmath193 . also the dimensionless weighting parameters are chosen as @xmath194 ; thus , the penalty on the control is taken to be smaller than the case of previous example . the initial and final time are taken to be @xmath195 and @xmath97 . figure [ fig : pulsecontrol ] ( a ) shows the comparison of the pulse function @xmath34 when the control signal is constant @xmath158 and when @xmath1 is optimized . figure [ fig : pulsecontrol ] ( b ) illustrates those control signals . clearly , the optimized pulse shape realized with the aid of time - varying control signal is simpler and thus more feasible , than the generalized rising exponential function . a notable fact is that the optimized pulse has a unimodal form , despite that the system is more involved than the previous example ; hence we obtain a positive answer to the question we had in the beginning of this subsection . on the other hand , the control signal @xmath1 has to vary in a complicated form in time , as shown in the solid red line in fig . [ fig : pulsecontrol ] ( b ) . however , recall now that @xmath1 is the time - varying coefficient of the _ local _ hamiltonian @xmath196 ; hence even such a complex modulation of @xmath1 is more feasible than the case of generating the generalized rising exponential @xmath2 shown in the dashed - blue line in fig . [ fig : pulsecontrol ] ( a ) . finally , the time - evolution of the mean photon number for each mode is shown in fig . [ fig : statdynamics ] , illustrating that certainly the single - photon of the input field is transferred perfectly into the target memory mode @xmath191 . note that we can transfer an arbitrarily photon superposition state @xmath197 where @xmath198 and @xmath199 are orthogonal functions and @xmath200 the coefficient ; in this case the transferred state is @xmath201 where @xmath202 is the state corresponding to @xmath203 ; see @xcite . , the single photon is completely transferred into the mode @xmath191 ( purple dot - dashed line ) . ] in this paper , we have formulated the optimal control problem that computes the best pair of a low - complexity unimodal input pulse function of a single - photon state and the corresponding control signal , which achieves the perfect state transfer . the numerical simulations demonstrated that , thanks to the aid of time - varying control signal , a unimodal input pulse function is obtained , which is simpler than the generalized rising exponential function obtained when a constant control is employed . we again note that the advantage of this method , which simplifies the pulse function at the expense of shaping the control signal , relies on the fact that implementing a time - varying control signal is in general more feasible than the task for shaping a complex waveform of a single - photon , and the fact that a flexible tuning of a unimodal pulse function is experimentally realizable . the future work includes verifying the actual shape of a single - photon input pulse which is feasible to generate in an experiment . we also point out that the analysis of this paper is limited to the case where the pulse function and the control signal have the exact form calculated from the numerical optimization . the performance may change significantly , if some unwanted noise are present , and thus the robustness analysis is crucial for practical application . this work was supported by jsps grant - in - aid no . 15k06151 and jst presto . first , multiplying @xmath204 from the right hand side of eq . , we have @xmath205 where @xmath206 denotes the vector of state vectors @xmath207 . the above differential equation can be solved explicitly as follows . first let us define the _ transition matrix _ @xmath208 $ ] , where @xmath209 denotes the time - ordered exponential . this satisfies the following properties : @xmath210 note that @xmath211 . now we define @xmath212 ; then from the differential equation in eq . together with the above properties we have that @xmath213 , where we have applied @xmath214 . the solution of this equation is , in terms of the original variable @xmath206 , given by @xmath215 which further yields @xmath216 . hence the output equation @xmath217 in eq . can be expressed as @xmath218 { |{\bm{0},0}\rangle}.\ ] ] as a consequence the mean photon number of the output field is given by @xmath219 because the phase change in the pulse function can be made irrelevant , we end up with @xmath220 let us now define @xmath221 it is then immediate to see that @xmath45 satisfies eq . . before closing this section , let us consider the meaning of @xmath45 . from the definition @xmath222^t$ ] , where @xmath27 is the joint unitary evolution on the system and the field , we have @xmath223 . now define @xmath224 , which is the joint system - field state in the schrdinger picture . also note that , for the passive system , @xmath225 holds . therefore , @xmath226 can be expressed as @xmath227 , where @xmath228 with @xmath87 appearing only in the @xmath229th entry . this means that @xmath226 represents how much the @xmath229th system mode is excited at time @xmath230 , by the single - photon driving . in particular , if the single photon field state is completely transferred to the system at time @xmath77 and the whole system - field state gains the form @xmath231 , then we have @xmath232 . thus , @xmath233 coincides with the superposition coefficient of the system state when the perfect state transfer is completed . here we present the procedure for solving the optimization problem studied in this paper . consider the following real - valued deterministic system : @xmath234 where @xmath14 is a vector of variables , @xmath235 is a vector of functions , and @xmath1 is the control signal . @xmath236 is a fixed initial state at the initial time @xmath237 . the problem is to find the optimal @xmath1 that minimizes the cost function @xmath238=\varphi(x(t_f))+\int_{t_i}^{t_f}l(x(t),u(t),t)dt,\end{aligned}\ ] ] where @xmath239 and @xmath240 are scalar - valued functions defined in @xmath241 $ ] . to solve the problem , we utilize the variational method and aim to find the minimum of the following functional : @xmath242 where @xmath243 is a vector of lagrange multipliers associated with eq . , and @xmath244 is the hamilton function . the variation @xmath245 is calculated as @xmath246^{t_f}_{t_i } + \int_{t_i}^{t_f}\left(\frac{\partial h}{\partial x}\delta x + \frac{\partial h}{\partial u}\delta u + \dot{p}^t\delta x\right)dt \nonumber\\ & = \left(\frac{\partial\varphi}{\partial x } -p^t(t_f)\right)\delta x(t_f ) + \int_{t_i}^{t_f}\left\{\left(\frac{\partial h}{\partial x } + \dot{p}\right)\delta x + \frac{\partial h}{\partial u}\delta u\right\}dt , \nonumber\end{aligned}\ ] ] where we have used @xmath247 since @xmath248 is fixed . the stationary condition of the functional is thus @xmath249 which are called the euler - lagrange equations . now , to apply the above euler - lagrange method to our case , we represent the complex - valued dynamics as the real - valued one as follows : @xmath250 = \left[\begin{array}{cc } -a_{0r}-a_{1r}u & a_{0i}+a_{1i}u\\ -a_{0i}-a_{1i}u & -a_{0r}-a_{1r}u \end{array}\right ] \left[\begin{array}{c } \bm{x}_r \\ \bm{x}_i \end{array}\right],\end{aligned}\ ] ] where the subscripts @xmath251 and @xmath252 denote the real and the imaginary component of the matrix or the vector ( recall @xmath75^t$ ] ) . also , the hamilton function is now given by @xmath253 \left[\begin{array}{c } \bm{x}_r \\ \bm{x}_i \end{array}\right ] . \nonumber\end{aligned}\ ] ] we utilize the following procedure @xcite for determining the optimal control @xmath1 : 1 . prepare the initial control @xmath1 defined in @xmath241 $ ] . 2 . calculate the backward solution @xmath14 subjected to eq . , starting from @xmath254 . [ enum : x ] 3 . using the solution obtained in the step , calculate the forward solution @xmath243 subjected to eq . , starting from @xmath237 . 4 . if @xmath255 is small enough , terminate . otherwise , go to the next step . let @xmath256 and search @xmath257 such that the cost function @xmath258 $ ] is minimal . then replace @xmath259 by @xmath260 , and go to the step . [ enum : alpha ] the procedure for finding the optimal @xmath261 in the step can be conducted by the line search algorithm . if the precise solution is not required , the following wolfe conditions @xcite are convenient to use : armijo rule : : : @xmath258\leq j[u]+\mu_1 j'[u]\epsilon$ ] , curvature condition : : : @xmath262\geq\mu_2 j'[u]$ ] , where @xmath262=\int_{t_i}^{t_f}\frac{\partial l(x , u+\epsilon s , t ) } { \partial \epsilon}dt$ ] is the derivative of the cost functional @xmath263 with respect to @xmath261 . if @xmath264 satisfies the above conditions for some constants @xmath265 , one may assume that the function @xmath266 $ ] has decreased sufficiently and take @xmath264 as the solution in the step . 10 x. bao , a. reingruber , p. dietrich , j. rui , a. dck , t. strassel , l. li , n. liu , b. zhao , and j. pan , efficient and long - lived quantum memory with cold atoms inside a ring cavity , nature physics * 8 * , 517/521 ( 2012 ) . g. k. gulati , b. srivathsan , b. chng , a. cere , d. matsukevich , and c. kurtsiefer , generation of an exponentially rising single - photon field from parametric conversion in atoms , phys . a * 90 * , 033819 ( 2014 ) . h. ogawa , h. ohdan , k. miyata , m. taguchi , k. makino , h. yonezawa , j. yoshikawa , and a. furusawa , real - time quadrature measurement of a single - photon wave packet with continuous temporal - mode matching , phys . lett . * 116 * , 233602 ( 2016 ) . s. ritter , c. nolleke , c. hahn , a. reiserer , a. neuzner , m. uphoff , m. mucke , e. figueroa , j. bochmann , and g. rempe , an elementary quantum network of single atoms in optical cavities , nature * 484 * , 195 ( 2012 ) . m. pechal , l. huthmacher , c. eichler , s. zeytinolu , a. a. abdumalikov , s. berger , a. wallraff , and s. filipp , microwave - controlled generation of shaped single photons in circuit quantum electrodynamics , phys . x * 4 * , 041010 ( 2014 ) . p. farrera , g. heinze , b. albrecht , m. ho , m. chavez , c. teo , n. sangouard , and h. de riedmatten , generation of single photons with highly tunable wave shape from a cold atomic quantum memory , nature commun . * 7 * 13556 ( 2016 ) .

a quantum memory is a system that enables transfer , storage , and retrieval of optical quantum states by on / off switching of the control signal in each stages of the memory . in particular , it is known that , for perfect transfer of a single - photon state , appropriate shaping of the input pulse is required . however , in general , such a desirable pulse shape has a complicated form , which would be hard to generate in practice . in this paper , for a wide class of linear quantum memory systems , we develop a method that reduces the complexity of the input pulse shape of a single - photon while maintaining the perfect state transfer . the key idea is twofold ; ( i ) the control signal is allowed to vary continuously in time to introduce an additional degree of freedom , and then ( ii ) an optimal control problem is formulated to design a simple - formed input pulse and the corresponding control signal . numerical simulations are conducted for @xmath0-type atomic media and a networked atomic ensembles , to show the effectiveness of the proposed method .

neuroendocrine tumours of the small bowel are the most common type of malignant neoplasm in the small intestine , accounting for 35% of small intestinal cancers [ 1 , 2 ] . small bowel neuroendocrine tumours ( nets ) are the most common type of gastrointestinal neuroendocrine tumours . the incidence and prevalence of these tumours are on the rise , as demonstrated in the surveillance epidemiology and end results ( seer ) data and the population - based study in norway [ 2 , 4 ] . a threefold increase in incidence has been demonstrated in the usa between 1973 and 2002 . the majority of these tumours do not cause carcinoid syndrome , often presenting late with metastatic disease . patients with non - hormone secreting tumours often present with vague symptoms , including intermittent abdominal pain or weight loss . a number of patients are identified coincidentally . approximately 40% of patients with metastatic disease at presentation have functionally active tumours leading to the development of carcinoid syndrome [ 710 ] . small bowel nets were generally thought to be indolent tumours ; however , their behaviour is more heterogeneous , and consequently a staging and grading system has been introduced by european neuroendocrine tumour society ( enets ) to help clinicians to optimize the management of these patients . the enets grading system incorporates ki67 index and mitotic rate to grade tumours ; these parameters had not previously been incorporated to the who 2000 classification of nets . yao et al . demonstrated a median survival from presentation of 65 months for patients with stage 4 ( distant metastatic ) well to moderately differentiated small bowel nets . more recent studies have demonstrated 5-year survival of > 70% for patients with metastatic small bowel nets [ 12 , 13 ] . a number of studies have assessed the survival benefit of primary tumour resection and other therapeutic interventions [ 12 , 1417 ] . however , there is still no consensus as to whether primary resection in patients with distal metastatic disease at presentation is beneficial . there is conflicting evidence regarding the survival benefit of liver resection , though it is generally recommended to offer liver resection if complete tumour removal or debulking of > 90% of the liver disease is possible . to date there is limited data regarding the prognostic relevance of the proposed enets tnm staging and grading system , which has been validated in foregut and a combined study of mid - and hindgut nets [ 13 , 19 ] . in this study we report our experience with small bowel nets over a 20-year period ( from 1990 to 2010 ) . the aims of this study were twofold : firstly to determine whether the enets tnm staging system predicts prognosis in patients with small bowel nets and secondly , to determine prognostic clinicopathological factors in patients with small bowel nets . patients with small bowel primary nets were identified through a search on the neuroendocrine tumour database at king 's college hospital , london , uk . patients with tumours arising from the ampulla of vater and ileocaecal valve were excluded from analysis . site of primary and assessment of metastatic disease were based on operative , cross - sectional , and/or nuclear medicine imaging . data collection was performed by two investigators ( r. srirajaskanthan and a. ahmed ) using a specifically designed database ( filemaker pro ) . cases histological diagnosis was based on the microscopy and when possible immunohistochemical staining with net markers . a second histological assessment was performed at king 's college hospital when possible to confirm accurate histological characterisation and grading of tumours . the tnm staging system proposed by enets was used to stage patients in whom complete histological and radiological assessment was possible [ 11 , 21 ] . radiological assessment included a ct of chest , abdomen , and pelvis plus an octreotide scan in all cases . mibg scans were performed in some instances . due to the small number of patients with stage 2a disease and stage 2b disease , the histological assessment for tumour grade using the proposed enets classification was performed in all cases where histology was available . grade 1 is classified as a ki67 2% , grade 2 ki67 320% , and grade 3 ki67 > 20% [ 11 , 21 ] . patients underwent a number of therapeutic interventions in this study including surgery and biotherapy with somatostatin analogues . peptide receptor targeted therapy in this study comprised of both yttrium - dotatate therapy and since 2008 lu - dotatate therapy . selective internal radiation therapy ( sirt ) was performed on carefully selected individuals ; a treatment was regarded as embolization of one lobe of the liver . therefore , if patients had both lobes treated , this would be regarded as two treatments . table 2 illustrates the number of different therapeutic interventions patients underwent during the course of their treatment . continuous variables are reported as mean sd or median ( range ) if not normally distributed . histological grade was assessed in univariate analysis but was excluded from multivariate analysis due to the amount of censored data leading to insufficient numbers to perform multivariate analysis . variables were removed stepwise from the model when p value exceeded 0.10 and variables with a p < 0.05 in the final model were considered significant predictors of death . data analysis was performed using graphpad prism software ( graphpad prism version 5.00 for windows , graphpad software , san diego california usa , http://www.graphpad.com/ ) and spss v.16 ( spss inc . ) . the median age of the 138 patients was 65 years ( range 2987 ) at time of diagnosis ; there were 68 males and 70 females . the 76 patients ( 55% ) had functional tumours , and the remainder were nonfunctional tumours . one hundred patients had the primary tumour resected , and 48 liver surgeries were performed in 37 patients . complete histological analysis was available in 76 cases , all of which were either g1 or g2 tumours . the remaining cases were all histologically confirmed neuroendocrine tumours ; however , ki67 analysis was not available in these cases . primary tumour resection was defined as resection of the primary tumour and if surgically possible resection of associated mesenteric mass and lymph node disease . not all primary resections were performed at the centre ; however , histological assessment of the resected specimen was performed at king 's college hospital in these cases . one hundred patients had the primary resected , and 4 patients had attempted resection of the primary but at laparotomy were found to be irresectable ; there were no postoperative deaths within 30 days of surgery . kaplan - meier curves were constructed to determine if there was any survival benefit for patients in whom the primary tumour was resected ( figure 1(a ) ) . there was improved survival in patients who underwent resection of primary tumour compared to those in whom the primary remained ( 120 versus 56 months , p < 0.05 ) . there was survival benefit in resection of the primary tumour in patients with stage 4 disease at the presentation compared to those in whom the primary was not resected ( 105 versus 56 months , p < 0.05 ) . of patients that did not undergo resection of the primary tumour the reasons were as follows : 9 cases were due to the primary being regarded as irresectable ; 4 patients had attempted resection , however , at laparotomy the primary could not be removed ; and 2 were due to not being considered for primary resection due to comorbidity . in one case the patient declined to surgery opting for conservative management . in the remaining cases surgery was not considered for the primary due to the volume of metastatic disease and/or impaired functional status due to carcinoid heart disease . thirty - seven patients had a total of 48 liver resection surgeries , including 2 patients who had a liver transplant . the median age of patients undergoing liver resection was 55 years ( range 3277 ) . all patients that underwent liver resection had the primary tumour resected previously or at the time of liver surgery . of the 37 patients undergoing liver surgery 14 patients also had the primary removed at the time of surgery . 1 patient had a postoperative - bleed , 1 bile leak , and 1 wound infection which required drainage . two patients underwent liver transplant during this study : one patient died 5 months following the surgery , due to development of pneumonia , and the other patient remains disease - free at 240 months posttransplant . there was a significant survival benefit in patients who underwent liver resection of hepatic metastases with stage 4 small bowel nets compared to patients with stage 4 small bowel nets and hepatic metastases who did not have liver resection ( 128 versus 76 months , p < 0.05 ) , figure 1(b ) . on univariate analysis , the following clinicopathological features were related to improved prognosis : not having carcinoid heart disease , resection of primary tumour , g1 histological grade , and liver resection . there was no difference in survival for the following factors : gender , uptake on octreoscan , presence of a functional syndrome , and treatment with somatostatin analogues . multivariate analysis was performed using cox regression analysis adjusting for all factors that showed a significant difference on univariate analysis . primary tumour resection and no carcinoid heart disease were identified as the only independent predictors of survival . not having the primary tumour resected was associated with a relative risk of 2.9 ( 1.36.1 ) , p < 0.005 . not having carcinoid heart disease was associated with a decreased relative risk 0.145 ( 0.060.36 ) , p < 0.005 . the tnm staging demonstrated significant difference in survival between stage 2 and 3 versus stage 4 disease ( p < 0.05 ) and also stage 3 versus stage 4 disease ( p < 0.05 ) . there was no significance in survival between stage 2 and stage 3 disease ( figure 2(a ) ) . therefore , improved survival in patients with localised / locoregional disease compared to patients with metastatic disease at the presentation was demonstrated . there was significantly improved prognosis between g1 compared to g2 tumours , p < 0.05 . there were no patients with g3 tumours for assessment , see figure 2(b ) . there were 4 patients with tnm stage 2 disease , 23 patients with tnm stage 3 disease , and 10 patients in whom the staging was not known but had no evidence of residual disease postoperatively and were regarded as r0/r1 resection . the remaining patients had clear evidence of distant metastatic disease prior to undergoing resection of the primary tumour . of the patients who underwent attempted curative resection without distal metastatic disease there was no recurrence in patients with stage 2 disease , and median duration of followup was 37 months ( 17180 months ) . median followup for patients with stage 3 disease was 37.5 months ( range 6119 months ) . recurrence occurred in 7 of 23 ( 30.4% ) patients , and median duration to recurrence was 47 months ( range 1196 months ) . the 5-year and 10-year survivals were 79.5% and 48.5% , respectively , for all patients independent of the stage of the disease . the median survival for patients with stage 4 disease was 98 months , with 5-year survival of 74.5% . there were 44 ( 32.8% ) deaths during the follow - up period of the study . 20.5% of patients died from nontumour - related deaths ; the most common causes were cardiovascular death and a second malignancy . we have demonstrated that the enets tnm staging system for midgut offers prognostic information , with the worst survival demonstrated in patients with stage 4 disease compared with stage 2 or stage 3 disease . furthermore , the proposed grading system based on ki67 and mitotic index provided statistically different prognosis between g1 and g2 nets . no difference in survival was demonstrated between stage 2 and stage 3 disease ; this could be in part due to the duration of followup and small numbers of cases with stage 2 disease . however , other studies have not demonstrated difference in survival between stage 2 and stage 3 disease . markers of cellular proliferation as measured by ki67 index and mitotic rate were incorporated in to the novel enets tnm staging and grading system . studies demonstrated these markers as predictors of survival in pancreatic and upper gastrointestinal nets and hence their incorporation into the enets guidance [ 11 , 22 , 23 ] . in this study we demonstrated significant improvement in survival for patients with g1 compared to those with g2 nets ; this supports the findings in other studies [ 14 , 24 ] . overall the 5-year and 10-year survivals were 79.5% and 48.5% , respectively , for all patients independent of stage of disease . this shows improvement in the 5-year survival when compared to previous studies , including the seer data . there appears to be a trend towards improvement in survival when looking at the 5-year survival data from recently published data looking at patient cohorts over the last two decades [ 6 , 12 , 14 ] . it may be in part related to increased use of somatostatin analogues and their antiproliferative effect . secondly , the management of patients in multidisciplinary teams and the more aggressive surgical management of these patients may have improved survival . the study cohort may be biased as it is not a population - based survival but instead a survival of patients managed in a specialist centre . finally , lead time bias may also be a factor ; however , there is no clear evidence to support that patients are being diagnosed at an earlier stage of the disease . the cause of death in this study demonstrated that 47.3% were related to tumour progression which is similar to that published in the ukinets study . a similar percentage of patients died from carcinoid heart disease and small bowel obstruction [ 14 , 2527 ] . interestingly 20.5% of patients died from tumour - unrelated causes , which is similar to that identified from previous studies [ 14 , 28 ] ; in part it could be related to the longer survival of patients with small bowel nets , leading to other causes of death accounting to a large percentage of deaths . this study demonstrates improved survival in patients in whom the primary tumour was resected , with univariate and multivariate analyses . furthermore , there was improved survival for patients who presented with stage 4 disease who had resection of primary tumour compared to those in whom the primary was not resected . previous studies have demonstrated a survival benefit in resection of primary tumour ; however , the study population has been rather heterogenous . a recent systematic review by capurso et al . concluded that there is a possible benefit of resection of the primary lesion in patients with unresectable liver metastases . this study demonstrates significant prognostic benefit of liver resection on survival using univariate analysis , though this is not a prognostic factor with multivariate analysis . numerous studies have demonstrated improved symptom control and quality of life following hepatic resection and tumour debulking [ 22 , 3032 ] . the role of hepatic surgery in patients with metastatic nets should still be considered in appropriate candidates [ 14 , 18 ] . a number of studies have demonstrated improved prognosis following liver resection in patients with small bowel nets in a univariate analysis [ 14 , 16 , 33 ] . there is limited data regarding the time to develop recurrent disease following curative resection in patients with local / locoregional disease . following what was regarded as r0/r1 resection we have demonstrated that median time to development of recurrence is 55 months . approximately 30% of patients with stage 3 disease will develop recurrence within a median period of 47 months . studies by le roux and landerholm have demonstrated recurrence rates around 30% following complete resection of primary tumour and locoregional disease [ 28 , 34 ] . followup of patients with stage 2 or 3 tumours should be extended beyond 5 years . this study is a single centre experience that has certain inherent limitations ; due to the nature of referrals it was not possible to accurately stage all patients who underwent surgical resection and perform complete histological analysis . the rate of disease recurrence following resection of locoregional disease may be overestimated due to referral bias ; however , similar rates have been reported in other studies . this study has demonstrated that enets tnm staging and grading system is able to prognosticate between stage of disease and grade of tumour . primary tumour resection and not having a carcinoid heart disease there may potentially be a role of determining the likelihood of recurrence following surgery using the tnm staging system .

introduction . small bowel neuroendocrine tumours ( nets ) are the most common type of gastrointestinal neuroendocrine tumours . the incidence and prevalence of these tumours are on the rise . the aims of this study were to determine prognostic clinicopathological features and whether the enets tnm staging system predicts prognosis and also . method . clinical data was collected retrospectively from 138 patients with histologically proven small bowel nets managed at king 's college hospital . histology was reviewed and small bowels tumours , were staged according to the enets tnm staging system . results . median age was 65 years ( range 2987 ) . the 5-year survival was 79.5% and the 10-year survival was 48.5% . resection of the primary tumour was associated with improved survival ( 120 versus 56 months , p < 0.05 ) . on multivariate analysis prognostic factors were primary tumour resection and not having a carcinoid heart disease . tnm staging significantly separated survival of stage 2 and stage 3 from stage 4 nets . conclusion . small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors . the enets tnm staging and grading system appears to be of prognostic relevance to small bowel nets .

in western countries , the prevalence of paediatric obesity and comorbidities , which cluster together in the metabolic syndrome ( mets ) , is going to reach epidemic proportions . data from the national heart lung and blood institute lipid research clinics and the princeton prevalence study ( 19731976 ) and princeton follow - up study ( 20002004 ) show that mets in 5- to 19-year olds represents a risk factor for cardiovascular disease in adulthood . this finding highlights the importance of early recognition of mets in obese children as a strategy for primary prevention of cardiovascular disease later in life . clinical studies have shown that low birth weight increases the risk of mets in adulthood . the association between birth weight and mets in childhood is far to be clear , and results are controversial , with studies showing a strong [ 46 ] or a weak [ 79 ] association between low or high birth weight and mets . moreover , several reports indicate that family history of diabetes and increased abdominal fat adiposity are strong risk factors for mets since childhood [ 5 , 1013 ] . additionally , the marked decrease of insulin sensitivity associated with the onset of puberty in growing individuals [ 14 , 15 ] may act as a further risk factor for the development of metabolic comorbidities , particularly in obese subjects . it is not clear if onset of puberty and its progression are characterized by different determinants of mets in adolescents , compared to children . the aim of the study was to evaluate whether family history of type 2 diabetes ( fhd ) in first - degree relatives , either low or high birth weight , and increased central body fat depot are independent risk factors for the development of mets in italian obese children and adolescents . the children who participated in the present cross - sectional investigation are a subsample of an ongoing longitudinal study exploring risk factors for the development of type 2 diabetes in young italian subjects . obese children and adolescents , referred to the endocrinology and diabetes unit of bambino ges children 's hospital for obesity from january 2003 to january 2010 , were included in the present investigation if they met the following criteria : ( 1 ) being overweight or obese according to the international obesity task force ; ( 2 ) absence of underlying diseases ; ( 3 ) italian origin ( all four grandparents of italian descent ) ; ( 4 ) availability of data relative to gestation , birth , and fhd among first - degree relatives . moreover , as we were interested in the role of fetal factor in the development of metabolic comorbidities , low and high birth weights ( as defined below ) were additional selection factors . participants were not following a weight - reducing diet , taking any medication , or carrying a previous clinical diagnosis known to influence body composition , glucose metabolism , physical activity , or dietary intake . the gestational age was determined by ultrasound in the first trimester , if available , and otherwise calculated from the date of the last menstruation . weight at birth was converted into percentiles for gestational age and sex , according to the italian birth weight curves . participants were defined on the basis of their birth weight percentile as small for gestational age ( sga ) ( birth weight 10th percentile ) , appropriate for gestational age ( aga ) ( birth weight > 10th and < 90th percentile ) , and large for gestational age ( lga ) ( birth weight 90th percentile ) . fhd was defined by the presence of type 2 diabetes in at least one parent . fhd , maternal gestational , and pre - existing diabetes were ascertained by a self - administered parents ' questionnaire . after a 12-hour overnight fast , at approximately 8:00 am , all subjects were admitted in the clinic for one - day inpatient visit . height was measured without shoes to the nearest 0.1 cm using a wall stadiometer , and weight was measured in underwear to the nearest 0.1 kg using a medical balance beam scale . to compare body mass index ( bmi ) across different ages and between genders , values of bmi were expressed as standard deviation score ( sds ) . blood pressure ( bp ) was measured using a standard mercury sphygmomanometer two times in the supine position , at the beginning and at the end of the visit , using the right arm after the subject had rested quietly for 5 minutes . on each occasion , three readings of blood pressure were obtained , and the average was recorded . physical maturation was assessed on the basis of breast development in girls and genitalia development in boys according to tanner . due to the well - known relationship between pubertal development and decrease in insulin sensitivity [ 14 , 15 ] , subjects were divided into two groups according to the pubertal stage : prepubertal ( tanner stage 1 ) , pubertal ( tanner stage from 2 to 5 ) . fasting blood samples were taken via antecubital vein catheter for measurement of glucose , insulin , c peptide , high density lipoprotein ( hdl ) , cholesterol , and triglycerides . then subjects ingested 1.75 g of glucose solution per kilogram of body weight ( to a maximum of 75 g ) . plasma samples were drawn for determination of glucose , insulin , and c peptide concentration every 30 minutes , until 2 hours after glucose load . insulin sensitivity index ( isi ) was calculated from oral glucose tolerance test ( ogtt ) . it has been demonstrated to strongly correlate with the euglycemic - hyperinsulinemic clamp in obese children and adolescents . to asses beta cell function , we used the insulinogenic index , calculated as the ratio of the increment in the plasma c peptide level to that in the plasma glucose level during the first 30 minutes after the ingestion of glucose . the disposition index ( di ) was defined as the product of isi and insulinogenic index . at least 10 days after the first inpatient visit children were admitted again for body composition evaluation . body composition was measured by dual - energy x - ray absorptiometry ( dexa ) using hologic qdr delphi ( hologic inc . , bedford , ma ) , as previously described . fat and lean mass were corrected for differences in height as follow fat mass / height ( fat bmi ) and lean mass / height ( lean bmi ) , expressed as kg / m . body fat distribution was evaluated by the central obesity index calculated as the ratio of the amount of fat tissue in the trunk region to the amount of fat tissue in the leg region . identification of mets among children was based on the adult criteria defined by the national cholesterol education program . in the adult definition , a minimum of three of five major criteria ( obesity determined by waist circumference , hypertension , low hdl cholesterol levels , elevated triglycerides , and glucose intolerance ) should be fulfilled . overweight and obesity were defined according to the obesity task force : hypertriglyceridaemia as triglycerides > 95th percentile for age and sex ; low hdl cholesterol as concentrations < 5th percentile for age and sex ; elevated bp as systolic or diastolic bp > 95th for age and sex ; glucose intolerance as fasting glucose 100 mg / dl and/or 2-hour post - ogtt glucose 140 . therefore , we defined mets as the presence of at least 2 other findings out of overweight / obesity . serum insulin and c peptide were measured by chemiluminescence on advia centaur analyzer ( kyowa , medex co. , tokyo , japan ) ; both assays are two - site sandwich immunoassays using direct chemiluminescent technology [ intra- and interassay coefficient of variation ( cv ) 3.34.6 and 2.65.9% ; 3.74.1 and 1.03.3% , resp . ] . quantitative determination of blood glucose , hdl cholesterol , and triglycerides was measured by enzymatic method on roche automated clinical chemistry analyser ( roche / hitachi 904 analyzer , roche diagnostics , mannheim , germany ) . intra- and interassay , cv for glucose , hdl cholesterol , and triglycerides were 0.9 and 1.8% ; 0.60.95 and 1.2 - 1.3% ; 1.5% and 1.8% , respectively . the kolmogorov - smirnov goodness - of - fit test was used for determining whether sample data are likely to derive from a normal distributed population . between - group differences were examined using independent sample t - test and chi - square test for numerical and categorical variables , respectively . first , bivariate logistic regression was used to determine the associations between mets and gender , age , fhd , diabetes during pregnancy , birth weight percentile , bmi sds , fat and lean bmi , central obesity index , isi , insulinogenic index , and di . then , variables significantly associated with mets were inserted into multivariate logistic regression analyses , with mets as dependent variable . , variables influencing mets were evaluated in the overall population . in the second step , study participants included 439 obese subjects ( 213 boys , 226 girls ) , aging 5.217.9 years ( mean age 11.3 2.6 ) with a mean bmi sds of 2.2 0.3 . mets was present in 17.1% of individuals with higher prevalence in pubertal than prepubertal subjects ( 21.4 versus 11.9% , p = .008 ) . clinical and metabolic characteristics of subjects with and without mets , divided according to pubertal development , are reported in table 1 . girls and boys were equally distributed among individuals with and without mets in both groups . as expected isi and central obesity index were significantly different , with subjects with mets being more insulin resistant ( prepubertal : 3.0 1.9 versus 4.1 2.3 , p = .010 ; pubertal : 2.5 1.9 versus 3.6 2.5 , p < .0001 ) and having more central fat depot ( prepubertal : 1.32 0.20 versus 1.19 0.39 , p = .017 ; pubertal : 1.30 0.29 versus 1.19 0.24 , p = .024 ) compared to individuals without mets . mean birth weight percentile and di were lower in individuals with mets compared to individuals without mets , but differences were statistically significant only in the pubertal group ( birth weight percentile prepubertal : 38.2 34.0 versus 47.0 32.2 , p = .117 ; pubertal 33.5 30.7 versus 45.0 31.8 , p = .011 ; di prepubertal : 0.36 0.22 versus 0.46 0.38 , p = .204 ; pubertal : 0.33 0.31 versus 0.41 0.28 , p = .012 ) . to further analyze the relation between birth weight and mets , we evaluated the prevalence of mets into the three birth weight categories . because low and high birth weights were selection factors , we had 22.3% of sga ( n = 98 ) , 62.2% of aga ( n = 273 ) , and 15.5% of lga ( n = 68 ) . prevalence of subjects with mets was significantly higher in the sga category ( 25.7% ) , with lga having the lowest ( 11.8% ) and aga the intermediate ( 14.5% ) prevalence ( p = .015 ) . this trend was maintained in the pubertal group ( p = .027 ) but not in the prepubertal one ( p = .423 ) ( figure 1 ) . as gestational diabetes is associated with large size at birth and is known to strongly influence the risk of developing mets in the offspring [ 6 , 28 ] , we evaluated the prevalence of mets in the different birth weight categories after excluding offspring of diabetic mothers . diabetes during pregnancy ( either gestational diabetes or pre - existing type 1 or 2 diabetes ) was present in 28 cases ( 6.3% ) . most cases of offspring of diabetic mothers were in the lga group ( 18 out of 28 ) . prevalence of mets in the different birth weight categories , after excluding offspring of mother with diabetes during pregnancy , did not change substantially ( in the whole population 26.1 , 13.7 , and 10.9% in sga , aga , and lga , resp . bivariate logistic regression analysis revealed age , lean bmi , insulinogenic index , and central obesity index to be positively associated with mets ( p = .033 , .004 , .027 , and .001 , resp . ) and birth weight , isi , and di to be negatively associated with mets ( p = .003 , < .001 , and = .002 , resp . ) . gender , fhd , diabetes during pregnancy , and degree of obesity expressed either as bmi sds or fat bmi did not influence the dependent variable . in the entire population , the multivariate logistic regression analysis revealed central obesity index to be positively and independently associated with mets and isi and birth weight to be negatively associated with mets , with central obesity index being the strongest predictor of mets ( table 2 ) . when the prepubertal and pubertal subjects were analysed separately , central obesity index remained the most powerful variable influencing mets in both groups , with isi similarly influencing mets in the two populations and birth weight being negatively associated to mets only in pubertal individuals ( table 2 ) . in the present study of italian growing obese individuals , our findings revealed that increased central fat depot is the strongest determinant of mets , no matter if subjects were children or adolescents , with central obesity index being more predictive of mets than insulin sensitivity . moreover , low birth weight appeared to be a less powerful risk factor for mets with significant association only in pubertal individuals . surprisingly , fhd , age , insulinogenic index , di , and degree of obesity , expressed either as bmi sds or total fat amount , were not significant determinants of mets in this cohort of obese subjects . the central role of abdominal adiposity and particularly of visceral adiposity in the development of mets has been widely demonstrated in adulthood [ 29 , 30 ] . similar findings have been described in children , where waist circumference and increased visceral fat depot have been confirmed to be strong and independent predictors of metabolic alterations [ 12 , 13 ] . in the present study , by directly measuring with the dexa technique the total fat amount and the body fat distribution , we showed that in , obese italian growing subjects , the preponderance of fat in the abdomen is the real determinant of mets , rather than the total body fat amount . as a matter of fact , neither bmi sds nor fat bmi appeared to be risk factors for mets . similar findings were reported by an italian study , where waist - to - height ratio was the only clinical parameter directly related to mets , with the same predictive power of insulin resistance . in our study , sga individuals showed a significant higher incidence of mets , with subjects born lga apparently protected from the development of mets . however , small size at birth was not an important predictor of mets as was central obesity index . the present data of increased metabolic risk in subjects born sga confirm a large body of the literature in adulthood and also in childhood . moreover , our findings on apparently protective role of large size at birth are in contrast with other studies conducted in different ethnic groups , like pima indians and mexican children , that have showed an increased risk for metabolic alterations in children born lga . we have previously showed that obese children and adolescents born sga manifest reduced insulin secretion in the context of increased insulin resistance milieu and more evident central repartition of fat than aga and lga , with lga presenting the highest insulinogenic index , despite comparable degree of insulin resistance . similar to our findings , a study conducted in french obese children has showed a favourable metabolic profile in children born lga , with obese children and adolescents born with high birth weight displaying approximately 60% higher insulin sensitivity and lower central fat distribution compared with those born eutrophic . one could hypothesize that the role of large size at birth is different in the different ethnic groups , with european obese children being protected from metabolic complications if born lga . as the pima indian study has showed that the increased risk of metabolic alterations among pima with high birth weight was largely explained by maternal diabetes during pregnancy , we evaluated the role of diabetes during pregnancy in our sample of obese children and adolescents . we found no association with diabetes during pregnancy , probably because cases of either gestational diabetes or pre - existing type 1 or 2 diabetes were only 28 and we had no statistical power to show any relation with mets . different findings have been reported by other authors , who described fhd to be a risk factor for mets and hyperinsulinemia in children and adolescents . one explanation for this discrepancy could be due to the fact that type 2 diabetes in adults is age dependent . additionally , we did not measure directly blood glucose in the parents . it is likely that in our study some currently healthy parents have silent diabetes or will develop diabetes in the future . the specific role of fhd in the development of mets could not be determined with certainty , and follow - up studies are needed to confirm our results . although our study has strengths , including the use of imaging technique to evaluate body fat portioning and a large representative sample of exclusively italian obese children and adolescents , we acknowledge some limitations . first , we did not distinguish visceral from subcutaneous abdominal fat ; secondly , we did not study insulin sensitivity with the gold standard hyperinsulinaemic euglycemic clamp technique for its complexity in pediatric patients ; thirdly , because this was a cross - sectional analysis , causation could not be inferred . in conclusion , simple clinical parameters like increased abdominal adiposity , eventually estimated by waist circumference and low birth weight , could be useful tools to identify obese growing european individuals at risk for metabolic complications . as not all obese adults display the clustering of metabolic and cardiovascular risk factors , with some of them being metabolically healthy but obese individuals , one could speculate that obese adolescents born lga , with predominantly peripheral fat portioning , could be healthy obese adolescents , having a favourable metabolic profile . prospective studies with serial measurements of cardiovascular risk factors are needed to confirm our findings .

aim . to evaluate whether body fat distribution , birth weight , and family history for diabetes ( fhd ) were associated with metabolic syndrome ( mets ) in children and adolescents . methods . a total of 439 italian obese children and adolescents ( 518 years ) were enrolled . subjects were divided into 2 groups : prepubertal and pubertal . mets was diagnosed according to the adapted national cholesterol education program criteria . birth weight percentile , central obesity index ( measured by dual - energy x - ray absorptiometry ) , insulin sensitivity ( isi ) , and disposition index were evaluated . multivariate logistic regression models were used to determine variables associated with mets . results . the prevalence of mets was 17% , with higher percentage in adolescents than in children ( 21 versus 12% ) . in the overall population , central obesity index was a stronger predictor of mets than insulin sensitivity and low birth weight . when the two groups were considered , central fat depot remained the strongest predictor of mets , with isi similarly influencing the probability of mets in the two groups and birth weight being negatively associated to mets only in pubertal individuals . neither fhd nor degree of fatness was a significant predictor of mets . conclusion . simple clinical parameters like increased abdominal adiposity and low birth weight could be useful tools to identify european obese adolescents at risk for metabolic complications .

in 1959 , when nanoscience as we know it today was still far from being a reality , richard feynman gave a talk at the annual meeting of the american physical society , entitled `` there s plenty of room at the bottom '' @xcite . in this talk feynman anticipated most of the experimental fields and issues of concern which , more than twenty years later , would become key issues in the understanding of phenomena at the nanometer scale . while talking about the possibility of building nanoscale electric circuits , he also posed the question : `` ... is it possible , for example , to emit light from a whole set of antennas , like we emit radio waves from an organized set of antennas to beam the radio programs to europe ? the same thing would be to beam the light out in a definite direction with very high intensity ... '' . today , we can safely state that feynman s suggestion has already become reality and the research on nanoantennas that work at optical frequencies has developed into a strong branch of nanoscience - nano - optics in particular - with many exciting perspectives . it is the goal of this report to summarize and explain the current understanding of optical antennas on the background of both , the highly developed field of antenna engineering @xcite and plasmonics @xcite . although feynman s work was right before the eyes of everybody for a long time , it took the solid development of near - field optics @xcite to acquire enough proficiency in using nanostructures to influence the flow of light at deep subwavelength scales with the required precision . although it is not the intention of this report to provide a detailed account on the chronological development of the field , we nevertheless would like to mention a few selected publications that inspired the authors to enter into the field of nanoantennas . first of all there is the visionary book chapter by dieter w. pohl @xcite , in which he points out the similarities between `` fluorescing molecules , small scattering particles etc . and telecommunication antennas '' and suggests to `` inspect antenna theory for concepts applicable and useful to near - field optics '' . another eye opener was the paper by grober _ et al . _ @xcite , in which the authors explicitly discuss the use of nanoantennas for scanning near - field optical microscopy and provide proof - of - principle experiments using microwave radiation - an idea later on brought close to realization by oesterschulze _ et al . _ many other efforts dealing with antenna - like structures date back into the eighties and even before , mostly driven by the need for efficient infrared ( ir ) detectors . a good account is given in recent reviews @xcite . antennas are used either to create electromagnetic ( e.m . ) waves with a well - defined radiation pattern , which can then travel over large distances , or to receive e.m . waves from a remote source in order to extract some encoded information , to measure changes in their intensity , or to exploit the transmitted power @xcite . today the importance of antennas is dominated by their ability to provide an interface between localized information processing using electrical signals and the free - space wireless transmission of information encoded in various parameters of e.m . waves , such as e.g. amplitude , phase , and frequency . due to these properties , antennas and e.m . radiation have become indispensable assets to science and technology as well as to our everyday life . the function of an antenna is based on the fact that free charge carriers are constricted into certain well - defined regions of space . these charges may start to oscillate if an ac - voltage is applied or an e.m . wave is reaching such a region . examples for such systems are the conduction electrons in pieces of metal @xcite as well as electrons and ions in a gas discharge tube @xcite . an ac - voltage applied to a piece of metal changes the spatial distribution of charges as a function of time , which in turn will eventually affect the electric field of the charge distribution at any distance from the source . due to the finite speed of light @xmath0 , any change in the charge distribution that occurs at time @xmath1 results in a change in the electric field at a remote point at a distance @xmath2 only after a time @xmath3 , where @xmath4 is the refractive index of the medium . a well - known fundamental source of such e.m . disturbances is a harmonically oscillating dipole which may be pictured as two metallic spheres connected by a thin wire as it was realized in h. hertz s pioneering experiments @xcite . if such a system is prepared in an initial state where some negative charge is on one sphere and the corresponding positive charge on the other one , the system - when left alone - will start to perform an exponentially damped harmonic oscillation at a frequency @xmath5 ( where we assume small damping ) , in which @xmath6 and @xmath7 are the inductance and the capacitance of the system , respectively . the fact that the system is exponentially damped , i.e. energy loss is proportional to the energy still stored within the system , has two reasons : ( i ) a finite ( ohmic ) resistance felt by the charge carriers in the metal wire and ( ii ) loss of energy due to radiation of e.m . waves . this so - called radiation loss occurs due to the fact that the oscillation eventually creates time - dependent electric fields at remote distances , which must then be accompanied by magnetic fields that vary according to maxwell s equations . at large enough distance these fields transform into plane waves which are free - space solutions of the wave equation . if the dipole oscillation would be suddenly switched off , those far - away fields , or simply far fields , would continue to propagate since they carry energy that is stored in the fields themselves and has been removed from the energy originally stored in the charge distribution we have been starting out with . on the contrary , the so - called near - field zone corresponds to the instantaneous electrostatic fields of the dipole , which do not contribute to radiation but return their energy to the source after each oscillation cycle or when the source is turned off ( reactive power ) . in order to tune an antenna in such a way that it is resonant at optical frequencies one needs to adjust both @xmath6 and @xmath7 to bring the resonance into the optical regime . as r. feynman already pointed out in 1959 , in order to achieve a resonance in the optical wavelength regime one would have to make both , @xmath6 and @xmath7 , very small @xcite . this can be achieved by shrinking the dimensions of the antenna to the scale of the wavelength @xcite . however , if we are moving to higher and higher frequencies in order to eventually end up with ir and visible light , metals no longer behave as perfect conductors . the main difference between the interaction of low - frequency and very - high - frequency e.m . waves with the conduction electrons in metals stems from a finite effective mass of electrons . such effective mass causes the electrons to react with increasing phase lag to the oscillating e.m . field as the frequency increases . this behavior is in perfect analogy to a mass on a spring excited by an oscillating external force . in the case of electrons in a metal , the restoring force is the coulomb interaction with the stationary metal ions . for low frequencies , the electrons follow the excitation without phase lag . for increasing frequency of the excitation , they exhibit an increasing oscillation amplitude as well as an increasing phase lag . as soon as the phase lag approaches 90@xmath8 the amplitude of the charge oscillation goes through a maximum and is only limited by the internal ( ohmic and radiation ) damping of the system . in metallic nanoparticles , this resonance corresponds to the localized plasmon resonance which for certain materials ( such as gold , silver , aluminum , and copper ) happens to appear in or close to the visible spectral range . plasmon resonances do not appear in `` perfect '' conductors ( metals at low enough frequencies ) since in those materials by definition no phase lag exists between excitation and charge response . the presence of localized plasmon resonances is therefore characteristic for optical frequencies and can be exploited to balance drawbacks of antenna systems in this frequency range , such as e.g. enhanced ohmic losses compared to the radio - frequency ( rf ) regime . it should be noted here for completeness that the metallic character of doped semiconductors at low frequencies makes it possible to excite surface plasmons resonant at mid infrared , thz , and microwave frequencies @xcite , while even perfect metals if periodically structured can support excitations which behave very similar to surface plasmon polaritons , so - called spoof plasmons @xcite . why would anybody be interested in antennas at optical frequencies ? what would be the advantage of using an antenna over standard means , such as lenses and mirrors , to manipulate e.m . waves at optical frequencies ? the wavelength of visible light in vacuum in the green spectral range is about 500 nm , corresponding to an energy of about 2.5 ev . photons with such an energy can interact with matter through transitions between electronic states of spatially confined electrons . using the simplest quantum mechanical approach to describe such a system , the particle - in - a - box model , it is easy to show that the length scale of electron confinement , i.e. the length of the box , must be on the order of 1 nm if we require the lowest energy transition to occur in the visible spectral range . [ fig : confinement - wavelength ] illustrates the quadratic relation between electronic confinement and wavelength of the related e.m . wave obtained within such a model . electrons that show such a spatial confinement are typically encountered in larger organic molecules and artificial quantum confined systems , e.g. quantum dots and the like , which we call `` quantum emitters '' for simplicity . note the strong mismatch between the electronic confinement length , which determines the spectroscopic properties and the local interactions of a quantum emitter on a nanometer scale , and the wavelength of the e.m . radiation . since the wavelength governs effects of diffraction , e.g. in the focusing of light , this mismatch prevents propagating photons from being confined to the same spatial extension as the electrons of a quantum emitter . this leads , for example , to a typical behavior of single molecules at ambient conditions , which is that they absorb only very little light even when illuminated with a tightly focused laser beam @xcite . similar arguments explain the small cross - section for the generation of excitons in a semiconductor material - the fundamental process for solar energy conversion . a further important consequence of the length - scale mismatch is a rather long lifetime of the excited state of a typical quantum emitter . since the size of the molecule is so much smaller than the free - space wavelength of light , the birth of a photon from a quantum emitter is a highly inefficient process @xcite . this is nicely illustrated considering the total power emitted by a time - harmonic line current element in a homogeneous space with a length @xmath9 much shorter than the wavelength @xmath10 , @xmath11 where @xmath12 is the current amplitude and @xmath13 @xmath14 the wave impedance of free space @xcite . classically , such a current element can be considered a model for the oscillatory motion of electrons in a molecule . obviously , the radiated power is proportional to the square of the length - to - wavelength ratio . for the typical extension of a molecule of 1 nm this expression well reproduces the experimentally found relatively low excited state decay rates on the order of @xmath15 . due to this - on a molecular timescale - very long excited state lifetime , there is plenty of time for the excited - state energy to be dissipated through alternative nonradiative channels or for the molecule to become destroyed by photochemical processes . furthermore , the maximum number of photons that can be emitted per unit time is relatively small . it is the low photon emission rate that limits the usability of single quantum emitters as sources of single photons @xcite and their detectability in sensing and spectroscopic applications . finally , as a third consequence of the mentioned size mismatch , we note that in a typical far - field experiment spatially - resolved spectroscopic analysis of photons emitted simultaneously by an ensemble of closely packed quantum emitters is hindered by diffraction , which limits spatial resolution to about half of the emission wavelength @xcite . since optical antennas are able to ( i ) confine e.m . radiation to very small dimensions and ( ii ) very efficiently release radiation from localized sources into the far field , they provide the possibility to tailor the interaction of light with nano - matter in such a way that the three mentioned fundamental shortcomings can be lifted to a large extent . therefore the idea of an `` optical antenna '' is a fundamental concept in the general field of light-(nano)matter interaction . potential applications of optical antennas are therefore closely related to their ability to strongly localize and enhance optical fields upon illumination into the feed point - e.g. the gap between two antenna arms . both field confinement and enhancement trigger strong interest related to nonlinear optical effects , ultrasensing , imaging , as well as solar energy conversion and opto - electronics , all of which will be discussed in more detail later on in this report . moreover , and as a further illustration , let us consider the field of optical communication : since the higher the frequency , the more information can be encoded , the visible and infrared wavelength band is widely used in today s high - speed data communication networks . as an interesting side effect , when entering the optical regime , the frequency becomes large enough such that detection of single radiation quanta is readily achievable and that quantum jumps in single molecules and atoms can be induced and observed @xcite . therefore , in the optical regime , quantum aspects of the interaction of radiation and matter can be exploited in the context of long distance communication @xcite . in this picture photons are considered as `` flying qubits '' , while the atoms and molecules act as immobilized qubits @xcite . due to the fact that antenna emission patterns can be tuned in such a way that radiation is emitted in specific directions with sharp angular characteristics , the use of single quantum emitters in combination with optical antennas opens up fascinating new perspectives for quantum communication and data processing @xcite . to provide a solid background , we will begin with a brief account on the theory of classical rf antennas and introduce important antenna parameters . in contrast to perfectly conducting antennas , antennas at optical frequencies consist of nanometer - sized metal particles . their interaction with light is determined by the frequency - dependent complex dielectric function , which we will introduce first . we then start out to investigate the resonant behavior of single wires which are the basic constituents of optical antennas . we then move to isolated structures that consist of at least two strongly interacting nanoparticles and then to more complex structures and to optical antennas interacting with a `` driving circuit '' . while analyzing the resonances of these systems we will pinpoint the similarities and differences in the behavior of optical antennas as compared to their rf counterparts . what follows is then a brief account on fabrication methods that can be used to create optical antennas as well as an overview of the most important nanoantenna geometries that have been investigated so far . once optical antennas have been fabricated , it is important to be able to verify the expected performance . here we provide an account of the currently used optical characterization techniques and their respective strengths . we conclude our discussion with a brief review of current applications and fields of intense study in the context of nanoantennas . classical antenna theory uses maxwell s equations to describe the interaction of time - dependent currents with electromagnetic waves . most characteristic features of classical antennas are related to the two facts that ( i ) antenna wires are represented by a perfect conductor and ( ii ) critical dimensions , such as the antenna feed - gap and wire thickness , can be considered to be negligibly small compared to the wavelength . we assume time - harmonic fields throughout this report . . field emitted by an antenna is completely determined as soon as the time - harmonic current density @xmath16 along the antenna wires is known , from which the charge density @xmath17 then follows according to the continuity relation @xmath18 . the reason for this is that in the lorenz gauge , @xmath19 , the vector potential @xmath20 and the scalar potential @xmath21 satisfy a set of four inhomogeneous scalar helmholtz equations @xmath22{\bf a}({\bf r } ) & = & -\mu_o\mu { \bf j}({\bf r } ) \\ \left[\nabla^2 + k^2\right]\phi({\bf r } ) & = & -\frac{1}{\varepsilon_o\varepsilon}\rho({\bf r } ) \label{2}\end{aligned}\ ] ] where @xmath23 , with @xmath10 being the free - space wavelength . the field distribution , radiation pattern and total power radiated by the antenna are then found e.g. by calculating a spatial convolution of the respective scalar green s function @xmath24 for the given problem with the current density and the charge density present on the antenna as @xmath25 the scalar green s function is the solution of eq . ( [ 2 ] ) for a dirac delta source distribution @xcite . once the potentials are known , the fields can be determined by straightforward differentiation according to the definitions @xmath26 it turns out , however , that the current distribution on the antenna is quite difficult to determine exactly . for center - fed antennas with small feed - gaps and thin wires , an approximate current distribution can be found by solving an integral equation ( see e.g. @xcite for details ) . here , for reasons of simplicity , we discuss important antenna parameters under the assumption that the current distribution on a dipole antenna has a sinusoidal shape inherited from the standing wave pattern that builds up in a two - wire transmission line terminated by an open end , driven by a high - frequency voltage source . this is the kind of circuitry that is often used to drive an antenna . the configuration is sketched in fig . [ fig : transmissionline ] ( a ) . harmonically driven two - wire transmission line terminated by ( a ) an open end and ( b ) a finite - length antenna . for a given instant of time , the arrows indicate magnitude and direction of the current , plus and minus signs indicate local charge accumulation , and the solid line indicates the standing current wave ; ( c ) equivalent circuit of the system including the internal impedance of the generator , @xmath27 , the characteristic impedance of the transmission line , @xmath28 , as well as the impedance of the antenna , @xmath29 , acting as a load.,scaledwidth=50.0% ] the transmission line itself , although it sustains time - harmonic currents with a spatially varying amplitude , does not radiate into the far field if the gap between the wires is small , since each current element in one wire has its antiparallel counterpart in the other wire oscillating @xmath30 out of phase and therefore radiation largely cancels in the far field albeit a strong near field that is localized between the wires . since good conductors are considered in rf circuits , the wavelength of the standing wave is practically the same as the wavelength in free space . for an infinitely - long transmission line the local ratio of the voltage between the wires and the current through a wire is a constant called _ characteristic impedance _ , @xmath31 , independent of the position @xmath32 along the line . it depends solely on the materials used and on the geometry of the transmission line @xcite . in the lowest approximation one may assume that this sinusoidal current distribution is not significantly changed when we start to bend the wires at a certain distance @xmath33 from the open end - one upwards and one downwards . the strongest radiation from such a system of total length @xmath34 is obtained for a bending angle of 90@xmath35 [ see fig . [ fig : transmissionline ] ( b ) ] . it can be shown that for antennas made of thin wires compared to the wavelength the current is indeed very well described by a sinusoidal distribution @xmath36\textrm{,}\ ] ] in which the amplitude becomes @xmath37 as expected from the simplistic standing - wave model @xcite . the actual current amplitude , however , differs from that found in the unbend transmission line . the reason for this behavior lies in the fact that the antenna itself can now be thought of as a resonant circuit with a total complex impedance @xmath38 , leading in general to a reflection at the bending point and a shift in the standing - wave pattern as sketched in fig . [ fig : transmissionline ] ( b ) . it is then natural to define the input impedance of an antenna by the ratio of the voltage measured over the input terminals and the current flowing into each antenna arm , @xmath39 . as for any frequency - dependent complex impedance , the equivalent circuit of the antenna shows a resonance for the driving frequency for which @xmath40 , which also leads to a maximum in the current amplitude . we will refer to such a resonance as an `` antenna resonance '' . the absorbed power is determined by the real part of the antenna impedance @xmath41 , which includes ohmic losses , @xmath42 , as well as losses due to radiation , @xmath43 , and accordingly @xmath44 once the radiation resistance is known , the radiated power can be calculated as @xmath45 . a corresponding relation holds for the nonradiative power dissipated into heat . the _ radiation efficiency _ of an antenna can therefore be defined as @xcite @xmath46 describing the ratio of the radiated power to the total power absorbed by the antenna , in analogy to the quantum yield of a fluorescent molecule @xcite . since ohmic losses for rf antennas are very small , radiation efficiencies are typically larger than 99% . together with a simple model for the high - frequency generator driving the antenna via the transmission line , which is described by a lossless ac - voltage source and a complex internal impedance @xmath27 , we can come up with the equivalent circuit model for the whole system depicted in fig . [ fig : transmissionline ] ( c ) . the equivalent circuit model allows one to describe all relevant parameters of the circuit . before we get involved with this in more detail we would like to discuss the _ radiation pattern _ @xmath47 of a linear antenna with sinusoidal current distribution ( eq . [ current_eq ] ) , which is described by @xcite @xmath48 where the angle @xmath49 is measured from the direction of the antenna wires and @xmath50 is the azimuthal angle . as one might expect , the emission pattern for antenna lengths up to @xmath10 is very similar to the pattern of a hertzian dipole ( @xmath51 ) only that its angular dependence becomes narrower . only when the antenna length increases beyond @xmath10 , current elements are introduced on the same wire that oscillate @xmath30 out of phase , causing strong interference effects which lead to the development of a multi - lobed pattern ( see fig . [ pattern ] ) . the radiation pattern can be further influenced by deviating from the linear shape of the antenna or by adding additional wires as passive elements at well - chosen positions as it is done in the famous yagi - uda antenna design @xcite to be discussed later on . ) and for perfectly conducting thin - wire antennas of length @xmath52 , @xmath10 , and @xmath53 @xcite . the gap antenna attached to an impedance - matched waveguide effectively behaves as a single - wire antenna . a sketch of the current standing wave is provided beside each emission pattern.,scaledwidth=50.0% ] in order to quantify and compare the ability of different antennas to radiate power preferentially into a certain direction , antenna engineers introduce _ directivity _ @xcite @xmath54 which is defined as the ratio of the radiation intensity @xmath47 to the total radiated power @xmath55 per unit solid angle ( corresponding to an ideal isotropic radiator ) . an equally important figure of merit is the antenna _ gain _ , which is defined as the ratio of @xmath47 to the total input power @xmath56 that is to be re - radiated per unit solid angle ( corresponding to the power that would be radiated by an antenna with no losses ) . obviously , gain @xmath57 and directivity @xmath58 are related by the radiation efficiency of the antenna : @xmath59 these and other relevant figures of merit are of course strongly frequency - dependent . therefore , in antenna design it is important to specify the _ bandwidth _ over which a certain performance is achieved . so far we have considered antennas mostly as devices which create e.m . however , naturally , antennas can also be used to collect e.m . one may ask whether there is a relation between the ability of an antenna to emit e.m . waves and its ability to collect them . indeed , such relations exist and are typically discussed by calling upon different forms of reciprocity theorems . we will not give any derivation here , but only state the most important reciprocity relation for antenna - like e.m . systems and mention the conclusions that can be drawn . assuming time - harmonic fields in linear media in which the tensors @xmath60 and @xmath61 are symmetric , the reciprocity theorem , sometimes referred to as the rayleigh - carson reciprocity theorem , reads as @xcite @xmath62 where @xmath63 @xmath64 are time - harmonic source currents which may run through antenna wires and @xmath65 @xmath64 are the corresponding fields that originate from the respective currents . note that eq . ( [ reciprocity ] ) describes a situation with two independent currents and the resulting fields , i.e. two antennas . the integrals in eq . ( [ reciprocity ] ) only run over the volume of the respective source currents because the integrands vanish everywhere else . ( [ reciprocity ] ) can be used to proof ( i ) that the shape of the angular receiving pattern of an antenna equals that of its angular emission pattern @xcite and ( ii ) that the ratio of the power delivered from the first antenna to the second antenna and the power supplied to the first antenna is equal to the ratio of the power delivered from the second to the first antenna and the power supplied to the second antenna @xcite . these two reciprocity relations for antennas are very useful in antenna engineering and remain valid also at optical frequencies where they are more and more frequently used @xcite . in the case of an optical antenna that is coupled to a quantum emitter in its vicinity , eq . ( [ reciprocity ] ) can be used to derive a reciprocity relation that links the polarization- and angle - of - incidence - dependent rate for excitation @xmath66 and the radiative decay rate @xmath67 via the polarization - dependent directivity @xmath68 @xcite @xmath69 where @xmath70 denotes the two polarization directions of the transverse radiated far fields and @xmath71 denotes quantities in absence of the antenna . in the derivation a second dipolar emitter is assumed in the far field of the antenna . the excitation rate @xmath66 is therefore the rate at which the antenna - coupled emitter is excited by a plane wave with polarization @xmath72 and direction @xmath73 . note that this reciprocity relation can not make any predictions about the nonradiative decay rate , i.e. ohmic losses that occur in the antenna , since nonradiative antenna modes are near - field effects and therefore are independent of the reciprocity consideration . the question which antenna performs best for a given application is often not easy to answer since contradicting requirements , e.g. a strongly directed emission pattern and a large bandwidth or a small overall size and a large radiation resistance , need to be combined . radiowave antenna engineering strongly benefits from the fact that metals at radio frequencies can be considered to be nearly lossless . this makes it possible to screen a very large variety of antenna shapes to achieve a certain performance without having to pay much attention to the radiation efficiency . things start to change as we move towards shorter wavelengths , and already for the microwave regime ( the thz domain ) losses become a constraint that antenna and circuit engineers have to deal with . the simplest antenna circuit we can think of has already been drawn in fig . [ fig : transmissionline](c ) . in the general case , the impedance discontinuity at the load will result in reflection of the forward - traveling voltage wave , with a reflection coefficient given by @xcite @xmath74 since impedances in general also possess an imaginary part related to their reactive properties , the reflection coefficient is a complex quantity , describing both the amplitude of the reflected back - traveling signal and its phase relation with the forward wave . from eq . ( [ reflection ] ) , it is clear that reflectionless coupling can be achieved when the characteristic impedance of the transmission line matches the antenna impedance , i.e. when @xmath75 . in an unmatched situation it is possible that the antenna is on resonance but very little power is delivered to it via the transmission line because of a large impedance mismatch . this is a situation that occurs for example for an antenna with @xmath76 in which the current vanishes in the gap according to eq . [ current_eq ] . although it has favorable properties , such an antenna can not be fed by connecting wires at the feed - gap since the related antenna impedance diverges leading to a strong impedance mismatch . in order to be able to efficiently deliver energy to an antenna , rf antenna engineers have developed strategies to achieve efficient impedance matching between the generator and the antenna even for exotic antennas . this is often achieved using external circuits , e.g. passive stubs , which consist of short pieces of transmission lines connected in series or parallel close to the antenna feed point @xcite . such matching circuits act as resonators , storing a considerable amount of power , and modify the phase and amplitude of the reflected voltage wave . for perfect conductors , only a small amount of power is consumed by such passive matching elements . therefore the overall radiation efficiency of the antenna including the matching circuit is only slightly smaller than that of the antenna alone . however , for higher frequencies , this is not true anymore , and standing - wave stub currents need to be properly minimized to keep losses low . therefore , for antennas at optical frequencies , such strategies can not be copied without careful consideration , since stub - like resonator structures as well as antenna circuits that exhibit a rather large number of passive elements may have rather strong losses and consequently a strongly reduced overall radiation efficiency . moreover , while everything can be intuitively understood in terms of voltage - wave reflection , things can become more subtle when power reflection is considered @xcite . the question of how to feed an antenna in an optimal way will be of particular importance for nanoantennas at optical frequencies as we will discuss later on . the constricted electron gas needed to build an antenna is very often provided by metals . however , at optical frequencies metals no longer behave as perfect conductors . their optical response is described by a complex frequency - dependent dielectric function @xmath77 , relating the electric field @xmath78 and the induced polarization density as @xmath79e(\omega)$ ] @xcite . in order to qualify for use in optical antennas , ohmic losses in the chosen metal should be as low as possible . ohmic absorption is proportional to the material conductivity @xmath80 , which in turn is related to @xmath81 by @xmath82 , and ohmic losses take place in close proximity to the surface within the so - called penetration depth @xcite . typical penetration depths for metals at visible frequencies are of the order of several tens of nm , e.g. about 13 and 31 nm for aluminum and gold at 620 nm wavelength , respectively @xcite . material losses in metal nanostructures can be kept low either by choosing a metal with large ( negative ) real part of @xmath81 , in order to reduce the penetration depth , or by selecting a low imaginary part of @xmath81 , in order to intrinsically keep the ohmic losses low . moreover the dielectric properties of a metal , as we will see , can cause a particle plasmon resonance in the visible spectrum , which is connected to large local fields and enhanced scattering . for small particles in vacuum , on resonance , the real part of @xmath81 takes on the value @xmath83 for a wavelength in the blue - green region , so that elongated particles and dimers show a resonance in the red or near - ir region , as will be discussed . since @xmath83 is not very large , the imaginary part of @xmath81 can not be neglected when discussing plasmonic resonances . the optical response in metals is dominated by the collective behavior of the free electron gas . to a first approximation , the conduction electrons in the metal can be treated as an ideal electron gas moving in the background of the positive metal ions . using the drude - sommerfeld model , the dielectric function of the metal can be expressed as @xmath84 where @xmath85 is the volume plasma frequency , which increases with increasing carrier density , and @xmath86 a damping constant @xcite . for noble metals at optical frequencies , typically @xmath87 ( e.g. for au @xmath88 s@xmath89 and @xmath90 s@xmath89 @xcite ) and therefore this model accounts for ( i ) a negative real part , meaning that the conduction electrons do not oscillate in phase with the external field , which is - by the way - the reason for the high reflectivity of metal surfaces , and ( ii ) a significant imaginary part . the drude - sommerfeld model does not account for the possibility that photons with high - enough energy cause interband transitions by promoting electrons from lower - lying valence bands to higher - energy conduction bands . this further degree of freedom is related to bound electrons and can classically be described by a collection of damped harmonic oscillators with well - defined resonance frequencies @xmath91 , yielding contributions to the dielectric response of the type @xmath92 where @xmath93 depends on the density of bound electrons involved in the absorption process and @xmath94 is a damping constant for the bound electrons . this absorption channel leads to a strong deviation from the free electron gas model near @xmath91 , leading to a maximum in the imaginary part of @xmath81 and therefore to strongly increased damping . in fig . [ fig : drude ] we schematically show the combined contribution of free and bound electrons to the complex dielectric constant of a typical metal in the visible . , is superimposed to the monotonic drude - like behavior of the free electron gas.,scaledwidth=50.0% ] the choice of the best plasmonic material for a given application is still a subject of discussion and research @xcite . mainly au , ag , al , and cu have been considered so far to be used as materials for metallic optical antennas . the respective material - dependent spectral behavior is discussed in @xcite . here we would like to mention the most relevant properties . gold and copper have very similar dielectric constants , with a drude - like response below 2.1 ev ( wavelength @xmath95 nm ) and an onset of interband transitions occurring around 2.3 ev ( 530 - 550 nm ) . this makes them excellent candidates to build antennas for the red and near - ir spectral region . other materials should be preferred for the blue - green part of the visible spectrum . for silver the first interband transition is above 3.1 ev ( wavelength @xmath96 nm ) , which makes it superior to gold for wavelengths around 450 - 550 nm . finally , aluminum has a larger ( negative ) real part of the dielectric function , and can therefore be considered the material which among these four metals best approximates an ideal metal , especially in the 400 - 600 nm spectral region . however , it has an interband absorption peak located around 800 nm wavelength , so that its use in the near - ir region is problematic . apart from the spectral properties of the dielectric function , also the chemical stability of antenna materials is an experimentally relevant issue . ag and cu are known to quickly corrode in ambient conditions ( formation of oxides and sulfides ) , while al is known to form thin passivation layers of al@xmath97o@xmath98 . au is the material that is mostly used experimentally , since it combines a favorable dielectric function in the red and near ir with excellent chemical stability . we now introduce important models for the description of _ optical _ antennas . in contrast to rf antennas that always appear as circuit elements connected to a feeding circuit , optical antennas often appear as _ isolated _ structures whose resonant properties will be discussed now . the most basic optical antenna geometries are single- and two - wire antennas , consisting of a single nanorod and of two end - to - end aligned rods separated by a small gap , respectively . scanning electron microscopy ( sem ) images of respective prototypes ( a single - crystalline colloidal rod @xcite and a nanostructured two - wire antenna @xcite ) are shown in fig . [ dipole_antenna ] . a single wire can be viewed as the fundamental building block of more complex antennas . we therefore start with a discussion of single - particle optical resonances first . we will introduce the mie description of optical resonances which is often used but is not very intuitive . much more physical insight can be obtained by introducing a mass - and - spring model as well as a fabry - prot model for the optical resonances of elongated particles . the fabry - prot model connects to the rf theory but takes into account the strongly reduced wavelength of plasmonic wire waves . towards more complex structures , the fundamental two - wire nanoantenna is of particular interest due to the strongly enhanced and deeply - subwavelength - confined fields that occur in its feed - gap upon external illumination . using the mass - and - spring model we will discuss the more complex spectra of two - wire nanoantennas which arise due to mode hybridization caused by the strong e.m . interaction between the particles . in order to illustrate these concepts we will present finite - difference time - domain ( fdtd ) simulations @xcite of fundamental prototype structures . finally , we will discuss the differences in the emission patterns between rf and optical antennas . ) scale bar is the same for both panels.,scaledwidth=50.0% ] localized plasmon resonances are resonant collective oscillations of the electron cloud in a metal nanoparticle , originating from the characteristic dielectric response of metals at optical frequencies . they are accompanied by resonantly enhanced polarizabilities and accordingly enhanced scattering and absorption as well as enhanced near - field intensities . the response of a spheroidal object to plane - wave illumination is analytically described in the frame of mie theory . when applied to sub - wavelength particles , only the first - order dipolar term needs to be considered @xcite . to illustrate this point of view , let us consider a sphere of polarizable material with radius @xmath99 and dielectric constant @xmath100 , embedded in a medium with dielectric constant @xmath101 , under the influence of a static electric field @xmath102 . the dipole moment induced in the sphere by the external field can be written as @xcite @xmath103 for @xmath104 ( vacuum ) this expression exhibits a resonance when the real part of @xmath100 approaches @xmath105 . when we move to optical frequencies and consider now a plane wave with wavelength @xmath10 illuminating a very small metal sphere ( radius @xmath106 ) , the external field can be considered constant over the particle . in this quasistatic approximation , the phase is also constant over the particle and retardation effects can be neglected . therefore eq . ( [ dipole1 ] ) is still valid , however , the static dielectric constant @xmath100 is replaced with @xmath77 @xcite . the resonance condition @xmath107 is met for particles consisting of au , ag , and cu around the visible range , and for al in the near - ultraviolet range . on resonance , the vanishing real part of the denominator of eq . ( [ dipole1 ] ) leads to a strongly increased induced dipole moment and therefore to enhanced local fields and scattering . however , due to the spectral position of the interband transitions , particles consisting of different materials still show different optical properties , as discussed in section [ comparison ] , and are therefore suitable for applications in different spectral regimes . let us now move from the plasmonic resonances of nanospheres to those of elongated prolate particles . we are interested in charge oscillations along the main axis ( length @xmath108 ) of such an ellipsoid . quantitatively , by means of a simple transformation of eq . ( [ dipole1 ] ) one can obtain the induced dipole moment of a prolate ellipsoid of volume @xmath109 , being the prototype of an elongated particle , which reads as @xcite @xmath110 here , @xmath111 is a function of the _ aspect ratio r _ , i.e. the ratio of the long axis radius @xmath112 to the short axis radius @xmath99 of the particle . detailed analysis of the resonance positions as a function of the aspect ratio using eq . ( [ dipole2 ] ) shows that the resonance position depends approximately linearly on the aspect ratio such that an increased aspect ratio leads to a red - shift of the resonance . roughly speaking , for gold , visible wavelengths are covered by sub - wavelength particles with aspect ratios ranging from 1 to 3 @xcite . although the quasistatic approximation of mie theory provides a good prediction of the resonances of prolate particles within its range of validity , it provides little physical insight into what is the cause of the linear scaling of the resonance energy with the aspect ratio . to capture the physics of a non - spherical plasmonic particle , we aim at representing the plasmon resonance by a simple mass - and - spring model with a resonance frequency @xmath113 , where @xmath58 and @xmath114 are the elastic constant of the restoring force and the total effective mass of the electron system , respectively . to estimate the restoring force we consider an elongated particle with dimensions given in fig . [ massandspringmodel](a ) . . the resulting positive and negative charge at the ends are treated as point - like charges that possess potential energy due to coulomb interaction . ( b ) the resulting oscillation can be modeled by an effective spring constant @xmath58 and the effective mass @xmath114 of the moving electron cloud.,scaledwidth=50.0% ] we assume that the particle has cylindrical shape . when the electron cloud in the particle is displaced by @xmath115 , opposite point charges @xmath116 build up at both ends whose magnitude depends on the charge carrier density @xmath4 and the cross - sectional area of the cylinder @xmath117 as @xmath118 , where @xmath119 is the elementary charge . the coulomb potential energy of the two charges is then @xmath120 the restoring force can now be determined as @xmath121 from which the spring constant @xmath58 is obtained . the linear relation between displacement and the resulting force leads to harmonic oscillations of the system , which allows drawing an analogy with a simple mass - and - spring model . the relevant mass that is involved is the mass of the whole electron cloud which is given by @xmath122 , where @xmath123 is the effective electron mass . we therefore obtain the approximate resonance frequency @xmath124 of the particle plasmon of an elongated particle @xmath125 where we substituted the plasma frequency @xmath126 as well as @xmath127 . due to the fact that in this simple model we assume that the charges at the end are more or less point - like , we can not expect the result to reproduce the exact resonance frequencies for shorter and thicker particles , however , the trend that the resonance frequency is inversely proportional to the aspect ratio @xmath2 is nicely reproduced . the physical reason for the aspect ratio scaling behavior lies in the fact that the electric field of the charge distribution has a dipolar character . here , it is worth noting that such a linear dependence on the aspect ratio no longer exists as the radius of the rod gets larger compared to the wavelength @xcite . for a homogeneous field , like in a plate capacitor , which would be a good description for a sufficiently extended system , a resonance in the plasma oscillations occurs at the bulk plasma frequency @xmath128 independent of the geometry @xcite . the possibility to describe the resonances and resonance shifts of plasmonic particles by using simple mechanical models will be picked up again for the discussion of coupling effects in more complex antenna systems . note that the mass - and - spring model also accounts for a shift in the resonance peak position between a resonance spectrum measured in the near field vs. a far - field spectrum . this shift is related to the ohmic damping of the resonance @xcite . in order to connect again to rf theory and to get a better idea about the nature of the eigenmodes of plasmonic structures , we introduce a further point of view . to understand the resonances of single - wire antennas , one may also start by considering the fundamental guided modes of thin metal wires with a complex dielectric function . modes that are propagating along such wires can be qualitatively classified as having mostly either `` surface '' or `` bulk '' character @xcite . due to the large imaginary part of the dielectric function and a skin depth that , in the optical regime , is often comparable to the wire diameter , all modes suffer from exponential damping and possess a finite propagation length . surface - like modes result from collective surface oscillations of electrons propagating along the wire . they are associated with near fields that evanescently decay into both the metal and the surrounding dielectric . as a consequence of the evanescent decay in the transverse direction , these guided modes must have a shorter effective wavelength and therefore a reduced propagation speed compared to light in vacuum @xcite . consider , for example , an infinitely long metal wire with a circular cross - section situated in vacuum . its fundamental tm0 mode is rotationally symmetric with respect to the wire axis , as shown in the inset of fig . [ tm0](a ) . the field amplitude of such a mode along the wire can be expressed as @xmath129 , where the @xmath32-axis coincides with the wire direction and @xmath130 is the complex propagation constant . as the wire radius is decreased , @xmath131 increases and diverges , thus resulting in an almost ideal , one - dimensional waveguide @xcite . this is an effect also exploited in the adiabatic focusing of plasmons in a tapered wire @xcite . although the mode has no cut - off , squeezing the radius results in a larger confinement of fields inside the metal wire and therefore increases the losses due to ohmic damping @xcite . for a fixed wire radius , the guided mode exhibits a dispersion relation as illustrated in fig . [ tm0](a ) . the deviation from the free - space light line is an important feature of surface plasmon modes on noble - metal nanowires , and the corresponding reduced wavelength plays a crucial role in optical antenna design @xcite , as we will discuss below . a single - wire antenna of length @xmath6 can be pictured as a finite piece of such a wire waveguide . while mode propagation along an infinitely long metal wire is not accompanied by radiation , the single - wire antenna can radiate significantly due to the broken translational symmetry . the two open ends represent mirror - like discontinuities with a near unity reflection coefficient for the fundamental tm0 mode . in such a one - dimensional cavity , a standing wave builds up once the accumulated phase per round trip equals an integer multiple of @xmath132 . in other words , a fabry - prot resonance builds up if the correct resonance length is chosen for the truncated wire @xcite . for a given wire cross - section and material , the resonance condition , when perfect reflection at the ends is considered , satisfies the simple relation @xmath133 , where @xmath134 is the resonance order . however , for plasmonic single - arm antennas , since the two open ends possess a strongly reactive character at optical frequencies @xcite , the fields extend outside the physical boundaries of the metal structure , which results in a phase shift @xmath135 of the fundamental tm mode upon reflection . such a phase shift has the same effect as some additional length of propagation @xcite . as a result , the effective length experienced by the mode bouncing back and forth along the wire is different from the actual rod length , and an offset must be added to take such a phase shift into account @xcite . a simple relation between the antenna length @xmath136 and the mode wavelength @xmath137 for the @xmath4-th order resonance therefore reads as : @xmath138 where @xmath135 is strongly dependent on the actual end - cap geometry . this description , which is also sketched in fig . [ tm0](b ) , retains its validity for arbitrary arm cross - section , provided the proper mode constant @xmath131 is considered . interestingly , it has been noticed that if the phase shift upon reflection can be engineered to become negative , plasmonic systems can support a so - called zero - order mode resonance for which @xmath139 @xcite . ( [ lambda_eff ] ) clearly shows a linear relation between the resonance length @xmath136 of the rod and the wavelength @xmath137 of the propagating mode . an effective wavelength scaling rule , relating the mode wavelength @xmath140 with the free - space wavelength @xmath10 , has also been analytically derived for a given wire radius @xcite . notably , for the case of drude - like dielectric properties , it has been shown that a linear relation of the form @xmath141 holds , where @xmath142 and @xmath143 are wavelength - independent coefficients @xcite . deviations from this ideal linear scaling law arise at frequencies where the optical response of the metal is dominated by interband transitions . from the two scaling laws that have just been discussed ( eqs . [ lambda_eff ] and [ novotny_scaling_law ] ) , it is then clear that for a drude - like material a linear relationship is also expected between the resonance length @xmath136 of a single wire and the free - space wavelength @xmath10 used for illumination . this fact is well established and has been discussed before in section [ mass_spring ] in terms of the linear dependence of the resonance position of an elongated particle on its aspect ratio @xcite . the end - to - end coupling between two wires over a narrow gap can create highly localized and strongly enhanced optical near fields inside the gap . it is this effect which makes such an arrangement a highly efficient antenna for light . to understand this coupling it is useful to consider again the mechanical analogue of a plasmon resonance based on harmonic oscillators @xcite . since the external field creates oscillating surface charges on the nanoparticle , each rod can be thought of as a spring with a respective effective mass attached to it . if two end - to - end - aligned particles come close to each other , an additional spring needs to be introduced which accounts for the interaction between the surface charges on the ends of both particles that are facing each other . this effect becomes significant for distances comparable with the wire diameters . [ coupling](a ) illustrates the basic idea of such a coupled - harmonic - oscillator system . the coupling of the two spring - mass systems ( antenna wires ) through a third spring ( antenna feed - gap ) in this picture results in the appearance of two new eigenmodes . one eigenmode exhibits in - phase oscillation of the two springs , for which the interaction spring has fixed length and therefore does not exert any additional force on the masses . the other eigenmode is characterized by a respective antiphase oscillation in which the interaction spring shifts the resonance to higher frequencies . this very simple and intuitive classical model already contains the most characteristic features of strongly coupled systems @xcite . the interparticle coupling can also be described in terms of a hybridization model @xcite which strongly relates to molecular orbital theory , where the overlap of wave functions is taken into account to derive the energy splitting and symmetry character of `` bonding '' and `` antibonding '' orbitals . in general , for ensembles of plasmonic particles one may state that whenever modes are spectrally and spatially overlapping , their coupling generates new resonances with an energy splitting , analogous to atomic orbital hybridization . we conclude that in a linear dipole nanoantenna consisting of two identical nanorods separated by a subwavelength gap , the two individual ( degenerate ) fundamental single - wire resonances split into two resonances . this behavior is sketched in fig . [ coupling](b ) @xcite . the bonding resonance mode , which is red - shifted compared to the original single - wire resonance , is characterized by dipole - like charge oscillations . due to its dipolar character , this oscillation mode can be excited by plane - wave illumination polarized along the antenna axis . it couples strongly with the radiation field via dipole radiation in addition to some ohmic damping . as a result , lower - energy bonding antenna modes appear `` bright '' in spectroscopic measurements under plane - wave excitation @xcite . it is noteworthy that the red shift of this mode is a feature that is not reproduced by the simple mass - spring model described above , where the in - phase oscillation frequencies of the two coupled systems are degenerate with those of each isolated system . this observation can still be interpreted in the frame of such a model if one allows for a reduced restoring force of the two single - particle springs . phenomenologically , such a weakened spring constant is related to the mutual induction of charges , which in the coupled system are displaced towards the gap , thus reducing the effective restoring force [ see also fig . [ sim](h ) and ( i ) later on ] . the higher - energy , antibonding mode is characterized by a charge distribution which exhibits mirror symmetry with respect to the feed - gap [ see fig . [ coupling](b ) ] . as a consequence , the antibonding mode does not efficiently emit into the far field since the two individual dipoles oscillate out of phase and therefore cancel each other to a large extent in the far field . furthermore , the antibonding mode can not be excited in far - field spectroscopy as long as the illumination path remains fully symmetric @xcite . the antibonding mode therefore is designated as a `` dark '' mode . for these two reasons , most of the experiments so far reported mainly on the red - shifted bonding modes ( see e.g. @xcite ) . to excite the dark antibonding mode , the symmetry of the system needs to be broken . for a symmetric antenna this can be achieved by using asymmetric excitation conditions , which is the case for excitation by a localized point - like source @xcite , total - internal - reflection @xcite , tilted plane wave excitation@xcite , or a displaced focused excitation beam @xcite . due to reduced radiation damping , dark resonances are also expected to have a higher quality factor @xcite . the coupling between the wires of a two - wire antenna strongly increases with decreasing gap width . the smaller the feed - gap size , the larger the energy splitting . the energy splitting between the antibonding and bonding antenna resonances is the analogue of the energy splitting in the avoided - crossing behavior seen in the adiabatic strong - coupling case of interacting quantum systems @xcite . since the resonance frequency of each antenna wire can be tuned by its length independently , two - wire antennas provide the opportunity to visualize the strong coupling between nanoparticles by tracing the shifts of the maxima of the involved resonances . [ coupling](c ) shows results from fdtd simulations of asymmetric two - wire antennas where we tune the resonance frequency of one wire from well above to well below the resonance frequency of the other one . the gap is set to be either 10 or 50 nm in order to visualize the gap - dependent coupling strength . the latter can be inferred from the energy splitting `` on resonance '' in analogy to the strong coupling between an atom and a cavity . a clear avoided - crossing behavior is observed . from an experimental point of view , provided a proper excitation geometry is used to excite both modes , such a clear avoided - crossing curve can only be obtained for small enough gaps because otherwise the splitting may not be sufficient to spectrally separate both rather broad resonances . the coupling between nanoparticles plays a very important role with respect to their spectral properties . in fact , by its engineering , for example by controlling the assembly geometry of the nanoparticles , one may , in principle , shape the spectral response of a more complex system and obtain desired optical properties @xcite . furthermore , coupling of bright and dark modes has found applications in plasmon - induced transparency in metamaterials @xcite and fano - like resonances @xcite , where such coupling produces sharp dips in the broad resonance peak which may be useful in sensing applications . in order to illustrate what was introduced so far , we are now discussing the results of a computer experiment using a set of fdtd simulations @xcite of single- and two - wire optical antennas concentrating only on the bonding mode resonance . each antenna wire is modeled as a au cylinder with hemispherical end caps and 10 nm radius , in vacuum . the system is symmetrically illuminated with a centered gaussian beam ( 0.6 numerical aperture ) , linearly - polarized along the wire axis , and near - field intensity spectra are recorded 5 nm away from the single - wire apex or in the middle of the gap for the two - wire antenna . the gap is set to be either 10 or 4 nm . from the simulated near - field spectra , the resonance wavelength and the quality factor for the antennas are determined . simulation results are shown in fig . [ sim ] . in panel ( a ) we plot the free - space wavelength @xmath144 at which the rod is resonant as a function of the rod length @xmath6 for single - wire and two - wire antennas . the linear scaling behavior , resulting from the combination of eq . ( [ lambda_eff ] ) and eq . ( [ novotny_scaling_law ] ) , is apparent in the red and near - ir portion of the spectrum , while deviations from linearity appear towards the green , where interband transitions become effective , as already discussed in section [ fabryperot ] . notably , the slopes of the linear segments are different for the single- and two - wire antennas . in the frame of the fabry - prot description of resonances in linear antennas , this observation can be attributed to a modified reflection coefficient at the gap ends in each wire of the two - wire antennas , due to the close proximity of the other wire . representative near - field intensity spectra are shown in panel ( b ) for 100 nm - long wires . a redshift due to inter - wire coupling can clearly be observed . the resonance wavelength redshifts from about 770 nm to about 830 nm when going from a single - wire structure to a 10-nm - gap two - wire structure and further shifts to about 845 nm when the gap is reduced to 4 nm . only the bonding mode resonance of the wires can be observed in these spectra due to the symmetric illumination . panel ( c ) displays the quality factor q of the resonances ( dots ) as a function of the resonance wavelength @xmath144 . it can be approximately calculated as the ratio @xmath145 , where @xmath146 is the full width at half maximum of the resonance . the higher the quality factor is , the longer the energy can be stored inside a resonator . here the simulated quality factors are compared to the results of analytic calculations [ solid line in panel ( c ) ] in the quasistatic limit @xcite , where only ohmic losses are considered for a point - like dipole plasmonic oscillator . the low q values obtained for the fundamental bonding modes in wire antennas can be attributed to the combined effect of ohmic losses and radiation losses . the fact that the simulated q factors qualitatively follow the trend obtained within the quasistatic approximation points to the fact that ohmic losses dominate in these structures . the quasistatic approximation represents a fundamental barrier only for small particles which can be described in the quasistatic limit . for larger systems retardation effects are expected to lead to deviations from this idealized model . it has been shown , for example , that a very small cavity with a zero - order resonance can be designed by accurately engineering the reflection phase shift , and that in this way quality factors far beyond the quasistatic limit can be achieved @xcite . similar effects may appear for particular antenna systems . antibonding modes , in this frame , are predicted to possess lower radiation losses and therefore larger quality factors @xcite . now that we have discussed the spectral properties of the fundamental antenna resonance , let us have a look at field , current , and charge distribution maps . [ maps](a),(b ) , and ( c ) show on - resonance near - field intensity enhancement maps of the nanostructures already considered in fig . [ sim](b ) . all intensities are normalized to the source . for the two - wire antenna in panel ( b ) , a larger near - field intensity enhancement exists in the gap which exceeds the cumulative effect of the individual wires . at the same time , the extent of the enhancement volume - if defined by an iso - intensity surface using the single wire peak value - also increases compared to the single wire . this provides better conditions for the coupling of nanomatter to the two - wire antenna . by comparing panels ( b ) and ( c ) , a clear increase in the enhancement as the gap width is reduced is also apparent . it is important to stress that the enhanced fields of a resonant linear antenna , because of the symmetry and boundary conditions , will be strongly polarized along the antenna axis . light - matter interaction via the antenna near fields is therefore restricted to well - defined dipolar transitions @xcite , unless special geometries are used @xcite . the total current distribution ( ohmic and displacement currents ) for the fundamental resonance of a single - wire antenna [ panel ( d ) ] strongly resembles that of a rf @xmath147 antenna , as expected ( see fig . [ pattern ] for a qualitative comparison ) . in the rf regime , when a very small feed - gap is added to a thin - wire antenna which is then connected to an impedance - matched waveguide , only small changes in the current distribution are expected for the two - wire antenna . in the plasmonic regime , however , the air gap is a strongly mismatched insertion for the rod , and causes strong deviations from this idealized situation . indeed , if we look at the total current distribution for the fundamental resonance of the two - wire nanoantenna , as depicted in panels ( e ) and ( f ) , two current maxima appear instead of one , making its behavior more similar to that of a @xmath140 antenna than to that of a @xmath147 antenna . notably , by comparing the 10 nm gap [ panel ( e ) ] with the 4 nm gap [ panel ( f ) ] , it can be seen that for the smaller gap the two current maxima are slightly shifted towards the gap , thus providing larger charge accumulation and therefore larger fields as discussed for panel ( c ) . finally , in panels ( g ) to ( i ) normalized surface charge density profiles are shown , where the dipolar charge separation , already discussed in the previous section [ mass_spring ] [ fig . [ massandspringmodel](a ) ] and [ section : coupling ] [ fig . [ coupling](a ) ] , is clearly visible . again , the effect of shrinking the gap results in increased charge accumulation at the gap and concurrent suppression of charge accumulation at the outer antenna ends . as we have just discussed , a strongly reduced wavelength is typical for propagating e.m . fields in plasmonic materials @xcite . this large mismatch between the wavelength of free - space plane waves and that of antenna modes is something which has no counterpart in the radio - frequency regime . as a consequence , as shown in fig . [ emission_pattern ] , antenna radiation patterns are strongly modified @xcite . in particular , all odd optical ( plasmonic ) modes present a strong emission in the direction perpendicular to the wire , something which is only weakly present in higher - order radio - frequency odd modes . the differences in the emission patterns - and by reciprocity , in the excitation patterns - have consequences for the coupling of optical antennas to quantum emitters placed in their proximity . the aim of this section is to discuss to which extent circuit theory , which is a standard for rf antennas , can be applied to optical antennas . in the previous section we have discussed solitary optical antennas driven by propagating fields . alternatively , one may also consider to drive a nanoantenna by a non - propagating localized field . to this end , a local source may be placed in the near field of the nanoantenna . the local source can be considered a nanometer - sized ac - voltage source , i.e. a nanometer - sized frequency generator in the quasistatic limit , which drives the nanoantenna via capacitive coupling . such a local source , realized experimentally e.g. by a single quantum emitter ( or a cluster of them ) , would only emit weakly in absence of the nanoantenna [ see eq . ( [ pointdipoletotalpower ] ) ] . however , when placed in close proximity to the antenna feed point it would drive a current in the optical antenna by means of its strong near field . the radiation ( or the ohmic losses for the case of coupling to a bad antenna mode ) due to this current then dominates the overall behavior of the coupled system . another possibility to drive an optical antenna is to rely on a nanoscopic two - wire transmission line as a feeding structure , as in the rf case discussed in section [ antennalanguage ] , which consists of wires that have roughly the same cross - section as those used in the nanoantenna itself @xcite . the two - wire transmission line supports a localized , nonradiative mode which oscillates at optical frequencies . however , as opposed to the radiowave regime , the finite width of the wire and the reduced wavelength of the propagating mode need to be taken into account . both types of `` driving circuits '' have to deal with the problem that the antenna impedance and impedance matching of the antenna to the driving circuit are difficult to define . on the one hand , this is because of the obvious experimental difficulty of direct probing nanoscale currents and voltages . on the other hand , there is the general problem that the rf - inspired lumped - circuit approach @xcite only holds _ strictly _ in the quasistatic limit in which all constituents of the driving circuit are supposed to be much smaller than the respective free - space wavelength , which is not easy to achieve in plasmonics . when placing a quantum emitter in close proximity to a nanoantenna , due to the modified local density of final states available for the decay of the system compared to the case of homogeneous space , the decay rate @xmath148 of the emitter is also modified . the description of such effects in principle requires a quantum analysis of the problem in which the so - called partial local density of states needs to be determined . it can be shown @xcite , however , that the partial local density of final states can be expressed via the imaginary part of green s dyadic of the system evaluated at the position @xmath149 of the emitter , i.e. purely based on electromagnetic theory , @xmath150 with @xmath151\textrm{,}\ ] ] where @xmath152 is the partial local density of states @xcite and @xmath153 is the unit vector pointing along the direction of the dipole moment @xmath154 . the green s dyadic @xmath155 of the system determines the electric field at a point @xmath156 that is generated by a dipole at point @xmath157 for the three fundamental dipole orientations as @xmath158 once the green s dyadic for a given system is known , all relevant electromagnetic properties of the system may be derived . the total decay rate @xmath148 of the quantum system coupled to the antenna is the sum of the radiative @xmath159 and the nonradiative decay rate @xmath160 . when a quantum emitter is coupled to the local fields of an optical antenna , the coupled system has a very large absorption cross section compared to that of the isolated emitter . qualitatively , this is explained by the high local fields that are created upon external far - field illumination . using the reciprocity theorem one can argue that an emitter placed in the feed - gap will itself produce a strongly localized field upon excitation , which then efficiently couples to an antenna mode and thus significantly increases both @xmath159 and @xmath160 . this is the result of a strongly reduced excited - state lifetime , with the benefit of a larger saturation rate for the generation of far - field radiation . this is shown in fig . [ emission](a ) , where the emission rate for an isolated emitter and for an emitter coupled to an optical antenna is qualitatively sketched . figs . [ emission](b ) and ( c ) show the results of fdtd simulations where a point dipole is coupled either to a single- or to a two - wire antenna with 10 nm gap . the distance of the emitter from the wire apex is 5 nm in both cases . by calculating the time - averaged flux of the poynting vector through boxes surrounding the antenna arms without including the emitting dipole , the ohmic losses in the antenna can be obtained @xcite . a significant increase in the radiated power can be observed for the case of the two - wire antenna compared to the single - wire antenna . moreover , by comparing the radiated power with the power dissipated to heat by ohmic losses , and by considering the resulting radiation efficiency , the improved performance achieved by coupling the emitter to the two - wire antenna , with a radiation efficiency improved by almost a factor of 2 compared to the single wire , becomes evident . finally , in panel ( d ) we show the effect of changing the position of the emitter by displacing it 10 nm away from the feed - gap center . while the radiation efficiency is largely unaffected , the overall radiation enhancement gets significantly lower . therefore , a single quantum emitter coupled to an optical antenna can have strongly improved emission and absorption properties while retaining its quantum character , e.g. its single - photon emission ability . such coupled systems have been investigated experimentally and are often referred to as `` superemitters '' for the just mentioned reasons @xcite . the term `` superemitter '' should not lead to the wrong assumption that the coupling of a point - like emitter to a nanoantenna can have no adverse effects . the emission rate of a point dipole coupled to an optical antenna is enhanced when the emitter efficiently couples to the fundamental dipolar antenna mode . as a general trend , it is observed that the coupling increases with decreasing emitter - to - antenna distance . however , for distances that are sufficiently small , the strong field gradients of the point dipole source can efficiently excite higher multipolar lossy modes of the antenna which are mostly dark or weakly coupled to the radiation field and therefore convert e.m . energy into heat @xcite . as a result , below a certain optimal distance which depends on geometry , material and wavelength , the non - radiative emission rate of the dipole will strongly increase and pull the overall radiation efficiency close to zero . this effect is also named `` quenching '' . we now assume an emitter at a distance to the antenna which is larger or equal than the optimum distance . in this case the emitter mainly couples to the dipolar mode of the nanoantenna . for the two fundamental orientations of the emitter , its radiative rate enhancement shows a nontrivial wavelength dependence around the antenna resonance , which depends on the relative phase of the antenna near fields and the orientation of the dipole with respect to the antenna . since a resonance is involved , a 180@xmath8 phase shift occurs when the resonance is crossed . as illustrated in fig . [ quenching ] , depending on the source dipole orientation , the latter will oscillate in phase with the induced dipole either only above or only below the antenna resonance frequency @xcite . while in - phase oscillation leads to emission enhancement , anti - phase oscillation leads to a reduced emission . such effects have been first predicted @xcite and then experimentally observed @xcite . they are also visible in the simulation results of fig . [ emission ] , where the radiation efficiency clearly decreases for photon wavelengths shorter than the resonance wavelength . within quasistatic limit , the concept of lumped circuit elements is a well - established method to simplify the analysis of complex electrical circuits . the concept of impedance is then introduced to describe the properties of each element and the interactions between different lumped elements in such a circuit . the extension of these concepts to the optical realm would allow one to describe the response of a nanoparticle , for which the quasistatic approximation reasonably holds , to visible light in terms of an `` optical impedance '' . such an impedance in perspective would allow for the engineering of complex optical circuits by providing a rationale for the interconnection between nanoelements . n. engheta and coworkers @xcite have proposed a model to calculate the impedance of a spherical nanoparticle in the quasistatic limit , and demonstrated that its plasmonic resonance can effectively be described as that of an equivalent rlc circuit constituted of two parallel impedances @xmath161 representing the ratio between the average potential difference and the displacement currents inside the sphere and in the surrounding vacuum , respectively . in particular , a plasmonic sphere ( @xmath162<0 $ ] ) can be described by the parallel connection of an inductor and a resistor , while a non - plasmonic sphere ( @xmath162>0 $ ] ) is equivalent to the parallel connection of a capacitor and a resistor , as shown in fig . [ fig : engheta ] . the surrounding vacuum behaves like a further capacitor connected in parallel . although the concept has been pushed forward over the years @xcite , it is not yet widely applied in the practical design of optical antennas and plasmonic circuits . the challenge for the practical application of the concept lies in the assumptions under which it is developed . first of all , the lumped circuit theory requires that the mutual influence of particles on each other s local fields can be neglected . since this is not generally the case for near - field coupling between nano - objects , a dependent current source should be added to the equivalent circuit of each element @xcite , which potentially constitutes an obstacle towards a straightforward application of these concepts . moreover , the quasistatic approximation is at the basis of the applicability of kirchhoff s voltage law , which locally requires @xmath163 . when the object size is increased and becomes comparable with the operating wavelength this might not be valid anymore . although antennas are clearly not sub - wavelength elements , their feed points are usually very close to each other , and in the specific region of the feed - gap - where the quasistatic - like fields closely resemble those of a parallel plate capacitor - the condition @xmath163 is fulfilled , thus justifying the introduction of an input impedance which relates the voltage and the currents at the feed points . for a linear dipole antenna , one can therefore calculate an input impedance by taking the voltage to ( displacement ) current ratio across the feed - gap . in this way , numeric calculations provide impedance values which overall compare well with those of standard rf antennas @xcite . moreover , the extension of standard radiowave concepts to optical antennas allows predicting the effect of filling the antenna gap with an arbitrary material , thus loading the antenna with an extra impedance in order to tune the overall input impedance ( e.g. for impedance matching to a transmission line ) @xcite . while such a treatment nicely illustrates the fact that nanoantennas can be described by equivalent resonant circuits as much as in the rf realm , one always needs to keep in mind that an impedance determined in this way might have limited meaning in terms of experimentally relevant impedances , since the waveguide wires that will be attached to the antenna will generally possess a finite width which makes the concept of feed points critical and might require particular care in its application . the calculation of the antenna impedance by straight application of its definition relies on the full knowledge of field distributions . since analytical approaches usually fail to accurately describe the antenna system , calculations based on numeric simulations are widely implemented . as an alternative and possibly more practical approach to determine a nano - optical impedance , one can rely on the relation between impedance mismatch and reflection coefficient when a transmission line is used to feed the antenna @xcite . the complex reflection coefficient @xmath164 [ see eq . ( [ reflection ] ) ] allows one to extract the antenna impedance once the characteristic impedance of the transmission line is known . experimentally , @xmath164 can be obtained by imaging the field distribution along the transmission line by means of near - field @xcite or photoemission electron microscopy @xcite techniques . once the characteristic impedance of the line is calculated , this approach allows one to measure the impedance of any optical circuit element connected to the line as a load . as an illustration of such concepts , fig . [ fig : nanolett ] shows simulation results for a prototypical gold antenna circuit constituted by a receiving and an emitting two - wire nanoantenna connected by a two - wire transmission line @xcite , as depicted in panel ( a ) . by illuminating the receiving antenna , a propagating mode along the transmission line can be launched , which eventually undergoes an impedance mismatch at the emitting antenna and builds up a standing - wave pattern [ fig . [ fig : nanolett ] ( b ) ] that can be fitted in order to extract the value of the reflection coefficient as a function of the antenna length [ fig . [ fig : nanolett ] ( c ) ] . finally , from @xmath164 one can calculate the antenna impedance by applying eq . ( [ reflection ] ) . it is worth noticing that the impedance plot in fig . [ fig : nanolett](d ) , while providing values that compare well with their rf counterparts , tends towards negative antenna reactances . this is a clear indication that parasitic reactances are present in the antenna equivalent circuit , due to the combined capacitive contribution of the substrate and the antenna gap . notably , a novel and generalized concept of optical impedance ( termed `` specific impedance '' ) has recently been proposed @xcite , which is able to elegantly provide a unified treatment of the interaction of single emitters with nano- and microstructures such as optical antennas and dielectric cavities in terms of generalized impedance matching concepts . by the formal analogy between the power radiated by a current element in a piece of a conductor and that of an optical dipole , the specific impedance can be introduced via the imaginary part of green s tensor . this generalized definition of impedance , which has the dimension of @xmath165 , has been applied to dipole emission in vacuum , in a microcavity , and in the vicinity of a spherical nanoparticle antenna , demonstrating that the green tensor point of view is indeed capable of reconciling concepts from largely separated fields of research . what we have learned in the previous sections is that optical antenna engineers in many cases will have to deal with isolated antennas that may be coupled to ( or fed by ) single emitters in their vicinity . the resonances of isolated antennas are well understood . there are generally applicable rules that can be used to qualitatively predict the resonances of moderately complex assemblies of nanoparticles which are based on effective wavelength concepts and resonance splittings due to strong coupling ( plasmon hybridization ) . for sharp corners and in nanogaps strong near fields may appear for eigenmodes that create opposing surface charge densities at both sides of the gap accompanied by strong electromagnetic coupling . optimization of the coupling between a localized emitter and a nanoantenna is a field of intense research which has no counterpart in rf antenna design . however , although significant steps have been made @xcite it is still an open problem how to optimize the transfer of energy between a single emitter and a nanoantenna , which represents its most important and practically relevant feeding mechanism . even if a perfect impedance match could be achieved , this still would only optimize the energy transferred to the antenna while its radiation efficiency may still be small . conditions for minimal ohmic losses and therefore optimal radiation efficiency might lead to different sets of optimal antenna parameters . for example , when complex optical antennas are build , each additional passive element lowers the overall radiation efficiency of the antenna , even though it might strongly improve certain properties . it is therefore advantageous for optical antenna engineers to look for antenna designs that realize a certain function in the simplest possible way . when integrating nanoantennas into complex plasmonic circuits the different behavior of rf and optical antennas should also be carefully taken into account . while , as extensively discussed , many efforts are made to apply lumped - circuit approaches and impedance - matching arguments to the optical realm , these concepts at optical frequencies still need to be interpreted and validated against experiments . so far , we emphasized both the close similarities of optical antennas and standard rf antennas as well as differences that arise in the optical realm because of the non - ideal conductive properties of metals and the occurrence of plasmonic resonances . it can be fairly said that all the significant differences between the behavior of radiowave and optical antennas stem from the fact that : ( i ) optical antennas are characterized by large ohmic losses and a finite skin depth and ( ii ) the wavelengths of plasmonic wire modes and of free space waves are largely mismatched . these observations hold many consequences for the behavior of isolated optical antennas as compared to the rf regime , among which the most important can be summarized as follows : ( i ) reduced radiation efficiency , ( ii ) lower quality factors of the resonances ( larger bandwidth ) , ( iii ) a peculiar scaling law for the antenna resonance length , ( iv ) deviating radiation patterns , and finally ( v ) a deviating current distribution . let us now consider in a bit more detail the question of what are the characteristic properties of an optical antenna as it has been discussed so far . since any interaction of light with matter leads to the formation of localized near fields @xcite one may ask the question what is the significance of the particular metal nanostructures we have introduced . indeed the term `` optical antenna '' is used in very broad sense in the literature . when categorized according to materials involved , besides metal antennas there are also `` antennas '' made of semiconducting @xcite and dielectric materials @xcite . in the following we will formulate some criteria to define a subset of nanostructures from all possible shapes of matter that we call `` optical antenna '' for the purpose of this report . we would like to emphasize that we do not intend to provide a universal definition of `` optical antennas '' , although , the very unspecific use of the term in the literature can cause some confusion . for the remainder of this report we will stick to these criteria in order to focus and limit our discussion . the first criterion for a structure to qualify as an optical antenna in the sense of this report is that it should be able to concentrate ( i.e. enhance and localize ) propagating fields of plane waves within a certain spectral bandwidth for a range of directions of incidence , thereby creating enhanced and localized and therefore non - propagating near fields in absence of inelastic processes . plane waves may be considered here without loss of generality since any propagating field can be decomposed into plane waves propagating in different directions @xcite . this first criterion does not yet exclude any specific structure according to ref . @xcite . the second criterion is that the reciprocity theorem should be applicable to the involved fields and currents ( see section [ reciprocitytheorem ] ) . the validity of the reciprocity theorem automatically implies also the reverse way of operation of an antenna : the structure can convert - again within a certain bandwidth - local fields into a superposition of plane waves with an emission pattern that equals the receiving pattern . here it is reasonable to require that the amplitude of at least some of the plane waves emitted in a range of directions must be larger in presence of the nanoantenna than without it . this second criterion together with the first one excludes structures from the following discussion that show stokes - shifted fluorescence , as well as optical processes in photosynthetic and other supramolecular complexes , where irreversible energy funneling towards a reaction center occurs . a third criterion is that the light confinement principle does not only rely on free - space propagating waves . if some part of a structure under consideration is based on such a description this part will not be considered a part of the actual antenna but rather a part of the illumination / detection optics . obviously this excludes mirrors and lenses of all kinds including fresnel lenses in 3d and in 2d ( plasmonic ) realizations . furthermore , to increase the field enhancement it is usually favorable if a plasmon resonance is involved which enlarges the absorption cross - section of the optical antenna beyond its projected geometrical area and increases the local intensity enhancement beyond a pure lightening rod effect . while based on rf antenna theory a resonance would be considered as an effect that limits the bandwidth @xcite , at optical frequencies the involved plasmon resonances are typically very broad and the quality factor is rather small . therefore bandwidth limitations due to a plasmonic resonance are usually not severe . finally , we note that the use of an optical antenna according to the criteria above may not always be the best solution for every experimental setting . there may be situations in which certain parameters of a system are improved while others get worse when trying to optimize an optical antenna . as a conclusion of these considerations , we limit the types of optical antennas that are discussed in the following to finite metal nanostructures that exhibit plasmon resonances in the visible to near - ir range . we will therefore not consider semi - infinite structures here , such as sharp tips , although they play an important role in tip - enhanced spectroscopies @xcite . since the resonances of optical antennas strongly depend on the exact geometry and dimensions , fabrication of nanoantennas requires reliable and reproducible structuring techniques with a typical resolution below 10 nm in order to accurately define critical dimensions , such as feed - gap size or antenna arm length . this pushes state - of - the - art nanostructuring techniques to their limit and can be considered one of the main challenges in the realization of optical antennas and plasmonic devices . various top - down and bottom - up nanofabrication approaches have been applied to experimentally realize optical antennas . top - down approaches , e.g. electron - beam lithography ( ebl ) and focused - ion beam ( fib ) milling , typically start from a thin multi - crystalline metal film on top of an optically transparent but electrically conductive substrate ( often indium tin oxide , ito ) , which is needed to avoid charging effects . in general , top - down approaches are capable of fabricating large arrays of nearly identical nanostructures with well defined orientations and distances . bottom - up approaches , on the other hand , take advantage of chemical synthesis and self - assembly of metal nanoparticles in solution with nearly perfect symmetry and crystallinity that can be put on any substrate . however , to be effective , bottom - up fabrication techniques often require precise size selection and nanopositioning as well as assembly strategies to create non - trivial structures . there are ongoing efforts to improve the resolution and reliability of nanostructuring and to better understand the role of crystallinity in the achievement of improved optical responses for plasmonic structures . rough surfaces and multi - crystalline materials can be detrimental both in terms of increased scattering of plasmons and ill - defined geometric parameters that arise due to the anisotropic response of multi - crystalline materials during nanofabrication . recently , a combination of both approaches has shown potential to fabricate high - definition nanostructures with fine details over large areas @xcite . one of the most popular techniques to fabricate nanoantennas on a flat substrate is ebl @xcite . in the typical implementation of ebl ( see fig . [ semfib ] ) a high - resolution electron - sensitive resist , e.g. pmma , is patterned by means of a focused electron beam @xcite . the patterns are then developed and selectively removed . a thin layer of metal with the desired thickness is then evaporated covering both the voids and the remaining resist . finally , the sample is subjected to a solvent which removes the remaining resist and leaves the metal structures in the voids unaffected ( lift - off ) . since the patterning is done by an electron beam , the spatial resolution of the pattern is usually below 5 nm . however , due to the multicrystallinity of the deposited metal layer , the final structural resolution is usually not as good . a state - of - the - art nanoantenna produced by ebl is shown in fig . [ fabric](a ) . in order to increase the stability of the fabricated nanostructures during lift - off , a thin layer of titanium or chromium ( typically @xmath166 5 nm ) is often used as adhesion layer . such layers can , however , significantly increase the damping of the surface plasmon @xcite . only larger patches of metal survive lift - off without such precautions . fib fabrication applied to such gold patches has been used to fabricate nanoantennas without adhesion layer @xcite . recently , other ebl - based techinques without adhesion layer have been proposed and developed @xcite . in addition to lithography , electron - beam induced deposition has been applied to build complex nanostructures @xcite or to produce masks for further dry etching @xcite . electron - beam induced deposition also holds promise to be applied to engineering of the dielectric properties of the antenna environment ( e.g. for dielectric loading of the antenna feed - gap ) or for the deposition of free - standing conductive wires for combination of optical and electrical processes in plasmonic circuits @xcite . another efficient machining technique for the realization of optical antennas is fib milling . fib structuring is based on the localized sputtering of material using accelerated ga ions extracted from a liquid metal ion source @xcite . the emitted ions are accelerated , focused into a beam with a few nanometer spot , and scanned over a conductive substrate to produce a desired pattern @xcite . ion collisions generate a cascade inside the solid , with atoms being knocked off their equilibrium position , giving rise to local surface erosion ( see the typical fabrication steps in fig . [ semfib ] ) . in the field of optical antennas , fib nanofabrication has been successfully applied in a number of cases , because it couples nanoscale resolution with the high versatility of the direct patterning approach @xcite . the main advantages of fib milling are the broad applicability to almost any type of ( sufficiently conductive ) material and the very good resolution , allowing for the fabrication of prototype surface nanostructures and gaps in the 10 - 20 nm range . when applied to chemically grown single - crystalline metal flakes @xcite , highly reproducible antenna gaps below 10 nm can be obtained [ see fig . [ fabric](b ) ] . fib is a unique structuring tool whenever the use of resist - based lithographies is difficult , for example with non - flat sample topographies such as optical antennas on atomic - force microscopy ( afm ) tips @xcite or when a resist must be avoided to allow for epitaxial growth of single - crystal metal substrates . on the other hand , since fib is a sputtering process , part of the sputtered material can be redeposited back to the surface and contaminate already fabricated structures . therefore , careful design of the fib pattern and the writing sequence is important . furthermore , gaps cut by fib usually show a tapered shape so that the gap width is not uniform across the section , an effect which might be less pronounced for ebl because of the absence of direct patterning and which can anyway be kept under control with careful procedure optimization . although fib sputters away the material , the accelerated ion beam can cause ga ion implantation into the target metal film and substrate . recently , an energy dispersive x - ray study on a fib structured gold edge @xcite has shown undetectable ga implantation , which corresponds to a ga concentration of @xmath167 . however , since even a weak ion implantation might influence the dielectric properties of the materials , the effects involved need further study . as an example , the influence of ga residues in the fib - cut nanogaps of au plasmonic antennas on the energy and quality factor of their resonances has clearly been demonstrated @xcite . a possible low - cost , high - throughput alternative to both fib and ebl patterning is nano - imprint lithography ( nil ) . as opposed to serial beam - based lithographies , where photons , electrons , or ions are used to define nanopatterns , the nil process utilizes a hard mold that contains all the surface topographic features to be transferred onto the sample and is pressed under controlled temperature and pressure into a thin polymer film , thus creating a thickness contrast @xcite . resolutions on the order of 10 nm have been demonstrated more than a decade ago . a promising variation of this technique is uv - nil , where a transparent mold , such as glass or quartz , is pressed at room temperature into a liquid precursor which is then cured by uv radiation . in order to reduce the cost of mold fabrication and to achieve patterning over larger areas at lower pressures , soft nano - imprinting techniques , based on polymeric flexible stamps replicated from a single master mold , have also been developed . in future , nil might become the ideal technique for low - cost , highly - reproducible realization of antenna arrays covering large areas , e.g. for the realization of bio - optical sensors on substrates or on fiber facets @xcite . in addition to top - down nanofabrication techniques , bottom - up approaches have also been widely used to obtain single - crystalline metallic nanostructures . chemically grown colloidal nanoparticles provide controlled shape , high purity , and a well - defined crystallinity . nanoparticles made of different materials in various shapes have been synthesized by using surfactants in the redox process @xcite . isotropic and anisotropic core - shell nanoparticles are also obtained chemically @xcite . use of chemically grown nanoparticles as nanoantennas typically requires to arrange them on a surface in well defined patterns in order to achieve the desired optical properties . such a controlled assembly can be achieved for example by nanomanipulation @xcite , electrophoresis @xcite , fluidic alignment @xcite , or micro - contact printing @xcite . recently , polymer spacer layers have also been introduced to control the interparticle distances in nanoparticle clusters @xcite . the fabrication of very small gaps in optical antennas is an important issue since it will allow studying effects that are expected to act against purely electromagnetic field enhancement effects , such as nonlocality @xcite and quantum tunneling @xcite . gaps required to reach the regime where such effects may occur are very small , on the order of 1 nm or less @xcite , and are difficult to achieve by standard nanofabrication . such gaps can , however , be readily achieved by means of chemical self - assembly of gold nanorods in solution [ see fig . [ fabric](c ) ] , where the gap is determined by the thickness of the surfactant layer that covers the particle surfaces @xcite . another approach that can produce very small gaps is afm nanomanipulation . nanostructures can be manipulated on a surface by pushing them in a controlled way using the tip of an afm . to perform the manipulation , the structures of interest are first localized using tapping - mode imaging . then the set point of the feedback loop is increased to the manipulation threshold and pushing is performed by parking the tip `` behind '' a particle and performing a piezo movement in a desired direction . in this way , the gap of a bow - tie antenna has been reduced until contact occurred @xcite . in other experiments , nanoantennas containing diamond nanoparticles were assembled by afm nanomanipulation @xcite . by exploiting the possibilities afforded by scanning probe technology , optical antennas fabricated at the apex of scanning probe tips can be positioned freely to probe different parts of a surface with nanometer precision . in this way it is possible to place a single emitter in close proximity to the antenna feed - gap while probing its optical response with an inverted confocal microscope . the fabrication of optical antennas at the apex of a scanning probe tip , however , poses a challenge to any microfabrication tool and fib milling is frequently used in this context . as an application example , emission enhancement and a related decrease in excited - state lifetime have been demonstrated for a bow - tie antenna on an afm tip which was coupled to a semiconductor nanocrystal @xcite . in order to obtain a reliable procedure for producing tip - based antennas that are parallel to the sample plane , flat plateaux at the tip apex are desirable as a starting point before metal evaporation and nanostructuring @xcite . however , antennas can also be realized perpendicular to the sample plane , following the already - established line of tip - on - aperture microscopy @xcite . the realization of @xmath168 monopole antennas at the apex of tapered optical fibers by fib @xcite and their interaction with single molecules @xcite have thus been investigated . an alternative approach to the fabrication of antenna probes consists in the chemical grafting of individual gold nanoparticles by means of a dielectric probe tip for which efficient techniques have been developed @xcite . these concepts have been applied to study the emission properties of molecules coupled to single resonant au nanoparticles attached to tapered optical fibers @xcite . the technique has also been applied to image the distribution of fluorescently labeled proteins in biological membranes with very high resolution @xcite . as grafting of nonspherical particles is not trivial , an alternative approach suggests to place nanorods inside quartz nanopipettes @xcite . the role played by the material quality in determining the quality factor and the resonance frequency of antenna oscillations , for a given geometry , is twofold : it can affect the scattering of individual electrons involved in the oscillation or it can increase scattering of plasmons into propagating waves . grain boundaries , voids , or surface contamination can result in changes of both the real and the imaginary part of the dielectric constant , thus modifying the conditions for plasmon propagation and antenna resonances @xcite . it has been shown for the case of au that changes in the above - bandgap dielectric properties can mainly be attributed to voids in multi - crystalline films , because of the fact that less polarizable material is available , while changes in the below - bandgap dielectric response can be strongly influenced by grain boundaries . this happens since at these energies the electron mean free path becomes quite large and comparable with the grain size @xcite . surface plasmons and antenna oscillations are interface e.m . waves , and as such they can be scattered by surface roughness . in optical antennas , this will result in additional dissipation channels in the form of background radiation losses ( i.e. radiation with unspecific or unwanted pattern ) , thus lowering the quality factor of the resonance . as a matter of fact , it has been clearly shown experimentally that the role of both limiting factors ( changes in the dielectric constant and/or wave scattering due to surface roughness ) can severely affect surface waves in noble metals @xcite . recently , novel procedures have been proposed to overcome these limitations . a combination of template stripping with precisely defined silicon substrates has been demonstrated , which , because of the very small roughness , is able to achieve plasmon propagation lengths comparable to those of perfectly flat films @xcite . moreover , the influence of crystallinity on plasmon resonances in single au nanorods has also been specifically discussed @xcite and improved optical properties have been observed in single - crystalline gold nanostructures @xcite . recently , single - crystal chemically grown au microflakes have been introduced as a means to achieve reproducible , high - resolution nanopatterning of plasmonic elements with superior optical properties @xcite . the use of single - crystal substrates as a starting point for fib milling and other top - down microfabrication processes is very promising since it avoids structure imperfections due to the anisotropic response of different grains in multi - crystalline materials which are clearly visible in fig . [ fabric](d ) , where a comparison is made between nanoantenna circuits realized starting from a single- and a multi - crystalline au patch . so far we have tried to convey a general understanding of optical antennas including possibilities to fabricate them . now we are going to introduce nanoantennas that have been proposed and investigated experimentally . we will start from very simple single - particle structures , like nanospheres and nanorods , then move to more complicated ones , like nanoparticle dimers , cross nanoantennas , and yagi - uda nanoantennas . for each structure we will discuss how the respective antenna properties benefit their experimental application . single gold nanospheres and nanorods exhibit a resonance spectrum that shifts with the particle s aspect ratio , as discussed before . their use is motivated mainly by the easy and well - established chemical synthesis methods that allow producing single - crystalline nanoparticles in solution . because of their very simple geometry , they also represent the ideal benchmark to test theoretical predictions for plasmon - coupled quantum emitters . they have been successfully applied to enhance the sensitivity of fluorescence and raman spectroscopy at a single - molecular level @xcite . elongated particles as opposed to spheres also show sensitivity to the polarization of the fields . typically , the field enhancement and confinement near the ends of nanorods is much larger than for a sphere , which can be attributed to the combined contribution of both a more favorable spectral location ( in terms of associated losses ) of the fundamental resonance and of enhanced lightning - rod effects . coupling of two nanoparticles results in increased near - field intensity enhancement and confinement in the gap , as discussed in sections [ section : coupling ] and [ somesimulations ] . it also goes along with a further degree of freedom in tuning the resonance frequency and a larger radiation efficiency , as shown by simulations in section [ nanoantenna+quantumemitter ] . while the nanorod dimers @xcite represent the simplest analogue to rf linear dipole gap antennas , the nanosphere dimers are proposed as the analogue of rf hertzian dipole antennas . although being physically small , such nanosphere dimers are expected to have a high radiation efficiency due to the reduced current density inside the spheres @xcite . bow - tie dimer antennas are constituted of two triangles facing each other tip - to - tip @xcite . they are being applied to enhance molecular fluorescence @xcite , raman scattering @xcite , and for high - harmonic generation @xcite . bow - tie antennas are expected to possess a rather broad bandwidth since they represent the two - dimensional analogue of a biconical antenna @xcite and are also considered to have higher field enhancement in the gap compared to two - wire antennas because of larger lightning - rod effect at the apex . however , taking fabrication constraints into account , it turns out that the latter effect is practically limited by the radius of curvature at the apex . because of this , if a two - wire and a bow - tie antenna with the same total length ( 300 nm ) , gap ( 30 nm ) , and radius of curvature ( 10 nm ) are compared , the largest resonant field enhancement is obtained for the two - wire antenna , since for the bow - tie structure losses are increased due to the larger volume , which decreases the quality factor ( see fig . [ bowtie ] ) . on the other side , compared to nanorod antennas , bow - tie antennas suppress more efficiently near - field intensity enhancement at their outer ends @xcite . yagi - uda nanoantennas for light have been theoretically proposed and experimentally demonstrated @xcite to take advantage of their very good directivity . their unidirectional response is appealing in terms of enhanced sensitivity for detection , possible use for improved single - photon sources , and concurrently modified excitation patterns . similarly to their rf counterparts , nanometer - sized yagi - uda antennas consist of a resonant single - wire antenna ( @xmath169 phase shift between the driving field and the induced charge oscillations ) arranged between a reflector ( phase shift @xmath170 ) and a set of directors ( phase shift @xmath171 ) . to this purpose , the inter - element distance is important to achieve the desired interference between direct and reflected radiation . since the existence of neighboring elements may increase ohmic losses and modify the resonance frequency of a nanoresonator via near - field coupling , the design of an optimal yagi - uda nanoantenna is demanding . very recently , the coupling between a single quantum dot and a yagi - uda nanoantenna has been demonstrated using multi - step e - beam lithography to fabricate the hybrid system @xcite . directionality of the emission pattern has been observed at the back focal plane of the objective , with a clear directional emission of single - quantum dot luminescence for optimized antenna dimensions ( fig . [ fig : yagiuda ] ) . since the fields in the gap of a two - wire nanoantenna are highly polarized along the antenna axis @xcite , linear nanoantennas enhance only such field component and thus can be used to control the polarization of the emission from single emitters @xcite . however , for some applications such as polarimetry , chiral molecule mapping or optical data storage and retrieval it is necessary to enhance the field without perturbing its polarization state . to this purpose , cross nanoantennas , consisting of two identical but perpendicular linear dipole antennas sharing a common gap [ see fig . [ fig : cross](a ) for a representative sem image ] , have been proposed @xcite . each linear antenna picks up and enhances the field component along its own axis . the two perpendicular field components then coherently add up in the gap region and build up a localized field with the same polarization properties as the excitation source . upon circularly polarized excitation , a highly confined spot with an almost unitary degree of circular polarization in the plane of the antenna can thus be obtained [ fig . [ fig : cross](b ) ] . based on the concept of tuning the phase of antenna oscillations with respect to that of the external field , cross antennas can be further modified not only to preserve but also to shape and control the near - field polarization . for example , a nanosized quarter waveplate has been proposed , by which a confined and enhanced circularly - polarized light field can be produced inside the common gap starting from a linearly - polarized excitation @xcite . along the same line , asymmetric bow - tie cross antennas have also been introduced as `` nano - colorsorters '' , which are able to control field localization by achieving spectrally distinct resonances on spatially separate hot spots , within distances of only a few tens of nm @xcite . based on the application of babinet s principle at optical frequencies @xcite and on the phenomenon of extraordinary transmission @xcite , resonant hole antennas have also been proposed as the optical counterparts of standard rf slot antennas , in order to achieve large field confinement on subwavelength regions @xcite . to this purpose , bow - tie @xcite , c - shaped @xcite , and crescent - shaped @xcite hole antennas have been proposed . also , hole arrays with specific symmetry properties have been demonstrated in order to control their spectral response and radiation directionality @xcite . patch antennas are largely used , especially in microwave wireless connections , because of their simplicity . they consist of a single metal patch , which radiates through the discontinuities at the edges . _ have shown by simulations that an optical patch antenna is a very promising system for coupling to single emitters , concurrently providing a large purcell factor and a larger spectral width than standard linear antennas @xcite . in addition to nanoantennas for electric fields , antennas for magnetic field detection have also been realized by fabricating a split ring at the facet of a coated fiber @xcite . for this antenna probe , the magnetic field generates a circulating current in the ring - a magnetic dipole - which then couples to a fiber mode thanks to the antenna gap which breaks the cylindrical symmetry of the system . a bow - tie nanoaperture antenna has also been designed to generate a confined and enhanced hot spot of magnetic fields at optical frequencies @xcite . very recently , planar stacked geometries have also been proposed for optical antennas , where the planar feed - gap is constituted by the separation layer between two stacked antenna arms @xcite . such a geometry holds promises because of its easier integration in planar device geometries and precise control of the gap width . as the reader may have noticed , it seems that the designs for optical antennas that have been used so far were strongly inspired by the large pool of antenna structures that have been developed by rf antenna engineers over the years . while this has indeed proven to serve its purpose for a while , it is expected that with improved understanding of the clear differences between optical and rf antennas as pointed out in section [ definition ] , and of the particular ways of using them as discussed in section [ antenna+circuits ] , soon new designs for optical antennas are going to be developed that have no direct rf counterpart but represent optimized realizations for the very high frequencies of visible and near - infrared light . it is important to note that , in view of practical applications , nanoantennas will generally be supported by a substrate . it is well - known from rf antenna theory that , when an antenna is positioned over `` ground '' , its impedance is modified by the presence of the image dipole which is generated by the interface nearby . similar arguments are true for optical antennas , where the substrate refractive index acts as a parasitic impedance and causes a red shift of the resonance frequency , as is well - established for plasmonic nanoparticles @xcite . for the special case of a linear antenna on and perpendicular to a conducting substrate at optical frequencies , the image dipole is ideally as strong as the antenna dipole , resulting in a resonance length which is only half the free - space length for a given working frequency . the optical counterpart of such a configuration has been demonstrated by realizing a tip placed on the metalized facet of an optical fiber used for near - field imaging @xcite . furthermore , the larger refractive index of the substrate compared to air strongly influences the emission pattern of the nanoantenna @xcite , an occurrence that is also well - known for rf antennas @xcite and for quantum emitters on a substrate @xcite . once antenna structures have been successfully fabricated , their performance needs to be characterized . this entails analysis of their geometry , position with respect to other structures , near - field intensity distributions , emission pattern , as well as their spectral properties . while sem , tem , or afm are typically used for the first two purposes , optical and spectroscopic characterization can be achieved by various techniques . as to be expected from the hybrid photonic and electronic character of plasmonic resonances , these techniques are based on interactions with photons , electrons , or combinations of both . characterization techniques involving electrons have been covered in a number of publications and reviews @xcite . such methods can provide detailed insight due to their potentially high spatial resolution but experiments require vacuum environments . here we concentrate on purely optical ( photon - in / photon - out ) techniques because they are straightforward to implement in any optics laboratory . optical characterization of nanoantennas requires a combination of spatial resolution ( possibly subwavelength , to resolve nanoscale features ) and spectral resolution ( to properly characterize antenna resonances ) . photons can interact with an optical antenna either elastically or inelastically . broadband elastic light scattering is the most natural way to spectrally probe antenna resonances but care needs to be taken in order to sufficiently suppress excitation light . very high sensitivity can be reached for inelastic interactions , since the measured signals are spectrally separated from the excitation wavelengths . inelastic interactions , e.g. photoluminescence , typically also bear signatures of the antenna response since the spectrum of the emitted photons may be strongly shaped by the antenna resonances . the overall efficiency of multiphoton - excited photoluminescence processes , as well as other nonlinear effects , can be used as a probe for the near - field intensity enhancement for a certain antenna mode , since the amplitude of such signals strongly depends on the local excitation intensity . in this section we concentrate on techniques that are able to address the optical response of _ individual _ nanostructures . although extended arrays of nanostructures can in principle be fabricated to provide larger signals during experiments , single - antenna measurements are important to circumvent inhomogeneous broadening of spectral features which may occur due to various structural inhomogeneities . single - antenna experiments require sufficient detection sensitivity since the scattering cross section for off - resonant structures can become small . there are two further requirements which need to be considered : ( i ) the response of a resonator to an applied external field is fully characterized only once both its amplitude and phase are known . to capture both quantities , interferometric techniques need to be applied . furthermore , ( ii ) control over light polarization is required to selectively probe distinct antenna modes . interaction of light with optical antennas can be either elastic or inelastic . elastic interaction is encountered when photons of a certain energy excite a certain antenna mode which then re - radiates photons of the same energy ( elastic scattering ) . inelastic interactions lead to the emission of photons of higher or lower energy . the respective increase or loss in energy is due to nonlinear and/or dissipative effects , respectively . one - photon photoluminescence ( 1ppl ) from noble metals is an example for a dissipative effect . it was first reported in 1969 after 488 nm wavelength excitation of au and cu @xcite . two - photon photoluminescence ( 2ppl ) is an example of a nonlinear effect . 2ppl in au relies on two sequential single - photon absorption events : a first near - ir photon excites an intra - band transition within the @xmath172 conduction band , while the second photon drives an inter - band transition between the @xmath108 and the @xmath172 bands @xcite . the resulting hole distribution in the @xmath108 band can eventually decay radiatively , by recombination with @xmath172 electrons , thus leading to a weak photon emission in the green - red spectral region . recently , 2ppl from ag and al nanorods has also been reported @xcite , rendering the method more universal . besides two - photon absorption , higher - order multiphoton absorption processes can also lead to photoluminescence in au nanoparticles . three - photon absorption is sometimes observed @xcite , while a broad emission spectrum depending on the fourth power of the excitation intensity has been reported for dipole antennas @xcite . even higher - order avalanche multiphoton photoluminescence ( up to 18th order ) has been reported in nanowire arrays @xcite . however , the origin of the photoluminescence processes with order higher than 2 so far is not fully understood . the concept of evaluating antenna performances by probing photoluminescence of the antenna material is based on the dependence of the photoluminescence signal on the strength of the local fields generated upon illumination . both 1ppl and 2ppl can be easily observed , however , 2ppl is often employed since many of the investigated structures exhibit a resonance in the near infrared such that for resonant excitation the energy of a single photon is too small to generate 1ppl . furthermore , the amount of recorded 2ppl emission quadratically depends on the excitation intensity , which allows one to clearly distinguish resonant structures with strong local fields from off - resonant structures that exhibit much lower near - field intensity . similar arguments apply for other nonlinear ( multiphoton ) processes that may occur , such as harmonic generation or frequency mixing @xcite . a way to optically probe the spatial distribution of near - field intensity of an antenna mode with reasonable resolution has been the use of a near - field scattering probe oriented perpendicular to the sample surface , which is scanned in close proximity to the antenna @xcite . the basic idea behind such experiments is that a certain antenna mode is being excited by far - field illumination with a well - defined polarization ( usually parallel to the antenna axis for linear antennas ) . at the wavelength of illumination , the near - field scattering probe is assumed to possess a non - negligible polarizability only along its main axis . this direction can be chosen to be perpendicular to the polarization of the illumination field . the probe is therefore not directly excited and its induced dipole can not contribute to any mode hybridization . however , around the antenna structure of interest , depolarization fields build up which possess vector components along the main axis of the scattering probe . the scattering probe then becomes efficiently polarized and scatters a signal into the far field which is polarized perpendicular to the fields directly scattered by the antenna . both signals can therefore be detected separately . in general , the scattering probe will be as small as possible , which in turn causes the scattering signal to be very small . it is therefore usually amplified by means of heterodyne and lock - in detection @xcite . it is important to note that the perpendicular orientation of scattering probe and antenna leads to a minimal back action of the probe on the antenna resonance . this explains why experimentally recorded antenna mode patterns match so well with theoretical expectations . [ tppl](a ) shows an example of such sub - diffraction mapping of an antenna mode , which is able to spatially resolve 5 individual intensity maxima of a higher - order antenna mode on a au single - wire antenna @xcite . since an interferometric setup with a reference beam is used , the phase of the measured fields can be determined as well . similar experiments have been performed for a number of different plasmonic oscillators @xcite . while scattering probes allow for sub - diffraction imaging of antenna near fields after far - field illumination , aperture probes - characterized by a sub - wavelength hole at the apex - offer the possibility of local excitation of an optical antenna . the antenna then emits light into the far field which is eventually collected by a standard objective @xcite . the measured spatial distribution of far - field photons is determined by the antenna mode and spatial resolution is roughly limited by the size of the aperture . however , the simplest and most common way to address the spatial pattern of antenna resonances is scanning confocal optical microscopy @xcite . although it only provides a diffraction - limited excitation spot of about 200 - 250 nm with blue - green light , this technique benefits from its ease of implementation , high photon throughput and good control over light polarization and therefore has been extensively used to characterize optical antennas @xcite . the overall lateral resolution ( convolution of excitation and detection volumes ) is usually sufficient to single out the response of an optical antenna within a larger ensemble , but it is usually not possible to resolve nanoscale features of the near - field intensity distribution of a single nanoantenna . this is because the excitation spot is of the order of the antenna dimension , unless the antenna dimensions are particularly large . it is , however , possible to observe pseudo - resolution in the measured excitation spot of a particular antenna in the sense that lines of zero excitation probability may occur in scan images where excitation of a probed antenna mode is forbidden due to symmetry @xcite . [ tppl](b ) shows an example of confocal mapping of the local fields of a two - wire gold antenna . here , since the antenna dimensions are particularly large , it is possible to resolve the individual intensity hot spots even with a diffraction - limited optical technique @xcite . the measurement is based on two - photon photoluminescence ( 2ppl ) imaging , which over the last decade has become one of the preferred tools to probe plasmonic and antenna resonances @xcite . it is here worth mentioning that a fixed - wavelength analysis of individual nanoantennas within an array of increasing length , and therefore variable near - field intensity enhancement , allows studying the antenna resonance without direct spectral analysis and with the advantage of a fixed dielectric constant @xcite . , for a fixed gap size @xmath173 nm . panel ( a ) reprinted with permission from dorfmller _ et al . copyright 2009 , american chemical society . panel ( b ) reprinted with permission from ghenuche _ et al . copyright 2008 , american physical society . panel ( c ) reprinted with permission from wissert _ et al . copyright 2009 , iop publishing . , scaledwidth=50.0% ] emission patterns of nanoantennas , i.e. the angular distribution of the radiated photons , are very important to characterize , since they can drastically differ from their rf counterparts , as discussed in section [ radiation_section ] . knowledge of the emission pattern of a particular antenna mode allows optimizing its coupling to light by way of the reciprocity theorem ( see section [ reciprocitytheorem ] ) and distinguishing between different antenna modes @xcite . typically , emission patterns of individual antennas are measured by first localizing a particular antenna in a confocal microscope and subsequent imaging of the back aperture of the microscope objective onto a ccd chip with a well - chosen magnification . the measured pattern corresponds to the intensity distribution in the fourier plane of the objective lens @xcite and therefore represents a two - dimensional projection of the emission pattern . an example of a yagi - uda angular emission pattern has already been discussed in fig . [ fig : yagiuda ] . the goal of spectrally - resolved experiments on optical antennas is to verify their performance over the frequency range of interest . the most straightforward way to spectrally characterize the behavior of a nanoantenna is to make use of elastic light scattering . elastic light scattering reveals characteristic resonances in the scattering cross section of nanoantennas . a broad - band , `` white - light '' source excites a nanoantenna simultaneously at a wide range of illumination wavelengths . the spectrum of the elastically scattered light , after proper normalization , then directly reveals the scattering cross section @xcite . a representative set of antenna scattering spectra , acquired for antennas of different lengths , is shown in fig . [ tppl](c ) . for elastic light scattering techniques , it is crucial to achieve sufficient suppression of the background caused by direct reflection of the excitation light . this can be achieved by decoupling the illumination and collection paths via dark - field microscopy techniques @xcite . as we have already mentioned , it is also possible to study the elastic scattering properties to observe resonant behavior by studying the antenna scattering as a function of its length for a fixed illumination wavelength @xcite . scattering spectra directly reveal the peak position and quality factor of observable ( `` bright '' , symmetry - allowed ) resonances that efficiently radiate into the far field . note that many symmetric structures support dark modes , which , due to their symmetry , can not be excited and therefore do not appear in scattering spectra . however , even with symmetric excitation , dark modes can become visible when they couple to a bright mode . such coupled resonances are also so - called fano resonances which recently gained much attention @xcite . in a particular type of dark - field setup the sample is illuminated via an evanescent field created by total internal reflection . this approach has the advantage that , by breaking the cylindrical symmetry of the illumination , dark modes can be excited and their weak emission can be recorded @xcite . a complete characterization of an antenna resonance requires both phase and amplitude of the local near fields to be investigated with respect to the driving field . in the far field , a combination of coherent white - light illumination and differential interference contrast microscopy is able to address the complex polarizability of single nanoparticles @xcite . near - field techniques , in addition to providing subwavelength resolution @xcite , combine a weak propagating field with a very strong local field , which makes the far - field interference between the illumination dipole and the particle s dipole very strong . therefore , the whole complex response ( amplitude and phase ) of the nanoantenna is encoded in the detected signal . spectrally - resolved near - field extinction is therefore a powerful means to address the response of plasmonic oscillators @xcite . when studying inelastic interactions of light with optical antennas , particularly with luminescence processes , not only the integrated emission efficiency provides valuable insight into the antenna response , but also its spectral shape . while imura _ _ reported that the 2ppl spectrum is dominated by two features related to the bulk au band structure @xcite , other groups showed that a plasmon resonance is able to shape the luminescence spectrum @xcite . the spectral properties of noble - metal nanostructure luminescence therefore seem to depend on a subtle interplay between the electronic density of states of the antenna material and the occurrence of a plasmon resonance and deserve further investigation . it is important to note that , in order to exploit the spectral shape of photoluminescence to study antenna resonances , one needs to illuminate the nanoantenna with an off - resonant excitation , so that the excitation wavelength does not overlap with the resonance of interest , which would then have to be cut off by the filters that block the excitation light . in addition to radiative modes , the local coupling of luminescence dipoles to the antenna resonance breaks the symmetry of the system and allows dark modes to become populated and observable , an advantage compared to elastic scattering with symmetric illumination . the topic of optical antennas is a young and aggressively progressing field of research . as outlined in the introduction , in particular in section [ potentialofopticalantennas ] , it holds promises for a variety of possible applications that take advantage of enhanced light - matter interaction . in the present section we review different fields in which nanoantennas are already applied today and in which they might play a significant role in the near future . since the number of publications using the key word `` optical antenna '' is increasing exponentially , this overview must be incomplete and is influenced by the personal taste of the authors . in order to make use of optical antennas as imaging and spectroscopic probes , a viable solution is to scan the antenna in close proximity over some area of a sample . to this end , nanoantennas need to be fabricated at the apex of a scanning probe . super - resolved imaging can then be achieved either by inverted confocal illumination of the antenna - sample system , or by realizing antenna - on - aperture probes to drive the antenna resonance by the localized field of a small aperture . single - molecule imaging with bow - tie @xcite and @xmath140/4 antennas @xcite , respectively , has been achieved in this way , with resolutions down to 25 nm in the latter case . in related experiments single gold spheres have been attached to dielectric tips in order to create well - controlled antenna probes . these probes were used to image single molecules at a resolution smaller than the sphere diameter but compatible with the expected extent of the localized field @xcite . using these single- and also multiple - sphere nanoantennas on optical fiber near - field probes , single proteins have been imaged at very high resolution in their native cell membranes @xcite . highly - sensitive spectroscopy represents another key area for nanoantenna applications , where the antenna serves the purpose of both providing enhanced excitation as well as enhanced emission of the nanoobject under investigation . in particular , raman signals can be largely enhanced following the already well - established route of surface - enhanced @xcite and tip - enhanced @xcite raman scattering . along this line , enhanced raman signals have been measured for ebl - fabricated bow - tie antennas covered with a layer of adsorbed molecules @xcite , showing signatures that are typical for single - molecule raman experiments . since the signal enhancement is known to strongly depend on the gap size and geometry , control over these parameters is crucial . in this respect , the gap in a plasmonic nanodimer for raman spectroscopy has been deterministically varied both by scanning an au nanoparticle attached to a fiber probe @xcite or by afm nanomanipulation of au - ag nanoshell particle pairs on the sample substrate @xcite . in view of practical sensing applications , an array of e - beam fabricated antennas has also been transferred to the facet of an optical fiber , used for illumination and collection @xcite . not only raman scattering , but also vibrational spectroscopies based on infrared absorption can largely benefit from suitably engineered resonances in plasmonic antennas @xcite . finally , following the original demonstration of fluorescence correlation spectroscopy ( fcs ) at high analyte concentrations using reduced sensing volumes in subwavelength hole arrays @xcite , recently a 10000 times reduction of the fcs sensing volume has been demonstrated by exploiting the field confinement in optical antennas @xcite . the highly localized near field of a nanoantenna also finds a natural application in optical lithography , where the fabrication of nanostructures has been accomplished via nonlinear photopolymerization of a photoresist by exploiting both the largely confined and enhanced fields in the gap of a bow - tie antenna and the nonlinearity of resist response @xcite . experimental studies of single emitters coupled to optical antennas address another key application of resonant optical antennas . if the emitter is placed in a `` hot spot '' of a resonant antenna most of the single emitter decay processes will not generate a free propagating photon but will rather create a single plasmon in the resonant mode of the antenna . upon radiative decay of these plasmons , single propagating photons are created that bear the properties of the antenna resonance , e.g. its resonance spectrum , polarization and emission pattern . one can therefore envisage the possibility to build single - photon sources @xcite with well - defined polarization , optimized radiation patterns ( see e.g. section [ yagiuda ] ) and several thousand times enhanced emission rates as discussed in section [ nanoantenna+quantumemitter ] by carefully adjusting the position of the emitter to avoid quenching . a simple way to achieve the positioning of single emitters in the feed - gap is to directly cover the antenna with a stochastically distributed ensemble of emitters . however , in such a configuration , depending on their density , many emitters are excited simultaneously and may interact via energy transfer with each other . this renders quantitative analysis of assumed single - emitter effects challenging . nevertheless , spin coating of a thin polymer films containing fluorescent molecules in a small concentration on top of antenna structures has been exploited to gain insight into the emission enhancement that can be achieved in the vicinity of an optical antenna @xcite . in this way , emission enhancements up to three orders of magnitude have been observed compared to the case without antenna @xcite , resulting from the combined enhancements in the excitation efficiency and quantum efficiency . deterministic positioning of single emitters in an antenna hot spot , e.g. the feed - gap of a two - wire antenna , would of course be a much better approach . this constitutes a technical challenge and so far has been achieved mainly in three ways : ( i ) by positioning of nanoantennas on scanning tips on top of emitters , ( ii ) by afm nanopositioning of the emitter and/or the antenna arms with respect to each others , and ( iii ) by spontaneous or directed self - assembly of antenna and emitter . using the first method , experimental investigations demonstrated that coupling between the antenna and a two - level system can lead to a significant reduction of the excited - state lifetime @xcite and to a re - direction of the emission dipole of the molecule along the antenna axis @xcite . the second method has been proven to be very effective for precise positioning of nanoparticles @xcite . in this way , antennas can be realized on a suitable substrate , onto which quantum emitters are co - deposited . an afm tip is used both for precise imaging of the position of the nanoparticles and to push them in a controlled way inside the antenna feed - gap . diamond nanocrystals between two au nanoparticles have been produced and studied in this way , obtaining an enhancement in the radiative decay rate of about one order of magnitude @xcite . as for the third method , quantum dots have been coupled to ag nanowires @xcite which support a propagating plasmonic mode ( see section [ fabryperot ] ) . when a single - photon emitter , such as a quantum dot , is coupled to the ag nanowire , it can excite plasmon quanta that propagate along it and are re - converted to single photons upon emission from the wire end . notably , non - classical photon correlation has been demonstrated between the emission from the quantum dot and single photons resulting from the decay of the plasmon quanta launched in the ag nanowire . very recently , even unidirectional emission of a quantum dot which was deterministically coupled to a yagi - uda nanoantenna by means of two - step electron - beam lithography has been experimentally demonstrated @xcite , as discussed in section [ yagiuda ] . optical tweezing based on field gradients in tightly - focused beams is nowadays a quite established tool in atomic physics and biology @xcite , where it is usually implemented by exploiting microscope objectives with high numerical aperture and properly shaped beam profiles . since highly localized optical near fields naturally possess strong gradients , their use as localized trapping spots is very appealing and has been proposed already more than a decade ago @xcite . more recently , the first experimental demonstrations of optical trapping with well - controlled hot spots in the gap of nanoantennas have been published , where the large antenna field enhancement allows trapping with lower excitation power and higher efficiency and stability @xcite . in the field of optical detectors and solar cells , plasmonic structures have been introduced as a means to achieve substantial absorption of incident light within small active volumes and thin layers . indeed , the earliest interest for resonant antennas in the sub - mm wavelength regime was mostly driven by the need for efficient ir detectors and , with first realization for 10 to 100 @xmath61 m wavelengths @xcite , dates back to the eighties and even before . dipole , spiral , cat - whisker or bow - tie nanoantennas were produced by means of ebl and the ir detected light was measured by means of a microbolometer or with a micrometer - sized metal - oxide - metal diode . more recently , an antenna - coupled ge nanodetector for near - ir wavelengths has been demonstrated @xcite . absorption enhancement is particularly crucial for modern solar cell technologies @xcite , especially for those realizations that move towards thin single - crystal films and intermediate - band nanocrystal insertions . in this context , efficient coupling of light must be achieved both with broad collection angles and wide spectral response @xcite . noticeably , semiconductor - based resonant nanostructures , also often called antennas , have been proposed to improve the performances of detectors and solar cells @xcite . in the field of optical detection and electrical conversion with nanoantennas , it was recently shown that nonlinear tunnelling conduction between gold electrodes separated by a subnanometer gap can lead to optical rectification , producing a dc photocurrent when the gap is illuminated @xcite . plasmonic sensors based on the adsorption of molecules onto functionalized noble - metal systems have nowadays become a reality and find many applications . gold is the preferred material in this field because of its biocompatibility and easy functionalization mainly by means of sulfur bonds between gold atoms and molecules . commercially applied plasmonic sensing is based on attenuated total internal reflection and exploits the fact that the wavevector of surface plasmon polaritons ( spp ) propagating at the interface between a thin gold film and an adjacent dielectric is very sensitive to changes in the refractive index of the dielectric @xcite . high sensitivity is thus achieved thanks to the strong confinement of fields in the close proximity of the interface . on the other side , such spp sensors are based on a relatively complicated setup , which does not always meet the criteria required for commercialization , mass production and use , especially for portable apparatuses and point - of - care testing . moreover , such systems require a rather large surface area and are therefore not suitable for parallelization and integration in view of lab - on - a - chip platforms . more recently , however , the demonstration of sensors based on localized particle resonances opened new perspectives for plasmonic sensing , where in principle much simpler transmission , reflection , or scattering measurements can be performed because the local refractive index change upon ligand binding directly translates into a shift of the particle s resonance frequency . sensing based on particle arrays on a fiber facet @xcite or on a substrate @xcite has thus been demonstrated , ultimately with sensitivities down to the single - particle level @xcite . while the improved field localization provides sensitivities comparable to commercial spp devices @xcite , there is also a potential for parallelization and miniaturization . along this road , since plasmonic nanoantenna systems display localized resonances that strongly depend on the dielectric properties of the environment , they are very good candidates for sensing applications down to extremely low concentrations . narrow resonances with large quality factors are advantageous in this context since they provide increased sensitivity . therefore the use of fano - like resonances @xcite and of dark antibonding antenna modes @xcite has been proposed in this context . so far , we mainly focused our attention on the field enhancement and spatial confinement in optical antennas as well as on their resonances in the frequency - domain . however , one may also consider the behavior of nanoantennas in the time - domain and discuss the temporal characteristics of the confined fields as well as their coherent control . it has been shown theoretically by m. i. stockman that , upon ultrafast excitation , random metal surfaces with nanoscale geometrical features can exhibit ultrafast nanoscale localization and enhancement in their near fields due to multiple interference @xcite . by controlling the temporal profile of the excitation pulse , field localization , i.e. the position of hot spots and the exact moment of time when they become active , can be coherently controlled @xcite . the temporal profile of the excitation pulse can be shaped at will by manipulating the spectral phase and amplitude of the laser pulses used for excitation @xcite . in this way coherent spatio - temporal control of localized near fields has been realized experimentally using antenna - like gold nanostructures @xcite . since the behavior of metallic nanostructures , including nanoantennas , is time - invariant , once the impulse response of the system under certain excitation conditions is known , one may apply shaped excitation pulses and coherently control the antenna near fields . using this concept , huang _ _ theoretically demonstrated that the temporal profile of the local fields in the gap of a nanoantenna or at a given position on an antenna nanocircuit can be optimized @xcite . similar techniques might facilitate signal processing in future plasmonic optical nanocircuitry . also recently , have shown that the near - field in a hybrid nanoplasmonic - photonic system induced by an ultrashort pulse can be enhanced or turned off by a well controlled pulse following the excitation pulse @xcite . such a switching control based on near - field interference should in principle be applicable to plasmonic nanoantennas as well . the detection and analysis of all such phenomena , however , experimentally relies on the generation of non - linear signals that propagate to the far field , such as e.g. third harmonic generation @xcite . as a general remark , it is worth recalling that noble metals are known to possess extremely large optical nonlinearities , but have generally not been considered as nonlinear materials because of their high reflectivity . in this context , nanostructured systems offer the possibility to engineer the field penetration inside the material and fully exploit their nonlinear response @xcite . it is also important to note that , when e.g. second - harmonic generation is considered for nanoparticles illuminated with a localized field , not only the symmetry of the bulk crystal structure , but also that of the field and of the nanoparticles needs to be taken into account in order to derive the relevant selection rules that can be significantly different from those of plane - wave illumination of bulk systems @xcite . second - harmonic enhancement at correspondence with a plasmonic resonance has clearly been shown @xcite . taking advantage of the field concentration ability of optical antennas , practical applications using nanoantennas to generate higher harmonic emission signals have been proposed and demonstrated experimentally . third - harmonic photons have been efficiently generated in isolated gold dipole antennas @xcite and a clear connection between third - harmonic efficiency and antenna resonances has been demonstrated . exploited the enhanced and confined field of nanosized bow - tie antennas on a sapphire substrate to reduce the excitation pulse energy required to generate extreme ultraviolet light by high - harmonic generation @xcite . nanoantennas can also be applied to enhance the efficiency of wave mixing of infrared laser beams . danckwerts _ et al . _ have shown that the four - wave mixing signal can be enhanced by 4 orders of magnitude as the gap of a nanoparticle pair shrinks @xcite . the four - wave mixing signal drastically changes when the two particles are in contact because the gap is shortened and the charge can redistribute via the conductive bridging . the use of the frequency mixing signal as a precise and sensitive indication of touching contact between two plasmonic nanoparticles has therefore been proposed @xcite . in perspective , the combination of laser pulse shaping and well - designed nanoantenna geometries might lead to a number of novel applications since it opens the possibility to manipulate the temporal behavior of the antenna near fields . also here , the rather broad antenna resonances are advantageous to achieve a very high temporal resolution . a very intriguing perspective is given by the possibility of using a plasmonic resonator as a localized cavity for surface plasmon amplification by stimulated emission of radiation ( spaser ) , as originally proposed by bergman and stockmann @xcite . a first step along this line has been achieved with the demonstration of stimulated emission of spps propagating at the interface with a gain medium @xcite . in one case , also laser - like emission accompanied by a clear threshold behavior and moderate line narrowing was observed @xcite , although no clear feedback mechanism could be identified . in this context , metal nanoparticles acting as optical antennas can play a role because of their large local field enhancement and extremely reduced interaction volume . very recently , subwavelength plasmon lasers based on the original spaser proposal have been demonstrated @xcite . larger enhancement and confinement , compared to single particles , can especially be encountered in the gap of two - wire or bow - tie nanoantennas . along this line , laser operation for bow - tie antennas coupled to semiconducting quantum dots or multiple quantum wells has been theoretically addressed @xcite . sub - diffraction propagation in plasmonic waveguides offers the possibility of distributing and processing e.m . signals on a very small footprint , thus offering the perspective of combining the speed of photonics with the high degree of integration of modern microelectronics @xcite . in this frame , optical antennas - working as receiving and transmitting devices - represent an interface between subwavelength localized modes that propagate along transmission lines and free - space propagating waves @xcite . wireless optical interconnects based on matched optical antennas have also been suggested @xcite , which could be used as high - speed links in chip architectures . in terms of interfacing electronics and plasmonics , it is of course mandatory to efficiently convert electrical signals into plasmon waves and vice - versa . recently , electrical sources @xcite and electrical detection @xcite of plasmons have been realized . also , electrical , mechanical , or optical tuning of nanoantennas by means of anisotropic load materials @xcite , stretchable elastomeric films @xcite , or photoconductive gap loads @xcite has been proposed and demonstrated . resonant metal nanoparticles at optical frequencies are very efficient absorbers mostly due to considerable ohmic losses . however , there are fields in which this supposed drawback turns into a dramatic advantage , since plasmonic nanoparticles can be viewed as nanolocalized heat sources that can be turned on and off by standard optical means at relatively low powers . this idea finds its most significant application in photothermal therapies , where functionalized metal nanoparticles and nanoshells have been used to demonstrate selective targeting of tumor tissues @xcite and drug delivery @xcite . plasmon - assisted photoacoustic imaging has been proposed as well @xcite . thermal hot spots are also at the basis of heat - assisted magnetic recording , in which writing heads equipped with nanoantenna systems are used to confine heating within a mesoscopic volume , thus achieving very small bit sizes @xcite . in the context of plasmonic nanostructures , localized thermal fields have also been successfully exploited to achieve thermal imaging of single au nanoparticle down to 2.5 nm @xcite and to develop hybrid heat - assisted nano - patterning techniques @xcite . many efforts have been devoted and are still needed to gain a correct understanding of heat flows at the nanoscale , where evanescent thermal fields play a significant role in radiative heat transfer @xcite . remarkably , when plasmonic nanostructures are used to generate localized thermal fields , care needs to be taken since optimization for local heating can lead to different requirements than for enhanced scattering of photons @xcite . consequently , also the localization of thermal hot spots can differ significantly form that of optical hot spots , as demonstrated experimentally by baffou _ et al . _ for a au dipole antenna @xcite . in addition to using the heat itself , the heat - induced morphology transformation of nanorods has also been utilized to achieve five - dimensional high density recording @xcite . while three dimensions are provided by controlling the position of the laser focal spot , two additional dimensions can be achieved utilizing the wavelength and polarization sensitive resonances of the nanorods , which work as optical antennas . finally , an intriguing possibility is provided by the use of nanoantennas that are specifically designed to achieve efficient radiation of thermal fields @xcite , as recently demonstrated with dielectric nanostructures @xcite . we hope that this _ tour de force _ on optical antennas has been able to show how lively and flowering this area of research is . the first ideas can be traced back to the efforts of bringing rf antennas down to the thz domain in the eighties and to the development of optimized optical near - field probes @xcite . the regime of optical frequencies has been fully addressed in 2004 - 2005 , which triggered an exponentially increasing interest in nanoantennas accompanied by numerous major breakthroughs which seems to continue with unwaning vigour . today the possibility of using optical antennas to manipulate light at the nanometer scale has become a reality and an enormous number of applications is at hand . during the preparation of this review , we obviously had to make choices about what to include and what to exclude from our discussion , as explicitly stated in section 6 . this unavoidably makes our report fragmentary but , as we hope , still complete within its subset of arguments . as we have seen , proof of principles which take advantage of the enhanced light - matter interaction afforded by optical antennas have already been demonstrated for many of their potential applications . this includes nanoscale microscopy , spectroscopy , lithography , quantum optics , sensing , trapping , photovoltaics , and many others . while all these results clearly show the potential of nanoantennas , we can probably safely state that a widespread use of all these possibilities in everyday research - not even to mention everyday life - is still far ahead . many big steps are still needed which so far could not be reached because of the difficulty in achieving the required levels of nanostructuring precision and reproducibility towards `` mass production '' of nanoantennas over extended areas . a second open key point , which is under intensive study both theoretically and experimentally , is how to achieve the best coupling between a quantum emitter and an optical antenna system . finally , in view of true plasmonic circuitry , the concepts of impedance matching and lumped plasmonic elements are still calling for a deeper understanding when it comes to the application of standard rf strategies to the plasmonic realm . hopefully , this review will help many researchers and students in particular to enter this exciting field of research . for people already working in the field , we hope that it will spark new discussions between colleagues and foster collaborations to soon make `` future '' applications a reality . the authors warmly acknowledge a. cattoni , c. de angelis , j. dorfmller , l. du , t. feichtner , m. finazzi , j. kern , d. w. pohl , j. prangsma , and m. savoini for stimulating discussions and for their help during the preparation of this manuscript . 400 j .- s . huang , v. callegari , p. geisler , c. brning , j. kern , j. c. prangsma , x. wu , t. feichtner , j. ziegler , p. weinmann , m. kamp , a. forchel , p. biagioni , u. sennhauser , and b. hecht . atomically flat single - crystalline gold nanostructures for plasmonic nanocircuitry . , 1:150 , 2010 . s. link , m. b. mohammed , and m. a. el - sayed . simulation of the optical absorption spectra of gold nanorods as a function of their aspect ratio and the effect of the medium dielectric constant . , 103:3073 , 1999 . yang , h. kobori , c .- he , m .- h . lin , h .- y . chen , c. li , m. kanehara , t. teranishi , and s. gwo . plasmon hybridization in individual gold nanocrystal dimers : direct observation of bright and dark modes . , 10:632 , 2010 . a. v. akimov , a. mukherjee , c. l. yu , d. e. chang , a. s. zibrov , p. r. hemmer , h. park , and m. d. lukin . generation of single optical plasmons in metallic nanowires coupled to quantum dots . , 450:402 , 2007 . a. locatelli , c. de angelis , d. modotto , s. boscolo , f. sacchetto , m. midrio , a .- capobianco , f. m. pigozzo , and c. g. someda . modeling of enhanced field confinement and scattering by optical wire antennas . , 17:16792 , 2009 . k. g. lee , x. w. chen , h. eghlidi , p. kukura , r. lettow , a. renn , v. sandoghdar , and s. gtzinger . a planar dielectric antenna for directional single - photon emission and near - unity collection efficiency . , 5:166 , 2011 . a. weber - bargioni , a. schwartzberg , m. schmidt , b. harteneck , d. f. ogletree , p. j. schuck , and s. cabrini . functional plasmonic antenna scanning probes fabricated by induced - deposition mask lithography . , 21:065306 , 2010 . s. frabboni , g. c. gazzadi , l. felisari , and a. spessot . fabrication by electron beam induced deposition and transmission electron microscopic characterization of sub-10-nm freestanding pt nanowires . , 88:213116 , 2006 . g. han , d. weber , f. neubrech , i. yamada , m. mitome , y. bando , a. pucci , and t. nagao . infrared spectroscopic and electron microscopic characterization of gold nanogap structure fabricated by focused ion beam . , 22:275202 , 2011 . m. kuttge , e. j. r. vesseur , j. verhoeven , h. j. lezec , h. a. atwater , and a. polman . loss mechanisms of surface plasmon polaritons on gold probed by cathodoluminescence imaging spectroscopy . , 93:113110 , 2008 . e. j. r. vesseur , r. de waele , h. a. atwater , f. j. garca de abajo , and a. polman . surface plasmon polariton modes in a single - crystal au nanoresonator fabricated using focused - ion - beam milling . , 92:083110 , 2008 . d. p. fromm , a. sundaramurthy , a. kinkhabwala , p. j. schuck , g. s. kino , and w. e. moerner . exploring the chemical enhancement for surface - enhanced raman scattering with au bowtie nanoantennas . , 124:061101 , 2006 . a. mcleod , a. weber - bargioni , z. zhang , s. dhuey , b. harteneck , j. b. neaton , s. cabrini , and p. j. schuck . nonperturbative visualization of nanoscale plasmonic field distributions via photon localization microscopy . , 106:037402 , 2011 . t. grosjean , m. mivellet , f. i. baidat , g . w. burr , and u. c. fischer . diabolo nanoantenna for enhancing and confining the magnetic optical field . , 11:1009 , 2011 . d. w. pohl , s. g. rodrigo , and l. novotny . stacked optical antennas . , 98:023111 , 2011 . w. swiech , g. h. fecher , ch . ziethen , o. schmidt , g. schnhense , k. grzelakowski , c. m. schneider , r. frmter , h. p. oepen , and j. kirschner . recent progress in photoemission microscopy with emphasis on chemical and magnetic sensitivity . , 84:171 , 1997 . p. biagioni , m. celebrano , m. savoini , g. grancini , d. brida , l. du s. mtfi - tempfli , m. mtfi - tempfli , b. hecht , g. cerullo , and m. finazzi . dependence of the two - photon photoluminescence yield of gold nanostructures on the laser pulse duration . , 80:045411 , 2009 . k. imura , y. c. kim , s. kim , d. h. jeong , and h. okamoto . two - photon imaging of localized optical fields in the vicinity of silver nanowires using a scanning near - field optical microscope . , 11:5876 , 2009 . m. castro - lopez , d. brinks , r. sapienza , and n. van hulst . polarized multiphoton emission from resonant al , ag and au nanoantennas . in _ 11th international conference on near - field optics , nanophotonics and related techniques ( nfo-11 ) _ , 2010 . t. hanke , g. krauss , d. trutlen , b. wild , r. bratschitsch , and a. leitenstorfer . efficient nonlinear light emission of single gold optical antennas driven by few - cycle near - infrared pulses . , 103:257404 , 2009 . r. l. olmon , m. rang , p. m. krenz , b. a. lail , l. v. saraf , g. d. boreman , and m. b. raschke . determination of electric - field , magnetic - field , and electric - current distributions of infrared optical antennas : a near - field optical vector network analyzer . 105:167403 , 2010 . m. d. wissert , a. w. schell , k. s. illin , m. siegel , and h .- j nanoengineering and characterization of gold dipole nanoantennas with enhanced integrated scattering properties . , 20:425203 , 2009 . c. snnichsen , s. geier , n. e. hecker , g. von plessen , j. feldmann , h. ditlbacher , b. lamprecht , j. r. krenn , f. r. aussenegg , v. z - h . chan , j. p. spatz , and m. mller . spectroscopy of single metallic nanoparticles using total internal reflection microscopy . , 77:2949 , 2000 . a. sundaramurthy , p. j. schuck , n. r. conley , d. p. fromm , g. s. kino , and w. e. moerner . toward nanometer - scale optical photolithography : utilizing the near - field of bowtie optical antennas . , 6:355 , 2006 . t. van der sar , e. c. heeres , g. m. dmochowski , g. de lange , l. robledo , t. h. oosterkamp , and r. hanson . nanopositioning of a diamond nanocrystal containing a single nitrogen - vacancy defect center . , 94:173104 , 2009 . m. righini , p. ghenuche , s. cherukulappurath , v. myroshnychenko , f. j. garca de abajo , and r. quidant . nano - optical trapping of rayleigh particles and _ escherichia coli _ bacteria with resonant optical antennas . , 9:3387 , 2009 . g. raschke , s. brogl , a. s. susha , a. l. rogach , t. a. klar , j. feldmann , b. fieres , n. petkov , t. bein , a. nichtl , and k. kurzinger . gold nanoshells improve single nanoparticle molecular sensors . , 4:1853 , 2004 . m. aeschlimann , m. bauer , d. bayer , t. brixner , s. cunovic , f. dimler , a. fischer , w. pfeiffer , m. rohmer , c. schneider , f. steeb , c. strber , and d. v. voronine . spatiotemporal control of nanooptical excitations . 107:5329 , 2010 . m. zavelani - rossi , m. celebrano , p. biagioni , d. polli , m. finazzi , l. du , g. cerullo , m. labardi , m. allegrini , j. grand , and p .- near - field second - harmonic generation in single gold nanoparticles . , 92:093119 , 2008 . j. wen , p. banzer , a. kriesch , d. ploss , b. schmauss , and u. peschel . experimental cross - polarization detection of coupling far - field light to highly confined plasmonic gap modes via nanoantennas , 98:101109 , 2011 . a. i. denisiuk , g. adamo , k. f. macdonald , j. edgar , m. d. arnold , v. myroshnychenko , m. j. ford , f. j. garca de abajo , and n. i. zheludev . transmitting hertzian optical nanoantenna with free - electron feed . , 10:3250 , 2010 . a. l. falk , f. h. l. koppens , c. l. yu , k. kang , n. de leon snapp , a. v. akimov , m - h . jo , m. d. lukin , and h. park . near - field electrical detection of optical plasmons and single - plasmon sources . , 5:475 , 2009 . j. barthelot , a. bouhelier , c. huang , j. margueritat , g. colas des francs , e. finot , j .- c . weeber , a. dereux , s. kostcheev , h. i. er ahrach , a .- baudrion , j. plain , r. bachelot , p. royer , and g. p. wiederrecht . tuning of an optical dimer nanoantenna by electrically controlling its load impedance . , 9:3914 , 2009 . s. mallidi , t. larson , j. tam , p. p. joshi , a. karpiouk , k. sokolov , and s. emelianov . multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer . , 9:2825 , 2009 . b. c. stipe , t. c. strand , c. c. poon , h. balamane , t. d. boone , j. a. katine , j .- l . li , v. rawat , h. nemoto , a. hirotsune , o. hellwig , r. ruiz , e. dobisz , d. s. kercher , n. robertson , t. r. albrecht , and b. d. terris . magnetic recording at 1.5 pb m@xmath175 using an integrated plasmonic antenna . , 4:484 , 2010 .

nanoantennas for visible and infrared radiation can strongly enhance the interaction of light with nanoscale matter by their ability to efficiently link propagating and spatially localized optical fields . this ability unlocks an enormous potential for applications ranging from nanoscale optical microscopy and spectroscopy over solar energy conversion , integrated optical nanocircuitry , opto - electronics and density - of - states engineering to ultra - sensing as well as enhancement of optical nonlinearities . here we review the current understanding of metallic optical antennas based on the background of both well - developed radiowave antenna engineering and plasmonics . in particular , we discuss the role of plasmonic resonances on the performance of nanoantennas and address the influence of geometrical parameters imposed by nanofabrication . finally , we give a brief account of the current status of the field and the major established and emerging lines of investigation in this vivid area of research . = 1

Abstract Conclusive evidence for sexual dimorphism in non-avian dinosaurs has been elusive. Here it is shown that dimorphism in the shape of the dermal plates of Stegosaurus mjosi (Upper Jurassic, western USA) does not result from non-sex-related individual, interspecific, or ontogenetic variation and is most likely a sexually dimorphic feature. One morph possessed wide, oval plates 45% larger in surface area than the tall, narrow plates of the other morph. Intermediate morphologies are lacking as principal component analysis supports marked size- and shape-based dimorphism. In contrast, many non-sex-related individual variations are expected to show intermediate morphologies. Taphonomy of a new quarry in Montana (JRDI 5ES Quarry) shows that at least five individuals were buried in a single horizon and were not brought together by water or scavenger transportation. This new site demonstrates co-existence, and possibly suggests sociality, between two morphs that only show dimorphism in their plates. Without evidence for niche partitioning, it is unlikely that the two morphs represent different species. Histology of the new specimens in combination with studies on previous specimens indicates that both morphs occur in fully-grown individuals. Therefore, the dimorphism is not a result of ontogenetic change. Furthermore, the two morphs of plates do not simply come from different positions on the back of a single individual. Plates from all positions on the body can be classified as one of the two morphs, and previously discovered, isolated specimens possess only one morph of plates. Based on the seemingly display-oriented morphology of plates, female mate choice was likely the driving evolutionary mechanism rather than male-male competition. Dinosaur ornamentation possibly served similar functions to the ornamentation of modern species. Comparisons to ornamentation involved in sexual selection of extant species, such as the horns of bovids, may be appropriate in predicting the function of some dinosaur ornamentation. Citation: Saitta ET (2015) Evidence for Sexual Dimorphism in the Plated Dinosaur Stegosaurus mjosi (Ornithischia, Stegosauria) from the Morrison Formation (Upper Jurassic) of Western USA. PLoS ONE 10(4): e0123503. https://doi.org/10.1371/journal.pone.0123503 Academic Editor: Matjaž Kuntner, Scientific Research Centre, Slovenian Academy of Sciences and Arts, SLOVENIA Received: October 31, 2014; Accepted: February 21, 2015; Published: April 22, 2015 Copyright: © 2015 Evan Thomas Saitta. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by Princeton University’s Office of the Dean of the College, Princeton University's Mountlake Field Research Fund, and Princeton University's Fred Fox Class of 1939 Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The author has declared that no competing interests exist. Introduction The genus Stegosaurus [1] can be found in the Upper Jurassic Morrison Formation of the western United States, although it has been recovered from Portugal as well [2]. It was an herbivorous quadruped with a small head, long tail, stout forelimbs, and long, columnar hind limbs. Stegosaurus had parasagittal dermal armor along its back consisting of vertically oriented plates that varied in size and shape from the neck to the tail and two pairs of long spikes at the end of the tail [3]. Once thought to have had 17 plates, a new specimen has been discovered with 18 [4]. The most common reconstruction puts the plates in two, staggered rows extending along the back of the animal, an idea supported by known articulated specimens [5] and the fact that no two plates on any individual were exactly the same size and shape [6]. Preserved Sharpey’s fibers indicate the orientation of ligaments that held the plates up in a vertical orientation [7]. The tail spikes were arranged in two pairs at the end of the tail, with the larger pair more anterior. The spikes are thought to have exhibited a more posterolateral orientation compared to the plates [5]. Studying sexual selection in dinosaurs poses a challenge because distinguishing sexual dimorphism from non-sex-related individual, interspecific, and ontogenetic variation is difficult [8,9]. Small sample sizes also hinder efforts to statistically demonstrate sexual dimorphism [10]. Previous attempts to identify sexual dimorphism in dinosaurs have not fully considered alternative explanations [11–23], and early work was not quantitative [24,25]. Despite strong evidence for sexual dimorphism in the pterosaurs Darwinopterus [26] and Hamipterus [27], some researchers have proposed that dinosaur ornamentation, such as the back plates of Stegosaurus, was not sexually dimorphic and instead was used for species recognition [28–32] or was under mutual sexual selection [33]. A lack of demonstrated instances of sexual dimorphism in dinosaurs is often cited as evidence for a lack of sexual selection occurring in the group [28–32]. Previous claims of sexual dimorphism within Stegosauria have suffered from the same issues as other attempts to observe sexual dimorphism in non-avian dinosaurs. Geometric morphometrics identified two types of proximal-end femur shape independent from overall size differences in Kentrosaurus aethiopicus [22]. The ratio of the occurrence of robust femora to gracile femora was about 2:1. However, slight differences in long bones could be a result of non-sex-related individual or ontogenetic variation. This study did not examine the ontogeny of these femora using histological thin sections. The long bones of dinosaurs grew along their long axis by ossification of cartilage at their proximal and distal ends [34]. As the ossified portions of these femora were the only parts preserved during fossilization, ontogeny might affect the morphology observed at their ends. Other studies found that in some individuals of K. aethiopicus [15] and Dacentrurus armatus [19], which normally have four pairs of sacral ribs, the first sacral vertebra provides an extra set of sacral ribs. Due to the isolated nature of these bones, this variation could not be correlated to any other variation in the skeleton. However, one specimen of K. aethiopicus has robust femora and four sacral ribs [35,36]. Both sacral types can be observed in different specimens of Stegosaurus. Variation in sacral rib count has been interpreted as sexual dimorphism without investigation into possible non-sex-related individual or ontogenetic explanations. Claims of sexual dimorphism in stegosaurs, like those for other non-avian dinosaurs, did not test all alternate hypotheses for the variation they observed, making them inconclusive. S. mjosi is the easiest species to diagnose within the genus. It should be noted that while S. mjosi is used here, this species has been previously referred to as Hesperosaurus mjosi, and its taxonomic status is debated [37–39]. Arguments for the validity of Hesperosaurus as a separate genus from Stegosaurus likely need further addressing. The holotype specimen is HMNS 14 (previously HMNS 001 [37]). Three more specimens have been discovered at the Howe Ranch in Wyoming [4,38,40]. These include SMA 0092 (previously SMA L02 [38]), VFSMA 001 (previously SMA 3074-FV01 [39] and SMA M04 [38]), and SMA 0018 (previously SMA V03 [38]). At least five new individuals are added here from the JRDI 5ES Quarry (S1 Fig) near Grass Range, Montana, along with at least two individuals from the Meilyn Quarry in Como Bluff, Wyoming [41], based on the number of pelves. Among other diagnostic characters (especially in the vertebral series and pelvis [37–39]), the most important diagnostic character of this species is the teardrop-shaped, non-bifurcated tips of neural spines on the anterior caudal vertebrae, making S. mjosi unique among North American stegosaurs. The shapes and sizes of forty S. mjosi plates were examined along with those from three articulated specimens of other species of Stegosaurus for comparison. Plate measurements were taken by hand using calipers and a tape measure as well as from scaled photographs. The most likely lateral outline was determined by examining the plate for broken edges, and each fairly complete plate was categorized as either complete enough for an accurate outline to be reconstructed (n = 26 for S. mjosi) or not entirely complete, but still allowing for a plausible outline to be reconstructed (n = 14 for S. mjosi). Principal component analysis (PCA) was carried out on the S. mjosi plates to observe variation in size and shape. In addition to investigating the taphonomy of the JRDI 5ES Quarry, the ontogenetic statuses of the stegosaur bones were examined using the same methodology of previous histological studies of Stegosaurus [42–44]. This histological analysis involved X-ray computed tomography (CT) scans of 11 plates and four tail spikes and thin sections of samples taken from the base, middle, and apex of nine plates as well as from the midshaft of a tibia and femur. Discussion The dimorphism in the plates could be explained by several alternative hypotheses other than sexual dimorphism: non-sex-related individual variation, one individual possessing both morphs of plates, interspecific variation, and ontogenetic variation. Alternate Hypothesis: Non-sex-related Individual Variation The dimorphism is not a result of non-sex-related individual variation. PCA, combined with simple observation, demonstrates that intermediately shaped plates are lacking. Clearly intermediate morphologies would typically be expected under non-sex-related individual variation. Results such as these satisfy previously proposed criteria for quantitative evidence of size- and shape-based dimorphism [20]. Alternate Hypothesis: One Individual Possessing Both Morphs of Plates The two plate morphs do not occur in any single individual. The dimorphism occurs along the entire plates series as both morphs can be classified into cervical, dorsal, or caudal plates. As plates of both morphs demonstrate a range of angle values similar to that seen in the complete, articulated specimens (S20 Fig), both represent plates from all regions of the plate series from head to tail. The size of S. mjosi plates also peaks at roughly the same angle value as seen on the articulated specimens (~70°). Furthermore, all isolated specimens of S. mjosi possess plates of solely one morph. SMA 0092 is a tall morph individual while HMNS 14, SMA 0018, and VFSMA 001 are wide morph individuals. Alternate Hypothesis: Interspecific Variation The dimorphism is not a result of interspecific variation. Taphonomy of the JRDI 5ES Quarry suggests that individuals of both morphs co-existed, and possibly comprised a social group, because they were likely together at the time of death and their bodies were not transported before burial. It should be noted that being together at the time of death does not necessarily imply sociality as mass death assemblages of asocial species can be found in the fossil record [46]. The single stratigraphic horizon implies a simultaneous burial for the different individuals. The paleocurrent was weak as indicated by the mudstone lithology as well as the lack of common orientation among the long axes of bones, suggesting a low energy depositional environment. The lack of other macroscopic fossil taxa in the stegosaur bed might have been due to eutrophic or ephemeral conditions. The presence of associated elements as well as small and fragile bones suggests little transportation before burial. As the bones show no polishing or wear and are not divided into Voorhies groups, any large degree of water transportation is unlikely. The lack of bite marks and shed teeth suggests that scavengers did not transport the bones. The jumbled pattern of bones in the quarry is likely due to disassociation as a result of decomposition of the carcasses prior to burial as well as movements of the bones post-burial as the clays swelled and contracted through hydration and desiccation. Bone disassociation as a result of swelling and contracting clays is seen in other Morrison dinosaur quarries such as the Cleveland-Lloyd Quarry [47]. The group in the JRDI 5ES Quarry appears to be monospecific. If the two morphs represented different species, morphological features that might indicate niche partitioning would be expected, such as in the skull or limbs. Instead, only the plates were found to be dimorphic after examination of the JRDI 5ES Quarry specimens and all other S. mjosi specimens. Although the largest isolated specimens of S. mjosi are wide morphs, there is not enough evidence as of yet to determine if the two morphs showed differences in body size. The JRDI 5ES Quarry is the first instance of a multi-individual, monospecific Morrison Formation site to contain Stegosaurus. While both tall and wide morphs plates have been found in the Meilyn Quarry, the lithology suggests fluvial transportation and other dinosaur species are found alongside the stegosaur individuals [41]. Alternate Hypothesis: Ontogenetic Variation The dimorphism is not a result of ontogenetic variation. Prior histological work has already provided some evidence against this alternate hypothesis. The wide morph is known from fully-grown, old adults specimens HMNS 14 [44] and SMA 0018 [43]. Wide morph specimen VFSMA 0001 and tall morph specimen SMA 0092 were sexually mature adults that were still growing [43]. The JRDI 5ES Quarry bone bed has produced a pair of femora only 70 cm in length (compared to the maximum size of S. mjosi femora at 96 cm) as well as the largest known tall morph plate. As the individuals from this quarry come in a range of sizes, the possibility of ontogenetic variation had to be examined. Initial observations hinted at the presence of maturity in the quarry, as there are very large plates of both morphs that often show well-developed external vasculature. Both morphs of plates in the quarry show indicators of sexual maturity described by previous researchers [42–44]. Internal, vascular piping in the plates is one such indication. Histological features further show reduced or halted growth and increased remodeling that appear after sexual maturity and as the individual reaches full size. The presence of an EFS in two of the tall morph plates indicates that these plates had ceased their growth and came from fully-grown adults. The wide morph plates tend to show features of young adults that are sexually mature, yet still growing, while the tall morph plates tend to show more features of fully-grown, old adults. The slight difference in ontogeny between the two morphs in the quarry is further evidence that the two morphs of plates come from separate individuals rather than from different positions along the back of one animal. However, it cannot be said with confidence how many individuals of each morph contributed to the collection of plates recovered at the JRDI 5ES Quarry. All that is known is that there are at least five individuals found in the quarry based on the number of pelves, and that the plates from this site must come from at least two individuals, one of each morph. The axial channels in the spikes are evidence of the presence of old adults [44] while the histology of the tibia and femur are evidence of the presence of sexually mature adults that are still growing [43]. In combination with previous histological studies on other specimens, plates of both morphs of S. mjosi came from sexually mature, young adults as well as fully-grown, old adults. The discovery of an old adult, tall morph individual that was fully-grown completes the expected ontogenetic ranges seen in both morphs under the premise of sexual dimorphism. One morph is not the immature form of the other. Conclusions With all alternate hypotheses apparently ruled out, sexual dimorphism is the most likely explanation for the observed variation in the plates. The evidence provided here is the first support for sexual dimorphism in a non-avian dinosaur that rules out all other possible explanations for the observed morphological variation. More importantly, the dimorphism occurs in the ornamentation. As a result, S. mjosi ornamentation was likely a secondary sexual characteristic. No medullary bone was found in the femur or tibia sampled from the JRDI 5ES Quarry that might allow for one of the morphs to be assigned as definitively female. Without this particular tissue, and without any specimens preserved with eggs inside the body cavity, it is not possible to assign sexes to the two morphs with absolute certainty. However, modern analogs might be able to provide clues. Stegosaurs were very unusual animals, and no extant species are perfect analogs. However, bovids might be one of the best options. In addition to both being large, quadrupedal herbivores, stegosaur plates and modern bovid horns are both composed of a boney core surrounded by a keratin sheath. Applying the same reasoning garnered from studies of modern bovid horns [48–50] to S. mjosi plates, the wide morph may represent the male while the tall morph could represent the female (Fig 4). Compared to females, males are typically expected to invest more energy into growing and maintaining their ornamentation. Wide morph plates are 45% larger in maximum surface area than tall morph plates, and an energetics perspective would assign the wide morph as male. The larger wide morph plates were probably under sexual selection like male bovid horns and functioned to create a broad, continuous display surface along the animal’s back, like a billboard. Unlike sparring male bovids, the nature of Stegosaurus plates suggests that sexual selection occurred through female mate choice rather than male-male competition. In contrast to the immobile, vertical plates, tail spikes might have been able to function in antagonistic behavior. However, male-male competition is unlikely due to the possible lethality of Stegosaurus spikes [5,51,52]. In contrast, the ornaments of male bovids are typically thought to have evolved for non-lethal confrontation [48,49]. Furthermore, if Stegosaurus used its spikes in male-male competition, dimorphism would be expected in the spikes rather than the plates. The tall morphs, due to their more erect angle and pointed apex, were probably under natural selection like female bovid horns and functioned as prickly predator deterrents. PPT PowerPoint slide PowerPoint slide PNG larger image larger image TIFF original image Download: Fig 4. Hypothetical silhouettes of male and female S. mjosi. The wide morph exhibits more overlap between adjacent plates than does the tall morph, leading to a more continuous display surface. Sexual dimorphism in the size and shape and plates might have also occurred with other sexual differences such as sexual dichromatism. https://doi.org/10.1371/journal.pone.0123503.g004 The function of Stegosaurus plates, along with the ornamentation of other dinosaur species, has been a long-running debate in paleontology. These results suggest that Stegosaurus plates possibly had multiple functions because, despite the presence of sexual dimorphism, females still possessed plates. Based on an understanding of modern species, these likely included sex-related display and defense. These results may suggest that previously described ornament variations in dinosaurs are actually cases of sexual dimorphism. For example, the ontogeny of Triceratops horns [53] seems to match sexual variation seen in modern bovid horns, where males have horns with downward pointing tips that are better for sparring and resistance of lateral stresses and females have thinner and straighter horns with tips that point up and away from the skull that are more efficient stabbing weapons [48]. With the first evidence of sexual dimorphism in a dinosaur species, future histological research could examine the possibility of some Triceratops specimens with “juvenile” horns being sexually mature and fully-grown. Materials and Methods The plate morphologies of all available S. mjosi specimens identified by this study were examined (HMNS 14, SMA 0018, SMA 0092, VFSMA 001, as well as newly identified specimens housed at the Wyoming Dinosaur Center and Judith River Dinosaur Institute). Additionally, several articulated Stegosaurus specimens not of the species S. mjosi (DMNS 2818, NHMUK R36730, and USNM 4934) were examined for comparison. NHMUK R36730 has been previously referred to as SMA DS-RCR-2003-02 [54], SMA RCR0603 [43], and SMA S01 [38]. Specimens used in this study are housed in the Denver Museum of Nature and Science (DMNS), Hayashibara Museum of Natural Sciences (HMNS), Judith River Dinosaur Institute (JRDI), Natural History Museum in London (NHMUK), Sauriermuseum Aathal (SMA), United States National Museum (USNM), Verein für das Sauriermuseum Aathal (VFSMA), and Wyoming Dinosaur Center (WDC). The CT scans, in CD-ROM format, and the histological thin section slides of the JRDI 5ES Quarry specimens are housed with the specimens themselves at the Judith River Dinosaur Institute. After establishing a quantitative basis for dimorphism in plate shape, this variation was tested against various alternate explanatory hypotheses. This involved further methodologies including examination of the taphonomy of the JRDI 5ES Quarry using the quarry map and basic sedimentology of the site, X-ray computed tomography (CT) scans of the JRDI 5ES plates and spikes, and the preparation of histological thin sections of samples taken from JRDI 5ES plates and long bones. Plate Measurements Measurements were made by hand and from scaled photographs taken with a Nikon D40 camera (18–55 mm lens) using Adobe Photoshop CC on a MacBook 7 with 2 GB of RAM and a 2.4 GHz Intel Core 2 Duo processor. As some plates were on mounted specimens and were difficult to get close to, the distance at which photographs were taken varied. Photographs were taken at a distance as close to the plate as possible such that the entire plate was included in the frame and the plate was viewed in lateral profile. Measurements for PCA were made of the angle between the center of the base and the apex in degrees, the length of the base in cm, the perimeter of the plate in cm, the ‘width’ of the plate in cm (typically the major axis in wide morphs and minor axis in tall morphs), the distance from the center of the base to the apex in cm, and the surface area of the plate in cm2 (Fig 5). The angle between the base of the plate and the apex was taken as the acute angle formed between the line connecting the anterior and posterior limits of the base and the line connecting the apex to the midpoint of the previous line. The shape of the large caudal plate on wide morph specimen HMNS 14 (#1 in S4A Fig) lent itself to have ‘width’ measured in the same manner as those of tall morph plates such that ‘width’ equals the minor axis. The shape of the first dorsal plate on tall morph specimen SMA 0092 (#1 in S3B Fig) lent itself to have ‘width’ measured in the same manner as those of wide morph plates such that the ‘width’ equals the major axis. Surface area was calculated to the nearest cm2 by measuring the area of one side of a plate from a scaled photograph, and then multiplying by two to get the whole surface area of the plate. The base of the plate, presumably embedded in the skin during life, was included in this measure since it is difficult to estimate what portion of a plate was exposed above the skin. A plausible lateral outline for each plate was determined to the highest accuracy that the completeness of the fossil allowed. To determine this, plates were examined for broken edges and thickness measurements were taken at various points along the edge using a pair of digital calipers. If a plate is unusually thick at one location, then it is likely that this edge is broken because most plates continuously thin from base to apex and from the center to the edges. The same outline used to calculate surface area was used to determine the perimeter of the plate. Principal component analysis was done using the prcomp() function of stats package version 3.1.0 in R version 0.98.501 (S1 Script). Default options were used for prcomp() except that scale = TRUE. S6 Fig and S20 Fig were also created in R. PPT PowerPoint slide PowerPoint slide PNG larger image larger image TIFF original image Download: Fig 5. Diagrammatic depiction of measurements. (A) Vertical oval/triangular plates (JRDI 5ES-579). Tall morph S. mjosi plates typically fall under this category. The minor axis, rather than the anteroposterior width, was the value used for ‘width’ in PCA. (B) Horizontal oval plates (JRDI 5ES-523). Wide morph S. mjosi plates typically fall under this category. The major axis was the value used for ‘width’ in PCA. (C) Sub-right trapezoidal plates (DMNS 2818). The major axis and anteroposterior width tend to converge. The major axis was the value used for ‘width’ in PCA. (D) Shoulder plates (NHMUK R36730). These plates have a distinctive diamond shape. The distance from the center of the base to the apex and the major axis tend to converge. https://doi.org/10.1371/journal.pone.0123503.g005 Histological Analysis CT scanning was done at the radiology department of Billings Clinic in Billings, Montana (Siemens Somatom Sensation 64, Siemens corporation, 0.6 mm acquisition, 1.0 mm slice thickness, 140 kV, 180 mA). Eleven plates (JRDI 5ES-237, JRDI 5ES-256, JRDI 5ES-296, JRDI 5ES-357, JRDI 5ES-401, JRDI 5ES-518, JRDI 5ES-523, JRDI 5ES-525, JRDI 5ES-552, JRDI 5ES-553, JRDI 5ES-579), one of which was only a fragment of a base, and four tail spikes (JRDI 5ES-232, JRDI 5ES-245, JRDI 5ES-258, JRDI 5ES-260) were scanned. Scans were saved onto CD-ROM and then viewed using Syngo FastView software on a Dell desktop with 32 GB of RAM and a 3.6 GHz Intel Core i7-3820 processor Samples for thin sectioning were taken from the base, middle, and apex of nine plates from the JRDI 5ES Quarry as well as from midshaft on the cranial surface of one femur (JRDI 5ES-229) and one tibia (JRDI 5ES-501) along the mediolateral plane. Wedge-shaped samples approximately 2 cm wide and 2 cm tall were cut from the plates and tibia using a dremel saw with a diamond-coated blade. The sample from the femur was taken using a drill press to retrieve a core approximately 1 cm in diameter from midshaft. These samples were then sent to Spectrum Petrographics, Inc. in Vancouver, Washington to be made into 27 mm by 46 mm slides embedded in EPOTEK 301 and cut to 30 microns in thickness. Slides were analyzed using a Leica DM750 light microscope with plane and crossed polarized light settings and equipped with a Leica ICC50 HD camera. These images were then viewed using Leica Acquire software. Plate Numbering of Articulated Specimens The following reasoning was applied in order to determine plate numbers on articulated Stegosaurus specimens for S6 Fig USNM 4934 has 17 plates [39,55], the anterior 11 of which are inaccessible due to the current position of the specimen in its display. It should be noted that previous reconstructions have also combined material from USNM 4934 and USNM 4714 [6], with some even adding an 18th plate [56]. DMNS 2818 has 16 plates [5,57,58]. NHMUK R36730 has 18 plates, more than any other stegosaur previously discovered [4]. Therefore, it is likely that all Stegosaurus individuals had 18 plates and it was assumed that specimens with fewer plates are incomplete rather than representing biological variation in plate number. The degree of articulation of USNM 4934 decreases from anterior to posterior along the specimen. It seems probable that USNM 4934 is missing its most posterior plate (plate #18) and that DMNS 2818 is missing its last two most posterior plates (plates #17 and #18). These posterior tail plates would be smaller than the tail plates that were preserved with the specimens, making them more likely to be transported away from the rest of the body. As for NHMUK R36730, the method of numbering the plates follows that used in the mounted cast at the Sauriermuseum Aathal [4] with three modifications (S21 Fig). First, in the mounted specimen, a gap in the series of plates was inferred and filled in with a hypothetical 19th plate (placed in the 14th plate position on the mount). There is no reason to add an extra plate when only 18 were discovered, so this hypothetical plate was ignored. Second, the plate originally described as the 5th plate is now plate #18 because its morphology clearly matches those of distal tail plates in other Stegosaurus specimens. Third, the plate originally described as the 15th plate is now plate #11 because this plate was found isolated from the rest of the body close to the anterior half of the skeleton. It was assigned the 11th position because it has a surface area in-between the plates directly anterior and posterior to it. By labeling this plate as a dorsal plate rather than a caudal plate, it results in plate #13 being the largest on the body. The largest plate on DMNS 2818 is also plate #13 [5,58]. Acknowledgments Most of this research was done while in the Department of Ecology and Evolutionary Biology at Princeton University, and I thank the University and others for support. The Judith River Dinosaur Institute (Billings, MT) excavated and prepared the JRDI 5ES Quarry specimens with the help of many volunteers. Billings Clinic (Billings, MT) carried out the CT scanning with technologists C. Banfield and J. Orendorff operating the scanner while J. Burton, J. Duncan, R. Hargrove, and M. Kongaika arranged for the scans to take place. N. Murphy (JRDI) and M. Lent (Billings, MT) assisted in taking samples for thin sections, as well as the CT scanning. M. Lent provided the drill press. Spectrum Petrographics, Inc. (Vancouver, WA) produced the thin sections. L. Goodell (Princeton University) provided access to the microscope. T. Bolliger (SMA), M. Brett-Surman (USNM), L. Ivy (DMNS), P. Larson (Black Hills Institute of Geological Research), and H. J. Siber (SMA) assisted me on my visits to various institutions. K. Carpenter (Utah State University Eastern) provided images of HMNS 14. H. Finlayson (DMNS), M. Lukens (Laramie, WY), T. Saitta (Jacksonville, FL), and W. Wahl (WDC) assisted in measuring bones. M. Benton (University of Bristol), J. Vinther (University of Bristol), J. Gould (Princeton University), A. Maloof (Princeton University), B. vonHoldt (Princeton University), D. Richmond (Devon Energy, Oklahoma City, OK), and N. Murphy provided comments. Author Contributions Conceived and designed the experiments: ETS. Performed the experiments: ETS. Analyzed the data: ETS. Contributed reagents/materials/analysis tools: ETS. Wrote the paper: ETS. ||||| Around 150 million years ago, it might not have been that difficult to look at a Stegosaurus and tell whether it was a male or a female. Today, however, it's a big challenge. Researchers find themselves staring at piles of bones, often unable to tell whether they're looking at multiple animals, different species, or one individual with a number of variations. Because of that, researchers seem to agree that there's been no convincing evidence so far for sex-based differences — like the mane on a male lion, a phenomenon scientists call "sexual dimorphism" — in any dinosaur, despite those differences being common among modern animals. "It's a feature we'd expect to see." Despite those difficulties, a researcher at the University of Bristol now says that he's found the "best evidence yet" for sexual dimorphism in one species of Stegosaurus. In a paper published this afternoon in PLOS One, Evan Saitta describes differences in the plates running along the spine of the Stegosaurus mjosi that may differentiate the species' males and females. "There's simply no other explanation" for the different plates, Saitta tells The Verge. In the work, performed while he was an undergraduate at Princeton University, Saitta identified two types of plates: one that was narrow and tall and another that was shorter but much wider. "By ruling out other possible explanations, I can say with some confidence that I think it is sexual dimorphism that's causing the two distinct types of plates," he says. The males, he posits, likely had the wider plates, potentially as a way to attract mates. To land on sexual dimorphism, Saitta first had to rule out quite a few other alternate possibilities — possibilities that papers in the past have failed to address. Those include whether these plates could have come from Stegosaurus of different ages, from different species of Stegosaurus, or from common variations within the species that would occur regardless of sex. Having eliminated those possibilities using aging techniques and observations of multiple specimens, Saitta settled on sexual dimorphism as the reason for the differences. "Male and female sexual dimorphism is the only thing that's left," he says. "It makes sense, too. It's a feature we'd expect to see." "I would not accept this as evidence of sexual dimorphism." While sexual dimorphism is certainly a possible explanation, other researchers aren't quite as convinced as Saitta. Kevin Padian, a paleontologist and professor of integrative biology at University of California, Berkeley who wasn't involved in the study, says that he sees "no evidence" of a distinction between the two plate types that Saitta identifies. "Without better association documented, or better skeletochronology, you can’t tell," Padian writes in an email to The Verge. "At any rate I would not accept this as evidence of sexual dimorphism, or of dimorphism at all." Basically, Padian sees Saitta's study as falling victim to the same gaps in research as prior reports on sexual dimorphism in dinosaurs. He doesn't see the study as being able to rule out the many alternate possibilities for why these differences exist. "There is no convincing evidence of how many animals are present, how the bones and plates may be associated, whether the animal(s) in question may be fully grown, or what the absolute age of any specimen is," Padian writes. Another paleontologist contacted by The Verge, who was not involved in the study and did not want to publicly criticize the work, agreed that there were issues with the findings. He said that the study presents a good case for dimorphism, but that it isn't necessarily sexual — it could still turn out to represent other differences, such as distinctions between species. If dimorphism is present, it could be for other purposes Saitta disagrees with their conclusions, writing in an email to The Verge that it sounded like Padian "looked for anything that might counter my claims without actually reading through the whole of the evidence." (Padian says that the study's supplemental material doesn't change the story.) "Determining sexual dimorphism is about ruling out other possibilities," Saitta writes. "I stand by my statement that these stegosaurs represent the best evidence yet for sexual dimorphism, as did my peer reviewers, since other possibilities have been tested for." Albert Prieto-Marquez, an evolutionary biology researcher who is also at the University of Bristol but was not involved in the study, reiterates that idea in an email to The Verge. "This is a rare case among dinosaurs in which sexual dimorphism could be shown to be the hypothesis that best fits the morphological data in the fossils," he writes. Concerns with the paper only underscore how difficult it remains to identify sexual dimorphism in dinosaurs. That is — if it existed at all. It's possible that dinosaurs' ornamentation, like the plates on the back of a Stegosaurus, were actually used for other purposes, such as identifying separate species, rather than identifying males and females within a species. "Some people were suggesting that maybe it was for species recognition and all that," Saitta says. "I think that's a generalization. Simply looking at living animals today, the presence of sexual dimorphism is so widespread ... that it's unbelievable to think that no dinosaurs were sexually dimorphic. I just don't see how that's possible." ||||| A member of staff from the Natural History Museum poses for a photograph next to the world's most complete Stegosaurus skeleton, in London December 3, 2014. WASHINGTON For extinct creatures like dinosaurs known only from fossils, it is notoriously difficult to differentiate the males from the females of a species because sex distinctions are rarely obvious from the skeletons. But in the case of the well-known Jurassic dinosaur Stegosaurus, a study published on Wednesday may provide a handy how-to guide on telling the boys from the girls based on the shape of the big bony plates protruding from its back. Stegosaurus, which roamed the western United States about 150 million years ago, was a large, four-legged plant-eater with two rows of plates along its back, as well as two pairs of spikes at the end of its tail to clobber predators. The largest Stegosaurus species reached about 30 feet (9 meters). The species in this study, Stegosaurus mjosi, measured roughly 21 feet (6.5 meters). A Montana Stegosaurus "graveyard" contained fossils of several individuals, with plates coming in two distinct varieties: some wide, others tall. The wide ones reached sizes 45 percent larger in surface area than the taller ones, which were nearly 3 feet (90 cm) high. "Males typically invest more into their ornamentation than do females, so the larger wide plates were likely from males," said Evan Saitta, a 23-year-old paleontology graduate student at Britain's University of Bristol whose study appears in the journal PLOS ONE. "The broad, thin structure of the plates and their positioning on the back of the animal suggests that they were used in sexual display, analogous to the tail of a peacock. The broad, wide plates likely made a continuous display surface along the animal's back to attract mates, like a billboard." To test whether the plate differences were instead because some individuals were young and others old, CT scans and microscopic analyses were performed that showed the bone tissue had ceased growing, meaning both varieties came from full-grown adults. Anatomical and other differences between the sexes of a single species, like a male lion's mane or a male deer's antlers, are called sexual dimorphism. Sexual dimorphism examples have been proposed in other dinosaurs, but many scientists find those inconclusive. Saitta said the Stegosaurus plates may be "the most convincing evidence for sexual dimorphism in dinosaurs to date." University of Bristol paleontologist Michael Benton added, "It suggests that many dinosaurs used sexual display, as birds and mammals do today, usually the males displaying or mock fighting to attract attention of females." (Reporting by Will Dunham; Editing by Sandra Maler) ||||| The first convincing evidence for sexual differences in a species of dinosaur has been described by University of Bristol MSc student, Evan Saitta, in a study of the iconic dinosaur Stegosaurus, published today in the scientific journal PLOS ONE. Stegosaurus, a large, herbivorous dinosaur with two staggered rows of bony plates along its back and two pairs of spikes at the end of its tail, lived roughly 150 million years ago during the Late Jurassic in the western United States. Some individuals had wide plates, some had tall, with the wide plates being up to 45 per cent larger overall than the tall plates. According to the new study, the tall-plated Stegosaurus and the wide-plated Stegosaurus were not two distinct species, nor were they individuals of different age: they were actually males and females. Professor Michael Benton, Director of the Masters in Palaeobiology at the University of Bristol said: “Evan made this discovery while he was completing his undergraduate thesis at Princeton University. It’s very impressive when an undergraduate makes such a major scientific discovery.” Sexual dimorphism (a term used to describe distinct anatomical differences between males and females of the same species) is common in living animals – think of the manes of lions or the antlers of deer – yet is surprisingly difficult to determine in extinct species. Despite many previous claims of sexual dimorphism in dinosaurs, current researchers find them to be inconclusive because they do not rule out other possible explanations for why differences in anatomy might be present between fossil specimens. For example, two individuals that differ in anatomy might be two separate species, a young and an old individual, or a male and a female individual. Having spent six summers in central Montana as part of an excavation crew digging up the first ever Stegosaurus ‘graveyard’, Evan Saitta was able to test these alternative explanations and others in the species Stegosaurus mjosi. The group of dinosaurs excavated in Montana demonstrated the coexistence of individuals that only varied in their plates. Other skeletal differences indicating separation of ecological niches would have been expected if the two were different species. The study also found that the two varieties were not a result of growth. CT scanning at Billings Clinic in Montana, as well as thin sections sampled from the plates for microscope analysis, showed that the bone tissues had ceased growing in both varieties. Neither type of plate was in the process of growing into the other. With other possibilities ruled out, the best explanation for the two varieties of plates is that one type belonged to males and the other, females. Speculating about which is which, Evan Saitta said: “As males typically invest more in their ornamentation, the larger, wide plates likely came from males. These broad plates would have provided a great display surface to attract mates. The tall plates might have functioned as prickly predator deterrents in females.” Stegosaurus may not have been the only dinosaur to exhibit sexual dimorphism. Other species showed extra-large crests or nose horns, which were potentially sexual features. Male animals often fight or display for mates, just like red deer or peacocks today. Not only does Saitta’s work show that dinosaurs exhibited sexual dimorphism, it suggests that the ornamentation of at least some species was used for sexual display. The presence of sexual dimorphism in an extinct species can provide scientists with a much clearer picture of its behaviour than would otherwise be possible. Paper ‘Evidence for Sexual Dimorphism in the Plated Dinosaur Stegosaurus mjosi (Ornithischia, Stegosauria) from the Morrison Formation (Upper Jurassic) of Western USA’ by Evan Saitta in PLOS ONE

– If the sight of broad, wide plates along the back of a stegosaurus fails to drive you wild with desire, that's probably because you're not a female stegosaurus. In what the University of Bristol calls the "first convincing evidence for sexual differences in a species of dinosaur," researcher Evan Saitta says you can tell the male stegosauruses from the ladies by their plates. He tells Reuters that in males, the "broad, wide plates likely made a continuous display surface along the animal's back to attract mates," serving much the same showoff function as a peacock's feathers. Females had taller, narrower plates that probably served to ward off predators, he says. Some paleontologists have their doubts about the conclusion of the study, which is published in the journal PLoS ONE, but Saitta tells the Verge he studied enough specimens to rule out other explanations, like age or variations within the species, for the differences in plates. And the study may be just the beginning of dinosaur sexing, as researchers take a fresh look at features like nose horns: The stegosaurus finding "suggests that many dinosaurs used sexual display, as birds and mammals do today, usually the males displaying or mock fighting to attract attention of females," a fellow University of Bristol paleontologist tells Reuters. (New research suggests the brontosaurus really did exist.)

bolometers are now the most sensitive receivers for astrophysical observations in the submillimetre spectral range . after decades of improvement , they are able to operate with a sensitivity limited by the photon noise of the observed source when operated outside of the atmosphere @xcite . the principle of a bolometer is that the heat deposited by the incoming radiation is measured by a thermometer . the theory of bolometers has been developed in founding papers @xcite and refined later @xcite . they have shown that their photometric responsivity strongly depends on its interaction with the readout electronics , through the variation of the electrical power deposited in the thermometer ( the electro - thermal feedback ) . these theories have been developed for a semiconductor thermometer element biased by a direct current ( dc ) voltage through a load resistor . the readout electronics for bolometers experienced a radical change more than a decade ago . most of them are now using a modulated bias current in order to get rid of low frequency noises that plague amplification systems @xcite . the theory developed for a dc bias must be altered for alternative current ( ac ) biased bolometers in the presence of stray capacitance in the circuit . this was evidenced in the planck - hfi instrument @xcite in spite of the fact that the readout electronics had been designed @xcite to mimic , as far as possible , the operation of a dc bias . very significant differences were found in absolute responsivity and even in value of the optimal bias current for the planck bolometers . this was shown to be mostly due to the effect of parasitic capacitances in the wiring , which can not be neglected in many practical experimental setups . this effects have been studied in several papers dedicated to the characterization of bolometers and calorimeters by measuring their effective impedance ( e.g. @xcite ) , but we are here essentially interested in effective tools able to predict the responsivity and optimise the tuning of bolometers in specific configurations . brute force modelling based on numerical integration of thermal and electrical equations of the bolometers proved to be feasible but computationally too heavy to be applied on wide ranges of the many parameters of the models . to facilitate the computation , we have developed an analytical model of the responsivity of ac biased semiconductor bolometers . this model was used as an aid to predict the behaviour of the bolometer of planck - hfi and to optimize their tuning . its numerical application proved to be flexible and fast enough to study the effects of all variable parameters . this paper describes this analytical model and its application with a set of parameters not too far from the realistic cases encountered in planck - hfi . the next section is dedicated to the differential equations driving the thermal and the electrical behaviour of the electro - thermal system comprising the bolometer and its readout electronics . it focuses on the derivation of an analytical solution giving the responsivity for both the dc and ac biased cases . section three addresses the various noises encountered and shows that the optimal bias currents are different in the two cases . in the fourth section the model is applied to analyze the effects of some essential parameters ( cold stage temperature , modulation frequency , value of the stray capacitance , optical background ) . section five deals with the shape of the periodic bias wave to cover the case of square bias current used in planck - hfi . let us consider a low temperature bolometer consisting of an absorber attached to a semiconductor thermometer . the bolometer is attached to a heat sink at temperature @xmath0 through a thermal link of thermal conductance @xmath1 . the incoming optical power deposits energy in the absorber and heats the whole bolometer including the thermometer . the absorbed optical power will determine the equilibrium temperature @xmath2 of the bolometer : @xmath3 where @xmath4 is the total power dissipated in the bolometer that is @xmath5 where @xmath6 is the absorbed radiant power and @xmath7 is the electrical power . @xmath1 can be well represented in many cases by : @xmath8 where @xmath9 is the static thermal conductance at temperature @xmath0 ( @xmath10 in the case we investigate here ) . the dominant electrical conduction mechanism in the thermometer is the variable range hopping between localised sites and the resistance of the device varies with both applied voltage and temperature . the relation between the resistance and the temperature of the bolometer @xcite is set by : @xmath11 where @xmath12 is a characteristic parameter of the material , @xmath13 is a parameter depending on the material and the geometry of the element , @xmath14 is related to the average hopping distance and @xmath15 is the electric field across the device . in absence of electrical non - linearities and other effects such as electron - phonon decoupling , the thermistor resistance depends only on temperature : @xmath16 the impedance changes induced by the temperature variations can be measured by an appropriate readout circuit that we are going to detail and discuss hereafter . the readout electronics is designed to measure the impedance of the temperature sensitive element of the bolometer . this is done by injecting a current , and therefore depositing power in the bolometer , which changes its temperature . consequently , the bolometer responsivity and performance strongly depend on the design of the readout electronics . the responsivity @xmath17 is the derivative of the bolometer voltage with respect to the optical absorbed power @xmath18 : @xmath19 it is a strong indicator of the coupling efficiency achieved by readout electronics for a given bolometer . we compare here after the responsivity obtained with a classical dc bias and a sine - shape ac bias . * dc responsivity :* the bolometer is biased with a dc bias voltage through a load resistance @xmath20 , and the voltage @xmath21 is measured with an amplifier with an high input resistance ( fig [ fig : acmod ] left ) . the general equation of a dc biased circuit is : @xmath22 where @xmath20 and @xmath23 are the impedances of the load and the bolometer . @xmath24 is the total input voltage . the electrical responsivity @xmath25 can be written using the zwerling formalism @xcite @xmath26 where : @xmath27 and @xmath28 is the equivalent thermal conductance : @xmath29 @xmath30 is the temperature coefficient of resistance of the bolometer : @xmath31 the advantage of this dc setup is the use of a well established theory @xcite . the optical power @xmath32 absorbed by the bolometer and the responsivity of the bolometer can be directly computed in the time domain . on the other hand , a dc bias current increases the level of low frequency noise , like flicker noise , making the detection of a faint and slowly varying optical signal impossible . in addition , the johnson noise produced by the load resistor forces us to put this element on the coldest cryogenic stage . * ac responsivity : * let us consider now an ac bias circuit as presented in fig . [ fig : acmod ] right . the voltage at the ends of bolometer is : @xmath33 if we assume that the ac bias frequency @xmath34 is much higher than the bolometer cut - off frequency ( @xmath35 ) , then we can consider only the average electrical power and a steady state responsivity and neglect short term variations . we can derive a modified zwerdling s formula for the responsivity by following the method used in the previous section for a dc biased bolometer : @xmath36 where @xmath37 the dynamic thermal conductance is equal to : @xmath38 here the @xmath39 factor is : @xmath40 where , if @xmath41 is a resistor : @xmath42 if we consider the module of the @xmath43 factor we can plot ( fig . [ fig : comp ] ) a responsivity versus bias current for dc and ac currents ( sine - shape ) bolometer . we can conclude that in terms of responsivity a dc electronics is preferable . for an ac bias the maximum in responsivity is lower and is obtained with higher bias current in the bolometer . we show in the next section that for slowly varying signals , ac bias has a decisive advantage in sensitivity . ) . for ac model we consider a sine wave bias with a stray capacitance of @xmath44 = 130 pf and plot the responsivity versus the r.m.s . value of the bias current . right : consistency of the ac model ( dashed curve ) with experimental measurements ( stars points ) taken from ground calibration of planck hfi . the disagreement is of the order of 1 % .,title="fig:",width=302 ] ) . for ac model we consider a sine wave bias with a stray capacitance of @xmath44 = 130 pf and plot the responsivity versus the r.m.s . value of the bias current . right : consistency of the ac model ( dashed curve ) with experimental measurements ( stars points ) taken from ground calibration of planck hfi . the disagreement is of the order of 1 % .,title="fig:",width=302 ] = 3 mm . right : total nep versus frequency for a dc and ac readout electronics at respective best bias currents.,title="fig:",width=302 ] = 3 mm . right : total nep versus frequency for a dc and ac readout electronics at respective best bias currents.,title="fig:",width=302 ] the noise equivalent power ( nep ) is : @xmath45 where @xmath46 is the power spectral density of the noise and @xmath47 is the responsivity of the detector . nep is measured in @xmath48 $ ] . in our model we take into account all the principal sources of noise in bolometric detection : johnson noise , phonon noise , photon noise , flicker noise and the preamplifier noise . the following is a review of the neps for the different sources of noise existing in literature ( see for instance @xcite ) : * johnson noise : * johnson noise is the electronic noise generated by the thermal agitation of electrons inside a bolometer at equilibrium . it has a white noise spectrum . the nep for dc biased bolometers is @xcite : @xmath49 where @xmath23 is the bolometer resistance and @xmath50 is its dynamic impedance . let us notice with mather @xcite that johnson noise does not depend on load impedance . let us assume here that it does not depend on stray capacitance in the case of ac biased bolometers . hereafter , we shall use eq . [ johnnoise ] indifferently with a dc model or an ac model . * phonon noise : * the parameters of the bolometer are strongly dependent on the temperature , so small variations in temperature inside the bolometer produce a voltage variation at the ends of the detector . it results @xcite : @xmath51 this result is independent of the readout electronics . * photon noise : * the photon noise comes from the fluctuations of the incident radiation due to the bose - einstein distribution of the photon emission . the nep is @xcite : @xmath52 where @xmath53 is the absorbed optical power per unit of frequency , @xmath54 is the coherence spacial factor ( equal to the inverse of the number of modes ; @xmath55 if diffraction limited ) and @xmath56 is the polarisation degree ( 0 non - polarised 1 polarised ) . this noise corresponds to the limitation in sensitivity of any instrument because it does not depends on performances of detectors and readout electronics . * flicker noise : * the flicker noise depends on a distribution of time constants due to the recombination and generation phenomena appearing in semiconductors . this noise shows a spectrum directly proportional to the bias current and inversly proportional to the frequency . to first order we have : @xmath57 the flicker noise is usually the dominant source of noise up to few hertz . in the case of ac electronics , we can choose the working modulation frequency in order to keep the flicker noise less then the photon noise ( see fig . [ fig : neps ] right ) . * preamplifier noise : * results from the impossibility to amplify a signal without adding noise , which is a consequence of the heisenberg uncertainty principle . it also depends on the available components and on the design of the amplifier . we assume that the power spectrum of signal fluctuation is constant and equal to : @xmath58\ ] ] the @xmath59 results from eq . [ nep ] as : @xmath60 the total nep of the instrument is : @xmath61^{1/2}\ ] ] fig . [ fig : neps ] ( left ) presents the influence of the different contributions to the total nep for an ac readout electronics . [ fig : neps ] ( right ) shows the advantage of using of an ac system instead of a dc solution at low frequencies . it is clear that flicker noise increases the dc total nep at low frequencies making the ac solution mandatory for the measurement of low and very low frequency signals ( less then few hertz ) . * optimization of the bias current :* from fig . [ fig : comp ] it is clear that in both cases ( ac and dc ) , the responsivity strongly depends on the bias current in the bolometer . the optimisation of this parameter is therefore a key point . we want to present a general result , not depending on the preamplifier noise level . since our practice and all the simulations ( see fig . [ fig : neps ] ) show that the minimum nep happens very near to the maximum responsivity ( to better than 1% in practical cases ) , we have chosen to use the responsivity to illustrate this point . the amplitude and the position of the peak responsivity are different for the two types of bias current . in the case presented in fig . [ fig : comp ] , the bias currents corresponding to the maximum of the responsivity are equal to @xmath62 = 0.12 na and @xmath63 = 0.22 na . we are now interested in establishing the performance of ac readout electronics biased with a sine wave . we will derive the responsivity , the nep and how the nep depends on the main parameters ( stray capacitance , modulation frequency , optical background and plate temperature ) for three typical bolometers optimized to observe the sky between 0.3 and 3 mm cooled to a temperature of 100 mk . in order to obtain an analytical solution to this problem , we developed a model in the frequency domain using the fourier formalism . the results could be also obtained in the case of a square ac model . the two methods are detailed in the appendices a and b. the first stage of preamplifiers for semiconductors bolometers are classically j - fets giving optimal performance at 100 k or more . rather long wiring is needed between the j - fets and the bolometer to avoid an excessive thermal load on the sub - kelvin stage supporting the bolometer . stray capacitance of tens and even hundreds of picofarads result from this design . in fig . [ fig : nepvscpsin ] , we plot for our three test bolometers the excess of nep versus the value of the stray capacitance . for a typical value of 150 pf , the nep excess is several percents ( from 4 % to 8 % ) . let us note here that the dc bias case is identical to an ac case without stray capacitance . as we have seen in previous section , the use of an ac bias has the advantage of presenting a noise spectrum flat down to very low frequencies , while dc biased readouts show a large 1/f component at frequencies less than about 10 hz . the modulation frequency of the electronics will be chosen therefore taking into account the requirement of keeping the flicker noise less then the johnson noise but also taking into account the scanning strategy of the instrument and the angular responsivity of the optics . in the case of planck hfi for example @xcite the full width at half maximum @xmath64 ranges from 5 to 9 arcmin and the scanning speed is 6 degrees per second . so , in the limit of small angles , the maximum frequency of interest is given by the relation : @xmath65 where @xmath66 is the frequency of the optical modulation . in fig . [ fig : nepvsfmodsin ] we consider the excess nep with respect to a 85 hz modulation frequency . in the worst case the excess nep is 0.5 % per hertz . the background strongly affects the static performance of a bolometer by changing the operating point . with respect to others parameters , the background is the most uncertain and variable parameter during an observational campaign . a good understanding of the effect of the optical background on the static performances of a bolometers is therefore a key point during the calibration of the instrument . in fig . [ fig : nepvswopthfi ] we present the relative variation of the total nep versus the nominal background for our test bolometers . for the 3 mm bolometer , the nominal background is 0.3 pw ; for 1 mm 0.6 pw and for 0.3 mm 3.6 pw . in the worst case the degradation in nep is 2 % with respect the nominal background for a background increase of + 16.5 % . following the first order thermal model of a bolometer ( eq . [ bolo ] ) , we know that a change in temperature of the plate corresponds exactly to a change of background power on the bolometer . in this case the equivalent power generated from a change of the plate temperature is : @xmath67 our test bolometers were designed for a plate temperture of 100 mk . the nep variation in the range 95 mk 105 mk is reported in fig . [ fig : nepvst0hfi ] . we find that a change of the plate temperature of 1 mk gives a change in nep of 0.8 % in the worst case . we want now to compare the performances , in terms of responsivity and nep , of a sine - wave and a square - wave ac electronics . the results are shown in fig . [ fig : nepcomp ] . the sine case is better for both responsivity and nep . this is more obvious for the responsivity ( better by about 10 % ) than for the total nep ( better by about 4 % ) . we conclude that in terms of nep , a bolometer connected to a sine ac biased readout electronics would be more sensitive . let us remark that the difference in nep is modest . let us also notice that an ac sine bias would induce significant variations in the temperature of the fastest bolometers , bringing them into the non - linear regime . on the contrary , the square bias deposits a nearly constant power in the bolometers , that deviate from their mean temperature only by small amounts . .__parameters of the test bolometers used to illustrate the results of the analytical model . _ _ [ cols="<,^,^,^,^,^,^",options="header " , ] the analytical model presented in this paper has been developed for the hfi on board planck satellite . it allowed us to predict the responsivity and the noise of semi - conductor bolometers cooled at 100 mk and biased by ac currents in a realistic environment . it sheds some light on the differences between ac and dc biased bolometer and on the different optimal bias currents for these two cases . three test bolometers rather similar to planck s ones were used to illustrate our results . our main conclusions are : * the ac responsivity is always lower than the dc responsivity . this is due to a more effective electro - thermal feedback . the resulting excess of nep depends on the relative part of the preamplifier noise in the total nep . in our test cases the excess nep ranges from 4 % to 10 % , which is more than compensated for by shifting of the low frequency noises out of the range of useful frequencies . frequencies down to 1 mhz are measurable with a well designed ac readout electronics . * the ac bias rms current providing to the maximum of the responsivity is about twice larger than that obtained for a dc bias . this concerns the current through the bolometer and results from the different electro - thermal feedback . * for a stray capacitance of @xmath68 150 pf we obtain an excess nep of 10 % in the worst case ( 3 mm bolometer ) and 4% in the best case ( 0.3 mm bolometer ) . * around a modulation frequency of 90 hz , the excess nep ranges between 0.2 % and 0.5 % per hz . * the sensitivity of nep to background is dlog(nep)/dlog(wbg ) = 0.22 to 0.42 * the sensitivity of nep to the plate temperature is dlog(nep)/dlog(tplate ) = 0.3 to 0.8 around 100 mk , but is rather non - linear . * the performances of a sine bias are better than the square bias . in our test cases , this result is more obvious in the responsivity ( better by about 10 % ) than in the total nep ( better by about 4 % ) . but non - linear effects may show up in the sine case for bolometers fast enough to respond to the modulation frequency . let us consider the bias circuit of fig . [ fig : acmod ] with a stray capacitance in parallel to the bolometer and a load capacitance in series . the value of the load capacitance is fixed to @xmath69 which is the typical value in hfi . let s also consider a range of temperatures starting from the temperature of the plate ( 100mk for example ) up to an arbitrary value . for each temperature we can calculate the impedance @xmath23 of the bolometer and its total power using eqs . [ bolo ] and [ resi ] . in this simulation we assume that the parameters of the bolometers ( @xmath13 , @xmath12 , @xmath70 , etc ...... ) are those of hfi . if the optical background is constant in this run of simulations , the dissipated electrical power in the bolometer is : @xmath71 so , the r.m.s . voltage at the ends of the bolometer is : @xmath72 and the r.m.s . bias current passing through the bolometer is : @xmath73 in general for a quadripole we have : @xmath74 where @xmath75 indicate the fourier transform and @xmath76 is the transfer function of the quadripole . using the quadripole obtained from eq . [ aceq ] , the module of the transfer function is : @xmath77 so , the r.m.s . input voltage is : @xmath78 in order to calculate the optical responsivity let us consider a small step in temperature for each bolometer . if we keep @xmath24 unchanged , the step in temperature is due to a change of the optical background that can be computed : @xmath79 where @xmath80 is calculated from the new temperature @xmath81 and @xmath82 is derived from : @xmath83 @xmath84 is equal to : @xmath85 assuming that @xmath24 is not varying , and using the @xmath86 calculated from @xmath87 the responsivity will be : @xmath88 with the responsivity and nep equations from the previous section , it is possible to calculate the total nep with the same bias circuit ( fig . [ fig : acmod ] ) , it is possible to derive the performances of a reu in which a square wave voltage applied to the bolometer , as in hfi . let us assume that if the reu is _ balanced _ , a perfect square wave bias is passing through the bolometer even in presence of a stray capacitance . in hfi this is achieved by using a triangular wave plus a square wave . if the temperature of the bolometer is given and the optical power is constant we can calculate the r.m.s . @xmath91 as we did for the sine bias case ( eq . [ veff ] and eq . [ wele ] ) so we have : @xmath93 the r.m.s . bias current passing through the bolometer is : @xmath73 on the other hand we can not derive the electrical power following the same logic : if we keep the same set up of the reu , after a small step in temperature the bias passing through the bolometer is not a square wave anymore so , the eq . [ hfivb ] is not applicable . we have to correct each term of the sum as follows : @xmath94 where @xmath95 j. j. a. bock , philip , l. armus , j. bally , d. benford , a. cooray , m. devlin , s. dodelson , d. dowell , p. goldsmith , s. golwala , s. hanany , m. harwit , w. holland , w. holzapfel , kenyon , matt , k. irwin , e. komatsu , a. e. lange , d. leisawitz , a. lee , b. mason , j. mather , h. moseley , s. meyer , s. myers , h. nguyen , v. novosad , b. sadoulet , g. stacey , s. staggs , p. richards , g. wilson , m. yun , and j. zmuidzinas , `` superconducting detector arrays for far - infrared to mm - wave astrophysics , '' in `` astro2010 : the astronomy and astrophysics decadal survey , '' , vol . 2010 of _ arxiv astrophysics e - prints _ ( 2009 ) , pp . 45+ . m. devlin , a. e. lange , t. wilbanks , and s. sato , `` a dc - coupled , high sensitivity bolometric detector system for the infrared telescope in space , '' ieee transactions on nuclear science * 40 * , 162165 ( 1993 ) . s. gaertner , a. benot , j .- lamarre , m. giard , j. bret , j. chabaud , f. dsert , j. faure , g. jegoudez , j. land , j. leblanc , j. lepeltier , j. narbonne , m. piat , r. pons , g. serra , and g. simiand , `` a new readout system for bolometers with improved low frequency stability , '' * 126 * , 151160 ( 1997 ) . e. kreysa , f. bertoldi , h. gemuend , k. m. menten , d. muders , l. a. reichertz , p. schilke , r. chini , r. lemke , t. may , h. meyer , and v. zakosarenko , `` laboca : a first generation bolometer camera for apex , '' in `` society of photo - optical instrumentation engineers ( spie ) conference series , '' , vol . 4855 of _ society of photo - optical instrumentation engineers ( spie ) conference series _ , t. g. phillips & j. zmuidzinas , ed . ( 2003 ) , vol . 4855 of _ society of photo - optical instrumentation engineers ( spie ) conference series _ , pp . 4148 . m. piat , j .- torre , e. brelle , a. coulais , a. woodcraft , w. holmes , and r. sudiwala , `` modeling of planck - high frequency instrument bolometers using non - linear effects in the thermometers , '' nuclear instruments and methods in physics research a * 559 * , 588590 ( 2006 ) .

bolometers are most often biased by alternative current ( ac ) in order to get rid of low frequency noises that plague direct current ( dc ) amplification systems . when stray capacitance is present , the responsivity of the bolometer differs significantly from the expectations of the classical theories . we develop an analytical model which facilitates the optimization of the ac readout electronics design and tuning . this model is applied to cases not far from the bolometers in the planck space mission . we study how the responsivity and the nep ( noise equivalent power ) of an ac biased bolometer depend on the essential parameters : bias current , heat sink temperature and background power , modulation frequency of the bias , and stray capacitance . we show that the optimal ac bias current in the bolometer is significantly different from that of the dc case as soon as a stray capacitance is present due to the difference in the electro - thermal feedback . we also compare the performance of square and sine bias currents and show a slight theoretical advantage for the last one . this work resulted from the need to be able to predict the real behaviour of ac biased bolometers in an extended range of working parameters . it proved to be applicable to optimize the tuning of the planck high frequency instrument ( hfi ) bolometers .

After Praying for Years to Have a Son, Mother Loses 22-Month-Old Toddler to Drowning in Church Baptistery Email Whatsapp Menu Whatsapp Google Reddit Digg Stumbleupon Linkedin A mother of two daughters, who had been praying to God asking Him to also give her a son, had her prayer answered 22 months ago when she gave birth to a baby boy, who she named Brayden King. Her joy, however, turned to mourning on Friday, when the Brayden drowned in her church's baptistery. Bishop TD Strong, pastor of the Pentecostal House of Prayer in Decatur, Alabama, told al.com that little Brayden was a "prayer baby" because his mother, Kim King, had prayed for many years to have him. "Twenty-two months ago He gave her a son," said Strong. "And 22 months later he was taken away. I've been preaching 30 years and pastoring for 20 years, this is the first time in my ministry I've been speechless." According to the report, Brayden was at the church with his mother and 13-year-old sister on Friday as the women of the church prepared for a missionary prayer meeting. The boy's mother had the role of narrator in a skit for the prayer meeting so she left the boy in the care of his sister. The teen lost track of her brother and after a search he was found unresponsive in the rectangular water tank in the baptistery. According to al.com, although the tank faces the congregation, it is obscured by an altar wall. "I'm just at a loss, because it is so close to home," said Strong, who noted how close he is to the family. "People die every day. And I've done many funerals, but for a child to die in church, in the baptistery, it's beyond ordinary and something that will never be forgotten by me." On Sunday, Strong tried being positive to his reeling congregation, according to a follow-up al.com report. "Rejoice in the Lord always. I will say it again: Rejoice!" he preached to his congregation while standing just a few yards from the baptistery where little Brayden died. "I don't know that I want to go to that pool for a while," said Strong after the service. He explained that he planned to do baptisms at another church. "I don't know how long it will take to heal." Strong said they are still trying to piece together what happened but he has not pressed the family for details. "A lot of this stuff we deal with is not good, but the Bible says it's for good," Strong said in his sermon. "You won't handle those problems with your emotions. God is not moved by emotions. God is moved by a relationship," he said. ||||| A toddler found submerged in a tank of baptismal water in an Alabama church died of accidental drowning, the local coroner said on Monday. Brayden King, who was two months shy of his second birthday, was under the supervision of a sister in her early teens when he fell into the tank on Friday at the Pentecostal House of Prayer in Decatur, about 75 miles north of Birmingham, said Morgan County Coroner Jeffrey Chunn. The toddler was found in 33 inches of water and declared dead after unsuccessful attempts to resuscitate him, Chunn said. The child's mother, who has two teenage daughters, had prayed for years for a son, the Huntsville Times newspaper quoted church pastor Bishop TD Strong as saying over the weekend. "Twenty-two months ago he gave her a son," Strong said, according to the newspaper. "And 22 months later he was taken away. I've been preaching 30 years and pastoring for 20 years, this is the first time in my ministry I've been speechless." Strong could not immediately be reached for comment. (Reporting by Jonathan Kaminsky in New Orleans; Editing by Sandra Maler)

– A mother in Decatur, Ala., says her prayers were answered when, after years of trying, she had a baby boy nearly two years ago. But tragedy struck when Brayden King was left in the care of his teen sister at church on Friday: She lost track of him for a short while, and he was found dead in 33 inches of water in the church's baptismal tank, reports Reuters. Brayden was 22 months old. "I've been preaching 30 years, this is the first time in my ministry I've been speechless," the pastor of the Pentecostal House of Prayer tells AL.com. "I know [God] is too wise to make mistakes, but in my humanity, I can't lie. I've had to get on my knees." He plans to do baptisms at another church for the time being, adds the Christian Post. "I don't know how long it will take to heal." An autopsy will likely be performed in the next few days. (Earlier this summer, a 2-year-old nearly drowned—hours after swimming in a pool.)

SECTION 1. SHORT TITLE. This Act may be cited as the ``Investors Rights and Corporate Accountability Act of 2009''. SEC. 2. FIDUCIARY STANDARD FOR BROKER-DEALERS. Section 15 of the Securities Exchange Act of 1934 (15 U.S.C. 78o) is amended-- (1) by redesignating subsection (i), as added by section 303(f) of the Commodity Futures Modernization Act of 2000 (114 Stat. 2763A-455), and as enacted into law by section 1(a)(5) of Public Law 106-554, as subsection (j); and (2) by adding at the end the following: ``(k) Standard of Care.--Notwithstanding any other provision of this title or the Investment Advisers Act of 1940 (15 U.S.C. 80b-1 et seq.), the Commission shall promulgate rules, not later than 1 year after the date of enactment of this subsection, to provide that the standard of care for all brokers and dealers in providing investment advice to retail customers or clients (and any other customers or clients as the Commission may by rule provide) shall be the fiduciary duty established under the Investment Advisers Act of 1940 (15 U.S.C. 80b-1 et seq.), including the duty to act solely in the best interest of the customer or client, without regard to the financial or other interest of the broker or dealer providing the advice.''. SEC. 3. CLAWBACK OF INCENTIVE COMPENSATION AND BONUSES. (a) Securities Exchange Act of 1934.--Section 21D(f)(2)(A) of the Securities Exchange Act of 1934 (15 U.S.C. 78u-4(f)(2)(A)) is amended-- (1) by striking ``Joint and several liability.--Any'' and inserting the following: ``Knowing violations.-- ``(i) Joint and several liability.--Any''; and (2) by adding at the end the following: ``(ii) Incentive compensation and bonuses.--If the trier of fact specifically determines that a covered person knowingly committed a violation of the securities laws, the covered person shall be ordered to reimburse an issuer for-- ``(I) any bonus or other incentive- based or equity-based compensation received by the covered person from the issuer during the period of the violation of the securities laws; and ``(II) any profits realized by the covered person from the sale of securities of the issuer during the period of the violation of the securities laws.''. (b) Sarbanes-Oxley Act of 2002.--Section 304 of the Sarbanes-Oxley Act of 2002 (15 U.S.C. 7243) is amended-- (1) in subsection (a)-- (A) in the matter preceding paragraph (1), by striking ``, as a result of misconduct,''; (B) in paragraph (1), by striking ``or filing with the Commission (whichever first occurs)''; and (C) in paragraph (2), by striking ``during that 12- month period''; and (2) by adding at the end the following: ``(c) Commencement of Action.--A shareholder of an issuer may commence an action on behalf of the issuer under this section if the chief executive officer or the chief financial officer of the issuer has not made a reimbursement required under this section before the expiration of the 90-day period beginning on the date on which the accounting restatement occurs.''. SEC. 4. PROTECTING THE CONFIDENTIALITY OF WHISTLEBLOWERS. Section 21D(b)(2) of the Securities Exchange Act of 1934 (15 U.S.C. 78u-4(b)(2)) is amended-- (1) by striking ``In any private action'' and inserting the following: ``(A) In general.--In any private action''; and (2) by adding at the end the following: ``(B) Confidential sources.-- ``(i) In general.--Allegations by a confidential source shall be considered to give rise to a strong inference that the defendant acted with the required state of mind, if the source is described in the complaint with sufficient particularity to support the probability that a person in the situation of the source would possess the information alleged. ``(ii) Considerations.--The weight accorded allegations by a confidential source shall depend on the level of detail provided by the source, the corroborative nature of the other facts alleged (including from other sources), the coherence and plausibility of the allegations, the number of sources, the reliability of the sources, and similar indicia. ``(iii) Protection.--A confidential source described in a complaint shall be accorded the same protection received by a confidential source who provides comparable information to the Commission. ``(iv) Nondisclosure requirements.--Upon motion, a court shall enter an order reasonably limiting the scope of nondisclosure required by a post-employment agreement. An order under this clause may not impair a legitimate interest of a former employer in the confidentiality of documents and information subject to the order.''. SEC. 5. PROHIBITION ON CERTAIN VOTING BY BROKERS. Section 6(b) of the Securities Exchange Act of 1934 (15 U.S.C. 78f(b)) is amended by adding at the end the following: ``(10) The rules of the exchange prohibit any member from granting any proxy to vote any security in connection with an election for membership to the board of directors or analogous governing body of any issuer of a listed security, in the absence of instructions from the beneficial owner of the security regarding the specific election.''. SEC. 6. INDEPENDENCE OF COMPENSATION ADVISERS. Section 16 of the Securities Exchange Act of 1934 (15 U.S.C. 78p) is amended by adding at the end the following: ``(h) Independent Compensation Advisers.--Not later than 1 year after the date of enactment of this subsection, the Commission shall, by rule-- ``(1) require any adviser retained by the board of directors or a committee of the board of directors of an issuer in conjunction with the negotiation of an employment contract or a compensation agreement with an executive of the issuer-- ``(A) to be independent of the issuer and the executives and directors of the issuer; and ``(B) to report solely to the board of directors or the committee of the board of directors responsible for executive compensation; and ``(2) prohibit an issuer from agreeing to indemnify or limit the liability of an adviser described in paragraph (1).''. SEC. 7. AIDING AND ABETTING LIABILITY. (a) Securities Exchange Act of 1934.--Section 21D of the Securities Exchange Act of 1934 (15 U.S.C. 78u-4) is amended by adding at the end the following: ``(g) Persons That Aid or Abet Violations.--Any person that provides substantial assistance to another person, with reckless disregard for whether the substantial assistance is in violation of this title, or of any rule or regulation issued under this title, shall be liable in a private action brought under this title, to the same extent as the person to whom the substantial assistance is provided.''. (b) Investment Advisers Act.--Section 209 of the Investment Advisers Act of 1940 (15 U.S.C. 80b-9) is amended by adding at the end the following: ``(f) Aiding and Abetting.--For purposes of any action brought by the Commission under subsection (e), any person that provides substantial assistance to another person, with reckless disregard for whether the substantial assistance is in violation of this Act, or of any rule, regulation, or order issued under this Act, shall be liable, to the same extent as the person to whom the substantial assistance is provided.''. SEC. 8. SHAREHOLDER APPROVAL OF GOLDEN PARACHUTE COMPENSATION. Section 16 of the Securities Exchange Act of 1934 (15 U.S.C. 78p), as amended by this Act, is amended by adding at the end the following: ``(i) Severance Agreements Tied to Performance.-- ``(1) Commission rules.-- ``(A) In general.--Not later than 270 days after the date of enactment of this subsection, the Commission shall, by rule, direct the national securities exchanges and national securities associations to prohibit the listing of any security of an issuer that is not in compliance with the requirements of any portion of paragraph (2). ``(B) Opportunity to cure.--The rules issued under subparagraph (A) shall provide for appropriate procedures for an issuer to have an opportunity to cure any defects that would be the basis for such a prohibition before the imposition of such prohibition. ``(C) Considerations.--The rules issued under subparagraph (A) shall be implemented with due regard for contracts in existence on the date of enactment of this subsection. ``(2) Severance agreements tied to performance.--The board of directors of an issuer, or a committee of such board of directors, may not enter into an agreement providing for severance payments to a senior executive officer who is terminated because of poor performance as an executive, as determined by the board of directors. To the extent that an issuer is able to terminate a senior executive officer for cause, poor performance by the executive, as determined by the board of directors, shall be considered as one such cause.''.

Investors Rights and Corporate Accountability Act of 2009 - Amends the Securities Exchange Act of 1934 (SEA) to direct the Securities and Exchange Commission (SEC) to apply to all brokers and dealers who provide investment advice to retail clients the fiduciary duty established under the Investment Advisers Act of 1940, including the duty to act solely in the best interest of the customer or client, without regard to the financial or other interest of the broker or dealer providing the advice. Requires the trier of fact to order any person who knowingly violated securities laws to reimburse an issuer (clawback) for: (1) any bonus or other incentive-based or equity-based compensation received from the issuer during the period of the violation; and (2) any profits realized by such person from the sale of securities of the issuer during the period of the violation. Amends the Sarbanes-Oxley Act of 2002 (SOX), with respect to forfeiture of certain bonuses and profits, to authorize a shareholder of an issuer to commence an action on behalf of the issuer if the chief executive officer or the chief financial officer of the issuer has not made the requisite reimbursement (for material noncompliance with any financial reporting requirement) within 90 days after an accounting restatement occurs. Amends the SEA to prescribe requirements for treating the allegations of a confidential source, in a securities fraud action, as giving rise to a strong inference that a defendant acted with the required state of mind. Prohibits specified proxy voting practices by brokers in connection with elections for membership to the board of an issuer's governing body in the absence of instructions from the security's beneficial owner regarding the specific election. Instructs the SEC to promulgate rules: (1) requiring the independence of any adviser retained by the board of directors of an issuer to advise on an executive employment contract or compensation agreement; (2) requiring such adviser to report solely to the board of directors responsible for executive compensation; and (3) prohibiting an issuer from agreeing to indemnify or limit the liability of an adviser. Amends the SEA and the Investment Advisers Act of 1940 to subject to liability for aiding and abetting any person that provides substantial assistance to another person with reckless disregard for whether the substantial assistance is in violation of either Act. Instructs the SEC to direct the national securities exchanges and national securities associations to prohibit listing any security of an issuer that is not in compliance with prohibitions against severance payments to a senior executive officer who is terminated for poor performance (golden parachute).

80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Candles burn next to a lighted tree at a makeshift shrine in Newtown, Connecticut, commemorating the victims of the mass shooting at Sandy Hook Elementary School on December 14, 2012. Hide Caption 1 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Erica Simmons rings the campus bell at Agnes Scott College in Decatur, Georgia, during a nationwide commemoration December 21, marking a week since the Newtown, Connecticut, mass shooting. Church bells rang out across the country at 9:30 ET Friday to remember those who died in the gun rampage. Hide Caption 2 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman pauses at a streetside memorial during a moment of silence on December 21 in Newtown. Hide Caption 3 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Connecticut State Police block the road to Sandy Hook Elementary School during a moment of silence on December 21. A week ago, a gunman forced his way into the school and shot and killed 26 people, including 20 children. Hide Caption 4 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman bows her head in Newtown's Sandy Hook village on December 21. Hide Caption 5 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People observe a moment of silence for the school shooting victims at the Blue Colony Diner in Newtown on December 21. Hide Caption 6 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Children in Newtown, excluding Sandy Hook Elementary, return to classes on Tuesday, December 18, four days after the shooting at the elementary school. Hide Caption 7 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – U.S. Rep. David Cicilline, D-Rhode Island, holds a news conference with the Brady Campaign to discuss gun violence. In attendance with the Brady Campaign were several survivors of gun violence and family members of victims of gun violence. Hide Caption 8 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Members of the human rights group Volunteers Against Crime and Corruption light candles showing the names of those killed during the shooting at Sandy Hook Elementary School, during a prayer vigil in front of the U.S. Embassy in Manila, Philippines on December 18. Hide Caption 9 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Children light candles to pay their respects to the victims of the Newtown, Connecticut, shooting at the main square in Tirana, Albania, on Monday, December 17. The deadly gun rampage at Sandy Hook Elementary School has provoked strong reactions from around the world. Hide Caption 10 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Protesters march on the National Rifle Association's Capitol Hill lobbyist offices in Washington on December 17. Hide Caption 11 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – New York Mayor Michael Bloomberg speaks out for stronger gun control at a press conference at City Hall on December 17. Bloomberg, co-chair of Mayors Against Illegal Guns, was joined by victims and survivors of gun violence. Hide Caption 12 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Chris Foye, whose son Chris Owens was killed by a stray bullet in 2009, stands with other survivors and family members of gun violence at Bloomberg's press conference on December 17 in New York. Hide Caption 13 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People pay their respects on December 17 at a makeshift shrine in Newtown to the victims of Friday's elementary school shooting. Funerals began Monday in the Connecticut town. Hide Caption 14 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Traders on the floor of the New York Stock Exchange hold a moment of silence on December 17 in honor of the shooting victims. Hide Caption 15 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Young people mourn at Newtown High School before a memorial service attended by President Obama on Sunday, December 16. Hide Caption 16 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – President Barack Obama waits to speak at an interfaith vigil for the shooting victims from Sandy Hook Elementary School December 16 at Newtown High School. Hide Caption 17 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Mourners comfort one another December 16 before U.S. President Barack Obama speaks at an interfaith vigil for the shooting victims. Hide Caption 18 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Two women embrace before the interfaith vigil at Newtown High School on Sunday evening. Hide Caption 19 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – From left: Newtown residents Claire Swanson, Kate Suba, Jaden Albrecht, Simran Chand and New London, Connecticut, residents Rachel Pullen and her son, Landon DeCecco, hold candles at a memorial for victims on Sunday, December 16, in Newtown, Connecticut. Hide Caption 20 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A young boy walks past Christmas trees set up at a makeshift shrine to the shooting victims in Newtown, Connecticut, on December 16. Hide Caption 21 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Ty Diaz is kissed by his mother, Yvette, at a memorial down the street from Sandy Hook on December 16. Hide Caption 22 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Teddy bears, flowers and candles in memory of those killed are left at a memorial down the street from the school on December 16. Hide Caption 23 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Two teenagers embrace at a makeshift shrine to the victims in Newtown on December 16. Hide Caption 24 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Nuns pay their respects at a makeshift shrine to the victims on December 16. Hide Caption 25 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Members of Sisters of Christian Charity go to lay flowers in front of the Sandy Hook Elementary School on December 16 in Newtown. Hide Caption 26 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman receives a hug as she leaves morning service December 16 at Trinity Church in Newtown near the elementary school. Hide Caption 27 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Parishioners pay their respects to the victims of the elementary school shooting while attending Mass at St. Rose of Lima Roman Catholic Church in Newtown on December 16. Hide Caption 28 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Police officers honor the victims of the school shooting at the St. Rose of Lima Roman Catholic Church on December 16 in Newtown. Hide Caption 29 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – The Jacksonville Jaguars have a moment of silence in honor of the Sandy Hook Elementary School shooting victims before their game against the Miami Dolphins on December 16. Hide Caption 30 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A parishioner kneels in front of a makeshift memorial at St. Rose of Lima Roman Catholic Church in Newtown on December 16. Hide Caption 31 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A police officer removes flowers from a busy intersection on December 16 in Newtown. Police said they were afraid the memorial, left for the victims of the Sandy Hook Elementary School shooting, would cause a traffic hazard. Hide Caption 32 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman hugs her daughter on the steps of Trinity Church on December 16 in Newtown. Hide Caption 33 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Angel wood cutouts for each of the 27 victims are set up on hillside in Newtown on December 16. Hide Caption 34 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People in Bangalore, India, hold cards and photographs of the slain at a candlelight vigil outside a Catholic church on December 16. Hide Caption 35 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – J.J. Watt of the Houston Texans shows his glove in remembrance of the victims before the start of a game against the Indianapolis Colts on December 16 in Houston. Hide Caption 36 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Donna Soto, right, mother of Victoria Soto, the first-grade teacher at Sandy Hook Elementary School who was shot and killed while protecting her students, hugs her daughter Karly while mourning their loss at a candlelight memorial at Stratford High School on Saturday, December 15, in Stratford, Connecticut. Hide Caption 37 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Firefighters kneel to pay their respects at a makeshift memorial near the school in Newtown on Saturday. Hide Caption 38 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A child lights a candle at a memorial filled with flowers, stuffed toys and candles outside of Saint Rose of Lima Church near Sandy Hook Elementary School in Newtown, Connecticut on Saturday. Hide Caption 39 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Candles light up a memorial outside of Saint Rose of Lima Church in Newtown. Hide Caption 40 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Lucas, Kelly and Michael DaSilva pray and embrace at a makeshift memorial near the school in Newtown. Hide Caption 41 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People are overcome with emotion Saturday at a makeshift memorial near Sandy Hook Elementary School in Newtown. Hide Caption 42 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Residents arrive Saturday to pay tribute to the victims of an elementary school shooting in Newtown, Connecticut. Hide Caption 43 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A couple carry balloons to place at a curbside shrine to in Newtown on Saturday. Hide Caption 44 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A mother and daughter attend a prayer service at St. John's Episcopal Church in Newtown on Saturday. Hide Caption 45 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Flowers and signs of sympathy adorn the street leading to Sandy Hook Elementary School. Hide Caption 46 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Claudia Urbiana and daughter Jocelyne Cardenas, left, hug outside of the entrance to the Sandy Hook school. Hide Caption 47 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A makeshift memorial with flowers, stuffed toys and candles sit outside Saint Rose of Lima Roman Catholic Church in Newtown, Connecticut, on Saturday. Hide Caption 48 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A man bows his head as he stands at a makeshift memorial, outside Saint Rose of Lima Roman Catholic Church in Newtown on Saturday, December 15. Hide Caption 49 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – New Jersey resident Steve Wruble, who was moved to drive out to Connecticut to support local residents, grieves for victims at the entrance to Sandy Hook village in Newtown on Saturday. Hide Caption 50 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People attend a prayer service in Newtown on Saturday to reflect. Hide Caption 51 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A mother hugs her children after paying tribute to the victims in Newtown on Saturday, December 15. Hide Caption 52 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Newtown High School student Trevor Lopez stands outside of a church where residents have come to pray and reflect on Saturday Hide Caption 53 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Andrea Jaeger places flowers and a candle at a makeshift memorial outside a firehouse near Sandy Hook Elementary School on Saturday. Hide Caption 54 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – The U.S. flag flies at half-staff above the White House on Saturday. Hide Caption 55 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Ken Kowalsky and his daughter Rebecca, 13, embrace while standing at the end of the road leading to Sandy Hook Elementary School on Saturday. Hide Caption 56 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman puts a flower near crosses planted by Rio de Paz (Rio of Peace), in memory of the victims of the Sandy Hook Elementary school shooting on Copacabana beach in Rio de Janeiro on Saturday. Hide Caption 57 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman sits during a service at the Asylum Hill Congregational Church in Hartford, Connecticut on Friday, December 14. Hide Caption 58 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Fans at the NBA game between the Utah Jazz and the Phoenix Suns participate in a moment of silence for the victims of the Newtown shooting on Friday in Phoenix. Hide Caption 59 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – An overflow crowd listens to a church service held at the St. Rose of Lima Catholic Church in Newtown on December 14. Hide Caption 60 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather for a prayer vigil at St. Rose Church on Friday. Hide Caption 61 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather for a vigil outside the White House in Washington following the Connecticut elementary school shooting on Friday. Hide Caption 62 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Candles burn as people gather for a vigil outside the White House. Hide Caption 63 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Hartford, Connecticut, Mayor Padro Segarra speaks emotionally about the students and teachers who died earlier in the day at Sandy Hook Elementary School in nearby Newtown at a candlelight vigil at Bushnell Park in Hartford on Friday. Hide Caption 64 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Cynthia Alvarez is comforted by her mother, Lilia, as people gather for a prayer vigil at St. Rose of Lima Roman Catholic Church in Newtown. Hide Caption 65 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather for a prayer vigil at St. Rose Church in Newtown. Hide Caption 66 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather for a prayer vigil at St. Rose Church. Hide Caption 67 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather inside the St. Rose Church to remember the shooting victims on Friday Hide Caption 68 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman bows her head during a vigil for the shooting victims at St. Rose Church. Hide Caption 69 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather in the St. Rose Church for a memorial service Friday. Hide Caption 70 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Women comfort each other during the vigil at St. Rose Church. Hide Caption 71 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A woman looks on during the vigil at St. Rose Church. Hide Caption 72 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People hug outside of the Newtown United Methodist Church on Friday, near the site of the shootings at the Sandy Hook school. Hide Caption 73 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – A flag at the U.S. Capitol flies at half-staff after President Barack Obama ordered the action while speaking from the White House. Obama called for "meaningful action" in the wake of the school shooting. Hide Caption 74 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Julie Henson of San Francisco joins other people outside the White House to participate in a candlelight vigil on Friday. Hide Caption 75 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Obama wipes tears as he makes a statement in response to the shooting on Friday. Hide Caption 76 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Washington resident Rachel Perrone, left, and her 5-year-old son, Joe, center, join others outside the White House in a candlelight vigil. Hide Caption 77 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – Faisal Ali, right, of Colorado Springs, Colorado, joins the vigil outside the White House. Hide Caption 78 of 80 80 photos: Reaction to Newtown school killings Reaction to Newtown school killings – People gather outside the White House to participate in a candlelight vigil. Hide Caption 79 of 80 ||||| A Connecticut judge on Tuesday ordered the release of the 911 recordings from the Sandy Hook Elementary School shooting, but the tapes will not be immediately unsealed. The state's Freedom of Information Commission ruled in September that the recordings should be provided to The Associated Press, but State's Attorney Stephen Sedensky III asked for a stay while he appeals that order. Sedensky has argued the release of the tapes could cause anguish for victims' families. New Britain Superior Court Judge Eliot Prescott denied his request Tuesday, but the tapes remain sealed until Dec. 4 to give the prosecutor a chance to appeal. Sedensky said he is reviewing the judge's decision to determine what action he might now take. "The court recognizes and is deeply sensitive to the fact that the families and friends of those who died in this tragedy, as well as others in the greater Newtown community, may desire that the 911 audio recordings never be released," the judge wrote. "The public airing by the media of some or all of the recordings that will undoubtedly follow their release will likely be a searing reminder of the horror and pain of that awful day." But the judge said the recordings are public, and he rejected arguments for keeping them sealed. He said that the release will help the public gauge the appropriateness of law enforcement's response. "In fact, public analysis of the recordings may serve to vindicate and support the professionalism and bravery of the first responders ... who themselves have undoubtedly been subject to emotional turmoil and pain in witnessing the scene at Sandy Hook Elementary School," Prescott wrote. "Delaying the release of the audio recordings, particularly where the legal justification to keep them confidential is lacking, only serves to fuel speculation about and undermine confidence in our law enforcement officials." The AP has sought the recordings in part to examine the police response to the massacre, which left 20 first-graders and six educators dead. If the recordings are released, the AP would review the content and determine what, if any, of it would meet the news cooperative's standards for publication.

– The 911 calls made during the Sandy Hook shooting will be unsealed next Wednesday, unless an appeal of the ruling proves successful. A Connecticut judge yesterday ordered their release, backing a Connecticut Freedom of Information Commission move despite opposition from state attorney Stephen Sedensky. The AP reports that it has been trying to obtain the recordings in part to examine the police response to the massacre. The judge said the recordings are public, and he rejected arguments for keeping them sealed, saying that the release will help the public gauge the appropriateness of law enforcement's response. He pointed out that their release could "vindicate and support the professionalism and bravery of the first responders." Now, "the plaintiff and Newtown respondents [have] a short period of time to attempt to obtain appellate relief from this decision," the judge said, per CNN. If the recordings are released, the AP says it would review the content and determine what, if any, of it would meet its standards for publication.

the calculations of the integral entering eq . ( [ kk ] ) are different for even @xmath4 ( integer @xmath73 ) and odd @xmath4 ( half - integer @xmath73 ) . let us begin with even @xmath4 . one makes use of the relation @xmath74 and obtains @xmath75 hence , the green s function is concentrated on the five - dimensional light cone @xmath76 . plugging this expression into eq . ( [ kk ] ) and then eq . ( [ 4 * ] ) one finds that the induced field on the brane is given by the following integral @xmath77 where @xmath78 and @xmath79 we further simplify this integral by making use of the identity @xmath80 which holds for arbitrary function @xmath81 . ( [ intega ] ) takes the form @xmath82 where subleading in @xmath83 terms have been omitted . now it is straightforward to perform the integration with the result @xmath84 where @xmath85 at @xmath61 eq . ( [ s5 * ] ) reduces to eq . ( [ 9 .. ] ) . let us now evaluate the integral entering eq . ( [ summode ] ) at odd @xmath4 ( half - integer @xmath73 ) . we make use of the relation @xmath86 then @xmath87 this expression is again plugged into eq . ( [ kk ] ) and then eq . ( [ 4 * ] ) . the integration over @xmath88 is performed by making use of the trick ( [ 7 * ] ) , and we find @xmath89 where @xmath90 at @xmath60 the integral ( [ last ] ) can be evaluated explicitly , and one obtains eq . ( [ 9 . ] ) . 99 l. b. okun and ya . b. zeldovich , phys . * b78 * ( 1978 ) 597 . m. b. voloshin and l. b. okun , pisma zhetf * 28 * ( 1978 ) 156 . a. y. ignatev , v. a. kuzmin and m. e. shaposhnikov , phys . lett . * b84 * ( 1979 ) 315 . a. y. ignatev , v. a. kuzmin and m. e. shaposhnikov , _ `` on the electric charge nonconservation in gauge theories and electron stability , '' _ _ in * kyoto 1979 , proceedings , 16th international cosmic ray conference , vol . 7 * , 400 - 404 _ ; a. y. ignatev , v. a. kuzmin and m. e. shaposhnikov , _ `` electron stability and charge fragmentation in gauge theories , '' _ inr preprint iyai - p-0142 , 1980 ; r. n. mohapatra , phys . * 59 * ( 1987 ) 1510 ; m. suzuki , phys . * d38 * ( 1988 ) 1544 ; m. m. tsypin , sov . j. nucl . * 50 * ( 1989 ) 269 ; m. i. dobroliubov and a. y. ignatev , phys . * 65 * ( 1990 ) 679 ; m. maruno , e. takasugi and m. tanaka , prog . * 86 * ( 1991 ) 907 ; r. n. mohapatra and s. nussinov , int . j. mod . * a7 * ( 1992 ) 3817 . a. y. ignatev and g. c. joshi , phys . * b381 * ( 1996 ) 216 . v. a. rubakov and m. e. shaposhnikov , phys . * b125 * , 136 ( 1983 ) . k. akama , in _ gauge theory and gravitation . proceedings of the international symposium , nara , japan , 1982 _ , eds . k. kikkawa , n. nakanishi and h. nariai ( springer verlag , 1983 ) . g. dvali and m. shifman , phys . * b396 * , 64 ( 1997 ) l. randall and r. sundrum , phys . * 83 * ( 1999 ) 4690 s. l. dubovsky , v. a. rubakov , p. g. tinyakov , _ ` brane world : disappearing massive matter,' _ , hep - th/0006046 n. arkani - hamed , s. dimopoulos and g. dvali , phys . * b429 * ( 1998 ) 263 ; phys . * d59 * ( 1999 ) 086004 i. antoniadis , n. arkani - hamed , s. dimopoulos and g. dvali , phys . * b436 * ( 1998 ) 257 l. randall and r. sundrum , phys . lett . * 83 * , 3370 ( 1999 ) j. lykken , l. randall , jhep * 0006 * ( 2000 ) 014 r. gregory , v. a. rubakov and s. m. sibiryakov , _ `` brane worlds : the gravity of escaping matter , '' _ hep - th/0003109 b. bajc and g. gabadadze , phys . * b474 * , 282 ( 2000 ) w. mueck , k. s. viswanathan and i. v. volovich , _ `` geodesics and newton s law in brane backgrounds , '' _ hep - th/0002132 . t. gherghetta , m. shaposhnikov , _ localizing gravity on a string - like defect in six dimensions _ , hep - th/0004014 i. oda , _ localization of matters on a string - like defect _ , hep - th/0006203

we discuss whether electric charge conservation may not hold in four - dimensional world in models with infinite extra dimensions , i.e. , whether escape of charged particles from our brane is consistent with effectively four - dimensional electrodynamics on the brane . we introduce a setup with photon localized on the brane and show that charge leakage into extra dimension is allowed within this setup . the electric field induced on the brane by escaping charge does not obey four - dimensional maxwell s equations ; this field gradually disappears in a causal way . we also speculate on the possibility of the escape of colored particles and formation of colorless free quark states on the brane . ( * is the electric charge conserved in brane world ? * + s. l. dubovsky@xmath0 , v. a. rubakov@xmath0 , p. g. tinyakov@xmath1 + the discussion of whether electric charge may not be exactly conserved has long history @xcite . in four - dimensional theories , even tiny non - conservation of electric charge leads to contradictions to low - energy tests of quantum electrodynamics unless exotic millicharged particles are introduced @xcite ( see , however , ref . @xcite ) . a new perspective emerges in theories describing our world as a brane embedded in higher dimensional space with infinite extra dimensions @xcite . it is conceivable that in these theories , particles initially residing on our brane may eventually leave the brane and disappear into extra dimensions . in fact , this leakage of particles has been found to be generic at least in a class of field theoretic models of localization of matter on a brane : once matter fields get small but non - vanishing masses , the localization becomes incomplete and particles tunnel from the brane into extra dimensions @xcite . if particles that leave our brane are electrically charged , their disappearance into extra dimensions would result in the non - conservation of electric charge , as seen by a four - dimensional observer . of course , in this scenario electric charge is conserved in the full multi - dimensional space ; the charge non - conservation in four - dimensional world is merely a consequence of incapability of our devices to detect the charges outside the brane . still , this scenario has distinctive experimental signatures such as literally disappearing electrons . hence , an observation of processes like @xmath2 would be a strong evidence for the existence of infinite extra dimensions . in a sence , this probe of extra dimensions is complementary to searches expoloiting the possibility of low fundamental gravity scale : the latter possibility exists irrespectively of whether extra dimensions are compact @xcite or infinite @xcite whereas the disappearance of matter emerges in theories with infinite extra dimensions but does not require the low fundamental scale of gravity . the rates of proccesses like @xmath2 are naturally small @xcite but presently can not be reliably predicted as they depend on the localization mechanism and unknown parameters of extra - dimensional physics . one may worry that non - conservation of electric charge in our world may be in contradiction with the fact that electrodynamics on the brane is effectively four - dimensional . indeed , the standard lore is that the charge conservation in our world is guaranteed by the four - dimensional gauss law ( and causality , i.e. , absence of action - at - a - distance ) . the purpose of this paper is to prove by example that there is no contradiction at all : in a model we consider , escape of charges into extra dimensions is perfectly consistent with localization of electromagnetism on the brane . the resulting picture is that physics becomes intrinsically multi - dimensional once the charged particles leave the brane ; the four - dimensional gauss law is no longer valid ; the electromagnetic field induced on the brane by escaping charges does not obey the four - dimensional maxwell s equations ; this induced field gradually decreases in a causal manner and finally disappears . the issue we discuss in this paper has a close gravitational analogy : matter leaking into extra dimensions carries away energy , so one may wonder whether this is consistent with the `` gauss law '' of four - dimensional general relativity describing gravity on our brane . the gravitational field of escaping particles has been studied in ref . @xcite with the results very similar to those outlined in the previous paragraph . we will closely follow ref . @xcite both in spirit and in some of the technicalities . to discuss the consistency of charge non - conservation on the brane with four - dimensional behavior of electromagnetism , we have in the first place to construct a model with a localized photon . a simple possibility is the localization of a photon due to gravity produced by the brane itself , which is very much the same mechanism as one leading to the localization of a graviton @xcite and a scalar @xcite . consider space - time with @xmath3 dimensions , @xmath4 of which are compact and one is infinite and `` warped '' . for simplicity we consider compactification on @xmath4-dimensional torus . let our world be a @xmath5-brane with @xmath4 compact dimensions of very small size ( smaller than tev@xmath6 ) . the brane has a certain tension , and there is a negative bulk cosmological constant . with this setup and appropriate fine - tuning between the bulk cosmological constant and brane tension , there exists a solution to @xmath3-dimensional einstein equations with metric similar to the randall sundrum @xcite one , @xmath7-dz^2\;,\ ] ] where @xmath8 is the four - dimensional minkowski tensor , @xmath9 $ ] are compact coordinates and @xmath10 are ( small ) sizes of compact dimensions . here @xmath11 and @xmath12 is determined by the bulk cosmological constant . let us now introduce the @xmath13 gauge field @xmath14 propagating in the background ( [ * ] ) . with appropriate rescaling , its free action is @xmath15 as we consider small @xmath10 and low energies , we truncate this action to the zero kaluza klein modes of compact @xmath4 dimensions , i.e. , take @xmath14 independent of @xmath16 . to see that there exists a photon localized on the brane , consider the action for four - vector components @xmath17 of the gauge potential , @xmath18 we see that the measure determining the normalization factor is @xmath19 hence , the @xmath20-independent mode , @xmath21 , is normalizable ; this is the wave function of the localized photon , up to a normalization factor proportional to @xmath22 . the reason of why we had to generalize the five - dimensional randall sundrum setup is now obvious : at @xmath23 there is no localized photon @xcite , but at @xmath24 gauge fields localize on the brane , and electrodynamics on the brane becomes four - dimensional at large distances . the main purpose of this paper is to calculate the gauge field induced on the brane by charges escaping into the non - compact dimension . we again take the charged fields independent of @xmath16 . the motion of charges along the @xmath20-direction is then treated in the classical approximation . let us consider for definiteness a single particle that has been at rest on the brane at @xmath25 and @xmath26 and then ( at time @xmath27 ) escapes the brane towards positive @xmath20 with zero initial velocity . ( the same calculation applies to the process of escape of a particle in an orbifold setup with fixed point @xmath28 . ) the particle moves perpendicular to the brane and gets accelerated towards large @xmath20 by the gravitational field @xcite . the world line of this particle is given by @xmath29 for a particle of charge @xmath30 , the non - vanishing components of the corresponding electromagnetic current are @xmath31 hereafter @xmath32 . this current induces the electromagnetic field everywhere in space - time according to maxwell s equations @xmath33 since @xmath34 , it is consistent to set @xmath35 , and also consider @xmath14 independent of @xmath16 . furthermore , we can choose the gauge @xmath36 then maxwell s equations ( [ max ] ) reduce to two equations . on the right to the brane these are @xmath37 where the four - dimensional indices are raised and lowered by the minkowski metric . as long as we are interested in the electromagnetic field _ on the brane _ , only eq . ( [ nu ] ) is important . this equation ( again on the right to the brane for definiteness ) can be written in the following way @xmath38a^{\nu}= -\delta^{\nu0}\sqrt{g}j^0+\e^{-nkz}\d^{\nu}\l\d_{\mu}a^{\mu}\r\;.\end{aligned}\ ] ] the last term in this equation can be explicitly found by making use of eq . ( [ z ] ) , but it produces pure gauge contribution _ on the brane_. indeed , the solution to eq . ( [ 6 * ] ) is expressed in terms of the retarded green s function , @xmath39 , of the operator entering the left hand side , @xmath40 the second term here is pure gauge on the brane ; it does not affect charges residing on the brane and hence can be omitted . the only relevant component of @xmath41 on the brane is then @xmath42 upon introducing a variable @xmath43 this expression is written in the following explicit form @xmath44 we will be interested in length scales much larger than @xmath45 , so we will set @xmath46 in the rest of our analysis . to proceed further , we need an explicit form of the retarded green s function , @xmath47\;,\ ] ] here the first term is the contribution of the zero mode , the second term comes from the continuum of non - zero modes . we can divide the continuum modes into symmetric and anti - symmetric subsets with respect to the brane . anti - symmetric modes vanish on the brane , so they do not contribute to the green s function at @xmath28 . since we are calculating the gauge field on the brane , we can neglect anti - symmetric modes in eq . ( [ summode ] ) . the symmetric modes are @xmath48 where @xmath49 these continuum modes are normalized to @xmath50 with the weight ( [ 3 + ] ) . the retarded four - dimensional massive propagators entering eq . ( [ summode ] ) are conveniently written in coordinate representation , @xmath51 @xmath52 as a consistency check of our calculation , we point out that had one boldly made use of the zero mode approximation , i.e. , neglected the continuum contribution in eq . ( [ summode ] ) , one would obtain from eq . ( [ 4 * ] ) that the induced gauge potential @xmath53 is a static coulomb potential , @xmath54 . this is not surprising , as electrodynamics is effectively four - dimensional in the zero mode approximation . the zero mode approximation is not justified when charges move outside the brane , so we proceed to evaluate the complete green s function . at large distances , @xmath55 , and well away from the light cone , @xmath56 , only relatively small masses @xmath57 are relevant , and we obtain @xmath58 where we set @xmath28 , as we are interested in the induced field on the brane . note that the first term in eq . ( [ 10 * ] ) cancels out due to completeness of the set of the modes ( including the zero mode ) . the induced electromagnetic potential is obtained by plugging the expression for the green s function , eq . ( [ kk ] ) , into eq . ( [ 4 * ] ) . the evaluation of the resulting integrals is somewhat cumbersome , and we outline this step in appendix . let us present the results for @xmath59 for @xmath60 and @xmath61 . @xmath62 @xmath63\;.\ ] ] @xmath64 @xmath65 these expressions are valid inside the light cone @xmath66 , whereas outside the light cone @xmath53 is still equal to the coulomb potential generated by the charge that has been at rest on the brane at negative times , @xmath67 the factor @xmath68 coming from the normalization of the zero photon mode . at both @xmath60 and @xmath61 , the gauge potential @xmath53 and electric field @xmath69 are continuous on the light cone . deep inside the light cone , i.e. , at @xmath70 , the electric field gradually disappears , @xmath71 the case of arbitrary even @xmath4 is also possible to treat analytically ; by making use of eq . ( [ s5 * ] ) we have checked that the same properties ( continuity of @xmath53 and @xmath72 across the light cone and the behavior ( [ 13 * ] ) at @xmath70 ) hold for all even @xmath4 . the electromagnetic field induced on the brane by escaping charges switches off in a causal way . we conclude that the electric charge non - conservation in the brane world via the leakage of charged particles into extra dimensions is consistent with effectively four - dimensional electrodynamics governing the long distance interactions of charges residing on the brane . in the setup we introduced in this paper , escaping charge induces spherical electromagnetic wave on the brane ; beyond this wave electromagnetic field gradually disappears . this wave is a collective effect of the photon zero mode and continuum modes . the existence of continuum bulk modes with arbitrarily small four - dimensional `` masses '' is crucial for this phenomenon , as it makes the problem intrinsically five - dimensional even at large distances , and in this way the 4-d gauss law obstruction to the electric charge non - conservation is avoided . we expect that the non - conservation of electric charge on the brane is possible in all models with localized photon and continuum of electromagnetic modes in the bulk that starts from zero four - dimensional `` mass '' . these properties are inherent , in particular , in the six - dimensional string setup of gherghetta and shaposhnikov @xcite ; the localization of a photon in the latter setup has been discussed recently by oda @xcite . on the other hand , those mechanisms of the photon localization which do not incorporate the bulk continuum starting from zero will not allow for the electric charge non - conservation in the brane world ; an example is the dvali shifman setup @xcite . it remains to be understood which possibility is preferable from the point of view of string / m - theory . may colored particles quarks escape from our brane too ? certainly not in theories with confinement of color both on the brane and in the bulk . however , if color is not confined in the bulk , one may speculate on the following possibility . consider a well separated pair of quark and anti - quark on the brane , with color flux tube stretching between them ( fig . 1a ) . suppose that the quark leaves the brane ( fig . 1b ) ; if color is not confined in the bulk , this does not cost very large energy even if the quark travels far away from the brane . after the quark has moved away , there remains an object on the brane ( shown by dashed line in fig . 1c ) which , from the four - dimensional point of view , behaves as a color triplet state with zero baryon number , electric and weak charges , etc . this object may combine with anti - quark to form a free anti - quark colorless state ( again as viewed from four dimensions ) with quantum numbers of anti - quark ( fig . 1d ) . it is worth trying to undertsand at a more quantitative level whether these exotic objects may indeed exist in models with infinite extra dimensions . we are indebted to f. bezrukov , d. gorbunov , s. dimopoulos , g. dvali , m. libanov , m. shaposhnikov , s. sibiryakov and s. troitsky for helpful discussions . this work is supported in part by rfbr grant 99 - 02 - 18410 , by the crdf grant 6603 and by swiss science foundation , grant 7supj062239 . the work of s.d . is also supported by the russian academy of sciences , jrp grant 37 and by issep fellowship . the work of p.t . is supported in part by the swiss science foundation , grant 21 - 58947.99 . + fig . 1a + + fig . 1b + + fig . 1c + + fig .

norbert wiener , the founder of cybernetics , wrote that it is the `` boundary regions of science which offer the richest opportunities to the qualified investigator . they are at the same time the most refractory to the accepted techniques of mass attack and the division of labor '' @xcite . he went on to explain that `` a proper exploration of these blank spaces on the map of science could only be made by a team of scientists , each a specialist in his own field but each possessing a thoroughly sound and trained acquaintance with the fields of his neighbors ; all in the habit of working together , of knowing one another s intellectual customs , and of recognizing the significance of a colleague s new suggestion before it has taken on a full formal expression . the mathematician need not have the skill to conduct a physiological experiment , but he must have the skill to understand one , to criticize one , and to suggest one . the physiologist need not be able to prove a certain mathematical theorem , but he must be able to grasp its physiological significance and to tell the mathematician for what he should look . '' indeed , three giants of science , wiener , von neumann and shannon , realised in the 1940s the need for understanding the brain in terms of the fundamental engineering principles applicable to any computational device : energy , entropy and feedback @xcite . this led to the macy conferences ( 19461953 ) which attracted leading scientists from across engineering and the physical and life sciences . the macy conferences were one of the earliest organised approaches to transdisciplinarity and hailed by some as the most important event in the history of science after world war ii . they demonstrated the need for , and the initial difficulties in , establishing a common language powerful enough to communicate the intricacies of the relevant fields across the physical and life sciences and engineering . while their dream was not realised , this was primarily due to insufficient experimental data . as time marched on , the barrier to bringing together the ever more specialised disciplines grew larger . with tremendous experimental advances having been made in the past 60 years , it is timely to stand on the shoulders of these giants and resume their quest . with this as motivation , the present article endeavours to whet the appetites of neuroscientists and information theorists alike for learning more of each other s fields . the human brain is often described as the most complex structure in the known universe @xcite . certainly , it is the most efficient signal processing device known . drawing only 20 watts of power , the brain significantly outperforms engineered devices at signal processing tasks such as source separation , feature extraction , and speech and image recognition @xcite . this is all the more remarkable because signals within the brain propagate very slowly compared with those in a computer . this suggests that the brain uses a paradigm for signal processing very different from any developed in engineering . why then should engineering in general and information theory in particular have relevance to understanding the brain ? the answer lies partially in the fact that engineers study fundamental laws pertinent to any system , including biological ones @xcite . indeed , john von neumann viewed the brain as a hybrid computer which performs control , communication and computation , and concluded that information theory is therefore essential for understanding its functionality @xcite . wiener too recognised that information theory was essential for a deeper understanding of feedback and thus life @xcite . anecdotal evidence suggests shannon himself , the father of information theory , may have been partially motivated by how his brain processed `` information '' when performing a complex task such as juggling balls . a few words on the concept of feedback are in order . feedback refers to achieving a task , such as keeping a car travelling at a constant speed , by repeatedly measuring the current state , such as the car s speed , and feeding those measurements back and using them to make the requisite changes at the input , such as applying more or less pressure to the accelerator of the car . feedback is a fundamental concept in engineering because it can militate errors caused by imprecisions and external interference . the brain too must use feedback to overcome imprecisions @xcite ; without feedback , we would fall over whenever we attempted to walk . within the sensory pathways there are tremendous numbers of feedback paths connecting regions of higher - level brain function to regions of lower - level functionality , giving rise to top - down processing theories of the visual pathways and providing a mechanism for selective attention . although they started out in different disciplines information theory emerged from communication theory while feedback was studied in control theory recent years have seen some convergence of feedback and information theory . a fundamental question is what is the slowest rate at which information must be fed back for the system to work . scientists have started to consider how fast the brain must be processing information if we are able to walk properly and can move our hand in a straight line even though random external forces are impeding its motion in experiments @xcite . this is an example of such convergence of two important theories . by virtue of being introductory , the present paper focuses on discussing information theory in `` one - way '' ( i.e. feed - forward exclusively ) biological contexts . a comprehensive account of the brain in engineering terms would necessarily involve the marriage of information theory and control theory . repeating the words of von neumann , the brain must be understood in terms of control ( feedback ) , communication ( information theory ) and computation . it must be recognised that the mathematical discipline of `` information theory '' does not ( and should not ) capture all aspects of how the word `` information '' is used in spoken language . failing to distinguish the two can lead to errors caused by flawed intuition in one direction , or the inappropriate application of information theory in the other . information theory was invented in response to practical problems faced by the designers of communication systems such as telephones and data modems . the basic problem is to find an efficient way of transmitting information from one place to another , whether it be a probe sending information from the moon back to earth or a mobile telephone sending and receiving voice and internet packets . indeed , consider the problem of one person trying to send a series of messages to another person on the other side of a brick wall ; for simplicity , assume this second person is not allowed to speak or send any other form of message to the first person such as an acknowledgement or request for clarification ( or `` retransmission '' ) . how should the first person send each message ? one thing is clear ; the louder the first person shouts , the greater the chance that the second person can understand the message over the background noise ( perhaps the neighbours are mowing their lawns ) . perhaps a little harder to appreciate but equally true in the digital world , if the first person were to speak more slowly the second person would have a greater chance of catching every word . the third parameter that can be adjusted is the level of redundancy . when we speak with a young child we tend to elaborate and use more words to describe a concept in an attempt to increase the chances of correct reception of the overall message . in information theory , these parameters are referred to formally as the transmission power , the transmission rate and coding ( or redundancy ) . the simplest form of coding is to repeat the message two or more times . this is known as a repetition code . shannon s pioneering work shattered a long - held belief that with finite power it was impossible to be able to transmit a message in such a way as to _ guarantee _ its _ perfect reception _ even in the presence of noise and other interference . indeed , even if i shouted at the top of my voice and repeated myself a hundred times , every so often the interference ( lawn mowers ? ) will prove too great and my message will be lost . the answer lies in coding ; repetition codes are not particularly good codes . shannon realised that there exist very clever codes which can ensure that any two messages are so different from each other that the receiver can correctly decide which message was sent despite the interference . technically , perfect reception requires the receiver to listen forever before deciding which message was sent but the key point is that given any positive but arbitrarily small probability of error ( such as one message being incorrectly received in @xmath0 messages ) then a code can be constructed which achieves this level of performance in finite time , and more importantly , the transmission power does not need to be increased . increasing transmission power to achieve a particular error rate is grossly inefficient compared with choosing a better code . in the example of one person trying to convey a message to the other person , the secret is to share a codebook beforehand , and a different sequence of sounds , one for each message that may be sent , is written in it . `` it will rain tomorrow '' might be encoded as ( a segment of ) beethoven s 5th symphony while `` it will be sunny tomorrow '' might be encoded as a hard rock song . these two encoded messages are `` sufficiently different from each other '' to have very little chance of being confused . more importantly , any small fragment of the two messages are different . this is how interference is overcome . because interference itself has limited power ( otherwise the game would not be fair ! ) then even if there are times when the interference is particularly bad , there will be other times when the interference is back to normal and in the long run , there is no confusing beethoven for hard rock . for the transmission rate to be acceptable the codebooks would need to contain more than just two messages . ( with two messages , each one encoded by a five - minute song , the transmission rate would be 1 bit per 5 minutes . ) in the same way that the transmission power does not need to go to infinity , the transmission rate need not go to zero . precisely , shannon discovered a quantity known as the channel capacity . if the transmission rate is less than the channel capacity then communication with any desired level of accuracy is possible whereas if the transmission rate exceeds the channel capacity then it becomes impossible to have arbitrarily good performance in finite time . as is to be expected , the channel capacity depends on the interference . the more destructive the interference the lower the channel capacity . messages are also passed around within an organism . information gathered by an organism s senses must be communicated for it to have any effect on the organism . within the brain and nervous system , information is manipulated in at least three different ways : * information acquisition ( sensory transduction ) ; * communication between spatially separated regions ( information transmission ) ; * memory formation and recall ( information storage @xcite ) . in brains , each of these are essential for the emergence of broader functions that might be termed ` computation ' . communication is perhaps most fundamental , since information from the senses needs to be communicated in order for it to have any affect on an organism , while information storage , whether in computers or brain memories , can be viewed as communication from the past to the present or future . understanding how the brain stores and transmits information is tantamount to understanding the brain as a whole because if we could `` listen in '' to brain messages it would surely be just a matter of time before we understood the computational side , too . that said , the possibility that the brain does not separate out information transmission from information processing must be considered . whereas computer architectures have mechanisms known as buses for moving information between different processing units , the brain might take a more efficient distributed approach and simultaneously process and communicate in a nonseparable fashion . it has been stated that `` computation in the brain always means that information is moved from one place to another '' @xcite . a comprehensive understanding of the brain s mechanisms for internal communication will likely form an integral part of more advanced theories about how ` computation ' arises within brain networks . regardless of how the brain actually processes information , at the end of the day the brain is an input - output system ( we react to what we sense ) and therefore subject to the same laws as any other input - output system . information theory is therefore relevant to understanding how the brain works , and conversely , it is highly likely that advances in the field of information theory will be made in synergy with new discoveries of the computing paradigms used by the brain @xcite . indeed , information theory may have to expand to address new neurobiologically relevant questions if it is to be powerful enough to explain all aspects of how the brain manipulates information . to demonstrate the relevance of even simply thinking in information theoretic terms , landauer estimated that humans learn information at a rate of about two bits per second @xcite . taking memory loss into account , a person will accumulate approximately two billion bits of information in a lifetime ( or approximately 240 mb in computing terms ) . since our brain has many more synapses than two billion , landauer concludes that `` possibly we should not be looking for models and mechanisms that produce storage economies but rather ones in which marvels are produced by profligate use of capacity . '' according to @xcite , biological science asks six kinds of questions about domains ranging from molecules and cells , up to the biosphere : 1 . how is it built ? ( structures ) 2 . how does it work ? ( mechanisms ) 3 . what is it for ? ( functions ) 4 . what goes wrong ? ( pathologies ) 5 . how is it fixed ? ( repairs ) 6 . how did it begin ? ( origins ) utilising information theory in neuroscience is ultimately useful only if it can address one or more of these questions . in this paper we advocate that information theory 1 ) can be a useful framework for finding answers to some of these questions ; but 2 ) must be broadened for its theorems to be directly applicable to neuronal networks . although information manipulation can happen at very different levels of organisation , such as storage of information in genes , or communication at the level of synaptic transmission between cells , or at that of spiking patterns of neurons in a network , in this paper we will be focusing on examples that involve spiked - based communication between neurons . in making these points , it is necessary for us to introduce the most basic and well - known information theoretic concepts in section [ sec : info ] , before discussing the challenges of applying the theory meaningfully to questions in neuroscience in section [ s : neuro ] . then in section [ sec : neuralcapacity ] we summarise a specific example which illustrates that information theoretic approaches depend critically on different assumptions that could be made about neural systems . finally in section [ s : conclusion ] we conclude the paper with some closing remarks on the material we cover and briefly summarise recent developments on information theoretic approaches in neuroscience that extend well beyond the classical ideas we present , thereby with increasing relevance to neurobiological systems . this section briefly explains key concepts from shannon information theory and hints at possible contributions in neuroscience . by _ shannon information theory _ we are referring to a specific sub - part of the broader field of _ information theory_. the latter , by definition , encompasses any _ mathematical theorems about information _ , and therefore is not confined to well - known concepts introduced by shannon , such as entropy and mutual information . as we discuss later , information theory beyond shannon theory may be very important in neuroscience . shannon s milestone paper @xcite that founded the field of information theory showed to the world that introducing the right kind of redundancy was the key to moving information from one place to another in an efficient and reliable manner . since information sources such as spoken voice or pdf ( portable document format ) documents generally contain the wrong kind of redundant information , shannon proposed a two - step process : first remove the existing redundancy by compressing the message to be sent , then introduce the right kind of redundancy for communicating the message through the channel at hand . these two important concepts are known as `` source coding '' and `` channel coding '' respectively . they motivate several fundamental questions including determining the maximum amount of compression possible of an information source . answers to these questions are given in terms of quantities such as _ entropy _ and _ mutual information_. it is important to realise that these quantities were given special names because they serve to answer important questions for a particular class of problems . it would be a mistake to assume without additional justification that they are applicable or even meaningful beyond the bounds of the original questions for which they serve as the answers to . see e.g. @xcite for more discussion . living in the digital age , readers will be familiar with compressing files . zipping up a file to send to a friend is an example of lossless compression . generally ( but not always ) the compressed file will be smaller than the original yet no information has been lost ; the friend can recover the original file by decompressing the compressed file ( fig . [ fig : sourcecoding ] ) . for compressing music or photos , significantly greater compression can be achieved by using lossy compression algorithms such as mp3 and jpeg . as the name suggests , some information is lost @xcite . the original can be recovered sufficiently well for a satisfactory compromise to have been reached ; a small amount of quality is sacrificed for a large saving in storage space . the remainder of this section discusses lossless compression only . consider the problem of compressing a short message of length 8 bits . a bit is simply a `` 0 '' or a `` 1 '' so an 8-bit message is a sequence of eight zeros and ones , such as `` 01011101 '' or `` 10101010 '' . a calculation ( or by writing out all the possibilities if need be , starting with `` 00000000 '' , `` 00000001 '' and continuing until `` 11111111 '' ) shows that there are precisely 256 different 8-bit messages . compressing a message would mean using fewer than 8 bits to store the message . a simple enumeration shows that this is impossible as stated ; there are only 128 7-bit messages , not enough to represent all possible 8-bit messages . how then does a computer compress a file losslessly ? the secret is that there is often redundancy in the kinds of information that people are interested in . equivalently , it is generally the case that not all messages have an equal chance of occurring . for argument s sake , assume that out of the 256 possible messages , there are 15 messages which occur most of the time . to exploit this , we may decide to use 4 bits to represent each of these messages . precisely , `` 0000 '' would represent the first message , `` 0001 '' the second , up to `` 1110 '' for the 15th message . to represent any other message , we would first write down `` 1111 '' to mean `` not one of the 15 '' and then we would write down the original message using 8 bits . this means that 15 of the messages can be written down using only 4 bits but the remaining @xmath1 messages now require @xmath2 bits for their storage . the only way to make this meaningful is to consider repeating this compression exercise many times . if we had to store a very large number @xmath3 of 8-bit messages using this scheme , how many bits will be required ? assume that @xmath4 out of the @xmath3 messages belong to the set of 15 special messages . these @xmath4 messages require 4 bits while the remaining @xmath5 messages require 12 bits , or in total , @xmath6 bits are required compared with @xmath7 bits had we not compressed the messages . provided @xmath4 is sufficiently large , we will have succeeded in compressing the data . for example , if @xmath8 and @xmath9 then we would require only 6,000 bits rather than the original 8,000 bits . the conventional way to describe the above scenario is to work with probabilities . we assume that the messages we are being asked to compress are being generated at random and there is no correlation between the message we are being asked to compress now and the messages we have already compressed . mathematically , we represent the original sequence of messages by a sequence of independent and identically distributed random variables @xmath10 , each having a probability density @xmath11 . in the above example , each @xmath12 would be an 8-bit message ( or equivalently , a number between 0 and 255 inclusive ) and @xmath11 would be the probability that a particular message @xmath13 is chosen . for concreteness , assume that each of the first fifteen messages have a 5% chance of occurrence ( meaning there is a 75% chance of a randomly chosen message being one of these 15 and thereby corresponding with the earlier choice of @xmath8 and @xmath9 ) . then @xmath14 . we assume that all other messages each have a probability of @xmath15 of occurring . the expected number of bits required to compress a single message can then be calculated by summing over @xmath16 the probability that the @xmath16 th message occurs multiplied by the number of bits required to represent the @xmath16 th message . when most of the probabilities are the same the calculation simplifies . with the values given above , the expected length is calculated to be @xmath17 . thus , on average , @xmath18 bits would be required to compress @xmath3 messages drawn at random if the above scheme were used . is there a better compression scheme , one which requires fewer than 6 bits per message on average ? in fact , what is the best possible ? as elucidated presently , shannon was able to answer these questions . first though , a technicality needs mentioning . coding each message separately , as was done above , is inefficient it is better to concatenate a series of messages and compress them all at once ; this provides more opportunity for better compression through the simple fact that there are more compression schemes to choose from . ( it also alleviates the wasted space caused by otherwise having to use an integer number of bits to represent each message . ) it is therefore quite standard to refer to each @xmath12 as a symbol rather than a message and ask how many bits per symbol on average must be used to compress the infinitely long sequence of independent and identically distributed symbols @xmath19 if each symbol has a probability @xmath11 of occurring . when @xmath13 is a random variable and its distribution is @xmath11 , its _ entropy _ is defined as @xmath20 , \label{eq : entropy_discrete}\end{aligned}\ ] ] where @xmath21 $ ] denotes the expectation with respect to @xmath11 . the practical operation is a summation when @xmath13 is discrete and an integration when @xmath13 is continuous . when @xmath22 is the base of logarithm , i.e. @xmath23 , the units of entropy are bits and @xmath24 is precisely the number of bits per symbol required on average to compress an infinitely long sequence of symbols when each symbol has probability @xmath11 of occurring . it is for this reason that people endeavour to explain entropy as quantifying the `` ambiguity '' or `` uncertainty '' about the random variable @xmath13 . when @xmath13 has only one possible state ( that must therefore occur with probability @xmath25 ) , there is no ambiguity about @xmath13 and the entropy is @xmath26 . however if @xmath13 takes one of two states with probability @xmath27 and @xmath28 , respectively , ( @xmath29 ) , entropy is maximised when @xmath30 and @xmath31 . this is exactly 1 bit and implies that a sequence of equally likely zeros and ones can not be compressed . note also that if @xmath32 , @xmath33 . _ shannon s source coding theorem _ states that ( in the limit as the number of symbols goes to infinity ) it is _ possible _ to compress each symbol to @xmath24 bits on average ( and _ impossible _ to do better ) . it does not however say how to design such a source code . furthermore , the practical construction of compression and decompression methods is complicated by considerations of algorithmic efficiency ( which affects battery life in portable equipment such as mobile telephones ) and latency ( how long the receiver must wait from the time a symbol is sent until that symbol can be received and decoded ) . that said , having a target to aim for is extremely useful and entropy provides that target for source compression . the reader may wish to verify that for the example introduced in this section , the corresponding entropy is @xmath34 bits per symbol . this represents the best any compression scheme can hope to achieve , and indeed , it is lower than the 6 bits per symbol scheme presented here . the following example of a binary symmetric channel will be used to add concreteness to the ensuing introduction of _ mutual information _ and _ channel capacity_. let @xmath35 denote a binary sequence which is to be transmitted to another person or device . it is called the source sequence . the medium through which a message can be sent from one person or device to another is called the channel . mathematically , a channel takes a sequence at its input and it generates another sequence at its output . if the channel were ideal , it would simply copy its input to its output and communication would be straightforward . generally though , the channel is not ideal . it introduces random errors . if @xmath36 is the binary input sequence ( which is shorthand notation for @xmath10 ) then the binary output sequence @xmath37 of a binary symmetric channel with error probability @xmath27 is given by the rules that 1 ) for each integer @xmath16 , the output @xmath38 at time @xmath16 depends only on the corresponding input @xmath39 at the same time @xmath16 ; and 2 ) the probability that @xmath40 differs from @xmath39 is @xmath27 . if @xmath41 then on average one in every ten symbols will be corrupted , meaning either a @xmath26 was sent and a @xmath25 was received , or a @xmath25 was sent and a @xmath26 was received . what sequence @xmath36 should be sent over the channel if the ultimate aim is to send @xmath42 reliably to the receiver , assuming of course that the receiver can process the output @xmath43 of the channel before deciding what it believes the message @xmath42 is ? this is illustrated in fig . [ fig : channelcoding ] where the operation of generating @xmath36 from @xmath42 is called ( channel ) encoding and the operation of generating @xmath44 , the receiver s best guess at the original message , is called ( channel ) decoding . for simplicity , often the encoding and decoding processes work on blocks of data . precisely , the original source sequence @xmath45 is divided up into subsequences of length @xmath4 . each of these is encoded to a longer binary sequence @xmath13 with length @xmath3 . for example , a simple @xmath46 , @xmath47 block code would be to add a parity bit ( i.e. a bit that is zero when the sequence has an even number of zeros , and a one when an odd number ) after every two symbols , so : `` @xmath48 '' becomes `` @xmath49 '' ; `` @xmath50 '' becomes `` @xmath51 '' ; `` @xmath52 '' becomes `` @xmath53 '' and `` @xmath54 '' becomes `` @xmath55 . '' therefore , the sequence `` @xmath56 '' becomes `` @xmath57 '' where the 3rd and 6th bits are the introduced parity bits . this coded sequence is transmitted through the channel . at the other end , the receiver reverses the process , converting each block of @xmath3 symbols back into a block of @xmath4 symbols . in this particular case , introducing just a single parity bit does not allow the receiver to have a better guess at what the original message is , but it does allow the receiver to detect if a single bit has been changed . this is called error detection . error correction , when the receiver is not only able to detect an error has occurred but can fix the error and therefore recover the original message , requires more redundancy to be introduced , that is , choosing @xmath3 to be larger than @xmath58 . ( if there are too many errors then error correction would fail , but the key point is that the probability that several consecutive bits are wrong is significantly smaller than if a single bit were wrong , therefore a small increase in redundancy allows a substantial increase in reliability . ) the two lengths @xmath4 and @xmath3 together define the `` rate '' of the code , which perhaps is better understood as measuring the decrease in throughput caused by the introduction of redundancy by the encoder . precisely , in the above example , the rate of the code is @xmath59 , meaning that if the channel can accept encoded symbols at a rate of 1 bit per second then the source symbols must have a rate of only @xmath60 bits per second . reducing the rate enables more redundancy to be introduced which can be used to increase the chance of the receiver being able to work out what message was sent . shannon s remarkable observation was that there is a much better way of increasing the chance of correct reception than by decreasing the rate towards zero . for a fixed rate @xmath60 , the block size @xmath4 can be increased ( thereby increasing @xmath3 according to the formula @xmath61 ) . this allows a more sophisticated form of redundancy to be introduced ( but at the price of introducing greater latency ; the receiver must receive @xmath3 symbols before it can work out what the corresponding @xmath4 message symbols were ) . shannon proved that there exists a rate @xmath62 , called the channel capacity , such that for any rate @xmath60 strictly less than @xmath62 and any desired error rate @xmath63 ( meaning that the probability that the receiver decodes a bit incorrectly is less than @xmath64 , which might be chosen to be @xmath65 or smaller in practice ) , there exists a @xmath4 ( possibly quite large ) and a block encoder and decoder pair such that the receiver can correctly decode each bit of the source message with error probability less than @xmath64 . this is customarily summarised by saying that error - free communication is possible at rates below the channel capacity . ] . shannon was able to give a formula for computing the channel capacity @xmath62 . when this formula ( described below ) is applied to the above example of a binary symmetric channel with probability of error @xmath27 , the channel capacity is found to be @xmath66 , meaning for example that if the channel can transfer one bit per second then the source symbols must arrive slower than @xmath62 bits per second . if @xmath41 then @xmath67 meaning that for every 1,000 source symbols , just over 1,883 encoded symbols are required for reliable communications . the formula for channel capacity involves a quantity called _ mutual information_. intuitively , the mutual information of the input and the output of the channel measures how much information the output provides about the input ; the more reliable the channel the higher the mutual information . it is therefore reasonable to expect that the larger the mutual information the greater the channel capacity . bearing in mind that `` information '' is a very general word and it is therefore not possible to capture all its nuances in a single mathematical definition , it is expedient to return to the idea in the previous section of using asymptotic compressibility as a measure of information . it turns out that this is the right definition to use when it comes to determining the capacity of a channel ( which in itself is an asymptotic measure ) . suppose there are two random variables , @xmath13 and @xmath68 , and they are somehow related to each other . for example , @xmath13 might denote temperature while @xmath68 denotes humidity . even simpler , @xmath13 might represent the outcome of rolling a 6-sided die while @xmath68 is given the value @xmath69 if the die landed on an even number , or @xmath70 if odd . knowing @xmath68 gives partial information about @xmath13 ; how can we measure how much information @xmath68 tells us about @xmath13 ? the fact that @xmath68 gives partial information about @xmath13 is reflected in the fact that if @xmath68 is known then @xmath13 can be compressed more than if @xmath68 were not known . in the above example , if @xmath68 were not known then it is impossible to compress @xmath13 because each of the outcomes is equally likely ; we are forced to use one of six possible symbols ( or @xmath71 bits ) to store each sample of @xmath13 ; the entropy of @xmath13 is @xmath72 . if @xmath68 is known though then only one of three possible symbols ( or @xmath73 bits ) needs to be stored ; the _ average conditional entropy _ is @xmath74 . the additional amount of compression possible , @xmath75 , is called the mutual information and measures the amount of information @xmath68 provides about @xmath13 . it turns out that mutual information is symmetric @xmath76 hence there is no need to specify the order of @xmath13 and @xmath68 . in the above example , if @xmath13 is known then @xmath68 is known , therefore no additional bits are required to store @xmath68 if @xmath13 is known : @xmath77 . since @xmath78 it is indeed the case that @xmath79 first then compress @xmath68 , or if we were to compress @xmath68 first then compress @xmath13 , we end up either way with having compressed optimally the joint sequence generated by @xmath13 and @xmath68 . mathematically , @xmath80 from which it follows immediately that @xmath76 . ] . returning to the channel capacity calculation , assume that a sequence generated by @xmath13 is sent through the channel . the output sequence is itself generated by a random variable , call it @xmath68 . if the receiver wants to recover @xmath81 it needs at least an extra @xmath82 bits of information ( for otherwise there would be an even more efficient scheme for compressing @xmath13 than the best possible , a contradiction ) . looking at it from another angle though , this implies that @xmath75 bits of information have somehow been transmitted successfully with each use of the channel ( since with an extra @xmath82 bits of carefully chosen information it is theoretically possible to recover @xmath13 ) . for the case of the binary symmetric channel with error probability @xmath27 , a reasonably straightforward calculation shows that if the input @xmath13 takes the value @xmath25 with probability @xmath83 and the value @xmath26 with probability @xmath84 then the mutual information of the input @xmath13 and the output @xmath68 is @xmath85 where @xmath86 is the number of bits required to compress a binary sequence taking the value @xmath25 with probability @xmath87 and the value @xmath26 with probability @xmath88 . although we must have the channel input @xmath13 represent the source message @xmath45 in some way , there is otherwise arbitrary freedom in how to choose @xmath13 . why not choose @xmath13 to maximise the mutual information ? the largest value @xmath89 can take is @xmath25 ( which occurs when @xmath90 ) . therefore , the largest number of bits we can ever expect to transmit reliably through the binary symmetric channel is @xmath91 bits per usage of channel . if @xmath41 then @xmath92 in this case , at most every @xmath93 bits of the source message must be expanded to @xmath25 bit ( since the channel transmits 1 bit per usage ) , or in other words , we must have the rate of the code ( see above ) satisfy @xmath94 . remarkably , shannon proved that this bound is achievable ; whenever the rate is less than the maximum of the mutual information , ( as close as you like to ) error - free communication is possible and @xmath4 goes to infinity , but did not show `` how to achieve it . '' in order to be close to the bound , we generally need a good error correction code and @xmath3 and @xmath4 must be very large . ] . it is of interest to note that while here we have considered an example where @xmath13 is a discrete random variable , the most well known case of a channel for which the capacity achieving input distribution is known , is the additive gaussian noise channel , with a power constraint on the input . in this case , the capacity achieving input distribution is in fact continuous , i.e. a gaussian distribution . as we discuss later though , it is far more common for the capacity achieving input to be discrete . we now summarise and precisely define the important information theoretic terms that we have introduced and discussed above without stating their formal definitions . each of these are defined mathematically as follows . we already introduced entropy , in eqn . . the average conditional entropy requires a double expectation : @xmath95\bigr ] . \label{eq : condentropy_discrete}\ ] ] as an aid to intuition , consider a single outcome of the random variable @xmath96 the entropy of @xmath68 given @xmath13 can be calculated from eqn . by calculating the expectation with respect to the conditional distribution of @xmath68 given @xmath97 . if this is carried out for all possible outcomes of @xmath13 , the result is a function of @xmath98 . this function can then be averaged with respect to the distribution of @xmath98 , and by definition , the result is the average conditional entropy , @xmath99 . as mentioned above , the mutual information can be expressed as @xmath100 . in what follows below we write mutual information in a different form based on another entity called _ relative entropy _ or _ kullback - leibler divergence_. this is defined as @xmath101 , % \label{eq : relentropy_discrete}\ ] ] where @xmath11 and @xmath102 are two distributions of the same random variable @xmath13 . note that the relative entropy is positive and is equal to 0 if @xmath11 is identical to @xmath102 . mutual information is defined as the relative entropy between the joint distribution of @xmath13 and @xmath68 , and the product of the marginal distributions of @xmath13 and @xmath68 : @xmath103 . \end{split } \label{eq : mi_discrete}\end{aligned}\ ] ] it is straightforward using @xmath104 to obtain the above stated relationships between mutual information and entropy . the definitions as written here hold for both discrete and continuous distributions of @xmath13 and @xmath68 . in this section we have considered only a simple discrete case , where @xmath13 and @xmath68 are both binary . in general they can have any number of states , or be continuous , as is the case below . in full generality , the channel capacity is defined as @xmath105 in this section , some of the challenges of integrating information theory into neuroscience are touched upon . in particular , we must make assumptions about the way in which information is represented in the brain , whereas in engineering this is specified by the designer . ultimately it will be necessary to extend the frontiers of information theory if it is to encompass in its entirety the information processing techniques of neuronal networks . such an expansion would involve in part the greater integration into information theory of systems and control theory from engineering and the theory of computation from mathematics . whereas engineers aim to keep separate communication circuitry from computation circuitry so as to simplify the design and analysis of engineered systems , there is no reason why nature should maintain such a separation . evolution tends to find efficient designs and not necessarily `` simple '' designs . it would be counter - productive though to assume that information theory in its current form could not be applied usefully in computational neuroscience . one place it is immediately applicable is the early sensory pathways where information is primarily flowing in one direction . considerably extra care must be taken when feedback loops are present . this is especially the case because ( in experiments ) we have control over the input signal itself and hence can investigate how a known signal is communicated from one neuron to another . the complication though is that it appears the information is being processed at the same time it is being communicated . the brain heavily compresses the information it receives from its sensory systems . since the entropy of a signal determines precisely how much ( lossless ) compression is possible , it sets fundamental limits which must be respected by any system , including biological systems . it is no surprise then that the estimation of entropy of neural signals based on experimental data is an active research area @xcite . in the brain , neurons communicate with each other and transfer information . the primary means of communication are the spikes of each neuron @xcite , and it is parsimonious to model their occurrences as depending randomly on the neuron s input @xcite . thus , neurons communicate through a noisy channel , and mutual information should therefore play an important role in understanding the nervous system and brain in order to consider a neuron as a communication channel , we need to consider what we mean by `` communication '' in the specific context of biological neurons . there are several important concepts to consider before we can begin to discuss a specific example of the application of information theory in neuroscience . a definition of communication requires the existence of a physical medium that allows propagation of energy from one place ( an `` energy source '' ) to another place where that energy has some causal effect ( an `` energy sink '' ) . we also need to define a means by which some property of the source can be altered in a way that results in an observable difference at the sink after propagation through the channel . in communications engineering theory , the energy propagation is called `` transmission , '' the source is known as a `` transmitter '' and the sink as a `` receiver . '' these concepts are not sufficient for communication . there also needs to be an `` information source '' that is initially observable at the transmitter s location , but not at the receiver s . communication requires the transmitter to alter the energy source in a manner that reflects the information source , and that can subsequently be observed at the receiver after propagation . this conversion from information source to energy source is known as `` modulation . '' a familiar example where each of these concepts is readily identified is analog am or fm radio transmission , in which recorded sound signals are communicated , and then reproduced via a speaker . in this example , the transmission medium can be a vacuum or air , the propagating energy source is electromagnetic radiation , and the transmitter modulates the electromagnetic waves in a manner that reflects the recorded sound signal . am is amplitude modulation , and means that a single frequency sinusoidal wave of e - m ( electromagnetic ) radiation has its amplitude changed over time . fm is frequency modulation , which means the amplitude remains constant , while the carrier frequency is changed over time . modulation of the energy source can be thought of as a code , since it requires a conversion from one kind of information representation to another . indeed , in neuroscience , modulation has a more general meaning than in communications engineering , and the conversion from an information source to variations in a parameter of the energy source is instead known as a `` code . '' this is largely in contrast with communications engineering , where `` code '' instead refers to conversion between different representations of the information source prior to transmission at the source , for example `` source coding '' and `` error correction coding . '' if we wish to consider communication between neurons , we need to identify the transmission medium , the form of energy propagation , and a modulation mechanism . from now on we will use neuroscience terminology , and refer to modulation as the `` code . '' further , we will refer to the information source as the `` input , '' and the observable effect at the receiver that results from the input as the `` output . '' although over longer time scales the plasticity of neurons can encode / carry information , in shorter time scales the primary physical medium for communication seems to be the axons of neurons , and the energy propagation is a pulse - like wave of voltage that travels along an axon where it may be received by other neurons at synaptic junctions . these pulses are known as action potentials , or spikes . typical cortical neurons transmit spikes to many other neurons , and receive spikes from many neurons . while there are a number of different `` communication channels '' in neuronal circuitry including segments of the dendritic tree which carry post - synaptic potentials towards the soma of the cell we choose to focus on action potentials because it is one of the most important communication mechanisms between two neurons . the other concept we must also attempt to identify is the way in which spikes are coded ( modulated ) in order to communicate information . two possibilities are the height and the width of each spike . however , these are observed to be close to identical in most cases , and do not seem to be information carrying parameters . instead , it is the interval between spikes ( isi : inter - spike interval ) that is thought to play an important role in carrying information through a neuronal channel . given this , how do isis represent information ? in neuroscience there are mainly two different ideas . one idea is that the isi itself ( see for example @xcite ) carries information . this is called `` temporal coding '' ( fig . [ fig : tc ] ) . the other is that the number of spikes in a fixed time interval ( see @xcite ) carries information . this is called `` rate coding '' ( fig . [ fig : rc ] ) . so far we have only stated that an input can be communicated to a receiver output . if this is a perfectly repeatable process , the rate at which information can be transmitted depends on the rate at which the input is updated , and in line with section [ sec : info ] also depends on the probability distribution of the input , via its entropy . the transmission is usually not perfect , and noise is introduced . this fact leads us to consider the information theoretic concepts of mutual information and channel capacity . information theory is not concerned with the type of modulation . it requires an abstraction that specifies only what the observable output variable should be . since we are not designing a system , we must make some guesses about aspects of the input and output for a neuronal communication channel , and then proceed to calculations of mutual information . therefore , in section [ sec : neuralcapacity ] where we consider the channel capacity of a neuron model , we necessarily begin by specifically defining the input and output of the channel , and state a model for the channel noise . in this section we present some of our results on the channel capacity for simple neuron models . one reason for providing this example , is to illustrate that there is no simple single formula for channel capacity , and hence assumptions about the underlying model are very important . if these assumptions change , the channel capacity also changes . as we have seen , channel capacity is the maximum amount of information that can be transferred through a noisy channel in a unit time . it may be much larger than the actual information transmission rate . this brings us to a natural question , that is , why do we need to know the capacity ? channel capacity is something similar to the maximum speed indicated in the speedometer of an automobile . while you will likely never drive with that speed , the maximum speed is useful because it tells you the potential of the automobile , even though you drive with moderate speed . channel capacity provides not only the upper limit of the possible information transmission rate , but also describes how good the channel is . although there is much interest in the quantity in neurophysiology @xcite , theoretical work is rare @xcite . we have obtained some interesting results on the capacity from two different viewpoints . the details will be given below . we consider here a single spiking neuron , and assume that the input to the neuron controls the expectation of the neuron s output isis . using the terminology introduced above , the information source modulates the isi . we introduce channel noise to the picture by assuming that the isi is a gamma - distributed random variable , when the input to the neuron remains constant . biologically , each cortical neuron receives inputs from a lot of ( pre - synaptic ) neurons and each sensory neuron receives physical stimuli . the above assumption is to model all the inputs to the neuron as a single parameter @xmath87 . although this assumption may seem too simple , @xmath87 is a time varying function and is able to represent a a lot of possible functions . in the gamma isi model , the expectation of the isi is given by @xmath106 . because @xmath107 is fixed , @xmath87 is the input to the neuron . due to refractoriness , a neuron can not fire too fast ; therefore the isi can not be 0 but must be larger than a few milliseconds . on the other hand , if the isi is too large , it means the neuron is not working . thus we assume the input to the neuron is trying to control the isi in a fixed range of time . the average isi , which depends on @xmath87 and @xmath107 , is limited between @xmath108 and @xmath109 , that is , @xmath110 thus , @xmath87 is bounded in @xmath111 . for a noisy channel , one important fundamental problem is to compute the capacity @xmath62 . another problem is to obtain the capacity achieving distribution . the family of all the possible distributions @xmath112 of inputs @xmath113 is defined as @xmath114 the mutual information and the capacity depends on the choice of an output variable . this is called `` coding '' in computational neuroscience , but `` modulation '' is an appropriate term in information theory . traditionally , two types of modulations have been considered in computational neuroscience . one is `` temporal coding '' and the other is `` rate coding '' ( see fig . [ fig : tcandrc ] ) . note that both temporal and rate coding may be used in the brain . for example , binaural sound localisation needs phase information and temporal coding seems natural while rate coding is appropriate for a motor neuron because muscles react according to the rate . we provide some results on the capacity of temporal and rate coding in the following . in temporal coding , the received information is @xmath115 . for a @xmath116 , we define the marginal distribution as @xmath117.\end{aligned}\ ] ] the mutual information between @xmath115 and @xmath118 is defined as @xmath119 \biggr].\end{aligned}\ ] ] the capacity per spike is defined as @xmath120 this optimisation problem can not be solved analytically . however , it has been proven that the capacity @xmath121 is achieved by a discrete distribution with a finite number of mass points ( see @xcite for the details ) . since the optimal distribution is a discrete distribution with a finite number of mass points , the optimisation problem becomes simple , and we can compute the capacity and the capacity achieving distribution numerically . figure [ fig : result_t ] shows the capacity achieving probability distribution for @xmath122 . the channel capacity @xmath123 is 34.68bps ( bit ber second ) ( see @xcite for further results ) . figure [ fig : result_t ] shows that the capacity is achieved when the input is a discrete memoryless distribution . ] with 3 states . this does not imply that the brain is using discrete states . it is more plausible that the brain is using continuous states ; it is likely that the actual information transmission rate in the brain is less than the numerically computed capacity . in rate coding , a time window is set and the number of spikes in this interval is counted . let us denote the interval and the rate as @xmath124 and @xmath60 , respectively , and define the distribution of @xmath60 as @xmath125 . the form of the distribution of @xmath60 is shown in @xcite . for @xmath116 , let us define the following marginal distribution @xmath126.\end{aligned}\ ] ] the mutual information of @xmath60 and @xmath87 is defined as @xmath127 \biggr ] . % \label{eq : mutual_informr}\end{aligned}\ ] ] hence , the capacity per channel use or equivalently per @xmath124 is defined as @xmath128 this optimisation problem can not be solved analytically either , but the capacity @xmath129 has been proven to be achievable by a discrete distribution with a finite number of mass points @xcite . figure [ fig : decode_r-1 ] shows the capacity achieving distribution for @xmath122 . the channel capacity @xmath129is 44.95 bits per second ( see @xcite for further results ) . the definition of channel capacity requires a maximisation over all possible input probability distributions . this definition arose in an engineering context , where a system designer is assumed to have control over the inputs to the channel , but not the channel itself . a different optimisation problem results if the input to the channel is assumed to be fixed , but some control over the channel is possible . this idea is particularly relevant for studies of biological sensory transduction . in this context , an external stimulus that can not be controlled by the sensing organism must be transduced and encoded into action potentials for communication to the brain . this stimulus can be thought of as an input to a communication channel . given internal noise in the transduction mechanisms , the encoded stimulus received by the brain is also noisy . since we introduced mutual information in the context of the channel coding theorem and digital data , and here our channel input is a sensory stimulus , mutual information may not seem relevant . however there are other reasons why it can be useful to ensure mutual information is as large as possible @xcite and we therefore are interested in how the channel might be altered to maximise mutual information . but what can be optimised when the stimulus can not be controlled ? the only other variable that can alter the mutual information is the conditional distribution of the channel output given its input . in the biological context this is the distribution of a neural response for a given stimulus . optimising this distribution means seeking to find the communication channel that it best suited to a fixed stimulus distribution . without some constraints on the form of the conditional distribution , this would not be a meaningful task . one such constraint is to consider a fixed form for the conditional distribution that has some parameters that can be optimised . clearly the optimal parameter set may change for different input distributions . one reason for considering such an optimisation might be to assess whether neuronal mechanisms exist for adaptively altering the conditional distribution to match non - stationary stimuli . another equally intriguing reason is the idea that evolution might have enabled neural systems to change parameters over eons with the end result that those parameters are information theoretically optimal . in this scenario , the underlying fixed form of the probability distribution must be what it is due to unavoidable constraints , or perhaps governed by criteria that are not information theoretic , e.g. energy considerations @xcite . there are several potentially important sets of parameters that might be chosen . however , in other contexts there has been much interest in determining the optimal form of neuronal _ tuning curves _ , and this is our sole focus here . experimentally produced tuning curves are plots of the _ mean _ response of a neural system , as a function of a stimulus parameter @xcite . classic examples of a stimulus parameter include the angle of a moving bar of light relative to the receptive field of visual cells , or the sound pressure level of a single frequency ( pure tone ) sound played by a speaker . in these examples the average response as a function of the stimulus defines the tuning curve . the former kind of tuning curve typically has a bell - shape , meaning that there is a stimulus that produces a maximal response , while more than one stimulus can produce the same lesser response . the latter kind has a sigmoidal shape , meaning that the mean firing rate monotonically increases with stimulus , and here we focus only on this case . we therefore wish to find the sigmoidal tuning curve that maximises mutual information , for a given fixed form of a conditional distribution . while this is generally a difficult optimisation problem , a simple solution exists for channels where the capacity achieving input distribution is discrete , like those considered in this paper . in fact , the mutual information maximising tuning curve can be derived for an arbitrary stimulus distribution , if the capacity achieving input distribution has been calculated first . the reason for this is explained in the following . we consider the same noisy channel as section [ subsec : channel capacity of a single neuron ] , that is the isis are governed by a gamma distribution . we now make a slight generalisation to the setup of sections [ subsec : inputs and noise of channel ] and [ subsec : channel capacity of a single neuron ] and consider the expectation of the isis to be governed by a random variable @xmath13 with a known distribution , such that @xmath118 is an arbitrary function of @xmath13 . we therefore write @xmath130 . for the gamma isi channel , the tuning curve is defined as the conditional expectation of the response variable ( either @xmath115 or @xmath60 ) given a specified outcome of @xmath13 . for timing coding or rate coding respectively , we write these expectations as @xmath131=\kappa f(x)\end{aligned}\ ] ] and @xmath132=\frac{\delta}{\kappa f(x)}.\end{aligned}\ ] ] since @xmath130 , when the capacity achieving distribution for @xmath118 is discrete with say @xmath133 states , the tuning curve will also consist of @xmath133 unique values . lets call these @xmath134, .. ,@xmath135 . while this discontinuous tuning curve achieves the largest possible mutual information for the channel , it is not unique ; other tuning curves are equally good . suppose @xmath13 is a continuous random variable , and that the tuning curve maps large intervals of @xmath13 to the same @xmath133 values @xmath136 , @xmath137 , @xmath138 . this tuning curve provides the same @xmath133 possibilities for the conditional expected isi . in order for it to provide the same mutual information achieved by the original discrete capacity achieving distribution , it is necessary that the probability with which each @xmath139 occurs is the same in both cases . it has been proven for a special case of the gamma distribution and rate coding that this can be achieved by appropriate choice for the ranges of @xmath13 that are mapped to each @xmath139 . the resulting optimal discrete tuning curve is then dependent only on the probability density function of @xmath13 @xcite . consequently , the capacity achieving input distributions derived in section [ subsec : tuning curves ] can be converted to an optimal tuning curve for any choice of the stimulus distribution . an example of the capacity achieving tuning curve is shown in figure [ fig : tuning-1 ] , for the special case of @xmath140 , which means the channel is equivalent to a poisson neuron @xcite . the maximum rate is restricted to 30 spikes per input sample . although such a result holds exactly only for discrete input distributions , similar derivations of information theoretically optimal continuous tuning curves have been made , which hold only in the low noise limit @xcite . see @xcite for related work in the high noise limit . we have shown our results on neuron channel capacity from two very different viewpoints . interestingly , both show that the capacity is achieved by a discrete distribution . the numerically computed capacities are similar to the range indicated by some biologically measured results of sensory neurons @xcite . the channel capacity depends on various factors , and we consider some of them below . we first discuss the input and output of the neuron channel in this subsection . let us start with the input . although each neuron receives information from many neurons , we have only considered a single input @xmath87 . this may seem too simple . we assumed that the single input @xmath87 summarises all the inputs to the neuron . moreover , @xmath87 has been assumed to be memoryless and can have any distribution within the support . considering the biological system , this is far from realistic . the net input of a neuron may not change quickly , that is , it has memory . moreover , a neuron s input is a collection of many neurons noisy outputs , therefore , it may follow a particular probability distribution . this implies that we have computed capacity under less restrictive assumptions , and the biologically achievable rate should be smaller than the capacity obtained in the numerical studies . a better understanding of the constraints on the input of a neuron would lead to a more accurate calculation of neuronal channel capacity . next , we discuss the output of a neuron from two viewpoints , decoding and demodulation . in order to achieve channel capacity , the receiver must act as an optimal decoder , meaning that when @xmath141 is observed , the receiver must compute the posterior distribution of the input @xmath13 as @xmath142 when @xmath98 takes discrete values @xmath143 , it becomes @xmath144 this is a real number for each @xmath145 . in engineering , this type of decoding is called `` soft decoding . '' it seems unlikely that a neuronal mechanisms for carrying this out could exist , since a computation of the posterior distribution is necessary . another standard decoding technique is `` hard decoding , '' that is , only a single value of @xmath145 is chosen by the decoder . the optimal hard decoder chooses the one which maximises the posterior distribution , that is @xmath146 . it is possible to implement the optimal hard decoder without requiring the online computation of the posterior distribution . indeed , the output space ( the space where @xmath141 lies ) can be divided into @xmath147 subspaces in advance , such that the @xmath148 th subspace contains all the points @xmath141 such that @xmath12 has the largest posterior probability given @xmath141 . therefore , the optimal hard decoder can be implemented by a `` quantisation '' or `` thresholding '' algorithm which simply checks to see which subspace @xmath141 lies in . such an algorithm is often computationally simpler than computing first the posterior distribution . when we consider information processing in the brain , a naive soft decoding seems difficult , at least for a single neuron . the hard decoding idea seems more natural . however , the information transmission rate of the best hard decoding is less than the best soft decoding . we should keep this point in mind . further discussion is found in @xcite . under the assumptions made , we have shown that the capacity of a neuron is achieved by a discrete distribution with a finite number of probability mass points . in information theory , there are many other known types of channels for which channel capacity is achieved by a discrete distribution @xcite . for example , although the capacity of an average power constrained additive gaussian white noise channels is achieved by continuously valued gaussian inputs , simply placing a constraint on the maximum amplitude of the channel means capacity is achieved by a discrete distribution @xcite . our results do not imply that `` neuron signals are only using discrete levels . '' on the contrary , we believe many neurons are using continuous levels . what is implied by our results is that those neurons can not achieve the capacity and the actual rate of information transfer is therefore less than the capacity . another implication is for the measurement of information capacity in neuroscience @xcite . our result implies that only a small number of discrete ranges are sufficient for the input distribution to measure the information capacity of neural coding . information theory provides a way of quantifying whether discrete or continuously distributed signals are better for any given communication channel corrupted by random fluctuations . many neuroscience studies quantify information using shannon s famous information _ capacity _ formula relating mutual information to signal - to - noise ratio . this formula is correct only for gaussian additive noise channels @xcite it relies on many assumptions , and if any are false it can significantly under- or over - estimate the true capacity @xcite . guessing the channel model is not straightforward . in particular , feedback is prevalent in many parts of the brain , which makes it much more difficult to relate changes in responses to inputs . one important example where it is known that the circuitry is solely feedforward is that of retinal cells @xcite . this example has been used to demonstrate that it is possible to rule out certain guesses of neural codes . because this is based on optimal bayesian decoding of a forced binary choice , it would be interesting to extend @xcite beyond the binary limitation to that where the signals being coded may have many possibilities what can we say about more complicated situations ? for example , information processing of cortical neurons are not strictly feedforward and the information is shared by many neurons . if we assume every neuron is performing the same computation , and each neuron encodes and decodes information in the same way , it seems possible to extend our results . however , when different neurons encode information differently , the problem becomes very different . understanding how the brain works in information theoretic terms is one of the grand challenges of this century . most information theory research to date has been predicated on an engineering viewpoint . the main thrust has been to _ design _ compression / decompression methods that compress source information to the limits given by its entropy ( source coding ) , or to _ design _ error correction schemes and encoding / decoding methods that allow communication close to capacity . on the other hand , the goal of neuroscience is instead to _ understand _ information processing in the brain . this does not mean that information theory has no place in computational neuroscience . information theory provides a way to _ measure _ information and to understand the _ limits _ of compression ( namely , entropy ) and communication ( namely , mutual information and channel capacity ) . a common `` information theoretic '' method in computational neuroscience is to obtain quantitative estimates of the mutual information between observed sets of data . since various methods for the ( difficult ) problem of accurately estimating mutual information exist , the bigger difficulty is with using the result to say something about how the system works . indeed , the actual goal of computational neuroscience is that of `` system identification , '' as engineers would call it . if the brain uses spikes to transmit information ( which on faster time - scales appears to be the case ) then understanding the neural code how the brain encodes information before sending it across the `` channel '' is tantamount to understanding how the brain works . indeed , if we would listen in to the messages as they are sent from one neuron to another , it would be relatively straightforward to determine what each neuron is doing . although system identification is not the forte of traditional information theory @xcite , this is merely for historical reasons . with computational neuroscience as a main motivator , we predict that the next decade will see the expansion of information theory to include more powerful techniques for system identification , and possibly even an integration of control , computation and information theory into a unified framework . some recent information theoretic approaches in neuroscience that go beyond standard shannon theory are summarized in the following list . * while it is traditional in engineering to separately code an information source , and then _ channel code _ it for communication across a channel , it has been shown for some simple but instructive examples , that non - separation of these two aspects can achieve an optimal communication system with a vastly reduced complexity compared to separation @xcite . this fact is potentially important for neurobiological systems , where separation mechanisms seem implausible . * many studies have investigated whether the brain might have mechanisms for implementing bayesian algorithms during decision making , prediction and pattern recognition @xcite . * the possibility of analog cortical error correcting codes has been proposed by @xcite . * one limitation of shannon theory is that its measures say nothing about directionality or causality . however , directed information theory has also been developed @xcite and has recently been applied in neuroscience @xcite . * the relationship between control , information theory and thermodynamics has been discussed by @xcite . summarising our own modest contribution , we carefully came up with a simple neuron channel model based on biological evidence and computed the channel capacity of this model . interestingly , it was proved that the channel capacity is achieved by a discrete distribution . mark d. mcdonnell s contribution was supported by the australian research council ( arc ) under arc grants dp1093425 ( including an australian research fellowship ) , rn0459498 and dp0770747 . jonathan h. manton wishes to acknowledge several interesting and thought - provoking conversations with professor iven mareels which facilitated the writing of parts of this paper . jm s contribution was supported in part by the australian research council . etienne burdet , rieko osu , david w. franklin , theodore e. milner , and mitsuo kawato . the central nervous system stabilizes unstable dynamics by learning optimal impedance . _ nature _ , 414:0 446449 , november 2001 . stefano panzeri , riccardo senatore , marcelo a. montemurro , and rasmus s. petersen . correcting for the sampling bias problem in spike train information measures . _ j. neurophysiol _ , 98:0 10641072 , 2007 . a. l. jacobs , g. fridman , r. m. douglas , n. m. alam , p. e. latham , g. t. prusky , and s. nirenberg . ruling out and ruling in neural codes . _ proceedings of the national academy of sciences of the usa _ , early edition:0 16 , 2009 .

this paper introduces several fundamental concepts in information theory from the perspective of their origins in engineering . understanding such concepts is important in neuroscience for two reasons . simply applying formulae from information theory without understanding the assumptions behind their definitions can lead to erroneous results and conclusions . furthermore , this century will see a convergence of information theory and neuroscience ; information theory will expand its foundations to incorporate more comprehensively biological processes thereby helping reveal how neuronal networks achieve their remarkable information processing abilities .

a maior desvantagem dos materiais reembasadores resilientes a dificuldade em mant - los limpos . esse trabalho avaliou o efeito de agentes de limpeza sobre a dureza de reembasadores resilientes . foram utilizados os materiais luci sof ( dentsply ) , molloplast - b ( dentax ) e sofreliner ( tokuyama ) , e os agentes de limpeza hipoclorito de sdio a 0,5% ( medicinallis - farmcia de manipulao ) e efferdent ( warner - lamber ) . foram realizados 2 tratamentos : 1 ) hipoclorito de sdio a 0,5% a 37 + 1c , durante 20 minutos ; 2 ) perxido alcalino , a 37 + 1c , durante 30 minutos . aps as imerses , as amostras foram lavadas e imersas em gua destilada , a 37 1c , pelo perodo restante das 24 h. esse processo foi repetido 8 vezes por dia , durante 90 dias . a dureza foi avaliada antes e aps 360 e 720 ciclos , correspondente a 1 e 2 anos de uso clnico , respectivamente . o ensaio de dureza shore a foi realizado em durmetro modelo gs-709 ( teclock - japo ) , com aplicao de carga de 10 n por 1 segundo . alteraes macroscpicas , como perda de cor e alterao da superfcie , foram avaliadas por um observador . os resultados obtidos foram submetidos anova com medidas repetidas e ao teste de tukey ( 5% ) . os materiais apresentaram diferena significante nos valores mdios de dureza , independente do tratamento e do tempo . luci sof e sofreliner aumentaram os valores mdios de dureza inicialmente , os quais diminuram aps 720 ciclos significativamente , para ambos os tratamentos . os tratamentos em agentes de limpeza no alteraram os valores de dureza dos reembasadores resilientes aps 2 anos de simulao clnica . sofreliner apresentou os menores valores de dureza , em todos os tempos e tratamentos , apresentando - se como o material mais macio . even though acrylic resin is commonly used for complete denture bases , patients often prefer resilient denture liners to conventional hard denture bases20 . the use of resilient liners is designed to distribute functional and nonfunctional stresses more evenly and to have a dampening effect because of elastic behavior4 . these properties make resilient liners useful for treating patients with atrophic ridge or resorption , bony undercuts , bruxism , congenital or acquired oral defects requiring obturation , xerostomia and dentures opposing natural teeth . commercially available products include rubbery acrylic- , silicone- , fluoric- and olefin - type materials . it has been shown that resilient liners are easily colonized by candida albicans 12 , which may cause an oral pathologic condition known as denture stomatitis when associated with poor oral and denture hygiene1 . prosthetic cleansing that removes candida albicans is a necessary and important factor in preventing non - traumatic causes of denture stomatitis18 . consequently , the greatest disadvantage of the resilient lining material is the difficulty to maintain it clean10 . routine methods commonly used for denture cleaning include the use of immersion cleansers and brushing2,7 . brushing with or without an abrasive cleanser is also very effective in removing plaque ; consequently , this cleansing method is very common2 . it is still questionable whether brushing causes abrasion of resilient lining materials10 , 17 . while wright20 and schmidt and smith17 observed no evidence that resilient liners are more difficult to clean than conventional dentures , neither were there any evidence of abrasion or wear of its surface , makila and honka10 found wear of the material when submitted to brushing . the immersion type denture cleansers may be defined as alkaline peroxides and hypochlorites , acids , disinfectants , and enzymes2 . ideally these solutions should be effective in removing stains and deposits from the denture ; it should be simple to use and compatible with all denture base materials7 . although chemical denture cleansers have been considered to be an efficacious method to prevent c. albicans colonization and denture plaque formation6 , 13 , it is cited that a daily use of denture cleansers can affect the properties of both denture acrylic resin and resilient liners8 , 11 . thus , dentists should choose denture cleansers by taking into account the compatibility of denture cleansers with resilient liners on both materials and biological aspects . these materials undergo chemical changes over time as patients immerse their dentures in either the aqueous environment of the mouth or , when not in use , in tap water or denture cleansers . since hardening of the material is one of the major reasons for failure of some resilient liners , and difficulty in cleaning these materials remains their disadvantage , the purpose of the present study was to investigate the effect of immersion denture cleansers on the hardness of three resilient liners . the hypothesis tested was that the immersion cleansers would not affect the hardness of the resilient liners evaluated . the resilient liner materials and the denture cleansers used in this study are listed in table 1 . the resilient liners , luci sof , molloplast - b and sofreliner were select because they are commonly used by clinicians . the test solutions consisted of one commercially available denture cleanser and one alkaline hypochlorite solution . thirty specimens ( 24 x 14 x 3 mm ) of each material were prepared by investing dies in a standard metal dental flask ( uraby ; dlc , so paulo , brazil ) . the thickness of the tested specimens chosen for this study was , as far as practical , representative of the clinical situation16 , 17 . the dies were invested in flexible silicone rubber ( zetalabor ; zhermack , badia polesine , rovigo , italy ) to allow easy removal of the processed specimens from the flask . the flask was then completed with type iii dental stone ( herodent soli - rock ; vigodent , rio de janeiro , brazil ) . after the complete setting of the gypsum , the two halves of the flask were separated and the dies removed . a separated medium ( cel lac ; s. s. white , rio de janeiro , brazil ) was applied to the exposed areas of the mold . specimens were made by processing the resilient denture liners in the resulting mold according to the manufactures ' instructions . luci sof was processed by heating the flask in a water bath at 100 c for 2 hours . molloplast - b was processed in a water bath at 100 c for 2 hours . after the polymerization , specimens were removed from the flask , and any flash was trimmed with a sharp knife . the specimens were then removed and stored in water at 37 c for 24 hours , and randomly divided into 2 groups . the alkaline peroxide solution was prepared by adding one tablet of efferdent to 200ml tap water ( equivalent to the dilution recommended by the manufacturer ) which was at initial temperature of 37 c . the solution changed from blue to clear , and after 15 minutes the specimens were immersed into 200 ml of 0.5% alkaline hypochlorite solution at initial temperature of 37 c for 20 minutes . ten specimens of each material were immersed into the solution of each denture cleanser 8 times each day for a total of 720 treatments extending over a period of 90 days . between the immersion periods , the specimens were stored in distilled water at 37 c for the remainder of the 24 hours period . the instrument consists of a blunt - pointed indenter attached to a scale by lever arrangement with a recording scale from 0 to 100 shore a units . the shaft was lowered onto the middle of the specimen , and the highest reading was noted . five readings were obtained for each specimen , and the final hardness mean value calculated for each specimen . the data from the each assay were subjected to analysis of variance with repeated measures and tukey test ( 5% ) . all specimens were examined visually on days 360 and 720 and were compared with the controls so that one observer could note any macroscopic changes such as loss of color or alteration in surface texture . all numeric data were submitted to analysis of variance followed by tukey 's test ( = 0.05 ) . the instrument consists of a blunt - pointed indenter attached to a scale by lever arrangement with a recording scale from 0 to 100 shore a units . the shaft was lowered onto the middle of the specimen , and the highest reading was noted . five readings were obtained for each specimen , and the final hardness mean value calculated for each specimen . the data from the each assay were subjected to analysis of variance with repeated measures and tukey test ( 5% ) . all specimens were examined visually on days 360 and 720 and were compared with the controls so that one observer could note any macroscopic changes such as loss of color or alteration in surface texture . all numeric data were submitted to analysis of variance followed by tukey 's test ( = 0.05 ) . table 2 lists the hardness mean values of the resilient liners subjected to the cleansing treatments . before the immersion treatments , sofreliner presented the lowest hardness mean values , followed by molloplast - b and luci sof . the denture cleansers treatment significantly increased the hardness mean values of luci sof and sofrelinef after 360 immersion cycles . the denture cleansers treatment did not significantly affect molloplast - b mean values , either after 360 or 720 immersion cycles . means followed by the same upper case letter in a column ( time and treatment ) and the same lower case letter in a row ( material and treatment ) do not differ statistically by tukey at a 5% probability level . resilient liners undergo through changes over time as patients immerse their dentures in either aqueous environment of the mouth or , when not in use , in tap water or denture cleansers . hardening of the material is one of the major reasons for failure of resilient liners9 . therefore , it is important to evaluate if denture cleansers can affect the hardness of the resilient liners . initial measurements showed that luci sof presented the highest hardness mean values , followed by molloplast - b and sofrelinef . hardness mean values for the heat - cured materials ( luci sof and molloplast - b ) were significantly greater than those for the self - curing one , in agreement with other studies9,14,15 . this difference might be explained because of the polymerization mode of the materials as well as their composition . increased processing temperatures were expected to result in a more complete polymerization reaction and thus a harder polymer15 . although luci sof and molloplast - b are heat - cured materials , they have different polymerization periods . luci sof was processed for 2 ^ 2 hours in boiling water , and molloplast - b was processed for 2 hours in boiling water , following the manufacturer 's directions . this different period of processing resulted in a more complete polymerization reaction14 , and this might lead to higher hardness mean values . sofreliner is a chemically cured material , and this processing type might result in incomplete initial polymerization and thus lower hardness values . this was likely due to continued polymerization of those , as cited by dootz , et al.4 ( 1993 ) . the materials softened during the remainder of the test period , approaching the initial hardness mean values by the end of the study period , in agreement with kiat - amnuay , et al.9 ( 2005 ) , who tested resilient liners ' hardness after water storage . silicone - based materials do not contain plasticizer , but does contain filler16 , and the absorption of water by the filler could lead to increased softness of the materials evaluated . the decrease of hardness mean values after immersion in denture cleansers occurred because of the absorption of water by the fillers . however , denture cleansers had no effect on molloplast - b mean hardness values , after either 360 or 720 cycles . tan , et al.19 ( 2000 ) did not find significant differences in molloplast - b mean values after immersion treatment in either hypochlorite or peroxide . the authors suggest that this was resulted because of an arbitrary test period and a small experimental group . however , the present study evaluated a longer test period and twenty specimens , and the material presented a linear behavior during it . although hypochlorite caused a marked loss of color in all materials tested , it is questionable whether this change would be of importance clinically . however , it is advisable to warn patients who are provided with a denture relined with these materials that although fading of the lining might occur , this does not indicate that the resilient liner is unsatisfactory . the resilient liners also showed some mirror surface change in the form of loss of sheen . davenport , et al.3 ( 1986 ) suggests that this is the result of an increase in surface roughness . however , this is less likely to be of significance when the denture cleanser being used is effective in removing plaque from prostheses . within the limitations of this study , sofreliner displayed the lowest hardness values before and after the immersion in denture cleansers . according to gonzalez5 resilient liners should have a shore a durometer hardness of approximately 20 to 25 units and not change hardness with service . only sofreliner presented values close to those suggested . in addition , selection of a resilient liner can not be based on any single property . lower hardness values is a desirable property for these materials , but other factors , such as bond strength to denture base , lower surface roughness values , tear strength , water sorption and solubility , must also be considered when selecting these materials . under the conditions of this study , the following conclusions were drawn : denture cleansers significantly increased luci sof and sofreliner hardness mean values after 360 immersion cycles , and decreased significantly after 720 cycles.denture cleansers had no effect on molloplast - b hardness mean values either after 360 or 720 immersion cycles.sofreliner was the smoothest material under the conditions of the present study , before and after the treatments . denture cleansers significantly increased luci sof and sofreliner hardness mean values after 360 immersion cycles , and decreased significantly after 720 cycles . denture cleansers had no effect on molloplast - b hardness mean values either after 360 or 720 immersion cycles . sofreliner was the smoothest material under the conditions of the present study , before and after the treatments .

purpose : difficulty in cleaning resilient denture liners remains a material disadvantage . the purpose of the present study was to evaluate the effect of denture cleansers on hardness of resilient liner materials.materials and methods : three resilient liners , luci sof ( dentsply ) , molloplast - b ( dentax ) , and sofreliner ( tokuyama ) , and two denture cleansers , efferdent ( warner - lamber ) , and 0.5% alkaline hypochlorite preparation were used . twenty specimens of each material were prepared , measuring 25x15x3 mm . two denture cleansing approaches were used : 1 ) alkaline hypochlorite , for 20 minutes ; 2 ) alkaline peroxide , for 30 minutes . this procedure was repeated 8 times a day , during 90 days . the specimens were evaluated before and after 360 and 720 cycles , to simulate 1 and 2 years of clinical cleaning procedures , respectively . the shore a hardness was evaluated in a durometer ( teclock gs-709a ) , with a penetrating load of 10n for 1 second . any macroscopic changes , such as loss of color or alteration in surface texture were recorded by one observer . all numeric data were subject to anova with repeated measures followed by tukey 's test ( = 0.05).results : all materials were significantly different , independently to time and treatment . initially , luci sof and sofreliner immersed in either hypochlorite or peroxide increased the hardness mean values significantly . these hardness mean values decreased significantly after 720 cycles . molloplast - b showed no significant difference after the treatments , in any time.conclusions:denture cleansers had no effect on hardness of the resilient denture liners evaluated after 2 years of in vivo simulated conditions of hygiene . sofreliner was the smoothest material before and after all treatments .

use of antiepileptic drugs ( aeds ) during pregnancy presents the dilemma of minimising the risk of seizure and avoiding adverse effects in the unborn child . various studies revealed that prenatal exposure of aeds imparts serious effects on infants [ 13 ] . further , prenatal exposures to aeds were also reported to produce cognitive impairment [ 4 , 5 ] . janz and fuchs reviewed that exposure to aed during pregnancy increases the risk of miscarriage and stillbirth rate . however , little attention was paid to the cellular effects of aeds during postnatal development and in adulthood . lamotrigine ( ltg ) , a phenyltriazine derivative , is one of the most widely used second - generation antiepileptic agents used for both partial and generalised seizures . in pregnant women , ltg is reported to produce side effects such as rash , mania , memory and cognitive problems , mood changes , runny nose , cough , nausea , indigestion , abdominal pain , weight loss , vaginitis , and leukopenia and retardation in development of fetus [ 810 ] . recently , exposure to ltg during pregnancy was shown to impart adverse outcome within different developmental domains . on the other hand its use in pregnancy is associated with risk of seizure deterioration , because its clearance is accelerated in pregnancy . this reveals the need of additional information on the therapeutic window of ltg or its possible toxic effects in pregnancy . prenatal exposure to ltg ( 520 mg / kg / day ) alone and in combination with mx-801 , phenobarbital , or phenytoin resulted in cell death in the neonatal rat brain . but , katz et al . showed no such effects in the same corresponding dose . thus the effects of ltg during pregnancy , offspring development , and behaviour are still needed to be studied . the present study was undertaken to investigate the effects of prenatal exposure of ltg on postnatal development and its impact on offspring behaviour in rats . ltg was a kind gift from m / s sun pharmaceutical pvt . ltd . , trizol reagent was purchased from sigma aldrich , usa . unless mentioned , all other chemicals and reagents were of analytical grade . animals were housed in polypropylene cages in a well - ventilated room ( air cycles : 1215 air changes / min , recycle ratio : 70 : 30 ) under an ambient temperature of 23 2c and 4065% relative humidity , with an artificial photoperiod of 12 h light / dark cycle . they were provided with rodent feed ( provimi animal nutrition india pvt . ltd . ) and purified water ad libitum . animals were acclimatized for a period of 7 days to the laboratory conditions prior to initiation of the experiment . guidelines of guide for the care and use of laboratory animals ( institute of laboratory animal resources , national academic press 1996 , nih publication number 85 - 23 , revised 1996 ) were strictly followed throughout the study . institutional animal ethics committee ( iaec ) , sri ramachandra university , chennai , india , approved the study protocol ( iaec / xiv / sru/99/2008 ) . following acclimatization , female rats were introduced with proven breeder during night time ( 18:00 ) and were isolated during day hours ( 09:00 ) in the ratio of 3 : 1 , respectively , for copulation . vaginal smear test was performed for each female rat every 24 h and the pregnancy were confirmed by the existence of diestrum stage for three consecutive days . the day of confirmation of pregnancy was designated as gnd 3 and the pregnant rat was isolated into a separate cage . the dose of ltg was arrived from the maximum recommended human dose ( 500 mg ) in the management of epilepsy ( http://www.drugs.com/ ) . pregnant rats were randomized into 4 groups ( 6 in each ) based on stratified body weight . group - i received vehicle ( 0.5% cmc ; 10 ml / kg , p.o . ) ; group - ii , iii , and iv received ltg at 11.5 , 23 , and 46 mg / kg , p.o . , respectively ( three - dose regimen was selected to investigate the dose dependent response ) . body weight gain was measured on postnatal days once in a week till the study termination . the day of occurrence for pinna detachment , incisor eruption , eye opening , vaginal opening , and testes descent was also recorded . offspring were allowed to mature for 90 days with free access to food and water ad libitum . elevated plus maze was constructed of black painted wood with two open arms ( 50 10 1 cm ) and two closed arms ( 50 10 40 cm ) extending from a common central platform ( 10 10 cm ) and elevated to 45 cm above floor level . experiments were carried out in a sound - attenuated , temperature - controlled room and illuminated by two 60 w fluorescent light . on pnd 91 , rats were individually placed in the center of the maze facing open arm . number of entries into open and closed and time spent in open and closed arms were recorded for a period of 5 min [ 1619 ] . open field apparatus consisted of a plywood floor ( 96 96 cm ) with high walls . the entire apparatus was painted black except for 6 mm thick white lines which divided the floor into 16 squares . on pnd 91 , each animal was placed at one corner of the apparatus and observed for next 5 min . the number of squares crossed , immobility period ( in seconds ) , and number of rearing and grooming were recorded . radial arm maze was made of black painted wood finished with a polyurethane coating and consisted of 8 arms with a center platform of 60 cm in diameter . a disposable plastic cup was placed at each end of the arm to reinforce the sweet smash and all arms were baited with either a food cup or an empty cup . the offspring were food - restricted to 8590% and maintained for the duration of training and testing period . the maze task was divided into three phases : adaptation , training , and retention phases . in adaptation phase , the rats were allowed to explore the radial arm maze by 3 5 min trials . during this period , all of the arms of the maze were baited with the food so that the rats received experience in gaining a feed reinforcement by completely traversing an arm and reaching into the food cup . time taken by the animal to move from the starting point ( lag period ) , number of working memory errors , and time taken by the animal to munch the food in all arms were recorded . during the training period , four the trial was terminated when the rat has entered and eaten from all the four baited arms . at the end of the three trials of each day , lag time , number of reference memory errors , working memory errors , correct entries , and total time taken by the animal to munch the food were recorded . after behavioural assessment , all the experimental animals were euthanized using co2 exposure and cortical brain structures were collected for gaba - a and gaba - b mrna expression . briefly , the total rna was extracted using trizol reagent ( sigma , usa ) . after homogenization , the tubes were incubated for 10 min and centrifuged at 1000 rpm for 5 min . 200 l of chloroform was added to the supernatant , allowed to incubate for 5 min at room temperature , and centrifuged at 12000 rcf for 20 min . then 500 l of isopropyl alcohol was added to the supernatant to precipitate total rna and centrifuged at 12000 rcf for 15 min following the incubation period of 10 min . supernatant was decanted carefully and pellet was washed thrice with 75% alcohol and centrifuged at 12000 rcf for 15 min and the pellet was dried . the pellet was resuspended in rnase - free water and stored in 80c until use . the isolated rna was allowed to undergo reverse transcription and polymerization reaction to get cdna using rt - pcr master cycler gradient ( genet bio , korea ) . the gene expression was analyzed using the bands formed in agarose gel electrophoresis , captured using gel documentation unit ( vilber laumar , germany ) and quantified by bio i d software . primers sequence used were as follows : gaba - a : sense , 5-aag gac cca tga cag tgc tc-3 ; antisense , 5-ggc tcc ctt gtc cac tca ta-3. gaba - b : sense , 5-gct gga tgg tta cca cat ag-3 ; antisense 5-ggt cac agg agc agt gat g-3 and -actin : sense , 5-tgc tgt ccc tgt atg cct ct-3 ; antisense , 5-agg tct tta cgg atg tca acg-3 . mean differences between the groups were analysed by one way anova followed by tukey 's multiple comparison as post - hoc test . administration of ltg , at 46 mg / kg , p.o , produced severe signs of toxicity such as hyperesthesia , vocalisation , recumbency , vaginal bleeding , nasal discharge , and finally death of the dam between gnd 15 and 17 . a significant decrease in body weight , food , and water consumption was observed in ltg ( 11.5 and 23 mg / kg , p.o ) administered dam on gnd 14 ( f(3,20 ) = 5.81 , p < 0.01 ; f(3,20 ) = 43.11 , p < 0.01 and f(3,20 ) = 15.51 , p < 0.01 , resp . ) and 21 ( f(2,15 ) = 6.74 , p < 0.01 ; f(2,15 ) = 55.23 , p < 0.01 and f(2,15 ) = 13.08 , p < 0.01 , resp . ) when compared to control ( table 1 ) . ltg ( 11.5 and 23 mg / kg , p.o ) significantly increased ( f(2,15 ) = 23.83 , p < 0.01 ) the gestational period when compared to control rats . no significant difference in litter size between the groups was observed . however , a nonsignificant decrease in pups viability index was observed in ltg administered group when compared to control group ( table 2 ) . ltg ( 11.5 and 23 mg / kg , p.o ) produced a significant delay in incisor eruption in both male ( f(2,15 ) = 6.96 , p < 0.05 ) and female ( f(2,9 ) = 6.36 , p < 0.05 ) offspring when compared to control offspring . a similar observation was recorded in vaginal opening in female offspring ( f(2,9 ) = 286.5 , p < 0.01 ) . there were no significant differences in the day of pinna detachment , eye opening , and testes decent observed between ltg and control offspring ( table 3 ) . no significant difference in body weight was observed in both male and female offspring in comparison to control offspring throughout the study ( figures 1 and 2 ) . ltg male showed no significant difference in number of entries and time spent between open and closed arms . however , ltg female ( 23 mg / kg , p.o ) showed a significant increase in number of entries ( f(2,9 ) = 5.14 , p < 0.05 ) and time spent ( f(2,9 ) = 58.57 , p < 0.01 ) in open arms and decreased number of entries ( f(2,9 ) = 20.88 , p < 0.01 ) and time spent ( f(2,9 ) = 58.57 , p < 0.01 ) in closed arms when compared to control rats ( table 4 ) . no significant difference was observed in number of squares crossed , immobility period , and between the experimental groups . however , a significant ( f(2,9 ) = 4.07 , p < 0.05 ) increase in rearing behaviour was observed in ltg ( 23 mg / kg , p.o ) female offspring when compared to control group ( table 5 ) . there was no significant difference in lag period , number of reference and working memory errors , number of correct entries , and total time taken by the animal to munch the food recorded between the experimental groups ( table 6 ) . mrna expression of gaba - a was found to be significantly ( f(2,3 ) = 17.07 , p < 0.05 ) downregulated in ltg female offspring ( 23 mg / kg , p.o ) when compared to counterparts ; whereas , no difference in gaba - b expression was observed between the experimental groups ( figure 3 ) . use of antiepileptic drugs , such as ltg and levetiracetam , during pregnancy has become challenging these days as they have toxic effects on the developing embryo . administration of ltg in the form of single therapy or polytherapy is at a high risk of developing signs and symptoms of fetal toxicity . the present study demonstrates that prenatal exposure of ltg in rats produced severe signs of toxicity in dam and gender differential behavior in female offspring . various studies demonstrated that prenatal ltg exposure at a dose of 250 mg / kg ( half the human equivalent dose ) increases stillbirth and postnatal death of the offspring [ 25 , 26 ] . in the current study , gestational ltg exposure at 46 mg / kg produced severe toxic signs such as hyperesthesia , vocalisation , recumbency , vaginal bleeding , nasal discharge , and finally death of the dam . . showed that lamotrigine administration increases the follicle stimulating hormone ( fsh ) and luteinizing hormone ( lh ) which in turn stimulated estrogen secretion . increased estrogen secretion results in maturation of graaffian follicle followed by ovulation which leads to embryo detachment . this may be the possible reason for the observed fetal death in the present study . in addition , ltg induces the secretion of parathyroid hormone ( pth ) thereby modulating calcium homeostasis leading to osteoporosis . it is well known that osteogenesis of the embryo occurs at gnd 1521 in rats . increased serum calcium levels by pth reduce the fetal osteogenesis during embryonic development which could also be one of the possible factors for observed fetal death at gnd 1517 in ltg high dose administered rats . decreased body weight gain and feed and water intake of dam treated with ltg revealing its possible maternal toxic effects . further , delayed vaginal opening and incisors eruption in offspring of ltg lower doses group might also be due to its maternal toxic effects . on the other hand , it is reported that ltg administration along with the estrogen - containing hormonal contraceptives reduces the serum ltg concentration . hence the dose has to be increased when administered with such contraceptives to maintain its level of action . in addition , increased estrogen level induces fsh and secretes progesterone and testosterone by feedback control process thereby lengthening the gestational period . although progesterone and testosterone levels were not measured in dams , the increased gestational length observed in our study of rats who administered ltg at lower doses may be due to impaired luteolysis and increased progesterone levels . earlier studies have shown that blockade of gaba - a receptor in rat brain induces hyperexcitability / anxiolytic behaviour in elevated plus maze [ 30 , 31 ] . further , estrogen suppresses gaba - a receptor expression thereby slowing down the gaba mediated inhibition . in the present study , the observed decrease in gaba - a expression and hyperactivation behaviour ( as evidenced by the elevated plus maze and open field test ) may be due to the overactivation of g - protein - coupled receptor 30 ( gpr30 ) by estrogen hormone in the female offspring . put together , the observations showed that the anxiolytic behaviour in female offspring but not the male may be due to the defect in gaba - a expression and also the alterations in gpr30 mediated estrogen secretion . in conclusion , the present study demonstrates the potential untoward effects of ltg in pregnant rats and also its influence on the postnatal development and gender based differential behavioural effects in offspring . our lab is further investigating the mechanisms and reason for these untoward effects so as to utilise the therapeutic benefits of ltg in a safer way .

use of antiepileptic drugs ( aeds ) in pregnancy warrants various side effects and also deleterious effects on fetal development . the present study was carried out to assess the effects of prenatal exposure to lamotrigine ( ltg ) on postnatal development and behavioural alterations of offspring . adult male and female sprague dawley rats weighing 150180 g b. wt . were allowed to copulate and pregnancy was confirmed by vaginal cytology . pregnant rats were treated with ltg ( 11.5 , 23 , and 46 mg / kg , p.o ) from gestational day 3 ( gnd 3 ) and this treatment continued till postnatal day 11 ( pnd 11 ) . offspring were separated from their dam on day 21 following parturition . ltg , at 46 mg / kg , p.o , produced severe clinical signs of toxicity leading to death of dam between gnd 15 and 17 . ltg , at 11.5 and 23 mg / kg , p.o , showed significant alterations in offspring 's incisors eruption and vaginal opening when compared to age matched controls . ltg ( 23 mg / kg , p.o ) exposed female offspring expressed hyperactive behaviour and decreased gaba - a receptor expression when compared to control rats . these results reveal that prenatal exposure to ltg may impart differential postnatal behavioural alterations between male and female rats which paves way for further investigations .

protein - energy malnutrition is prevalent in 1654% of patients undergoing maintenance hemodialysis ( mhd).[13 ] subjective global assessment ( sga ) is a tool that integrates various tests to derive a combined overall score of malnutrition that has been used to determine the nutritional status of patients and other populations at risk of protein energy malnutrition . however , due to its subjective nature , kalanter - zadeh et al . modified it into a fully quantitative scoring system called the dialysis malnutrition score ( dms ) that is more reproducible and accurate . noted that increased psychological stress and related depression in 85% of dialysis patients was regarded as a major predictor of patient outcome and also influenced long - term compliance with diet and medication . regular assessment of physical functioning and encouragement of increased physical activity are still given minimal attention within the nephrology community . thus , a need was felt by the authors to develop a new tool using additional subjective and objective tests to assess the holistic health of renal patients on mhd . thirty subjects ( 13 males and 17 females ) in the age group of 2565 years and maintained on hemodialysis for 3 months were selected using purposive sampling technique after obtaining written informed consent . patients in a disoriented state or with severe multiple complications were excluded from the study . the study protocol was approved by the ethics committee for research in human subjects ( ecrhs ) of seth g.s . the subjects were administered the holistic health assessment tool ( hhat - d ) as well as the dms ( modified sga tool ) . the details of the scoring system for dms and hhat - d tools are given in table 1 . salient features of the dms and hhat - d various anthropometric indicators of body composition including bmi , percent usual body weight ( % ubw ) and percent standard body weight ( % sbw ) , skin fold thickness [ triceps ( tsf ) , biceps ( bsf ) , subscapular ( scsf ) , suprailiac ( sisf ) ] , body fat mass ( bfm ) , lean body mass ( lbm ) , and limb muscle measurements [ midarm circumference ( mac ) and arm muscle area ( ama ) ] were recorded . biochemical tests : total protein , serum albumin , blood urea nitrogen , and hemoglobin levels were noted from patients records . clinical assessment : in addition to gi symptoms , the presence and severity of respiratory symptoms were also recorded since impaired pulmonary function is associated with malnutrition and inflammation and predicts mortality in ckd patients . dietary assessment : dietary nutrient consumption and eating patterns of the patients were recorded using a 24 h diet recall . psychological assessment : a detailed questionnaire was used to assess knowledge about the disease , causes and dietary restrictions and needs ( occupational , physical , social , emotional , spiritual , and financial ) of the patients . the importance of learning to cope with stress in preventing severe malnutrition was evaluated using coping effectiveness inventory ( cei ) . this tool originally developed by almeida and agarwal was modified to include 15 statements dwelling on the five themes such as containment of feelings , generation of hope , self esteem , relationships , and well being with score ranging from 15 ( poor ) to 60 ( high ) . three statements related to each of the five themes were included containing two negative and one positive statement [ table 2 ] that were graded according to the scale [ table 3 ] . modified coping effectiveness inventory scoring system for coping effectiveness inventory assessment of functional capacity : the subjects were asked to perform a simple test for flexibility i.e. sit and reach test to understand readiness for initiating exercise program among them . 2004 ) , patients were scored on two additional parameters including respiratory symptoms and coping effectiveness inventory . each component had a score from 1 ( normal ) to 5 ( very severe ) thereby obtaining scores ranging from 9 ( well nourished / normal ) to 45 ( severely malnourished ) [ table 3 ] . patients with the lower score were considered to have near normal nutritional status while those with higher scores had greater risk of complications . data were analyzed using descriptive statistics including frequencies , percentage , mean , s.d . and advanced statistics such as pearson 's correlation coefficient test to assess the strength of association between the variables using spss ( version 12.0 ) . various anthropometric indicators of body composition including bmi , percent usual body weight ( % ubw ) and percent standard body weight ( % sbw ) , skin fold thickness [ triceps ( tsf ) , biceps ( bsf ) , subscapular ( scsf ) , suprailiac ( sisf ) ] , body fat mass ( bfm ) , lean body mass ( lbm ) , and limb muscle measurements [ midarm circumference ( mac ) and arm muscle area ( ama ) ] were recorded . biochemical tests : total protein , serum albumin , blood urea nitrogen , and hemoglobin levels were noted from patients records . clinical assessment : in addition to gi symptoms , the presence and severity of respiratory symptoms were also recorded since impaired pulmonary function is associated with malnutrition and inflammation and predicts mortality in ckd patients . dietary assessment : dietary nutrient consumption and eating patterns of the patients were recorded using a 24 h diet recall . psychological assessment : a detailed questionnaire was used to assess knowledge about the disease , causes and dietary restrictions and needs ( occupational , physical , social , emotional , spiritual , and financial ) of the patients . the importance of learning to cope with stress in preventing severe malnutrition was evaluated using coping effectiveness inventory ( cei ) . this tool originally developed by almeida and agarwal was modified to include 15 statements dwelling on the five themes such as containment of feelings , generation of hope , self esteem , relationships , and well being with score ranging from 15 ( poor ) to 60 ( high ) . three statements related to each of the five themes were included containing two negative and one positive statement [ table 2 ] that were graded according to the scale [ table 3 ] . modified coping effectiveness inventory scoring system for coping effectiveness inventory assessment of functional capacity : the subjects were asked to perform a simple test for flexibility i.e. sit and reach test to understand readiness for initiating exercise program among them . 2004 ) , patients were scored on two additional parameters including respiratory symptoms and coping effectiveness inventory . each component had a score from 1 ( normal ) to 5 ( very severe ) thereby obtaining scores ranging from 9 ( well nourished / normal ) to 45 ( severely malnourished ) [ table 3 ] . patients with the lower score were considered to have near normal nutritional status while those with higher scores had greater risk of complications . data were analyzed using descriptive statistics including frequencies , percentage , mean , s.d . and advanced statistics such as pearson 's correlation coefficient test to assess the strength of association between the variables using spss ( version 12.0 ) . hhat - d was found to be as effective as the dms in determining the extent of malnutrition among the patients as there was no major difference in the percentage of patients identified at different levels of malnutrition [ figure 1 ] . according to the % ubw , majority ( 46.6% ) of the subjects were found to have mild to moderate malnutrition whereas the % sbw was within the normal range . the hhat - d scores showed a highly significant negative correlation with anthropometric parameters such as bmi , lbm , mac , ama , bsf , % ubw , and % sbw ( p<0.01 ) [ table 4 ] . also , loss of subcutaneous fat showed a significant negative correlation with the body fat mass ( p<0.05 ) calculated from the skin fold measurements at four sites . similarly subjective evaluation of muscle wasting correlated significantly and negatively with the lean body mass measurements ( p<0.05 ) . degree of malnutrition assessed using the dialysis malnutrition score ( dms ) and holistic health assessment tool for dialysis patients ( hhat - d ) correlation between hhat - d scores and various objective tests no significant correlation was found between the hhat - d scores and biochemical parameters , except for total protein that showed a significant negative correlation ( p<0.05 ) indicating that low serum protein was associated with greater malnutrition . the mean serum albumin level ( 3.32 g % ) was toward the lower range of the normal value 3.55.0 g% [ table 4 ] . the bun values were found to be higher than normal while haemoglobin levels were found to be much lower than normal range in the patients [ table 4 ] . cough ( 26.6% ) and shortness of breath ( 46.6% ) were the most commonly reported respiratory symptoms in the subjects . nutrient intake showed a negative but non significant correlation with hhat - d scores indicating that poor food intake in terms of both macronutrients as well as micronutrients lead to the high degree of malnutrition among the patients . however , potassium was consumed in much larger quantities through the diet than recommended [ table 5 ] . psychological assessment revealed moderate ( 36.6% ) to high ( 60% ) coping effectiveness in the patients [ table 6 ] which showed significant negative correlation with hhat - d scores ( r=0.418 , p<0.05 ) indicating that poor ability to cope with stress was associated with severe malnutrition and/or vice versa . simple flexibility test ( sit and reach ) to assess functional capacity showed average ( 40% ) to poor ( 36.6% ) flexibility level [ table 7 ] and a positive correlation with the hhat - d scores , though non - significant . the cronbach 's alpha score for hhat - d ( 0.836 ) was found to be similar to that of dms ( 0.832 ) . average nutrient intake of the subjects coping effectiveness inventory scores and grading of the patients mean flexibility scores of subjects the institution of appropriate medical and nutritional care for the patients could be delayed due to underestimation of the degree of malnutrition , giving rise to increased health risks . the hhat - d included measurement of the % ubw and % sbw of the patients as per guidelines of the national kidney foundation kidney disease outcomes quality initiative to help predict the level of malnutrition . the negative correlation between hhat - d scores and most of the anthropometric parameters indicated compromised nutritional status among the patients [ table 4 ] . the determination of lbm and bfm values included in hhat - d provided for more critical assessment of body composition and can serve as a reference when long term nutritional follow - up is desirable . hypoalbuminemia , as observed in most subjects [ table 4 ] , is highly predictive of future mortality risk when present during the course of mhd . higher than normal bun values and very low hemoglobin levels as noted in the hhat - d helped to pay attention towards metabolic disturbances requiring immediate medical supervision . the nkf kdoqi workgroup have emphasized the importance of treating patients to hemoglobin of greater than 11 g% and hence essential with analyze and monitor . the frequency and duration of gastrointestinal and respiratory symptoms have an impact on the nutritional status . poor respiratory function which is reflective of impact of malnutrition and inflammation on respiratory muscle performance influences clinical outcome but was not part of the modified sga tool and hence considered in the hhat - d . in subjects who developed nausea , vomiting , cough , shortness of breath and pneumonia , poor respiratory functions persisted for > 2 weeks further causing sleep disturbances and compromising physical activity functioning . anorexia and restriction of certain foods that are rich in water - soluble vitamins owing to their high potassium content lead to poor food intake and thereby low nutrient intake among renal patients . in the present study also , the average dietary consumption of total calorie , protein , fiber and several micronutrients was found to be much lower than the recommended level while fat intake of the subjects was adequate [ table 5 ] . anemia is a very common problem among ckd patients caused by the deficiency of erythropoietin and/or iron . ensuring sufficient iron intake through diet could be considered in the management of anemia , though intravenous infusion of iron is unavoidable in certain cases . hypercalcemia in hemodialysis patients resulting from excess calcium and phosphorous intake increases risk of calcification of soft tissues . hence , the calcium needs are individualized based on careful evaluation of serum calcium and phosphorous levels , use of supplements , phosphate binders , dialysate calcium concentration and sufficiency of dietary intake . individualized attention to the calcium and iron needs of the patients is necessary due to the changes in mineral metabolism in order to plan suitable management strategies . opined that evaluation of psychological status should be part of the care provided to hemodialysis patients . this contention was supported by other experts who observed chronic depression among dialysis patients and other psychiatric disorders having an impact on overall quality of life . knowledge about the clinical condition can serve as a key element to overcome stress since patients gain a sense of control over their experiences and environment and helps reduce feelings of vulnerability , whereas lack of awareness can lead to patients harboring wrong notions and faulty beliefs further hindering recovery . current study recorded poor knowledge base and inadequate information about the disease condition and associated dietary changes among the patients . interestingly , women were less vocal about their needs as compared to men and both the sexes showed high social and emotional needs which would help them tide over the stressful state more easily . the cei tool has been found to be reliable ( cronbach 's alpha 0.80 ) and valid for assessment of coping strategies among indian population suffering from end stage renal disease . in the present study , the total cei scores revealed that better coping was associated with lower degree of malnutrition for both the sexes [ table 6 ] thereby highlighting the need to pay attention to this vital aspect of nutritional status . ersoy - kart and guldu reported lower coping scores and greater vulnerability to stress among 55 patients receiving hd in turkey . the reduced physical capacity and activity level in hemodialysis patients as assessed through the flexibility test [ table 7 ] may be responsible for the increased incidence of depression observed among them which reduces the patients ability to perform familiar pleasant activities . opined that establishing the validity and reliability of each version of nutritional assessment tool in different patient populations is very essential to facilitate correct application of the same by clinicians and researchers . the cronbach 's coefficient alpha - test showed a high degree of inter - item correlation indicating a high internal consistency of each item in the tool . the reliability scores signify that the items in the tool ( anthropometry , body composition , etc ) truly measured the construct ( assessment of health status ) they were aimed to measure . also , the selected objective tests showed significant negative correlation with the hhat - d scores ( based on subjective evaluation ) thereby enhancing the validity of the tool . thus , the holistic health assessment tool for dialysis patients ( hhat - d ) can be considered as a valid and reliable tool which throws light on the various crucial indicators of malnutrition associated with kidney dysfunction and hence can be used to improve the overall quality of life of these patients . however , there is a need to further assess the inter and intra - observer reliability as well as validity of the hhat - d tool by administering it on larger subject population with the help of more comparative and longitudinal studies .

the recent emphasis on assessment of the psychological status , availability of newer and better methods of interpreting the anthropometric measurements of renal patients on dialysis therapy prompted the authors to develop the holistic health assessment tool for dialysis patients ( hhat - d ) . a total of 30 subjects ( 2565 years ) , enrolled from dialysis centers in mumbai were administered the hhat - d tool to assess anthropometric , biochemical , functional , and psychological status ( knowledge , needs , that coping strategies ) along with dietary intake . the results showed that majority of the patients ( 73.3% ) were mild to moderately malnourished . a highly significant negative correlation of anthropometric measurements ( bmi , lean body mass , mid arm circumference , arm muscle area , bicep skin fold thickness , % usual body weight , and % standard body weight ) with the hhat - d scores ( p<0.01 ) confirmed the validity of the tool in assessing the degree of malnutrition . the poor health status of the patients was further confirmed by the average ( 40% ) to poor ( 36.6% ) flexibility status and poor dietary nutrient intake . moderate ( 36.6% ) to high ( 60% ) coping effectiveness was recorded in the patients as assessed using the coping effectiveness inventory . a high degree of interitem correlation ( cronbach 's coefficient alpha - test value 0.836 ) also proved the reliability of the hhat - d tool . thus , the hhat - d was found to be a specific and reliable tool for assessment of holistic health status of patients on maintenance hemodialysis to improve quality of life and facilitate faster recovery .

type i cytokine receptors , such as receptors for erythropoietin ( epo ) , thrombopoietin ( tpo ) , granulocyte colony stimulating factor ( g - csf ) and most interleukins ( il ) receptors , and type ii interferons ( ifn ) lack intrinsic catalytic activity . in order to initiate downstream signaling these receptors bind one or several members of cytoplasmic tyrosine kinases of the janus kinase ( jak ) family ( fig . after binding of the cytokine to the receptor extracellular domain two scenarios are possible : ( 1 ) the receptor exists as preformed dimer at the cell surface and ligand binding induces a conformational change ; or ( 2 ) dimerization or oligomerization is induced after ligand binding and thus induces a conformational change of the receptor . the conformational change brings the cognate jak proteins in close enough proximity that they transphosphorylate each other ( fig . in turn , activated jak proteins phosphorylate tyrosine residues in the receptor cytoplasmic domain and in jaks themselves and provide docking sites for signaling proteins such as signal transducer and activators of transcription ( stat ) . stat proteins become thus substrates and are phosphorylated by jaks , form dimers and translocate to the nucleus where they modify gene expression . in particular the jak2 v617f mutant has been studied in great detail and our current understanding about its function is highlighted in this review . ( a ) ligand binding induces a conformational change of the cytokine receptor and allows transphosphorylation of jak proteins . activated jaks phosphorylate tyrosine residues in the receptor cytoplasmic domain and provide docking site for stat proteins . phosphorylated stats dissociate from the receptor , dimerize and translocate to the nucleus where they modulate gene expression . ( b ) in case of the jak2 v617f , mutant cytosolic tyrosines are constantly phosphorylated , leading to constitutive activation of stat proteins . myeloproliferative neoplasms ( mpns ) are a group of blood disorders characterized by an overproduction of one or more of the myelo - erythroid lineages ( fig . the three most common mpns are polycythemia vera ( pv ) , essential thrombocythemia ( et ) and primary myelofibrosis ( pmf ) . features of pv are the overproduction of mature , functional red blood cells , leading to an increased red - cell mass and hematocrit , while et patients have an increase in platelet numbers and pmf is characterized by scarring of the bone marrow with fibrosis and extramedullary hematopoiesis . the jak2 v617f mutation was first described in 2005 as the major underlying molecular event of bcr - abl negative mpn . it is found in approximately 95% of pv and 50% of et and pmf patients . the point mutation occurs in the pseudokinase domain of jak2 and causes a substitution of valine at position 617 by phenylalanine ( jak2 v617f ) . the pseudokinase domain has high sequence homology to kinase domains , but lacks key residues necessary for catalytic activity . it is thought that the v617f mutation either releases the inhibitory function of the pseudokinase domain on the jak2 catalytic domain , or that it induces a conformational change to the pseudokinase domain that in turn activates the kinase domain ( fig . it has been shown that overexpression of jak2 v617f promotes cytokine independent growth of the il-3 dependent pro b cell line ba / f3 ( basel f3 cell line ) in the absence of cytokines ; however , at low jak2 v617f expression , dimeric cytokine receptors such as epor , tpor or g - csfr have to be present to promote cytokine independent baf3 growth . it is thought that the jak2 v617f mutant gains full transforming activity only when the mutant jak2 dimerization is promoted by receptor dimerization . this is supported by the need for oncogenic jak2 v617f activation of an intact ferm ( homologous to protein 4.1 , ezrin , radixin , moesin)-like domain , a domain that normally mediates jak binding to cytokine receptors . this is the case for epor , tpor or g - csfr , but other receptors can support jak2 v617f activation . a second model predicts that the jak2 v617f mutant is a weak , constitutively active kinase and that receptor binding is necessary to induce its full kinase activity . in any case , binding of jak2 v617f to epor , tpor or g - csfr is predicted to stimulate expansion of the erythroid , megakaryocytic and granulocytic lineages which are affected in pv , et and pmf . ( a ) myeloid blood cell development starts with the hematopoietic stem cell ( hsc ) that either self - renews or gives rise to a common myeloid progenitor ( cmp ) . the cmp in turn differentiates into more restricted progenitors of the megakaryocyte ( mk)-erythroid ( e ) lineages or granulocyte - monocyte progenitor ( gm ) . these cells give then rise to terminally differentiated erythrocytes , megakaryocytes / platelets , granulocytes ( eosinophils , neutrophils and basophils ) and monocytes . cytokines and their receptors control cell proliferation and differentiation during hematopoiesis and ensure the balance between renewal and cell differentiation . ( b ) several reports have confirmed that the jak2 v617f mutation occurs at the level of an hsc . there is , however , still controversy to whether the jak2 v617f mutant expands the true hsc pool or whether it acts downstream on a more committed progenitor . further studies are necessary to clarify the exact role of jak2 v617f on hsc or progenitor expansion . since the jak2 v617f mutant only influences myeloid differentiation , we have restricted the schematic to the myeloid lineage . the jak2 v617f mutant induces several downstream signaling pathways , recapitulating in a persistent manner the pathways transiently activated by cytokines , i.e. , stat5/3 , map - kinase , pi-3-kinase / akt and mtor pathways . pv patients exhibit high stat5 and stat3 phosphorylation , while et patients exhibit high stat3 but low stat5 phosphorylation . several lines of evidence indicate that constitutive activation of jak2-stat5 and stat3 signaling is the basis of pv , et and pmf . recently , it was shown that knockout of stat5a / stat5b prevents induction of the myeloproliferative phenotype by jak2 v617f , thereby establishing an obligatory role of stat5 in mpns . furthermore , the choice and relative levels of activated stats can have profound consequences on the lineage that is amplified . for example , down - modulation of stat5 in cd34 cells promotes megakaryocyte differentiation , while activation of stat5 promotes erythropoiesis . x - linked polymorphism studies showed that mpns are clonal disorders and several groups could show that the jak2 v617f mutation can be detected in cells with an hsc signature ( lin- cd34cd38cd90 and cd34cd38 ) , confirming that the jak2 v617f mutant arises in an hsc . previously , delhommeau et al . reported that jak2 v617f is present in a multipotent cell that can give rise to both myeloid and lymphoid cells . much effort has been made to study the in vivo significance of jak2 v617f with mouse models in order to decipher the molecular mechanisms causing initiation and progression of mpns . several groups performed reconstitution assays using bone marrow cells ectopically expressing the jak2 v617f mutant and showed that mice indeed developed hallmarks of pv . . generated stable transgenic mouse models expressing the mouse jak2 v617f cdna under control of the major histocompatibility complex h-2 kb promoter or the human jak2 v617f cdna under control of the vav promoter , respectively . both h-2 kb and vav promoters drive transgene expression efficiently throughout the nucleated hematopoietic cell types and both groups demonstrated that the mice developed key features of pv or et with erythrocytosis and thrombocytosis . interestingly , a later study used a floxed version of the human jak2 v617f cdna under control of a human jak2 promoter and showed that the disease outcome correlates with the relative expression levels of endogenous wild type ( wt ) vs. human mutant jak2 . for example , lower levels of human jak2 v617f mutant than endogenous wtjak2 induced an et - like phenotype , whereas higher jak2 v617f levels induced a pv - like phenotype . more recently , several knock - in models have been published where the jak2 v617f mutant is expressed from the endogenous jak2 locus thereby allowing expression in blood cells at physiological levels . observed a pv - like phenotype in hetero- and homozygous mice including increased number of red blood cells and hematocrit levels with homozygous mice frequently progressing to myelofibrosis . additionally , in this particular model heterozygous and homozygous jak2 v617f mice showed significant expansion of hematopoietic stem cells ( hsc ) [ linsca1ckit ( lsk ) population ] and myeloid progenitor cells in the bone marrow . in another study by marty et al . where a murine jak2 v617f was knocked - in , mice developed a marked pv - like phenotype accompanied by erythrocytosis , leukocytosis and splenomegaly and myelofibrosis around 9 mo of age . a third study showed similar results with the jak2 v617f knock - in mouse developing a pv phenotype . however , the mice progressed faster to pmf and had an average survival rate of only 150 d , while mice described by marty et al . mullaly and colleagues further showed that the hsc compartment has the unique capacity for disease initiation , but does not exhibit a competitive advantage over wild - type hscs . in contrast , myeloid progenitor populations are expanded and skewed toward the erythroid lineage , but could not transplant the disease . consistent with these data are microarray analysis that indicated that gene expression profiles of lsk cells were similar to those of wild - type lsk cells . in a fourth study , li et al . generated knock - in mice encoding the human jak2 v617f cdna . in contrast to the above mentioned models , the authors could only observe an et - like phenotype with mild increase in platelets and hematocrit , and no sign of myelofibrosis . interestingly , li et al . reported that mice at 26 weeks of age had 50% reduced numbers of lsk with increased dna damage , reduced cell cycling and reduced apoptosis . also , bone marrow transplantation experiments showed decreased stem cell activity in cells expressing jak2 v617f compared with wild - type controls . consistent with this , direct comparison of the wild - type vs. jak2 v617f bone marrow cells in competitive transplantation experiments demonstrated that jak2 v617f confers a mild but significant disadvantage to hscs , an effect that was most striking in secondary transplantations . the above described mouse models ( summarized in table 1 ) were addressing the question of how the jak2 v617f mutant affects hsc expansion . the reasons behind the opposite conclusions between the study of li et al . several studies have directly focused on the role of jak2 v617f in primary mpn patient samples . jamieson and colleagues isolated hsc and myeloid progenitors from patients and healthy controls in order to investigate whether jak2 v617f positive cells have altered differentiation potential . the authors analyzed cells with a hsc signature ( lincd34cd38cd90 ) and showed that the majority of hsc obtained from pv patients harbor the jak2 v617f mutation with the mutation being transmitted to more committed progenitors . moreover , the authors demonstrated that the hsc numbers and the common myeloid progenitor ( cmp ) pool are increased and that differentiation is skewed toward the erythroid lineage . in contrast to this report are studies performed by james et al . and anand et al . the first study by james and colleagues used xenograft assays to study the properties of jak2 v617f positive cd34 cells from pv , pmf and post - pv mf patients and demonstrated that the jak2 v617f repopulating cells are present in the three diseases , but the proportion of jak2 v617f compared with jak2wt was markedly different between pv and pmf . the authors did however not find major differences in the proliferation and self - renewal properties of jak2 v617f repopulating cells between pv , pmf and post - pv mf indicating that the jak2 v617f mutant does not confer a proliferation advantage to the hsc compartment . the second study by anand et al . examined the effects of the jak2 v617f mutant on hsc homeostasis through analysis of bone marrow samples from pv , et and mf patients . the study revealed that the jak2 v617f mutant does not alter the lincd34cd38 , cmp and granulocyte - monocyte progenitor ( gmp ) compartments in et and pv patients , but rather affects the later erythroid cd34cd71gpa cell compartment . a third study by ishii et al . the authors showed that cd34 cells from healthy donors as well as imf patients and pv patients with high jak2 v617f burden reconstituted mice , whereas cells from pv patients with low jak2 v617f burden did not . one possible explanation for this observation is a qualitative difference between low- and high - burden jak2 v617f hsc . as a second possibility is that high burden jak2 v617f cells contain higher numbers of authentic long - term hscs , while cd34 cell fractions from patients with low jak2v617f burden contain less hscs that engraft in immuno - deficient mice . based on the result of latter study the level of jak2 v617f decides whether or not jak2 v617f positive hscs have an engraftment and repopulating advantage compared with healthy hsc ( fig . 2 ) . in conclusion , the results obtained by the different studies have to be compared in order to define the differences in cell populations used and to determine what the possible explanations are for the discrepancies obtained with the different analyses . stat5 was reported to be involved in self - renewal of mouse and human hscs and to regulate renewal vs. differentiation as a function of its levels of expression . using a tamoxifen - inducible stat5a(1 * 6)-estrogen receptor fusion protein , it was shown that high stat5 levels block myelopoiesis and promote erythropoiesis , while intermediate levels of transactivation induce hsc and cd34 proliferation . self - renewal of hscs was promoted by the same intermediate levels of stat5 activation . these results indicate therefore that levels of stat5 activation are decoded in self - renewal vs. differentiation signals . one caveat of such models is that a double mutant stat5 is used , which is constitutively active , but might have properties different from those of cytokine - activated stat5 . indeed , in cell lines persistently activated stat5 was shown to induce common , but also different genes than transiently activated stat5 . stat5 was shown to induce long - term self - renewal only in human hscs , not in progenitors . one target gene of stat5 that is induced by stat5 in hscs was identified to be hypoxia - induced factor 2 ( hif2 ) . expression of this gene is apparently required for stat5-induced hsc amplification , but not for hsc differentiation . one model has been proposed where stat5 maintains expression of hypoxia - induced genes , in the absence of hypoxia , in order to promote hsc self - renewal . another gene that is modulated by stat5 is c / ebp , and this gene is the major downregulated gene by stat5 in hscs . re - expression of c / ebp impairs the effects of constitutively active stat5 on hscs , indicating that part of the mechanism by which mutant stat5 expands long - term hscs is represented by down - modulation of c / ebp. while interferons are classical antiproliferative agents , several studies reported that ifn- and ifn- induce cycling of hscs . ifn- binds to the interferon receptor 1 and 2 ( ifnar1 and ifnar2 ) and thus activates the jak tyrosine kinase family members jak1 and tyk2 to signal via a complex formed of stat1/stat2/irf9 ( reviewed in ref . ifn gamma signal activates jak1 and jak2 via the interferon gamma receptor 1 ( ifngr1 ) and ifngr2 receptor subunits and signals via stat1 homodimers . in response to treatment of mice with ifn- , signaling via stat1 and akt induces the transition of hscs from quiescence into cell cycle . similarly , ifn- induced in several infections , signals via stat1 and induce hsc cycling . the implications of these data might be relevant for the treatment of mpns with ifn-. at this moment , approximately 40% of pv and et patients respond positively to ifn- treatment , and for jak2 v617f patients , this leads to a decrease or disappearance of jak2 v617f positivity . the effect is quite slow , requiring many month to one year , suggesting that the effect is mainly on hscs , and that somehow ifn treatment leads to exhaustion of the mutated clone , with preservation of the normal clones . in patients with mpns where the jak2 v617f mutation occurs on the background of a clone where tet ( ten 11 translocation ) methylcytosine dioxygenase 2 ( tet2 ) , a protein that converts 5-methylcytosine in dna to 5-hydroxymetylcytosine is deleted / mutated on both alleles , clonal analysis showed that ifn-2a treatment targets the jak2 v617f - positive clone , but does not affect the tet2 clone . interestingly , the presence of biallelic loss of tet2 did not impair the effect of ifn on jak2 v617f hscs . it will therefore be important to determine the molecular basis of the effect of ifn specifically on the jak2 v617f hscs . the roles of jak - stat signaling in hsc renewal and amplification remain poorly defined . results obtained from studies examining the role of stat5 in hsc homeostasis on one hand , and the effects of interferons on the other , provided evidence that the jak - stat pathway can profoundly influence hscs . the recent discovery of the unique somatic acquired jak2 v617f mutation , which is at the basis of the majority of bcr - abl negative mpns provided novel models for exploring the question of whether jak - stat pathway plays an important role at the hsc level . there are two major biological questions that to date have been answered with apparently contradictory reports : ( 1 ) does jak2 v617f confer an advantage to hscs , in terms of proliferation , self - renewal , differentiation or transplantation ( fig . 2 ) , and ( 2 ) is jak2 v617f at the hsc level inducing a skew in the type of downstream differentiation , in contrast to mere amplification of the downstream progenitors without any skew of hsc potential ? while the acquisition of jak2 v617f at the hsc level has been confirmed by several groups , the reasons behind it remain unclear . it is still not known whether the mutation is constantly acquired ( like bcr - abl ) , but only some individuals select for it ( i.e. , hypersensitivity to cytokines due to snps or unknown previous mutations ) , whether the mutation protects against an insult , and its selection is favored by such pressure , or whether there are dna replication defects that favor such mutation acquisition . the g to t mutation occurs in a region with repeated tt sequences ; it is possible that it occurs from slipped mispairing , however , the actual mechanism of mutation acquisition remains still to be determined . how can we explain the contradictory results coming from mouse models and from xenotransplantation and colony assays , where both an advantage and a disadvantage of the mutated hscs ( or no change ) were observed , or where differentiation skewing or absence of it was each observed ? one possibility is that any transplantation approach requires homing and renewal in a foreign niche , events that are not relevant for the disease . another is that , as opposed to mouse models where all hscs are knocked - in or transgenic , in humans the disease starts from one mutated cell that must make its way to differentiation and gain clonal dominance . it is possible that events linked to the latter are very important , and remain unexplored by mouse models . finally , hscs exist in several subtypes , such as myeloid - biased , lymphoid - biased and several others and we have little idea at the moment in which such hsc jak2 v617f must arise in order to induce et , or pv or pmf and which events are necessary for progression of et and pv to secondary mf . in any case , it appears that the jak2 v617f burden at cd34 or at hsc level is the most important , and that mf is associated with a loss of wt hscs and preservation of mutated hscs , which also exit the marrow , have down - modulated cxcr4 and can be found in periphery . directly linked to the subtype of hscs targeted by the mutation , recently it was shown that a precursor of endothelial / hsc cells can also acquire the mutation , and might be involved in the deep venous thrombosis events linked to jak2 v617f . clearly a much more detailed understanding of the hsc subtypes , their niches , pressures and response to cytokines will be necessary for understanding of relevant effects of jak2 v617f on hscs . the major goal of therapy in mpns is to reduce the source of cytokine - independent myeloid progenitors that is the hscs with mutations . for this purpose a major advance is required to distinguish mutated disease - initiating hscs from possibly non - disease initiating hscs and non - mutated hscs . the prediction is that the effect of jak - stat signaling in each such cell will be different .

janus kinases ( jaks ) are non - receptor tyrosine kinases essential for activation of signaling mediated by cytokine receptors that lack catalytic activity , including receptors for erythropoietin , thrombopoietin , most interleukins and interferon . upon hormone binding , jaks phosphorylate tyrosine residues in the receptor cytoplasmic domains and in jaks themselves leading to recruitment and activation of downstream signaling proteins such as signal transducer and activator of transcription ( stat ) . the jak - stat pathway is important for functional hematopoiesis and several activating mutations in jak proteins have recently been described as underlying cause of blood disorders . one of the best studied examples is the jak2 v617f mutant which is found in 95% of polycythemia vera patients and 50% of patients suffering from essential thrombocythemia and primary myelofibrosis . much effort has been made to understand how the jak2 v617f affects hematopoietic stem cell ( hsc ) renewal and lineage differentiation , since convincing evidence has been provided to support the notion that the mutation is acquired at the hsc level . we discuss several in vivo models that support contrary conclusions with respect to the advantage given to hscs by jak2 v617f . moreover , we provide the current knowledge about stat5 activation and its link to hsc expansion as well as amplification of the erythroid compartment . evidence for both jak2 v617f mutated hscs exhibiting skewed differentiation potential and for amplification occurring after erythroid commitment has been provided , and we will discuss whether this evidence is relevant for the disease .

nortriptyline ( nt ) has been used to treat various forms of depression , often in conjunction with psychotherapy . common adverse effects associated with tricyclic antidepressant ( tca ) therapy include dry mouth , blurred vision , tachycardia , constipation , urinary retention , sedation , and orthostatic hypotension ( 1 , 2 ) . these usually occur in association with toxic concentration of tca . nt is extensively metabolized in the liver . the main metabolic pathway of nt is benzylic hydroxylation in the c-10 position , mediated by cyp2d6 ( 1 - 3 ) . genetic polymorphism of cyp2d6 is responsible for the great interindividual variability in the pharmacokinetics of nt . cyp2d6 poor metabolizers may experience severe adverse effects ( 4 - 7 ) , because of high nt concentrations . alternatively , nt may be ineffective in ultrarapid metabolizers of cyp2d6 ( 4 ) . in this report , we present a case on nt therapy with cyp2d6 * 5/*10b , which results in decreased activity of cyp2d6 . high plasma nt concentrations associated with adverse effects after standard doses of nt was found in this case . a 54-yr - old man was hospitalized following a suicide attempt . for the last 2 months the patient had suffered from depression , anxiety , insomnia , and delusion . at the time of admission , physical examination of nt ( 50 mg / day ) , lorazepam ( 1 mg / day ) , and risperidone ( 2 mg / day ) were initially prescribed . the patient 's dose of nt was then increased gradually to 100 mg / day , administered on a divided - dose schedule . determination of plasma nt level was performed by high - performance liquid chromatography using hewlett packard 1090 system ( hewlett packard gmbh , waldbronn , germany ) . the plasma concentration of nt after 6 days of treatment with 100 mg of daily dose was 181.4 ng / ml ( recommended therapeutic range : 50 - 150 ng / ml ) . however , in an attempt to achieve further clinical improvement , the nt dosage was increased to 150 mg / day over 20 days , which resulted in plasma concentrations of 470.6 ng / ml after 6 days . because of this unexpectedly high drug level and worsening of anticholinergic side effects , the patient 's dosage was reduced to 100 mg / day . the following measurements indicate that nt concentrations were reduced ( 198.7 - 222.7 ng / ml ) but still remained higher than the recommended therapeutic range . the patient was discharged after 1 month of hospitalization with a maintenance dose of 100 mg / day . cyp2d6 gene was amplified by long pcr , to analyze all 9 exons of cyp2d6 gene ( 8) . all pcr products were sequenced using abi prisim bigdye terminator cycle sequencing kit ( applied biosystems , foster city , ca , u.s.a . ) and an abi prism 3100 genetic analyzer ( applied biosystems ) . cyp2d6 * 5 allele was detected using long pcr as described by hersberger et al . a fragment specific for deletion of cyp2d6 gene was obtained with the forward primer specific for exon 9 of cyp2d7 and the reverse primer specific for the 3'flanking region of cyp2d6 . the patient was found to have cyp2d6 * 5/*10b , which results in low cyp2d6 activity ( fig . 1 , 2 ) . he has been continuing supportive psychotherapy at the outpatient clinic monthly and remains improved , even though his nt dose has been reduced to 50 mg / day . plasma concentrations of tcas have been found to correlate well with drug responses ( 1 ) . the recommended therapeutic plasma levels of nt are between 50 ng / ml and 150 ng / ml ( 1 , 2 ) . levels above this range have been associated with an increased incidence of side effects . generally , medications of nt begin at low doses ( 50 - 75 mg / day ) . the dose is then increased gradually to an average dose of 150 mg / day until the optimal therapeutic range is reached . however , steady - state concentrations in plasma observed in the course of treatment with tcas are poorly related to the administered dose , and values in patients who were given similar doses of tcas can vary from 10- to 35- fold ( 1 - 4 ) . patients on the same dose can develop sub - optimal , therapeutic or toxic concentrations depending on their clearance rate ( 1 ) . interindividual variation in the metabolism of nt is one of the important determinants for plasma levels or adverse effects of the drugs . cyp2d6 , which is involved in the hepatic metabolism of nt , contributes to broad interpatient variability . previous reports have suggested that the steady - state concentrations of the drugs were genetically controlled ( 4 - 7 ) . subjects with more than one inactive cyp2d6 allele demonstrate poor metabolizer phenotype and develop high plasma nt concentrations ( 5 , 7 ) . accordingly , poor metabolizers of cyp2d6 are more prone to nt overdose . about 5 - 10% of caucasians and 1% of asians are poor metabolizers with regard to cyp2d6 substrates ( 4 , 10 ) . the frequency of non - functional allele cyp2d6 * 5 , with deletion of the entire cyp2d6 gene , is 4 - 6% of the populations ( 10 , 11 ) . cyp2d6 * 10 is the most prevalent allele in asians and its frequency ranges from 38 - 70% ( 10 - 12 ) . cyp2d6 * 10 allele is associated with significantly reduced metabolic activity , approximately 60% of normal activity ( 10 ) . in this report , the patient revealed decreased cyp2d6 enzyme activity with the genotype of cyp2d6 * 5/*10b . therefore , he attained drug concentrations above the therapeutic range at the standard doses and might be at a higher risk of developing adverse reactions . this patient could have taken appropriate therapeutic changes earlier and maintained his psychiatric gains at a lower dose , if he had been genotyped at the beginning of his nt therapy . treatment with two or more drugs metabolized by the same cyp enzyme may result in interactions such as competition of the enzyme and decreased rates of metabolism ( 4 ) . shim et al . ( 13 ) reported that paroxetine , a potent cyp2d6 inhibitor , increased the blood levels of tricyclic antidepressant in 10 korean schizophrenic patients . as risperidone is a weak inhibitor of cyp2d6 enzyme and its metabolite is pharmacologically equipotent to the parent drug , drug interactions related to polymorphic metabolism would be expected to have limited clinical significance ( 4 , 14 ) . clinicians are used to adjusting the dose based on clinical response and plasma drug concentrations . additional cyp2d6 genotyping can serve as an important guide for more rapid dosage adjustment and prediction of drug response in each individual . cyp2d6 genotyping is recommended to complement therapeutic drug monitoring especially when the unusual metabolic capacity of nt is suspected . moreover , due to the potential seriousness and cost of adverse effect including cardiac toxicity ( 15 ) , we can emphasize the importance of cyp2d6 genotyping in dosage adjustment of nt .

we present a case with decreased metabolic activity of cyp2d6 , a cytochrome p450 enzyme catalyzing the metabolism of nortriptyline ( nt ) . conventional dosage regimen led to toxic plasma concentration of nt and adverse effects such as dry mouth , constipation , and dizziness in this case with genotype cyp2d6 * 5/*10b . this case suggests the clinical usefulness of pharmacogenetic testing in individualized dosage adjustments of nt .

soybean- and cruciferous vegetable - enriched diets seem to be particularly protective , but the mechanisms for this anticarcinogenicity are not fully understood . genistein , a dietary phytoestrogen belonging to the isoflavone class of flavonoids , is thought to have anticarcinogenic activities , particularly for breast and prostate cancer [ 1 , 2 ] . dietary soy has been shown in mice to inhibit prostate tumor growth through inhibition of cell proliferation , increased apoptosis , and reduced microvessel density . epidemiology studies of asian women indicate that consumption of a traditional diet high in soy confers significant protection against breast cancer . 3,3-diindolylmethane ( dim ) , a breakdown product of glucobrassicins , which are found in cruciferous vegetables , has been shown in vivo to have protective effects for breast cancer . we have shown previously that dim lowers the levels of cxcr4 and cxcl12 , a chemokine receptor and its unique ligand required for the metastasis of breast cancer [ 6 , 7 ] . in addition to mediating the directional homing of primary breast cancer cells to secondary organ sites , cxcr4 and cxcl12 are important in other aspects of cancer progression , such as adhesion , proliferation , and angiogenesis . these effects are not limited to breast cancer , as the interaction between cxcr4 and cxcl12 is implicated in the progression of many different types of cancer . the biological effects of genistein are extensive and include antioxidant activity , weak estrogenic / antiestrogenic activity , upregulation of apoptosis , inhibition of angiogenesis , inhibition of dna topoisomerase ii , and inhibition of protein tyrosine kinases ( ptks ) . genistein has been shown to regulate specific sex steroid receptors , inhibit nfkb , downregulate tgf- , and inhibit efg - stimulated growth . furthermore , genistein inhibits 2,3,7,8-tetrachlorodibenzo - p - dioxin ( dioxin)-induced cyp1a1 activity , and isoflavones can prevent the cyp1a1-mediated binding of benzo[a]pyrene ( b[a]p ) metabolites to dna . our previous observations that dim downregulates cxcr4 and cxcl12 in breast and ovarian cancer cells represent a novel mechanism for the chemoprotective effects of this phytochemical . here , we demonstrate that these effects are not unique to dim , but can also be seen with genistein . interestingly , we see that the combined effect of dim and genistein elicits a greater downregulation of cxcr4 and cxcl12 than either compound alone , indicating that the phytochemicals used in combination may be even more potent in their chemoprotective properties . we also demonstrate that like dim , genistein specifically inhibits chemotaxis and chemoinvasion of breast and ovarian cancer cells toward cxcl12 in vitro . genistein was purchased from sigma ( st . louis , mo , usa ) , dim was purchased from lkt laboratories ( st . paul , minn , usa ) , and the remaining phytochemicals were a kind gift from dr . david heber ( university of california , los angeles , calif , usa ) . kenneth korach ( national institute of environmental health sciences , nc , usa ) . mcf-7 and mda - mb-231 cells were purchased from the american type culture collection ( atcc , manassas , va , usa ) . mda - mb-231 cells were maintained in dulbecco 's modified eagle 's medium containing 4 mm l - glutamine . all media were purchased from invitrogen ( carlsbad , calif , usa ) and supplemented with 10% fetal bovine serum ( fbs ; omega , tarzana , calif , usa ) , 100 u / ml penicillin/100 g / ml streptomycin solution ( gemini bio - products , west sacramento , calif , usa ) , and 0.25 u / ml amphotericin b ( omega ) for all experiments , chemicals were dissolved in dmso and administered to cells with a final concentration of dmso at 0.1% in the medium . rna isolation , cdna synthesis , and taqman multiplex real - time pcr were performed as previously described . cxcr4 and cxcl12 cdnas were amplified using assays on demand ( affinity bioreagents , golden , colo , usa ; product numbers hs00607978_s1 and hs00171022_m1 , resp . ; sequences proprietary ) . the forward and reverse primers used for 36b4 quantification were 5-ccacggtgctgaacatgct-3 and 5-tcgaacacctgctggatgac-3 , respectively . the 36b4 probe sequence was 5-texas red - accatctcccccttctcctttgggct - iowa black-3. all primers and probes were purchased from integrated dna technologies ( coralville , iowa , usa ) . real - time pcr was carried out using the icycler iq ( biorad , hercules , calif , usa ) or 7500 fast ( applied biosystems , foster city , calif , usa ) under standard protocols . data were analyzed using the icycler or abi software and microsoft excel , and significance was evaluated using student 's t - test . for surface staining of cxcr4 and intracellular staining of cxcl12 , cells were grown to 70% confluence and treated with genistein for 24 or 48 hours . in the case of cxcl12 quantification , the cells were also cotreated with 1 g / ml brefeldin a ( glogiplug ; bd pharmingen , franklin lakes , nj , usa ) for the final six hours of incubation to inhibit protein secretion . cells were harvested and stained as previously described [ 6 , 9 ] with either primary cxcl12 antibody ( r&d cat . mab350 ; minneapolis , minn , usa ) , primary cxcr4 antibody ( affinity bioreagents cat . opa1 - 01101 ; ill , usa ) or the appropriate primary igg isotype control antibody , followed by staining with either goat antimouse or antirabbit igg - fitc secondary antibodies ( bd - pharmingen and caltag , carlsbad , calif , usa , resp . ) . fluorescence was quantified using a facscan analytic flow cytometer ( becton dickinson , ucla flow cytometry core facility ) . cells were pretreated with genistein , dim , or the combination , followed by chemotaxis and invasion assays , performed as we have described previously . after migration / invasion , mts assays ( promega , madison , wis ) were performed in each individual transwell to control for small variations in cell number . after detection of the formazan product at 490 nm , cells on the inserts were washed with pbs and those on the upper layer were gently removed with a prewet q - tip . cells on the lower layer were fixed in 100% methanol and stained with crystal violet . membranes were manually excised from the inserts , mounted on microscope slides , and divided into 8 equal sections . cells in one random viewing field from each section were counted at 40x magnification , and the average was calculated . data are expressed as chemotaxis or chemoinvasion indices , which were defined as the normalized number of cells in the experimental group relative to the control group . statistical analyses were performed using a two - tailed student 's t - test . mcf-7 and mda - mb-231 breast cancer cells and bg-1 ovarian cancer cells were treated with concentrations of genistein ranging from 1100 m ( at a constant final dmso concentration ) for 24 hours , after which time cxcr4 and cxcl12 mrnas were quantified by real - time pcr . cxcr4 mrna levels were significantly decreased at 1 m genistein in all three cell lines ( figures 1(a)1(c ) ) . maximal downregulation was seen at 100 m , 50 m , and 30 m genistein in each cell line , respectively . significant downregulation of cxcl12 mrna occurred at a concentration of 50 m genistein in mcf-7 cells and 10 m genistein in bg-1 cells ( figures 1(a)1(c ) ) . interestingly , low doses of genistein ( 110 m ) significantly increased cxcl12 mrna levels in mcf-7 cells , but had the opposite effect in bg-1 cells at these doses . flow cytometric analysis was used to quantify surface cxcr4 and intracellular cxcl12 expression . cells were treated with 30 , 70 , or 100 m genistein for 24 hours , harvested , stained , and analyzed for surface expression levels of cxcr4 . relative to dmso - treated controls , cxcr4 was found to be downregulated by genistein in mcf-7 , mda - mb-231 , and bg-1 cells at all three doses ( figures 2(a)2(c ) ) . analysis of cxcl12 intracellular expression showed that relative to dmso - treated control cells , cxcl12 levels were reduced by all three doses of genistein in both mcf-7 and bg-1 cells ( figures 2(a ) , 2(c ) ) . we previously found that dim downregulates cxcr4 and cxcl12 mrnas and proteins in invasive breast and ovarian cancer cells . we therefore tested whether the downregulation elicited by cotreatment with both dim and genistein was additive or synergistic in these cell lines . using real - time pcr , we quantified gene expression after treatment of mda - mb-231 ( cxcr4 only ) or bg-1 ( both cxcr4 and cxcl12 ) with 20 m dim , 100 m genistein , or the combination . we found that in both cell lines , the degree of downregulation of cxcr4 was greater after treatment with both phytochemicals in combination ( figures 3(a)-3(b ) ) . in mda - mb-231 cells , dim reduced levels of cxcr4 by 57% , genistein by 51% , and the combination by 85% ( figure 3(a ) ) . in bg-1 cells , dim downregulated cxcr4 by 49% , similarly , dim lowered the levels of cxcl12 by 50% , genistein lowered levels by 84% , and genistein by 91% ( figure 3(b ) ) . these effects can not be attributed to cytotoxicity , since neither dim , genistein , nor the combination was cytotoxic at these doses for the 24 hour time period ( data not shown ) . since cxcr4 and cxcl12 mediate directional migration , and since we saw previously that dim inhibited chemotaxis and chemoinvasion of these cells , we performed assays to determine whether genistein could inhibit migration through fibronectin and/or invasion through matrigel . we found that pretreatment with genistein inhibited the directional migration of mcf-7 cells , with a resulting migration rate similar to the background rate ( dmso - treated cells exposed to no cxcl12 gradient , figure 4(a ) ) . however , we did not see a further reduction in migration after cotreatment with genistein and dim , presumably because both chemicals used independently at these doses fully reduced migration to background levels . this result indicates that the degree to which genistein and dim downregulate surface cxcr4 levels at these doses may be sufficient to significantly impact the homing of breast cancer cells to areas of high cxcl12 expression . as we have seen previously with dim , the inhibition of chemotaxis by genistein specifically affects migration toward cxcl12 , since an inhibition of mcf-7 cell chemotaxis toward fbs was not observed . mcf-7 cells do not invade through matrigel ( a synthetic extracellular matrix ) , and we were therefore unable to evaluate invasive potential in these cells . however , mda - mb-231 breast cancer cells are invasive and we were able to quantify both chemotactic and chemoinvasive potential in this cell line . we found that genistein , dim , and the combination significantly inhibited chemotaxis and chemoinvasion of these cells toward cxcl12 , but not toward il-6 , a known in vitro chemoattractant for mda - mb-231 cells ( figures 4(b)-4(c ) ) . this result indicates that the inhibitory effects of dim and genistein are specific for cxcl12-induced chemoattraction / chemoinvasion and is not merely a general effect on migration or invasion . a similar result was seen with bg-1 ovarian cancer cells , which are also invasive in vitro ( figure 4(d ) ) . these cells do not migrate through matrigel toward il-6 ( data not shown ) , but did exhibit moderate chemoinvasion toward fbs . the antiestrogenic activity of genistein may mediate , in part , the protective effects of soy for breast and other cancers . although other nonestrogenic mechanisms of action such as ptk and topoisomerase ii inhibition likely play a role in these protective effects , we describe here an additional novel mechanistic pathway in which genistein and possibly other phytochemicals may be protective . we have found that genistein downregulates cxcr4 in the er - positive ( er+ ) breast cancer cell line , mcf-7 , the er - negative ( er ) breast cancer cell line , mda - mb-231 , and the er+ ovarian cancer cell line , bg-1 . furthermore , cxcl12 , the unique ligand for cxcr4 , is downregulated by genistein in both mcf-7 and bg-1 cells . we show that this downregulation results in a subsequent inhibition of migration and invasion of these cells toward cxcl12 in vitro . we found previously that dim downregulates cxcr4 and cxcl12 in mcf-7 , mda - mb-231 , and bg-1 cells . we show here that when used in combination , the effects of dim and genistein on cxcr4 and cxcl12 mrna levels are greater than with either compound alone , suggesting that phytochemicals used in combination may increase the efficacy of their protective effects . at 20 m dim and 70 m genistein , we did not find the combination to further inhibit chemotaxis or chemoinvasion of breast or ovarian cancer cells since these concentrations of the phytochemicals fully inhibit these processes . however , at the slightly lower doses of 10 m dim and 50 m genistein , the combination does appear to be more effective at inhibiting chemotaxis of mda - mb-231 cells . at these latter doses , the individual phytochemicals did not fully reduce chemotaxis of these cells to background levels . these results therefore suggest that lower doses of the phytochemicals used in combination may be equally or more effective in chemoprotection than a higher dose of a single phytochemical . the mechanisms of action of dim and genistein in the downregulation of cxcr4 and cxcl12 remain to be determined . dim and genistein both act as weak agonists / antagonists of the estrogen receptor , and it is therefore possible that the compounds can act through the same mechanism . importantly however , we see downregulation of cxcr4 and a subsequent inhibition of chemotaxis and chemoinvasion in mda - mb-231 cells , which do not express the estrogen receptor . on the other hand , dim is a ligand for the ahr , whereas genistein has not been shown to bind the ahr in the cell lines we used . genistein is a specific ptk inhibitor as well as an inhibitor of topoisomerase ii , and may modulate tgf- signal transduction [ 11 , 12 ] . interestingly , both genistein and dim are known to inhibit nfkb in breast , prostate , and pancreatic cancer cells [ 1315 ] . since cxcr4 is regulated at the transcriptional level by nfkb , it is plausible that the mechanism of cxcr4 and/or cxcl12 downregulation by dim and/or genistein could be through nfkb inactivation or downregulation [ 16 , 17 ] . condoning the general use of genistein as a supplement is at this point controversial . soy products are extensively consumed in asian populations without apparent adverse effects , but experimental data have led to concerns about the safety of genistein and other constituents of soy . although it was well tolerated , high doses of genistein in chronic studies caused an increase in the weights of the kidney , spleen , adrenal , and testes in male rats and an increase in liver , kidney , spleen , ovary , and uterus weights in female rats . in the same study , histological changes were seen in the reproductive organs of both male and female rats . genistein can behave as both an estrogen and an antiestrogen , and the net estrogenic effect of the chemical has proven difficult to quantify . a chronic exposure study very recently carried out by the national toxicology program showed a significant increase in the incidence of mammary gland adenoma and adenocarcinoma ( combined ) . importantly , the time of administration appears to significantly impact whether genistein elicits a protective , adverse , or no effect . for example , dimethylbenzanthracene ( dmba)-induced mammary cancer was reduced after prepubertal and combined prepubertal and adult administration of genistein , but not after prenatal - only or adult - only treatments . dose also plays a critical role in the biological effects of genistein ; although doses greater than 10 m over an extended period of time inhibit the growth of both er+ and er breast cancer cells , low doses of genistein ( < 1 m ) appear to stimulate the growth of er+ breast cancer cells [ 21 , 22 ] . interestingly , cxcl12 has been shown to mediate the proliferative effects of estradiol in breast cancer cells . we noted a significant increase in cxcl12 mrna after treatment with low doses ( 110 m ) of genistein in mcf-7 cells , although this effect was not seen in mda - mb-231 or bg-1 cells . an upregulation of cxcl12 by low doses of genistein remains to be confirmed in tissues that serve as common sites of metastasis such as the lung and bone . however , in light of what is known about the toxic and potentially carcinogenic effects of genistein , this observation underscores the importance of thorough safety analyses prior to condoning the use of phytochemicals as dietary supplements . in particular , it highlights the importance of dose , especially at the tissue level , when assessing the impact of genistein on the development and progression of breast and other cancers . the doses of genistein and dim described here are likely achievable in humans upon supplementation , especially at the tissue level . total genistein plasma concentrations of up to 20 m were obtained after feeding human volunteers a genistein supplement [ 2426 ] . furthermore , genistein was found to accumulate in certain organs to considerably higher concentrations , and this is likely to be the case for fatty tissues , such as the breast , in particular . when mice were administered a single oral dose of dim , a serum concentration of approximately 5 m was achieved . thus , the concentrations of genistein and dim that we have used in our studies are likely to reflect attainable doses in the human . since cxcr4 and cxcl12 are implicated in the progression of many different cancers , it is of interest to determine whether dim and/or genistein downregulate these proteins in cancer cell lines of other origins . it will also be important to investigate whether cxcl12 is downregulated by phytochemicals in tissues that serve as preferred sites of metastasis for these cancers , such as the lung and bone . furthermore , since many other phytochemicals have been implicated in cancer protection , it will be prudent to determine whether phytochemicals other than dim and genistein exert similar effects on cxcr4 and cxcl12 levels . finally , phytochemicals in combination should be tested in vivo to determine whether a potentiated effect can be achieved . dim has been suggested as a potential chemotherapeutic for er+ breast cancers . surprisingly however , we have found that dim and genistein downregulate cxcr4 and cxcl12 in both er+ and er cell lines , indicating that these phytochemicals may be effective in the treatment of both early- and late - stage breast cancers . effective therapies for advanced disease are lacking , and the potential use of compounds as innocuous as phytochemicals for treatment of either early- or late - stage cancers is an attractive alternative . furthermore , the increased response of cxcr4 and cxcl12 downregulation by dim and genistein in combination may prove useful in eliciting a potentiated effect in vivo and perhaps allow for optimization of the associated biological responses .

cxcr4 is a chemokine receptor frequently overexpressed on primary tumor cells . organs to which these cancers metastasize secrete cxcl12 , the unique ligand for cxcr4 , which stimulates invasion and metastasis to these sites . similar to our previous work with the chemoprotective phytochemical , 3,3-diindolylmethane ( dim ) , we show here that genistein also downregulates cxcr4 and cxcl12 and subsequently lowers the migratory and invasive potentials of breast and ovarian cancer cells . moreover , genistein and dim elicit a significantly greater cumulative effect in lowering cxcr4 and cxcl12 levels than either compound alone . our data suggest a novel mechanism for the protective effects of phytochemicals against cancer progression and indicate that in combination , these compounds may prove even more efficacious .

as medical advances increase the survival of critically ill neonates , the need for neonatal intensive care units ( nicus ) increases concomitantly . this growth is occurring within a health - care environment that is increasingly competitive and consumer driven . responding to these pressures , neonatal intensive care is rapidly evolving in both facility design and health - care delivery practice . nicus are trending away from multi - patient , open bay wards ( open ) , to single family room ( sfr ) designs , while neonatal health - care practices are becoming more family centered . parent by affording greater privacy , environmental control and space customization to the patient 's individual developmental needs caregivers can feel more isolated from their colleagues and patient charges and may get fewer opportunities for experiential learning . administrators must commit greater space and financial resources to accommodate this transition and remain competitive . to date , there are minimal data to document the contradictory aspects of this trend as it affects patients , parents and health - care staff . carter et al . , approached this informational deficiency by surveying parents of preterm infants during a transition from an older , multi - patient ward into a new , private room facility . their methodology , by addressing transitional parents , established a means to avoid the subject naivet ' ambiguity encountered when surveying parents whose experience with the nicu environment is minimal and limited to only one facility design . cabell huntington hospital in huntington , west virginia , usa , recently completed construction of a sfr nicu to replace an older , open bay ward . constructed in the 1950s , the previous 419 m open unit accommodated 29 neonates , with no more than a 3.35 m space for the patient , visiting parents and medical equipment . the new , 1302 m sfr unit occupies a half floor of a multi - story addition to the existing facility and accommodates 36 patient positions split between 20 private and 8 semi - private rooms . semi - private rooms are intended to be reserved for twins or triplets , rather than shared by two families . the notable contrast between the two facilities provides an ideal scenario for comparing the relative satisfaction experienced by parents and professional staff as it relates to facility design before , during and after the relocation . three groups of parents were surveyed over the course of the study using the nurse parent support tool copyrighted and validity - tested by margaret s miles . the nurse parent support tool is a 21-question , likert scaled questionnaire , designed to measure parents ' perceptions of nursing support during their child 's hospitalization . fourteen similarly styled questions were appended to the nurse parent support tool to determine perceptions of the physical facility ( 11 questions ) and to collect demographic data ( 3 questions ) . parent groups were established based on the nicu facility in which their child was treated : one group experienced only the old , open bay ward , while another was treated in the new , private a third group of transitional parents was present during the move from the old to the new nicu and uniquely experienced both facility environments . except for the transitional group , parental surveying was timed to avoid the interval around and including the actual move by suspending data collection for at least 90 days before and after the relocation . marshall university institutional review board approval was secured for the study protocol , and parent participation was anonymous and entirely voluntary . all parent groups were convenience sampled based on availability around the time of their infant 's discharge . each completed questionnaire was tagged with the length of stay ( los ) of their infant and with the physician 's estimate of mortality risk ( pemr ) assigned by the research neonatologist as an index of initial illness . using this scale , the severity of illness increases with the pemr value with pemr 4 being the most severely ill child included in the study . this triage ' protocol was simpler to administer than the neonatal therapeutic intervention survey score adopted by wielenga et al . mortality rates over the course of the study were monitored in both facilities and separated by prognosis into expected ' ( pemr 5 ) and unexpected ' ( pemrs 1 to 4 ) categories for comparison . the staff survey was internally generated by the researchers with input from neonatologists , neonatal nurse practitioners , practicing staff nurses and nurse managers . the questionnaire consisted of 36 likert scaled items covering demographics along with perceptions of the work environment , the physical facility , the accommodation of health - care practice and the extent of parental involvement in health - care procedures and decision making . specific questions were included to address the issues affecting neonatal nurse job satisfaction as advanced by archibald . as with the parental survey protocol , staff members were surveyed before and after the move to the new facility while avoiding the actual time interval around the move . the same survey was repeated 18 months post - relocation to detect changes in staff perceptions with extended experience in the new facility . as no new staff were added in preparation for the move , no transitional group was necessary . all surveyed staff experienced both facility designs , and survey results were sorted into medical doctor / nurse practitioner ( md / np ) and nurse subgroups . responses for each survey subgroup were compiled , averaged and the means were compared for statistical significance using the mann whitney rank sum nonparametric analysis . sound measurements were conducted in both facilities by a consultant from performance heating , ventilating , air conditioning ( hvac ) systems using a quest soundprobe dl-2 ( quest technologies , oconomowoc , wi ) . measurements were made within a closed omnibed in bays or rooms located near the entrances and nursing stations of both facilities at peak activity during shift change and visitation . survey participation / return rates were as follows : parent group , open=45% , sfr=74% md / np subgroup , open=67% , sfr=78% nurse subgroup , open=69% , sfr=59% . the difference in parental participation rates between the two facilities reflected the increased staff access to parents in the sfr unit . research staff administering the surveys anecdotally reported parents spending more time in the sfr unit compared with the open facility . mortality incidences in the two facilities for the study time intervals showed 11 events in the open unit and 9 in the sfr . in the open facility , 3 of the 11 mortality events ( 27% ) were unexpected with causes of death of necrotizing enterocolitis , severe intracranial hemorrhage and nosocomial sepsis . the sfr showed only one unexpected event ( 11% ) from necrotizing enterocolitis . except for los , survey results from these parents were separated according to los by subdividing the parental groups by the pemr categories of their infants ( table 1 ) . pemrs 1 and 2 were combined as short stay parents and pemrs 3 and 4 represented the long stay group . the short stay parents showed mean loss of 9.1 and 7.9 days for the open and the sfr facilities , while long stay parents averaged 32.2 and 26.2 days , respectively . it is significant to note that the sfr parents had 8% more seriously ill infants ( table 1 ) , but had average loss reduced by 13% with the short stay subgroup and 18% with their long stay cohort . when physical facility issues were compiled from the inexperienced parental subgroups , who had observed only one of the two facilities , los generally increased favorable perceptions of the sfr ( table 2 ) . even the short stay parents , with their limited exposures to the two facilities , appreciated the ability to control light levels in the sfr facility . with experience in only one facility design , the parents in the sfr facility significantly preferred the comfort , privacy and light control aspects of that unit . although noise levels were shown higher in the open unit ( leq levels were approximately 20 db higher ) , neither of the inexperienced parental subgroups in either facility perceived noise as being a significant disturbance for their infants . however , 56% of the transitional controls felt that noise was a greater disturbance in the open unit . short stay parents were less discriminating between the two units when queried regarding aspects of the physical facility and , like their longer stay cohorts , were strongly positive regarding staff performance ( table 2 ) . the most important observation from these data was the fact that scores for all staff performance topics were comparably high for both facilities . on a likert scale from one to five , with one being almost never and five being almost always , the means never dropped below four . both subgroups of inexperienced parents tended to be quite favorable in their evaluations of staff performance in both facilities so much so that subject naivet had to be ruled out before staff performance could be concluded better or worse in either of the facility designs . transitional parents , who were present during the move , uniquely experienced both facilities and served as naivet controls ( table 3 ) . with this parent group , better in the sfr ' ( 25% ) or about the same in both ' ( 68% ) . the open bay facility never scored above 25% preference on any staff performance issue with this control group , indicating an element of naivet bias in the inexperienced parent data . it is noteworthy that inter - parental socialization difficulties were posed by the relative isolation of parents in the sfr design . this issue was reflected in the responses of both transitional and inexperienced parents alike . when asked regarding the ease of meeting other parents ' and the role of parental support in making the hospital stay better ' , the open facility outperformed the sfr with both parental groups regardless of previous experience . neonatologists nurse practitioners and staff nurses completed the same questionnaire , but the results were analyzed separately . within these two staff subgroups , interesting differences and similarities emerged with certain survey topic areas ( tables 4 and 5 ) . with the initial staff survey , the md / np subgroup 's perceptions in all topic categories trended toward favoring the sfr facility , while nurses favored the open design in every topic category except for privacy and environmental quality aspects . perceptual differences between these two subgroups diminished somewhat with the second staff survey with noteworthy shifts in impressions of the sfr work environment . when specific work environment topics were examined , the md / np subgroup showed no statistically significant preference between the two facilities . however , initial data from this subgroup trended toward work in the open unit being more physically demanding , more mentally stressful and more rewarding . over time , this subgroup found work in the sfr somewhat less physically demanding , but more stressful and more rewarding than in the open unit . the nurse subgroup showed the greater shift in perception of the work environment with the second survey . nurses initially perceived their work in the sfr to be more physically demanding , more stressful and less rewarding with workloads more difficult to manage . however , the second survey showed a shift in perceptions of this subgroup toward more favorable opinions of the sfr unit , but never to the same extent observed in the open facility . to determine whether nursing experience might have influenced these survey results , pearson 's product moment correlations were performed to assess the extent to which health - care experience correlated with perceptions of the demands and manageability of nursing workloads in the sfr facility . when asked if their work was physically demanding , the responses significantly positively correlated with health - care experience ( r=0.39 , p=0.029 ) . however , when asked if their workload was manageable , the responses were significantly negatively correlated with total health - care experience ( r=0.42 , p=0.018 ) . these correlations had disappeared with the second sfr survey . in addition , the same correlations with the same nurses from the open facility were not statistically significant in that environment . experienced nurses were more likely to perceive the sfr workload as more demanding and more difficult to manage than were their less experienced coworkers , and their initial concerns were allayed somewhat with accrued experience in the new sfr . when aspects of parental involvement were queried , the md / np subgroup showed no significant differences between the two facilities , but trended toward favoring the sfr unit . nurses trended toward agreeing that the convenience of parental visits was better in the sfr . however , they perceived the availability of parents to be significantly better in the open unit in both surveys . this perception contradicted the anecdotal research staff reports that parents were easier to reach in the sfr unit as evidenced by the greater survey questionnaire response level observed with parents in that facility . concerns for the level of parental preparedness at discharge and for patient care issues in the sfr were reflected in the nurses perceptions on both surveys . the md / np group initially disagreed on this issue , but showed increased agreement over time . nurses similarly felt that the capacity to care for critical patients and the general adequacy of time for patient attention were less satisfactory in the sfr . the md / np subgroup trended toward disagreement . over time , however , the perceptions of these two subgroups came closer to agreement that the open unit outperformed the sfr on these topics . in the category of patient care , the early detection of medical crises was observed by both staff subgroups as better in the open facility . with the nurses subgroup , physical aspects of the two facilities revealed areas in which both staff subgroups agreed . regarding the issues of meeting health insurance portability and accountability act ( hipaa ) guidelines , noise disturbance , lighting control , problematic foot traffic and general privacy , both staff subgroups preferred the sfr facility over the open unit . major differences were observed between the md / np and nurse subgroups regarding interpersonal communication topics . nurses perceived communication among coworkers to be more difficult and coworker access to be less convenient in the sfr . they also found the sfr environment to be less conducive to mutually supportive communication among parents , and all parental groups affirmed this communication problem . survey participation / return rates were as follows : parent group , open=45% , sfr=74% md / np subgroup , open=67% , sfr=78% nurse subgroup , open=69% , sfr=59% . the difference in parental participation rates between the two facilities reflected the increased staff access to parents in the sfr unit . research staff administering the surveys anecdotally reported parents spending more time in the sfr unit compared with the open facility . mortality incidences in the two facilities for the study time intervals showed 11 events in the open unit and 9 in the sfr . in the open facility , 3 of the 11 mortality events ( 27% ) were unexpected with causes of death of necrotizing enterocolitis , severe intracranial hemorrhage and nosocomial sepsis . survey results from these parents were separated according to los by subdividing the parental groups by the pemr categories of their infants ( table 1 ) . pemrs 1 and 2 were combined as short stay parents and pemrs 3 and 4 represented the long stay group . the short stay parents showed mean loss of 9.1 and 7.9 days for the open and the sfr facilities , while long stay parents averaged 32.2 and 26.2 days , respectively . it is significant to note that the sfr parents had 8% more seriously ill infants ( table 1 ) , but had average loss reduced by 13% with the short stay subgroup and 18% with their long stay cohort . when physical facility issues were compiled from the inexperienced parental subgroups , who had observed only one of the two facilities , los generally increased favorable perceptions of the sfr ( table 2 ) . even the short stay parents , with their limited exposures to the two facilities , appreciated the ability to control light levels in the sfr facility . with experience in only one facility design , the parents in the sfr facility significantly preferred the comfort , privacy and light control aspects of that unit . although noise levels were shown higher in the open unit ( leq levels were approximately 20 db higher ) , neither of the inexperienced parental subgroups in either facility perceived noise as being a significant disturbance for their infants . however , 56% of the transitional controls felt that noise was a greater disturbance in the open unit . short stay parents were less discriminating between the two units when queried regarding aspects of the physical facility and , like their longer stay cohorts , were strongly positive regarding staff performance ( table 2 ) . the most important observation from these data was the fact that scores for all staff performance topics were comparably high for both facilities . on a likert scale from one to five , with one being almost never and five being almost always , the means never dropped below four . both subgroups of inexperienced parents tended to be quite favorable in their evaluations of staff performance in both facilities so much so that subject naivet had to be ruled out before staff performance could be concluded better or worse in either of the facility designs . transitional parents , who were present during the move , uniquely experienced both facilities and served as naivet controls ( table 3 ) . better in the sfr ' ( 25% ) or about the same in both ' ( 68% ) . the open bay facility never scored above 25% preference on any staff performance issue with this control group , indicating an element of naivet bias in the inexperienced parent data . it is noteworthy that inter - parental socialization difficulties were posed by the relative isolation of parents in the sfr design . when asked regarding the ease of meeting other parents ' and the role of parental support in making the hospital stay better ' , the open facility outperformed the sfr with both parental groups regardless of previous experience . neonatologists nurse practitioners and staff nurses completed the same questionnaire , but the results were analyzed separately . within these two staff subgroups , interesting differences and similarities emerged with certain survey topic areas ( tables 4 and 5 ) . with the initial staff survey , the md / np subgroup 's perceptions in all topic categories trended toward favoring the sfr facility , while nurses favored the open design in every topic category except for privacy and environmental quality aspects . perceptual differences between these two subgroups diminished somewhat with the second staff survey with noteworthy shifts in impressions of the sfr work environment . when specific work environment topics were examined , the md / np subgroup showed no statistically significant preference between the two facilities . however , initial data from this subgroup trended toward work in the open unit being more physically demanding , more mentally stressful and more rewarding . over time , this subgroup found work in the sfr somewhat less physically demanding , but more stressful and more rewarding than in the open unit . the nurse subgroup showed the greater shift in perception of the work environment with the second survey . nurses initially perceived their work in the sfr to be more physically demanding , more stressful and less rewarding with workloads more difficult to manage . however , the second survey showed a shift in perceptions of this subgroup toward more favorable opinions of the sfr unit , but never to the same extent observed in the open facility . to determine whether nursing experience might have influenced these survey results , pearson 's product moment correlations were performed to assess the extent to which health - care experience correlated with perceptions of the demands and manageability of nursing workloads in the sfr facility . when asked if their work was physically demanding , the responses significantly positively correlated with health - care experience ( r=0.39 , p=0.029 ) . however , when asked if their workload was manageable , the responses were significantly negatively correlated with total health - care experience ( r=0.42 , p=0.018 ) . these correlations had disappeared with the second sfr survey . in addition , the same correlations with the same nurses from the open facility were not statistically significant in that environment . experienced nurses were more likely to perceive the sfr workload as more demanding and more difficult to manage than were their less experienced coworkers , and their initial concerns were allayed somewhat with accrued experience in the new sfr . when aspects of parental involvement were queried , the md / np subgroup showed no significant differences between the two facilities , but trended toward favoring the sfr unit . nurses trended toward agreeing that the convenience of parental visits was better in the sfr . however , they perceived the availability of parents to be significantly better in the open unit in both surveys . this perception contradicted the anecdotal research staff reports that parents were easier to reach in the sfr unit as evidenced by the greater survey questionnaire response level observed with parents in that facility . concerns for the level of parental preparedness at discharge and for patient care issues in the sfr were reflected in the nurses perceptions on both surveys . the md / np group initially disagreed on this issue , but showed increased agreement over time . nurses similarly felt that the capacity to care for critical patients and the general adequacy of time for patient attention were less satisfactory in the sfr . the md / np subgroup trended toward disagreement . over time , however , the perceptions of these two subgroups came closer to agreement that the open unit outperformed the sfr on these topics . in the category of patient care , the early detection of medical crises was observed by both staff subgroups as better in the open facility . with the nurses subgroup , this perceptual difference was highly significant . physical aspects of the two facilities revealed areas in which both staff subgroups agreed . regarding the issues of meeting health insurance portability and accountability act ( hipaa ) guidelines , noise disturbance , lighting control , problematic foot traffic and general privacy , both staff subgroups preferred the sfr facility over the open unit . major differences were observed between the md / np and nurse subgroups regarding interpersonal communication topics . nurses perceived communication among coworkers to be more difficult and coworker access to be less convenient in the sfr . they also found the sfr environment to be less conducive to mutually supportive communication among parents , and all parental groups affirmed this communication problem . although the survey questionnaire has become an established tool for measuring staff and parental opinions regarding nicu design issues , it is essential to emphasize that data compiled from such questionnaires measure only the perceptions of polled individuals regarding a given topic . these perceptions can be influenced by the different experiential backgrounds of individual participants and can introduce biases into any interpretations . consequently , this study protocol collected sufficient demographic data with all surveys to allow better identification of trends , both negative and positive , that appeared with each demographic subgroup of participants . white and walsh et al . , recognized that the evolution ' of nicu design from multi - patient , open wards toward sfrs was paradoxical in its effects on parents , hospital staff and administrators . although favoring neonates and their parents by providing increased environmental control and privacy , it disadvantaged staff by isolating them from coworkers and patient charges and placed greater demands on hospital administrators for increased space and financial commitments . this study supported , in part , these contradictory effects while showing that subsets of parental and staff subjects varied in their perceptions of the two nicu designs . whenever the perceptions of inexperienced subjects are polled , data interpretation should take into consideration some degree of naivet . in this study , the inexperienced parents ' perceptions of staff performance had naivet bias . simply averaging the responses of inexperienced parents to questions pertaining only to staff performance produced highly favorable ratings with means of 4.7 of 5 in the open and a comparably high 4.6 in the sfr . averaging the responses to the same questions from the transitional parent group , who had observed both facilities , showed that only 7% found staff performance to be better in the open bay . even with the specific issue of timely response to needs ' , 63% of the transitional parents saw no difference between the two facilities . in fact , this was the only aspect of staff performance in which the open bay facility received noteworthy preference with this control group . although this suggests a degree of naivet , it is probably not the only factor influencing these data . the fact that 68% of these experienced parents found no difference in staff performance in the two units also suggests that staff , even with no additional hires , were able to sustain a perceptibly high level of patient care in the larger sfr facility . thus , both staff adaptability and parental naivet were likely operative and impossible to separate quantitatively through this study protocol . even the long stay , inexperienced parents gave the open and the sfr units comparably high average scores of 3.8 and 4.1 , respectively . when experienced , transitional parents ' responses to the same question block were averaged , 59% preferred the sfr facility with only 18% seeing them as similar . carter et al . , surveyed transitional parents with an abbreviated questionnaire and found them to be appreciative of the advantages of an sfr facility . clearly , parents with experience in both nicu designs prefer the sfr environment . separating staff into md / np and both subgroups agreed that the sfr facility was superior when privacy for breastfeeding and bonding , hipaa compliance and environmental quality topics were queried . on issues regarding the work environment and parental involvement , their perceptions diverged , with only the md / np 's favoring the sfr . this finding was unexpected because previous literature reports of similar transitions found nurses to be generally favorable regarding the sfr design with only modest concerns for workload issues . this perceptual divergence between the two study subgroups may have had an experiential basis ; the second survey , after 18 months ' acclimation , showed some convergence of opinion regarding the sfr . physicians have been accustomed through training to treating critically ill patients in private room environments . nurses were more likely to have been trained in open bay units because of the relative scarcity of sfr facilities . the workloads of md / np staff are less influenced by the physical environment than are those of neonatal nurses . specifically , the larger facility , with its isolation from coworkers and greater dependence on electronic communication and monitoring , would have been a more drastic departure from the experiential norm for nurses and could have negatively influenced their perceptions of the sfr unit . after 18 months acclimation , the md / np subgroup trended toward favoring the open bay environment only on patient care issues regarding adequacy of patient attention and early detection of medical crises . although statistically insignificant , this trend may reflect safety concerns that are addressed later in the discussion . nurses shared these concerns regarding the sfr environment , and their perceptions were highly significant . nurses initially found every aspect of the work environment and some aspects of parental involvement to be better in the open unit . their perceptions of the sfr improved by the second survey , suggesting that some of their concerns may have been experientially based and were moderated with acclimation to the sfr unit . of particular interest was their perception that parents were better prepared for infant care in the open facility . md / nps perception of parental preparedness for care shifted more in line with that of the nurses by the second survey . although irresolvable from the survey data , this may reflect some unanticipated parental education or parent staff communication difficulty with the sfr design . regarding other communication issues , the nurses significantly perceived the open bay to be better for staff communication , mutual parental support and coworker access . as these differences were resolving by the second survey , they may relate to initial dissatisfaction with the increased isolation and dependence on electronic communication in the sfr . nurses also perceived the mutually supportive interactions among parents to be consistently better in the open unit , and parental surveys supported their perceptions on this issue . both the inexperienced and transitional parent surveys affirmed that inter - parental socialization and the associated development of informal peer support groups suffered in the sfr . harris et al . , reported that while the sfr design eliminated undesirable foot traffic , parent - to - parent contact became limited to chance encounters in hallways or other public spaces . although a parent lounge area was provided in this study 's sfr unit , both inexperienced and transitional parents preferred the open design for meeting other parents ' . this finding emphasizes an inherent socialization difficulty in the sfr design that merits future attention by hospital designers and health - care administrators . whether the sfr is , in reality , less safe for critical patients than the open bay , or whether it is just perceived to be so , is an important issue in nicu health - care practice . given the isolation of patient charges in separate rooms of the sfr with limited line of sight ' and with increased dependence on electronic monitoring and communication , concerns for patient safety among staff would be expected . md / np perceptions of patient care in the two facilities were not significantly different . nurses ' perceptions were more definitively in favor of the open bay for early crisis detection and for managing intensive care patients . parental surveys did not reveal major concerns with this issue . among the experienced , transitional parents only 25% of this group perceived the responses to their child 's needs to be more timely in the open ward . even the inexperienced parents showed no significant preference between the two facilities on these topics , and these questionnaire items should be less influenced by their naivet . this study focused on perceived satisfaction with the two facility designs and was not constructed to distinguish true safety issues . however , given the reduced los and lower unexpected ' mortality rates observed in the sfr , we found no convincing evidence that it was less safe than the open unit . whenever the perceptions of inexperienced subjects are polled , data interpretation should take into consideration some degree of naivet . in this study , the inexperienced parents ' perceptions of staff performance had naivet bias . simply averaging the responses of inexperienced parents to questions pertaining only to staff performance produced highly favorable ratings with means of 4.7 of 5 in the open and a comparably high 4.6 in the sfr . averaging the responses to the same questions from the transitional parent group , who had observed both facilities , showed that only 7% found staff performance to be better in the open bay . even with the specific issue of timely response to needs ' , 63% of the transitional parents saw no difference between the two facilities . in fact , this was the only aspect of staff performance in which the open bay facility received noteworthy preference with this control group . although this suggests a degree of naivet , it is probably not the only factor influencing these data . the fact that 68% of these experienced parents found no difference in staff performance in the two units also suggests that staff , even with no additional hires , were able to sustain a perceptibly high level of patient care in the larger sfr facility . thus , both staff adaptability and parental naivet were likely operative and impossible to separate quantitatively through this study protocol . even the long stay , inexperienced parents gave the open and the sfr units comparably high average scores of 3.8 and 4.1 , respectively . when experienced , transitional parents ' responses to the same question block were averaged , 59% preferred the sfr facility with only 18% seeing them as similar . carter et al . , surveyed transitional parents with an abbreviated questionnaire and found them to be appreciative of the advantages of an sfr facility . separating staff into md / np and nurse subgroups revealed noteworthy similarities in perceptions of the sfr design . both subgroups agreed that the sfr facility was superior when privacy for breastfeeding and bonding , hipaa compliance and environmental quality topics were queried . on issues regarding the work environment and parental involvement , their perceptions diverged , with only the md / np 's favoring the sfr . this finding was unexpected because previous literature reports of similar transitions found nurses to be generally favorable regarding the sfr design with only modest concerns for workload issues . this perceptual divergence between the two study subgroups may have had an experiential basis ; the second survey , after 18 months ' acclimation , showed some convergence of opinion regarding the sfr . physicians have been accustomed through training to treating critically ill patients in private room environments . nurses were more likely to have been trained in open bay units because of the relative scarcity of sfr facilities . the workloads of md / np staff are less influenced by the physical environment than are those of neonatal nurses . specifically , the larger facility , with its isolation from coworkers and greater dependence on electronic communication and monitoring , would have been a more drastic departure from the experiential norm for nurses and could have negatively influenced their perceptions of the sfr unit . after 18 months acclimation , the md / np subgroup trended toward favoring the open bay environment only on patient care issues regarding adequacy of patient attention and early detection of medical crises . although statistically insignificant , this trend may reflect safety concerns that are addressed later in the discussion . nurses shared these concerns regarding the sfr environment , and their perceptions were highly significant . nurses initially found every aspect of the work environment and some aspects of parental involvement to be better in the open unit . their perceptions of the sfr improved by the second survey , suggesting that some of their concerns may have been experientially based and were moderated with acclimation to the sfr unit . of particular interest was their perception that parents were better prepared for infant care in the open facility . md / nps perception of parental preparedness for care shifted more in line with that of the nurses by the second survey . although irresolvable from the survey data , this may reflect some unanticipated parental education or parent staff communication difficulty with the sfr design . regarding other communication issues , the nurses significantly perceived the open bay to be better for staff communication , mutual parental support and coworker access . as these differences were resolving by the second survey , they may relate to initial dissatisfaction with the increased isolation and dependence on electronic communication in the sfr . nurses also perceived the mutually supportive interactions among parents to be consistently better in the open unit , and parental surveys supported their perceptions on this issue . both the inexperienced and transitional parent surveys affirmed that inter - parental socialization and the associated development of informal peer support groups suffered in the sfr . harris et al . , reported that while the sfr design eliminated undesirable foot traffic , parent - to - parent contact became limited to chance encounters in hallways or other public spaces . although a parent lounge area was provided in this study 's sfr unit , both inexperienced and transitional parents preferred the open design for meeting other parents ' . this finding emphasizes an inherent socialization difficulty in the sfr design that merits future attention by hospital designers and health - care administrators . whether the sfr is , in reality , less safe for critical patients than the open bay , or whether it is just perceived to be so , is an important issue in nicu health - care practice . given the isolation of patient charges in separate rooms of the sfr with limited line of sight ' and with increased dependence on electronic monitoring and communication , concerns for patient safety among staff would be expected . md / np perceptions of patient care in the two facilities were not significantly different . nurses ' perceptions were more definitively in favor of the open bay for early crisis detection and for managing intensive care patients . parental surveys did not reveal major concerns with this issue . among the experienced , transitional parents only 25% of this group perceived the responses to their child 's needs to be more timely in the open ward . even the inexperienced parents showed no significant preference between the two facilities on these topics , and these questionnaire items should be less influenced by their naivet . this study focused on perceived satisfaction with the two facility designs and was not constructed to distinguish true safety issues . however , given the reduced los and lower unexpected ' mortality rates observed in the sfr , we found no convincing evidence that it was less safe than the open unit . survey data supported previously predicted disparate effects of nicu design on the perceptions of neonate parents and their clinical staff . it was shown that these perceptions varied with demographics and the experiential status of study participants . although all parent groups perceived the open bay unit to be more conducive to social interaction with other parents , when physical aspects of open bay versus sfr designs were queried , parental perceptions varied with los . when los tripled , parents were more appreciative of the comfort , privacy and environmental control aspects of the sfr facility . in addition , transitional parents , familiar with both facilities , showed a strong preference for the sfr design , indicating that naivet bias decreases as experience and los increase . inexperienced parents , who had observed only one of the two contrasting designs , evaluated staff performance extremely favorably in both facilities . that naivet bias was minimal in these data were confirmed by comparison with experienced parents that had observed both facilities . approximately , two - thirds of these experienced parents found staff performance about the same ' in both facilities . perceptions of md / np staff generally favored the sfr unit while nurses preferred the open bay . this difference was most pronounced with survey topics regarding the work environments of the two facility designs , and the initial differences diminished somewhat after 18 months in the sfr . however , both staff subgroups concurred that the sfr facility was preferable regarding issues of hipaa compliance , environmental control , and privacy for bonding and breastfeeding . staff perceptions reflected concerns for early detection of medical crises and adequate patient care in the sfr , suggesting an issue with patient safety in the sfr . however , reduced mortality and shortened los in the sfr did not support this perception , and parents did not detect significant differences in patient care between the two facilities . consequently , in survey studies of this type , it is important to determine demographic variables and relative experience levels of survey subjects , both of which can influence data interpretations when subjective perceptions are surveyed .

objective : with neonatal intensive care units ( nicus ) evolving from multipatient wards toward family - friendly , single - family room units , the study objective was to compare satisfaction levels of families and health - care staff across these differing nicu facility designs.study design : this prospective study documented , by means of institutional review board - approved questionnaire survey protocols , the perceptions of parents and staff from two contrasting nicu environments.result:findings showed that demographic subgroups of parents and staff perceived the advantages and disadvantages of the two facility designs differently . staff perceptions varied with previous experience , acclimation time and employment position , whereas parental perceptions revealed a naivet bias through surveys of transitional parents with experience in both nicu facilities.conclusion:use of transitional parent surveys showed a subject naivet bias inherent in perceptions of inexperienced parents . grouping all survey participants demographically provided more informative interpretations of data , and revealed staff perceptions to vary with position , previous training and hospital experience .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Express Appeals Act of 2016''. SEC. 2. DEPARTMENT OF VETERANS AFFAIRS PILOT PROGRAM ON FULLY DEVELOPED APPEALS. (a) In General.--The Secretary of Veterans Affairs shall carry out a pilot program to provide the option of an alternative appeals process that shall more quickly determine such appeals in accordance with this section. (b) Election.-- (1) Filing.--In accordance with paragraph (2), a claimant may elect to file a fully developed appeal under the pilot program under subsection (a) by filing with the Secretary the following: (A) The notice of disagreement under chapter 71 of title 38, United States Code, along with the written election of the claimant to have the appeal determined under the pilot program. (B) All evidence that the claimant believes is needed for the appeal as of the date of the filing. (C) A statement of the argument in support of the claim, if any. (2) Timing.--A claimant shall make an election under paragraph (1) as part of the notice of disagreement filed by the claimant in accordance with paragraph (1)(A). (3) Reversion.-- (A) Elected reversion.--At any time, a claimant who makes an election under paragraph (1) may elect to revert to the standard appeals process. Such a reversion shall be final. (B) Automatic reversion.--A claimant described in subparagraph (A), or a claimant who makes an election under paragraph (1) but is later determined to be ineligible for the pilot program under subsection (a), shall revert to the standard appeals process without any penalty to the claimant other than the loss of the docket number associated with the fully developed appeal. (4) Outreach.--In providing claimants with notices of the determination of a claim during the period in which the pilot program under subsection (a) is carried out, the Secretary shall conduct outreach as follows: (A) The Secretary shall provide to the claimant (and to the representative of record of the claimant, if any) information regarding-- (i) the pilot program, including the advantages and disadvantages of the program; (ii) how to make an election under paragraph (1); (iii) the limitation on the use of new evidence described in paragraph (3) of subsection (c) and the development of information under paragraph (4) of such subsection; and (iv) the ability of the claimant to seek advice and education regarding such process from veterans service organizations, attorneys, and claims agents recognized under chapter 59 of title 38, United States Code. (B) The Secretary shall collaborate, partner with, and give weight to the advice of the three veterans service organizations with the most members to publish on the Internet website of the Department of Veterans Affairs an online tutorial explaining the advantages and disadvantages of the pilot program. (c) Treatment by Department and Board.-- (1) Process.--Upon the election of a claimant to file a fully developed appeal pursuant to subsection (b)(1), the Secretary shall-- (A) not provide the claimant with a statement of the case nor require the claimant to file a substantive appeal; and (B) transfer jurisdiction over the fully developed appeal directly to the Board of Veterans' Appeals. (2) Docket.-- (A) In general.--The Board of Veterans' Appeals shall-- (i) maintain fully developed appeals on a separate docket than standard appeals; (ii) decide fully developed appeals in the order that the fully developed appeals are received on the fully developed appeal docket; (iii) except as provided by subparagraph (B), decide not more than one fully developed appeal for each four standard appeals decided; and (iv) to the extent practicable, decide each fully developed appeal by the date that is one year following the date on which the claimant files the notice of disagreement. (B) Adjustment.--Beginning one year after the date on which the pilot program under subsection (a) commences, the Board may adjust the number of standard appeals decided for each fully developed appeal under subparagraph (A)(iii) if the Board determines that such adjustment is fair for both standard appeals and fully developed appeals. (3) Limitation on use of new evidence.-- (A) In general.--Except as provided by subparagraphs (B) and (C)-- (i) a claimant may not submit or identify to the Board of Veterans' Appeals any new evidence relating to a fully developed appeal after filing such appeal unless the claimant reverts to the standard appeals process pursuant to subsection (b)(3); and (ii) if a claimant submits or identifies any such new evidence, such submission or identification shall be deemed to be an election to make such a reversion pursuant to subsection (b)(3). (B) Evidence gathered by board.--Subparagraph (A) shall not apply to evidence developed pursuant to paragraphs (4) and (5). The Board shall consider such evidence in the first instance without consideration by the Veterans Benefits Administration. (C) Representative of record.--The representative of record of a claimant for appeals purposes, if any, shall be provided an opportunity to review the fully developed appeal of the claimant and submit any additional arguments or evidence that the representative determines necessary during a period specified by the Board for purposes of this subparagraph. (4) Prohibition on remand for additional development.--If the Board of Veterans' Appeals determines that a fully developed appeal requires Federal records, independent medical opinions, or new medical examinations, the Board shall-- (A) in accordance with paragraph (5), take such actions as may be necessary to develop such records, opinions, or examinations in accordance with section 5103A of title 38, United States Code; (B) retain jurisdiction of the fully developed appeal without requiring a determination by the Veterans Benefits Administration based on such records, opinions, or examinations; (C) ensure the claimant, and the representative of record of a claimant, if any, receives a copy of such records, opinions, or examinations; and (D) provide the claimant a period of 90 days after the date of mailing such records, opinions, or examinations during which the claimant may provide the Board any additional evidence without requiring the claimant to make a reversion pursuant to subsection (b)(3). (5) Development unit.-- (A) Establishment.--The Board of Veterans' Appeals shall establish an office to develop Federal records, independent medical opinions, and new medical examinations pursuant to paragraph (4)(A) that the Board determines necessary to decide a fully developed appeal. (B) Requirements.--The Secretary shall-- (i) ensure that the Veterans Benefits Administration cooperates with the Board of Veterans' Appeals in carrying out subparagraph (A); and (ii) transfer employees of the Veterans Benefits Administration who, prior to the enactment of this Act, were responsible for processing claims remanded by the Board of Veterans' Appeals to positions within the office of the Board established under subparagraph (A) in a number the Secretary determines sufficient to carry out such subparagraph. (6) Hearings.--Notwithstanding section 7107 of title 38, United States Code, the Secretary may not provide hearings with respect to fully developed appeals. If a claimant requests to hold a hearing pursuant to such section 7107, such request shall be deemed to be an election to revert to the standard appeals process pursuant to subsection (b)(3). (d) Duration; Application.--The Secretary shall carry out the pilot program under subsection (a) for a five-year period beginning one year after the date of the enactment of this Act. This section shall apply only to fully developed appeals that are filed during such period. (e) Reports.--During each year in which the pilot program under subsection (a) is carried out, the Secretary shall submit to the Committees on Veterans' Affairs of the House of Representatives and the Senate a report on the pilot program. The first such report shall be submitted by not later than 180 days after the date on which the pilot program commences. Each report shall include the following: (1) For the period covered by the report-- (A) the number of claimants who filed a fully developed appeal under the pilot program; (B) the average processing time for each such appeal, measured by each phase of the appeal, and, if the processing time for appeals exceed one year, the reasons for such processing time; (C) a summary of reasons for which the development of evidence was required under subsection (c)(5); (D) the number of issues decided, listed by the disposition of the issue; (E) of the number identified in subparagraph (D), the number of issues for which evidence was not so developed, listed by the disposition of the issue; (F) of the number of fully developed appeals decided by the Board of Veterans' Appeals, the number of cases from each agency of original jurisdiction, listed by the disposition of the issue; (G) the number of fully developed appeals appealed to the Court of Appeals for Veterans Claims, listed by the disposition of the case; (H) the number of reversions made under subsection (b)(3); and (I) any reasons for why a claimant was determined to be ineligible to participate in the pilot program. (2) A review, made in conjunction with veterans service organizations, of the efforts of the Secretary to provide clear rating decisions and improve disability rating notification letters, including with respect to-- (A) the opinions of veterans service organizations regarding such efforts; and (B) how the pilot program improves such efforts. (3) A recommendation for any changes to improve the pilot program. (4) An assessment of the feasibility and advisability of expanding the pilot program. (f) Regulations.--Not later than one day after the date of the enactment of this Act, the Secretary shall publish interim guidance on the pilot program under subsection (a). Not later than 90 days after such date of enactment, the Secretary shall prescribe regulations to carry out such pilot program. (g) Definitions.--In this section: (1) Claimant.--The term ``claimant'' has the meaning given that term in section 5100 of title 38, United States Code. (2) Compensation.--The term ``compensation'' has the meaning given that term in section 101 of title 38, United States Code. (3) Fully developed appeal.--The term ``fully developed appeal'' means an appeal of a claim for disability compensation that is-- (A) filed by a claimant in accordance with subsection (b)(1); and (B) considered in accordance with this section. (4) Standard appeal.--The term ``standard appeal'' means an appeal of a claim for disability compensation that is not a fully developed appeal.

Express Appeals Act of 2016 This bill directs the Department of Veterans Affairs (VA) to: (1) carry out a five-year pilot program to provide the option of an alternative appeals process to determine appeals of claims for disability compensation more quickly, and (2) inform claimants about such program. Appeals filed under the pilot program are described as &quot;fully developed appeals.&quot; A claimant may elect to file a fully developed appeal by filing with the VA: (1) a notice of disagreement along with the claimant's written election to have the appeal determined under the pilot program, (2) all evidence that the claimant believes is needed for the appeal, and (3) a statement of the argument in support of the claim. A claimant who elects the pilot program may elect to revert to the standard appeals process at any time. Such reversion, however, shall be final. Such a claimant or an electing claimant who is later determined to be ineligible for the pilot program shall revert to the standard appeals process without any penalty other than the loss of docket number. The VA shall transfer jurisdiction over a fully developed appeal directly to the Board of Veterans' Appeals. The Board shall: maintain fully developed appeals on a separate docket; hear fully developed appeals in the order received; decide not more than one fully developed appeal for each four traditional appeals decided, though this ratio may be adjusted for fairness purposes beginning one year after the pilot program begins; and decide each fully developed appeal within one year of a claimant's filing the notice of disagreement. A claimant may not submit or identify to the Board any new evidence relating to a fully developed appeal after filing such appeal unless the claimant reverts to the standard appeals process. The Board shall establish an office to develop necessary federal records, independent medical opinions, and new medical exams. The Board may not provide hearings for fully developed appeals.

microbial fuel cells are renewable bioelectrochemical transducers that convert biochemical energy into electricity . mfcs empower simultaneous treatment of waste - water and energy extraction from mixed organic media via the usage of microbial consortia as bio - catalysts . in addition to treating anthropogenic waste and wastewater , whilst producing rather than consuming electrical energy , mfcs have the ability of degrading toxic pollutants and the advantage of not burdening further the carbon cycle in the way fossil fuels do @xcite . they bear some resemblance to conventional fuel cells , given that they comprised two compartments , the anode and the cathode , divided by a proton exchange membrane ( pem ) , where oxidation and reduction reactions occur . a major difference is that mfcs use abundant , renewable fuels , such as organic substrates , that are metabolised by bacteria , whereas chemical fuel cells are fuelled by pure compounds ( which could be toxic as methanol or explosive as hydrogen ) oxidised by precious metals . as a result , their inexpensive functionality and maintenance designate mfcs as a viable solution for producing energy in isolated areas . despite the fact that mfcs were proposed more than a century ago @xcite , it is still a subject of rigorous research , due to the increased power densities that have been achieved in the last decade . in addition , since they operate in ambient conditions ( ambient environment temperature , atmospheric pressure , neutral ph ) and given the aforementioned advantages , they can efficiently support systems for applications like remotely deployed sensors and robotics @xcite . nonetheless , their analysis in copious conducted experiments reveal significant limitations on their performance due to low microbial activity ( low growth rate or metabolic rate , due to non - optimal growth conditions or unsuitable microcosm insuficient anodophiles ) , ohmic losses , mass transfer limitations on the electrode surfaces , non - optimised electrode architectures and transfer potential through the pem . the process of defining the factors that limit the performance of mfcs can lead to more efficient designing methods . although some techniques used in the conventional chemical fuel cells could be adopted , they can not be expected to provide the same results due to the fundamental differences of the systems particularly due to the biological nature . mfcs are complicated devices that contain bio - electrochemical reactions , mass and charge balance principles , biotic or abiotic transformation processes . as a result , their analysis and design process require a multidisciplinary approach with background in electrochemistry , microbiology , physics and engineering . on top of that , there are numerous differentiations in the mfcs studied which range from their configurations ( having two chambers separated by a pem or a membrane - less single - chamber mfcs ) to the type of their incorporated mechanism of donating electrons to the anode electrode ( mediated or mediator - less mfcs ) . given the complexity of these systems , the number of parameters that affect their outputs and the costs in time and money needed to perform laboratory experiments , the development of computerised mathematical models simulating these systems is of great importance . the implementation of modelling techniques can contribute to the investigation of the principles covering their operation and affecting their performance , producing better arrangement designs of mfcs and working circumstances . to address spatial dynamics of biophysical processes in a mfc we designed a cellular non - linear network ( cnn ) model . a cnn is a uniform regular array of locally connected continuous - state machines , or nodes , which update their states simultaneously in discrete time @xcite . essentially , cnn is a finite - difference scheme with time step 1 . a cnn is a subset of cellular automata ( ca ) . a ca is the same as cnn but states of nodes are discrete . ca and cnn are often mixed , many researchers do not differentiate these two types of machines . what is imitated in ca can be imitated in cnn and both offer powerful modelling capability as well . there are several studies published on cnn / ca or hybrid models of reaction - diffusion @xcite and prototyping of chemical computers @xcite and molecular computers @xcite , spatial dynamics of bacterial colonies @xcite . other approaches relevant to cnn modelling of mfcs are ca models of fuel loading patterns in nuclear reactors @xcite , dynamics of nuclear reactors @xcite , neutron transport @xcite , waste water treatment by aerobic granules @xcite , sequencing batch reactor @xcite , fluid flow in a porous medium @xcite . the proposed cnn - based model simulates biochemical and electrochemical reactions in a mfc based on synthetic redox mediators . to the best of the authors knowledge this is the first attempt to simulate the outputs of a mfc with a cnn model . despite the fact that the application of cnns have been widely used to simulate several biological , chemical and physical processes as indicted previously , the novelty of this study can be pinpointed in the fact that all the processes and , thus , the behavior of a batch - fed mfc has not been previously presented in a single cnn lattice with a local state comprised of all the critical quantities ( several chemical species concentrations , biomass concentrations and current produced ) . such a model will allow for a detailed analysis of integral outcomes of spatial processes inside mfcs , including a possible uneven distribution of nutrients in the mfc chamber , patterns of bacterial population in biofilms covering electrodes and distributions of diffusing metabolites . nonetheless , the use of cnn as the mathematical basis for the model allows the employment of the inherent fully parallel nature of synchronised locally interconnected simple unities . the subject device is a two chamber mfc with the presence of electroactive microbes in suspension in the bulk liquid and forming biofilms on the surface of a planar anode electrode and assuming electron transfer from the microbes to the electrode with the use of an externally added diffusible chemical mediator . that mechanism can be differentiated to emulate various types of mfcs , that will be the aim of future works . nonetheless , the present study can lead towards exploiting the parallelism of the simulating tools and , as a result , intensively accelerating the simulation of mfcs , by the implementation of the cnn - based algorithm on parallel hardware , as illustrated in @xcite . despite the intense investigation in the laboratory experimental field to optimise the performance of mfcs , results from computational models are not derived with the same rate . moreover , the few models developed are targeting specific mfc configurations each and are so strictly specified that they become impractical for implementation on different configurations . the first model presented @xcite , investigated a single population using an external mediator as receptor of electrons . that model analysed the correlation of the concentration of the external mediator with the higher possible power output . the authors of @xcite introduced the simulation of a mfc with an added mediator and several populations of suspended and attached biofilm microorganisms . the model was developed on two or three dimensions providing the resultant current produced by homogeneous or not biofilms . the results were derived by taking into account several parameters , like the content of different microbial species , the amount of suspended microbes compared with ones attached , the potential of the mediator , the initial concentrations of the mediator and the substrate and many more . the results provided were compared with experimental data from a batch mfc fed with acetate and inoculated with geobacter and found in a good agreement . the model presented in @xcite was updated in @xcite with the incorporation of international water association ( iwa s ) anaerobic digestion model ( adm1 ) @xcite . the coexistence of several types of methanogenic and electroactive bacteria is simulated , taking into account whether they are suspended or attached to the anode electrode . a batch mfc was simulated to test the effects of the electrical circuit on the population of the microorganisms and the results were compared with laboratory data . the model is also based on a one , two or three dimensions partial differential equations system to represent the spatial distribution of solutes in the biofilm . in @xcite , a model simulating a mfc with only suspended microorganisms and externally inserted mediator was studied . in this model the conservation of mass for the dissolved ingredients has a basic role . the biomass growth is not studied in that model while a batch mode mfc which was periodically fed was simulated . the results were compared with laboratory data from mfcs inhabited with suspended _ proteus _ cells and incorporating thionine as a mediator , proving accurate representation of the system . the model introduces the ideas of endogenous metabolism or intracellular substrate storage to justify a small amount of current present between the feeding pulses . as the conditions and concentrations in the anode were considered uniform , a one dimensional solution of the algorithm s equations was presented . some key parameters of the equations used were extracted from fitting the outputs to the experimental data , while some others were estimated . another study @xcite proposing a mathematical model for mfcs , was based on two dimensional macroscale mass balance equations and microscale biofilm evolution . the model contains hydrodynamic calculations and mass and charge balances through diffusion , convection and electromigration to simulate the current output , species concentrations and ph distributions throughout the anode . nonetheless , the possibility of depicting on two or three dimensions irregular biofilm and electrodes configurations and simulate the effects on the mfc operation and outputs was provided . the model was used to reproduce the system s outputs such as its ph distributions , the effect of multiple communities of electroactive , methanogenic and fermentative bacteria existing in the anode biofilm and the effect of the flow over or through complex electrodes . the authors of @xcite presented a model simulating a mfc with inspiration of models simulating chemical fuel cells . a mediator - less two - chamber configuration was studied in steady and dynamic states , with the combination of biochemical reactions , butler volmer expressions , mass and charge balance equations . also , given the assumption that the anode is under anaerobic conditions the adm1 was used to simulate the biochemical reactions . the authors argue that the effects imposed by the reactions in the cathode on the performance of the mfc are noteworthy . there were some laboratory experiments conducted in the context of this study to determine some of the parameters required by the model . despite that , it was not possible to extract some parameters that were estimated by a mathematical method of best fitting the results of the model with the experimental data . a one dimensional model of a steady state mfc incorporating charge , heat and mass transfer and biofilm formation was suggested @xcite . the model simulates the electrical performance of the mfc and the evolution of the biofilm formation that are affected by the inputs , like temperature and substrate concentration . the configurations simulated were the same as in @xcite , however a minor improvement in the results agreement was realised mainly because of the addition of the effects that heat transfer has on the anode and the cathode . the authors of @xcite presented a model that concentrates on the effects that the operational parameters of a mfc , such as the external ohmic resistance and organic loads , have on communities of anodophilic and methanogenic microbes . the ordinary differential equations that are included by the model were subjected to fast numerical solution techniques in order for the model to be more efficient than the one presented in @xcite but not oversimplified as the one presented in @xcite . moreover , the model was calibrated with the analysis of two single - chamber membrane - less air cathode mfcs and then validated on two other mfcs . another type of mfcs , namely the membrane - less single - chamber mfc , with molasses as fuel was modelled in @xcite . the model consisted of a system of differential equations depicting the diffusion and concentration profiles of the molecules , which are solved with a numerical approximation technique , namely the implicit finite difference method . despite the fact that the authors find the results of the model in accordance with the theoretical principles , they suggest that more detailed evaluation of the model is required in order to serve the optimisation of the performance of mfcs . the novel model based on cnn simulating the performance of mfcs proposed here , was motivated by the limitations imposed by the previously reported models . some of these limiting factors are the representation of the mfc compartments in one dimension disregarding possible inhomogeneities in the electrodes or the biofilms and the implementation of complicated differential equations that make models time consuming and compute - intensive . moreover , the use of cnn is advantageous compared with past models , as complicated computations are emerging from synchronised local interactions of basic simplistic entities . the given homogeneity of cnns and the local interconnections are essential features for mapping great amounts of cells in digital circuit systems , taking full advantage of a parallel implementation of the model . the model proposed here is simulating the performance of a two - chamber acetate - fed mfc with a biofilm attached on the anode electrode in batch mode . the following assumptions are made : 1 . the electrode is considered to be a 2d solid , which although is in contrast with best practices @xcite , it is a necessary simplification for the model . important characteristics such as low biofilm populations due to the limited available outer area for colonisation and biofilm erosion will be considered in future studies . 2 . the microbial growth is proportional to the spatial concentrations of growth - limiting factors like acetate and oxidised mediator ; however the metabolic products formed are not considered as primary factors effecting the performance of the mfc and , thus , neglected by the model ; 3 . an ideal pem is considered , allowing only protons to pass through but nothing else ( like other cations , carbon dioxide , acetate and oxygen ) and does not limit the performance of the mfc ; 4 . an added mediator mechanism is used ; as a result , electrons are shuttled from the microbes to the anode electrode by the reduced form of a chemical which is oxidised at the surface of the electrode ; 5 . the heat generation by electrochemical reactions occurring on both electrodes , anode compartment and biofilm and the heat flux is not considered ; 6 . temperature is considered fully controlled and kept constant ; 7 . solute materials are transported in space through molecular diffusive forces and migration of charged molecules , due to the electrical potential field . the latter is not studied in the current version of the model ; 8 . no gravity forces were included for any of the material to keep the model as straightforward as possible ; 9 . the anode compartment is defined as a continuously stirred tank reactor ; 10 . the reactions in the cathode side are prescribed as constant and are not a limiting factor of the mfc s performance . note here , that neglecting the migration of charged molecules in the electrical potential field generated by the voltage outputs of the mfc can not be treated as an oversimplification of the model . that assumption stands , given that the effects of that phenomenon are minor due to the low voltages produced by the system and the high conductivity of the anolyte solution . moreover , previously published models of mfcs @xcite suggested that the results with and without the incorporation of the phenomenon of electrical migration provides results with an average difference in power densities of 1.92% throughout the range of mfc voltage outputs . nonetheless , most of the previous work done on the field of mfc modelling neglected that phenomenon @xcite . the grid of the cnn model is @xmath0 ( here is consisted of @xmath1 cells for illustration reasons ) , and is representing a cross section of an area in the anode compartment near the electrode of a given batch - mode mfc . the size of the simulated area , represented by one cnn cell is set with the actual geometrical distances in mind . the size of each cell has been chosen to be sufficient to illustrate an area where the abstraction of homogeneous reactions occurring can be justified and fluxes of soluble chemicals can be depicted . namely , the area of a cnn cell is defined as a 1@xmath2 @xmath3 1@xmath2 area of the anode compartment , an area comparable with the typical dimensions of some species of bacteria . as a result , the cnn cell is small enough to accommodate the two dimensional projection of the existence of a single bacterium in a the specified area . the size of a cnn cell can be trivially increased after the appropriate decrease of the dimension - related parameters and without changing anything in the algorithmic configurations of the model . this procedure would effect negatively the accuracy of the model , as a higher level of abstraction will be assumed , however the execution time will be decreased as a smaller amount of elements will be calculated . the von neumann neighbourhood was used , meaning that each cell has five neighbours , the four closer adjacent cells to the central one ( located in the north , south , west and east directions ) , including the central one . note here that while the moore neighbourhood could be used to provide more realistic results ( as a more extended neighbourhood would be used including nine cells ) , the von neumann neighbourhood was chosen to maintain an efficient point in the trade - off between complexity and accuracy . while the accuracy of the calculations is slightly reduced and the complexity of the model is reduced , its speed of execution is considerably enhanced . each cell is defined by its state consisted of several parameters that are simultaneously updated throughout the simulation time steps , according to the states of its neighbours and by the local rule . the parameters consisting the state of each cell are the following : @xmath4 \end{split}\ ] ] where @xmath5 and @xmath6 are the dimension indexes that establish the location of each cell in the grid and @xmath7 is the current time step . @xmath8 is illustrating the way the relative area , represented by each cell , can be classified depending on its characteristic structure . this parameter can change through the simulation time steps and can have the following values : @xmath9 parameters @xmath10 and @xmath11 indicate the concentrations of ingredients that participate in the significant reactions in a mfc which are investigated for designing the model . note here , that the units of all the parameters in the following equations and their values for an example configuration presented in the following section can be found in table [ tab : table1 ] . namely , * @xmath12 represents the bacteria populations present in the anode compartment either in suspension or constituting a biofilm on the electrode , * @xmath13 represents the electron donor material for the microbes ( the fuel of the mfc ) , here assigned as acetate , * @xmath14 represents the added mediator chemical in reduced form , while * @xmath15 represents the added mediator chemical in oxidised form , * @xmath11 represents protons / hydrogen ions that are released from the reactions occurring in the anode electrode surface . parameters @xmath16 and @xmath17 represent the locally imposed over - potential and produced current density in each cell @xmath18 . the @xmath16 parameter studied is the activation over - potential , while the effects from the ohmic and concentrations over - potentials are implemented in the local rule calculations @xcite . the definition of the anode compartment as a continuously stirred tank reactor is based on the fact that phase mixture is quite faster than the electrochemical and biochemical reaction rates @xcite . as a result , all cells representing an area of anode bulk liquid will obtain the same state at the same time step . also , the cells representing borders , theoretically undergo no changes throughout time , thus , their states are regulated to a constant set of values , equal to zeros . the local rule used in the model simulates the kinetics and reactions of all materials . the calculations depend on the type of the cell represented ( @xmath19 ) at the given time step and employ the concentrations of chemicals in the predefined area ( the neighbourhood of each cell ) to provide the concentrations throughout time for each cnn cell . the concentrations within cells simulating the biofilm is given by the following expression : @xmath20 where @xmath21 is the diffusion coefficient of acetate , @xmath22 is the number of available neighbour cells of the cell @xmath18 ( not borders or the electrode ) and @xmath23 represents the rate at which the acetate is consumed by bacteria . this consumption rate depends on the local concentrations of acetate , biomass and oxidised mediator and is defined as a double monod limitation kinetic equation @xcite : @xmath24 where @xmath25 is the monod half - saturation coefficient for acetate , @xmath26 is the monod half - saturation coefficient for the oxidised mediator and @xmath27 is the maximum specific rate constant for microbial consumption of acetate . equation [ eq3 ] is actually the numerical approximation of the implicit finite difference method ( eq . [ eq3a ] ) of fick s second law in two dimensions @xcite , with the addition of the consumption rate of acetate by bacteria . fick s second law ( eq . [ eq3b ] ) is used to simulate the transport of solutions or liquids in other liquids , states that the change through time of concentration is depending on the differences of concentration and is derived from mass balance principle of a species in a fluid continuum @xcite . @xmath28 @xmath29 where @xmath30 is the concentration of a species , @xmath31 is the diffusion coefficient , @xmath7 is time and @xmath32 is the length . furthermore , the concentration of acetate in the bulk liquid is equal for all cells , as mentioned previously , due to the assumption of the anode as a continuously stirred tank reactor . also , biofilm development , along with substrate consumption rate , and solute mass transport , through diffusion , occur at different time scales , in the order of hours and seconds , respectively . consequently , an immediate effect of the substrate consumption in the biofilm on the bulk concentration will be demonstrated in the mathematical formulas . taking all the above into consideration , the concentration of acetate in the bulk liquid is given by the following equation : @xmath33 where @xmath34 is the net rate of reactions in the bulk , @xmath35 is the overall reaction rates in the whole biofilm ( @xmath36 that @xmath37 ) , @xmath38 is the overall reaction rates in the surface of the electrode ( @xmath39 that @xmath40 ) and @xmath41 is the volume of the bulk liquid , here measured by cells that have an area of @xmath42 . the rates of reactions in the bulk liquid ( @xmath43 ) are calculated the same way as the rates of reactions in the biofilm ( @xmath44 ) , specifically by eq . [ eq4 ] with the use of local concentrations for the bulk liquid . similar rules apply for the rest of chemical species that are important in the functionality of a mfc , namely the mediator in reduced and oxidised form and hydrogen ions . the following equations describe the evolution of the concentrations in the biofilm region : @xmath45 @xmath46 @xmath47 where @xmath48 and @xmath49 are the diffusion coefficients of the mediator in reduced and oxidised form and the hydrogen ions , respectively . @xmath50 and @xmath51 are the yield of mediator in both forms and protons from the acetate substrate , respectively . the concentration of the aforementioned chemical species in the bulk liquid are calculated by the following : @xmath52 } } { v_a^t } + \frac{\sum{({re_{mred})}^t_{m , n } } } { v_a^t } \end{split}\ ] ] @xmath53 } } { v_a^t } + \frac{\sum{({re_{mox})}^t_{m , n } } } { v_a^t } \end{split}\ ] ] @xmath54 } } { v_a^t } + \frac{\sum{({re_{h})}^t_{m , n } } } { v_a^t } \end{split}\ ] ] it must be mentioned here that the reaction rates on the electrode surface for the model are designed having in mind the oxidation mechanism of the mediator and the fact that the electrode stands theoretically as an impermeable border for all the other solute materials . as a result the reaction rate for the acetate substrate is equal to zero ( @xmath55 ) , whilst , for the both mediator forms is depending on the produced current density and calculated as : @xmath56 @xmath57 the reduction reactions that involve the hydrogen ions , are occurring in the cathode electrode , which is not studied in detail in the present study . thus , in order to simulate the decrease in the concentration of hydrogen ions in the anode compartment , which is due to the flux of the ions towards the cathode electrode , an upper limit was imposed in all the anode area . if the concentration of hydrogen ions exceeds a predefined value ( namely @xmath58 ) anywhere in the anode , its value will be fixed to the limit . the over - potential imposed locally on the surface of the electrode is based on the concentrations of protons , reduced and oxidised mediator and the current produced . @xmath59 where @xmath60 is the constant value assumed for the cathode potential , @xmath61 is the total resistance ( internal and externally connected ) , @xmath62 is the standard reduction potential for the mediator , @xmath63 is the gas constant , @xmath64 is the temperature and @xmath65 is the faraday constant . for the calculation of the current density produced on the anode electrode s surface , the widely used butler - volmer equation @xcite is implemented in the model : @xmath66 where @xmath67 is the exchange current density for mediator oxidation in reference conditions and @xmath68 is the tafel coefficient for mediator oxidation ( or referred to as the anodic / cathodic tafel slope , representing the over - potential increase required for a @xmath310 increase in current : @xmath69 , where @xmath70 is the anodic transfer coefficient ) . it is worth - mentioning that the over - potential and current density are meaningful only on the cells representing the electrode s surface . thus , the aforementioned equations provide these parameters for cells that have @xmath71 , otherwise they are equal to zero . as the calculations of the over - potential and the current density are implicit , a random positive value of the total current is assumed and then a numerical method is used to approximate the lowest error in the calculation of the total current , given the concentrations of chemical species on the electrode surface . on the first step , the randomly chosen current value is used ( in eq . [ eq6 ] ) to calculate the over - potential , which is then used to calculate the new current density ( in eq . [ eq7 ] ) and , thus , the total current produced . the current density error , which is targeted to be minimised , is given by : @xmath72 where @xmath73 is the randomly assumed value for the first step or the calculated value by the previous step . the evolution of the biofilm is proportional to the concentrations of chemical species as described by a double monod limitation kinetic equation ( as in eq . [ eq4 ] ) . the calculation of its expansion in the area of the bulk liquid of the anode is based on a simple algorithm to keep the overall computational model as straightforward and fast as possible . the concentration of biomass material in the biofilm cnn cells is calculated by the following equation : @xmath74 where @xmath75 is the rate of the biomass production in the biofilm and equals : @xmath76 where @xmath77 is the biomass yield on acetate substrate . the same equations are used for the approximation of the suspended biomass in the bulk liquid , with the usage of the appropriate local concentrations . @xmath78 where @xmath79 is the rate of the biomass production in the bulk liquid and equals : @xmath80 an upper limit on the concentration of biomass in the bulk liquid ( @xmath81 ) is imposed to control the biomass growth . moreover , the following method , which is written in pseudo - code , is performed to simulate the release of pressure produced by the creation of new biomass inside the region of the biofilm . this is to ensure a more realistic expansion of the biofilm attached on the anode electrode towards the bulk liquid . the algorithm is performed with initial cells that are part of the biofilm ( for cells @xmath82 that have parameter @xmath83 ) . despite the fact that the model is specifically designed to simulate a mfc in batch mode , a system with continuous flow can be studied by changing the boundary conditions . that approach is the subject of a future study . the configuration of parameters used by the model to produce the results presented in this section , are depicted in table [ tab : table1 ] . each time step represents a time period of one tenth of day . the time period of a time step was chosen based on the trade - off between accuracy of the results and execution time . as for smaller time periods the results were not significantly different the execution speed was not burdened with a smaller period of time steps . .parameters used in the execution of the model . [ cols="^,^,^,^",options="header " , ] the results derived by the model are illustrated in figs . [ fig : days ] and [ fig : tot ] . figure [ fig : days ] depicts how the average of the columns of cells along the length of the electrode concentrations of materials are changing in one dimension illustrated in the @xmath32-axis of the graphs , namely from the electrode moving outwards to the bulk liquid , throughout the time steps of the model that represent the days of the real experiment . note here that the thickness of the biofilm can be identified as the distance in @xmath32 axis from the electrode surface position to the point where the stable values of concentrations start . these stable values depict the existence of the continuously stirred tank reactor , namely the bulk liquid . moreover , fig . [ fig : tot ] describes the evolution of the concentrations of every material in the bulk liquid , the current produced and the expansion of the biofilm . 0.6 0.6 0.6 0.6 0.6 0.6 the results depicted in fig . [ fig : tot ] are in good agreement with the theoretical principles covering the functionality of mfcs in batch mode with added mediators which are also depicted in previously proposed models investigating similar systems @xcite . it must mentioned here that , despite the biomass initial concentrations , all the other parameters used in previous models @xcite to provide results are the same inserted in the model presented here and illustrated in table [ tab : table1 ] . also , the biomass simulation and the limitation of hydrogen ions are simplified compared to the previous models . the following statements which are easily observed in the results of the model presented in fig . [ fig : tot ] are following the general theoretical performance of batch mode mfcs with added mediators . the current output reaches its maximum value within three to four days that retains for a short period ( less than a day ) and then its value is asymptotically reduced . the concentration of acetate is reduced to zero in the first ten days , while the biomass concentration in the biofilm increases and reaches a plateau when the acetate concentration is low enough . the mediator is a constant quantity that can be found in either oxidised or reduced form , thus adding the concentrations in any time step equals to @xmath84 which is the initially defined concentration . the oxidised mediator follows the reduction of the acetate substrate , until the current produced is high enough to cause the oxidation reaction in the electrode to overcome the reduction reactions occurring in the biomass . then , as there is no more acetate to fed reduction reactions , the concentration of oxidised mediator is asymptotically reaching its initial concentration as a product of the oxidation reaction in the electrode . that is also the reason for the asymptotic reduction of the current , namely the lower ratio between reduced and oxidised mediator . similar explanation of the progress of the oxidised mediator stands for the reduced mediator . the advantages of cnn towards other mathematical methods are their simplicity that does not have an effect on their robustness and capability to simulate complicated phenomena , their inherent parallel nature that make them ideal for implementation in contemporary parallel computing devices and their local activity character that combined with the aforementioned features empower their execution on specialised hardware . as a result , the novelty of the model proposed here can be found in the method of numerical approximation , namely cnn , of the equations giving the kinetics of reactions occurring in a mfc and its performance . as mentioned before , cnn is a simple method as it uses a group of simple cells located on a grid , characterised by a state ( a set of parameters ) and updated based on the same local rule . it has been proved @xcite that complex computations can emerge from local interactions of basic entities . moreover , the synchronised functionality of the basic entities enables a fully parallel execution of computations throughout the grid , accelerating significantly the production of results by the model . in addition to the ability of cnns to be efficiently executed in parallel computers , their homogeneity , simplicity , synchronised activity and the local characteristic of the interconnections allows an effortless implementation in hardware , aiming further acceleration of the computations @xcite . these computing circuits can be cost efficient and pre - manufactured field programmable gate arrays ( fpgas ) and graphics processing units ( gpus ) or fully custom , providing higher performance efficiency application specific integrated circuits ( asics ) . the present study is based on a time explicit scheme which , despite the fact that might not be as accurate as implicit scheme in general , and especially with large simulation time steps , allows a less complicated implementation and requires a lower computational effort . a major advantage of the cnn - based model is that the possible inhomogeneities in the progress of the biofilm or in the structure of the anode electrode can be easily illustrated by the local rule or the initialisation of the cells states . some models presented previously , simulate the mfc in just one dimension @xcite , oversimplifying the reactions occurring . on the other hand , in @xcite two dimensional and three dimensional representations are provided that can account for complicated electrode sizes and biofilm formation ; however , inhomogeneities would be difficult to implement . the model presented here can easily be scaled to three dimensions and as cnn are the basis of the model , inhomogeneities in the whole volume of the mfc ( pem , electrodes and biofilms ) can easily be studied and efficiently recreate a wide variety of actual systems . despite the fact that an homogeneous area ( in the x dimension ) was studied here as a proof of concept , the ability of the model to simulate inhomogeneities in two dimensional paradigms is trivial . moreover , in @xcite the competition of two different species , fed on the same substrate used , was investigated , while in @xcite several communities of methanogenic and electroactive bacteria were simulated . the cnn based model is simulating the operation of a mfc inoculated with a single species of bacteria . however , the local dynamics of cnn allow the investigation of more complicated bacterial communities . that is an aspect of an ongoing study . nonetheless , some models are designed to calculate significant parameters of a mfc after it has reached its steady state @xcite . here , the evolution of the outputs of the mfc through time given its inputs is investigated because the process of reaching the steady state is a demanding procedure and should be optimised . the notion of modelling key procedures of complicated processes that occur in real life , enables the scientific community to recreate and study time consuming and expensive laboratory experiments . as a result , scientists can investigate the conditions and parameters of a phenomenon that are difficult to measure in real life . the model proposed here can serve as a virtual lab , which scientists and engineers can utilise to test and justify their theoretical approach to the functionality of mfcs . moreover , a more efficient designing of these systems can be based on the successful modelling of the processes occurring in mfcs . the cnn - based model simulating the performance of a two - chamber acetate - fed mfc described here , is designed in two dimensions and studies cross - section of an area near the anode electrode . the concentrations of chemicals that are involved in the process of producing current and biomass , throughout time , are studied . the local rule of the cnn structure is designed to reflect the double monod limitation equation , fick s second law of diffusion and the butler - volmer equation . during the process of designing and evaluating the model the following conclusion was reached . the biofilm s distribution , its initial concentration and the way it evolves and expands through time are greatly affecting the mfc s outputs . biofilms are difficult to predict and it is challenging to formulate algorithms that simulate their behaviour . that is a major aspect that limits the production of a plethora of mfc models , compared with the ones describing conventional fuel cells . the results provided by the model are in good agreement with the theory and the general concepts described in the literature for the functionality of mfcs as well the results of previously published works on mfc modelling . note that the results produced by the proposed model simulating the performance of the mfc in 15 days is executed in less than a minute in a contemporary computer . consequently , shifting from two dimensions to three to get more accurate results , given the possible inhomogeneities in mfc compartments or electrodes , will not be prohibited in terms of execution times . nonetheless , the fact that the model is based on cnn can be proved further advantageous , as its simplicity , repeatability and local interactions enable its implementation on hardware . that will in turn hugely accelerate the execution of the calculations of the described equations . the incorporation of the reduction reactions that occur in the cathode side of the mfc and the study of their effects on the performance of the system are aspects of future work . moreover , multi - species biofilms will be investigated including non- and electroactive bacteria to illustrate the possible competition over the common substrate . furthermore , the simulation of a mfc under constant flow will be presented with minor alterations in the local rules of the bulk liquid which will be the first step to study systems that are interconnected . this work was funded by the european union s horizon 2020 research and innovation programme under grant agreement no . + https://ec.europa.eu/programmes/horizon2020/ taghavi m , stinchcombe a , greenman j , mattoli v , beccai l , mazzolai b , et al . self sufficient wireless transmitter powered by foot - pumped urine operating wearable mfc . bioinspiration & biomimetics . 2016;11(1):016001 . suzuki y , takayama t , motoike in , asai t. striped and spotted pattern generation on reaction - diffusion cellular automata theory and lsi implementation. in : proceedings of the 2005 workshop on unconventional computing : from cellular automata to wetware . luniver press ; 2005 . p. 41 . hiratsuka m , aoki t , higuchi t. a model of reaction - diffusion cellular automata for massively parallel molecular computing . in : multiple - valued logic , 2001 . 31st ieee international symposium on . ieee ; 2001 . p. 247252 . odagiri k , takatsuka k. threshold effect with stochastic fluctuation in bacteria - colony - like proliferation dynamics as analyzed through a comparative study of reaction - diffusion equations and cellular automata . physical review e. 2009;79(2):026202 . hadad k , pirouzmand a , ayoobian n. cellular neural networks ( cnn ) simulation for the tn approximation of the time dependent neutron transport equation in slab geometry . annals of nuclear energy . 2008;35(12):23132320 . benzhai h , lei l , ge q , yuwan p , ping l , qingxiang y , et al . simulation of wastewater treatment by aerobic granules in a sequencing batch reactor based on cellular automata . bioprocess and biosystems engineering . 2014;37(10):20492059 . zhang f , qiao j , liu c , yu n , ruan x. a cellular automata model for the sequencing batch reactor of activated sludge processes . in : 2006 6th world congress on intelligent control and automation . vol . 1 . ieee ; 2006 . p. 15581562 . picioreanu c , katuri kp , head i m , van loosdrecht mcm , scott k. mathematical model for microbial fuel cells with anodic biofilms and anaerobic digestion . water science and technology . 2008;57(7):965971 . picioreanu c , katuri kp , van loosdrecht mcm , head i m , scott k. modelling microbial fuel cells with suspended cells and added electron transfer mediator . journal of applied electrochemistry . 2009;40(1):151162 . santoro c , artyushkova k , gajda i , babanova s , serov a , atanassov p , et al . cathode materials for ceramic based microbial fuel cells ( mfcs ) . international journal of hydrogen energy .

a cellular non - linear network ( cnn ) is a uniform regular array of locally connected continuous - state machines , or nodes , which update their states simultaneously in discrete time . a microbial fuel cell ( mfc ) is an electro - chemical reactor using the metabolism of bacteria to drive an electrical current . in a cnn model of the mfc , each node takes a vector of states which represent geometrical characteristics of the cell , like the electrodes or impermeable borders , and quantify measurable properties like bacterial population , charges produced and hydrogen ions concentrations . the model allows the study of integral reaction of the mfc , including temporal outputs , to spatial disturbances of the bacterial population and supply of nutrients . the model can also be used to evaluate inhomogeneous configurations of bacterial populations attached on the electrode biofilms . microbial fuel cells , cellular non - linear network , spatial models

the main aim of this article is an attempt to derive a new theory for dark matter and dark energy , and to derive a new set of gravitational field equations . the primary motivation of this study is the great mystery of the dark matter and dark energy . the natural starting point for this study is to fundamentally examine the einstein field equations , given as follows : @xmath7 where @xmath8 is the ricci curvature tensor , @xmath9 is the scalar curvature , @xmath1 is the riemannian metric of the space - time , and @xmath5 is the energy - momentum tensor of matter ; see among many others @xcite . the einstein equations can also be derived using the principle of lagrangian dynamics to the einstein - hilbert functional : @xmath10 whose euler - lagrangian is exactly @xmath11 , which is the left hand side of the einstein field equations ( [ 1.1 ] ) . it is postulated that this euler - lagrangian is balanced by the symmetric energy - momentum tensor of matter , @xmath5 , leading to the einstein field equations ( [ 1.1 ] ) . the bianchi identity implies that the left hand side of the einstein equations is divergence - free , and it is then postulated and widely accepted that the energy - momentum tensor of matter @xmath5 is divergence - free as well . however , there are a number of difficulties for the einstein field equations : first , the einstein field equations failed to explain the dark matter and dark energy , and the equations are inconsistent with the accelerating expansion of the galaxies . in spite of many attempts to modify the einstein gravitational field equation to derive a consistent theory for the dark energy , the mystery remains . second , we can prove that there is no solution for the einstein field equations for the spherically symmetric case with cosmic microwave background ( cmb ) . one needs clearly to resolve this inconsistency caused by the non - existence of solutions . third , from the einstein equations ( [ 1.1 ] ) , it is clear that @xmath12 where @xmath13 is the energy - momentum density . a direct consequence of this formula is that the discontinuities of @xmath14 give rise to the same discontinuities of the curvature and the discontinuities of space - time . this is certainly an inconsistency which needs to be resolved . fourth , it has been observed that the universe is highly non - homogeneous as indicated by e.g. the `` great walls '' , filaments and voids . however , the einstein equations do not appear to offer a good explanation of this inhomogeneity . these observations strongly suggest that further fundamental level examinations of the einstein equations are inevitably necessary . it is clear that any modification of the einstein field equations should obey three basic principles : * the principle of equivalence , * the principle of general relativity , and * the principle of lagrangian dynamics . the first two principles tell us that the spatial and temporal world is a 4-dimensional riemannian manifold @xmath15 , where the metric @xmath16 represents gravitational potential , and the third principle determines that the riemannian metric @xmath16 is an extremum point of the lagrangian action . there is no doubt that the most natural lagrangian in this case is the einstein - hilbert functional as explained in many classical texts of general relativity . the key observation for our study is a well - known fact that the riemannian metric @xmath1 is divergence - free . this suggests two important postulates for deriving a new set of gravitational field equations : * the energy - momentum tensor @xmath5 of matter need not to be divergence - free due to the presence of dark energy and dark matter ; and * the field equations obey the euler - lagrange equation of the einstein - hilbert functional under the natural divergence - free constraint , with divergence defined at the extremum riemannian metric @xmath17 : @xmath18 here @xmath19 is the contra - variant derivative with respect to the extremum point @xmath17 , and @xmath20 are the variational elements . namely , for any @xmath21 with @xmath22 , @xmath23=(\delta f(g_{ij } ) , x)=0.\ ] ] for this purpose , an important part of this article is to drive an orthogonal decomposition theorem of tensors on riemannian manifolds , which we shall explain further in the last part of this introduction . under these two postulates , using the orthogonal decomposition theorem of tensors , we derive the following new set of gravitational field equations with scalar potential : @xmath24 where the scalar function @xmath25 is called the scalar potential . the corresponding conservations of mass , energy and momentum are then replaced by @xmath26 and the energy - momentum density @xmath27 and the scalar potential energy density @xmath28 satisfy @xmath29 the scalar potential energy density @xmath30 has a number of important physical properties : * gravitation is now described by the riemannian metric @xmath1 , the scalar potential @xmath0 and their interactions , unified by the new gravitational field equations ( [ 1.3 ] ) . * this scalar potential energy density @xmath30 represents a new type of energy / force caused by the non - uniform distribution of matter in the universe . this scalar potential energy density varies as the galaxies move and matter of the universe redistributes . like gravity , it affects every part of the universe as a field . * this scalar potential energy density @xmath30 consists of both positive and negative energies . the negative part of this potential energy density produces attraction , and the positive part produces repelling force . the conservation law ( [ 1.6 ] ) amounts to saying that the the total scalar potential energy density is conserved . * the sum of this new potential energy density @xmath4 and the coupling energy between the energy - momentum tensor @xmath5 and the scalar potential field @xmath0 , as described e.g. by the second term in the right - hand side of ( [ 1.9 - 1 ] ) , gives rise to a new unified theory for dark matter and dark energy : the negative part of @xmath31 represents the dark matter , which produces attraction , and the positive part represents the dark energy , which drives the acceleration of expanding galaxies . * the scalar curvature of space - time obeys ( [ 1.5 ] ) . consequently , when there is no normal matter present ( with @xmath32 ) , the curvature @xmath9 of space - time is balanced by @xmath33 . therefore , there is no real vacuum in the universe . * the universe with uniform distributed matter leads to identically zero scalar potential energy , and is unstable . it is this instability that leads to the existence of the dark matter and dark energy , and consequently the high non - homogeneity of the universe . hereafter , we further explore a few direct consequences of the above new gravitational field equations . first , the new field equations are consistent with the spherically symmetric case with cosmic microwave background ( cmb ) . namely , the existence of solutions in this case can be proved . second , our new theory suggests that the curvature @xmath9 is always balanced by @xmath34 in the entire space - time by ( [ 1.5 ] ) , and the space - time is no longer flat . namely the entire space - time is also curved and is filled with dark energy and dark matter . in particular , the discontinuities of @xmath9 induced by the discontinuities of the energy - momentum density @xmath14 , dictated by the einstein field equations , are no longer present thanks to the balance of @xmath35 . third , this scalar potential energy density should be viewed as the main cause for the non - homogeneous distribution of the matter / galaxies in the universe , as the dark matter ( negative scalar potential energy ) attracts and dark energy ( positive scalar potential energy ) repels different galaxies ; see ( [ 1.9 - 1 ] ) below . fourth , to further explain the dark matter and dark energy phenomena , we consider a central matter field with total mass @xmath36 and radius @xmath37 and spherical symmetry . with spherical coordinates , the corresponding riemannian metric must be of the following form : @xmath38 where @xmath39 and @xmath40 are functions of the radial distance . with the new field equations , the force exerted on an object with mass @xmath41 is given by @xmath42 , \qquad r = \phi \qquad \text { for } r > r_0.\la{1.9 - 1}\ ] ] where @xmath43 , @xmath9 is the scalar curvature , and @xmath0 is the scalar potential . the first term is the classical newton gravitation , the second term is the coupling interaction between matter and the scalar potential @xmath0 , and the third term is the interaction generated by the scalar potential energy density @xmath30 as indicated in ( [ 1.5 ] ) ( @xmath33 for @xmath44 ) . in this formula , the negative and positive values of each term represent respectively the attracting and repelling forces . it is then clear that the combined effect of the second and third terms in the above formula represent the dark matter , dark energy and their interactions with normal matter . also , importantly , this formula is a direct representation of the einstein s equivalence principle . namely , the curvature of space - time induces interaction forces between matter . in addition , one can derive a more detailed version of the above formula : @xmath45,\la{f0}\ ] ] where @xmath46 . the conservation law ( [ 1.6 ] ) of @xmath34 suggests that @xmath9 behaviors as @xmath47 for @xmath48 sufficiently large . consequently the second term in the right hand side of ( [ f0 ] ) must dominate and be positive , indicating the existence of dark energy . in fact , the above formula can be further simplified to derive the following approximate formula : @xmath49 , \la{1.9}\\ & k_0=4 \times 10^{-18 } km^{-1 } , \qquad k_1=10^{-57 } km^{-3}.\la{1.10}\end{aligned}\ ] ] again , in ( [ 1.9 ] ) , the first term represents the newton gravitation , the attracting second term stands for dark matter and the repelling third term is the dark energy . the mathematical part of this article is devoted to a rigorous derivation of the new gravitational field equations . first , as mentioned earlier , the field equations obey the euler - lagrange equation of the einstein - hilbert functional under the natural divergence - free constraint , with divergence defined at the extremum riemannian metric @xmath17 : @xmath50 as the variational elements @xmath51 are divergence - free , ( [ el ] ) does not imply @xmath52 , which is the classical einstein equations . in fact , ( [ el ] ) amounts to saying that @xmath53 is orthogonal to all divergence - free tensor fields @xmath51 . hence we need to decompose general tensor fields on riemannian manifolds into divergence - free and gradient parts . for this purpose , an orthogonal decomposition theorem is derived in theorem [ t3.1 ] . in particular , given an @xmath54 tensor field @xmath55 , we have @xmath56 the gradient part is acting on an @xmath57 tensor field @xmath58 . second , restricting to a @xmath59 symmetric tensor field @xmath60 , the gradient part in the above decomposition is given by @xmath61 then using symmetry , we show in theorem [ t3.4 ] that this @xmath62 tensor @xmath58 can be uniquely determined , up to addition to constants , by the gradient of a scalar field @xmath0 : @xmath63 and consequently we obtain the following decomposition for general symmetric @xmath59 tensor fields : @xmath64 finally , for the symmetric and divergence free @xmath59 field @xmath53 , which is the euler - lagrangian of the einstein - hilbert functional in ( [ el ] ) and is orthogonal to all divergence - free fields , there is a scalar field @xmath65 such that @xmath66 which , by adding the energy - momentum tensor @xmath5 , leads to the new gravitational field equations ( [ 1.3 ] ) . we remark here that the orthogonal decompositions ( [ rsd ] ) and ( [ 02d ] ) are reminiscent of the orthogonal decomposition of vectors fields into gradient and divergence parts , which are crucial for studying incompressible fluid flows ; see among many others @xcite . this article is divided into two parts . the physically inclined readers can go directly to the physics part after reading this introduction . let @xmath15 be an @xmath67-dimensional riemannian manifold with metric @xmath68 , and @xmath69 be an @xmath70-tensor bundle on @xmath36 . a mapping @xmath71 is called a section of the tensor - bundle @xmath72 or a tensor field . in a local coordinate system @xmath73 , a tensor field @xmath60 can be expressed component - wise as follows : @xmath74 where @xmath75 are functions of @xmath76 . the section @xmath60 is called @xmath77-tensor field or @xmath77-section if its components are @xmath77-functions . for any real number @xmath78 , let @xmath79 be the space of all @xmath80-integrable sections of @xmath72 : @xmath81 equipped with the norm @xmath82^{{1}/{p}}=\left[\int_m\sum|u^{j_1\cdots j_r}_{i_1\cdots i_s}|^pdx\right]^{1/p}.\ ] ] for @xmath83 , @xmath84 is a hilbert space equipped with the inner product @xmath85 where @xmath68 is riemannian metric , @xmath86 , @xmath87 , and @xmath88 is the volume element . for any positive integer @xmath89 and any real number @xmath90 , we can also define the sobolev spaces @xmath91 to be the subspace of @xmath79 such that all covariant derivatives of u up to order @xmath89 are in @xmath79 . the norm of @xmath91 is always denoted by @xmath92 . as @xmath83 , the spaces @xmath91 are hilbert spaces , and are usually denoted by @xmath93 equipped with inner product @xmath94 and norm @xmath95 . let @xmath96 be an @xmath70-tensor field , with the local expression @xmath97 then the gradient of @xmath60 is defined as @xmath98 where @xmath99 is the covariant derivative . it is clear that the gradient @xmath100 defined by ( [ ( 2.6 ) ] ) is an @xmath101-tensor field : @xmath102 we define @xmath103 as @xmath104 for an @xmath105-tensor field @xmath106 the divergence of @xmath60 is defined by @xmath107 therefore , the divergence @xmath108 defined by ( [ ( 2.8 ) ] ) is an @xmath70-tensor field . likewise , for an @xmath101-tensor field @xmath109 the following operator is also called the divergence of @xmath60 , @xmath110 where @xmath111 , which is an @xmath70-tensor field . for the gradient operators ( [ ( 2.6)])-([(2.7 ) ] ) and the divergent operators ( [ ( 2.8)])-([(2.9 ) ] ) , it is well known that the following integral formulas hold true ; see among others @xcite . let @xmath15 be a closed riemannian manifold . if @xmath60 is an @xmath112-tensor and @xmath113 is an @xmath70 tensor , then we have @xmath114 where @xmath103 is as in ( [ ( 2.7 ) ] ) and @xmath115 is as in ( [ ( 2.8 ) ] ) , the inner product @xmath116 is as defined by ( [ ( 2.1 ) ] ) . if @xmath60 is an @xmath117-tensor and @xmath113 is an @xmath70 tensor , then @xmath118 where @xmath100 is as in ( [ ( 2.6 ) ] ) and @xmath119 is as in ( [ ( 2.9 ) ] ) . let @xmath120 be a hilbert space equipped with inner product @xmath121 and norm @xmath122 , and @xmath123 be a mapping . we say that @xmath124 is weakly continuous if for any sequence @xmath125 weakly converging to @xmath126 , i.e. @xmath127 we have @xmath128 if the operator @xmath124 is linear and bounded , then @xmath124 is weakly continuous . the following theorem is called the acute - angle principle @xcite . if a mapping @xmath123 is weakly continuous , and satisfies @xmath129 for some constants @xmath130 , then for any @xmath131 there is a @xmath132 such that @xmath133 the aim of this section is to derive an orthogonal decomposition for @xmath70-tensor fields with @xmath134 into divergence - free and gradient parts . this decomposition plays a crucial role for the theory of gravitational field , dark matter and dark energy developed later in this article . let @xmath36 be a closed riemannian manifold , and @xmath135 @xmath136 . we say that @xmath113 is divergence - free , i.e. , @xmath137 , if for all @xmath138 , @xmath139 here @xmath140 or @xmath141 , and @xmath116 is the @xmath142-inner product defined by ( [ ( 2.1 ) ] ) . we remark that if @xmath143 satisfies ( [ ( 3.1 ) ] ) , then @xmath113 is weakly differentiable , and @xmath144 in the @xmath142-sense . if @xmath145 is not differential , then ( [ ( 3.1 ) ] ) means that @xmath113 is divergence - free in the distribution sense . let @xmath36 be a closed riemannian manifold , and @xmath146 with @xmath147 . the following assertions hold true : * the tensor field @xmath60 has the following orthogonal decomposition : @xmath148 where @xmath149 or @xmath150 , and @xmath151 . * if @xmath36 is compact , then @xmath60 can be orthogonally decomposed into @xmath152 where @xmath0 and @xmath113 are as in ( [ ( 3.2 ) ] ) , and @xmath153 is a harmonic field , i.e. @xmath154 in particular the subspace of all harmonic tensor fields in @xmath155 is of finite dimensional : @xmath156 we proceed in several steps as follows . step 1 proof of assertion ( 1 ) . let @xmath157 , @xmath69 @xmath136 . consider the equation @xmath158 where @xmath159 is the laplace operator defined by @xmath160 without loss of generality , we only consider the case where @xmath161 . it is clear that if the equation ( [ ( 3.6 ) ] ) has a solution @xmath162 , then by ( [ ( 3.7 ) ] ) , the following vector field must be divergence - free @xmath163 moreover , by ( [ ( 3.1 ) ] ) we have @xmath164 namely @xmath113 and @xmath165 are orthogonal . therefore , the orthogonal decomposition @xmath166 follows from ( [ ( 3.8 ) ] ) and ( [ ( 3.9 ) ] ) . it suffices then to prove that ( [ ( 3.6 ) ] ) has a weak solution @xmath162 : @xmath167 to this end , let @xmath168 then we define a linear operator @xmath169 by @xmath170 it is clear that the linear operator @xmath171 is bounded , weakly continuous , and @xmath172 based on theorem [ t2.3 ] , for any @xmath131 , the equation @xmath173 has a weak solution @xmath174 . hence for @xmath175 the equation ( [ ( 3.6 ) ] ) has a solution , and assertion ( 1 ) is proved . in fact the solution of ( [ ( 3.6 ) ] ) is unique . we remark that by the poincar inequality , for the space @xmath176 , ( [ ( 3.12 ) ] ) is an equivalent norm of @xmath120 . in addition , by theorem [ t2.1 ] , the weak formulation ( [ ( 3.10 ) ] ) for ( [ ( 3.6 ) ] ) is well - defined . step 2 proof of assertion ( 2 ) . based on assertion ( 1 ) , we have @xmath177 where @xmath178 define an operator @xmath179 by @xmath180 where @xmath181 is the canonical orthogonal projection . we know that the laplace operator @xmath159 can be expressed as @xmath182 where @xmath183 is the lower order derivative linear operator . since @xmath36 is compact , the sobolev embeddings @xmath184 are compact , which implies that the lower order derivative operator @xmath185 where the integer @xmath186 is the dimension of the tensor bundle @xmath72 . according to the elliptic operator theory , the elliptic operator in ( [ ( 3.14 ) ] ) @xmath187 is a linear homeomorphism . therefore the operator in ( [ ( 3.14 ) ] ) is a linear completely continuous field @xmath188 which implies that the operator of ( [ ( 3.13 ) ] ) is also a linear completely continuous field : @xmath189 by the the spectral theorem of completely continuous fields @xcite , the space @xmath190 is finite dimensional , and is the eigenspace of the eigenvalue @xmath191 . by theorem [ t2.1 ] , for @xmath192 @xmath193 it follows that @xmath194 where @xmath120 is the harmonic space as in ( [ ( 3.5 ) ] ) . thus we have @xmath195 the proof of theorem [ t3.1 ] is complete . in theorem [ t3.1 ] , a tensor field @xmath146 with @xmath134 can be orthogonally decomposed into @xmath196 now we address the uniqueness problem of the decomposition ( [ ( 3.15 ) ] ) . in fact , if @xmath60 is a vector field or a co - vector field , i.e. @xmath197 then the decomposition of ( [ ( 3.15 ) ] ) is unique . we can see that if @xmath146 with @xmath198 , then there are different types of the decompositions of ( [ ( 3.15 ) ] ) . for example , for @xmath199 , the local expression of @xmath60 is given by @xmath200 in this case , @xmath60 has two types of decompositions : @xmath201 it is easy to see that if @xmath202 then both ( [ ( 3.16 ) ] ) and ( [ ( 3.17 ) ] ) are two different decompositions of @xmath203 . namely @xmath204 if @xmath205 is symmetric , @xmath60 can be orthogonally decomposed into the following two forms : @xmath206 and @xmath0 and @xmath58 satisfy @xmath207 by @xmath205 we have @xmath208 . hence , ( [ ( 3.18 ) ] ) and ( [ ( 3.19 ) ] ) are the same , and @xmath209 . therefore , the symmetric tensors @xmath203 can be written as @xmath210 from ( [ ( 3.20)])-([(3.21 ) ] ) we can deduce the following theorem . let @xmath199 be symmetric , i.e. @xmath205 , and the first betti number @xmath211 for @xmath36 . then the following assertions hold true : * @xmath60 has a unique orthogonal decomposition if and only if there is a scalar function @xmath212 such that @xmath60 can be expressed as @xmath213 * @xmath60 can be orthogonally decomposed in the form of ( [ ( 3.22 ) ] ) if and only if @xmath203 satisfy @xmath214 where @xmath215 and @xmath8 are the ricci curvature tensors . * if @xmath216 in ( [ ( 3.20 ) ] ) is symmetric : @xmath217 , then @xmath60 can be expressed by ( [ ( 3.22 ) ] ) . we only need to prove assertions ( 2 ) and ( 3 ) . we first prove assertion ( 2 ) . it follows from ( [ ( 3.20 ) ] ) that @xmath218 where @xmath219 . by the weitzenbck formula @xcite , @xmath220 and @xmath221 is the laplace - beltrami operator . we know that for @xmath222 , @xmath223 where @xmath224 is the gradient operator , and @xmath225 namely @xmath226 hence , we infer from ( [ ( 3.25 ) ] ) that @xmath227 thus , by ( [ ( 3.24 ) ] ) and ( [ ( 3.26 ) ] ) , we obtain that @xmath228 holds true if and only if the tensor @xmath229 in ( [ ( 3.20 ) ] ) is a gradient @xmath230 . assertion ( 2 ) is proven . now we verify assertion ( 3 ) . since @xmath216 in ( [ ( 3.20 ) ] ) is symmetric , we have @xmath231 note that @xmath232 where @xmath233 is the levi - civita connection , and @xmath234 . we infer then from ( [ ( 3.27 ) ] ) that @xmath235 by assumption , the 1-dimensional homology of @xmath36 is zero , @xmath236 and it follows from the de rham theorem and ( [ ( 3.29 ) ] ) that @xmath237 for some scalar function @xmath0 . thus assertion ( 3 ) follows and the proof is complete . hereafter we always assume that @xmath36 is a closed manifold . a riemannian metric @xmath124 on @xmath36 is a mapping @xmath238 which is symmetric and nondegenerate , i.e. , in a local coordinate @xmath239 can be expressed as @xmath240 and the matrix @xmath68 is invertible on @xmath36 : @xmath241 if we regard a riemannian metric @xmath242 as a tensor field on manifold @xmath36 , then the set of all metrics @xmath242 on @xmath36 constitutes a topological space , called the space of riemannian metrics on @xmath36 . we denote @xmath243 the space for riemannian metrics on @xmath36 is denied by @xmath244 which is a metric space , but not a banach space . however , it is a subspace of the direct sum of two sobolev spaces @xmath245 and @xmath246 : @xmath247 a functional defined on @xmath248 @xmath249 is called the functional of riemannian metric . usually , the functional ( [ ( 4.6 ) ] ) can be expressed as @xmath250 since @xmath251 is the inverse of @xmath68 , we have @xmath252 therefore , @xmath253 in ( [ ( 4.7 ) ] ) also depends on @xmath254 , i.e. putting ( [ ( 4.8 ) ] ) in ( [ ( 4.7 ) ] ) we get @xmath255 we note that although @xmath256 is not a linear space , for a given element @xmath257 and any symmetric tensor @xmath20 and @xmath258 , there is a number @xmath259 such that @xmath260 due to ( [ ( 4.10 ) ] ) , we can define the derivative operators of the functional @xmath261 , which are also called the euler - lagrange operators of @xmath261 , as follows @xmath262 where @xmath263 is the dual space of @xmath264 , and @xmath265 are given by @xmath266 for any given metric @xmath267 , the value of @xmath268 and @xmath269 at @xmath1 are second - order contra - variant and covariant tensor fields respectively , i.e. @xmath270 moreover , the equations @xmath271 are called the euler - lagrange equations of @xmath261 , and the solutions of ( [ ( 4.15 ) ] ) and ( [ ( 4.16 ) ] ) are called the extremum points or critical points of @xmath261 . let @xmath261 be the functionals defined by ( [ ( 4.6 ) ] ) and ( [ ( 4.9 ) ] ) . then the following assertions hold true : * for any @xmath272 and @xmath273 are symmetric tensor fields . * if @xmath274 is the extremum point of @xmath261 , then @xmath275 is also an extremum point of @xmath261 , i.e. @xmath16 satisfies ( [ ( 4.15 ) ] ) and ( [ ( 4.16 ) ] ) if and only if @xmath275 satisfies ( [ ( 4.15 ) ] ) and ( [ ( 4.16 ) ] ) . * @xmath268 and @xmath269 have the following relation @xmath276 where @xmath277 and @xmath278 are the components of @xmath269 and @xmath268 respectively . we only need to verify assertion ( 3 ) . noting that @xmath279 we have the variational relation @xmath280 it implies that @xmath281 in addition , in ( [ ( 4.13 ) ] ) and ( [ ( 4.14 ) ] ) , @xmath282 therefore , by ( [ ( 4.17 ) ] ) we get @xmath283 hence @xmath284 thus assertion ( 3 ) follows and the proof is complete . we know that the critical points of the functional @xmath261 in ( [ ( 4.6 ) ] ) are the solution @xmath285 in the following sense @xmath286 where @xmath287 . hence , the critical points of functionals of riemannian metrics are not solutions of ( [ ( 4.18 ) ] ) in the usual sense . it is easy to see that @xmath288 can be orthogonally decomposed into the direct sum of the symmetric and contra - symmetric spaces , i.e. @xmath289 since @xmath290 is symmetric , by ( [ ( 4.20 ) ] ) the extremum points @xmath16 of @xmath261 satisfy more general equality @xmath291 thus , we can say that the extremum points of functionals of the riemannian metrics are solutions of ( [ ( 4.18 ) ] ) in the usual sense of ( [ ( 4.21 ) ] ) , or are zero points of the variational operators @xmath292 now we consider the variations of @xmath261 under the divergence - free constraint . in this case , the euler - lagrangian equations with symmetric divergence - free constraints are equivalent to the euler - lagrangian equations with general divergence - free constraints . hence we have the following definition . let @xmath293 be a functional of riemannian metric . a metric tensor @xmath294 is called an extremum point of @xmath261 with divergence - free constraint , if @xmath16 satisfies @xmath295 where @xmath296 is the space of all divergence - free tensors : @xmath297 it is clear that an extremum point satisfying ( [ ( 4.22 ) ] ) is not a solution of ( [ ( 4.18 ) ] ) . instead , we have the scalar potential theorem for the extremum points of divergence free constraint ( [ ( 4.22 ) ] ) , which is based on the orthogonal decomposition theorems . this result is also crucial for the gravitational field equations and the theory of dark matter and dark energy developed later . assume that the first betti number of @xmath36 is zero , i.e. @xmath211 . let @xmath261 be a functional of the riemannian metric . then there is a @xmath298 such that the extremum points @xmath16 of @xmath261 with divergence - free constraint satisfy @xmath299 let @xmath16 be an extremum point of @xmath261 under the constraint ( [ ( 4.22 ) ] ) . namely , @xmath53 satisfies @xmath300 by theorem [ t3.1 ] , @xmath301 can be orthogonally decomposed as @xmath302 by theorem [ t2.1 ] , for any @xmath303 , @xmath304 therefore it follows from ( [ ( 4.24)])-([(4.26 ) ] ) that @xmath305 let @xmath306 . since @xmath307 we have @xmath308 thanks to @xmath309 . inserting @xmath306 into ( [ ( 4.27 ) ] ) leads to @xmath310 which implies that @xmath311 . thus , ( [ ( 4.25 ) ] ) becomes @xmath312 by theorem [ t4.1 ] , @xmath290 is symmetric . hence we have @xmath313 it follows from ( [ ( 3.28 ) ] ) that @xmath314 by assumption , the first betti number of @xmath36 is zero , i.e. the 1-dimensional homology of @xmath36 is zero : @xmath315 . it follows from the de rham theorem that if @xmath316 then there exists a scalar function @xmath0 such that @xmath317 thus , we infer from ( [ ( 4.29 ) ] ) that @xmath318 therefore we get ( [ ( 4.23 ) ] ) from ( [ ( 4.28 ) ] ) . the theorem is proved . if the first betti number @xmath319 , then there are @xmath320 number of 1-forms : @xmath321 which constitute a basis of the 1-dimensional de rham homology @xmath322 . we know that the components of @xmath323 are co - vector fields : @xmath324 which possess the following properties : @xmath325 or equivalently , @xmath326 namely , @xmath327 are symmetric second - order contra - variant tensors . hence theorem [ t4.3 ] can be extended to the non - vanishing first betti number case as follows . let the first betti number @xmath319 for @xmath36 . then for the functional @xmath261 of riemannian metrics , the extremum points @xmath16 of @xmath261 with the constraint ( [ ( 4.22 ) ] ) satisfy the equations @xmath328 where @xmath329 are constants , @xmath212 , and the tensors @xmath330 are as given by ( [ ( 4.31 ) ] ) . the proof of theorem [ t4.4 ] is similar to theorem [ t4.3 ] , and is omitted here . the general theory of relativity is based on three basic principles : the principle of equivalence , the principle of general relativity , and the principle of lagrangian dynamics . the first two principles tell us that the spatial and temporal world is a 4-dimensional riemannian manifold @xmath15 , where the metric @xmath16 represents gravitational potential , and the third principle determines that the riemannian metric @xmath16 is an extremum point of the lagrangian action , which is the einstein - hilbert functional . let @xmath15 be an @xmath67-dimensional riemannian manifold . the einstein - hilbert functional @xmath331 is defined by @xmath332 where @xmath333 is defined by ( [ ( 4.5 ) ] ) , @xmath334 and @xmath335 are the scalar and the ricci curvatures , @xmath336 is the stress tensor , @xmath124 is the gravitational constant , and @xmath337 is the speed of light . the euler - lagrangian of the einstein - hilbert functional @xmath261 is given by @xmath338 where @xmath5 is the energy - momentum tensor given by @xmath339 and the ricci curvature tensor @xmath8 is given by @xmath340 by ( [ ( 5.3)])-([(5.5 ) ] ) , the euler - lagrangian @xmath53 of the einstein - hilbert functional is a second order differential operator on @xmath16 , and @xmath341 is symmetric . the general theory of relativity consists of two main conclusions : 1 . the space - time of our world is a 4-dimensional riemannian manifold @xmath342 , and the metric @xmath16 represents gravitational potential . the metric @xmath16 is the extremum point of the einstein - hilbert functional ( [ ( 5.2 ) ] ) . in other words , gravitational field theory obeys the principle of lagrange dynamics . the principle of lagrange dynamics is a universal principle , stated as : * principle of lagrange dynamics . * _ for any physical system , there are a set of state functions @xmath343 which describe the state of this system , and there exists a functional @xmath344 of @xmath60 , called the lagrange action : @xmath345 such that the state @xmath60 is an extremum point of @xmath344 . usually the function @xmath346 in ( [ ( 5.6 ) ] ) is called the lagrangian density . _ based on this principle , the gravitational field equations are the euler - lagrange equations of the einstein - hilbert functional : @xmath347 which are the classical einstein field equations : @xmath348 by the bianchi identities , the left hand side of ( [ ( 5.8 ) ] ) is divergence - free , i.e. @xmath349 therefore it is required in the general theory of relativity that the energy - momentum tensor @xmath350 in ( [ ( 5.8 ) ] ) satisfies the following energy - momentum conservation law : @xmath351 motivated by the mystery of dark energy and dark matter and the other difficulties encountered by the einstein field equations as mentioned in introduction , we introduce in this section a new set of field equations , still obeying the three basic principles of the general theory of relativity . our key observation is a well - known fact that the riemannian metric @xmath1 is divergence - free . this suggests us two important postulates for deriving the new gravitational field equations : * the energy - momentum tensor of matter need not to be divergence - free due to the presence of dark energy and dark matter ; and * the field equation obeys the euler - lagrange equation of the einstein - hilbert functional under the natural divergence - free constraint . under these two postulates , by the scalar potential theorem , theorem [ t4.3 ] , if the riemannian metric @xmath16 is an extremum point of the einstein - hilbert functional ( [ ( 5.2 ) ] ) with the divergence - free constraint ( [ ( 4.22 ) ] ) , then the gravitational field equations are taken in the following form : @xmath352 where @xmath212 is called the scalar potential . we infer from ( [ ( 5.9 ) ] ) that the conservation laws for ( [ ( 5.13 ) ] ) are as follows @xmath353 using the contraction with @xmath254 in ( [ ( 5.13 ) ] ) , we have @xmath354 where @xmath355 represent respectively the energy - momentum density and the scalar potential density . physically this scalar potential density @xmath34 represents potential energy caused by the non - uniform distribution of matter in the universe . one important property of this scalar potential is @xmath356 which is due to the integration by parts formula in theorem [ t2.1 ] . this formula demonstrates clearly that the negative part of this quantity @xmath34 represents the dark matter , which produces attraction , and the positive part represents the dark energy , which drives the acceleration of expanding galaxies . we shall address this important issue in the next section . the topological structure of closed universe is given by @xmath357 where @xmath358 is the time circle and @xmath359 is the 3-dimensional sphere representing the space . we note that the radius @xmath9 of @xmath359 depends on time @xmath360 , @xmath361 and the minimum time @xmath362 , @xmath363 is the initial time of the big bang . for a closed universe as ( [ 4.3 ] ) , by theorem [ t4.3 ] , the gravitational field equations are in the form @xmath364 where @xmath365 the scalar potential , @xmath366 the vector potential , and @xmath367 is a constant . the conservation laws of ( [ 4.4 ] ) are as follows @xmath368 we know that the metric of a central gravitational field is in a diagonal form @xcite : @xmath369 and physically @xmath370 is given by @xmath371 where @xmath58 is the newton gravitational potential ; see among others @xcite . if the central matter field has total mass @xmath36 and radius @xmath37 , then for @xmath44 , the metric ( [ 5.1 ] ) is the well known schwarzschild solution for the einstein field equations ( [ ( 5.8 ) ] ) , and is given by @xmath372 we derive from ( [ 5.2 ] ) and ( [ 5.3 ] ) the classical newton gravitational potential @xmath373 we now consider the metric determined by the new field equations ( [ ( 5.13 ) ] ) , from which we derive a gravitational potential formula replacing ( [ 5.4 ] ) . equations ( [ ( 5.13 ) ] ) can be equivalently expressed as @xmath374 where @xmath375 for the central matter field with total mass @xmath36 and radius @xmath37 , by the schwarzschild assumption , for @xmath44 , there exists no matter , i.e. @xmath376 therefore the conservation laws of ( [ 5.5 ] ) are @xmath377 the tensors @xmath1 in ( [ 5.1 ] ) are written as @xmath378 noting that the central field is spherically symmetric , we assume that @xmath379 for the metric ( [ 5.8 ] ) , the non - zero components of the levi - civita connection are as follows @xmath380 hence the ricci tensor @xmath381 are given by @xmath382,\\ & r_{11}=\frac{u^{\prime\prime}}{2}-\frac{v^{\prime}}{r}+\frac{u^{\prime}}{4}(u^{\prime}-v^{\prime}),\\ & r_{22}=e^{-v}\left[1-e^v+\frac{r}{2}(u^{\prime}-v^{\prime})\right]\\ & r_{33}=r_{22}\sin^2\theta , \\ & r_{ij}=0\qquad \forall i\neq j. \end{aligned}\label{5.12}\ ] ] furthermore , we infer from ( [ 5.8 ] ) , ( [ 5.9 ] ) and ( [ 5.11 ] ) that @xmath383,\\ & d_1d_1\varphi -\frac{1}{2}g_{11}\phi = \frac{1}{2}\left[\varphi^{\prime\prime}-\frac{1}{2}(v^{\prime}+u^{\prime}+\frac{4}{r})\varphi^{\prime}\right],\\ & d_2d_2\varphi -\frac{1}{2}g_{22}\phi = -\frac{r^2}{2}e^{-v}\left[\varphi^{\prime\prime}+\frac{1}{2}(u^{\prime}-v^{\prime})\varphi^{\prime}\right],\\ & d_3d_3\varphi -\frac{1}{2}g_{33}\phi = \sin^2\theta\left(d_2d_2\varphi -\frac{1}{2}g_{22}\phi\right ) . \end{aligned}\label{5.13}\ ] ] thus , by ( [ 5.12 ] ) and ( [ 5.13 ] ) , the equations ( [ 5.5 ] ) are as follows @xmath384 we need to consider the existence and uniqueness of solutions of the equations ( [ 5.14])-([5.16 ] ) . first , in the vacuum case , the classical einstein equations are in the form @xmath385 two of which are independent . the system contains two unknown functions , and therefore for a given initial value ( as @xmath386 is basic in ( [ 6.1a ] ) ) : @xmath387 the problem ( [ 6.1a ] ) with ( [ 6.2a ] ) has a unique solution , which is the schwarzschild solution @xmath388 where @xmath389 now if we consider the influence of the cosmic microwave background ( cmb ) for the central fields , then we should add a constant energy density in equations ( [ 6.1a ] ) : @xmath390 namely , @xmath391 where @xmath392 is the density of the microwave background , whose value is @xmath393 . then it is readily to see that the problem ( [ 6.4a ] ) with ( [ 6.2a ] ) has no solution . in fact , the divergence - free equation @xmath394 yields that @xmath395 which implies that @xmath396 . hence @xmath397 , a contradiction to ( [ 6.4a ] ) . furthermore , if we regard @xmath392 as an unknown function , then the equations ( [ 6.4a ] ) still have no solutions . on the other hand , the new gravitational field equations ( [ 5.14])-([5.16 ] ) are solvable for the microwave background as the number of unknowns are the same as the number of independent equations . equations ( [ 5.14])-([5.16 ] ) have the following equivalent form : @xmath398 equipped with the following initial values : @xmath399 it is classical that ( [ 6.5a ] ) with ( [ 6.6a ] ) possesses a unique local solution . in fact , we can prove that the solution exists for all @xmath400 . we now derive the gravitational interaction formula from the basic model ( [ 5.14])-([5.16 ] ) . first , we infer from ( [ 5.14])-([5.16 ] ) that @xmath401 . \end{aligned}\label{6.8a}\ ] ] consequently , @xmath402 by ( [ 5.2 ] ) and ( [ 5.8 ] ) , we have @xmath403 as the interaction force @xmath261 is given by @xmath404 it follows from ( [ 6.8a ] ) and ( [ 6.9a ] ) that @xmath405 , \la{6.10a } \\ & \varphi^{\prime\prime}= - e^v r + \frac12 ( u ' - v ' + \frac4r ) \varphi^\prime . \la{6.10b}\end{aligned}\ ] ] of course , the following energy balance and conservation law hold true as well : @xmath406 where @xmath9 is the scalar curvature and @xmath407 . equation ( [ 6.10b ] ) is derived by solving @xmath408 using ( [ r - conservation ] ) . namely , for @xmath44 where @xmath32 , @xmath409.\ ] ] we now consider the region : @xmath410 . physically , we have @xmath411 hence @xmath60 and @xmath113 in ( [ 6.10a ] ) can be replaced by the schwarzschild solution : @xmath412 as @xmath413 is small for @xmath48 large , by ( [ 6.11a ] ) , the formula ( [ 6.10a ] ) can be expressed as @xmath414.\la{6.13a}\ ] ] this is the interactive force in a central symmetric field . the first term in the parenthesis is the newton gravity term , and the added second term @xmath415 is the scalar potential energy density , representing the dark matter and dark energy . in addition , replacing @xmath60 and @xmath113 in ( [ 6.10b ] ) by the schwarzschild solution ( [ 6.12a ] ) , we derive the following approximate formula : @xmath416 consequently we infer from ( [ 6.13a ] ) that @xmath42 , \qquad r=\phi \quad \text { for } r > r_0 . \la{6.16a}\ ] ] the first term is the classical newton gravitation , the second term is the coupling interaction between matter and the scalar potential @xmath0 , and the third term is the interaction generated by the scalar potential energy density @xmath34 . in this formula , the negative and positive values of each term represent respectively the attracting and repelling forces . integrating ( [ 6.15a ] ) yields ( omitting @xmath417 ) @xmath418 where @xmath419 is a free parameter . hence the interaction force @xmath261 is approximated by @xmath45,\la{f2}\ ] ] where @xmath420 , @xmath33 for @xmath44 , and @xmath421 we note that based on ( [ r - conservation ] ) , for @xmath422 , @xmath9 is balanced by @xmath34 , and the conservation of @xmath34 suggests that @xmath9 behaviors like @xmath47 as @xmath48 sufficiently large . hence for @xmath48 large , the second term in the right hand side of ( [ f2 ] ) must be dominate and positive , indicating the existence of dark energy . we note that the scalar curvature is infinite at @xmath423 : @xmath424 also @xmath9 contains two free parameters determined by @xmath386 and @xmath113 respectively . hence if we take a first order approximation as @xmath425 where @xmath426 and @xmath427 are free yet to be determined parameters . then we deduce from ( [ 6.1b ] ) and ( [ 6.2b ] ) that @xmath428 therefore , @xmath429.\ ] ] physically it is natural to choose @xmath430 also , @xmath426 and @xmath431 are much smaller than @xmath432 for @xmath433 . hence @xmath434 . \la{f3}\ ] ] where @xmath435 and @xmath436 can be estimated using the rubin law of rotating galaxy and the acceleration of the expanding galaxies : @xmath437 we emphasize here that the formula ( [ f3 ] ) is only a simple approximation for illustrating some features of both dark matter and dark energy . dark matter and dark energy are two of most remarkable discoveries in astronomy in recent years , and they are introduced to explain the acceleration of the expanding galaxies . in spite of many attempts and theories , the mystery remains . as mentioned earlier , this article is an attempt to develop a unified theory for the dark matter and dark energy . a strong support to the existence of dark matter is the rubin law for galactic rotational velocity , which amounts to saying that most stars in spiral galaxies orbit at roughly the same speed . namely , the orbital velocity @xmath438 of the stars located at radius @xmath48 from the center of galaxies is almost a constant : @xmath439 typical galactic rotation curves @xcite are illustrated by figure [ f6.1](a ) , where the vertical axis represents the velocity ( km / s ) , and the horizontal axis is the distance from the galaxy center ( extending to the galaxy radius ) . however , observational evidence shows discrepancies between the mass of large astronomical objects determined from their gravitational effects , and the mass calculated from the visible matter they contain , and figure [ f6.1 ] ( b ) gives a calculated curve . the missing mass suggests the presence of dark matter in the universe . in astronomy and cosmology , dark energy is a hypothetical form of energy , which spherically symmetrically permeates all of space and tends to accelerate the expansion of the galaxies . the high - z supernova search team in 1998 and the supernova cosmology project in 1998 published their observations which reveal that the expansion of the galaxies is accelerating . in 2011 , a survey of more than @xmath440 galaxies from austrian astronomers confirmed the fact . thus , the existence of dark energy is accepted by most astrophysicist . with the new gravitational field equation with the scalar potential energy , and we are now in position to derive the nature of the dark matter and dark energy . more precisely , using the revised newton formula derived from the new field equations : @xmath441 we determine an approximation of the constants @xmath442 , based on the rubin law and the acceleration of expanding galaxies . first , let @xmath443 be the total mass in the ball with radius @xmath48 of the galaxy , and @xmath444 be the constant galactic rotation velocity . by the force equilibrium , we infer from ( [ 6.2 ] ) that @xmath445 which implies that @xmath446 this matches the observed mass distribution formula of the galaxy , which can explain the rubin law ( [ 6.3 ] ) . second , if we use the classical newton formula @xmath447 to calculate the galactic rotational velocity @xmath448 , then we have @xmath449 inserting ( [ 6.4 ] ) into ( [ 6.5 ] ) implies @xmath450 as @xmath451 , ( [ 6.6 ] ) can approximatively written as @xmath452 which is consistent with the theoretic rotational curve as illustrated by figure [ f6.1](b ) . it implies that the distribution formula ( [ 6.4 ] ) can be used as a test for the revised gravitational field equations . third , we now determine the constants @xmath435 and @xmath436 in ( [ 6.2 ] ) . according to astronomic data , the average mass @xmath453 and radius @xmath454 of galaxies is about @xmath455 where @xmath456 is the mass of the sun . taking @xmath457 , then we have @xmath458 based on physical considerations , @xmath459 by ( [ 6.7])-([6.9 ] ) , we deduce from ( [ 6.4 ] ) that @xmath460 now we consider the constant @xmath436 . due to the accelerating expansion of galaxies , the interaction force between two clusters of galaxies is repelling , i.e. for ( [ 6.2 ] ) , @xmath461 where @xmath462 is the average distance between two galactic clusters . it is estimated that @xmath463 we take @xmath464 as the distance at which @xmath465 . namely , @xmath466 hence we derive from ( [ 6.10 ] ) and ( [ 6.11 ] ) that @xmath467 thus , the constants @xmath435 and @xmath436 are estimated by @xmath468 in summary , for the formula ( [ 6.2 ] ) with ( [ 6.12 ] ) , if the matter distribution @xmath443 is in the form @xmath469 then the rubin law holds true . in particular , the mass @xmath470 generated by the revised gravitation is @xmath471 where @xmath472 is the theoretic value of total mass . hence @xmath473 namely , the revised gravitational mass @xmath470 is four times of the visible matter @xmath474 . thus , it gives an alternative explanation for the dark matter . in addition , the formula ( [ 6.2 ] ) with ( [ 6.12 ] ) also shows that for a central field with mass @xmath36 , an object at @xmath475 ( @xmath462 as in ( [ 6.11 ] ) ) will be exerted a repelling force , resulting the acceleration of expanding galaxies at @xmath476 . thus the new gravitational formula ( [ 6.2 ] ) provides a unified explanation of dark matter and dark energy . in this section , we prove that if the matter is homogeneously distributed in the universe , then the scalar potential @xmath0 is a constant , and consequently the scalar potential energy density is identically zero : @xmath477 . it is known that the metric for an isotropic and homogeneous universe is given by @xmath478,\la{7.1}\ ] ] which is called the friedmann - lematre - robertson - walker ( flrw ) metric , where the scale factor @xmath479 represents the cosmological radius , and @xmath89 takes one of the three numbers : @xmath480 . for the flrw metric ( [ 7.1 ] ) , the energy - momentum tensor @xmath350 is given by @xmath481 where @xmath392 is the mass density , @xmath482 is pressure , and @xmath483 by ( [ 7.1 ] ) and ( [ 7.2 ] ) , the einstein field equations ( [ 1.1 ] ) are reduced to two equations : @xmath484 and the conservation law @xmath485 gives @xmath486 then only two of the above three equations ( [ 7.3])-([7.5 ] ) are independent , and are called the friedman equations . on the other hand , for the metric ( [ 7.1 ] ) with ( [ 7.2 ] ) , the new gravitational field equations ( [ 1.3 ] ) with scalar potential are reduced to @xmath487 and the conservation equation @xmath488 again two of the above three equations ( [ 7.6])-([7.8 ] ) are independent . it follows from ( [ 7.6 ] ) and ( [ 7.7 ] ) that @xmath489 in the following we shall prove that @xmath490 namely , @xmath491constant . in fact , let @xmath408 and @xmath392 have the form : @xmath492 inserting ( [ 7.11 ] ) in ( [ 7.6 ] ) , ( [ 7.8 ] ) and ( [ 7.9 ] ) , we arrive at @xmath493 multiplying both sides of ( [ 7.12 ] ) by @xmath494 we obtain @xmath495 + \frac{4\pi g}{3 } \frac{\theta'}{a } - \frac16 \frac{\psi'}{a } = - \frac{4\pi g}{c^2 } p a a ' - \frac12 ( a')^2 \varphi ' . \la{7.15}\ ] ] it follows then from ( [ 7.13])-([7.15 ] ) that @xmath496 which implies that ( [ 7.10 ] ) holds true . the conclusion ( [ 7.10 ] ) indicates that if the universe is in the homogeneous state , then the scalar potential energy density @xmath30 is identically zero : @xmath477 . this fact again demonstrates that @xmath0 characterizes the non - uniform distribution of matter in the universe . we have discovered new gravitational field equations ( [ 1.3 ] ) with scalar potential under the postulate that the energy momentum tensor @xmath5 needs not to be divergence - free due to the presence of dark energy and dark matter : @xmath497 second , associated with the scalar potential @xmath0 is the scalar potential energy density @xmath30 , which represents a new type of energy / force caused by the non - uniform distribution of matter in the universe . this scalar potential energy density varies as the galaxies move and matter of the universe redistributes . like gravity , it affects every part of the universe as a field . this scalar potential energy density @xmath30 consists of both positive and negative energies . the negative part of this potential energy density produces attraction , and the positive part produces repelling force . also , this scalar energy density is conserved with mean zero : @xmath498 third , using the new field equations , for a spherically symmetric central field with mass @xmath36 and radius @xmath37 , the force exerted on an object of mass @xmath41 at distance @xmath48 is given by ( see ( [ 6.16a ] ) ) : @xmath42 , \qquad r=\phi \quad \text { for } r > r_0.\ ] ] where @xmath499 . fourth , the sum @xmath500 of this new potential energy density @xmath501 and the coupling energy between the energy - momentum tensor @xmath5 and the scalar potential field @xmath0 @xmath502 gives rise to a new unified theory for dark matter and dark energy : the negative part of @xmath31 represents the dark matter , which produces attraction , and the positive part represents the dark energy , which drives the acceleration of expanding galaxies . fifth , the scalar curvature @xmath9 of space - time obeys : @xmath503 consequently , when there is no normal matter present ( with @xmath32 ) , the curvature @xmath9 of space - time is balanced by @xmath33 . therefore , there is no real vacuum in the universe . height 2pt depth -1.6pt width 23pt , _ geometric theory of incompressible flows with applications to fluid dynamics _ , vol . 119 of mathematical surveys and monographs , american mathematical society , providence , ri , 2005 .

the main objective of this article is to derive a new set of gravitational field equations and to establish a new unified theory for dark energy and dark matter . the new gravitational field equations with scalar potential @xmath0 are derived using the einstein - hilbert functional , and the scalar potential @xmath0 is a natural outcome of the divergence - free constraint of the variational elements . gravitation is now described by the riemannian metric @xmath1 , the scalar potential @xmath0 and their interactions , unified by the new gravitational field equations . associated with the scalar potential @xmath0 is the scalar potential energy density @xmath2 , which represents a new type of energy caused by the non - uniform distribution of matter in the universe . the negative part of this potential energy density produces attraction , and the positive part produces repelling force . this potential energy density is conserved with mean zero : @xmath3 . the sum of this new potential energy density @xmath4 and the coupling energy between the energy - momentum tensor @xmath5 and the scalar potential field @xmath0 gives rise to a new unified theory for dark matter and dark energy : the negative part of this sum represents the dark matter , which produces attraction , and the positive part represents the dark energy , which drives the acceleration of expanding galaxies . in addition , the scalar curvature of space - time obeys @xmath6 . furthermore , the new field equations resolve a few difficulties encountered by the classical einstein field equations .

Breaking News Emails Get breaking news alerts and special reports. The news and stories that matter, delivered weekday mornings. / Updated By Kiara Alfonseca and Anna Brand Thousands of students and organizations across the country are joining in school walkouts in honor of those who died in the Parkland, Florida, shooting last month and to call on legislators for stricter gun laws. On March 14, at 10 a.m. ET, administrators, allies, and students of all ages will collectively leave classrooms in protest of Congress’ “inaction” on gun reform. The National School Walkout, with over 1,000 protests organized so far, is just one of several upcoming events being held in wake of the Parkland shooting, including the March For Our Lives in Washington, spearheaded by the Parkland students, on March 23. The March 14 walkout is led by the Women’s March’s Youth EMPOWER group. Select your state below to see where they are being held: ||||| As TV cameras swarmed around the speakers, most students huddled around makeshift memorials to those who died in the shooting last month — where a white cross for each of the 17 victims was planted on a field surrounded by candles, bouquets of flowers, soft toys and balloons.

– Ten days before a massive rally against gun violence in Washington, DC, students across the country will walk out of school Wednesday to mark one month since the mass shooting at Marjory Stoneman Douglas High School in Parkland, Fla. Students at elementary schools, high schools, and universities will walk out at 10am local time for 17 minutes to honor the 17 victims killed and to call for stricter gun laws, reports USA Today. A website for Empower, the youth branch of the Women's March, shows more than 3,100 walkouts planned (NBC News has an interactive map to help you find those near you), and not only in the US. Students in Germany, Israel, and Australia, are taking part. Non-students are also encouraged to participate by wearing orange or walking out of their jobs. Democrats in Congress will do so. They're expected to join students following a march from the White House to the Capitol, where a haunting memorial was seen Tuesday. Some students will face suspension, per the Los Angeles Times. But "my peers and I feel there is no time more critical than this to make clear that we have had enough of gun violence," says a senior at University High School in Tucson, Ariz., where students plan to call lawmakers, per USA Today. "For far too long, it has made us feel unsafe in our communities and in our classrooms." The walkouts are a precursor to the March For Our Lives, expected to draw 500,000 people to Washington on March 24. Thousands more will participate in sister marches. Another walkout is planned for April 20, the 19th anniversary of the Columbine shooting.

most of the scientific community which has an interest in the physics of neutron stars believes that radio emission from rotation powered pulsars ( rpps ) has its origin in the relativistic outflow of electron - positron pairs along the polar magnetic field lines of a dipole magnetic field frozen into the rotating neutron star ( e.g. , arons 1992 , meszaros 1992 ) . the evidence for dipole magnetic fields in rpps ( and in any other neutron star ) is indirect , coming primarily from the electromagnetic theory of rpp spindown . the observed increasing pulse periods are readily explained using standard theoretical moments of inertia plus order of magnitude estimates , derivable from dimensional analysis ( dyson 1971 , arons 1979 , 1992 ) , of rotational energy loss driven by relativistic electromagnetic spindown torques , @xmath2 here @xmath3 is the magnetic moment , @xmath4 is the stellar angular velocity with respect to inertial space far from the star , and @xmath5 is a function of any other parameters of significance , with magnitude on the order of unity . in the vacuum theory ( deutsch 1955 ) , @xmath6 , with @xmath7 the angle between the magnetic moment and the angular velocity . theoretical work on the torques due to conduction currents steming back to goldreich and julian ( 1969 ) , coupled to the observation that spindown rates appear to be independent of observationally estimated values of @xmath7 ( lyne and manchester 1988 ) , suggest that in reality @xmath5 does not substantially depend on @xmath7 . in the subsequent discussion , i assume k = 4/9 , the average of the vacuum value over the sphere . application of ( [ rotloss ] ) to the observations of rpps periods ( @xmath8 and period derivatives ( @xmath9 ) yields @xmath10 cgs for `` normal '' rpps , and @xmath11 cgs for millisecond rpps . these results are reasonably firm , the main uncertainty coming from the derived values of @xmath3 being proportional to @xmath12 . the electromagnetic torque interpretation of pulsar spindown constrains only the exterior dipole moment of the magnetic field . however , not long ago rankin ( 1990 ) presented strong evidence in favor of a low altitude ( @xmath13 ) dipole geometry for the site of the core component of pulsar radio emission . arons ( 1993 ) gave evidence that spun up millisecond pulsars must have a substantially dipolar large scale field at low altitute . electron - positron pair creation at low altitude above the polar caps has long been hypothesized to be an essential ingredient of pulsar radio emission , starting with sturrock s ( 1971 ) pioneering work . if so , all observed pulsars must lie in the region of @xmath14 space where polar cap acceleration has sufficient vigor to lead to copious pair production . yet , to date , all _ internally consistent _ theories of polar cap pair creation have required hypothesizing a large scale ( _ e.g. _ , quadrupole ) component of the magnetic field with strength comparable to that of the dipole ( ruderman and sutherland 1975 , arons and scharlemann 1979 , barnard and arons 1982 , gurevich and istomin 1985 ) . these non - dipole components were invoked in order to increase the opacity of the magnetic field to pair creating gamma rays . non - dipole low altitude fields can have magnetic radii of curvature on the order of @xmath15 or less , a factor of 50 - 100 smaller than the radii of curvature of star centered dipole field lines near the magnetic poles . the resulting increase of optical depth allowed the pair creation models to cover the whole @xmath16 diagram . however , such strong magnetic anomalies contradict the evidence in favor of an apparently dipolar low altitude geometry ; the alteration of the magnetic geometry also ruins the internal consistency of many models electrodynamics . both early ( sturrock 1971 ) and more recent work on polar cap electrodynamics and its implications for the occurrence of pair creation in @xmath16 space either employ incomplete ( e.g. sturner _ et al . _ 1995 ) or erroneous ( sturrock 1971 , mestel and shibata 1994 , bjornsson 1996 ) theories of polar cap particle acceleration . most of the internally consistent theories also violate other observational constraints , especially with regard to polar cap heating ( arons 1992 ) , which creates pulsed thermal x - ray emission from hot spots in excess of what is seen ( becker and trmper 1997 , pavlov and zavlin 1997 ) . while the arons and scharlemann ( 1979 ) model does not have this problem , in star centered dipole geometry it dramatically fails to account for pulsar emission over most of the @xmath14 diagram and predicts radio polarization variations in contradiction to the observations ( narayan and vivekanand 1982 ) . here i describe a low altitude polar cap acceleration theory which successfully associates pulsar `` death '' with the cessation of pair creation in an _ offset _ dipolar low altitude magnetic field . the basic acceleration physics is that of a space charge limited relativistic particle beam accelerated along the field lines by the starvation electric field , as in the arons and scharlemann theory , but with the additional effect of inertial frame dragging , first pointed out by muslimov and tsygan ( 1990 , 1992 ) and by beskin ( 1990 ) . this effect causes the accelerating electric field to be about an order of magnitude larger than that calculated by arons and scharlemann for pulsars near the death line , which substantially improves the size of the region in @xmath16 space in which polar cap pair creation occurs , but still does not allow the theory to fully account for the observed pulsar distribution , in star centered dipole geometry . if the dipole s center is offset from the stellar center along a vector parallel to the dipole moment itself , an offset which automatically preserves the symmetries built into the highly successful radhakrishnan and cooke ( 1969 ) model of polarization swings , the magnetic field at one pole becomes substantially stronger than it would be if the same magnetic dipole were star centered . if the offset is substantial ( as much as 80% of the stellar radius turns out to be required ) , all pulsars can be accommodated within a single pair creation theory . the location of an individual pulsar s pair creation death depends on the magnitude of the offset , thus yielding a `` death valley '' ( chen and ruderman 1993 ) for the whole pulsar population . prior to the work of muslimov and tsygan and of beskin , study of polar cap relativstic particle acceleration in the 1970 s had led to the conclusion that acceleration of a space charge limited particle beam from the stellar surface with energy / particle high enenough to emit magnetically convertible curvature gamma rays occurs because of curvature of the magnetic field ( scharlemann _ et al . _ 1978 , arons and scharlemann 1979 ) . with field line curvature , matching of the beam density to @xmath17 occurs only at the surface . along field lines which curve toward the rotation axis ( `` favorably curved '' field lines , @xmath18 ) , the beam fails to short out the vacuum , with @xmath19 . @xmath20 km is the stellar radius and @xmath21 is the radius of curvature of the magnetic field lines . therefore , particles accelerate along @xmath22 through a potential drop @xmath23 where @xmath24 is the rotation period in seconds , and the numerical value assumes field lines have dipolar radius of curvature . here @xmath25 with @xmath26 and @xmath27 g-@xmath28 . particles drop through the potential ( [ eq : saf - pot ] ) over a length @xmath29 ( an electric field of magnitude @xmath30 volts / meter , for normal _ and _ millisecond pulsars ) . note that @xmath31 is proportional to the magnetic flux contained in the tube of open field lines . therefore , the total potential of a pole is independent of the magnetic topology , _ if , and only if , the open field lines map onto a single , more or less round polar cap_. curvature gamma rays have typical energy @xmath32 , while the optical depth for pair creation , due to one photon conversion of gamma rays emitted by electrons ( or positrons ) accelerating through the unshorted potential ( [ eq : saf - pot ] ) , can be shown to be ( arons and scharlemann 1979 , luo 1996 , bjornsson 1996 ) @xmath33 $ ] , where @xmath34 is a pure number ( typically @xmath35 ) and @xmath36 is a combination of the basic parameters which is quite large ( @xmath37 ) . pair creation does not short out the acceleration if @xmath38 ; thus , if pairs are important for radio emission , a reasonable theoretical definition of the death line is @xmath39 . a more precise definition requires estimating the number of charges that must be added to restore the total charge density to @xmath17 and reduce @xmath40 to zero . this refinement is included in the results shown in figures [ fig : death - valley ] and [ fig : phi - p ] using @xmath41 , the potential ( [ eq : saf - pot ] ) and setting @xmath42 equal to unity yields the death line , expressed as @xmath43 such that stars @xmath44 do not make pairs . this death line , first found by arons and scharlemann ( 1979 ) , appears as the dashed line in figure [ fig : centered ] , when @xmath21 assumes the star centered dipole value @xmath45 . the expression for @xmath42 shows that @xmath46 . arons and scharlemann argued , following ruderman and sutherland ( 1975 ) , that if magnetic anomalies reduced @xmath21 to be on the order of @xmath15 , better agreement with the cessation of radio emission might be achieved , for `` normal '' pulsars , almost all of which have periods between 0.1 and 1 second . figure [ fig : centered ] shows clearly that the large dynamic range in @xmath47 space made available by the cataloging of millisecond pulsars falsifies even this `` fudged '' version of the theory - the scaling with period , @xmath48 , flatly disagrees with the shape of the boundary of pulsar radio emission in the @xmath47 diagram . when combined with the more recent arguments in favor of dipolar topology for the low altitude magnetic field , i drew the conclusion either that something else governs the low altitude acceleration which leads to pair creation , or that pair creation is not important to radio emission . muslimov and tsygan ( 1990 , 1992 ) revivified this subject by uncovering a previously overlooked effect on the acceleration of the non - neutral beam from the stellar surface . stellar rotation drags the inertial frame into rotation , at the angular velocity @xmath49 , where i is the moment of inertia . therefore , the electric field required to bring a charged particle into corotation is @xmath50 \times { \bf b}$ ] ; the rotation of the magnetic field with respect to _ local _ inertial space , not inertial space at infinity , determines the electric field which in turn sets a charged particle s @xmath51 drift velocity . the charge density required to support this _ local _ corotation electric field therefore is @xmath52 , \label{eq : ltcorotdens}\ ] ] where @xmath53 . relativistic space charge limited flow from the surface has a beam charge density @xmath54 . above the surface , this charge density is too small to short out @xmath40 on _ all _ polar field lines , not just the favorably curved part of a polar flux tube , thus restoring the possibility of polar cap acceleration models being in accord with the observed rough symmetry of radio emission with respect to the magnetic axis ( e.g. , lyne and manchester 1988 ) . one can graphically describe this general relativistic origin of electrical starvation simply as the consequence of the field lines rotating faster with respect to inertial space as the radius increases , at the angular speed @xmath55 $ ] . the constraint of relativstic flow along @xmath22 allows the beam to provide only a charge density sufficient to support corotation at the angular speed @xmath56 . the difference not surprisingly leads to a accelerating potential drop @xmath57 . \label{eq : polarpot}\ ] ] for normal pulsars with dipole fields , @xmath58 , so that the effect of dragging of inertial frames on the beam s acceleration can yield curvature gamma ray energies 1000 times greater than occur in the arons and scharlemann pair creation theory , for normal pulsars ; for msps , the theories yield comparable results , although of course the symmetry of the beam with respect to the magnetic axis differs . expression ( [ eq : polarpot ] ) applies to the polar flux tube at altidudes greater than the width of the polar flux tube ; closer to the surface , fringe fields cause the potential to be smaller . when curvature emission is the only source of gamma rays , and curvature emission does not limit an accelerating particle s energy , the condition that the number of pairs created be just such as to reduce both @xmath40 and @xmath59 to zero ( which is almost the same as the optical depth unity condition ) yields the death line for a star centered dipole ( arons , in preparation ) : @xmath60 this result appears in figure [ fig : centered ] the effects of curvature radiation reaction , important at short periods , are also included . dragging of inertial frames clearly improves the agreement between the boundary of pair activity in the @xmath61 diagram and the region where pulsars occur , but the discrepancy is still too large - something else is missing . if the field geometry must be _ locally _ dipolar at low altitude , then the only ingredients still not included are 1 ) offset of the dipole from the stellar center and 2 ) additional gamma ray emission and absorption processes . i discuss only the simplest dipole offset here , namely , when the magnetic field is that of a point dipole , with the center of the dipole displaced from the stellar center by an offset vector @xmath62 parallel to @xmath63 . this has the effect of increasing the magnetic field at one pole to strength @xmath64 , with a resulting drastic increase in the gamma ray opacity , while leaving the accelerating potential unaltered . the result is the death valley shown in figure [ fig : death - valley - curv ] clearly , dipole offsets do allow the `` classical '' theory of pulsar death to survive modern observations , although at the price of displacements of the dipole center from the stellar center comparable to moving the dipole s center to the base of the crust . this estimate of death valley s extent assumes curvature emission and magnetic conversion to be the only sources for gamma ray emission and absorption . rosat observations have revealed the long sought thermal x - rays from neutron star surfaces ( becker and trmper 1997 ) . resonant compton scattering creates magnetically convertible gamma rays at a spatial rate @xmath65 , ( e.g. , luo 1996 ) where @xmath66 is the temperature of the cooling neutron star ( polar cap heating is unimportant near the death line ) and @xmath67 is the lorentz factor of an electron or positron in the beam . compton scattering thus can become a significant source of gamma rays in stars with smaller accelerating potentials . in contrast , the spatial rate of curvature emission , @xmath68 , shows that curvature emission dominates gamma ray emission for stars with large voltages . compton scattering thus may contribute significantly for stars with low overall voltage , just where the theory based solely on curvature emission encounters the most trouble in accounting for the data . indeed , this expectation is correct , _ if _ internal heating ( e.g. , umeda _ et al . _ 1993 ) keeps the surface temperature above @xmath69 k to spindown ages in excess of @xmath70 years . in this case , resonant compton scattering of thermal photons by a polar electron beam _ does _ extend death valley to include all the observed pulsars , with somewhat less drastic offsets required , as is shown in figure [ fig : death - valley ] satisfactory agreement with the observations occurs with the enhancement of polar acceleration discovered by muslimov and tsygan , but still requires introducing a special kind of magnetic anomaly ( an offset dipole ) . this kind of anomaly , however , _ is _ consistent with the evidence adduced for _ low altitude _ dipolar structure in the magnetic fields of rotation powered pulsars . if temperatures decline slower than exponentially with age , resonant compton scattering eases the magnitude of the required offset , and creates a gap between the observed edge of the pulsar distribution and the theoretical boundary of death valley , as is shown in figure [ fig : phi - p ] in addition to the edge of death valley shown in figure [ fig : phi - p ] , i have included a line of constant polar magnetic field equal to the `` critical '' field , @xmath71 gauss , corresponding to magnetic moments exceeding @xmath72 cgs . the apparent absence of pulsars with magnetic moments exceeding @xmath73 can not simply be due to rapid spin down and therefore a paucity of observable objects because of this simple evolutionary effect - the empty region would have included stars with ages in excess of @xmath69 years , if such strong field objects exist . one solution ( the conventional one ) is to assume , for reasons unknown , that stars with magnetic moments in excess of @xmath73 simply never form . another intriguing possibility is that pair creation is suppressed in such strong fields . positronium formation ( usov and melrose 1996 ) is a likely candidate ( arons 1996 ) . provided the bound pairs are not ionized close to the star ( photoionization is the most likely possibility ) , the pairs form a neutral gas , not a quasi - neutral plasma , which would suppress the low altitude radio emission while still providing the outflow needed to power plerions which appear to be driven by strong field pulsars but do nt show any radiative sign of a central compact source ( helfand , becker and white 1995 ) . photon splitting ( baring and harding 1998 ) is another means of preventing photons from converting to pairs in strong fields , thus suppressing radio emission . however , as the photons with degraded energy propagate into regions of weaker field above the surface , they will convert to pairs as if the star had had a smaller magnetic moment in the first place . i have shown that polar pair creation based on acceleration of a steadily flowing , space charged limited non - neutral beam in a locally dipolar magnetic geometry at low altitude is consistent with pulsar radio emission throughout the @xmath74 diagram , provided 1 ) the effect of dragging of inertial frames is included in estimates of the starvation electric field ; 2 ) the dipole center is strongly offset from the stellar center , perhaps as much as @xmath75 ; and 3 ) inverse compton emission of thermal photons from a neutron star cooling slower than exponentially at ages in excess of @xmath76 years plays an important role in the emission of magnetically convertible gamma rays . the development of new diagnostics of the low altitude magneic field , and gamma ray observations sensitive to low altitude emission , will eventually provide tests of these ideas . my research on pulsars is supported in part by nsf grant ast 9528271 and nasa grant nag 5 - 3073 , and in part by the generosity of california s taxpayers . arons , j. 1979 , space sci . rev . , 24 , 437 . 1992 , _ proc . iau colloq . 128 , ` the magnetospheric structure and emission mechanisms of raio pulsars ' _ , t.h . hankins , j.m . rankin and j. a. gil , eds . ( zielona gora : pedagogical university press ) , 56 . 1996 , _ proc . iau colloq . 160 , ` pulsars : problems and progress ' _ , s. johnston , m.a . walker and m. bailes , eds ( san francisco : astronomical society of the pacific ) , 177 arons , j. , and scharlemann , e.t . 1979 , ap.j . , 231 , 854 beskin , v.s . 1990 , pisma ast . , 16 , 665 ( sov . ast . - letters , 16 ) baring , m.g . , and harding , a.k . 1998 , proc . 4th compton symposium , c.d . dermer and j.d . kurfess , eds . ( new york : aip ) barnard , j.j . , and arons , j. 1982 , ap.j . , 254 , 713 becker , w. , and trmper , j. 1997 , a&a , 326 , 682 bjornsson , c .- i . 1996 , ap.j . , 471 , 321 chen , k. , and ruderman , m.a . 1993 , ap.j . , 402 , 264 deutsch , a.j . 1955 , ann . , 18 , 1 dyson , f.j . 1971 , `` neutron stars and pulsars : fermi lectures 1970 '' ( rome : acadmia nazionale dei lincei ) , 25 - 26 helfand , d.j . , becker , r.h . , and white , r.l . 1995 , ap.j . , 453 , 741 goldreich , p. and julian , w. 1969 , ap.j . , 157 , 869 gurevich , a.v . , and istomin , ya.n . 1985 , zh.eksp.teor.fiz . , 89,3 ( soviet physis - jetp , 62 , 1 ) groth , e.j . 1975 , ap.j . ( supp . ) , 29 , 453 kaspi , v.m . _ 1994 , ap . j. lett . , 422 , l83 luo , q. 1996 , ap.j . , 468 , 338 lyne , a.g . , and manchester , r.n . 1988 , mnras , 234 , 477 mestel , l. , and shibata , s. 1994 , 271 , 621 meszaros , p. 1992 , `` high energy raiation from magnetized neutron stars '' ( chicago : university of chicago press ) muslimov , a. , and tsygan , a.i . 1990 , ast . , 67 , 263 ( soviet ast . , 34 , 133 ) . 1992 , mnras , 255 , 61 narayan , r. , and vivekanand , m. 1982 , a&a , 113 , l3 pavlov , g.g . , and zavlin , v.e . 1997 , ap.j.lett . , 490 , l91 rankin , j.m . 1990 , ap.j . , 352 , 247 ruderman , m.a . , and sutherland , p.g . 1975 , ap.j . , 196 , 51 scharlemann , e.t . , arons , j. , and fawley , w.m . 1978 , ap.j . , 222 , 297 sturner , s.j . , dermer , c.d . , and michel , f.c . 1995 , ap.j . , 445 , 736 sturrock , p.a . 1971 , ap.j . , 164 , 529 tademaru , e. 1974 , ap . and space sci . , 30 , 179 umeda , h. , _ et al . _ 1993 , ap.j . , 408 , 186 usov , v.v . , and melrose , d.b . 1996 , ap.j . ,

i summarize the theory of acceleration of non - neutral particle beams by starvation electric fields along the polar magnetic field lines of rotation powered pulsars , including the effect of dragging of inertial frames which dominates the acceleration of a space charge limited beam . i apply these acceleration results to a new calculation of the radio pulsar death line , under the hypotheses that pulsar `` death '' corresponds to cessation of pair creation over the magnetic poles _ and _ that the magnetic field has a locally dipolar topology . while the frame dragging effect in star centered dipole geometry does improve comparison of the theory with observation , an unacceptably large fraction of the observed stars outside the bounds of pair creation theory still persists . offsetting the dipole improves the correspondence between theory and observation . the result is a `` death valley '' for pulsars ; acceptable comparison of observation and theory occurs if the boundary of death valley corresponds to offsets of the dipole center from the stellar center @xmath0 . i also point out that pulsars are absent for magnetic moments corresponding to star centered polar fields in excess of @xmath1 gauss , and i suggest that this absence is due to pairs forming as bound positronium atoms in such strong fields , creating a neutral , relativistically outflowing gas which can not participate in low altitude collective radio emission processes in such strongly magnetized objects .

insulin resistance is a metabolic disorder that reflects low capability to wash glucose out of the bloodstream to target tissues . unlike type 1 diabetes mellitus , which results from disrupted insulin secretion from pancreatic cells , type 2 diabetes mellitus is a representative metabolic disease attributable to increased insulin resistance and decreased insulin sensitivity . type 2 diabetes mellitus comprises > 90% of all cases of diabetes and affected > 350 million people in 2011 . in particular , the population of diabetes mellitus is gradually increasing in korea , and about 15,000 diabetic patients die every year owing to the associated complications . metabolic syndrome , a clinically prediabetic condition characterized by abdominal obesity , hypertension , hyperglycemia , and dyslipidemia , is closely associated with increased insulin resistance in etiology . approximately 25% of the adult population is considered to be at risk of metabolic syndrome globally , and about 35% of the adult population in the united states is reported to have metabolic syndrome . in korea , the population with metabolic syndrome increased from 25% in 1998 to 31% in 2007 . metabolic syndrome and type 2 diabetes mellitus are etiologically similar because they share two common causes : insulin resistance and abdominal obesity . thus , patients with metabolic syndrome have about five times higher possibility to progress into type 2 diabetes mellitus compared with those without metabolic syndrome . patients with type 2 diabetes mellitus or metabolic syndrome are usually at elevated risk of cardiovascular disease.2 , 8 , 9 degenerative alterations in vascular structure and function in the metabolic diseases result in atherosclerosis , a main cause of cardiovascular disease . atherosclerosis results from dysfunction of the vascular endothelium , which is closely related to decreased no bioavailability and increased endothelium - derived contraction factors in blood vessels . previous studies have indicated that excessive oxidative stress in the vasculature of patients with with metabolic disease is a possible mechanism to cause reduction in no bioavailability and to impair vascular endothelial function.9 , 11 , 12 , 13 however , few studies have demonstrated the physiological mechanisms from vascular cells in patients with metabolic disease . regular physical activity is known as a strategy to reverse vascular dysfunction and to prevent future cardiovascular disease . however , a few studies have investigated the effect of exercise training on vascular function in patients with type 2 diabetes mellitus and metabolic syndrome.14 , 15 , 16 , 17 thus , the purpose of this review is to introduce potential physiological mechanisms by which vascular function is impaired in augmented insulin resistance , to summarize previous studies to investigate the effects of exercise training on vascular function in type 2 diabetes mellitus and metabolic syndrome , and to facilitate related studies in the future . increased insulin resistance leads to augmented glucose level in the bloodstream . since vascular endothelium is the single innermost layer in the vascular structure , vascular endothelial cells are likely to be damaged by hyperglycemic stress , suggesting that metabolic dysfunction such as insulin resistance and type 2 diabetic mellitus may result in vascular dysfunction . it has been demonstrated that the generation of reactive oxygen species ( ros ) is increased in both large and small vascular beds collected from hyperglycemic animal models . in a hyperglycemic environment , elevated ros generation in vascular cells can be influenced by various biological signaling pathways . aldose reductase , in hyperglycemic conditions , converts glucose to sorbitol by using nicotinamide adenine dinucleotide phosphate as a cofactor , thus the regeneration of reduced glutathione is reduced and intracellular oxidative stress level is increased.2 , 20 , 21 increased advanced glycation end - products lead to increased receptor activity , which facilitates ros and inflammatory cytokine production.2 , 22 , 23 activation of the diacylglycerol protein kinase c pathway also contributes to the elevated generation of ros and inflammatory cytokines.2 , 24 , 25 , 26 in the overloaded glycolytic pathway induced by hyperglycemia , uridine diphosphate n - acetyl glucosamine has a negative effect on endothelial no synthase activity by obstructing its phosphorylation at serine 1177 and increases the expression of proinflammatory cytokines such as transforming growth factor-1 and plasminogen activator inhibitor-1.2 , 27 , 28 , 29 in the vascular endothelium , oxidative stress induced by increased ros generation not only directly plays a pivotal role in reducing no bioavailability , but also leads to increased expression of proinflammatory cytokines so that proatherogenic and prothrombotic processes are abnormally facilitated . thus , the structural and functional integrity of vascular endothelium is likely to be damaged with insulin resistance , which increases the risk of cardiovascular disease in those who are continuously exposed to hyperglycemia in the circulation . thus , the increase in insulin resistance in the vasculature has a negative effect on vascular endothelial function and cardiovascular morbidity and mortality . regular physical activity and exercise are known to promote cardiovascular health in those with insulin resistance . there are no specific exercise guidelines for metabolic syndrome patients to preserve and promote their cardiovascular health . even though their joint statements were published in both 2000 and 2010 , the american college of sport medicine and the american diabetes association only provide generic exercise regimens for diabetic patients.32 , 33 in the two previous position standards , the experts recommended aerobic exercise or aerobic exercise combined with resistance exercise to prevent and promote cardiovascular disease risk in patients with diabetes . however , the effect of either aerobic or combined exercise training on both micro- and macrovascular endothelial function is still in debate . some studies presented positive results of exercise training,17 , 34 , 35 , 36 but others did not show any positive effect of exercise on vascular health in type 2 diabetic patients.37 , 38 , 39 for individuals with metabolic syndrome , a small number of studies have explored the effect of exercise training on vascular endothelial function , but the training effect has presented a positive tendency,14 , 15 , 40 , 41 and had a close relationship with increased no bioavailability . it is established that insulin resistance contributes to impaired vascular endothelial function , and either aerobic or combined exercise training programs might help to reverse endothelial dysfunction in those who have insulin resistance.14 , 15 , 17 , 34 , 35 , 36 , 40 , 41 exercise intensity also seems to be a main factor influencing exercise effects in people with insulin resistance . although both moderate - intensity continuous training and high - intensity interval training have shown improvement in vascular endothelial function , in the same caloric expenditure , high - intensity interval training presents superior effect on vascular endothelial function and glycemic control.15 , 36 the physiological mechanisms by which either aerobic or combined exercise training enhances vascular endothelial function in insulin resistance are not fully elucidated . positive changes in oxidative stress and inflammatory biomarkers after exercise training are thought to be potential mechanisms from animal and systemic biomarker studies,8 , 43 , 44 , 45 but no study has investigated the local alterations of potential biomarkers in human vasculature in response to acute or chronic exercise training in insulin resistance . furthermore , it is also necessary to figure out a mechanistic linkage between exercise intensity and functional alteration of vascular endothelium . table 1 shows a summary of studies examining the effect of exercise on endothelial function in individuals with insulin resistance . current evidence indicates that metabolic disease such as insulin resistance or metabolic syndrome induced vascular dysfunction in various animal models ( table 2 ) . even though a majority of previous studies have indicated that insulin resistance or metabolic syndrome induced vascular dysfunction , some studies also showed that these prediabetic conditions did not change endothelial function . these discrepant conclusions suggest that alteration of vascular function is affected by multiple factors including duration of certain diseases and vascular beds . for example , a number of studies showed that obesity ( high - fat diet ) induced insulin resistance caused acetylcholine - induced endothelial dysfunction in various blood vessels , including coronary arterioles , gracilis artery , femoral artery and aorta in mouse models,46 , 47 , 48 , 49 whereas some studies indicated that insulin resistance did not induce vascular dysfunction in femoral artery , mesentery arterioles and aorta.48 , 50 , 51 in addition , some studies showed that type of agonists induced inconsistent results in the same vascular beds.50 , 52 , 53 for instance , insulin resistance caused impaired insulin - dependent vasorelaxation , however , acetylcholine - induced vasorelaxation was identical in mesenteric arterioles of c57bl/6j mice.50 , 52 by contrast , in the femoral artery of c57bl/6j mice , insulin resistance did not change insulin - induced vasorelaxation , but acetylcholine - induced vasorelaxation was reduced by insulin resistance . table 2 summarizes the effect of insulin resistance or metabolic syndrome on vasorelaxation in various vasculatures in experimental animal models . it is well documented that exercise or regular physical activity has beneficial effects on metabolic diseases in animal models . considering previous studies , most exercise protocols improved vascular function in various vascular beds such as coronary arterioles , arterioles , feed arteries from skeletal muscle and aorta ( table 3 ) . however , it is still unclear which mechanisms are involved in these beneficial effects of exercise . table 3 summarizes the effect of exercise on vascular dysfunction induced by insulin resistance or metabolic syndrome in experimental animal models . there are no specific exercise guidelines for metabolic syndrome patients to preserve and promote their cardiovascular health . even though their joint statements were published in both 2000 and 2010 , the american college of sport medicine and the american diabetes association only provide generic exercise regimens for diabetic patients.32 , 33 in the two previous position standards , the experts recommended aerobic exercise or aerobic exercise combined with resistance exercise to prevent and promote cardiovascular disease risk in patients with diabetes . however , the effect of either aerobic or combined exercise training on both micro- and macrovascular endothelial function is still in debate . some studies presented positive results of exercise training,17 , 34 , 35 , 36 but others did not show any positive effect of exercise on vascular health in type 2 diabetic patients.37 , 38 , 39 for individuals with metabolic syndrome , a small number of studies have explored the effect of exercise training on vascular endothelial function , but the training effect has presented a positive tendency,14 , 15 , 40 , 41 and had a close relationship with increased no bioavailability . it is established that insulin resistance contributes to impaired vascular endothelial function , and either aerobic or combined exercise training programs might help to reverse endothelial dysfunction in those who have insulin resistance.14 , 15 , 17 , 34 , 35 , 36 , 40 , 41 exercise intensity also seems to be a main factor influencing exercise effects in people with insulin resistance . although both moderate - intensity continuous training and high - intensity interval training have shown improvement in vascular endothelial function , in the same caloric expenditure , high - intensity interval training presents superior effect on vascular endothelial function and glycemic control.15 , 36 the physiological mechanisms by which either aerobic or combined exercise training enhances vascular endothelial function in insulin resistance are not fully elucidated . positive changes in oxidative stress and inflammatory biomarkers after exercise training are thought to be potential mechanisms from animal and systemic biomarker studies,8 , 43 , 44 , 45 but no study has investigated the local alterations of potential biomarkers in human vasculature in response to acute or chronic exercise training in insulin resistance . furthermore , it is also necessary to figure out a mechanistic linkage between exercise intensity and functional alteration of vascular endothelium . table 1 shows a summary of studies examining the effect of exercise on endothelial function in individuals with insulin resistance . current evidence indicates that metabolic disease such as insulin resistance or metabolic syndrome induced vascular dysfunction in various animal models ( table 2 ) . even though a majority of previous studies have indicated that insulin resistance or metabolic syndrome induced vascular dysfunction , some studies also showed that these prediabetic conditions did not change endothelial function . these discrepant conclusions suggest that alteration of vascular function is affected by multiple factors including duration of certain diseases and vascular beds . for example , a number of studies showed that obesity ( high - fat diet ) induced insulin resistance caused acetylcholine - induced endothelial dysfunction in various blood vessels , including coronary arterioles , gracilis artery , femoral artery and aorta in mouse models,46 , 47 , 48 , 49 whereas some studies indicated that insulin resistance did not induce vascular dysfunction in femoral artery , mesentery arterioles and aorta.48 , 50 , 51 in addition , some studies showed that type of agonists induced inconsistent results in the same vascular beds.50 , 52 , 53 for instance , insulin resistance caused impaired insulin - dependent vasorelaxation , however , acetylcholine - induced vasorelaxation was identical in mesenteric arterioles of c57bl/6j mice.50 , 52 by contrast , in the femoral artery of c57bl/6j mice , insulin resistance did not change insulin - induced vasorelaxation , but acetylcholine - induced vasorelaxation was reduced by insulin resistance . table 2 summarizes the effect of insulin resistance or metabolic syndrome on vasorelaxation in various vasculatures in experimental animal models . it is well documented that exercise or regular physical activity has beneficial effects on metabolic diseases in animal models . considering previous studies , most exercise protocols improved vascular function in various vascular beds such as coronary arterioles , arterioles , feed arteries from skeletal muscle and aorta ( table 3 ) . however , it is still unclear which mechanisms are involved in these beneficial effects of exercise . table 3 summarizes the effect of exercise on vascular dysfunction induced by insulin resistance or metabolic syndrome in experimental animal models . there is no doubt that physical activity or regular exercise has beneficial effects on vascular function . however , it should be noted that some discrepancies exist among these studies according to experimental design including type of exercise , intensity and duration of exercise , and heterogeneity of vascular beds . it seems that vascular function in smaller resistant arteries may be altered differently compared to larger vessels such as aorta and conduit arteries , based on the status of disease , exercise type , duration , and intensity .

insulin resistance associated with metabolic syndrome and type 2 diabetes mellitus is an epidemic metabolic disorder , which increases the risk of cardiovascular complications . impaired vascular endothelial function is an early marker for atherosclerosis , which causes cardiovascular complications . both experimental and clinical studies indicate that endothelial dysfunction in vasculatures occurs with insulin resistance . the associated physiological mechanisms are not fully appreciated yet , however , it seems that augmented oxidative stress , a physiological imbalance between oxidants and antioxidants , in vascular cells is a possible mechanism involved in various vascular beds with insulin resistance and hyperglycemia . regardless of the inclusion of resistance exercise , aerobic exercise seems to be beneficial for vascular endothelial function in both large conduit and small resistance vessels in both clinical and experimental studies with insulin resistance . in clinical cases , aerobic exercise over 8 weeks with higher intensity seems more beneficial than the cases with shorter duration and lower intensity . however , more studies are needed in the future to elucidate the physiological mechanisms by which vascular endothelial function is impaired in insulin resistance and improved with aerobic exercise .

the aharonov - bohm effect predicted in ref.@xcite has been investigated in numerous papers , see review @xcite . due to this quantum effect , the vector potential affects the electron even in the case when the electron can not penetrate the region of non - zero magnetic field . this effect has been investigated within non - relativistic @xcite and relativistic @xcite wave equations . in quantum field theory , similar effect has been investigated in refs.@xcite . one of the consequences of the aharonov - bohm effect is scattering of a charged particle in the field of an infinitesimally thin solenoid . it was shown in refs.@xcite that the dirac hamiltonian in the background of the field of infinitesimally thin solenoid requires a self - adjoint extension . this extension can be parametrized by one extension parameter @xmath2 . as a result , the eigen functions of the hamiltonian and the corresponding scattering cross section depend on this parameter . after recent fabrication of a monolayer graphite ( graphene ) , ref.@xcite , new possibilities to study the aharonov - bohm effect have appeared . the single electron dynamics in graphene is described by the massless dirac equation in ( 2 + 1 ) dimensions , see refs.@xcite . using the green s function of this equation in the field of infinitesimally thin solenoid , the induced current density has been investigated analytically in ref.@xcite . calculations have been performed exactly in a magnetic flux tube in the case when an electron can not penetrate the region of nonzero magnetic field . in the recent paper @xcite , the local density of states in graphene was obtained in the field of infinitesimally thin solenoid . in the present paper , we derive the induced current density , corresponding to the massless dirac equation in ( 2 + 1 ) dimensions , in the background of the magnetic flux tube of finite radius @xmath1 . we investigate in detail the asymptotics @xmath3 of this current density at fixed magnetic flux through the tube but for arbitrary distribution of a magnetic field inside the tube . we consider two cases . in the first case an electron can not penetrate the region of nonzero magnetic field , and in the second case this is allowed . naturally , the result obtained in the first case is independent of the distribution of magnetic field inside the flux tube and coincides with the result of ref.@xcite . more interestingly , in the second case the induced current density is also independent of the magnetic field distribution at @xmath4 . in another words , we find the explicit value of the extension parameter @xmath2 , refs.@xcite , and show that it is independent of the magnetic field distribution . the article is organized as follows . in sec . [ section2 ] we derive the green s function of an electron in a magnetic field of the flux tube and obtain the induced current density at distances @xmath5 . calculation of the induced current density in the first and the second cases of the problem is performed in sec . [ section3 ] and sec . [ section4 ] , respectively . we conclude with a brief summary of our results . the induced current density , corresponding to the massless dirac equation in ( 2 + 1 ) dimensions in a magnetic field , has the form , ref.@xcite : @xmath6 where the green s function @xmath7 obeys the equation @xmath8{g}(\bm r,\bm r'|\epsilon)=\delta(\bm r-\bm r')\,.\end{aligned}\ ] ] here @xmath9 , and @xmath10 are the pauli matrices ; @xmath11 is the momentum operator , @xmath12 , @xmath13 is the vector potential of the magnetic field , @xmath14 is the electron charge , the system of units @xmath15 . according to the feynman rules , the contour @xmath16 of integration over @xmath17 goes below the real axis in the left half plane and above the real axis in the right half plane of the complex @xmath17 plane . the magnetic field of the flux is @xmath18 , where @xmath19 is the unit vector directed along z axis , @xmath20 is a continuous function which obeys the condition @xmath21 for @xmath22 . it is convenient to choose the vector potential in the form @xmath23}{2\pi r}v(r)\,,\end{aligned}\ ] ] where @xmath24 is the total magnetic flux through the tube , and a function @xmath25 is @xmath26 using the analytical properties of the green s function , we deform the contour of integration over @xmath17 in eq . ( [ inducedcurrent ] ) so that it coincides with the imaginary axis . thus it is necessary to find the function @xmath27 which we represent as @xmath28{d}(\bm r,\bm r'|i\epsilon)\,,\end{aligned}\ ] ] where @xmath29 is the green s function of the squared dirac equation @xmath30{d}(\bm r,\bm r'|i\epsilon)=-\delta(\bm r-\bm r')\,.\nonumber\\\end{aligned}\ ] ] substituting the function @xmath31 in the form @xmath32 and the @xmath33-function as @xmath34 to eq . ( [ equation_for_d ] ) , we obtain the following equations for the functions @xmath35 @xmath36{\cal d}^{(\pm)}_m(r , r'|i\epsilon)=\frac{\delta ( r- r')}{\sqrt{r r'}}\,.\label{eqd+-}\end{aligned}\ ] ] here @xmath37 , @xmath38 , and @xmath39 is the elementary magnetic flux . in the region @xmath40 , the function @xmath25 is @xmath41 so that the term with @xmath42 in eq . ( [ eqd+- ] ) vanishes . as a result , the general solution of eq . ( [ eqd+- ] ) in this region has the form @xmath43 here @xmath44 and @xmath45 are the modified bessel functions of the first and third kind , respectively , @xmath46 , @xmath47 , and @xmath48 . the coefficient in front of the first term in eq . ( [ general_solution_d ] ) follows from the matching condition for the functions @xmath35 at @xmath49 . the coefficients @xmath50 depend on the distribution of the magnetic field in the tube . they can be found from the matching condition at @xmath51 for the solutions ( [ general_solution_d ] ) and the solutions of eq . ( [ eqd+- ] ) in the region @xmath52 . substituting eqs . ( [ g_through_d ] ) and ( [ d_partialexpansion ] ) to eq . ( [ inducedcurrent ] ) , we arrive at the following representation for the induced current density at @xmath22 @xmath53}{4\pi^2 r } \sum_{m=-\infty}^\infty \int_{-\infty}^\infty d\epsilon\left [ \frac{\lambda}{r}\left ( { \cal d}^{(+)}_m(r , r'|i\epsilon ) + { \cal d}^{(-)}_m(r , r'|i\epsilon)\right)\right . -\left.\frac{\partial}{\partial r}\left ( { \cal d}^{(+)}_m(r , r'|i\epsilon ) -{\cal d}^{(-)}_m(r , r'|i\epsilon)\right ) \right]_{r'=r}\ , .\end{aligned}\ ] ] then we use the solution ( [ general_solution_d ] ) for @xmath35 and finally obtain @xmath54}{\pi^2 r^2 } \sum_{m=-\infty}^\infty \lambda \int_0^\infty d\epsilon \ , i_{|\lambda|}(|\epsilon|r ) k_{|\lambda|}(|\epsilon|r)= \frac{env_f[\bm\nu \times\bm r]}{4\pi r^3}\left ( \frac{1}{2 } -|\tilde{\gamma}|\right)^2\tan(\pi\tilde{\gamma } ) \ , , \label{current_j1}\\ \bm j_{ind}^{(2)}(\bm r ) & = & -\frac{e[\bm\nu \times\bm r]}{2\pi^2 r } \sum_{m=-\infty}^\infty \int_0^\infty d\epsilon\ \epsilon\left(\beta_m^{(+ ) } k_{|\lambda|+\mu}(|\epsilon|r ) - \beta_m^{(- ) } k_{|\lambda|-\mu}(|\epsilon|r ) \right)k_{|\lambda|}(|\epsilon|r ) \ , , \label{current_j2}\end{aligned}\ ] ] where @xmath55 , the quantity @xmath56 is the fractional part of @xmath57 , @xmath58 . it is defined as @xmath59 for @xmath60 , and @xmath61 for @xmath62 , @xmath63 is the maximal integer number less than @xmath64 . the first contribution , @xmath65 , coincides with the result of ref.@xcite for the induced current density in the field of infinitesimally thin solenoid . this result has been obtained under assumption that an electron can not penetrate the region of nonzero magnetic field . the contribution @xmath66 is a periodical function of the magnetic flux , it depends on the fractional part of the quantity @xmath57 . it is equal to zero at the integer values of @xmath57 but also at half - integer values of this quantity . the contribution @xmath67 depends on the radius @xmath1 and distribution of the magnetic field inside the magnetic tube through the coefficients @xmath68 . these coefficients are the functions of @xmath17 , @xmath1 , @xmath57 , and @xmath69 . in the pure aharonov - bohm effect , an electron can not penetrate the region @xmath52 of nonzero magnetic field . the corresponding boundary condition is @xmath70 . in this case @xmath71 and we obtain from eq . ( [ current_d ] ) for the induced current density @xmath72}{\pi^2 r^2 } \sum_{m=-\infty}^\infty \lambda\int_0^\infty d\epsilon\ , { \cal d}^{(+)}_m(r , r'|i\epsilon ) \ , .\end{aligned}\ ] ] the boundary condition gives the following form of the coefficient @xmath73 in eq . ( [ general_solution_d ] ) @xmath74 at @xmath75 , the coefficient @xmath73 in the leading order in @xmath76 reads @xmath77 using this expression , we obtain the asymptotics of the term @xmath78 in eq . ( [ current_j2 ] ) at large distances @xmath5 @xmath79}{2\pi r^3}\sum_{m=-\infty}^{\infty } \lambda |\lambda| \frac{\gamma(|\lambda|+1/2)\gamma(2|\lambda|+1/2)}{\gamma^3(|\lambda|+1 ) } \left(\frac{{r}}{2r}\right)^{2|\lambda|}\label{current_j3_3 } \ , .\end{aligned}\ ] ] the contribution @xmath67 is equal to zero at integer and half - integer values of @xmath57 due to cancelation between different terms . for other values of @xmath57 we introduce the quantity @xmath80 , where @xmath81 minimizes the value @xmath82 , and obtain @xmath83 in the leading and next - to - leading order in @xmath84 @xmath85}{4\pi r^3}\left[\left ( \frac{1}{2 } -|\tilde{\gamma}|\right)^2\tan(\pi\tilde{\gamma } ) + 2\tilde{\lambda}|\tilde{\lambda}| \frac{\gamma(|\tilde{\lambda}|+1/2 ) \gamma(2|\tilde{\lambda}|+1/2)}{\gamma^3(|\tilde{\lambda}|+1 ) } \left(\frac{\tilde{r}}{2r}\right)^{2|\tilde{\lambda}| } \right]\ , .\ ] ] the leading term @xmath66 tends to zero at @xmath86 as @xmath87 , and the correction @xmath78 diminishes as @xmath88 . in this section we assume that an electron can penetrate into the magnetic tube . let us start with a simple case of the magnetic field distribution of the form @xmath89 , where @xmath90 is the step - function . in this case the function @xmath25 reads @xmath91 this function is continuous one at @xmath51 so that the matching conditions for the functions @xmath35 at @xmath51 , following from eq . ( [ equation_for_d ] ) , are @xmath92 the solution of eq . ( [ eqd+- ] ) in the region @xmath52 , @xmath93 has the form : @xmath94 where @xmath95 are some functions which can be found from the conditions ( [ matching ] ) , @xmath96 is the confluent hypergeometric function . using eqs . ( [ general_solution_d ] ) , ( [ matching ] ) , and ( [ solution_r < r ] ) we obtain for the coefficients @xmath68 @xmath97 -2|\gamma|{\cal f}^{\prime}i_{|\lambda|}(x ) } { { \cal f } \left[bk_{|\lambda|}(x ) - x k_{|\lambda|+1}(x)\right ] -2|\gamma|{\cal f}^{\prime}k_{|\lambda|}(x)}\ , , \nonumber\\ & & { \cal f}={}_1f_1\left(a^{(\pm)},|m|+1,|\gamma|\right)\,,\nonumber\\ & & { \cal f}^{\prime}=\dfrac{a^{(\pm)}}{|m|+1}{}_1f_1\left(a^{(\pm)}+1,|m|+2,|\gamma|\right)\,,\nonumber\\ & & b=|\lambda|+|\gamma|-|m|\,,\quad x=|\epsilon|r\,.\end{aligned}\ ] ] it follows from eqs . ( [ beta_explicit ] ) and ( [ current_j2 ] ) that the induced current density is the odd function of the parameter @xmath57 , which is a consequence of the furry theorem . below for simplicity we assume that @xmath60 . using eqs.([beta_explicit ] ) and ( [ current_j2 ] ) it is easy to obtain the asymptotics of the term @xmath67 at distances @xmath5 . in this case , the main contribution to the integral over @xmath17 in eq . ( [ current_j2 ] ) is given by the region @xmath98 so that @xmath99 . the main contribution to the sum over @xmath69 in eq . ( [ current_j2 ] ) is given by the term proportional to @xmath73 with @xmath100 $ ] , where @xmath101 $ ] means the integer part of @xmath102 . for this @xmath69 the asymtotics of the coefficient @xmath103 at @xmath75 is @xmath104 substituting this expression to eq . ( [ current_j2 ] ) and taking the integral over @xmath17 we find @xmath105}{4\pi r^3}\left ( \frac{1}{2 } -|\tilde{\gamma}|\right)\tan(\pi\tilde{\gamma } ) \ , .\end{aligned}\ ] ] taking a sum of @xmath66 and @xmath78 we finally obtain @xmath106}{16\pi r^3 } f(\gamma)\,,\nonumber\\ f(\gamma)&= & ( 1 - 4\tilde{\gamma}^2)\tan(\pi\tilde{\gamma})\,.\end{aligned}\ ] ] the function @xmath107 is shown in fig.[fig1 ] . , eq . ( [ currentj1_f ] ) , on the @xmath108 , where @xmath24 is the magnetic flux.,scaledwidth=35.0% ] ( 0,0 ) ( 80,30)@xmath57 ( -105,120)@xmath107 as it was shown in ref.@xcite , the induced current in the case of pure aharonov - bohm effect is the periodical function of a magnetic flux . the reason is very simple . when an electron can not penetrate the region of nonzero magnetic field , the integer part of @xmath57 can be eliminated from the wave equation by the gauge transformation . in opposite case considered in this section , we can not eliminate the integer part of @xmath57 . as a result , as it is seen from eq . ( [ current_j2_rezult ] ) and fig.[fig1 ] , the induced current density is not a periodical function of the magnetic flux . the result ( [ currentj1_f ] ) , obtained for the magnetic field @xmath89 , coincides with the corresponding result of ref.@xcite for the extension parameter @xmath109 . now we show that the leading asymptotics of the induced current density at @xmath110 is independent of the distribution of magnetic field at the fixed magnetic flux . as it was pointed out above , at @xmath110 the main contribution to the integral over @xmath17 in eq . ( [ current_j2 ] ) is given by the region @xmath98 so that @xmath111 . for @xmath40 the solution ( [ general_solution_d ] ) is valid for any distribution of magnetic field . we use this solution for @xmath112 . for @xmath113 we can neglect the term @xmath114 in eq . ( [ eqd+- ] ) and write the equations for the functions @xmath115 in the form : @xmath116 the regular at @xmath117 solutions of the eq . ( [ neweqfordpm ] ) have the form @xmath118 @xmath119 here @xmath120 are some functions of @xmath121 . substituting the solutions ( [ general_solution_d ] ) , ( [ d+solution ] ) , and ( [ d - solution ] ) to the matching condition ( [ matching ] ) and using the asymptotics of the functions @xmath122 and @xmath123 at small @xmath76 we obtain the coefficients @xmath68 . in the limit @xmath124 , only @xmath125}^{(+)}$ ] does not vanish and coincides with the result obtained for the magnetic field @xmath89 , see eq . ( [ beta_leading ] ) . thus the leading asymptotics of the induced current density is independent of the distribution of the magnetic field in the magnetic flux tube . in our consideration we do not use any assumptions concerning the value of magnetic flux . we have investigated the induced current density , corresponding to the massless dirac equation in ( 2 + 1 ) dimensions in a magnetic flux tube of small radius . this problem is important for graphene for which all formulas for the induced current density obtained in our paper should be multiplied by the factor @xmath126 , the fermi velocity is @xmath127 . in the case of pure aharonov - bohm effect , when an electron can not penetrate the region of nonzero magnetic field , this current is the odd periodical function of the magnetic flux . in the opposite case , when the region inside the magnetic tube is not forbidden for penetration of electron , the induced current is not a periodical function of the magnetic flux . however in the limit @xmath0 this function has the universal form which is independent of the magnetic field distribution inside the magnetic tube at fixed value of the magnetic flux . thus it is shown that the extension parameter @xmath2 introduced in the previous papers has the universal value @xmath128 . in the same way it is easy to show that the wave functions corresponding to the massless dirac equation in ( 2 + 1 ) dimensions in a magnetic flux tube have also the universal form in the limit @xmath0 .

the induced current density , corresponding to the massless dirac equation in ( 2 + 1 ) dimensions in a magnetic flux tube of small radius is considered . this problem is important for graphene . in the case , when an electron can not penetrate the region of nonzero magnetic field , this current is the odd periodical function of the magnetic flux . if the region inside the magnetic tube is not forbidden for penetration of electron , the induced current is not a periodical function of the magnetic flux . however in the limit @xmath0 , where @xmath1 is the radius of magnetic flux tube , this function has the universal form which is independent of the magnetic field distribution inside the magnetic tube at fixed value of the magnetic flux .

the study of @xmath3 hypernuclei has provided us with important information on the properties of @xmath3 in a nuclear medium and the effective @xmath3-n interaction @xcite . on the other hand , the situation for @xmath4 and @xmath5 hypernuclei is quite different . the special case of @xmath6he aside , there is no experimental evidence for any @xmath4 hypernuclei @xcite , despite extensive searches . it seems likely that the @xmath4-nucleus interaction is somewhat repulsive and that there are no bound @xmath4 hypernuclei beyond a=4 . in the case of the @xmath5 , the experimental situation is very challenging , but we eagerly await studies of @xmath5 hypernuclei with new facilities at j - parc and gsi - fair . to understand further the properties of hypernuclei , we apply the latest version of the quark - meson coupling ( qmc ) model @xcite , and calculate the single - particle energies @xcite and phtoproduction cross sections @xcite . the major improvement in the latest version is the inclusion of the effect of the medium on the color - hyperfine interaction . this has the effect of increasing the splitting between the @xmath3 and @xmath4 masses as the density rises . this is the prime reason why our results yield no middle and heavy mass @xmath4 hypernuclei @xcite . the qmc model was created to provide insight into the structure of nuclear matter , starting at the quark level @xcite . nucleon internal structure was modeled using the mit bag , while the binding was described by the self - consistent coupling of the confined quarks to the scalar-@xmath7 and vector-@xmath8 meson fields generated by the confined quarks in the other `` nucleons '' in the medium . the self - consistent response of the bound quarks to the mean @xmath7 field leads to a novel saturation mechanism for nuclear matter , with the enhancement of the lower components of the valence dirac wave functions . the model has been successfully used to study various nuclear phenomena @xcite . to calculate the hyperon levels , we use a relativistic shell model . details on the calculations are described in refs . results for the hypernuclear single - particle energies are shown in tables [ spe1 ] and [ spe2 ] . first , we emphasize that the present calculation yields no @xmath4 hypernuclei in the nuclei considered . this is consistent with the empirical fact of no finding of the middle and heavy mass @xmath4 hypernuclei . second , overall agreement with the experimental energy levels of @xmath3 hypernuclei across the periodic table is quite good . in particular , the parameter free result of -26.9 mev for the @xmath9 level of @xmath10pb is impressive . the discrepancies which remain may well be resolved by small effective hyperon - nucleon interactions which go beyond the simple , single - particle shell model . once again , we stress the very small spin - orbit force experienced by the @xmath3 , which is a natural property of the qmc model @xcite . finally , this model supports the existence of a variety of bound @xmath5-hypernuclei . for the @xmath11 the binding of the @xmath9 level varies from 5 mev in @xmath12o to 15 mev in @xmath13pb . the experimental search for such states at facilities such as j - parc and gsi - fair will be very important . [ spe1 ] [ spe2 ] concerning the absence of the @xmath4 hypernuclei in the present calculation , it is especially interesting to examine the effective non - relativistic potential felt by the @xmath14 in a finite nucleus . this is shown in fig . [ fig : pot ] for @xmath15ca and @xmath10pb nuclei . in the central region the vector interaction dominates over the scalar one leading to a repulsive effective potential which reaches respectively 30 mev and 12 mev at the center . it is only at the surface that the scalar attraction becomes dominant . in existing several theoretical studies of photoproduction of hypernuclei , it has been usually employed nonrelativistic models to obtain the relevant initial and final state wave functions ( except for ref . @xcite ) . in this study , we follow ref . @xcite and use a fully covariant model to calculate the cross sections for the @xmath0c ( @xmath16b reaction . we explore the feasibility of studying the photoproduction of hypernuclei within the relativistic model of ref . @xcite , but employing the bound @xmath3 spinors obtained by the latest qmc model @xcite . this provides an opportunity to investigate the role of the quark degrees of freedom in the hypernuclear production , which may be a novel feature . the relevant processes included in the present study are shown in figs . 1(a ) and 1(b ) , the elementary @xmath17 and the hypernuclear production reactions , @xmath18 , respectively . in principle , although the @xmath19- and @xmath20-channels should also be included , they contribute to the non - resonant background terms which are insignificant to both elementary as well as in - medium photon induced reactions for energies below 1.5 gev . ( see , e.g. , refs . we use plane waves to describe the relative motion of the outgoing particle which is justified by the relatively weaker kaon - nucleus interaction in the final channel . all ingredients necessary in the calculation , such as effective lagrangians and resonance propagators , are described in refs . the coupling constants have been determined by comparing our calculations [ graph 1(a ) ] with the total and differential cross section data for the elementary @xmath21 reaction in the relevant photon energy region @xcite . the threshold for the kaon photoproduction on @xmath0c is about 695 mev . the momentum transfer involved in the reaction at 10@xmath22 kaon angle , in which we focus , varies between approximately 2 @xmath23 to 1.4 @xmath23 in the photon energy range of 0.7 gev to 1.2 gev @xcite . in fig . [ dsigma ] , we compare the differential cross section calculated @xcite with the bound @xmath3 spinors obtained in the latest qmc model @xcite , and the phenomenological models @xcite for the @xmath0c ( @xmath16b reaction . the hole state spinor is taken from the phenomenological model @xcite in both cases . the cross sections are shown for photon energies in the range of 0.7 - 1.2 gev corresponding to the outgoing kaon angle of 10@xmath22 . the hypernuclear states populated are @xmath24 , @xmath25 , and @xmath26 , @xmath27 corresponding to the particle - hole configurations of @xmath28 and @xmath29 , respectively . we see that in each case the qmc cross sections are smaller than those obtained with phenomenological hyperon spinors . in this figure we further note that the peaks of the qmc cross sections are somewhat shifted toward lower photon energies as compared to those of the phenomenological model . detailed explanations for these features are given in ref . @xcite . we further note that within each group the highest @xmath30 state is most strongly excited , which is in line with the results presented in refs . furthermore , unnatural parity states within each group are preferentially excited by this reaction . the unnatural parity states are excited through the spin flip process . thus , this confirms that kaon photo- and also electro - production reactions on nuclei are ideal tools for investigating the structure of unnatural parity hypernuclear states . we have studied the properties of hypernuclei using the latest version of the quark - meson coupling model , which includes the effect of the medium on the color - hyperfine interaction between quarks . this latest version leads to some important results : ( 1 ) the agreement between the parameter free calculations and the experimental ground state levels for @xmath3-hypernuclei from calcium to lead is impressive . ( 2 ) a number of @xmath5-hypernuclei are predicted to be bound , although not as deeply as in the @xmath3 case . ( 3 ) the additional repulsion arising from the enhancement of the color - hyperfine interaction in the @xmath4-hyperon in - medium ( together with the effect of the @xmath31 channel coupling on the intermediate range scalar attraction @xcite ) yields to predict `` no bound '' @xmath4-hypernuclei . we have also studied photoproduction of hypernucleus by the @xmath0c ( @xmath16b reaction within a covariant model , using the bound @xmath3 spinors obtained by the latest quark - meson coupling model . this is the first time that quark degrees of freedom has been explicitly invoked in the description of the hypernuclear production . k.t . would like to thank the organizers of sendai08 , o. hashimoto , h. tamura , s. n. nakamura and k. maeda for a warm hospitality in entire period of the conference . notice : authored by jefferson science associates , llc under u.s . doe contract no . de - ac05 - 06or23177 . government retains a non - exclusive , paid - up , irrevocable , world - wide license to publish or reproduce this manuscript for u.s . government purposes . 99 for example , o. hashimoto and h. tamura , _ prog . part . phys . _ * 57 * , 564 ( 2006 ) . k. saha _ et al . _ , _ phys . c _ * 70 * , 044613 ( 2004 ) . j. rikovska - stone , p. a. m. guichon , h. h. matevosyan and a. w. thomas , _ nucl . a _ * 792 * , 341 ( 2007 ) . p. a. m. guichon , a. w. thomas and k. tsushima , _ nucl . a _ * 814 * , 66 ( 2008 ) . r. shyam , k. tsushima and a. w. thomas , arxiv:0812.1547 [ nucl - th ] . a. m. guichon , _ phys . b _ * 200 * , 235 ( 1988 ) . for a review , k. saito , k. tsushima and a. w. thomas , _ prog . phys . _ * 58 * , 1 ( 2007 ) . k. tsushima , k. saito , j. haidenbauer and a. w. thomas , _ nucl . phys . a _ * 630 * , 691 ( 1998 ) ; k. tsushima , k. saito and a. w. thomas , _ phys . lett . b _ * 411 * , 9 ( 1997 ) [ _ erratum - ibid . b _ * 421 * , 413 ( 1998 ) ] . c. bennhold and l.e . wright , _ phys . c _ * 39 * 927 , ( 1989 ) ; + _ phys . _ * b191 * , 11 ( 1987 ) . r. shyam , h. lenske and u. mosel , _ phys . c _ * 77 * , 052201(r ) ( 2008 ) . lee , t. mart , c. bennhold , h. haberzettl , and l. e. wright , _ nucl . * a695 * , 237 ( 2001 ) . r. shyam and o. scholten , _ phys . c _ * 78 * , 065201 ( 2008 ) . r. shyam , h. lenske and u. mosel , _ phys c _ * 69 * , 065205 ( 2004 ) ; + r. shyam , h. lenske and u. mosel , _ nucl . phys . _ * a764 * , 313 ( 2006 ) . r. shyam , _ progr . phys . _ * 61 * , 212 ( 2008 ) . a. s. rosenthal et al . , _ ann . ( n.y . ) * 184 * , 33 ( 1988 ) .

we study the binding of hypernuclei based on the latest version of quark - meson coupling model , and estimate the phtoproduction cross sections for the @xmath0c(@xmath1)@xmath2b reaction using the bound @xmath3 spinors obtained in the model .

the number of people worldwide with diabetes has increased enormously ; 382 million people were reported to have diabetes in 2013 and this is expected to rise to 592 million in 2035,1 which will create a significant health care burden worldwide . nutrition therapy and exercise therapy are fundamental for diabetes , while pharmacotherapy is adopted when necessary . therefore , not only are physicians and nurses greatly involved in patient treatment for people with diabetes , but so too are registered dietitians , physiotherapists , clinical laboratory technicians , and pharmacists . thus , the disease requires the skill and talents of multiple health care providers , and as such , interprofessional teamwork is extremely important for diabetes care.2,3 successful interprofessional teamwork in other words , when multiple health workers from different professional backgrounds work together and are able to provide comprehensive services effectively by working with patients , their families , caregivers , and communities leads to better patient care and safety , and improves health outcomes for patients.47 therefore , it is not an exaggeration to say that the level of success of interprofessional teamwork may determine diabetes care outcomes . however , levels of perceptions of , and satisfaction with , interprofessional teamwork in multiple health care providers , who are actually involved in diabetes care , are unclear and often unexpressed . to clarify these points , the national center for global health and medicine ( ncgm ) in japan has been conducting free educational seminars five to six times per year for more than 5 years for various professional groups that are involved and interested in diabetes care.8 participants from ncgm educational seminars and other related seminars , as well as ncgm medical personnel who are engaged in diabetes care , were asked to inform us of their profession and complete a survey featuring three questions . question 1 ( q1 ) was do you think multidisciplinary teamwork for diabetes patients in your facility works sufficiently ? which required a yes , no , or not sure response . question 3 ( q3 ) was please state your ideas regarding how to resolve this problem . the answers for q1 were broken down into percentages for yes , no , or not sure in each profession . those who answered no and not sure to q1 were further analyzed by combining the answers for q2 , and the substantially similar answers for q2 were grouped and categorized into themes . from a total of 465 people who were asked to take the questionnaire ( 432 seminar participants and 33 ncgm medical staff ) 275 people answered the questionnaire ( 243 seminar participants and 32 ncgm medical staff ) . the percentages of each occupation that answered yes , no , and not sure to q1 are shown in table 1 . these figures show that less than 30% of the participants in each of the professions surveyed were satisfied regarding the current state of interprofessional teamwork . the percentages of yes answers in each profession were as follows : physicians , 20.5% ; nurses , 12.7% ; registered dietitians , 29.6% ; pharmacists , 21.9% ; physiotherapists , 18.2% ; and clinical laboratory technicians , 15.4% . the answers for q2 were varied , and those who answered no and not sure to q1 were classified into five thematic categories . the answers that considered lack of interprofessional communication as the main obstacle to interprofessional teamwork were categorized in insufficient communication : for example , answers such as because we do not have regular interprofessional meetings , we have no opportunity to communicate and exchange patients information , or we can communicate with physicians , but it is hard to communicate with other professions , such as physical therapists or clinical laboratory technicians . the answers that consider lack of a leader , such as a diabetologist or a certified diabetes educator , as the main problem were categorized under the answers that considered lack of labor as the fundamental problem in other words , that lack of labor leads to busy medical staff and makes them devote so much to their own professional daily duties that they can not participate in any additional interprofessional teamwork were categorized under the answers that considered the conditions of medical facilities as the main problem for example , because there are only one doctor and two nurses in our clinic , we can not work together with dietitians or pharmacists were categorized under condition of facilities . finally , the answers that considered inconsistencies of staff motivation levels among relevant staff as the main problem were categorized in inconsistent motivation ( eg , answers such as there are big gaps of motivation among the professions or among the individual team members . the percentages for each occupation s answers that were classified into the thematic categories of insufficient communication , lack of leader , lack of labor , condition of facilities , and for physicians , nurses , pharmacists , and physical therapists , insufficient communication is the most concerning issue as the obstacle to interprofessional teamwork , whilst registered dietitians and clinical laboratory technicians considered inconsistent motivation as the most concerning issue . the present questionnaire survey indicated that the current situation regarding interprofessional teamwork for diabetes care is considered problematic and insufficient among the medical personnel surveyed and that there is much room for improvement . previous research regarding multidisciplinary teamwork has shown that successful interprofessional teamwork helped to achieve intensive glycemic control in certain patient groups.4 however , interprofessional teamwork in general , not solely within diabetes care , has certain difficulties in clinical settings . caldwell and atwal9 summarized the problems associated with interprofessional teamwork as involving four issues : ideological differences between health care professions , unequal power relations between the health professions , communication within and between the professional groups , and role overlap and confusion . the results of the present questionnaire survey also showed the communication difficulties within diabetes care . the diabetes attitudes wishes and needs 2 ( dawn2 ) study10 aims to provide a holistic assessment of diabetes care and management among people with diabetes , family members , and health care professionals . the questionnaire results in the dawn2 study showed that 63.0% of responders recognized the need for formal training in effective communication for all diabetes care specialists , and 56.1% of responders recognized that there should be better communication within the team.11 in the present study , physicians considered insufficient interprofessional communication , condition of medical facilities they worked at , and lack of labor as problems needing to be solved . nurses considered insufficient communication with physicians or with other professions to be the main problems , as well as inconsistencies of staff motivation levels . both physicians and nurses considered that insufficient interprofessional communication was the main problem ; physicians were not likely to realize that relationships between physician and nonphysician staff are key , while nurses specifically consider that physicians should be more cooperative with them and should understand the need for open communication with them . in addition , physicians seem not to care so much about inconsistent motivation among the team members , while nurses are very concerned about it . other professions also considered insufficient interprofessional communication or inconsistencies of staff motivation levels as the main problem to be solved . all professions considered that interprofessional meetings or conferences were necessary and essential ; however , many people were not satisfied with the ongoing meetings and considered that the meeting content and structure , as well as the members , needed to be changed . frequent , high - quality communication and strong relationships among health care providers are important to maximize the quality of care , improve the efficiency of care , and improve clinical outcomes.5,1214 however , according to the present survey results , some medical personnel have difficulty communicating with other professionals or have never experienced interprofessional meetings or conferences . unequal power in other words , hierarchy is another main issue regarding teamwork and communication difficulties.5,1519 while better communication and the development of relationships between health care professionals can be valuable , even within a hierarchical system,12 nonphysician staff remain reluctant to complain to other professionals , particularly physicians . a previous study using a questionnaire to clarify physicians traits that impede effective nurse physician communication revealed that physicians reluctance to communicate with nurses and physicians emotional difficulties were the main reasons for the communication barrier.20 the authors suggested that educating future physicians or residents to have a positive attitude toward open communication with nurses might reduce the communication barrier.20 although physicians are often the leaders of interprofessional teamwork , diabetes educators2124 can be leaders in facilitating open communication among members and preventing the problems associated with hierarchical relationships . any division of health care across multiple professions can provoke conflict , particularly in areas featuring potential role overlap.12 it is desirable for professionals to support each other and assist with work that one may be unable to conduct because of a lack of labor or personal inexperience . however , when there are instances of overlapping work with two or more professions involved for example , a nurse and a pharmacist teaching the same patient at different times how to self - inject insulin via different procedures and each professional does not share their information with the other , the situation may become confusing , leaving the patient in a potentially dangerous situation . in order to resolve this , each profession should define its role in the team and teams should establish strategies to encourage working partnerships.9 if each profession can teach consistent content to patients , it will be beneficial for patients to obtain reinforcement from different professionals . previous reports suggest the effectiveness of postgraduate medical education or interprofessional training programs to educate professionals regarding the importance of interprofessional teamwork.2,6,25,26 interprofessional education is believed to enhance learners understanding of other professions roles and responsibilities , while fostering mutual respect and understanding between members of a health care team.7 to evaluate the kinds of education or program(s ) that will be effective in improving interprofessional teamwork , further study featuring a large sample size and a well - thought - out design will be necessary . firstly , because of the nature of the term interprofessional teamwork , its meaning may vary between individuals and respondents might have difficulties in answering questions . this might be one of the reasons why many respondents answered not sure to q1 , instead of giving more definite answers such as yes or no . secondly , because the questionnaire was conducted for the participants of the educational diabetes seminars who might be more enthusiastic and highly motivated in diabetes care than persons who did not attend the seminars , the results might be biased and not representative in general . the lack of data regarding number of persons who refused to answer the questionnaire raises questions about the representativeness of the samples . thirdly , the questionnaire did not ask age , sex , or type of facility at which the respondents were working . the information about these factors actually , as shown in tables 2 and 3 , some respondents answered that interprofessional teamwork is insufficient because they are working at medical facilities that are either too small or too big for example , a small clinic or a university hospital . therefore , we should have asked in the questionnaire about the types of medical facilities at which respondents were working . further study that includes this information with a larger number of medical personnel will be necessary . in conclusion , the results of the questionnaire survey regarding interprofessional teamwork in diabetes care revealed some difficulties in conducting teamwork . changing the organizational structure and team - leadership style in a short period may be difficult , but continuous efforts to change each profession s perception of multidisciplinary teamwork and efforts to improve the quality of interprofessional meetings are vital . in addition , physicians need to be better at recognizing the need for open communication and at accepting feedback or input from other professions . to promote this , certain training in effective communication at the start of their professional career , such as when they are students , may be effective .

backgrounddiabetes is a multifactorial disease and its nature means that interprofessional teamwork is essential for its treatment . however , in general , interprofessional teamwork has certain problems that impede its function . to clarify these problems in relation to diabetes care , a questionnaire survey was conducted.methodsthe participants who were involved in diabetes - related educational seminars , and medical personnel who were engaged in diabetes care from the national center for global health and medicine , were asked to complete the questionnaire about perceptions of , and satisfaction with , interprofessional teamwork across multiple health care providers , who were actually involved in diabetes care.resultsfrom 456 people who were asked to take the questionnaire , 275 people answered . the percentages of the respondents according to profession who considered multidisciplinary teamwork sufficient were as follows : physicians , 20.5% ; nurses , 12.7% ; registered dietitians , 29.6% ; pharmacists , 21.9% ; physiotherapists , 18.2% ; and clinical laboratory technicians 15.4% . insufficient interprofessional communication and inconsistency in motivation levels among staff were frequently cited as causes of insufficient teamwork . all professions considered interprofessional meetings or conferences necessary and essential for teamwork.conclusionthe survey revealed that interprofessional teamwork in diabetes care is currently insufficient . continuous efforts to change each profession s perceptions about interprofessional teamwork and efforts to improve the quality of interprofessional meetings are necessary .

A baby recently diagnosed with a rare condition is now seeing the world for the first time. The baby, Leopold Reppond, was recently outfitted with glasses after his diagnosis of oculocutaneous albinism, a condition that affects the coloring of the eyes, skin and hair, according to the National Institutes of Health (NIH). Baby Leo’s dad, David Reppond, filmed the moment his son saw his mom, Erin Reppond, for the first time. “When he finally did look up that second time and you see that recognition on his face, that’s a smile we just hadn’t really seen before,” Erin Reppond told ABC News. “He’s a pretty happy baby and he smiles and I feel like he generally is pretty happy but that smile was something that was so different for me to see.” David Reppond, who lives with his family in Washington state, added that he used to let Leo see the world by touching things, including his dad’s beard. The video of Leo lighting up at the sight of his mom has been viewed on Facebook more than 15,000 times. An estimated 1 in 20,000 people worldwide are born with oculocutaneous albinism, according to the NIH. ||||| Ajoutée le 2 avr. 2016 Our son Leopold was recently diagnosed with a rare disorder called Oculocutaneous Albinism (OCA). This affects the coloring of his skin, hair, and eyes and leaves him with extremely impaired vision. But today he received his glasses....and can now see the world clearly for the very first time. ||||| 4-Month-Old Baby Sees His Mom for the First Time After Receiving New Glasses A video of a Seattle, Washington, baby smiling and giggling after receiving glasses for the first time has captured the Internet's heart.In the 30-second heartwarming YouTube video that has been viewed over 19,000 times, 4-month-old Leopold Wilbur Reppond is gifted with special rubber baby-safe specs – clearly seeing his parents for the first time ever.And his reaction couldn't be any cuter.The baby boy suffers from a disorder called oculocutaneous albinism, which affects the coloring of his skin, hair and eyes – and often causes extremely impaired vision."But today he received glasses….and can now see the world clearly for the very first time," reads the video's caption.David Reppond, Leo's father, filmed the touching moment, which sees mom Erin putting the glasses on her baby boy."Hi honey!" Erin says to her son.Little Leo beams, looking curious and delighted as he sees his mother for the first time."Hi lovey, honey, sweetie. I love you!" coos Erin.Grinning ear to ear, Leo chuckles as his eyes widen."He's a pretty happy baby and he smiles and I feel like he generally is pretty happy, but that smile was something that was so different for me to see," Erin said to ABC News "That's a smile we just hadn't really seen before."

– A 4-month-old boy sees his mom clearly for the first time in an awww-inspiring viral video uploaded to YouTube over the weekend, People reports. Little Leopold Wilbur Reppond of Seattle has oculocutaneous albinism, which can cause severe vision impairment, "but today he received his glasses....and can now see the world clearly for the very first time," writes his dad in the video's description. The video shows a big smile dawning on Leo's face as he focuses on his mom's face. "When he finally did look up that second time and you see that recognition on his face, that’s a smile we just hadn’t really seen before," mom Erin Rippond tells ABC News.

it is well - known that the sunspot penumbra ( the outer part of sunspots ) has a very complicate filamentary structure and a strong non - stationary outflow . this outflow is responsible for the so - called evershed effect , a doppler shift of the spectral lines emerging from sunspots @xcite . the magnetic structure of the penumbra can be represented as a mixture of two magnetic field components with different inclinations and strengths ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) . however , the radial evershed flow ( in particular , the high - speed evershed coluds ) is associated with the more strongly inclined , almost horizontal field ( e.g. * ? ? ? * ; * ? ? ? * ; * ? ? ? recently , significant progress in our understanding of the evershed effect was made by numerical simulations @xcite . these studies suggested that the evershed flow is a consequence of overturning magnetoconvection in the presence of inclined magnetic fields , and that the driving mechanism is associated with traveling convective waves that propagate in the direction of the magnetic field inclination @xcite . the issue is not resolved and other interpretations are possible ( see * ? ? ? thus , it is important to confront the simulations with as many observations as possible . in this letter , we examine the idea that the sea - serpent penumbral field lines detected by @xcite in high - resolution hinode measurements are related to the same mechanism of overturning convection and traveling convective waves in a strong inclined magnetic field . our analysis is based on the radiative mhd simulations of @xcite . analyses of visible and near - infrared spectro - polarimetric observations from the ground revealed that in the mid and outer penumbra the evershed flows are directed downward and have magnetic polarities opposite to that of the spot ( * ? ? ? * see bellot rubio 2009 for a detailed description ) . the spectro - polarimeter aboard hinode @xcite made it possible to identify isolated magnetic patches of opposite polarity associated with strong , even supersonic , evershed downflows @xcite . this provided a beautiful confirmation of the results obtained from ground - based observations at lower resolution . @xcite then discovered that the opposite polarity patches move radially outward , often accompanied by another patch having the polarity of the spot and being located further away from the umbra . @xcite and @xcite also detected the evolution of reversed - polarity patches in the penumbra using soho / mdi observations @xcite , but their bipolar nature could not be established . taken together , these results provide an indication that the moving magnetic features observed in the penumbra and the evershed flow belong to the same physical mechanism . the magnetic patches move between the more vertical filaments of the penumbra with a typical velocity of @xmath0 km / s , their length is 23 arcsec , the mean width is @xmath1 arcsec , and they have a lifetime of 0.5 7 hours @xcite . sometimes , the bipolar pairs appear one behind another along the same filament . this can be the signature of a wave - like behavior , similar to the wave behavior of magnetoconvection in the penumbra found in numerical simulations @xcite . based on the observational data , @xcite proposed a sea - serpent model which explains the existence of moving bipolar structures as wavering magnetic field lines . in this model , almost horizontal field lines return to the solar interior and then come back to the photosphere , thus forming bipolar patches . this scenario is similar to that discussed by schlichenmaier ( 2002 ) in the context of the moving tube model . it is also similar to the model proposed by @xcite for moving magnetic features in the sunspot moat ( mmfs ; * ? ? ? indeed , it has been suggested that mmfs represent the continuation of similar features in the penumbra @xcite . for numerical simulations of sunspot penumbra conditions we use the 3d radiative mhd code `` solarbox '' @xcite . this code takes into account all essential physics and includes sub - grid scale turbulence modeling based on the large - eddy simulation ( les ) approach . a dynamic smagorinsky turbulence model provides the best agreement with observations in terms of the acoustic oscillation power . however , in these simulations we use a computationally more efficient hyperviscosity model , because it shows results qualitatively very similar to the dynamic model . the code uses a real - gas equation of state , takes into account ionization and excitation of all abundant species in the lte approximation , and includes radiative transfer and magnetic effects @xcite . we simulate the behavior of solar magnetoconvection for an initial background magnetic field of various strengths , from 600 to 2000 g , but with the same inclination of @xmath2 to the vertical axis . our previous results have shown that these condition provide a very good model for the evershed effect @xcite . the computational domain is @xmath3 mm@xmath4 and the grid resolution is 50 km . the results were verified using a higher resolution of 25 km and a larger horizontal size of 25 mm . the lateral boundary conditions are periodic , and we keep the mean initial inclination of the field in the whole box domain by setting up top and bottom boundary conditions that conserve the total magnetic flux , but locally the field strength and inclination can freely change . the magnetic field strongly influences convective motions . for instance , in the case of vertical magnetic fields , convective granules become smaller with increasing field strength @xcite and also move faster , generating more high - frequency turbulence @xcite . a strong inclined magnetic field deforms the granules , making them elongated along the field lines . when the field becomes almost horizontal the convective cells form a filamentary structure , and high - speed flows ( reaching 5 - 6 km / s ) appear in the direction of the magnetic field inclination @xcite . these flows share many similarities with the observed evershed flows , including their nearly - supersonic speeds . for illustration of our results we use a simulation run with initial magnetic field of @xmath5 g and inclination angle of @xmath6 pointing in the direction of the horizontal @xmath7-axis . figure [ 2d ] shows a time sequence of 2d snapshots of the horizontal and vertical components of the magnetic field , @xmath8 , and velocity , @xmath9 , with 8-min cadence for five time moments : 0 , 8 , 16 , 24 and 32 mins . the overplotted curves are projections of the magnetic field lines . the black and white areas seen in the vertical magnetic field ( fig . [ 2d]a ) correspond to patches of negative and positive polarities . the horizontal magnetic field component ( fig . [ 2d]b ) shows variations of the magnetic filamentary structure , which is a result of magnetoconvection in the inclined field . the dark areas correspond to magnetic gaps " , areas with a weaker ( but not zero ) magnetic field , that correspond to observations @xcite . it is clear that the areas of weaker horizontal magnetic field correspond to the transitions between negative and positive polarities of the vertical field . in these transition regions , strong downward flows are observed ( fig . the transition regions are also characterized by strong @xmath10 km / s horizontal velocities ( fig . [ 2d]d ) . the strongest horizontal flow in the direction of the magnetic field inclination is associated with the negative polarities . the correlation between downflows and negative polarity patches is in agreement with the observations , which show that the downward penumbral motions occur along magnetic fields returning back to the solar surface @xcite . figure [ 3d ] displays the 3d structure of magnetic field lines ( red curves ) , temperature variations , and the velocity field ( arrows ) . the top horizontal slice corresponds to the solar surface . the results demonstrate a strong coupling between the fluid flow and magnetic field . in particular , the upflows correspond to magnetic field lines rising above the surface ( positive polarity ) while the downward flows correlate with the negative polarity . this corresponds very well to the observed properties of the penumbra and the sea - serpent model . in this letter , we have used the results of numerical simulations of magnetoconvection in strong inclined magnetic field to interpret polarimetric observations of a sunspot penumbra . the results reproduce the moving bipolar magnetic elements observed in high - resolution soho / mdi and hinode / sot data and also their properties , supporting the sea - serpent model proposed by @xcite . the simulations explain the sea - serpent structure and dynamics of the penumbral field as a consequence of solar magnetoconvection in a highly inclined , strong magnetic field , which forms filamentary structures and has properties of traveling convective wave . the physical picture schematically illustrated in figure [ scheme ] is the following . convective cells in sunspot penumbrae are deformed under the action of the inclined magnetic field , forming filamentary structures and producing high - speed evershed flows @xcite . the magnetic field lines are stretched by the downward flows and dragged under the surface . the points where the magnetic field lines cross the solar surface are observed as magnetic patches of positive and negative polarities . note that the negative patch is closer to the umbra , in agreement with the observations . the convective cells move in the direction of the magnetic field inclination because of the traveling convective wave behavior . therefore , the bipolar magnetic patches also move in the same direction . thus , the numerical simulations connect the sea - serpent structure of the moving bipolar magnetic pathes observed in the penumbra with the process of overturning magnetoconvection , traveling convective waves , and the evershed flow . this work was partly supported by nasa , the center for turbulence research ( stanford university ) , nordita , albanova univ . center ( stockholm ) , and the spanish ministerio de ciencia e innovacin through project aya2009 - 14105-c06 - 06 and by junta de andaluca through project p07-tep-2687 . bellot rubio , l.r . 2009 , in magnetic coupling between the interior and the atmosphere of the sun , ed . hasan & r.j . rutten , astrophysics and space science proceedings , ( berlin : springer ) , in press , ( arxiv:0903.3619 ) .

recent spectro - polarimetric observations of a sunspot showed the formation of bipolar magnetic patches in the mid penumbra and their propagation toward the outer penumbral boundary . the observations were interpreted as being caused by sea - serpent magnetic fields near the solar surface @xcite . in this letter , we develop a 3d radiative mhd numerical model to explain the sea - serpent structure and the wave - like behavior of the penumbral magnetic field lines . the simulations reproduce the observed behavior , suggesting that the sea - serpent phenomenon is a consequence of magnetoconvection in a strongly inclined magnetic field . it involves several physical processes : filamentary structurization , high - speed overturning convective motions in strong , almost horizontal magnetic fields with partially frozen field lines , and traveling convective waves . the results demonstrate a correlation of the bipolar magnetic patches with high - speed evershed downflows in the penumbra . this is the first time that a 3d numerical model of the penumbra results in downward directed magnetic fields , an essential ingredient of sunspot penumbrae that has eluded explanation until now .

recently , using the radiative return method @xcite , a new state , the @xmath8 ( also named @xmath10 in the literature ) , was observed in @xmath11 with the dipion invariant mass close to the @xmath12 region , explicitly , for @xmath13 mev @xcite . later on this state was also detected at bes in the @xmath14 reaction @xcite and belle in @xmath15 @xcite . in an update of the analysis of ref . @xcite , results on the channel @xmath16 were presented in the form of number of events as a function of the dikaon invariant mass @xcite . indeed , in this work , the cross section for @xmath17 was measured as a function of the center of mass energy up to @xmath18 and it is shown there that this reaction is dominated by events where one kaon pair comes from the decay of a @xmath19 . selecting events with a kaon pair within @xmath20 of the @xmath19 mass , an enhancement in the invariant mass of the other kaon pair close to threshold is observed and suggested to be due to the @xmath12 tail , but the low statistics and uncertainties in the @xmath21 line shape prevent the authors to present a cross section for @xmath22 using the @xmath23 final state . inspired in the physics behind the radiative @xmath24 decay @xcite , a detailed theoretical study of @xmath25 for pions in @xmath26-wave was performed in @xcite . the process @xmath27 has been also studied in the context of nambu - jona - lasinio models @xcite . in ref . @xcite , it was shown that the tree level contributions through the @xmath28 mixing are negligible and @xmath25 proceeds through the production of off - shell @xmath29 and @xmath4 pairs , the successive decay of the off - shell kaon or @xmath30 into an on - shell @xmath19 and an off - shell @xmath31 and subsequent @xmath32 scattering . the starting point was the @xmath2 lagrangian @xcite supplemented with the anomalous term for the @xmath33 interactions . the corresponding predictions , valid for low virtualities of the exchanged photon and low dipion invariant mass were improved in two respects . first , the @xmath26-wave @xmath34 amplitudes entering the loop calculations were replaced by the full @xmath34 isoscalar amplitudes as calculated in @xmath5 , which contain the scalar poles @xcite . second , the lowest order terms of the kaon form factor were replaced by the full kaon form factor as calculated in @xmath5 @xcite which describes satisfactorily the scarce data for energies around @xmath35 @xcite . likewise , the @xmath4 isoscalar transition form factor arising from @xmath2 and the anomalous term , was replaced by the transition form factors as extracted from data on @xmath36 @xcite . the @xmath12 couples strongly to the @xmath37 system and it should contribute to the mechanisms studied in @xcite in the case of @xmath38 production . therefore it is worthy to study this channel also . as discussed above , some experimental data has been released for @xmath16 . we devote this work to the study of this reaction in the framework developed in ref . in contrast to the @xmath39 final state , the @xmath23 final state is induced at tree level in this framework . furthermore , as noticed in @xcite , the @xmath12 pole is close to the threshold for the production of the dikaon system and the loop contributions can be enhanced by this pole thus a complete analysis requires to calculate rescattering contributions . in this concern , we know that the @xmath40 meson couples strongly to the @xmath41 system but not to the @xmath42 system . therefore , in addition to the @xmath12 contributions we also expect contributions from the @xmath40 meson to the @xmath23 final state . the @xmath12 and @xmath40 poles lie slightly below @xmath43 , hence their complete shapes are not expected to be seen in this reaction but their respective tails could give visible effects close to the reaction threshold . contributions from intermediate vector mesons , @xmath44 , are forbidden by charge conjugation . an important improvement with respect to the formalism used in @xcite is the more accurate characterization of the @xmath4 form factors . indeed , recently , the cross section for @xmath45 was precisely measured in the @xmath46 @xmath47 region @xcite . we use the @xmath4 isoscalar and isovector transition form factors as extracted from this data in our analysis instead of the old data from @xcite . the paper is organized as follows : in section ii we outline the calculation . results for the tree level contributions to @xmath16 are given in section iii . in section iv we adapt previous calculations for the rescattering effects in the @xmath48 final state to the @xmath23 final state . section v is devoted to the extraction of the @xmath4 transitions form factors from data . in section vi we analyze the different contributions . section vii is devoted to estimate the intermediate @xmath8 contribution . our summary and conclusions are given in section viii . the calculation of the cross section for the @xmath49 reaction is a non - trivial task . indeed , the leading electromagnetic contributions to this reaction are due to a single photon exchange in whose case we need to calculate the @xmath50 vertex function for a hard virtual photon ( @xmath51 ) . this is an energy scale far beyond the well grounded calculations based on @xmath52 , its @xmath53 saturated version @xmath54 or even the unitarized formalism , @xmath5 , which is expected to be valid up to energies of the order of @xmath55 ; therefore it is not evident that one can perform reliable calculations at the energy of the reaction . however , whatever the responsible mechanisms for the reaction be , they must leave their fingerprint at low energies , i.e. for low photon virtualities in the @xmath50 vertex function , which can be calculated using the effective theory for qcd at low energies . we use this fact to attempt a reasonable calculation of @xmath49 . we calculate the @xmath50 vertex function at low photon virtualities using @xmath2 supplemented with the anomalous lagrangian for the @xmath33 interactions . as a result we obtain the electromagnetic part of the @xmath50 vertex function dominated by form factors while the pure hadronic interactions are within the scope of @xmath2 in the case of tree level contributions and involve the leading order on - shell @xmath52 meson - meson amplitudes in the case of one loop contributions . these results , valid at low energies are improved using the unitarized kaon form factors ( which account for the scarce experimental data at the energy of the reaction ) and experimental data on the @xmath4 transition form factors . similarly , the leading order on - shell meson - meson interactions are iterated following @xcite to obtain the unitarized meson - meson amplitudes containing the scalar poles . we start with the calculation of the tree level contributions to @xmath16 within @xmath2 and consider also intermediate vector meson exchange using the conventional anomalous lagrangian for @xmath33 interactions . we follow the conventions in @xcite and the relevant interactions are given in ref . the reaction @xmath16 is induced at tree level by the diagrams shown in fig ( [ tree ] ) . in addition to the vertices quoted in ref . @xcite there is a tree level @xmath56 point interaction whose vertex is given by@xmath57 with the labels @xmath58 and all incoming particles . : a ) pseudoscalar mesons exchange with point - like @xmath59 interaction plus contact term , b ) pseudoscalar mesons exchange with vector meson mediated @xmath59 interaction , c ) intermediate vector mesons.,width=377,height=302 ] a straightforward calculation of the set of diagrams a ) in fig.([tree ] ) yields @xmath60 \eta^{\alpha\nu } \label{mpcontact}%\ ] ] where @xmath61 , @xmath62 . the tensor @xmath63 is given by @xmath64 where @xmath65 . it can be easily shown that this tensor satisfies@xmath66 where @xmath67 denotes the antisymmetric tensor used to describe the @xmath19 field in @xmath2 . the second term in eq . ( [ mpcontact ] ) is explicitly gauge invariant , thus the @xmath50 vertex function in the amplitude ( [ mpcontact ] ) is gauge invariant . diagrams b ) in fig . ( [ tree ] ) involve the propagation of vector particles . these diagrams yield@xmath68 w_{\mu\nu } q_{\alpha}\eta^{\alpha\nu}.\ ] ] with the gauge invariant tensor @xmath69 using the gauge invariance property in eq . ( [ gi ] ) it is possible to relate this tensor to @xmath70 as@xmath71\ ] ] thus the amplitude can be rewritten as@xmath72 q_{\alpha } \eta^{\alpha\nu}%\ ] ] where@xmath73 adding up contributions from diagrams 1a ) and 1b ) we obtain@xmath74 q_{\alpha}\eta^{\alpha\nu}\label{mptree}\\ & + \frac{e^{2}\sqrt{2}}{f^{2}}\left ( g_{v}-\frac{f_{v}}{2}\right ) \frac{l^{\mu}}{k^{2 } } g_{\mu\nu}k_{\alpha } \eta^{\alpha\nu},\end{aligned}\ ] ] where@xmath75 notice that the second term in eq . ( [ mptree ] ) contains the vector meson contributions to the kaon form factor , but the constant term due to the electric charge is missing . a similar result was obtained in @xcite . this term should come from lagrangians with higher derivatives of the fields , specifically from the term @xmath76 , which is absent in our basic interactions . we will assume in the following that the constant term due to the charge is provided by such missing interactions ; hence , we will write @xmath77 instead of @xmath78 in the second term of eq . ( [ mptree ] ) . also , notice that the function @xmath79 accounts for the lowest order terms of the charged kaon form factor and describes it properly at low @xmath80 . the high virtuality of the exchanged photon in our process requires to work out the complete @xmath81 vertex function . the calculation of the kaon form factors has been done in the context of @xmath5 in ref . @xcite . although this calculation misses the contributions of the first radially excited vector mesons which are important around @xmath82 @xmath47 , the existing experimental data close to the @xmath83 threshold are properly described by the unitarized kaon form factors as shown in fig ( [ kff ] ) where the results for the unitarized charged kaon form factor are plotted together with data from the dm2 coll . @xcite . thus in the following we will replace the lowest order terms so far obtained , @xmath79 , by the full unitarized form factor @xmath84 . in addition to the terms associated to the kaon form factor we get a contact term with the combination @xmath85 . this combination is small and it vanishes in the context of vector meson dominance @xcite . clearly , this term can not be extrapolated to high photon virtualities without its dressing by a form factor . the impact of this term on the cross section for the @xmath39 final state upon its dressing with the kaon form factors was found to be very small in @xcite . its contribution turns out to be small also in this case when it is dressed with the charged kaon form factor , thus we will skip it in the following . with these considerations the amplitude reads @xmath86 q_{\alpha}\eta^{\alpha\nu}. \label{mptprel}%\ ] ] in terms of the conventional polarization vector @xmath87 satisfying@xmath88 we finally obtain the tree level contribution from the exchange of pseudoscalar mesons as@xmath89 \eta^{\nu}. \label{mpt}%\ ] ] the amplitude for the diagrams c ) in fig . ( [ tree ] ) is@xmath90 here , we get the @xmath91 transition form factor to leading order as@xmath92 and @xmath93 stands for the tensor@xmath94 \epsilon_{\sigma \tau\alpha\nu},\ ] ] with @xmath95 , which is explicitly gauge invariant . it can be shown that @xmath96 where@xmath97 q^{\alpha}.\ ] ] the amplitude in eq . ( [ mcprel ] ) contains the leading order terms for the @xmath91 transition form factor valid for low photon virtualities . the photon exchanged in @xmath16 has @xmath98 and we should work out this form factor for such high photon virtualities . in the numerical computations we replace the leading order terms by the complete transition form factor , @xmath99 , extracted from recent data on @xmath36 , @xmath100 to be discussed below . with these considerations@xmath101 the final state @xmath23 can get contributions from the @xmath102 rescattering . furthermore , this final state can also be reached through the production of @xmath103 and the rescattering @xmath104 . excitation of higher mass states such as @xmath4 is also possible and the final state @xmath23 can be produced by the initial production of an off - shell @xmath105 ( @xmath91 ) pair , the subsequent decay of the off - shell @xmath106 ( @xmath107 ) into a @xmath108(@xmath109 ) and the rescattering @xmath104 ( @xmath102 ) . this section is devoted to the study of these contributions . we calculate the rescattering effects to lowest order in the chiral expansion from @xmath2 supplemented with the anomalous term for the @xmath33 interactions . these results are improved by the unitarization of meson - meson amplitudes proposed in @xcite which dynamically generates the scalar resonances . the relevant diagrams in @xmath2 are shown in fig . ( [ loops ] ) , where for simplicity a shaded circle and a dark circle account for the diagrams @xmath110 plus @xmath111 and @xmath112 plus @xmath113 respectively , which differentiate the direct photon coupling from the coupling through an intermediate vector meson . in @xmath114 at one loop level.,width=377,height=377 ] the factorization of the meson - meson chiral amplitudes on - shell out of the loop integrals has been discussed in @xcite in the case of the @xmath39 final state . the same considerations apply to the @xmath115 final state and we refer the reader to ref . @xcite for the details . to account for the whole rescattering effects in @xmath102 and @xmath104 in these diagrams we iterate the lowest order chiral amplitudes in the scalar channel , @xmath116 and @xmath117 to obtain the unitarized scalar amplitudes , @xmath118 and @xmath119 ( in the following we skip the suffix @xmath120 used in @xcite for the scalar meson - meson amplitudes in order to handle isospin labels that will be necessary below and denote @xmath121 the @xmath122 unitarized amplitude in the isospin channel @xmath123 ) . unlike the @xmath39 case where only the isoscalar meson - meson unitarized amplitude containing the @xmath12 pole is involved , in the case of the @xmath23 final state the necessary @xmath118 and @xmath119 amplitudes are linear combinations of the isoscalar and isovector scalar amplitudes @xmath124 and @xmath125 . the last one contains the @xmath40 pole . notice that we are using the scalar amplitudes @xmath118and @xmath119 instead of the full amplitudes which in principle contain higher angular momentum contributions . this is expected to be a good approximation for energies near the reaction threshold due to the small tri - momentum of the dikaon system . furthermore , at these energies the dikaon mass is near the @xmath12 and @xmath40 poles and the @xmath126-wave amplitudes ( containing vector poles ) give vanishing contribution to this process due to charge conjugation . higher @xmath127 ( tensor ) contributions are expected to be important at much higher center of mass energy . the dominance of s - waves near threshold has been observed in alike processes as @xmath128 @xcite . the loop calculations go similarly to those of the @xmath39 final state done in ref . we adopt the same convention of all external particles incoming and refer the reader to that work for the details . for kaons in the loops we obtain @xmath129 \eta^{\nu } \label{mkfinal}%\ ] ] with the lorentz structures@xmath130 and @xmath131 i_{p},\\ b_{p } & = \frac{\sqrt{2}m_{\phi}g_{v}}{2f^{2}}\left [ t_{k^{+}k^{+}}f_{k^{+}% } ( k^{2})+t_{k^{0}k^{+}}f_{k^{0}}(k^{2})\right ] \left ( j_{p}+\frac{m_{k}^{2}% } { 4k^{2}}g_{k}\right ) .\end{aligned}\ ] ] the loop functions are given by@xmath132 with @xmath133 . notice that the only change from the final @xmath134 state @xcite , to the present case , is the substitution of the factor @xmath135 by @xmath136 . it is convenient to write the meson - meson scalar amplitudes in isospin basis . with the conventions in refs . @xcite , we get @xmath137 thus , in terms of the isoscalar ( @xmath138 @xmath139 ) and isovector ( @xmath125 , @xmath140 ) meson - meson amplitudes and kaon form factors respectively we obtain@xmath141 i_{p},\label{ap}\\ b_{p } & = \frac{m_{\phi}g_{v}}{2\sqrt{2}f^{2}}\left [ t_{kk}^{0}f_{k}% ^{0}(k^{2})+t_{kk}^{1}f_{k}^{1}(k^{2})\right ] \left ( j_{p}+\frac{m_{k}^{2}% } { 4k^{2}}g_{k}\right ) , \label{bp}%\end{aligned}\ ] ] with the isoscalar and isovector form factors@xmath142 similarly to the tree level contributions , the calculation of kaon loops yields also a contact term with the combination @xmath85 not shown in eq.([mkfinal ] ) . for the same reasons we neglected the analogous term in the previous section , we will also neglect it here . the process @xmath143 can also proceed through the diagrams shown in fig . ( [ fdv ] ) . again , the calculations are similar to the case of @xmath39 in the final state calculated in ref . @xcite and we refer to this work for details on the notation and conventions . . , width=302,height=151 ] the amplitude from the diagram in fig . ( [ fdv ] ) gets contributions from charged and neutral @xmath4 in the loops . we obtain the amplitude from these diagrams as@xmath144 \eta^{\nu } \label{mvfinal}%\ ] ] with @xmath145 i_{v},\\ b_{v } & = -\frac{gm_{\phi}^{2}}{4\sqrt{2}}\left [ f_{k^{\ast+}k^{-}}% ( k^{2})t_{k^{+}k^{+}}+f_{k^{\ast0}\overline{k^{0}}}(k^{2})t_{k^{0}k^{+}% } \right ] j_{v}\\ i_{v } & = m_{k}^{2}\left ( i_{g}-i_{2}+2+\frac{1}{2}\log\frac{m_{k}^{2}}% { \mu^{2}}\right ) + q\cdot k\ j_{v}.\end{aligned}\ ] ] here @xmath99 stands for the leading order terms in the @xmath91 transition form factor in eq . ( [ tfflo ] ) and @xmath146 denotes the @xmath105 leading order terms of the neutral transition form factor given by @xmath147 the loop functions are given by @xmath148\label{i2}\\ i_{g } & = -2+\log\frac{m_{k}^{2}}{\mu^{2}}+\sigma\log\frac{\sigma+1}% { \sigma-1}.\end{aligned}\ ] ] notice again that the only change from the final @xmath134 state to the present case is the replacement of the factor @xmath149 by @xmath150 . in terms of the isoscalar and isovector amplitudes and transition form factors we get@xmath151 i_{v},\qquad b_{v}=-\frac{gm_{\phi}^{2}% } { 8\sqrt{2}}\left [ t_{kk}^{0}f_{k^{\ast}k}^{0}(k^{2})+t_{kk}^{1}f_{k^{\ast}% k}^{1}(k^{2})\right ] j_{v}. \label{avbv}%\ ] ] with@xmath152 finally , taking into account both pseudoscalars ( eq.([mkfinal ] ) ) and vectors ( eq.([mvfinal ] ) ) in the loops we obtain the total amplitude as@xmath153 \eta^{\nu}%\ ] ] where@xmath154 with the specific functions in eqs.([ap],[bp],[avbv ] ) . recall these results are valid for ingoing particles . for the numerical computations in the following section we reverse the momenta of the final particles to obtain@xmath155 \eta^{\nu } \label{finalamp}%\ ] ] with@xmath156 where the functions @xmath157 @xmath158 @xmath159 @xmath160 are obtained from the untilded functions in eqs . ( [ ap],[bp],[avbv ] ) just changing the sign of @xmath161 in the integrals @xmath162 @xmath163 @xmath164 and @xmath165 in eqs . ( [ iab],[jab],[jv],[i2 ] ) . our results involve the @xmath4 isoscalar and isovector transition form factors at the center of mass energy of the reaction . our calculation based on lagrangians suitable for low energies yields the lowest order terms in the chiral expansion for these form factors . since a calculation of these form factors at such huge energies as @xmath166 @xmath47 is beyond the scope of the effective theories used here , we consider our calculation as a convenient procedure to identify the main physical effects ( form factors and meson - meson amplitudes ) and must find a way to enlarge the range of validity of the calculation to high energies . we do this by replacing the leading order terms in the transition form factors by an appropriate characterization of these form factors at the energy of the reaction . in the case of the @xmath39 final state , only the isoscalar transition form factor is required and in @xcite it was extracted from data on @xmath167 at @xmath168 @xmath169 reported in @xcite . in the present case , also the isovector transition form factor is required . this form factor can not be extracted from this data due to the low statistics . indeed , in @xcite it is assumed that the isovector amplitude is dominated by a @xmath170 with a mass and width fixed to @xmath171 @xmath172 and @xmath173 @xmath172 in the interpretation of the data . fortunately , high precision measurements for the cross section of @xmath174 , @xmath175 were recently released where the contributions from intermediate @xmath30are identified @xcite . the first reaction involves the charged @xmath4 transition form factor while the second gets contributions of both charged and neutral transition form factors . using this data , the isoscalar and isovector components of the cross section for @xmath45 at @xmath168 @xmath176 were extracted along with an energy dependent phase which signals another resonance below @xmath177 @xmath47 which could not be resolved @xcite . we extract the form factors from this data as follows . first we calculate the @xmath178 vertex function in @xmath2 and replace the lowest order terms in the transition form factor by the full one to obtain @xmath179 with all incoming particles . a straightforward calculation of the @xmath180 cross section using this effective vertex yields@xmath181 where@xmath182 in ref . @xcite a fit was done to the isovector and isoscalar components of @xmath183 , @xmath175using also data on the cross section for the production of @xmath184 where the @xmath185 peak is visible . the analysis below @xmath177 @xmath47 required the introduction of an energy dependent relative phase pointing to the existence of an unresolved resonance in this energy region , in addition to the @xmath170 and the @xmath185 . here , we are interested only in an appropriate characterization of the isoscalar and isovector form factors in the @xmath186 @xmath47 region where the effect of this phase should be small . the experimental points for the squared absolute value of the form factors are obtained using eq . ( [ sigksk ] ) and tables vi and vii of ref . physically , these form factors are dominated by the exchange of resonances ; hence in their characterization we complement the lowest order terms obtained in @xmath2 with the exchange of heavy mesons @xmath187 with the energy dependent widths used in @xcite @xmath188 \\ \gamma_{\rho^{\prime}}(s ) & = \gamma_{\rho^{\prime}}\left [ \frac { \mathcal{p}_{4\pi}(s)}{\mathcal{p}_{4\pi}(m_{\rho^{\prime}}^{2})}b_{4\pi } ^{\rho^{\prime}}+(1-b_{4\pi}^{\rho^{\prime}})\right ] , \end{aligned}\ ] ] where@xmath189 the values for the constants appearing here are extracted from the central values of tabel xv in @xcite as @xmath190 , @xmath191 , @xmath192 , @xmath193 @xmath172 , @xmath194 @xmath172 , @xmath195 @xmath172 , @xmath196 @xmath172 . the parameters @xmath197 , @xmath198 are fitted to the data for the isoscalar and isovector cross sections reported in tables vi and vii of @xcite respectively . the fit to the isoscalar cross section yields @xmath199@xmath200 . the fit to the isovector cross section yields @xmath201 @xmath200 . notice that these values are nearly equal , pointing to the @xmath185 and @xmath170 as members of an @xmath202 nonet . our results for the corresponding cross sections are shown in figs . ( [ csis],[csiv ] ) , where the shadowed bands correspond to the @xmath203 regions for the paramenters @xmath197 and @xmath198 . a good description of the isoscalar cross section is obtained but more accurate data on the isovector @xmath204 cross section is desirable . the discrepancy in this case is due to the effects another intermediate resonance around @xmath205 in @xmath204 which however could not be resolved in @xcite . in the isoscalar channel . the band corresponds to the @xmath206 region of our parametrization of the form factors in eq.([ksktffi0 ] ) . data points are taken from table vi of ref . ] in the isovector channel . the band corresponds to the @xmath206 region of the parametrization of the form factors in eq.([ksktffi1 ] ) . data points are taken from table vii of ref . ] as a cross check , we calculate the full cross section for @xmath183 from the exchange of @xmath30 which involves only the charged transition form factor and obtain a proper description of data in table iii of ref . @xcite up to @xmath207 . with respect to the @xmath39 production with @xmath26-wave pions studied in @xcite , there is now the novelty of the tree level contributions in @xmath115 production with @xmath41 pairs in all possible angular momentum states . in the case of loops , our calculations consider only s - wave @xmath41 in the final state because we are using the unitarized amplitudes for @xmath208 which per construction are projected onto well defined angular momentum ( @xmath209 ) and isospin ( @xmath210 ) . in the appendix we give details on the integration of phase space and state our conventions . the dikaon spectrum turns out to be @xmath211 where @xmath212 and these amplitudes are given in eqs . ( [ mpt],[mvt],[finalamp ] ) respectively . we refer the reader to the appendix for further details on the notation and integration of phase space . we evaluate numerically the integrals and the differential cross section using the physical masses and coupling constants . we remark that all the parameters entering this calculation have been fixed in advance and , in this sense , there are no free parameters . in our numerical analysis we use @xmath213 , @xmath214 , @xmath215 , @xmath216 , @xmath217 , @xmath218 , and @xmath219 . concerning the rescattering effects we remark that the @xmath220 and @xmath104 scattering between the kaons in the loops and the final kaons takes place at the dikaon invariant mass independently of the value of @xmath221 and of the momenta in the loops . as a consequence , when replacing the lowest order terms for this amplitude by the unitarized amplitude , we can safely use the results of @xcite and take a renormalization scale @xmath222 @xmath47 for the function @xmath223 @xcite , in spite of the fact that the reaction @xmath224 takes place at a much higher energy @xmath225 . the unitarized amplitudes naturally contain the scalar poles and there is no need to include explicitly these degrees of freedom in the calculation . we obtain the dikaon spectrum shown in fig . ( [ dsdm ] ) for @xmath226 @xmath172 . in order to compare with the dikaon spectrum in fig . ( 26 ) of @xcite , we should collect all events from threshold up to @xmath227 @xmath47 as included in the sample for that figure . this amounts to integrate our differential cross section on @xmath221 in this energy range . although a precise comparison can not be carried out since data is presented in the form of number of events , our results in fig . ( [ spectrum ] ) follow a similar pattern to those of fig . ( 26 ) of @xcite . in order to check the conjecture in @xcite that the enhancement close to the dikaon threshold in the integrated spectrum is due to the presence of the @xmath12 pole , in this plot we also show the individual contributions coming from tree level and rescattering . the dashed plots are obtained integrating on @xmath221 the tree level and rescattering individual contributions to the dikaon spectrum at different @xmath221 shown in figs . ( [ dsdmtree],[dsdmloops ] ) . the analogous spectrum for the interference between tree level and rescattering contributions is shown in fig.([dsdmint ] ) . the enhancement near threshold for rescattering effects in fig . ( [ dsdmloops ] ) is due to the tails of the @xmath12 and the @xmath40 whose poles are well reproduced in the unitarization of meson - meson @xmath26-wave amplitudes present in our calculation . in contrast to the @xmath39 final state studied in @xcite where the complete @xmath12 resonance is visible in the dipion spectrum , here the peaks of both , @xmath228 and @xmath229 , lie below @xmath43 in the dikaon invariant mass , i.e. below the threshold for the production of the dikaon system in the reaction @xmath16 , thus , it is only the tail of these resonances what the kinematics allows us to see . close to the threshold for the dikaon production , rescattering effects are enhanced by the scalar poles . however , the integrated spectrum in fig.([spectrum ] ) shows that these contributions are of the same order than tree level ones close to threshold only . beyond this region tree level contributions become dominant . we can also see a constructive interference between these contributions close to threshold and a destructive interference beyond @xmath230 in the integrated dikaon spectrum . a closer analysis of tree level contributions shows that they are dominated by the exchange of @xmath30 , thus the enhancement close to threshold in the integrated dikaon spectrum in fig.([spectrum ] ) is due to both , the scalar poles and tree level @xmath30 exchange . events beyond threshold are mainly due to @xmath30 exchange at tree level . the interference is more transparent at the level of the dikaon spectrum as a function of @xmath221 shown in fig.([dsdmint ] ) . the sign depends both on @xmath231 and @xmath221 but for a fixed @xmath221 it is positive close to the dikaon threshold and evolves to a negative interference beyond this threshold . this interference shows up differently in the total cross section for @xmath16 obtained upon integration of the dikaon invariant mass in fig . ( [ dsdm ] ) . our result for the cross section is shown in fig . ( [ sig ] ) . here , we get a constructive interference close to the reaction threshold which evolve to a destructive interference beyond @xmath232 . in this figure our results are compared with measurements of the cross section for @xmath17 from ref . this comparison makes sense since , as shown in fig . ( 25 ) of @xcite , for most of the considered events one of the final @xmath41 pairs comes from a @xmath19 . using the narrow width approximation ( quite appropriate for the @xmath19 ) it can be shown that the measured cross section coincides with the cross section for @xmath16 . in fig . ( [ sig ] ) we see that the interference between tree level and rescattering effects is crucial in the proper description of data . above @xmath233 we expect higher @xmath127 dikaon contributions ( exchange of tensor mesons in the @xmath29 rescattering ) not considered in the unitarized amplitudes which per construction are the @xmath209 projected amplitudes . as a function of the center of mass energy ( solid line ) . short - dashed lines correspond to the @xmath206 region of the transition form factors in figs . ( [ csis],[csiv ] ) . long - dashed line corresponds to tree level contributions . the experimental points are taken from ref . @xcite and correspond to the cross section for @xmath234 with one of the kaon pairs coming from a @xmath19 ( see the discussion in the body of the paper ) . ] in ref . @xcite the authors observed a peak , named @xmath8 , around @xmath235 in the cross section of the @xmath236 with the dipion invariant mass in the @xmath12 peak region . the @xmath237 mode was also observed at bes and belle thus the @xmath8 must be an isoscalar @xmath238 state . the mass and width measured in the @xmath239 channel , @xmath240 , @xmath241 , disagree with the predictions of quark models for the @xmath242 state ( e.g. @xcite predicts @xmath243 , @xmath244 ) , thus alternative structures have been proposed for this resonance @xcite . in particular , a narrow peak with a mass close to the experimental value has been generated solving the faddeev equations for the three body problem involving chiral interactions of the @xmath245 system @xcite . the peak appears for a @xmath246 invariant mass close to the @xmath228 pointing to the @xmath8 as a @xmath247 dynamically generated resonance . clearly , there must exist contributions from the intermediate @xmath8 to @xmath16 . furthermore , since the @xmath41 system in this reaction can also be in an isovector state , in principle this reaction could get contributions from an isovector companion of the @xmath8 if it exists and in this concern it is worth to remark that in the approach of @xcite no peak is generated in the isovector channel . since our calculation accounts for most of the experimental data , we would expect these contributions to be small except perhaps around @xmath248 where there is a point out of region obtained using the characterization of the @xmath4 transition form factors within @xmath206 . this point is slightly above the @xmath8 peak observed by babar and bes collaborations and could be a signal of intermediate resonances whose shape is distorted by their own interference and interference with the mechanisms studied here . in this concern it is desirable to have a rough estimate of the contributions of the intermediate @xmath8 via the chain @xmath249 with a slightly off - shell @xmath228 . we devote the following section to the calculation of these contributions . @xcite , the product @xmath250 was obtained . this allows us to estimate the intermediate @xmath8 contributions depicted in fig . ( [ x ] ) . for the @xmath251 and @xmath252 interactions we use the phenomenological lagrangians @xmath253 contributions to @xmath254 . ] from these interactions , in the corresponding center of momentum system ( c.m.s . ) we obtain @xmath255 the amplitude for fig . ( [ x ] ) reads @xmath256 using the babar central values @xmath257 , the product @xmath258 as extracted from eqs.([gammas ] ) , @xmath259 @xcite and the particle data group values @xmath260 @xcite we obtain the cross section shown in fig . ( [ sigx ] ) . close to the peak of the @xmath8 these contributions are of the same order as the ones previously considered thus they must be included in our calculation . the relative sign between this amplitude and the previous contributions can not be fixed thus we explore both constructive and destructive interference . our results are shown in figs . ( [ sigtotal],[sigdest ] ) for constructive and destructive interference respectively . contributions to @xmath254 as a function of the center of mass energy . ] as a function of the center of mass energy including all contributions(solid line ) and constructive interference . short - dashed lines correspond to the @xmath206 region of the transition form factors in figs . ( [ csis],[csiv ] ) . ] for destructive interference as a function of the center of mass energy including all contributions(solid line ) . short - dashed lines correspond to the @xmath206 region of the transition form factors in figs . ( [ csis],[csiv ] ) . ] in the case of constructive interference , our calculation suggests that the effects of the @xmath8 could be seen in @xmath254 over the background generated by the intermediate light vectors and the rescattring effects . in the case of destructive interference , a dip is generated instead of a peak and this seems to be the case favoured by data . however , definite conclusions require a more precise extraction of the isovector @xmath4 transition form factor at @xmath261 ( see fig . ( [ csiv ] ) ) because the tree level intermediate light vectors and rescattering contributions are sensistive to this form factor . indeed , using only data in the @xmath262 region in the fit of the isovector form factor we obtain an increase of roughly @xmath263 in the cross section shown in figs . ( [ sigtotal],[sigdest ] ) with a similar energy dependence for @xmath264 . furthermore , intermediate contributions of an hypotetical isovector companion of the @xmath8 can not be excluded at this point . the prediction of the absence of isovector companions of the @xmath8 in the framework of the dinamically generated resonances @xcite makes interesting to measure more accuratelly the cross section for @xmath254 in the near threshold region . the possible isovector resonance could be seen cleanly in the pure isovector @xmath265 final state thus we encourage experimentalists to measure also the @xmath266 cross section around @xmath267 . we study electron - positron annihilation into @xmath23 . we start with the @xmath2 lagrangian which yields tree level contributions to this reaction involving both pseudoscalar and vector exchange . for the latter we use the conventional anomalous lagrangian . the dynamics is dominated by the kaon form factors and the @xmath4 transition form factors , whose lowest order terms ( valid for low photon virtualities ) , arise in the calculation with the effective theory . this result is improved replacing the lowest order terms provided by @xmath2 for the kaon form factors , by the full form factor as calculated in @xmath268@xcite . the @xmath4 transition form factors are extracted from recent data on @xmath269 @xcite and used in the numerics instead of the lowest order terms arising from the anomalous @xmath3 lagrangian . we consider also rescattering of the final charged kaons and @xmath115 production through intermediate @xmath103 production and subsequent rescattering @xmath104 . the corresponding results , valid for low energy dikaon mass are improved using the unitarized meson - meson amplitudes containing the scalar poles @xcite instead of the lowest order terms obtained in the calculation with @xmath52 . the dynamical generation of the scalar resonances in the meson - meson unitarized amplitudes enhances the rescattering effects close to the reaction threshold . the poles of the scalar resonances lie below the dikaon threshold energy but the tail of the @xmath12 and @xmath40 mesons are visible in the dikaon spectrum of rescattering contributions . in spite of this , beyond the close to threshold region , the tree level vector exchange contribution turns out to be dominant . the calculated cross section is sensitive to the @xmath4 form factors but within @xmath206 in their fit to @xmath269 recent data , we obtain results in agreement with measurements of the cross section for @xmath17 , where one of the kaon pairs comes from the decay of a @xmath19 , except in a narrow region near @xmath270 . since the @xmath8 has been observed in the @xmath271 reaction , and the @xmath12 couples strongly to the @xmath272 system , the @xmath8 could also show up in the cross section for @xmath16 slightly beyond the threshold energy of the reaction in spite of the fact that it is not possible to see the whole @xmath12 shape in the dikaon invariant mass because it lies below the kinematical threshold for the production of two kaons . we estimate these contributions using phenomenological lagrangians and extracting the product of the @xmath273 and @xmath274 couplings from the babar value for @xmath7 . we obtain a sizable contribution of intermediate @xmath8 to the @xmath16 at the @xmath8 peak . including all contributions we get the results shown as shown in figs . ( [ sigtotal],[sigdest ] ) . the large uncertainties in the extraction of the isovector @xmath4 transition form factor from data do not allow for definite conclusions but the data around @xmath270 hints to a destructive interference between the intermediate @xmath8 contributions and to possible contributions from an isovector companion of the @xmath8 . in the light of a recent calculation of the @xmath8 as a three body structure where no isovector companion is generated @xcite , it is important to have more precise data on the isovector @xmath4 transition form factor and on the cross section for @xmath16 near threshold . a cleaner signal of an hypothetical isovector companion of the @xmath8 could be detected in a pure isovector final state and in this concern it is worthy to study the @xmath275 channel from both the experimental and theoretical point of view . this work was partly supported by dgicyt contract number fis2006 - 03438 and the generalitat valenciana . this research is part of the eu integrated infrastructure initiative hadron physics project under contract number rii3-ct-2004 - 506078 . the work of m. napsuciale was also supported by dinpo - ug and conacyt - mxico under project conacyt-50471-f . selim gmez - avila wish to acknowledge support by conacyt - mxico under the mixed grants program . m.n and s.g . wish to thank the hospitality of the theory group at ific . we thank e. p. solodov for useful mail exchange concerning data presented in @xcite . the differential cross section is given by@xmath276 integrating @xmath277 variables we obtain@xmath278 next we integrate the @xmath279 variables . we work in the center of momentum system ( cms ) . the kinematical constriction in this frame reads@xmath280 where @xmath281 @xmath282 and @xmath283 . in order to directly integrate the @xmath279 variables we choose our frame as shown in fig.([frame ] ) . with these conventions the @xmath284 angle @xmath285 is the @xmath279 polar angle and can be integrated using the @xmath286 function to obtain@xmath287 where we neglected @xmath288 terms in the flux factor . the squared amplitude @xmath289 is a function of the scalar products of @xmath290 momentum conservation requires @xmath291 furthermore @xmath292 thus@xmath293 hence the squared amplitude for this process in general depends only on the following scalar products@xmath294 the momentum @xmath295 thus @xmath296 integration of @xmath297 requires the explicit form of the average squared amplitude since the dependence on @xmath298 introduces a dependence on @xmath299 . here we must take into account that this angle is related to the @xmath300beam angle @xmath301 and the @xmath302beam angle @xmath303 as@xmath304 thus there is a non - trivial dependence on @xmath297 . the integration of the azimuthal angle of the @xmath19 is straightforward . then we integrate the polar angle of the @xmath19 . integration on @xmath305 requires to calculate the maximum and minimum kaon energy allowed by the kinematical constraint @xmath306 for @xmath307 respectively . these are the solutions to@xmath308 which turn out to be @xmath309\ ] ] this way we get the spectrum@xmath310 this spectrum can be written in terms of the dikaon invariant mass related to @xmath311 and @xmath312 as @xmath313 defined in eq . ( [ lambda]).the dikaon spectrum is@xmath314 it is convenient to work with the dimensionless quantities@xmath315 in terms of these quantities@xmath316 in terms of these variables the scalar products read@xmath317 the range of values for @xmath311 are @xmath318 @xmath319 thus@xmath320 m. benayoun , s. i. eidelman , v. n. ivanchenko and z. k. silagadze , mod . a * 14 * , 2605 ( 1999 ) [ arxiv : hep - ph/9910523 ] . a. denig , nucl . suppl . * 162 * , 81 ( 2006 ) [ arxiv : hep - ex/0611024 ] ; d. leone [ kloe collaboration ] , nucl . * 162 * , 95 ( 2006 ) ; h. czyz , a. grzelinska , j. h. kuhn and g. rodrigo , eur . j. c * 47 * , 617 ( 2006 ) [ arxiv : hep - ph/0512180 ] ; a. g. denig [ kloe collaboration ] , int . j. mod . phys . a * 20 * , 1935 ( 2005 ) . j. h. kuhn , eur . j. c * 33 * , s659 ( 2004 ) . s. e. muller [ kloe collaboration ] , nucl . suppl . * 126 * , 335 ( 2004 ) ; a. g. denig _ et al . _ [ the kloe collaboration ] , nucl . suppl . * 116 * , 243 ( 2003 ) [ arxiv : hep - ex/0211024 ] ; b. aubert _ et al . _ [ babar collaboration ] , phys . d * 70 * , 072004 ( 2004 ) [ arxiv : hep - ex/0408078 ] . b. aubert _ et al . _ [ babar collaboration ] , phys . d * 71 * , 052001 ( 2005 ) [ arxiv : hep - ex/0502025 ] . b. aubert _ et al . _ [ babar collaboration ] , phys . d * 73 * , 012005 ( 2006 ) [ arxiv : hep - ex/0512023 ] . b. aubert _ et al . _ [ babar collaboration ] , phys . d * 73 * , 052003 ( 2006 ) [ arxiv : hep - ex/0602006 ] . r. baldini ferroli [ babar collaboration ] , int . j. mod . a * 21 * , 5565 ( 2006 ) ; b. a. shwartz [ belle collaboration ] , nucl . suppl . * 144 * , 245 ( 2005 ) ; h. czyz , a. grzelinska , j. h. kuhn and g. rodrigo , eur . j. c * 39 * , 411 ( 2005 ) [ arxiv : hep - ph/0404078 ] . h. czyz , j. h. kuhn , e. nowak and g. rodrigo , eur . j. c * 35 * , 527 ( 2004 ) [ arxiv : hep - ph/0403062 ] . h. czyz , a. grzelinska , j. h. kuhn and g. rodrigo , eur . j. c * 27 * , 563 ( 2003 ) [ arxiv : hep - ph/0212225 ] . v. m. aulchenko _ et al . _ [ snd collaboration ] , phys . b * 440 * , 442 ( 1998 ) [ arxiv : hep - ex/9807016 ] ; r. r. akhmetshin et al . [ cmd-2 collaboration ] , phys . b * 462 * , 380 ( 1999 ) [ arxiv : hep - ex/9907006 ] ; a. aloisio _ et al . _ [ kloe collaboration ] , phys . lett . b * 537 * , 21 ( 2002 ) [ arxiv : hep - ex/0204013 ] ; f. ambrosino _ et al . _ [ kloe collaboration ] , eur . j. c * 49 * , 473 ( 2007 ) [ arxiv : hep - ex/0609009 ] . f. ambrosino _ et al . _ [ kloe collaboration ] , phys . b * 634 * , 148 ( 2006 ) [ arxiv : hep - ex/0511031 ] . a. bramon , r. escribano , j. l. lucio m , m. napsuciale and g. pancheri , eur . j. c * 26 * , 253 ( 2002 ) [ arxiv : hep - ph/0204339 ] ; d. black , m. harada and j. schechter , phys . d * 73 * , 054017 ( 2006 ) [ arxiv : hep - ph/0601052 ] ; d. black , m. harada and j. schechter , phys . lett . * 88 * , 181603 ( 2002 ) [ arxiv : hep - ph/0202069 ] . e. marco , s. hirenzaki , e. oset and h. toki , phys . b * 470 * , 20 ( 1999 ) [ arxiv : hep - ph/9903217 ] ; v. e. markushin , eur . j. a * 8 * , 389 ( 2000 ) [ arxiv : hep - ph/0005164 ] ; j. e. palomar , l. roca , e. oset and m. j. vicente vacas , nucl . a * 729 * , 743 ( 2003 ) [ arxiv : hep - ph/0306249 ] ; j. a. oller , nucl . a * 714 * , 161 ( 2003 ) [ arxiv : hep - ph/0205121 ] . m. napsuciale , e. oset , k. sasaki and c. a. vaquera - araujo , phys . rev . d * 76 * , 074012 ( 2007 ) [ arxiv:0706.2972 [ hep - ph ] ] . m. bystritskiy , m. k. volkov , e. a. kuraev , e. bartos and m. secansky , phys . d * 77 * , 054008 ( 2008 ) [ arxiv:0712.0304 [ hep - ph ] ] . g. ecker , j. gasser , a. pich and e. de rafael , nucl . b * 321 * , 311 ( 1989 ) . j. a. oller , e. oset and j. r. pelaez , phys . * 80 * , 3452 ( 1998 ) [ arxiv : hep - ph/9803242 ] ; j. a. oller , e. oset and j. r. pelaez , phys . rev . d * 59 * , 074001 ( 1999 ) [ erratum - ibid . d * 60 * , 099906 ( 1999 ) ] [ arxiv : hep - ph/9804209 ] . g. ecker , j. gasser , h. leutwyler , a. pich and e. de rafael , phys . b * 223 * , 425 ( 1989 ) . u. g. meissner and j. a. oller , nucl . phys . a * 679 * , 671 ( 2001 ) [ arxiv : hep - ph/0005253 ] ; a. falvard _ et al . _ [ dm2 collaboration ] , phys . d * 38 * , 2706 ( 1988 ) ; m. ablikim _ et al . _ [ bes collaboration ] , phys . b * 607 * , 243 ( 2005 ) [ arxiv : hep - ex/0411001 ] ; j. z. bai _ et al . _ [ bes collaboration ] , phys . d * 68 * , 052003 ( 2003 ) [ arxiv : hep - ex/0307058 ] . t. barnes , n. black and p. r. page , phys . d * 68 * , 054014 ( 2003 ) [ arxiv : nucl - th/0208072 ] . g. j. ding and m. l. yan , phys . b * 650 * , 390 ( 2007 ) [ arxiv : hep - ph/0611319 ] ; g. j. ding and m. l. yan , phys . b * 657 * , 49 ( 2007 ) [ arxiv : hep - ph/0701047 ] ; z. g. wang , nucl . a * 791 * , 106 ( 2007 ) [ arxiv : hep - ph/0610171 ] ; h. x. chen , x. liu , a. hosaka and s. l. zhu , phys . d * 78 * , 034012 ( 2008 ) [ arxiv:0801.4603 [ hep - ph ] ] .

in this work we study the @xmath0 reaction . the leading order electromagnetic contributions to this process involve the @xmath1 vertex function with a highly virtual photon . we calculate this function at low energies using @xmath2 supplemented with the anomalous term for the @xmath3 interactions . tree level contributions involve the kaon form factors and the @xmath4 transition form factors . we improve this result , valid for low photon virtualities , replacing the lowest order terms in the kaon form factors and @xmath4 transition form factors by the form factors as obtained in @xmath5 in the former case and the ones extracted from recent data on @xmath6 in the latter case . we calculate rescattering effects which involve meson - meson amplitudes . the corresponding result is improved using the unitarized meson - meson amplitudes containing the scalar poles instead of the lowest order terms . using the babar value for @xmath7 , we calculate the contribution from intermediate @xmath8 . a good description of data is obtained in the case of destructive interference between this contribution and the previous ones , but more accurate data on the isovector @xmath4 transition form factor is required in order to exclude contributions from an intermediate isovector resonance to @xmath0 around @xmath9 .

the ramachandran plot @xcite , @xcite is the paradigm technique of protein visualization . it describes backbone atoms in a peptide group around a given c@xmath6 carbon in terms of dihedral rotations . ramachandran plot can also been extended to the side - chain atoms in terms of the dihedral rotamers . this gives rise to janin plot @xcite and its variants . in the present article we develop new visualization techniques to describe proteins . our goal is to visualize all atoms both in a given peptide unit and those in the neighboring units , beyond the regime of the ramachandran plot . this will enable us to search for new relations between the positioning of various atoms and the backbone geometry . our approach draws from developments in three dimensional visualization that have taken place after the ramachandran plot was originally introduced @xcite , @xcite . in particular , in lieu of toroidal geometry we utilize the geometry of a two - sphere . it enables us to describe the various atoms exactly as they are seen by an observer who roller - coasts along the backbone . of particular interest to us is the visual analysis of the modular components of which all folded proteins are built . these have been recently identified as the soliton solutions to a generalized discrete nonlinear schrdinger equation ( dnls ) @xcite-@xcite . soliton solutions to nonlinear difference equations share a long history with biological physics of proteins . the discrete version of the nonlinear schrdinger equation is an embodiment of this relationship . it was originally introduced by davydov @xcite to describe energy transfer along the protein @xmath0-helices . subsequently the dnls equation has found many additional applications in biological physics and elsewhere @xcite . the dnls equation has also the remarkable mathematical property of integrability , it is commonly viewed as the archetype integrable system @xcite . when the dnls soliton propagates along the @xmath0-helix , the protein changes its shape . in @xcite , @xcite it has been shown that when the soliton becomes trapped , the protein folds . it now appears that practically all folded proteins can be built in a modular fashion from a relatively small number of such trapped solitons @xcite . in the present article we combine the notion of soliton with modern visualization techniques @xcite . we are particularly interested in the ramifications of the backbone dnls soliton in protein side - chain geometry . our ultimate goal is to develop a graphical characterization and eventually a full classification of protein structures in terms of their soliton modules . as a prelude , we here utilize the soliton concept to visually inspect and analyze those protein conformations that are located in the left handed @xmath0-helix ( @xmath7-@xmath0 ) region of the ramachandran plot @xcite , @xcite . this region is a relatively small subset of all different protein conformations , and as such amenable to an explicit analysis . of particular interest to us are the common geometric aspects of the asparagine ( asn ) and aspartic acid ( asp ) . asparagine is the predominant residue in the so - called non - glycyl @xmath7-@xmath0 region . according to the prevailing point of view this is due to a _ localized _ non - covalent attractive carbonyl - carbonyl interaction between the side - chain and backbone @xcite-@xcite . such a carbonyl - carbonyl interaction can only be present in asn , asp , glutamine ( gln ) and glutamic acid ( glu ) . indeed , the propensity of asp that is structurally very similar to asn is also clearly amplified in the @xmath7-@xmath0 region , while the somewhat lower propensity of gln and glu has been explained in the literature to be a consequence of steric suppressions @xcite . here we show that the presence of a @xmath7-@xmath0 site goes beyond the regime of a single peptide unit . we find that it involves a coordinated interplay of up to seven consecutive amino acids . we argue that this extended correlation over several amino acids is symptomatic to solitons . we perform a detailed visual investigation and propose a graphical classification of these solitons . we argue that all protein structures could be characterized and classified similarly , in terms of general selection rules that we formulate . we find that the continuous geometry of the two - sphere gives a more perceptible characterization of protein conformations than the toroidal ramachandran plot . in fact , the three dimensional visualization techniques we utilize have been largely introduced and developed after the publication of @xcite , @xcite . our approach exploits the properties of a piecewise linear _ framed _ chain , as it is being applied to visualization problems in aircraft and robot kinematics , stereo reconstruction , and increasingly in computer graphics and virtual reality @xcite , @xcite . in these applications different framings correspond to different camera gaze positions , that one introduces and varies for the purpose of extracting diverse and complementary information on geometrical aspects and physical properties of the system under investigation . however , largely due to the success and systematics provided by ramachandran plot , thus far this kind of approach has been sparsely applied to the analysis of protein conformations . among our goals is to demonstrate that these modern visualization techniques can provide a powerful complementary tool for the visual description of folded proteins . in particular , they enable the study of visual correlations between nearby peptide units , which is not possible in the ramachandran approach that is limited to to describe a single peptide unit only . finally , we note that the investigation of the physical properties of our concrete examples asn and asp is also of substantial biological interest . these two amino acids are more frequently than any other amino acid subject to _ in vivo _ post - translational modifications including spontaneous nonenzymatic deamidation from asn to asp @xcite and racemization from @xmath7-asp into @xmath8-asp @xcite . these processes are presumed to have consequences to cellular and organismal ageing @xcite , @xcite . they might also have a rle in enhancing the emergence of amyloid based neurodegenerative diseases @xcite , @xcite . we interpret a protein backbone in terms of framed chain , with vertices located at the @xmath2 carbons @xcite . depending on the application , the framing can be introduced in various different ways . examples include the geometric frenet frame @xcite , @xcite , the geodesic bishop frame @xcite , and protein specific @xmath3 carbon frame that we obtain by utilizing the direction of the c@xmath9 carbon along a protein backbone to construct an orthonormal framing @xcite . here we propose that in particular the frenet framing provides a powerful tool for protein side - chain visualization , also beyond our explicit example of the @xmath7-@xmath0 ramachandran region . the additional advantage of the frenet framing is that it relates directly to an energy function . but we also advertise the closely related c@xmath9 framing that may sometimes have certain visual advantages . the framing of a piecewise linear chain is conventionally based on the denavit - hartenberg @xcite formalism . this formalism was originally introduced in robotics but has been subsequently extensively applied also in other disciplines . here we resort to a variant , that has been developed in @xcite for the purpose of framing protein backbones . it utilizes the transfer matrix formalism @xcite to describe a protein with @xmath10 residues using the coordinates @xmath11 of the backbone @xmath2 carbons ( @xmath12 ) . these coordinates can be downloaded from the protein data bank ( pdb ) @xcite . for each of the segments that connect the backbone @xmath2 central carbons we compute the unit length tangent vector @xmath13 , binormal vector @xmath14 and normal vector @xmath15 using @xmath16 @xmath17 @xmath18 thus the tangent vector @xmath13 points from the @xmath19 central @xmath2 carbon to the direction of the @xmath20 central @xmath2 carbon , the way how it is seen by an observer who is located at the position of the @xmath19 carbon . the @xmath14 and @xmath15 determine a frame that enables the observer to orient herself at the location @xmath11 , on the plane that is orthogonal to the direction @xmath13 . together the right - handed triplet @xmath21 constitutes the orthonormal discrete frenet frame for each residue along the backbone chain , with base at the position of the vertex @xmath11 . the corresponding backbone bond @xmath22 and torsion @xmath23 angles can be computed from ( [ tbn ] ) as follows , @xmath24 @xmath25 alternatively , if the bond and torsion angles are known we can construct the frames iteratively by starting from the @xmath10 terminus and using @xcite @xmath26 @xmath27 where the @xmath28 @xmath29 are the adjoint so(3 ) lie algebra generators . once the @xmath13 have been constructed from ( [ dfe ] ) and the bond lengths @xmath30 have been determined we recover the entire backbone from @xmath31 the set of all frenet frames defines a framing of the backbone . according to ( [ kappa])-([dfe ] ) the bond and torsion angles are link variables , they relate a frame at the vertex @xmath11 to a frame at the vertex @xmath32 . we note that the definition of the bond angle involves three vertices while the definition of the torsion angle involves a total of four vertices . the c@xmath9 framing @xcite is a complement to the frenet framing . it can be introduced for all non - glycyl residues . we define these frames similarly , in terms of three mutually orthogonal unit vectors at each c@xmath6 carbon . consequently the frenet framing and the c@xmath9 framing are related to each other by peptide unit dependent so(3 ) rotations . the first unit vector of the c@xmath9 basis is obtained as follows , @xmath33 is the location of the @xmath34th c@xmath6 atom , and @xmath35 is the location of the corresponding c@xmath9 atom . the second unit vector is @xmath36 where @xmath13 is the frenet frame unit tangent vector . finally , the third unit vector in the c@xmath9 frame is @xmath37 since ( @xmath38 ) is an orthonormal frame located at each c@xmath6 , it can be used like the frenet frame to visualize the various atoms along the protein backbone . moreover , since @xmath39 we can likewise use the c@xmath9 framing to construct the entire backbone using ( [ back ] ) . we wish to employ the various frames together with the discrete frenet equation ( [ dfe ] ) to inspect the structure of folded proteins . as our principal data set we utilize all those proteins that are presently in pdb and have an overall resolution that is better than 2.0 angstrm . we introduce no additional curation or data pruning in this set . but we have confirmed that all our results and conclusions stand when we restrict ourselves to those proteins with resolution better than 1.5 a and with less than 30@xmath40 homology relation , or to those proteins that have a resolution which is better than 1.0 a. finally , as a control set we also utilize the highly curated version v3.3 library of chopped pdb files for representative cath domains @xcite . since the conclusions we draw are indifferent of the data set that we use we only describe explicitly the results for the first one , as it allows for the visually most complete presentation . we start by describing how to visualize the protein backbone in terms of the frenet frames @xcite . here we go beyond the regime of the ramachandran plot , that does not provide any direct visual correlation between neighboring peptide groups . we introduce an observer who maps all the atoms in the protein by traversing along the backbone . the observer moves between the @xmath2 carbons like on a roller - coaster with an orientation that is determined by the discrete frenet framing : we take the base of the tangent vector @xmath13 defined in ( [ tbn ] ) to be at the location @xmath41 of the @xmath19 central @xmath2 carbon . the tip of @xmath13 then determines a point on the surface of a unit two - sphere that surrounds our observer at the location of this @xmath2 carbon . the observer uses this two - sphere to constructs a map of the various atoms exactly the way how she sees them on the surface of the sphere , as if the atoms were stars in the sky . for this she always orients the two - sphere at the site @xmath34 so that the north - pole coincides with the tip of @xmath13 _ i.e. _ the north - pole is always in the direction of the next @xmath2 at the site @xmath32 . she takes the bond angle to measure the latitude of the two - sphere from its north pole . the torsion angle measures the longitude starting from the great circle that passes both through the north pole and through the tip of the binormal vector @xmath14 . in terms of these angles she can characterize the direction of the vector @xmath42 _ i.e. _ the direction towards site @xmath43 to which the roller coaster turns at the next @xmath2 carbon . consequently she acquires information about the geometric relations between neighboring peptide units , and this goes beyond the regime of the ramachandran plot . she proceeds as follows : she first translates the center of the two - sphere from the location of the @xmath19 central carbon towards its north - pole and all the way to the location of the @xmath20 central carbon , without introducing any rotation of the sphere . she then records the direction of @xmath42 as a point on the surface of the two - sphere . this defines the corresponding coordinates ( @xmath44 ) and marks a point on the map . it gives an instruction to the observer at the point @xmath11 , how she should turn at site @xmath32 , to reach the @xmath45 central @xmath2 carbon at the point @xmath43 . she then continues to construct the mapping with the next @xmath2 carbon along the backbone . she rotates the two - sphere at @xmath32 so that the north pole of the rotated sphere coincides with the tip of @xmath42 , and so that the torsion angle measures the longitude from the great circle determined by the north - pole and the tip of @xmath46 . she repeat the procedure for all @xmath2 , until she has mapped the entire backbone . we note that for a folded protein the two vectors @xmath13 and @xmath42 are never exactly parallel to each other so there is never any ambiguity due to an inflection point . when we repeat this mapping procedure for every @xmath2 in all proteins in our data set , we obtain a ( @xmath47 ) distribution that characterizes the overall geometry of protein backbones . this provides non - local information on the backbone geometry that extends over several peptide units . in particular , we now have a map that shows _ exactly _ how the central carbons are seen by our roller - coasting observer when she gazes at them from her frenet frame positions along the backbone . we find that the @xmath2 distribution for all proteins in our data set determines an annulus on the surface of the two - sphere . for visualization it then becomes convenient to employ the geometry of the stereographically projected two - sphere . it is obtained by projecting our @xmath48 coordinates to the north pole tangent plane of the two - sphere . if ( @xmath49 ) are the coordinates of this tangent plane the projection is defined by @xmath50 when we perform this projection for all @xmath2 carbons in all proteins that are in our data set and separately display the results for the different groups of @xmath0-helices , @xmath1-strands , @xmath51-helices and loops as these structures are defined in pdb , we arrive at the angular distributions that we show in figures 1 . for our observer who always fixes her gaze position towards the north - pole of the surrounding two - sphere at each @xmath2 carbon , _ i.e. _ towards the black dot at the center of the annulus , the color intensity reveals the likely direction to which the roller coaster who is located at position @xmath11 turns at the next @xmath2 carbon , when she starts moving from its location at @xmath32 towards @xmath43 . in particular , the four maps in figure 1 are in a direct visual correspondence with the way how the frenet frame observer perceives the backbone geometry . the four maps in figure 1 portray non - local features that are not available in conventional ramachandran plots . moreover , instead of a discontinuous toroidal square as in the case of the ramachandran plots , the predominant feature in all of the present maps is that the pdb data is concentrated in a continuous annulus which is roughly between the circles @xmath52 and @xmath53 . the exterior of the annulus @xmath54 is an excluded region , it describes conformations that are subject to steric clashes . the interior @xmath55 is sterically allowed but practically excluded as long as proteins remain in the collapsed phase ; the interior region becomes occupied when we cross the @xmath56-point and proteins assume their unfolded conformations . we notice that loops appear to have a slightly higher tendency to bend towards left _ i.e. _ @xmath57 . we also note that in the figures for @xmath0 , @xmath1 and @xmath51 the blue regions correspond to residues where the present hydrogen - bond based pdb classification is in a miss - match with the geometric structure that is commonly associated with these configurations . moreover , the figure reveals that the pdb data displays innuendos of various underlying reflection symmetries : in the figure 1d ( loops ) there is a clearly visible mirror of the standard right - handed @xmath0-helix region , located in the vicinity of the outer rim with @xmath58 and with torsion angle close to the value @xmath59 . a helix in this regime would be left - handed and tighter than the standard @xmath0-helix . there is also a clear mirror structure in the figure 1b for @xmath1 strands , the standard region is @xmath60 and its less populated mirror is located around @xmath61 . the mirror symmetry between the ensuing extended regions persists in the figure 1d for loops . finally , in the figure 1d we observe a small elevated ( yellow ) region in the vicinity of @xmath62 . this is the region of helices that are spatial left - handed mirror images of the standard @xmath0-helices . there is also a ( slightly ) elevated ( green ) mirror of this region around @xmath63 . this is like the @xmath64 mirror of the standard right - handed @xmath0 helices . we can similarly visualize the geometry of side - chain atoms , as they are seen by our roller - coasting observer . this gives us local information on the given peptide unit . now the results turn out to be isomorphic to those revealed by the standard ramachandran plot . moreover , this enables us to develop a visual complement to the existing rotamer libraries . we assume that the observer is oriented according to the discrete frenet framing that is determined by the transfer matrix ( [ dfe ] ) at each @xmath2 . at the location of the @xmath2 the observer then looks at the side - chain atoms and records the direction of each of them as points on the surface of the two - sphere that surrounds the observer , with the north - pole of the sphere always coinciding with the direction towards the next @xmath2 exactly as in the case of the backbone . in figure 2 ( top ) we display the angular distribution of the @xmath3 carbons on the surface of the two - sphere for all the @xmath2 carbons , as recorded by our frenet frame observer who is located at the origin of the sphere . recall that a @xmath3 carbon is present in all non - glycyl residues . we note that our framing is determined entirely in terms of the backbone . according to prevailing paradigm the directions of the @xmath3 carbons should then be directly computable from the geometry of the tetrahedral covalent bond structure of the pertinent @xmath2 carbon . however , figure 2 ( top ) reveals that the directions of the @xmath3 carbons are not determined only by the local covalent bond structure . in addition , these directions are clearly subject to secondary structure dependent but amino acid independent nutations . this confirms that at the level of accuracy of our data , the stereochemical restraints fail to be fully universal . they reflect the secondary structure environment @xcite-@xcite . in fact , despite being based entirely on the c@xmath9 atoms the figure 2 is fully isomorphic to the standard ramachandran plot , for all amino acids except for glycine that has no c@xmath9 . a important feature of the nutation is the presence of the highly localized , isolated island denoted @xmath7-@xmath0 that is clearly visible in figure 2 ( top ) . we have confirmed that this isolated island coincides exactly with the conventional non - glycyl @xmath7-@xmath0 region of the standard ramachandran plot . this is shown in figure 2 ( middle ) where we display the direction of the @xmath3 carbons solely for those non - glycyl residues that are in the @xmath7-@xmath0 ramachandran region . finally , in the figure 2 ( bottom ) we display the discrete frenet frame distribution of the @xmath3 carbons for those asn that are located in loops only , according to pdb classification . the relatively high propensity of asn in the @xmath7-@xmath0 island is prominent . in the sequel we shall concentrate our attention solely on the isolated @xmath7-@xmath0 island in figure 2 ( middle ) . we start by noting the propensity of different amino acids in the @xmath7-@xmath0 island . the result ( in percent ) is shown in figure 3 . this figure confirms the high propensity of asn ( n ) that is also visible from figure 2 ( bottom ) . we find that asp ( d ) has also relatively high relative propensity . but the propensity of histidine ( h ) is practically equal . furthermore , several non - carbonylic amino acids have a higher propensity than glu ( e ) . finally , the @xmath1-branched isoleucine ( i ) , valine ( v ) and threorine ( t ) all have clearly suppressed propensities and proline ( p ) is practically absent , presumably reflecting the presence of steric constraints @xcite , @xcite . we now proceed to map the directions of the @xmath4 carbons for those side - chains where @xmath3 is located in the @xmath7-@xmath0 island of figure 2 . we continue to utilize the framing determined by our observer who roller - coasts the @xmath2 backbone with orientation determined by the discrete frenet frames , and north - pole always in the direction of the next c@xmath6 . the result is presented in figure 4 . it reveals that at the level of @xmath4 , the single @xmath7-@xmath0 island of the @xmath3 becomes divided into two separate but still _ highly _ localized islands . this reflects the sp3 hybridization of the c@xmath9 : there is a putative _ gauche_- ( @xmath65- ) island where around 70@xmath40 of the residues in the @xmath7-@xmath0 island are located , and a putative _ trans _ island for the rest . interestingly , we do not really see any putative _ gauche_@xmath66 ( @xmath67 ) island . the amino acid propensities of these two islands is displayed in figure 5 . asn is the most populous in both @xmath4 islands . however , the propensity of asp is elevated only in _ trans _ island . in the _ g_- island both non - carbonylic his ( h ) and lys ( k ) and even the carbonylic gln ( q ) have a higher propensity than asp . at the moment we have no good explanation for this observation , and we leave it as challenge . in figure 6 we plot the percentage ratios of the different amino acids as they appear in the two @xmath4 islands . we note that around @xmath68 of residues in the putative @xmath69 island are non - carbonylic , while in the putative @xmath70 island the number is much lower , close to @xmath71 . we proceed to the next level along the side - chain , to map the @xmath5 carbons . in figure 7 we plot these carbons for those side - chains where @xmath3 is located in the @xmath7-@xmath0 island . in the figure 7 on top , we show them as they are seen by by our discrete frenet frame observer who sits at the locations of the @xmath2 carbons . in the figure 7 on bottom we show them as they are seen in the c@xmath9 frame for an observer now sitting at the c@xmath9 location , this time using the stereographic projection . since asn ( and asp ) has no @xmath5 carbon , we display instead the direction of the side - chain @xmath72 atom for asn , the result is shown in figure 8 . in the top figure 8 we use the c@xmath6 based frenet frame observer and in the middle and bottom figure 8 we use the c@xmath9 frame observer in combinations with stereographic projection . from figure 7 we observe that the directions of the @xmath5 continue to be highly localized , independently of the type of amino acid . but unlike in the case of @xmath4 , we find quite surprisingly , that now there is only one clearly visible island . we do not have any definite stereochemistry or physics based explanation why the clearly visible sp3 hybridization based doubling that we observe at the level of @xmath4 has now completely disappeared . however , we do observe the formation of a second , relatively very weakly occupied island at larger values of the latitude angle and with longitude angle @xmath73 . this island is clearly visible in figure 7 ( right ) . there is also a third , very faint island in the direction @xmath74 that ( barely ) becomes visible in the stereographically projected figure 7 ( left ) . at the moment we do not have a basis to conclude whether the extremely low population of the second and third island is a real effect or only a reflection of problems in the experimental data . we refer to @xcite , that there are presently an estimated half a million incorrectly positioned side - chain atoms pdb data . in this light , the reason for the sparse population of the two additional sp3 hybridized islands should be subjected to experimental curiosity , to determine the cause . since asn has no @xmath5 carbon , in figure 8 we display instead the @xmath72 atoms of the asn side - chain according to pdb identification . in the top figure 8 we use discrete frenet frame of the @xmath2-carbons , and in the middle and bottom we use the stereographically projected c@xmath9 frame . we note that the two @xmath4 islands appear to become divided into four distinct but still highly localized islands . however , we recall that the identification between the asn side - chain @xmath72 and @xmath10 can be very difficult , and there are apparently numerous errors in the @xmath72 and @xmath10 identifications in pdb data @xcite . thus we have displayed in figure 8 ( top ) the @xmath10 atoms according to pdb identification as well . by comparing the figures 8 ( middle ) and ( bottom ) we propose that _ most likely _ the two inner - most islands denoted * a * and * b * in figure 8 describe @xmath10 instead of @xmath72 atoms . if so , our visualization technique could become a useful tool in detecting erroneously identified @xmath72 and @xmath10 atoms and help to resolve the kind of issues raised in @xcite . this could be scrutinized by a careful re - analysis of high resolution x - ray crystallography data . finally , in figure 9 we have mapped the locations of the c@xmath75 atoms in our entire dataset ( except for prolines ) as they are seen in the stereo graphically projected c@xmath76 frame . in the figure at top we show all atoms except those that have c@xmath9 in the @xmath7-@xmath0 , and in figure at bottom we show only the @xmath7-@xmath0 atoms . the sp3 hybridization of the c@xmath9 covalent bond structure is clearly visible . furthermore , in each of the three regions in left we recognize the substructure that correspond to the @xmath0-helices , @xmath1-strands and the interconnecting loops . each of the three regions is then isomorphic to figure 2a . obviously , it is straightforward to continue the present analysis to inspect additional side - chain atoms . however , here our goal is not to perform a detailed and complete analysis of all the side - chain atoms , we simply aim to describe a method . the localization we have observed in the @xmath7-@xmath0 side - chain atoms proposes that there is an organizational principle in the side - chain orientations that extends beyond a single peptide unit . hence it can not be detected by the ramachandran plot or in terms of the standard rotamer libraries , these only provide information on a given peptide unit . the backbone c@xmath6 atoms we have inspected all correspond to the @xmath7-@xmath0 position of the c@xmath9 , this region is known to commonly appear in connection of loops in lieu of regular secondary structures . thus the order we have observed is _ a priori _ not a reflection of any apparently regular secondary structure category at the level of the backbone geometry , but a characteristic of loops . we propose that it is due to the presence of a soliton solution to a discrete version of nonlinear schrdinger ( dnls ) equation that universally describes the backbone c@xmath6 geometry in ( practically ) all folded proteins . for the soliton description we do not need to know the atomic level details of the energy function . we only need to apply general symmetry principles to the abstract full quantum mechanical , all - atom hamiltonian operator @xmath77 $ ] . here the index i = 1 , ... , n labels all pairs of canonical coordinates @xmath78 that describe the elementary constituents . these include the individual c , o , n , h and every other atom in the protein and in the solvent . we also account for the valence electrons , and for every local and long range interaction between all the atoms both in the protein and in the solvent . for simplicity we take all the variables to be point - like , that is we work at the first quantized level . the canonical partition function is computed by the path integral , @xmath79 e^{-\frac{1}{\hbar } \mathcal s(q , \dot q)}\ ] ] where @xmath80 is the classical euclidean action of @xmath77 $ ] . the integration extends over all period configurations ( anti - periodic in the case of fermions ) . with the partition function we obtain the thermodynamical helmholtz free energy as follows : we introduce external sources @xmath81 and extend the partition function into the generating functional of connected green s functions , @xmath82 = \ln \left \ { \int [ dq ] e^ { - \frac{1}{\hbar } \mathcal s_\beta + \frac{1}{\hbar } \int\limits_0^\hbar \beta j\dot q } \right\}\ ] ] we introduce the legendre transformation @xmath83 = - \frac{1}{\beta } \left \ { w[j ] - \int\limits_0^{\hbar \beta } \frac{\delta w}{\delta j}\cdot j \right\}\ ] ] this defines the effective action that coincides with the helmholtz free energy when we take the limit @xmath84 . there are various methods to compute the helmholtz free energy @xmath85 . here we introduce a finite difference version of the gradient expansion . in the leading nontrivial order we have @xmath86 = \sum_{i } v^{(i)}(q_i ) + f^{(i ) } ( q_i , q_{i+1 } ) + \dots\ ] ] @xmath87 the potentials @xmath88 are all local and the @xmath89 are bi - local . the higher order terms in the expansion are either higher order polynomials in the nearest neighbor variables , or terms that introduce couplings between next - to - nearest neighbor variables . in the expansion ( [ grad ] ) , in the case of the backbone we identify the generalized coordinates @xmath90 with the bond and torsion angles ( @xmath44 ) in ( [ kappa ] ) , ( [ tau ] ) . we assume that all the additional variables that appear in the full hamiltonian operator @xmath77 $ ] have been integrated over in constructing the partition function . they affect the detailed functional form of the coefficients @xmath88 , @xmath89 _ etc . _ in ( [ grad ] ) . since ( [ back ] ) contains only the @xmath13 , it is clear that the expansion ( [ grad ] ) in terms of ( @xmath44 ) must remain invariant if we introduce a local frame rotation in the normal plane spanned by ( @xmath91 ) . this introduces a strong constraint to its functional form . in @xcite , @xcite this has been utilized to show that in the leading order the expansion ( [ grad ] ) is uniquely determined . it can only contain the following terms @xcite-@xcite , @xcite , @xmath92 @xmath93 here the first sum together with the three first terms in the second sum coincide with the integrable energy function of the conventional dnls equation with a potential that displays spontaneous symmetry breaking . the fourth ( @xmath94 ) and the fifth ( @xmath95 ) terms are the _ only _ two lower order nontrivial conserved quantities that appear in the integrable dnls hierarchy prior to the energy . these are the momentum and the helicity , respectively . the last ( @xmath96 ) term is the standard proca mass term . the parameters are all global and specific only to a super - secondary structure such as helix - loop - helix . in particular they are independent of the detailed nature of amino acids . unlike a force field in molecular dynamics , the energy function ( [ e1 ] ) does not describe the fine details of the atomary level interactions such as coulomb , van der waals , hydrogen bonding _ etc_. instead , like an effective landau - lifschitz theory it describes the properties of a folded protein backbone in terms of universal physical arguments . full details and motivation of ( [ e1 ] ) are presented in @xcite-@xcite , @xcite the remarkable property of ( [ e1 ] ) is that the torsion angle @xmath97 is only subject to local interactions , all explicit non - local interactions are carried by the bond angle @xmath98 . furthermore , since @xmath97 appears at most quadratically we can solve for it in terms of @xmath98 , @xmath99 when we substitute this into the variational equation of @xmath98 that follows from ( [ e1 ] ) , we arrive at a generalized version of the dnls equation . its soliton solution has been constructed in @xcite-@xcite . in particular , it has been observed that the soliton can be approximated by the discretized version of the soliton solution of the continuum dark nlse soliton @xcite-@xcite , @xmath100 here the various parameters each have a natural interpretations , see @xcite-@xcite for a detailed description : the parameter @xmath101 determines the backbone site location of the center of the fundamental loop that is described by the soliton . the values of the parameters @xmath102 \ mod(2\pi)$ ] are entirely determined by the bond angles of the adjacent helices and strands . finally , _ only _ the @xmath103 and @xmath104 are intrinsically loop specific parameters , they specify the length of the loop . the soliton profile of @xmath98 determines the torsion angles @xmath97 by ( [ taueq ] ) . according to @xcite practically all pdb proteins can be constructed as the sum of terms of the form ( [ bonds ] ) , in a modular fashion from a relatively small number of soliton profiles . following @xcite we argue that in the frenet frames , the angular positions of the side - chain atoms can be similarly determined in terms of the corresponding @xmath98 values only . for this we denote by ( @xmath105 ) the standard spherical latitude and longitude angles of the sphere that surrounds the c@xmath6 observer . we propose that to leading order in the expansion ( [ grad ] ) , in these coordinates each of the side - chain atoms has an energy function that has the same functional form as the energy function of the backbone torsion angles . consequently , for each side - chain atom we introduce only the following two leading contributions to the energy @xmath106 @xmath107 note that these contributions have been _ carefully selected _ so that they will _ not _ change the functional form of([e1 ] ) . the addition of ( [ e2a ] ) , ( [ e2b ] ) will only redefine the coefficients in the @xmath98 dependent terms in ( [ e1 ] ) which does not lead to any change in the underlying soliton structure . in particular , we can still utilize the approximative soliton profile ( [ bonds ] ) . in parallel with ( [ taueq ] ) the spherical angles ( @xmath108 ) for each of the side - chain atoms are then dynamically determined by the dnls soliton profile of the backbone bond angles @xmath98 , @xmath109 @xmath110 the present visual analysis implies that in the case of a @xmath7-@xmath0 residue the numerical values of both ( @xmath111 ) and ( @xmath112 ) are vanishingly small for the c@xmath9 , c@xmath75 and c@xmath113 carbons , and for the side - chain @xmath10 and @xmath72 atoms in the case of asn and asp . but both ( @xmath114 ) and ( @xmath115 ) have amino acid independent , finite and _ universal _ values that can be directly inferred from the figure 2 ( middle ) , 4 , 7 and 8 respectively , @xmath116 @xmath117 we now proceed to argue that these universal values can be understood in terms of relatively few dnls solitons . we then show how these solitons can be classified using our graphical tools . it has been argued in the literature that in the case of asn and asp the @xmath7-@xmath0 ramachandran region become stabilized by a local but non - covalent attractive interaction between the side - chain and backbone carbonyls , with the backbone oxygen atom in a special rle @xcite , @xcite . unlike the ramachandran plot , our frenet framing can provide information on the neighboring peptide units and we have investigated the directions of all backbone @xmath72 atoms in our data set , in a group of residues around the @xmath19 side - chain @xmath3 that is located in the @xmath7-@xmath0 island . the result shown in figure 10 displays how these @xmath72 atoms are seen by our frenet frame observer who is located at the @xmath19 central @xmath2 carbon . our observer finds that the directions of the nearby backbone @xmath72 atoms are very srongly localized and correlated . the localization is residue _ independent _ and extends itself over at least four different residues : @xmath118 for the @xmath119 site there is strong localization with a three - fold degeneracy that is reminiscent of the _ trans / gauche _ ( sp3 hybridization ) degeneracy . the data is consistent with vanishing values of both ( @xmath111 ) and ( @xmath112 ) . @xmath118 for the site @xmath120 we have very strong localization along the longitudinal ( @xmath121 ) direction , with a tiny oscillation in the latitudinal ( @xmath122 ) direction . for the corresponding energy , ( @xmath112 ) are again vanishingly small while ( @xmath111 ) are now small but non - vanishing . @xmath118 for the site @xmath34 we have a single localized oscillator in the longitudinal direction . thus ( @xmath112 ) are now small but non - vanishing while ( @xmath111 ) vanish . @xmath118 for the site @xmath123 we again find the three - fold _ trans / gauche _ degeneracy : there are three oscillators in the longitudinal direction , and they are all located very close to the north - pole . consequently ( @xmath111 ) vanish while ( @xmath112 ) do not . in fact , the @xmath124 amplitudes are quite large . the localization pattern of the backbone @xmath72 atoms means that for our frenet frame observer the backbone geometry around a @xmath7-@xmath0 residue shows very little variations . only a very limited set of extended backbone geometries are accessible . since the regime that covers the sites from the @xmath125 to the @xmath20 involves four sets of bond and torsion angles , each of them defined in terms of three _ resp . _ four residues we conclude that the geometries reflect the non - local collective interplay of _ at least up to seven _ different residue sites along the backbone . this is in line with our proposal that the positions of the side - chain atoms are determined dynamically by the backbone , in terms of a small number of different dnls soliton profiles according to ( [ e2a ] ) , ( [ e2b ] ) . to expose the soliton structures that surround the @xmath7-@xmath0 island , we consider the distribution of the backbone bond and torsion angles that are attached to those @xmath2 carbons where the @xmath3 atom is in the @xmath7-@xmath0 position . the result is shown in figure 11 on a stereographically projected two - sphere , separately for asn and asp and for the remaining non - glycyl amino acids . we observe no practical difference between the residues . nor do we find any practical difference between the various _ trans _ and @xmath65- positions . instead , we do observe the following general pattern : for the backbone @xmath2-@xmath2 link that precedes the @xmath7-@xmath0 island , three different regions on the @xmath48 plane are probable . these are the regions that we have denoted with * a * , * b * and * c * respectively in the figure 12 ( top ) ; in this figure we have combined all the data that are displayed separately in the parts * a , b , c * and * d * of figure 11 . after the @xmath7-@xmath0 island there are also three different regions that are probable . we denote these regions with letters * b * and * d * and * e * respectively in the figure 12 ( bottom ) , now combining the data in parts * e , f , g , h * in figure 11 . note that the regions * b * in the two parts of figure 12 practically overlap . by inspecting the protein structures in our data set we conclude that the presence of a residue in the @xmath7-@xmath0 island causes the following phenomenological _ selection rules _ between the regions displayed in figure 12 . when we roller - coast along the backbone : 0.4 cm @xmath118 the region * a * can only precede regions * d * and * e*. @xmath118 both regions * b * and * c * can be followed by any of the three regions * b * , * d * and * e*. @xmath118 the residue preceding either * a * or * c * is not located in the @xmath7-@xmath0 island . @xmath118 both the residue preceding and following * b * can be located in the @xmath7-@xmath0 island . @xmath118 if the two residues following * c * are both in the @xmath7-@xmath0 island , the first residue connects * c * to * b * and the second connects * b * to * b*. 0.4 cm these are the selection rules , that limit the available global topology of the backbone solitons when we pass the @xmath7-@xmath0 site . notice that since the region * b * has the same bond angle as the standard @xmath0-helix region and since the torsion angles are equal in magnitude but have an opposite sign , a repeated structure in * b * is the right - handed mirror image of the standard @xmath0-helix . consequently this is truly the region of _ left - handed @xmath0-helices_. these selection rules classify the different possible dnls soliton profiles in the presence of the @xmath7-@xmath0 island . in particular , we have found that there seems to be no more than four solitons that are particularly common around a residue with @xmath3 located in the @xmath7-@xmath0 island . we now describe these solitons qualitatively using our visual tools , as transition trajectories between the different regions that appear in the maps of figure 1 . these transitions illustrate how our observer turns at the location of each @xmath2 as she roller - coasts through the soliton . the results are shown in figure 13 . in each case the pink arrow corresponds to a site where @xmath3 is located in the @xmath7-@xmath0 island ; recall that the bond and torsion angles are link variables , they connect two @xmath2 carbons according to ( [ dfe ] ) . clearly , the figure 13 is but an example of a general method to visually classify solitons in a manner that directly reflects the geometry of the underlying backbone . @xmath118 in figure 13a , the first residue takes our observer away from an @xmath0-helix region to the region * a * in the figure 12 left ( black arrow ) . this is followed by a residue in the @xmath7-@xmath0 island , that takes the observer to the region * d * in the figure 12 right ( pink arrow ) . finally , there is a transition to the @xmath1-strand region ( black arrow ) . consequently this is a short soliton that takes us from the ground state which is an @xmath0-helix to the other ground state which is a @xmath1-strand . @xmath118 the second soliton trajectory shown in figure 13b starts from the @xmath1-strand region with a residue that takes the observer into region * c * in figure 12 left . the following residue that is located in the @xmath7-@xmath0 island then causes a transition into region * d * in figure 12 right ( pink arrow ) . this is followed by a transition back to a @xmath1-strand region . since the initial and final positions are in a @xmath1-strand , this is an example of a soliton that combines the @xmath1-strand with another @xmath1-strand . @xmath118 the third trajectory that we have described in figure 13c starts from the @xmath1-strand region and proceeds to region * c * in figure 12 left . from there the trajectory proceeds to region * b * in figure 12 left , with the transition caused by a residue in the @xmath7-@xmath0 island . this is followed by a transition to region * d * and then back to the @xmath1-strand region . this trajectory is also an example of a soliton that combines the @xmath1-strand with another @xmath1-strand . @xmath118 finally , the fourth trajectory that is also common in our data set is the one displayed in figure 13d . it is similar with the trajectory described in figure 13c , except that now the residue that is located in @xmath7-@xmath0 island causes the transition from * b * to * d * in figure 12 . this trajectory is also an example of a soliton that combines the @xmath1-strand with another @xmath1-strand . the remarkable property of solitons c ) and d ) in figure 13 is , that they have similar overall topology and differ from each other only by the location of the @xmath7-@xmath0 along the trajectory . it is quite plausible that in some proteins these two solitons are but two states of an oscillating discrete `` breather '' soliton . the ensuing proteins are presumable unstructured . finally , for the purposes of soliton taxonomy we note that when we analyze the proteins in the version v3.3 library of chopped pdb files for representative cath domains we find that the propensity of our solitons is largest in the ( mainly-@xmath1 ) ca level classes 2.90 , 2.160 where over 5@xmath40 of all residues are in the @xmath7-@xmath0 island . we also find that any ca level family has at least 1@xmath40 of their residues in the island , except 1.40 where the single representative with pdb code 1ppr has no residues in the island . we have developed a new visualization method of proteins . in the case of backbones our method provides information about the geometry of neighboring peptide units . this enables us to go beyond the regime of the canonical ramachandran plot which does not contain information on the neighboring units . as an example of side chains , we have visually investigated the non - glycyl residues that are located in the @xmath7-@xmath0 region of the ramachandran plot . _ independently _ of the amino acid , we find that for a discrete frenet frame observer who roller - coasts along the backbone @xmath2 carbons the corresponding side - chain @xmath3 carbons are always localized in the same direction which is clearly different from the direction of the @xmath3 carbons in the right - handed region . this universality in the orientation persists when we investigate the @xmath4 and @xmath5 carbons , and the side chain @xmath72 and @xmath10 atom in the case of asn and asp . the results suggest that instead of reflecting _ only _ a local interaction between a given backbone unit and its residue , the @xmath7-@xmath0 island is also associated with a largely residue independent backbone conformation . when we proceed to analyze the distribution of those backbone bond and torsion angles that are associated with the links that both precede and follow a residue that is located in the @xmath7-@xmath0 island , we find that independently of the residue these angles display very similar patterns . since the definition of a bond angle takes three @xmath2 carbons and the definition of a torsion angle takes four , this prompts us to propose that the geometrical structure associated with the presence of a residue in the @xmath7-@xmath0 island is a soliton that reflects the interplay of at least seven consecutive backbone units . in particular , we have not been able to pin - point any obvious local reason ( charged , polar , acidic , hydrophobic / philic ) to explain the presence or absence of a residue on the @xmath7-@xmath0 region . our approach is based on a novel visualization method to depict proteins . this method is based on advances in three dimensional visualization techniques that have been developed after ramachandran presented his plot . in the course of our analysis we have been able to observe several systematic patterns including potential anomalies in the pdb data . the visualization method we have developed shows promise to become a valuable tool for both experimental and theoretical protein structure analysis and fold description , in particular for visually describing and classifying the backbone solitons and as a complement to existing side - chain rotamer libraries . 0.5 cm we thank s. hu and j. aqvist for discussions .

folded proteins have a modular assembly . they are constructed from regular secondary structures like @xmath0-helices and @xmath1-strands that are joined together by loops . here we develop a visualization technique that is adapted to describe this modular structure . in complement to the widely employed ramachandran plot that is based on toroidal geometry , our approach utilizes the geometry of a two - sphere . unlike the more conventional approaches that only describe a given peptide unit , ours is capable of describing the entire backbone environment including the neighboring peptide units . it maps the positions of each atom to the surface of the two - sphere exactly how these atoms are seen by an observer who is located at the position of the central @xmath2 atom . at each level of side - chain atoms we observe a strong correlation between the positioning of the atom and the underlying local secondary structure with very little if any variation between the different amino acids . as a concrete example we analyze the left - handed helix region of non - glycyl amino acids . this region corresponds to an isolated and highly localized residue independent sector in the direction of the @xmath3 carbons on the two - sphere . we show that the residue independent localization extends to @xmath4 and @xmath5 carbons , and to side - chain oxygen and nitrogen atoms in the case of asparagine and aspartic acid . when we extend the analysis to the side - chain atoms of the neighboring residues , we observe that left - handed @xmath1-turns display a regular and largely amino acid independent structure that can extend to seven consecutive residues . this collective pattern is due to the presence of a backbone soliton . we show how one can use our visualization techniques to analyze and classify the different solitons in terms of selection rules that we describe in detail .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Textiles and Apparel China Safeguard Act''. SEC. 2. FINDINGS. The Congress finds the following: (1) Since January 1, 2001, the United States textiles and apparel industries have lost 345,000 jobs. (2) Under the terms of the Agreement on Textiles and Clothing of the World Trade Organization, on January 1, 2005, the United States will be required to eliminate all quotas on textiles and apparel products maintained against other World Trade Organization members, including the People's Republic of China. (3) Job losses are expected to continue, and to accelerate after the elimination of United States quotas, with at least one study estimating that an additional 630,000 United States jobs in the textiles and apparel sector will be lost by the end of 2006. (4) Many analysts believe that the People's Republic of China's dominance of the United States textiles and apparel market will grow after the elimination of quotas, with some studies indicating that imports from the People's Republic of China will account for more than two-thirds of total United States consumption by 2006. (5) President Clinton negotiated the right to use a special textiles and apparel safeguard as an integral part of the agreement allowing the People's Republic of China to join the World Trade Organization. The safeguard allows the United States to impose quotas on exports to the United States of textiles and apparel products of the People's Republic of China if such exports result in or threaten disruption of the United States market. (6) The current Administration delayed in applying the special textiles and apparel safeguard by failing to implement it for 17 months after the accession to the World Trade Organization of the People's Republic of China. During this delay, exports to the United States of textiles and apparel products of the People's Republic of China increased substantially, while significant numbers of United States textiles and apparel workers lost their jobs. (7) When the executive branch finally issued procedures to implement the safeguard on May 21, 2003, those procedures severely restricted the ability of the United States textiles and apparel industries and their workers to employ the safeguard in ways not required by the Accession Agreement of the People's Republic of China to the World Trade Organization. (8) To date, the executive branch has refused to self- initiate a case under the special textiles and apparel safeguard, notwithstanding the significant increase in exports to the United States of textiles and apparel products of the People's Republic of China and concurrent job losses in the United States in the textiles and apparel industries. (9) Large bipartisan groups of Members of the House of Representatives and Senate urged the President to support a special session of the World Trade Organization to discuss the impact that expiration of textiles and apparel quotas will have on trade and employment in this sector throughout the world. (10) Despite studies showing major employment loss in the United States and disruptions in trade throughout the world, the President did not support such a special session at the World Trade Organization and has not created a comprehensive plan to address the expiration of the quota regime. (11) As part of the Doha Round negotiations of the World Trade Organization, the President has proposed to eliminate textiles and apparel tariffs. SEC. 3. MODIFICATION OF REGULATIONS. The President shall, upon the enactment of this Act, modify the procedures for considering requests from the public for safeguard actions on imports of textiles and apparel products of the People's Republic of China, as published in the Federal Register on May 21, 2003, so that import relief will be provided, in accordance with the Accession Agreement of the People's Republic of China to the World Trade Organization, if a claim is supported by data showing that imports of textiles or apparel products of Chinese origin are, due either to market disruption, or to the threat of market disruption, threatening to impede the orderly development of trade in such products, including products not produced in the United States if such products include components of United States origin. SEC. 4. COMPREHENSIVE AGREEMENT ON TEXTILES AND APPAREL PRODUCTS. The President shall, upon the enactment of this Act, initiate consultations with the People's Republic of China for the purpose of reaching an agreement with that country on the application of quantitative limitations on imports into the United States of all textiles and apparel products that-- (1) are products of the People's Republic of China; (2) as of September 1, 2004, are subject to quotas under the Agreement on Textiles and Clothing of the World Trade Organization; and (3) meet the requirements for applying safeguards on such imports, as modified under section 3. SEC. 5. IMPOSITION OF QUANTITATIVE LIMITATIONS. If, within 90 days after consultations under section 4 are initiated, an agreement described in section 4 is not reached, the President shall impose the quantitative limitations provided for in the Accession Agreement referred to in section 3 on imports of all textiles and apparel products that were the subject of the consultations.

Textiles and Apparel China Safeguard Act - Requires the President to modify the procedures for considering requests from the public for safeguard actions on imports of textiles and apparel products of the People's Republic of China (PRC), as published in the Federal Register on May 21, 2003, so that import relief will be provided, in accordance with the Accession Agreement of the PRC to the World Trade Organization (WTO), if a claim is supported by data showing that imports of textiles or apparel products of Chinese origin are threatening to impede the orderly development of trade in such products, including products not produced in the United States if such products include components of U.S. origin. Requires the President to: (1) initiate consultations with the PRC to reach an agreement on the application of quantitative limitations on U.S. imports of all PRC textiles and apparel products that are subject, as of September 1, 2004, to quotas under the Agreement on Textiles and Clothing of the WTO, and meet the requirements for applying safeguards on such imports; and (3) impose the quantitative limitations on such textiles and apparel products provided for in the Accession Agreement if, after consultations are inititated, an agreement is not reached.

improving end - of - life care in the critical care setting has justifiably become an increasing priority . in patients with severe neurological impairment due to stroke , head trauma , hypoxic ischemic brain injury after cardiac arrest , and other conditions , decisions to limit or withdraw care are often made based on perception of a poor prognosis for functional outcome . the decision to limit care , however , the possibilities that prognostic inaccuracy early after stroke and head trauma might lead to decisions to limit care and that these care limitations might create ' self - fulfilling prophecies ' of poor outcome in individual patients have been considered . is it also possible that a hospital milieu in which care limitation is commonly sought might also influence overall aggressiveness of care for other patients as well ? the 1983 us president 's commission on deciding to forgo life - sustaining treatment stated ' any dnr policy should ensure that the order not to resuscitate has no implications for any other treatment decisions . ' even so , do - not - resuscitate ( dnr ) orders are often the first step in a continuum of limitations of care , especially in acutely hospitalized patients . furthermore , the effect of dnr orders is frequently manifested by physicians being more likely to withhold other therapeutic interventions , and even being less likely to institute them in the first place . considerable variability has also been documented in the use of dnr orders , which raises the concern that variability in decision - making regarding dnr orders might reflect larger variability in aggressiveness of care that could influence patient outcome irrespective of code status . we sought to begin to address this question using spontaneous intracerebral hemorrhage ( ich ) as a case example . ich accounts for about 15% of all stroke . with a 30-day mortality rate of about 40% and only about 20% of survivors independent at a year , ich prognosis is often poor although prognosis is dependent on a variety of factors such as the glasgow coma scale score on admission , hemorrhage location and size , concurrent intraventricular hemorrhage and hydrocephalus , and patient age . as of writing the present article , ich is also without an approved treatment of proven benefit in reducing mortality and morbidity . this has led to great heterogeneity in ich care , with approaches ranging from the very aggressive to the nihilistic . we hypothesized that the rate at which a hospital uses dnr orders within the first 24 hours after ich influences patient outcome irrespective of other hospital and patient characteristics . early dnr orders were chosen because this means that one of the very first medical decisions made for an ich patient was to limit care in some manner . from a california - wide hospital discharge database , interestingly , the rate at which a hospital used dnr orders for ich patients within the first 24 hours independently increased the odds of individual patient death , even after adjusting for numerous patient characteristics ( age , race , gender , insurance status , medical comorbidities , mechanical ventilation as a surrogate for coma ) and hospital characteristics ( number of ich patients treated , trauma center or rural hospital , teaching hospital , rate of craniotomy for ich ) . even more importantly , there was an interaction between an individual patient 's dnr status and the hospital dnr rate ( adjusted for case mix ) . this means that it not only mattered whether a patient was dnr ( within 24 hours of admission ) , but it mattered in which hospital that patient was of dnr status . patients with the same dnr status were treated differently in different hospitals , even accounting for other patient and hospital characteristics , and this influenced their outcome . interestingly , the group of hospitals with the highest early dnr rate ( adjusted for case mix ) had lower rates of intubation and mechanical ventilation , craniotomy , ventriculostomy , and cerebral angiography for ich patients . what this means is that there is something in the way overall care is delivered in these ' high - dnr ' hospitals that is increasing the risk of death in individual patients treated at those hospitals , irrespective of code status . the early dnr rate of the hospital ( case mix adjusted ) is acting as a proxy for overall aggressiveness of care . even in the absence of a proven treatment for ich , it is possible that the physicians in high - dnr hospitals are vastly superior at predicting long - term functional outcome within 24 hours of acute stroke than physicians at low - dnr hospitals , thereby sparing patients destined to have a poor functional outcome by allowing them to die during hospitalization . more probably , this represents an overall nihilistic approach that extends to most or perhaps all ich patients within a specific institution , probably based on the fallibility of attempting to prognosticate too early and too precisely . the ripple effect of an approach that emphasizes early care limitation leads to an overall milieu of nihilism that , perhaps unexpectedly , may influence attitudes of care for patients beyond those with the dnr orders themselves . so what are we to do ? just instituting a policy prohibiting dnr orders within 24 hours of hospital admission is not the answer . it is not the dnr orders themselves , but it is the care environment that emphasizes high use of early care limitations in patients that are critically ill . this is actually not surprising given that the same physicians and nurses instituting early dnr orders in one patient may be responsible for determining the need for aggressive care in others . whether these findings extend to other neurological conditions such as traumatic brain injury or non - neurocritical care is not known . as we increase our emphasis in critical care on end - of - life issues and compassionate palliative care , it is essential not to lose sight of several important principles . precise prognostication in individual patients remains challenging , especially early after neurological catastrophes such as ich . an overly nihilistic approach may influence global care , potentially leading to a ripple effect beyond an individual patient . part of the art of critical care medicine is balancing aggressive care with realistic expectations and avoiding self - fulfilling prophecies of poor outcome . this article is part of a thematic series on end of life decision making , edited by david crippen .

do - not - resuscitate ( dnr ) orders are commonly implemented in the critical care setting as a prelude to end - of - life care . this is often based on presumed prognosis for favorable outcome and interpretation of patient , family , and even physician wishes . while dnr orders explicitly apply only to an individual patient , the hospital culture and milieu in which dnr orders are implemented could potentially have an overall impact on aggressiveness of care across patients . as illustrated by the example of intracerebral hemorrhage , this may unexpectedly influence outcome even in patients without dnr orders in place .

recent advances in nanoscience and nanotechnology offer opportunities for the development of innovative and promising applications in fields ranging from electronics to the food industry and medicine . expectations for nanomedicine applications are high , and research targeting numerous applications for nanocarriers , such as medical imaging and diagnostics , tissue engineering , and targeted drug delivery , is well under way.1 as of 2006 , most research activity and marketing in nanomedicine were related to targeted drug delivery using nanocarriers , with 18 us food and drug administration - approved products and 88 new products at clinical - study stage.2 although advances in the development of nanocarriers encourage high hopes,3 uncertainty surrounds nanocarriers use . toxicity and long - term adverse effects are causes for concern among scientists , clinicians , and stakeholders.4 nanocarriers potential use also raises ethical , environmental , economic , legal , and social ( els ) issues that are often overlooked.5 failure to consider els issues can compromise the acceptance and acceptability encountered by new technologies . for example , in europe and north america , the rejection of genetically modified ( gm ) foods and past and current public sentiment against transgenesis clearly indicate the existence of public apprehensions that had been hard to anticipate.6 rejections like these reflect the inadequacies of traditional methods for risk assessment and for research on the public s acceptance and perceptions in relation to emerging technologies . anchored in a behaviorist paradigm targeting qualitative factors such as voluntariness of exposure and controllability in predicting and explaining the use of a technology,79 these approaches have typically used perceived risk where risk refers to the danger of death or injury and acceptance as the main outcomes of analysis . to take the example of gm foods , while deemed safe by governing bodies , they have been perceived as risky by the general public , a situation that has generated social tension.10 but in addition to harboring toxicological and environmental concerns about genetically modified organisms ( gmos ) , members of the public have also raised more metaphysical questions : the need for gmos creation , the legitimacy of their creation , and the nature of trends implicit in technological development all considerations that exceed the limitations of traditional approaches to assessment.11 in this light , it has become clear that there is a need to develop a fresh approach to impact perception , acceptance , and acceptability in relation to new technologies . building on the case of gm foods , what can we expect when it comes to nanomedicine applications such as the use of drug - delivery nanocarriers ? empirical studies have been published on the public s impact perception , acceptance , and acceptability judgments regarding nanotechnologies.1216 one finding emerging from research with respondents having little familiarity with these technologies is that the attitude of uninformed members of the public is significantly influenced by their affective and emotional responses.16 existing associations with more familiar technologies , functioning as cognitive shortcuts and often fed by information conveyed by the mass media , can also influence perceptions of nanotechnologies risks and benefits.12 individual values influence the perception of nanotechnologies more heavily when respondents are more familiar with the technologies.16 generally , members of the public display a high degree of enthusiasm about nanotechnologies positive impacts and a low degree of concern about negative impacts,15 which they deem less prevalent than the benefits ; thus , the public is more hopeful than anxious on this subject.14 it is important , however , to nuance this generalization with a cultural perspective : the american public tends to be enthusiastic about nanotechnologies , while the european community tends to adopt a more pragmatic attitude.13 few studies , however , have examined responses to nanomedicine applications as part of health care delivery.1719 a study on perceptions of nanotechnologies and nanomedicine as displayed in social media revealed that nanomedicine is expected by most users to have an economic impact and that nearly 50% of users consider theranostics to be the optimal nanomedicine application.19 it has also been found that a medication s frequency of administration can have a greater impact on attitude toward a treatment than whether a treatment is of a nano - nature.17 at the same time , it has been shown that when four scenarios were presented , the scenario involving conventional treatment repeatedly administered and the scenario involving a nanotreatment administered just once were more negatively perceived . that is , the adverse effects of conventional treatment are deemed to be important in long - term use , whereas the positive effects of a nanotreatment are deemed to override adverse effects in long - term use . as with nanotechnologies in general , nanomedicine technologies appear to be associated with public optimism tinged with concerns relating not just to health but also to impacts on the environment and on social considerations.18 a big picture has emerged for impact perception and acceptance in relation to nanomedicine , but the lack of data on the acceptability of specific applications raises important questions about developments in this field . will these technologies and their applications conform to individual and societal values?3 how will nanomedicine applications be accepted by the general public , and will patients understand the issues surrounding nanomedicine?20 an understanding of lay opinion is essential to ensure the success of any new technology.21 furthermore , advocacy for or against the use of nanotechnologies often comes from researchers involved in the development of new technologies . the process of conveying scientific knowledge and opinion to the public is complex.22 across numerous fields of study , these opinions can shape lay perception.2325 the relationship between public and expert opinion makes it important to investigate researchers perceptions and acceptability judgments in the field of new technologies . work on experts views about societal responses , risk perception , and acceptance of nanotechnologies2629 reveals diverse points of view on the risks and benefits of the outcomes of research in nanotechnology . confidence in government agencies also seems to be a significant predictor of risk perceptions about nanotechnology applications.27 while the environment and health concerns are the issues most often raised as potentially susceptible to the greatest negative impact and as requiring more stringent government regulation , researchers in nanotechnology are also currently raising concerns about social risks.28 the nature of applications also appears to influence researchers expectations around impact perceptions and social acceptance.26 nevertheless , major variations in assessment frameworks and risk perceptions have been reported among researchers from different settings , the likelihood being that researchers are influenced by differing disciplinary backgrounds29 and diverse epistemologies.30 some work done on nanomedicine as seen through the prism of experts perceptions of ethical issues31 suggests that nanomedicine practitioners are interested in reflecting on ethical issues in their work but overall do not consider ethical issues associated with nanomedicine to be new issues.31 no studies so far have directly reported on researchers perceptions , acceptance , and acceptability judgments in relation to specific applications in nanomedicine . the objectives of the study reported on here were to examine , among researchers active in the field of new technologies , impact perception , acceptance , and acceptability judgments regarding two kinds of drug - delivery nanocarriers ( one made of carbon , the other of synthetic dna ) in two different contexts of use ( treatment of lung cancer , treatment of seasonal flu ) , and to explore the relationships between impact perception , acceptance , and acceptability judgments . given the emergent nature of the area of research and the research questions to be answered , an exploratory design with sequential data triangulation was preferred.32 a mixed - methods approach ( quantitative qualitative ) allowed for the initial collection of quantitative data from responses to a web - based questionnaire with the aim of studying the following : impact perception , acceptance , and acceptability judgments ; the relationships among these variables ; and the influence of respondents profiles on the variables . then , to complement the information regarding the initial research objectives and deepen the exploration of the concept of acceptability , preliminary conclusions about the quantitative data were used in developing an interview guide focused mainly on acceptability . in this paper , only the project s quantitative phase will be addressed . impact perception , acceptance , and acceptability are key concepts in the study of new technologies and their applications , for example , targeted drug delivery in nanomedicine . in our study , these concepts were operationalized from an applied ethics perspective and within a conceptual framework developed by an interdisciplinary research group ( internels),11 took the form of a web - based questionnaire on two scenarios for the use of nanocarriers . briefly , the framework defines impact perception ( where an impact is defined as a positive or negative consequence resulting from the development or use of a new technology ) , acceptance , and acceptability ( table 1 provides the conceptual definitions ) . the framework is based on the premise that a decision about acceptance and acceptability rests not only on risks to be avoided but also on a weighting of the negative and positive impacts for certain social issues . acceptance and acceptability can be weighted from an individual perspective ( personal intention of use and individual justification ) or a social perspective ( level of development of a technology desirable for society , justification ) . the web - based questionnaire was introduced by a short video describing nanotechnologies , nanomedicine , and targeted drug - delivery treatments . an informational section also presented two kinds of drug - delivery nanocarriers ( one composed of carbon , the other of synthetic dna ) in two different contexts of use ( lung cancer treatment , seasonal flu treatment ) . the questionnaire proposed closed - ended questions based on the operationalization of the core concepts for each scenario presented ( questionnaire is given in figure s1 ) . questions about impact perception and acceptability were based on a list of positive and negative impacts of the treatments , presented as better chances of a cure and fewer adverse effects , cell toxicity , greater environmental friendliness , environmental toxicity , decreased costs to the health care system in the long run , and unequal patient access to treatments ( table 2 provides a complete description ) . data reduction of responses to these questions yielded scores on five variables : perception index ( pi ) , individual acceptability index ( indai ) , social acceptability index ( socai ) , individual issue of preponderant concern ( indpissue ) , and social issue of preponderant concern ( socpissue ) . the section on acceptability included a subquestion about the treatments individual and social perceived usefulness ( useful / ind , useful / soc ) , a core concept of the technology assessment model33 that was revealed as important to include by the pretest phase of the questionnaire ( described in the results section ) . questions about individual acceptance ( indatce ) were based on a four - point likert scale , with respondents being asked to indicate whether or not they would use the nanocarriers presented ( carbon composition , synthetic dna composition ) in each context of use ( to treat lung cancer , to treat seasonal flu ) . questions were formulated to measure social acceptance ( socatce ) by asking whether or not respondents deemed it desirable to have widespread use of the two kinds of nanocarriers in the two clinical contexts of use . see table 1 for details of conceptual and operational definitions and data reduction . prior to the posting of the questionnaire online , an iterative pretest using a cognitive interviewing approach34 was conducted to check instructions , key concepts , the presentation of the two kinds of nanocarriers , questions and response options , and the adequacy of response options , as well as to optimize comprehension . three rounds of interviews were conducted with individuals representing the targeted participants ( first round , n=8 participants ; second round , n=17 participants ; third round , n=10 participants ) . changes were made between rounds and validated in the next round until a final version was established for implementation online . in the last round , in order to test the design and improve user experience , usability tests were conducted on the questionnaire assessing completion time , ease of administration , and visual considerations . mean respondent completion times for every section and for the questionnaire as a whole during the last round were used as standard times to establish quality cutoffs . time stamps for login and completion of the questionnaire were automatically collected for every participant . the study was approved by a research ethics board of the centre hospitalier universitaire de sherbrooke . participation in the study was anonymous ( no personal identifiers ) and by invitation only . researchers were identified as potential participants after an exhaustive literature review of numerous databases using combinations of keywords such as nanotechnology , nanomedicine , ethics , social sciences , and new technologies . a language limitation restricted the geographical areas of recruitment to french - speaking regions of europe and canada . the electronic addresses of corresponding authors were recorded in a private database ; other authors addresses were found online on the institutional or personal websites of the identified researchers . french and canadian thematic research groups involved in research in nanotechnology and nanomedicine were also targeted for recruitment using institutions such as nels network on nanotechnology35 ( canada ) and pacte social science research laboratory36 ( france ) . in total , a list of 1,527 potential participants , including graduate research trainees , was established ; for 207 , addresses were no longer valid . an email invitation to participate , containing a link to the web - based questionnaire , was sent out in september 2013 to 1,320 potential participants . following initial contact , a first reminder was sent in october 2013 and a final reminder in december 2013 . data from respondents who did not meet the minimum completion quality outcome , defined a priori ( all questions completed , questionnaire completed in more than 11 minutes ) , were also excluded from the analyses . the influence of nanocarrier composition on variables related to impact perception , acceptance , and acceptability and the influence of context of use on acceptance and acceptability were assessed using the wilcoxon signed - rank test , mcnemar s test , the mcnemar bowker test , and the pearson test . a multiple correspondence analysis ( mca ) logistic and ordinal regression models were calculated to assess the predictive values of core variables in relation to each other . analyses were carried out using spss statistics ( v20 ) ( ibm corporation , armonk , ny , usa ) . given the emergent nature of the area of research and the research questions to be answered , an exploratory design with sequential data triangulation was preferred.32 a mixed - methods approach ( quantitative qualitative ) allowed for the initial collection of quantitative data from responses to a web - based questionnaire with the aim of studying the following : impact perception , acceptance , and acceptability judgments ; the relationships among these variables ; and the influence of respondents profiles on the variables . then , to complement the information regarding the initial research objectives and deepen the exploration of the concept of acceptability , preliminary conclusions about the quantitative data were used in developing an interview guide focused mainly on acceptability . in this paper , only the project s quantitative phase will be addressed . impact perception , acceptance , and acceptability are key concepts in the study of new technologies and their applications , for example , targeted drug delivery in nanomedicine . in our study , these concepts were operationalized from an applied ethics perspective and within a conceptual framework developed by an interdisciplinary research group ( internels),11 took the form of a web - based questionnaire on two scenarios for the use of nanocarriers . briefly , the framework defines impact perception ( where an impact is defined as a positive or negative consequence resulting from the development or use of a new technology ) , acceptance , and acceptability ( table 1 provides the conceptual definitions ) . the framework is based on the premise that a decision about acceptance and acceptability rests not only on risks to be avoided but also on a weighting of the negative and positive impacts for certain social issues . acceptance and acceptability can be weighted from an individual perspective ( personal intention of use and individual justification ) or a social perspective ( level of development of a technology desirable for society , justification ) . the web - based questionnaire was introduced by a short video describing nanotechnologies , nanomedicine , and targeted drug - delivery treatments . an informational section also presented two kinds of drug - delivery nanocarriers ( one composed of carbon , the other of synthetic dna ) in two different contexts of use ( lung cancer treatment , seasonal flu treatment ) . the questionnaire proposed closed - ended questions based on the operationalization of the core concepts for each scenario presented ( questionnaire is given in figure s1 ) . questions about impact perception and acceptability were based on a list of positive and negative impacts of the treatments , presented as better chances of a cure and fewer adverse effects , cell toxicity , greater environmental friendliness , environmental toxicity , decreased costs to the health care system in the long run , and unequal patient access to treatments ( table 2 provides a complete description ) . data reduction of responses to these questions yielded scores on five variables : perception index ( pi ) , individual acceptability index ( indai ) , social acceptability index ( socai ) , individual issue of preponderant concern ( indpissue ) , and social issue of preponderant concern ( socpissue ) . the section on acceptability included a subquestion about the treatments individual and social perceived usefulness ( useful / ind , useful / soc ) , a core concept of the technology assessment model33 that was revealed as important to include by the pretest phase of the questionnaire ( described in the results section ) . questions about individual acceptance ( indatce ) were based on a four - point likert scale , with respondents being asked to indicate whether or not they would use the nanocarriers presented ( carbon composition , synthetic dna composition ) in each context of use ( to treat lung cancer , to treat seasonal flu ) . questions were formulated to measure social acceptance ( socatce ) by asking whether or not respondents deemed it desirable to have widespread use of the two kinds of nanocarriers in the two clinical contexts of use . see table 1 for details of conceptual and operational definitions and data reduction . prior to the posting of the questionnaire online , an iterative pretest using a cognitive interviewing approach34 was conducted to check instructions , key concepts , the presentation of the two kinds of nanocarriers , questions and response options , and the adequacy of response options , as well as to optimize comprehension . three rounds of interviews were conducted with individuals representing the targeted participants ( first round , n=8 participants ; second round , n=17 participants ; third round , n=10 participants ) . after answering the questionnaire , changes were made between rounds and validated in the next round until a final version was established for implementation online . in the last round , in order to test the design and improve user experience , usability tests were conducted on the questionnaire assessing completion time , ease of administration , and visual considerations . mean respondent completion times for every section and for the questionnaire as a whole during the last round were used as standard times to establish quality cutoffs . time stamps for login and completion of the questionnaire were automatically collected for every participant . the study was approved by a research ethics board of the centre hospitalier universitaire de sherbrooke . participation in the study was anonymous ( no personal identifiers ) and by invitation only . researchers were identified as potential participants after an exhaustive literature review of numerous databases using combinations of keywords such as nanotechnology , nanomedicine , ethics , social sciences , and new technologies . a language limitation restricted the geographical areas of recruitment to french - speaking regions of europe and canada . the electronic addresses of corresponding authors were recorded in a private database ; other authors addresses were found online on the institutional or personal websites of the identified researchers . french and canadian thematic research groups involved in research in nanotechnology and nanomedicine were also targeted for recruitment using institutions such as nels network on nanotechnology35 ( canada ) and pacte social science research laboratory36 ( france ) . in total , a list of 1,527 potential participants , including graduate research trainees , was established ; for 207 , addresses were no longer valid . an email invitation to participate , containing a link to the web - based questionnaire , was sent out in september 2013 to 1,320 potential participants . following initial contact , a first reminder was sent in october 2013 and a final reminder in december 2013 . data from respondents who did not meet the minimum completion quality outcome , defined a priori ( all questions completed , questionnaire completed in more than 11 minutes ) , were also excluded from the analyses . the influence of nanocarrier composition on variables related to impact perception , acceptance , and acceptability and the influence of context of use on acceptance and acceptability were assessed using the wilcoxon signed - rank test , mcnemar s test , the mcnemar bowker test , and the pearson test . a multiple correspondence analysis ( mca ) logistic and ordinal regression models were calculated to assess the predictive values of core variables in relation to each other . analyses were carried out using spss statistics ( v20 ) ( ibm corporation , armonk , ny , usa ) . an invitation to participate in an anonymous web - based questionnaire study was sent via email to 1,320 active researchers and graduate research trainees in the field of new technologies . the questionnaire was available online from 4 september 2013 to 15 march 2014 ( 192 days ) . by the end of this period , 585 of persons contacted had accessed the questionnaire ( 44.32% access rate ) , and 214 had completed it ( 16.21% response rate meeting quality criteria ) . average completion time ( excluding extreme values ) from access to the last question was 25 minutes 38 seconds ( 14 minutes 47 seconds ; minimum 11 minutes 7 seconds to maximum 89 minutes 32 seconds ) . respondents ( n=214 ) identified themselves as researchers ( 71% ) or graduate students ( 29% ) in the fields of the natural sciences ( 67% ) or the social sciences and humanities ( 33% ) . sixty - six percent of the respondents were from europe ( france = 58% ; belgium = 5% ; switzerland = 2% ; italy = 1% ) , and the rest from canada . response frequencies for carbon and synthetic dna nanocarriers on scales for impact perception , acceptance , and acceptability are presented in table 3 . comparison of the pi for carbon and synthetic dna nanocarriers reveals a significant difference ( p<0.01 , wilcoxon signed - rank test ) in the way respondents identified and assessed the impacts of the two drug - delivery carriers . impacts of the synthetic dna nanocarrier on health , the environment , and social cohabitation were perceived more positively ( 38.3% ) as compared with the impacts of the carbon nanocarrier ( 27.1% ) . in contrast , impacts of the carbon nanocarrier on health , the environment , and social cohabitation were perceived more negatively ( 33.9% ) as compared with the impacts of the synthetic dna nanocarrier ( 29% ) . for both nanocarriers , clear differences in individual and social acceptance are observed as between the two contexts of use ( p<0.05 , mcnemar s test ) . , 92.5% of respondents reported that they would use a treatment delivered by carbon nanocarrier and 90.7% that they would use a treatment delivered by synthetic dna nanocarrier . to treat seasonal flu , only 19.2% of respondents reported that they would rely on carbon nanocarrier delivery and 19.6% that they would use synthetic dna nanocarriers . the concept of acceptability is divided into two variables , acceptability index ( ai ) and preponderant issue ( pissue ) . when explaining why they would or would not use a treatment relying on carbon nanocarriers to treat lung cancer ( indai ) , 76.2% of respondents cited positive impacts , 15.4% were ambiguous , and 8.4% mentioned negative impacts . in the same clinical context , to explain why they would or would not use a treatment relying on synthetic dna nanocarriers , the same percentage of respondents cited positive impacts , 12.6% were ambiguous , and 11.2% mentioned negative impacts . when explaining why they would or would not use a treatment relying on carbon nanocarriers to treat seasonal flu , 23.8% of respondents cited positive impacts , 21.5% were ambiguous , and 54.7% mentioned negative impacts . in the same clinical context , to explain why they would or would not use a treatment relying on synthetic dna nanocarriers , the same percentage of respondents cited positive impacts , 23.4% were ambiguous , and 52.8% mentioned negative impacts . here too , significant differences ( p<0.05 ) are observed between contexts of use . in contrast , similar percentages were obtained for socai ( table 3 ) , with no significant differences between indai and socai . analysis of preponderant issues ( figure 1 ) reveals that the individual acceptability of carbon and synthetic dna nanocarriers for treating lung cancer mainly centers on health issues : for both carbon and synthetic dna nanocarriers , 82.2% of respondents based their acceptability judgment on health issues . in this context of use , respondents were less inclined to take into account environmental ( carbon = 1.9% , dna = 1.9% ) and social ( carbon = 2.8% , dna = 2.3% ) issues as a priority in justifying their acceptance . in the context of the treatment of seasonal flu , the individual acceptability of carbon and synthetic dna nanocarriers proved much more complex : in addition to health issues ( carbon = 45.8% , dna = 49.1% ) , respondents considered issues related to the environmental ( carbon = 9.8% , dna = 7.5% ) and social cohabitation ( carbon = 11.2% , dna = 10.3% ) . similar results were observed for social acceptability : health issues preponderated , and respondents were more likely to accept both carbon and synthetic dna nanocarriers to treat lung cancer than to treat seasonal flu . significant differences ( p<0.05 , mcnemar bowker test ) were observed between contexts of use , but no difference was noted based on composition . as a first step in preparing to describe relationships between variables , logistic and ordinal regression models helped determine which factors shape the core variables . five models were tested for prediction of the main variables ( pi , indatce , indai , socatce , and socai ) . six factors were included , comprising the core variables plus perceived usefulness ( useful / ind and useful / soc ) as a sub - variable of acceptability . indatce and socatce logistic regression models presented a high proportion of variance explained ( associations between variables are reported by nagelkerke pseudo - r measures ) : 67.6% of variance is explained for the indatce model and 71.4% for the socatce model . they also both present high classification accuracy : 90.7% for the indatce model and 91.6% for the socatce model . in the indatce model , of the six predicting factors , only three were statistically significant ( p<0.05 , two - tailed t - test ) : indai ( odds ratio [ or ] = 2.52 ) , socatce ( or = 8.02 ) , and useful / ind ( or = 14.6 ) . in the socatce model , of the six predicting factors , again , only three were statistically significant : indatce ( or = 7.36 ) , socai ( or = 3.61 ) , and useful / soc ( or = 13.1 ) . the pi , indai , and socai ordinal regression models presented a lower proportion of variance explained ( pi , r = 21.9% ; indai , r = 37.2% ; socai , r = 40.9% ) . in the pi model , of the six predicting factors , only two were statistically significant : indai ( negative indai , or = 0.37 ) and socai ( negative socai , or = 0.30 ; neutral socai , or = 0.28 ) . in the indai model , of the six predicting factors , only three were statistically significant : pi ( negative pi , or = 0.40 ) , indatce ( or = 0.21 ) , and socai ( negative socai , or = 0.17 ) . in the socai model , of the six predicting factors , only three were statistically significant : pi ( negative pi , or = 0.32 ; neutral pi , or = 0.44 ) , indai ( negative indai , or = 0.21 ) , and socatce ( or = 0.14 ) . in order to look more closely at the relationships between impact perception , individual and social acceptance , and individual and social acceptability , a single scenario was chosen ( carbon nanocarrier to treat seasonal flu ) which presented great variability in answers for all variables . this data reduction approach , used both in the social sciences and in clinical and epidemiological research , is designed for the study of associations within one set of variables.37 mca is part of a family of descriptive methods ( such as clustering and factor analysis and principal components analysis ) that reveal patterning in complex data sets but are specific to categorical variables and enable the visualization of independent clusters on a multidimensional plane . the application of mca to the data ( n=214 ) from the chosen scenario showed that the total inertia explained is equal to 97.5% , with 56.8% due to the first dimension and 40.7% to the second dimension . the first dimension corresponds to the orientation of modalities ( positive / negative ) and the second to their polarization ( low / strong ) . indatce ( d1 = 71.9% ; d2 = 67.4% ) , useful / ind ( d1 = 66.6% ; d2 = 69% ) , socatce ( d1 = 76.7% ; d2 = 59% ) , and useful / soc ( d1 = 73.5% ; d2 = 81.4% ) presented strong correlations with dimension 1 and dimension 2 , as observable in the percentages noted in parentheses . a look at the coordinate graph of modalities reveals six clusters : cluster 1 : there is a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who strongly agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers strongly agreed with its widespread use in society and deemed this treatment to be really useful to them and to society.cluster 2 : there is a strong correlation on both dimensions between pi , indai , and socai . respondents who perceived positive impacts for a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing positive impacts.cluster 3 : as with cluster 1 , a strong correlation is observed on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers agreed with its widespread use in society and deemed this treatment useful to them and to society.cluster 4 : as with clusters 1 and 3 , this cluster presents a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who disagreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers disagreed with its widespread use in society and deemed this treatment useless to them and to society.cluster 5 : a relationship is observable between neutral modalities for pi , indai , and socai . however , the possibilities for interpretation are limited because of the proximity of the modalities to the center of the plot.cluster 6 : there appears to be a global correlation of negative modalities for all variables . thus respondents who strongly disagreed with the individual and social acceptance of seasonal flu treatment relying on carbon nanocarriers deemed such treatment totally useless to themselves and to society . as was seen in clusters 2 and 5 , there is a correlation between pi , indai , and socai : respondents who perceived negative impacts for the use of a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing negative impacts . cluster 1 : there is a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who strongly agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers strongly agreed with its widespread use in society and deemed this treatment to be really useful to them and to society . cluster 2 : there is a strong correlation on both dimensions between pi , indai , and socai . respondents who perceived positive impacts for a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing positive impacts . cluster 3 : as with cluster 1 , a strong correlation is observed on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers agreed with its widespread use in society and deemed this treatment useful to them and to society . cluster 4 : as with clusters 1 and 3 , this cluster presents a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who disagreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers disagreed with its widespread use in society and deemed this treatment useless to them and to society . cluster 5 : a relationship is observable between neutral modalities for pi , indai , and socai . however , the possibilities for interpretation are limited because of the proximity of the modalities to the center of the plot . cluster 6 : there appears to be a global correlation of negative modalities for all variables . thus respondents who strongly disagreed with the individual and social acceptance of seasonal flu treatment relying on carbon nanocarriers deemed such treatment totally useless to themselves and to society . as was seen in clusters 2 and 5 , there is a correlation between pi , indai , and socai : respondents who perceived negative impacts for the use of a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing negative impacts . response frequencies for carbon and synthetic dna nanocarriers on scales for impact perception , acceptance , and acceptability are presented in table 3 . comparison of the pi for carbon and synthetic dna nanocarriers reveals a significant difference ( p<0.01 , wilcoxon signed - rank test ) in the way respondents identified and assessed the impacts of the two drug - delivery carriers . impacts of the synthetic dna nanocarrier on health , the environment , and social cohabitation were perceived more positively ( 38.3% ) as compared with the impacts of the carbon nanocarrier ( 27.1% ) . in contrast , impacts of the carbon nanocarrier on health , the environment , and social cohabitation were perceived more negatively ( 33.9% ) as compared with the impacts of the synthetic dna nanocarrier ( 29% ) . for both nanocarriers , clear differences in individual and social acceptance are observed as between the two contexts of use ( p<0.05 , mcnemar s test ) . , 92.5% of respondents reported that they would use a treatment delivered by carbon nanocarrier and 90.7% that they would use a treatment delivered by synthetic dna nanocarrier . to treat seasonal flu , only 19.2% of respondents reported that they would rely on carbon nanocarrier delivery and 19.6% that they would use synthetic dna nanocarriers . the concept of acceptability is divided into two variables , acceptability index ( ai ) and preponderant issue ( pissue ) . when explaining why they would or would not use a treatment relying on carbon nanocarriers to treat lung cancer ( indai ) , 76.2% of respondents cited positive impacts , 15.4% were ambiguous , and 8.4% mentioned negative impacts . in the same clinical context , to explain why they would or would not use a treatment relying on synthetic dna nanocarriers , the same percentage of respondents cited positive impacts , 12.6% were ambiguous , and 11.2% mentioned negative impacts . when explaining why they would or would not use a treatment relying on carbon nanocarriers to treat seasonal flu , 23.8% of respondents cited positive impacts , 21.5% were ambiguous , and 54.7% mentioned negative impacts . in the same clinical context , to explain why they would or would not use a treatment relying on synthetic dna nanocarriers , the same percentage of respondents cited positive impacts , 23.4% were ambiguous , and 52.8% mentioned negative impacts . here too , significant differences ( p<0.05 ) are observed between contexts of use . similar percentages were obtained for socai ( table 3 ) , with no significant differences between indai and socai . analysis of preponderant issues ( figure 1 ) reveals that the individual acceptability of carbon and synthetic dna nanocarriers for treating lung cancer mainly centers on health issues : for both carbon and synthetic dna nanocarriers , 82.2% of respondents based their acceptability judgment on health issues . in this context of use , respondents were less inclined to take into account environmental ( carbon = 1.9% , dna = 1.9% ) and social ( carbon = 2.8% , dna = 2.3% ) issues as a priority in justifying their acceptance . in the context of the treatment of seasonal flu , the individual acceptability of carbon and synthetic dna nanocarriers proved much more complex : in addition to health issues ( carbon = 45.8% , dna = 49.1% ) , respondents considered issues related to the environmental ( carbon = 9.8% , dna = 7.5% ) and social cohabitation ( carbon = 11.2% , dna = 10.3% ) . similar results were observed for social acceptability : health issues preponderated , and respondents were more likely to accept both carbon and synthetic dna nanocarriers to treat lung cancer than to treat seasonal flu . significant differences ( p<0.05 , mcnemar bowker test ) were observed between contexts of use , but no difference was noted based on composition . as a first step in preparing to describe relationships between variables , logistic and ordinal regression models helped determine which factors shape the core variables . five models were tested for prediction of the main variables ( pi , indatce , indai , socatce , and socai ) . six factors were included , comprising the core variables plus perceived usefulness ( useful / ind and useful / soc ) as a sub - variable of acceptability . indatce and socatce logistic regression models presented a high proportion of variance explained ( associations between variables are reported by nagelkerke pseudo - r measures ) : 67.6% of variance is explained for the indatce model and 71.4% for the socatce model . they also both present high classification accuracy : 90.7% for the indatce model and 91.6% for the socatce model . in the indatce model , of the six predicting factors , only three were statistically significant ( p<0.05 , two - tailed t - test ) : indai ( odds ratio [ or ] = 2.52 ) , socatce ( or = 8.02 ) , and useful / ind ( or = 14.6 ) . in the socatce model , of the six predicting factors , again , only three were statistically significant : indatce ( or = 7.36 ) , socai ( or = 3.61 ) , and useful / soc ( or = 13.1 ) . the pi , indai , and socai ordinal regression models presented a lower proportion of variance explained ( pi , r = 21.9% ; indai , r = 37.2% ; socai , r = 40.9% ) . in the pi model , of the six predicting factors , only two were statistically significant : indai ( negative indai , or = 0.37 ) and socai ( negative socai , or = 0.30 ; neutral socai , or = 0.28 ) . in the indai model , of the six predicting factors , only three were statistically significant : pi ( negative pi , or = 0.40 ) , indatce ( or = 0.21 ) , and socai ( negative socai , or = 0.17 ) . in the socai model , of the six predicting factors , only three were statistically significant : pi ( negative pi , or = 0.32 ; neutral pi , or = 0.44 ) , indai ( negative indai , or = 0.21 ) , and socatce ( or = 0.14 ) . as a first step in preparing to describe relationships between variables , logistic and ordinal regression models helped determine which factors shape the core variables . five models were tested for prediction of the main variables ( pi , indatce , indai , socatce , and socai ) . six factors were included , comprising the core variables plus perceived usefulness ( useful / ind and useful / soc ) as a sub - variable of acceptability . indatce and socatce logistic regression models presented a high proportion of variance explained ( associations between variables are reported by nagelkerke pseudo - r measures ) : 67.6% of variance is explained for the indatce model and 71.4% for the socatce model . they also both present high classification accuracy : 90.7% for the indatce model and 91.6% for the socatce model . in the indatce model , of the six predicting factors , only three were statistically significant ( p<0.05 , two - tailed t - test ) : indai ( odds ratio [ or ] = 2.52 ) , socatce ( or = 8.02 ) , and useful / ind ( or = 14.6 ) . in the socatce model , of the six predicting factors , again , only three were statistically significant : indatce ( or = 7.36 ) , socai ( or = 3.61 ) , and useful / soc ( or = 13.1 ) . the pi , indai , and socai ordinal regression models presented a lower proportion of variance explained ( pi , r = 21.9% ; indai , r = 37.2% ; socai , r = 40.9% ) . in the pi model , of the six predicting factors , only two were statistically significant : indai ( negative indai , or = 0.37 ) and socai ( negative socai , or = 0.30 ; neutral socai , or = 0.28 ) . in the indai model , of the six predicting factors , only three were statistically significant : pi ( negative pi , or = 0.40 ) , indatce ( or = 0.21 ) , and socai ( negative socai , or = 0.17 ) . in the socai model , of the six predicting factors , only three were statistically significant : pi ( negative pi , or = 0.32 ; neutral pi , or = 0.44 ) , indai ( negative indai , or = 0.21 ) , and socatce ( or = 0.14 ) . in order to look more closely at the relationships between impact perception , individual and social acceptance , and individual and social acceptability , a single scenario was chosen ( carbon nanocarrier to treat seasonal flu ) which presented great variability in answers for all variables . the relationships between these categorical variables were studied using mca . this data reduction approach , used both in the social sciences and in clinical and epidemiological research , is designed for the study of associations within one set of variables.37 mca is part of a family of descriptive methods ( such as clustering and factor analysis and principal components analysis ) that reveal patterning in complex data sets but are specific to categorical variables and enable the visualization of independent clusters on a multidimensional plane . the application of mca to the data ( n=214 ) from the chosen scenario showed that the total inertia explained is equal to 97.5% , with 56.8% due to the first dimension and 40.7% to the second dimension . the first dimension corresponds to the orientation of modalities ( positive / negative ) and the second to their polarization ( low / strong ) . indatce ( d1 = 71.9% ; d2 = 67.4% ) , useful / ind ( d1 = 66.6% ; d2 = 69% ) , socatce ( d1 = 76.7% ; d2 = 59% ) , and useful / soc ( d1 = 73.5% ; d2 = 81.4% ) presented strong correlations with dimension 1 and dimension 2 , as observable in the percentages noted in parentheses . a look at the coordinate graph of modalities reveals six clusters : cluster 1 : there is a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who strongly agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers strongly agreed with its widespread use in society and deemed this treatment to be really useful to them and to society.cluster 2 : there is a strong correlation on both dimensions between pi , indai , and socai . respondents who perceived positive impacts for a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing positive impacts.cluster 3 : as with cluster 1 , a strong correlation is observed on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers agreed with its widespread use in society and deemed this treatment useful to them and to society.cluster 4 : as with clusters 1 and 3 , this cluster presents a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who disagreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers disagreed with its widespread use in society and deemed this treatment useless to them and to society.cluster 5 : a relationship is observable between neutral modalities for pi , indai , and socai . however , the possibilities for interpretation are limited because of the proximity of the modalities to the center of the plot.cluster 6 : there appears to be a global correlation of negative modalities for all variables . thus respondents who strongly disagreed with the individual and social acceptance of seasonal flu treatment relying on carbon nanocarriers deemed such treatment totally useless to themselves and to society . as was seen in clusters 2 and 5 , there is a correlation between pi , indai , and socai : respondents who perceived negative impacts for the use of a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing negative impacts . cluster 1 : there is a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who strongly agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers strongly agreed with its widespread use in society and deemed this treatment to be really useful to them and to society . cluster 2 : there is a strong correlation on both dimensions between pi , indai , and socai . respondents who perceived positive impacts for a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing positive impacts . cluster 3 : as with cluster 1 , a strong correlation is observed on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who agreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers agreed with its widespread use in society and deemed this treatment useful to them and to society . cluster 4 : as with clusters 1 and 3 , this cluster presents a strong correlation on both dimensions between indatce , socatce , useful / ind , and useful / soc . researchers who disagreed with individual use of a treatment for seasonal flu relying on carbon nanocarriers disagreed with its widespread use in society and deemed this treatment useless to them and to society . cluster 5 : a relationship is observable between neutral modalities for pi , indai , and socai . however , the possibilities for interpretation are limited because of the proximity of the modalities to the center of the plot . cluster 6 : there appears to be a global correlation of negative modalities for all variables . thus respondents who strongly disagreed with the individual and social acceptance of seasonal flu treatment relying on carbon nanocarriers deemed such treatment totally useless to themselves and to society . as was seen in clusters 2 and 5 , there is a correlation between pi , indai , and socai : respondents who perceived negative impacts for the use of a seasonal flu treatment relying on carbon nanocarriers were more likely to justify their individual and social acceptance by citing negative impacts . this study aimed to answer three questions : do nanocarrier composition and medical context of use influence researchers impact perception , acceptance , and acceptability judgments in relation to treatments ? overall , the results showed that without regard for the context of use , nanocarrier composition does not seem to affect individual and social acceptance or individual and social acceptability . within a precise context of use of nanocarriers the treatment of lung cancer , for example the fact that the pharmacological agent delivered by both kinds of nanocarriers was perceived as the same may explain why composition is not a relevant concern . however , it should be noted that the details on the exact composition of the nanocarriers ( type , methodology of preparation ) were not provided to the participants and could have influenced their judgment . a medical context in which what matters to patients is usually effectiveness and nothing else may partly account for the drug carrier s composition having little or no influence on acceptance and acceptability . in contrast to what is observed for cosmetology a context of use in which a great deal of importance is assigned to nanoparticle composition and public perception38,39 it has been reported that in medical contexts with health outcomes , treatment composition ( nanoformulated drug versus regular drug ) seems not to govern product acceptance.17 on the other hand , impact perception differs significantly as between the two kinds of nanocarriers . the very different biochemical structures may account for the differences in impact perception : a carbon nanocarrier may be perceived as being more costly to produce and less ecofriendly , while synthetic dna may appear less threatening in terms of biological compatibility and environmental degradability . as well , currently concerns are being aired about the toxicity of carbon nanostructures , which may account for researchers less optimistic view of the carbon nanocarrier . nevertheless , although impact perception differed as between different nanocarrier compositions , composition does not appear to be a factor governing and accounting for clinical decisions . it has been reported that when little is known about a new technology , as is the case for nanoparticle use in the food industries and food packaging , the context of use itself seems to be an important factor in attitude and acceptance.40 in contrast to what we found regarding nanocarrier composition , our results showed that the clinical context significantly influences individual and social acceptance and individual and social acceptability in relation to nanocarriers . respondents did not really accept seasonal flu treatment as a suitable context of use of nanocarriers . this rejection may largely be accounted for by the fear of negative outcomes for health and social cohabitation . in contrast , lung cancer received high acceptance as a suitable context of use , perhaps because of its horrifying consequences and the lack of effective and safe treatments for it . our results on this score confirm what we found in the literature , namely that the nature and context of applications can influence impact perception and social acceptance.26 along with context of use , perceived usefulness of treatments appears to be a significant factor influencing acceptance . this relationship between acceptance and perceived usefulness has been documented in the literature on technology acceptance models.41,42 perceived usefulness , defined as the individual s perception that using a technological system will enhance job performance,43 has been reported as an important factor in accounting for a technology s acceptance . this may also apply to clinical contexts : a lung cancer treatment may meet with quick acceptance if the person to whom it is offered fears dying of cancer and is prepared to fight the adverse effects but be rejected if treatment is offered as a third - line therapy . nanocarrier treatment for the seasonal flu may be accepted by a self - employed person who does not want to miss a day of work ; it may be rejected by another person who believes the human body benefits from fighting viruses . the significant relationship between perceived usefulness and acceptance again suggests a consideration of the user s personal assessment of the clinical situation as well as consideration of the context of use . the mca revealed a relationship between impact perception and acceptability whose strength was unexpected , given that perceived impacts can differ from impacts invoked in making an acceptability judgment . the relationship between these variables may have been accentuated by the process of operationalizing the framework for these two related but distinct concepts . little is known about the relationship between impact perception and acceptability , and our result points toward continuing the research on the general public s perception of the impact of new technologies . our study is in line with previously reported findings19,29 that , even if efforts are invested in reducing the toxicity of new technologies such as nanocarriers and in maximizing their economic benefits , many other factors , such as concerns about social cohabitation and the environment , play a role in the formation of individual and social acceptability judgments . these issues must be taken into consideration in ensuring the responsible development and implementation of use of nanocarriers in medicine . regression analyses on core variables from a single case study ( using the synthetic dna nanocarrier to treat the seasonal flu ) demonstrated the differences in predicting these variables . the two models related to indatce and socatce were the more accurate ones ( 67.6% and 71.4% of variance explained , 90.7% and 91.6% classification accuracy ) and exceeded expectations , given that the range of explained variances in the recent literature is 29%70%.43 the high percentages of variance explained for the indatce and socatce regression models reveal that a considerable amount is already known about the concept of acceptance and that the questionnaire we developed may help predict usage of the two kinds of nanocarriers in the contexts presented . impact perception and models for individual and social acceptability , on the other hand , presented lower percentages of variance explained ( 21.9% , 37.2% , and 40.9% ) and were less accurate in predicting the variables studied . fewer independent variables in regression models were significant in predicting pi , indai , and socai when compared with the indatce and socatce models . this may suggest that although certain factors do help predict impact perception and individual and social acceptability , these concepts are more complex than acceptance and may reflect more complex contextual factors that were not included in the present study . but it may also suggest that the predictive approach used with acceptance and implicit in the traditional psychosocial paradigm may not be adequate for the study of these variables and there is a need to go further.13 the latter interpretation is in fact supported by the results of our analysis of the preponderant issues , which reveals that the acceptability judgment is characterized by a certain depth produced by the variability in the nature of the impacts on the different issues taken into account in an acceptability judgment . while acceptability judgment can be treated in a scalar manner by categorizing it as positive , neutral , or negative , it would gain from a deepened approach and by being treated not as a variable subject to prediction but as a whole approach allowing for a greater understanding of users motivations and fears in the face of a new technology . the nanocarriers described in both scenarios are examples of envisioned targeted drug - delivery applications . they were specifically chosen in order to provide an initial analysis of perceived impacts and acceptability of these nanocarrier - based envisioned applications . conclusions from this exploratory study are drawn to open discussion on nanocarriers composition and contexts of use , but the results might not be used to infer any general conclusions regarding all nanocarriers for targeted drug - delivery applications or nanomedicine in general . in order to go beyond the limitations of traditional approaches to predicting behaviors , which have reflected the assumption that behavior is guided mainly by economic and toxicological considerations , the survey questionnaire developed for this study was based on impact assessment and the balancing of impacts against each other to yield an acceptability judgment guided mainly by ethical considerations . this constitutes a previously unexplored avenue of research that could lead , through an understanding of users value judgments , to a better understanding of the issues surrounding the nanocarriers studied . although we have here presented only the quantitative phase of this mixed - methods project , the semi - directed interviews we conducted made possible a deepened exploration of the main concepts . we intend to produce further publications to present these results . the exploratory context of the study design accounts for certain limitations in the project . although the questionnaire we employed was pretested in successive rounds of cognitive interviews , we can not claim that it could be considered to have been validated . furthermore , in recruiting participants , we preferred to rely on convenience sampling , which entails selection bias ; for example , only francophone researchers active in their fields were included in the study . thus , it is somewhat hard to transfer our results to the general research community of canada and europe . finally , the length of the questionnaire , the recurrence of questions , and the cognitive load entailed by the complexity of the concepts under examination could also constitute a limitation on the quality of the data gathered . nanotechnology applications offer the potential for many improvements in the spheres of health care and medical treatment . integrating patients values and social concerns into the process of developing new medical technologies and products could help nanomedicine to flourish by ensuring clinical compliance and enhancing the general acceptability of treatments . though it has been reported that , because its applications often consist of forms of medical intervention , nanomedicine comes under heavier scrutiny than does nanotechnology in general,44 our study s results suggest that context of use must also be taken into account in any assessment in the field of nanomedicine . our study highlights researchers degree of acceptance of both kinds of nanocarriers from the perspectives of both composition and context of use , and it reveals what factors account for researchers positions . using the same approach with other targeted populations could lead to a better understanding of the concerns of all stakeholders , including the general public , about a wide range of technological and medical products .

backgrounddespite marked optimism in the field of nanomedicine about the use of drug - delivery nanocarriers , uncertainties exist concerning nanocarriers possible unintended impacts and effects . these uncertainties could affect user acceptance and acceptability . acceptance refers to the intention to put a technology or a device to a specified use . acceptability refers to a value judgment that accounts for acceptance . the objectives of this study were to characterize impact perception , acceptance , and acceptability in relation to drug - delivery nanocarriers in different contexts of use , and to explore relationships among these concepts.methodsa sample of european and canadian researchers and graduate research trainees active in the field of new technologies was recruited by targeted email invitation for participation in a web - based questionnaire study . the questionnaire presented scenarios for two contexts of use ( lung cancer , seasonal flu ) of drug - delivery nanocarriers with two compositions ( carbon , synthetic dna ) . respondents impact perception , acceptance , and acceptability judgment in relation to each kind of nanocarrier in each context of use were measured with likert scale questions and scored using categorical values.resultstwo hundred and fourteen researchers and graduate research trainees completed the questionnaire . the results showed that nanocarrier composition influenced impact perception : as compared with the carbon nanocarrier impact perception , the positive impacts of the synthetic dna nanocarrier were perceived as more significant and more likely to occur than its negative impacts . composition did not influence acceptance or acceptability . context of use significantly influenced acceptance and acceptability of both kinds of nanocarriers : researchers were more likely to accept the use of nanocarriers to treat lung cancer than the seasonal flu . the results also showed a significant relationship between acceptance and the perceived usefulness of the treatments.conclusionnanocarrier composition does not appear to influence acceptance or acceptability . on the other hand , the nanocarriers perceived usefulness and context of use are both major factors in accounting for acceptance and acceptability .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Health Insurance Claim Prompt Payment Act of 1997''. SEC. 2. PROMPT PAYMENT OF PROVIDER CLAIMS. (a) Group Health Plans.-- (1) Public health service act amendments.--Subpart 2 of part A of title XXVII of the Public Health Service Act (as added by section 604(a) of the Newborns' and Mothers' Health Protection Act of 1996 and amended by section 703(a) of the Mental Health Parity Act of 1996) is amended by adding at the end the following new section: ``SEC. 2706. STANDARDS RELATING TO PROMPT PAYMENT OF PROVIDER CLAIMS. ``(a) In General.--To the extent that a group health plan, or a health insurance issuer offering group health insurance coverage, fails to provide for the issue, mailing, or transmission of payment for a clean claim within 30 calendar days after the date the plan or issuer receives a clean claim, the plan or issuer shall provide for payment of interest on the unpaid balance at the rate of interest and for the same period specified in section 1842(c)(2)(C) of the Social Security Act for purposes of part B of title XVIII of such Act. ``(b) Contract Limitations.--No provision of a contract between a group health plan and a provider of health services, or between a health insurance issuer and a provider of health services in relation to provision of items and services in connection with group health insurance coverage by the issuer, shall be given effect to the extent it prevents the application of subsection (a). Such a provision may be given effect to the extent it-- ``(1) requires payment to be made more promptly than as provided in subsection (a), ``(2) provides for a higher interest rate than that provided under subsection (a), or ``(3) otherwise provides for greater sanctions or remedies in the case of a failure by a plan or issuer to make prompt payment on claims under the plan or under the health insurance coverage involved. ``(c) Clean Claim Defined.--For purposes of this section, the term `clean claim' means a claim that has no defect or impropriety (including any lack of any required substantiating documentation) or particular circumstance requiring special treatment that prevents timely payment from being made on the claim under the group health plan or health insurance coverage involved.''. (2) ERISA amendments.--(A) Subpart B of part 7 of subtitle B of title I of the Employee Retirement Income Security Act of 1974 (as added by section 603(a) of the Newborns' and Mothers' Health Protection Act of 1996 and amended by section 702(a) of the Mental Health Parity Act of 1996) is amended by adding at the end the following new section: ``SEC. 713. STANDARDS RELATING TO PROMPT PAYMENT OF PROVIDER CLAIMS. ``(a) In General.--To the extent that a group health plan, or a health insurance issuer offering group health insurance coverage, fails to provide for the issue, mailing, or transmission of payment for a clean claim within 30 calendar days after the date the plan or issuer receives a clean claim, the plan or issuer shall provide for payment of interest on the unpaid balance at the rate of interest and for the same period specified in section 1842(c)(2)(C) of the Social Security Act for purposes of part B of title XVIII of such Act. ``(b) Contract Limitations.--No provision of a contract between a group health plan and a provider of health services, or between a health insurance issuer and a provider of health services in relation to provision of items and services in connection with group health insurance coverage by the issuer, shall be given effect to the extent it prevents the application of subsection (a). Such a provision may be given effect to the extent it-- ``(1) requires payment to be made more promptly than as provided in subsection (a), ``(2) provides for a higher interest rate than that provided under subsection (a), or ``(3) otherwise provides for greater sanctions or remedies in the case of a failure by a plan or issuer to make prompt payment on claims under the plan or under the health insurance coverage involved. ``(c) Clean Claim Defined.--For purposes of this section, the term `clean claim' means a claim that has no defect or impropriety (including any lack of any required substantiating documentation) or particular circumstance requiring special treatment that prevents timely payment from being made on the claim under the group health plan or health insurance coverage involved.''. (B) Section 732(a) of such Act (29 U.S.C. 1191a(a)), as amended by section 603(b)(2) of Public Law 104-204, is amended by striking ``section 711'' and inserting ``sections 711 and 713''. (C) The table of contents in section 1 of such Act is amended by inserting after the item relating to section 712 the following new item: ``Sec. 713. Standards relating to prompt payment of provider claims.''. (b) Individual Health Insurance.--Part B of title XXVII of the Public Health Service Act (as added by section 605(a) of the Newborn's and Mother's Health Protection Act of 1996) is amended by inserting after section 2751 the following new section: ``SEC. 2752. STANDARDS RELATING TO PROMPT PAYMENT OF PROVIDER CLAIMS. ``The provisions of section 2706 shall apply to health insurance coverage offered by a health insurance issuer in the individual market in the same manner as it applies to health insurance coverage offered by a health insurance issuer in connection with a group health plan in the small or large group market.''. (c) Effective Dates.--The amendments made by this section shall apply with respect to payment for items and services furnished on or after the date this is 1 year after the date of the enactment of this Act.

Health Insurance Claim Prompt Payment Act of 1997 - Amends the Employee Retirement Income Security Act of 1974 and the Public Health Service Act, as amended by the Newborns' and Mothers' Health Protection Act of 1996 and the Mental Health Parity Act of 1996, to: (1) require group health plans and group and individual health insurance coverage to pay interest on clean provider claims that are not paid within 30 days; and (2) establish standards relating to prompt payment of such claims.

let @xmath10 be a compact design space and let @xmath11 be the set of all designs ( i.e. , finitely supported probability measures ) on @xmath7 . for any @xmath12 , let @xmath13 denote the information matrix . suppose that there exists a design with nonsingular information matrix and let @xmath14 be the set of such designs . let @xmath15 denote a @xmath0-optimum design , that is , a measure in @xmath11 that maximizes @xmath16 , see , e.g. , @xcite . note that a @xmath0-optimum design always exists and that the @xmath0-optimum information matrix @xmath17 is unique . for any @xmath18 denote @xmath19 the variance function defined by @xmath20 the celebrated kiefer - wolfowitz equivalence theorem ( 1960 ) writes as follows . [ thm : eq ] the following three statements are equivalent : ( i ) : : @xmath21 is @xmath0-optimum ; ( ii ) : : @xmath22 ; ( iii ) : : @xmath21 minimizes @xmath23 , @xmath24 . notice that @xmath25 hence , ( ii ) of theorem [ thm : eq ] implies that for any support point @xmath6 of the design @xmath15 ( i.e. , for a point satisfying @xmath26 ) , we have @xmath27 in the next section we show that the equality ( [ eq : sup ] ) can be used to prove that @xmath28 where @xmath29 depends on @xmath1 only via the maximum of @xmath30 over the design space @xmath31 . hence , we can test candidate support points by using any finite number of design measures @xmath32 , e.g. , those that are generated by a design algorithm on its way towards the optimum : any point that does not pass the test defined by @xmath33 of iteration @xmath34 need not be considered for further investigations and can thus be removed from the design space . for @xmath1 a design in @xmath14 denote @xmath35 , @xmath36 and @xmath37 the eigenvalues of @xmath38 . notice that @xmath39 and that the eigenvalues depend on the design @xmath1 as well as on the @xmath0-optimum information matrix @xmath40 . let @xmath6 be a support point of a @xmath0-optimum design and let @xmath41 . the equality ( [ eq : sup ] ) can be written in the form @xmath42 which implies : @xmath43 to be able to use the inequality ( [ ineq : megn ] ) , we need to derive a lower bound @xmath29 on @xmath44 that does not depend on the unknown matrix @xmath40 . theorem [ thm : eq]-(ii ) implies @xmath45 also , @xmath46 where we used the notation @xmath47 for @xmath48 we directly obtain the lower bound @xmath49 . for @xmath50 , the lagrangian for the minimisation of @xmath44 subject to @xmath51 and @xmath52 is given by @xmath53 with @xmath54 , @xmath55 . the stationarity of @xmath56 with respect to the @xmath57 s and the kuhn - tucker conditions @xmath58 give @xmath59 for @xmath60 , with @xmath44 and @xmath61 satisfying @xmath62 the solution is thus @xmath63 and @xmath64 , @xmath60 . notice that the bound ( [ ineq : lb ] ) gives @xmath65 when @xmath48 and can thus be used for any dimension @xmath66 . by substituting @xmath29 for @xmath44 in ( [ ineq : megn ] ) we obtain the following result . the inequality in @xcite uses @xmath71\,.\ ] ] notice , that @xmath72 for all integer @xmath66 and all @xmath73 , and that @xmath74 while @xmath75 . the new bound is thus always stronger , especially for large values of @xmath76 , i.e. when the design @xmath1 is far from being optimum . although in practice the improvement over ( [ tildeh ] ) can be marginal , see the example below , the important result here is that the bound ( [ * * ] ) can not be improved . indeed , when @xmath48 , @xmath77 for any @xmath78 which is clearly the best possible bound . when @xmath79 , @xmath80 is the tightest lower bound on the variance function @xmath9 at a @xmath0-optimal support point @xmath81 that depends only on @xmath82 and @xmath76 , in the sense of the following theorem . for any integer @xmath79 and any @xmath83 there exist a compact design space @xmath84 , a design @xmath1 on @xmath7 and a point @xmath85 supporting a @xmath0-optimum design on @xmath31 such that @xmath86 and @xmath87 _ proof . _ denote @xmath88 and @xmath89 . let @xmath90 correspond to the @xmath34 vectors of @xmath91 of the form @xmath92 and let @xmath93 correspond to the @xmath34 vectors @xmath94 . take @xmath95 with @xmath96 , @xmath7 as the finite set @xmath97 and let @xmath1 be the uniform probability measure on @xmath98 . note that @xmath99 is a diagonal matrix with diagonal elements @xmath100,\ldots,(h-1)/[h(m-1)]\right)$ ] . one can easily verify that @xmath101 the uniform probability measure @xmath102 on @xmath103 is @xmath0-optimum on @xmath104 , as can be directly verified by checking ( ii ) of the equivalence theorem [ thm : eq ] . on the other hand , @xmath102 is not @xmath0-optimum on @xmath7 since @xmath105 , which implies that @xmath6 must support a @xmath0-optimum design on @xmath7 . we consider a series of problems defined by the construction of the minimum covering ellipse for an initial set of 1000 random points in the plane , i.i.d.@xmath106 . these problems correspond to @xmath0-optimum design problems for randomly generated @xmath107 , see @xcite . the following recursion can thus be used:@xmath108 where @xmath109 , @xmath110 is the weight given by the discrete design @xmath33 to the point @xmath111 and @xmath112 is the cardinality of @xmath31 at iteration @xmath34 . in the original algorithm , @xmath113 for all @xmath34 and , initialized at a @xmath114 that gives a positive weight at each point of @xmath31 , the algorithm converges monotonically to the optimum , see @xcite and @xcite . the tests ( [ * * ] ) and ( [ tildeh ] ) can be used to decrease @xmath112 : at iteration @xmath34 , any design point @xmath115 satisfying @xmath116 $ ] , see ( [ epsilon ] , [ * * ] ) , or @xmath117 $ ] , see ( [ epsilon ] , [ tildeh ] ) , can be removed from @xmath31 . the total weight of the points that are cancelled is then reallocated to the @xmath111 s that stay in @xmath31 ( e.g. , proportionally to @xmath118 ) . figure [ f : ellips ] presents a typical evolution of @xmath112 as a function of @xmath119 for @xmath114 uniform on @xmath31 and shows the superiority of the test ( [ * * ] ) over ( [ tildeh ] ) . the improvement is especially important in the first iterations , when the design @xmath33 is far from the optimum . define @xmath120 as the number of iterations required to reach a given precision @xmath121 , @xmath122 with @xmath123 defined by ( [ epsilon ] ) . notice that from the concavity of @xmath124 we have @xmath125}{\partial\alpha}_{|\alpha=0 } \\ & & = \int_{\sx } d(\xi^{k^*(\delta)},\xb)\ , \xi^*(d\xb ) - m < \delta \,.\end{aligned}\ ] ] table [ tb : ellips ] shows the influence on the algorithm ( [ recursion ] ) of the cancellation of points based on the tests ( [ * * ] ) and ( [ tildeh ] ) , in terms of @xmath120 , of the corresponding computing time @xmath126 , the number of support points @xmath127 of @xmath128 and the first iteration @xmath129 when @xmath33 has 10 support points or less , with @xmath130 . the results are averaged over 1000 independent problems . the values of @xmath120 and @xmath129 are rounded to the nearest larger integer , the computing time for the algorithm with the cancellation of points based on ( [ * * ] ) is taken as reference and set to 1 ( the algorithm without cancellation was at least 4.5 times slower in all the 1000 repetitions ) . although cancelling points has little influence on the number of iterations @xmath120 , is renders the iterations simpler : on average the introduction of the test ( [ * * ] ) in the algorithm ( [ recursion ] ) makes it about 30 times faster . the influence of the cancellation on the performance of the algorithm can be further improved as follows . let @xmath131 denote the subsequence corresponding to the iterations where some points are removed from @xmath31 . we have @xmath132 , the cardinality of the initial @xmath31 , and the convergence of the algorithm ( [ recursion ] ) is therefore maintained whatever the heuristic rule used at the iterations @xmath133 for updating the weights of the points that stay in @xmath31 ( provided these weights remain strictly positive ) . the following one has been found particularly efficient on a series of examples : for all @xmath134 , the set of indices corresponding to the points that stay in @xmath31 at iteration @xmath133 , replace @xmath135 by @xmath136 for some @xmath137 . a final remark is that by including the test ( [ * * ] ) in the algorithm ( [ recursion ] ) one can in general quickly identify potential support points for an optimum design . when the number @xmath138 of these points is small enough , switching to a more standard convex - programming algorithm for the optimization of the @xmath138 associated weights might then form a very efficient strategy . titterington , d. , 1976 . algorithms for computing d - optimal designs on a finite design space . in : proc . of the 1976 conference on information science and systems . dept . of electronic engineering , john hopkins university , baltimore , pp . 213216 . torsney , b. , 1983 . a moment inequality and monotonicity of an algorithm . in : kortanek , k. , fiacco , a. ( eds . ) , proc . int . symp . on semi - infinite programming and applications . springer , heidelberg , pp .

we improve the inequality used in @xcite to remove points from the design space during the search for a @xmath0-optimum design . let @xmath1 be any design on a compact space @xmath2 with a nonsingular information matrix , and let @xmath3 be the maximum of the variance function @xmath4 over all @xmath5 . we prove that any support point @xmath6 of a @xmath0-optimum design on @xmath7 must satisfy the inequality @xmath8 . we show that this new lower bound on @xmath9 is , in a sense , the best possible , and how it can be used to accelerate algorithms for @xmath0-optimum design . and @xmath0-optimum design , design algorithm , support points 62k05 , 90c46

in this paper we present an application of explanation - based learning ( ebl ) in the parsing module of a real - time english - spanish machine translation ( mt ) system designed to translate closed captions . the core idea of ebl is to convert previous analyses into some generalized form that can be called on when similar new examples are encountered (; ) . the main motivation for using an explanation - based learning approach to parsing is to increase efficiency . dramatic increases in speed can be obtained , at the expense of some coverage and increased memory requirements . in our mt system , efficiency is a major priority because the closed captions included with television and video broadcasts will be translated in real - time . in this paper we discuss the various efficiency / coverage trade - offs that are available within the ebl approach and describe the techniques we use to maximize coverage while maintaining efficiency as the primary focus . this paper is organized as follows . in section 2 we introduce the ebl approach as it has been used in natural language processing . section 3 introduces the translation system in which the ebl parser is embedded and discusses the consequences of efficiency versus coverage in this domain . in section 4 we introduce our ebl parser and describe the means we use to maximize efficiency and coverage . the performance of the system is discussed in section 5 . concluding comments can be found in section 6 . the ebl approach has been extended to natural language processing ( nlp ) by @xcite ( @xcite ) , @xcite ( @xcite ) , among others . they use existing wide - coverage grammars ( or a tree bank @xcite ) to analyze a set of training examples . the analyses are then generalized in various ways so that they are applicable to a wide range of examples beyond the original input string . in some cases these analyses are manually - checked before generalization to ensure they are the correct interpretation for the given input string @xcite . typically , the generalized parse is stored with a key that is used to subsequently identify when this parse is applicable to a new example . @xcite ( @xcite ) , for example , use the part of speech sequence of the input string as the key . the generalized structures that are saved during ebl training are referred to as ` generalized parses , ' ` macro - rules , ' ` generalized macro - rules , ' or ` rule - chunks ' . for our purposes these terms are inter - changeable . it is a characteristic of general wide - coverage grammars that they are extremely ambiguous . hence , parsing involves many options and can be quite slow . the advantage of ebl is that the run - time complexity of parsing is reduced since the majority of the parsing occurs off - line . at run - time , the system need only identify the most similar parse from those available . in theory the accuracy of the system can be increased since an ebl grammar is tuned to the rules actually used in the training domain . the one disadvantage of the ebl approach is that there is a loss of coverage since the ebl grammar is a subset of the original grammar used to derive it . if an example is not covered by the generalized examples in the ebl grammar then an analysis can not be provided . @xcite ( @xcite ) note that there are two main parameters that can be adjusted in the ebl learning phase : training corpus size and the number and type of macro - rules . they note that the larger the corpus the smaller the loss in coverage . however , it should be noted that the size / coverage correlation only holds within a corpus . comparisons can not be made across different corpora . for example , @xcite ( @xcite ) conduct tests on three different corpora . the coverage details of the ebl grammars they developed are given in table 1 . both the largest and the smallest corpora have extremely poor coverage . the median - sized corpus exhibits the best coverage . hence , the coverage of a given corpus depends both on the variability of the structures contained in the corpus as well as on its size . .coverage on 3 different corpora , srivinas & joshi 1995 [ cols="^,^,^",options="header " , ] these results indicate that the ebl approach will successfully meet the needs of our real - time english - spanish translation system . in addition , they provide clear indication of the areas in which we should focus to improve performance . for example , the coverage rate of 78.6% needs to be increased . to do this we plan to integrate our ebl approach with a partial parser . secondly , for the cases where a parse is found , we need to increase the accuracy of the found parse . we will be analyzing our results to determine whether the correct parse is not available or if it is available but not selected . thirdly , we plan to extend the ebl approach to the generation phase of the translation system . the explanation - based learning approach to parsing provides an efficient means of providing analyses at the expense of some coverage . in this paper we described how we took advantage of these efficiency gains in order to minimize the analysis time in a real - time english to spanish mt system . we found that even when efficiency is the prime objective , there are techniques that can be used to minimize the coverage loss . on several levels we were able to maximize coverage while focussing on efficiency . this was achieved by making sure that the examples selected for training were instances of the most frequent constructions , by generalizing the input so that the parses produced would be of the most general type , and by generalizing the saved macro - rules and their key to the minimum needed for subsequent components of the system . fred popowich , davide turcato , olivier laurens , paul mcfetridge , j. devlan nicholson , patrick mcgivern , maricela corzo - pena , lisa pidruchney , and scott macdonald . 1997 `` a lexicalist approach to the translation of colloquial text . '' , in _ proceedings of the 7th international conference on theoretical and methodological issues in machine translation _ , pages 7686 , new mexico , usa . rayner , m. 1988 . `` applying explanation - based generalization to natural language processing '' , in _ proceedings of the international conference on fifth generation computer systems _ , kyoto , pages 12671274 . rayner , m. and c. samuelsson . `` corpus - based grammar specialization for fast analysis '' , agnas et al . in _ spoken language translator : first year report _ , sri technical report crc-043 . http://www.cam.sri.com , pages 4154 .

in this paper we present an application of explanation - based learning ( ebl ) in the parsing module of a real - time english - spanish machine translation system designed to translate closed captions . we discuss the efficiency / coverage trade - offs available in ebl and introduce the techniques we use to increase coverage while maintaining a high level of space and time efficiency . our performance results indicate that this approach is effective .

the ability to quickly respond and adapt to environmental flux is central for microbial colonization and persistence in a given niche or host organism . bacteria sense and respond to changes in their environment using a variety of mechanisms such as twocomponent sensing and quorum sensing . in twocomponent systems ( tcs ) , an environmental signal ' is detected by a sensor histidine kinase , which initiates a signal transduction cascade that in many cases results in transcriptional regulation of target genes . although tcs are broadly distributed in bacteria , for many tcs the specific signal that activates the sensor kinase and the target genes that are regulated upon its activation have not been identified . the qsebc tcs is conserved in a broad spectrum of bacterial species ( clarke et al . , 2006 ) and is closely associated with quorumsensing mechanisms ( sperandio et al . , 2002 ; novak et al . , 2010 ) and generally functions as a global regulator of virulence . as shown in fig . 1 , the qsec histidine kinase is comprised of a periplasmic sensor domain , two membranespanning domains , and a cytoplasmic kinase domain . the qseb response regulator is comprised of a receiver domain and a helixturnhelix ( hth ) dna binding domain . qsebc is one of the few tcs where the signal that activates the sensor has been identified for several organisms and the regulon that is controlled by the system has been characterized . this review focuses on the distribution of the qsebc tcs , the mechanisms of activation of the sensor kinase and response regulator , the signal transduction pathways that are initiated upon activation of the system , and the regulons and functional outcomes of qsebc . it will also highlight the similarities and differences of this system in pathogens that colonize mucosal surfaces in the human oral cavity and in the gastrointestinal and urogenital tracts . schematic illustrating the structural domains of the qsec histidine kinase and the qseb response regulator . the national center for biotechnology information ( ncbi ) protein database contains over 12,000 proteins that exhibit similarity to the conserved protein domain family prk10337 , which is designated as sensor protein qsec . however , prk10337 encompasses the cytoplasmic kinase and atpase domains that are highly conserved across a wide range of sensor kinase polypeptides . hence , it is likely that many of these 12,000 proteins are not paralogs of qsec but instead represent sensor kinases of other tcs . in contrast , a search of the ncbi gene database for genes that are annotated as qsec yielded a more limited set of only 164 genes . of these , 159 are encoded by , and proteobacteria and the remaining five are contained in eukaryotic genomes . consistent with this , a protein blast search carried out by clarke et al . ( 2006 ) using only the periplasmic sensor domain of escherichia coli qsec identified related sequences in the genera shigella , salmonella , erwinia , haemophilus , pasteurella , actinobacillus , chromobacterium , rubrivivax , thiobacillus , ralstonia , psychrobacter and aspergillus . similar results were obtained using the periplasmic sensor domain of aggregatibacter actinomycetemcomitans qsec ( residues 37169 ) as a probe . this search identified qseclike sequences primarily in the , and proteobacteria ( see table 1 ) . a further comparison of the periplasmic sensor domains of qseclike sequences encoded by organisms in the enterobacteriaceae and pasteurellaceae families showed that the eyrdd motif ( boxed in fig . 2 ) which was previously shown to be essential for qsec signal recognition in a. actinomycetemcomitans ( weigel et al . , 2015 ) and haemophilus influenzae ( steele et al . , 2012 ) was conserved in all sequences . a similar acidic motif is also present in multiple copies in the pmrb sensor of salmonella enterica , which is closely related to qsec . further examination of the qseclike sequences in fig . 2 identified two additional acidic motifs that are highly conserved ( shown in red ) . comparison of qseclike proteins with the periplasmic sensor domain of aggregatibacter actinomycetemcomitans qsec coverage represents the portion ( in per cent ) of the probe sequence that exhibits similarity to the target sequence . the acidic motifs present in the periplasmic signal domain of a. actinomycetemcomitans qsec are highlighted in red in fig . 1 . ' + ' indicates that the motif was conserved in all of the sequences that were examined ; ' indicates that the motif was conserved in some of the sequences ; ' indicates that the motif was not conserved in the sequences that were examined . only one organism in this family , basilea psittacipulmonis , exhibited 54% sequence identity with the periplasmic signal domain of a. actinomycetemcomitans qsec and contained all three acidic motifs . the mediterranean fruit fly , ceratitis capitata , exhibited 43% sequence identity across 80 residues in the periplasmic domain and contains the three acidic motifs present in qsec of enterobacteria and pasteurellales . alignment of sequences derived from the qsec periplasmic sensor domains of the following organisms : aa , aggregatibacter actinomycetemcomitans ; ec , escherichia coli ; se , salmonella enterica ; sf , shigella flexneri ; pa , pectobacterium atrosepticum ; ecl , enterobacter cloacae ; pan , pantoea ananatis ; sm , serratia marsescens ; kp , klebsiella pneumonia ; ap , actinobacillus pleuropneumoniae ; hi , haemophilus influenzae ; pm , pasteurella multocida ; bp , basilea psittacipulmonis ; cc , ceratitis capitatta ; and lh , laribacter hongkongensis . three conserved acidic motifs are shown in red text and the motif that is essential for signal binding is boxed . only two qseclike sequences outside the enterobacteriaceae and pasteurellaceae families showed similar high levels of sequence identity of the periplasmic sensor domain and conservation of the acidic motifs described above ; qsec of basilea psittacipulmonis in the family alcaligenaceae and , surprisingly , qsec encoded by the mediterranean fruit fly , ceratitis capitata . both of these proteins also possess the cytoplasmic kinase , dimer interface and atpase domains that are present in the other qsec polypeptides . as shown in table 1 , the qseclike proteins encoded by the remaining families and orders of organisms either exhibited lower overall sequence identity ( typically < 40% ) , exhibited similarity to only a portion of the a. actinomycetemcomitans sensor domain or both . these qseclike proteins also lacked the conserved acidic motif(s ) that is essential for qsec signal recognition . as a representative example , the qseclike sequence from laribacter hongkongensis ( family neisseriaceae ) is included in fig . this sequence exhibits only 30% identity to the sensor domain of a. actinomycetemcomitans qsec and lacks the eyrdd motif involved in signal recognition . together , the comparisons described above suggest that qsec is structurally and functionally conserved mainly in the enterobacteriaceae and pasteurellaceae and in a limited number of organisms outside of these groups . furthermore , the observation that the eyrdd motif involved in qsec signal recognition is not conserved in the qseclike sequences in the other organisms suggests that these sensors may respond to different stimuli . however , it is also possible that sensor proteins exist that are functionally related to qsec but without significant sequence similarity in the sensory domain . for example , the qseclike sensor of francisella tularensis is reported to be functionally interchangeable with qsec of e. coli ( rasko et al . , 2008 ) but the periplasmic domain of this protein exhibits no homology with the sensor domain of the e. coli or a. actinomycetemcomitans qsec proteins . this review will focus primarily on the properties and activities of qsec in the enterobacteriaceae and pasteurellaceae . in many organisms , the qsebc locus is associated with another gene , designated ygiw , that encodes a putative periplasmic protein in the ob fold family ( ginalski et al . , 2004 ) , but transcription and genetic organization of ygiw relative to the qsebc operon varies . as shown in fig . ( 2013 ) have shown that an attenuator stem loop exists in the intergenic region between ygiw and qsebc in h. influenzae and a. actinomycetemcomitans , respectively . hence , primary transcripts encoding ygiw alone and ygiwqsebc are produced by these organisms and the overall expression of qsebc is reduced relative to ygiw ( steele et al . , 2012 ) . a similar attenuation of qsebc transcription probably occurs in actinobacillus pleuropneumoniae and b. psittacipulmonis as both of these operons also contain an inverted repeat in the ygiwqseb intergenic region that may form a stem loop resembling a rhoindependent terminator . ygiw also resides upstream of qsebc in many of the available enterobacteriaceae genome sequences , but in these organisms it is transcribed from the opposite strand ( see fig . finally , in organisms such as serratia marsescens , pasteurella multocida and l. hongkongensis , ygiw is not adjacent to the qsebc locus ( see fig . comparison of the organization of the qsebc locus . in many organisms in the enterbacteriaceae and pasteurellaceae families , ygiw is adjacent to qsebc and is either cotranscribed with qsebc ( a ) or transcribed from the opposite strand as qsebc ( b ) . for other organisms , ygiw is not adjacent to qsebc ( c ) and is either located elsewhere in the genome or is not present at all . transcription of ygiw has been shown to be regulated by the qseb response regulator s. enterica ( merighi et al . , 2009 ) , a. actinomycetemcomitans ( juarezrodriguez et al . , 2013 ) and h. influenzae ( steele et al . , 2012 ) , and presumably in the other organisms shown in fig . ( 2013 ) showed that visp ( ygiw ) encodes a protein that binds to the sugar moiety of peptidoglycan and inhibits fe/ketoglutaratedependent dioxygenase ( lpxo ) . this results in decreased lpxodependent modification of lipopolysaccharide and increased resistance to stressors within the vacuole during intramacrophage replication . however , visp was also shown to function independently of lpxo in a murine colitis model and conferred resistance to cationic antimicrobial peptides ( moreira et al . , 2013 ) . similarly in e. coli , ygiw has been suggested to be part of a stress response circuit that confers resistance to hydrogen peroxide , cadmium and acid stress ( lee et al . sperandio et al . ( 1999 ) showed that expression of the locus of enterocyte effacement ( lee ) operon encoding the type iii secretion system ( ttss ) of enterohaemorrhagic e. coli ( ehec ) serotype o157:h7 was induced by autoinducer2 ( ai2)dependent quorum sensing and to identify other potential quorumsensingregulated virulence genes and regulatory components , a gene array was hybridized with cdna derived from e. coli o157:h7 or an isogenic luxs mutant . the quorumsensing e. coli regulator b and c ( qsebc ) was identified in these studies as a tcs that was regulated by ai2dependent quorum sensing ( sperandio et al . , 2002 ) . this study also showed that the motility of a luxs , but not qsec , mutant could be restored by exogenous ai2 , suggesting that qsebc is necessary to respond to ai2 . ( 2006 ) subsequently showed that ai2 increased biofilm growth of wildtype e. coli mg1655 but not an isogenic qsebc mutant . ( 2010 ) showed that qsebc expression in a. actinomycetemcomitans was induced by exogenous ai2 and that induction required the putative ai2 receptors , lsrb and rbsb . athough each of these studies suggested that qsebc may represent a part of the ai2 signaling circuit , they did not directly demonstrate that ai2 functions as a signal that activates the qsec sensor . indeed , ai2 that was partially purified by chromatography on a c18 sep pack column was shown to induce bioluminescence of a vibrio harveyi reporter strain , but this preparation failed to induce expression of the lee1 operon , restore type iii secretion , or induce qsebc expression in ehec . in contrast , a fraction that was eluted with methanol increased transcription of lee1 and qsebc ( sperandio et al . , the structure of this compound , designated autoinducer3 ( ai3 ) has not yet been determined but electrospray mass spectroscopy demonstrated a major peak of 213.1 da and several minor peaks between 109.1 da and 222.9 da . ( 2006 ) also suggested that ai2 does not directly activate the qsec sensor and showed that stimulation of e. coli biofilm growth by ai2 requires the protein encoded by open reading frame b3022 , which in turn regulates qsebc . b3022 was designated mqsr ( motility quorumsensing regulator ) and is now known to be a cguspecific mrna interferase ( yamaguchi & inouye , 2009 ) . this signaling mechanism may also function in a. actinomycetemcomitans , which encodes a homolog of mqsr ( novak et al . , 2010 ) , but not in e. coli o157:h7 which lacks this gene . hence , ai2 is not the signal that activates qsec and it is possible that the link between ai2 quorum sensing and qsebc function may exist only in organisms that also express mqsr . in contrast , ai3 represents an autoinducer that directly signals through qsec but its initial identification was confounded by the fact that ai3 production is reduced as a result of the metabolic deficiency that is caused by the inactivation of the ai2 synthase luxs ( walters et al . , 2006 ) . ( 2006 ) also showed that ai3 is produced by other enterobacteria such as shigella sp . however , it is not known if ai3 is more widely produced by other groups of organisms , as is ai2 . for example , we have so far been unable to identify ai3 in a. actinomycetemcomitans ( weigel et al . , ( 2003 ) also showed that the ability of the ehec luxs mutant ( deficient in ai3 production ) to generate attaching and effacing ( a / e ) lesions on hela cells was indistinguishable from the parent strain . this was surprising because in the absence of ai3 , the expression of the lee operon encoding the ttss required for the development of a / e lesions should be significantly reduced . consistent with this , type iii secretion of the luxs mutant was restored when bacteria were incubated with conditioned medium from hela cells that were size fractionated for compounds > 1 kda . it was subsequently shown that purified epinephrine ( ep ) or norepinephrine ( ne ) at physiologic concentrations ( i.e. 50 m ) increased expression of lee1 and activated type iii secretion in the luxs mutant . furthermore , complementation of ai3 deficiency by these hormones was blocked by and adrenergic antagonists ( sperandio et al . in addition , a qsec mutant was not complemented by exogenous ai3 or ep whereas each compound complemented the ehec luxs mutant , suggesting that both ai3 and ep may signal via the qsec sensor . ( 2006 ) , who showed that ne and ai3 bound to the periplasmic domain of qsec and induced autophosphorylation of the sensor . binding and autophosphorylation of qsec were significantly reduced in the presence of an adrenergic receptor antagonist . hence , the e. coli qsec sensor mediates both interspecies and interkingdom signaling and is activated by signals that are produced by bacteria ( ai3 ) and the eukaryotic host ( ep , ne ) . in addition , moreira & sperandio ( 2012 ) suggest that the qsec paralog in s. enterica ( preb ) functions as an adrenergic receptor whereas merighi et al . although biochemical identification of the signals that activate many of the other qsec paralogs shown in fig . 2 has not been reported , some surprising differences exist for those that have been characterized . ( 2015 ) showed that a. actinomycetemcomitans qsec is activated by a combination of catecholamine hormones and iron , but not by either compound individually . this suggests that a catecholamine iron complex may be the signal that is recognized by the a. actinomycetemcomitans sensor , or alternatively that catecholamines and iron interact individually with the sensor and activation of qsec occurs only when both are bound . in addition , as production of ai3 by a. actinomycetemcomitans has not yet been demonstrated ( weigel et al . , 2015 ) , catecholamine hormones and interestingly , qsebc expression in e. coli is also induced by elevated levels of fe but qsec is not directly activated by iron . instead , iron activates the pmrb sensor , which in turn phosphorylates response regulator pmra . ( 2013 ) showed that the pmrb sensor phosphorylates the noncognate qseb response regulator , which autoregulates the qsebc operon ( see below ) . the pmrab genes are not present in the a. actinomycetemcomitans genome but the qseb binding site in the ygiwqsebc promoter is identical to the consensus pmra binding sequence in the pmrab operon of e. coli ( juarezrodriguez et al . , 2014 ) . hence , it is possible that in the absence of pmrab , the a. actinomycetemcomitans qsec sensor may have evolved to integrate the iron and catecholamine sensory functions of the pmrab and qsebc tcss of e. coli . in contrast with qsec from e. coli and a. actinomycetemcomitans , the qsec paralog of h. influenzae is activated only by ferrous iron or zinc , and does not appear to respond to ep or ne . hence this tcs was designated as a ferrousironresponsive system ( firs ) ( steele et al . , 2012 ) . iron activation of the firs also differed from iron activation of a. actinomycetemcomitans qsec in that both ferrous and ferric iron activates a. actinomycetemcomitans qsec in the presence of catecholamines ( weigel et al . , 2015 ) whereas only ferrous iron activates h. influenzae firs ( steele et al . , 2012 ) . this is interesting because a dyred motif in the periplasmic domain of firs is conserved in a. actinomycetemcomitans qsec ( eyrdd , see fig . 2 ) and both sequences have been shown to be essential for activation of the respective sensors ( steele et al . , 2012 ; hence , as summarized in table 2 , a variety of signals including ai3 , catecholamine hormones , iron and zinc , have been shown to activate qsec and the responsiveness of qsec to each of these signals can differ among organisms . furthermore , there is increasing evidence that other signaling mechanisms that are independent of qsec may mediate the response of some organisms to catecholamine hormones ( karavolos et al . , 2013 ) and it is possible that h. influenzae responds to catecholamines via one of these pathways rather than qsec ( firs ) . finally , qsebc expression in actinobacillus pleuropneumoniae is also induced by ep and ne ( li et al . , 2012 ) , suggesting that catecholamine hormones may function to activate the qsec sensor in this organism , but this has not yet been directly demonstrated . signals that activate the qsec sensor activation of qsec occurs only in the presence of both the catecholamine and iron . similar to most other tcs , the activation of qsec leads to phosphorylation of the qseb response regulator and several studies have confirmed this either by directly demonstrating phosphate transfer ( clarke et al . , 2006 ) or by showing that sitespecific mutation of the conserved asp inhibits qseb function ( kostakioti et al . , 2009 ; juarezrodriguez et al . , 2014 ) . in addition , using a mobility shift assay , clarke & sperandio ( 2005a , b ) demonstrated that phosphorylation of qseb is required for it to bind to qsebregulated promoters in vitro . one of the initial outcomes resulting from activation of qseb is the autoinduction of the qsebc operon and ygiw and the induction of ygiw expression occurs regardless of the architecture of the ygiwqsebc locus ( see fig . the promoter that drives ygiwqsebc expression resides completely within a fragment of 138 bp upstream from the ygiw start codon ( juarezrodriguez et al . , 2013 ) and two transcriptional start sites at nucleotides 15 and 53 have been mapped in this region ( juarezrodriguez et al . , 2014 ) . the distal initiation site at nucleotide 53 is the main transcriptional start site and although both sites are associated with putative 10 and 35 elements , only the upstream promoter is regulated by qsebc . within this promoter , qseb binds to the direct repeat sequence cttaan6cttaa where the cttaa repeats flank the 35 element . similar to a. actinomycetemcomitans , the qsebc promoter of ehec also contains two transcriptional initiation sites at nucleotides 27 and 77 relative to the qseb start codon ; each is associated with putative 10 and 35 elements and the distal promoter is regulated by qsebc . however , using dnase footprinting , two qseb binding sites were mapped in this promoter , a highaffinity site that appears to overlap the distal transcriptional start site and a lowaffinity site located upstream between nucleotides 409 and 423 ( clarke & sperandio , 2005b ) . comparison of these sites with the promoter sequence of the qsebregulated flhdc operon generated a qseb binding consensus sequence , caattacgaatta , where the underlined residues are most highly conserved ( clarke & sperandio , 2005a ) . however , a direct repeat cttaan6cttaa identical to the qseb binding site in a. actinomycetemcomitans overlaps the 10 element of the qsebregulated distal promoter and this site was suggested by guckes et al . ( 2013 ) to be the site in the qsebc promoter that is bound by the pmra response regulator . given the proximity of this repeat sequence to the protected region identified by dnase footprinting ( clarke & sperandio , 2005b ) , it is possible that this direct repeat also represents the qseb binding site in ehec . there is also growing evidence that activation of qseb may be modulated by several additional mechanisms . ( 2014 ) showed that lacz expression from the ygiwqsebc promoter was significantly reduced in a qsebc strain of a. actinomycetemcomitans and that expression was complemented to wildtype levels by a singlecopy chromosomal insertion of qsebc . interestingly , partial complementation of lacz expression was obtained by a single copy insertion of qseb but not by qsebda . this suggests that qseb can be phosphorylated and partially activated in the absence of qsec . a similar reaction occurs in e. coli ( kostakioti et al . , 2009 ) . in e. coli , the absence of qsec results in constitutively high qseb transcription that arises from bidirectional crossregulation between the structurally related qsebc and pmrab tcs ( guckes et al . , 2013 ) . without qsec , the noncognate pmrb sensor phosphorylates qseb and this reaction exhibits kinetics similar to phosphorylation of qseb by its cognate sensor ( guckes et al . , 2013 ) . as a result , in contrast , transcription of ygiwqsebc is not constitutively high in the absence of qsec in a. actinomycetemcomitans . one explanation for this is that a. actinomycetemcomitans genome does not encode the pmrab tcs . partial activation of qseb in the absence of qsec in a. actinomycetemcomitans may instead result from inefficient phosphorylation by other noncognate sensors , or alternatively by the transfer of a phosphate from the small phosphate donor acetylphosphate ( wolfe , 2005 ) . consistent with the latter possibility , the genes that encode enzymes required for the production of acetyl phosphate are present in a. actinomycetemcomitans genome . qseb activation can also be modulated by dephosphorylation mediated by either qsec or pmrb ( kostakioti et al . incubation of phosphoqseb with vesicles containing qsec resulted in the rapid loss of phosphate from the response regulator and a concomitant increase in phosphoqsec , indicating that qsec can reverse phosphate flow via dephosphorylation of qseb . a similar reaction occurs with pmrb , but although the kinetics of pmrbmediated activation of qseb are similar to qsec , the kinetics of pmrbmediated dephosphorylation are significantly slower than qsec . together , these results suggest that qseb activation can occur through interaction with either cognate or noncognate sensors but is modulated primarily by the phosphatase activity of the cognate qsec . ( 2009 ) suggested that unphosphorylated qseb may play an active role in regulating e. coli motility by repressing flhdc expression . overexpression of qseb in a qsec strain resulted in a decrease in cell motility and a fivefold reduction in lacz activity from a reporter construct containing the flhdc promoter , presumably arising from an overabundance of unphosphorylated qseb . unphosphorylated qseb was also shown by motility shift experiments to bind to the flhdc promoter at a site between the high and lowaffinity qseb binding sites that are bound by phosphoqseb ( hughes et al . , 2009 ) . together , this suggests that qsec controls transcription of flhdc via qseb and that qseb plays a dual role in its phosphorylated and unphosphorylated forms to fine tune this process . these results also suggest the possibility that qseb may play a broader regulatory role in gene expression by controlling the transcription of other genes in its unphosphorylated form . ( 2009 ) also suggest that the qsec sensor is capable of activating several noncognate response regulators . by screening a panel of 31 purified e. coli response regulators , qsef is a response regulator that is also activated by its cognate sensor , the qsee adrenergic receptor ( reading et al . , 2009 ) , indicating that cross talk occurs between the two catecholamine responsive tcs of e. coli . kdpe is also activated by its cognate sensor kdpd , which responds to changes in osmolarity and various metabolites ( hughes et al . , 2009 ) . of the 344 genes induced by qsec that have been identified ( see below ) , 336 are present in the regulons of these three response regulators that are activated by phosphorylation via qsec . finally , two recent studies suggest that the transcription of the qsebc operon is also regulated by nucleoidassociated proteins . sharma & casey ( 2014 ) demonstrated that deletion of hha resulted in a decrease in motility of ehec and compared the contribution and hierarchy of hha and qsebc in controlling ehec motility . using single and double gene deletion mutants , they showed that transcription of qsec was significantly reduced in a hhadeficient background relative to wildtype or a complemented strain and that hha was hierarchically superior to qsebc in regulating motility . ( 2014 ) identified three integration host factor ( ihf ) binding sites in the ygiwqsebc promoter region of a. actinomycetemcomitans . one of these sites was located just upstream from the qseb binding direct repeat sequence and deletion of this region reduced ygiwqsebc expression by approximately 2.5fold , suggesting that binding of ihf to this site positively regulates transcription of ygiwqsebc . the other ihf binding sites mapped to the region between the 10 and 35 elements of the proximal promoter and a sequence near the 5end of the ygiw open reading frame . presumably , one or both of these sites function as negative regulators of expression since deleting ihfa or ihfb in a. actinomycetemcomitans results in a net twofold increase in ygiwqsebc expression . in many organisms for which qsebc has been characterized , this tcs functions as a global regulator that controls complex phenotypes such as biofilm formation and virulence . ( 2010 ) showed that inactivation of qsec in a. actinomycetemcomitans reduced total biofilm biomass and average biofilm depth by greater than 90% and complementation of the mutant with a plasmidborne copy of qsec restored biomass and biofilm depth to levels even greater than the wildtype , presumably due to the presence of qsec in multicopy . ( 2014 ) also obtained a similar biofilm phenotype using a strain of a. actinomycetemcomitans that expressed qsec with an inframe deletion of the periplasmic sensor domain . this suggests that the interaction of catecholamines and iron with the sensor domain of qsec is required for stimulation of biofilm growth and consistent with this , an increase in biofilm biomass occurs when a. actinomycetemcomitans is cultured in the presence of ep or ne and iron ( w.a . weigel and d.r . ( 2014 ) showed that ep and ne increased e. coli k12 biofilm formation by approximately 50% over control cultures that were grown without the hormone . furthermore , an isogenic qsec mutant exhibited a reduction in biofilm growth of approximately 80% in control medium and exhibited little increase in biofilm biomass when cultured in the presence of catecholamines . 2012 ) also showed that a qsecdeficient strain of h. influenzae exhibited a significant decrease in biofilm formation relative to wildtype when cultured under static , semistatic or open flow conditions . catecholamine hormones have also been shown to stimulate the planktonic growth of other organisms such as bordetella , e. coli , and s. enterica ( freestone et al . , 2000 , 2008 ) , suggesting that activation of qsebc by catecholamines may promote sessile growth of these organisms as well . however , it is also important to note that induction of actinobacillus pleuropneumoniae growth by ep and ne has recently been demonstrated to occur independently of qsebc ( li et al . , 2015 ) , suggesting that alternative mechanisms may exist to promote growth by catecholamines . ( 2013 ) suggest that other sensor kinases such as qsee , bass and cpxa may also play a role in catecholamine interkingdom communication . comparing wildtype and qsebc mutant strains using a variety of in vitro and in vivo model systems qsebc has been shown to regulate the expression of genes associated with production of flagella and motility of ehec ( sperandio et al . , 2002 ) and a qsec mutant exhibited attenuated virulence after intragastric inoculation in a rabbit model ( clarke et al . the lee pathogenicity island encoding a ttss and various effector proteins are also under qsecdependent regulation but this does not occur through direct activation by qseb ( hughes et al . , 2009 ) . instead , qsec activates a noncognate response regulator , kdpe , which in turn induces the expression of ler , the main activator of the lee loci . finally , qsec also regulates the expression of a second tcs , qseef , which is essential for pedestal formation and the formation of attaching and effacing ( a / e ) lesions ( reading et al . , 2007 ) . indeed , as discussed in greater detail below , qsebc initiates a complex signaling cascade that integrates both positive and negative controls of ehec virulence factors ( hughes et al . , 2009 ; pifer & sperandio , 2014 ) . in uropathogenic e. coli , deletion of qsec resulted in reduced bladder titers and decreased formation of intracellular bacterial communities in a mouse acute infection model ( kostakioti et al . , 2009 ) , and a decreased ability to establish chronic cystitis ( kostakioti et al . , 2012 ) . this was partially explained by a reduction in the production of the type 1 pilus , which led to decreased adherence and invasion of bladder epithelial cells . restoration of type 1 pilus production in the qsec mutant increased adherence , invasion , and the ability to establish a chronic infection . however , the complemented strain still exhibited a fitness disadvantage relative to wildtype ( kostakioti et al . , 2012 ) , suggesting that a functional qsec sensor is necessary for maintaining chronic uropathogenic e. coli infections . several studies have shown that catecholamine hormones enhance salmonella virulence ( williams et al . , 2006 ; methner et al . , 2008 ) but there is some controversy over whether qsebc mediates this process . in s. enterica serovar typhimurium , qsebc was shown to be required for invasion of hela cells and for intracellular replication in j774 macrophages ( moreira et al . , 2010 ; moreira & sperandio , 2012 ) . in addition , a qsec mutant exhibited attenuated virulence in a mouse systemic infection model ( rasko et al . 2010 ) and decreased colonization of the swine gastrointestinal tract ( bearson & bearson , 2008 ) . similarly , a qsec mutant of s. enterica serovar dublin was reported to be attenuated after oral infection of cattle ( pullinger et al . , 2010b ) . in contrast , virulence of a qsec mutant of s. enterica serovar typhimurium did not differ from wildtype in a bovine ligated ileal loop model ( pullinger et al . this inconsistency has not yet been fully explained but may arise from differences in the strains , media , assay systems and/or constructs used in these studies . there is also differing evidence to correlate the function of qsebc and virulence in oral and respiratory pathogens . using a mouse model of periodontitis , novak et al . ( 2010 ) showed that after oral infection , wildtype a. actinomycetemcomitans significantly induced the resorption of alveolar bone , one of the main clinical symptoms of periodontal disease in humans . in contrast , a qsec mutant was avirulent and bone loss in the group of mice infected with the mutant strain was indistinguishable from that in the shaminfected controls . similar to a. actinomycetemcomitans , expression of the qsebc operon in actinobacillus pleuropneumoniae is induced by both ep and ne ( li et al . , 2012 ) and catecholamines induce several other virulence factors as well , including apxla ( encoding a toxin in the rtx family ) , pgab ( production of extracellular matrix carbohydrate ) and apl_0443 ( autotransporter adhesion ) . inactivation of the qsebc operon also resulted in reduced expression of 17 actinobacillus pleuropneumoniae genes including hugz , encoding a putative heme / iron utilization protein , and pilm encoding a tfp pilus assembly protein ( liu et al . , pilm mediates adherence of actinobacillus pleuropneumoniae to porcine lung cells and qseb was shown to directly bind to the pilm promoter ( liu et al . , 2015 ) . however , following intratracheal challenge , virulence of the qsebc mutant did not significantly differ from wildtype in a porcine pneumonia model ( liu et al . , 2015 ) . interestingly , although pilm expression is reduced in the qsebc strain , deletion of pilm resulted in a significant attenuation of virulence . hence , qsebc regulates an essential virulence factor of actinobacillus pleuropneumoniae but deletion of qsebc does not generate a detectable phenotype . one explanation for this may be that actinobacillus pleuropneumoniae possesses redundant mechanisms that respond to catecholamine hormones and the loss of qsebc is complemented by other pathways . alternatively , pilm expression may be reduced but not completely eliminated in the qsebc mutant and it is possible that the basal level of pilm expression is sufficient to still allow tfp pilus assembly to occur . the qsebc tcs of the fish pathogen eduardsiella tarda also responds to catecholamine hormones and is phylogenetically related to qsebc of ehec and s. enterica . ( wang et al . , 2011 ) and eduardsiella tarda causes intramuscular infections exhibiting hemorrhagic necrotic lesions and suppurative abscesses , suggesting that the organism is capable of cell invasion and systemic spreading . similar to ehec , deletion of qsec or qseb significantly reduced the expression of flagellar genes fldh , flia and mota and the mutated strain exhibited impaired motility . replication of eduardsiella tarda in macrophages is dependent on a ttss and consistent with this , expression of the ttss genes esac and eseb were significantly downregulated in the mutated strain . furthermore , the qseb and qsec mutants were attenuated in virulence by 8 to 16fold in a zebra fish infection model and were outcompeted by the wildtype strain ( wang et al . , 2011 ) . together , these results clearly indicate that the qsebc two tcs of eduardsiella tarda also functions as a global regulator of virulence . finally , the association of qsebc and virulence is not limited to organisms that infect animal hosts , but plant hosts as well . pectobacterium carotovorum causes soft rot in a variety of crop plants including cabbage , onion , radish , and potato and a screen of a transposon library for mutations exhibiting reduced virulence in chinese cabbage identified 14 different loci , including qsec ( lee et al . , 2013 ) . subsequent characterization of the mutant showed that in addition to reduced virulence , the loss of qsec function resulted in an 80% reduction in biofilm growth . in addition , although motility is important for pectobacterium carotovorum virulence ( cui et al . , 2008 ) , qsec did not regulate the expression of flagellar genes as in ehec and the qsec mutant exhibited motility similar to the wildtype strain . given the range of organisms that express qsebc , the broad scope of host organisms that these bacteria infect , and the different virulence strategies tha t are used by these pathogens , it is likely that the qsebc regulon and signaling cascade may be speciesspecific . at present , the qsebc regulons for many of the organisms listed in fig . 2 have not been thoroughly characterized . however , qsecregulated genes and its signaling cascade have been characterized in ehec ( see fig . 4 ) and in the oral pathogen a. actinomycetemcomitans ( see fig . 5 ) . this section will focus on comparing these systems as a model to highlight how the qsebc regulons and signaling cascades may differ . the qsec sensor is activated by autoinducer3 ( ai3 ) and/or catecholamine hormones [ epinephrine ( ep ) , norepinephrine ( ne ) ] and phosphorylates its cognate response regulator qseb and two noncognate response regulators , qsef and kdpe . each of the response regulators induces the expression of specific sets of genes shown in boxes . the noncognate regulators qsef and kdpe can also be activated by their cognate sensors , qsee and kdpd , respectively . like qsec , qsee is activated by ep , ne but it does not interact with ai3 , and kdpd senses osmolarity and potassium . in addition , two quorum sensingregulated lysrtype transcriptional regulatory proteins , qsea and sqsed , contribute to the regulation of the lee locus and qsea also induces the expression of qseef . fuskr senses fucose and functions to downregulate lee expression and the expression of the fuskr operon itself can be downregulated by the qsef response regulator . the qsec sensor is activated by both epinephrine ( ep ) and norepinephrine ( ne ) , and iron and primarily signals through its cognate response regulator qseb to induce genes associated with anaerobic metabolism and energy production and downregulate genes encoding highaffinity iron acquisition proteins ( shown in boxes ) . expression of qsebc is induced by autoinducer2 ( ai2 ) and may involve the mqsr regulator , similar to escherichia coli k12 mg1655 . using a microarray that represented all of the genes in e. coli k12 mg1655 , ehec strains edl933 and sakai , uropathogenic e. coli strain cft073 , and 700 probes representing intergenic regions , hughes et al . ( 2009 ) showed that when ehec was grown in luria bertani broth , 708 genes were upregulated and 126 genes were downregulated in a qsec mutant relative to wildtype . most of the differentially expressed genes represent genes that are in the core e. coli genome ( rasko et al . , 2008 ) and are present in all pathovars . many of these genes code for proteins with metabolic functions . however , 260 of the differentially expressed genes were specific for ehec , indicating that the qsebc regulon differs among the e. coli pathovars . bertani medium , the majority of differentially expressed genes are repressed upon activation of qsec . in contrast , when ehec was cultured under conditions that are conducive to virulence gene expression , e.g. in dulbecco 's modified eagle 's medium containing ai3 , ep , or a combination of both , the overall pattern of differentially expressed genes changed dramatically . under these growth conditions in the presence of ai3 , 106 genes were upregulated and 273 were downregulated , whereas in medium containing both ai3 and ep , 70 genes were upregulated and 311 were downregulated . hence , in dulbecco 's modified eagle 's medium , the expression of the majority of qsecregulated genes was induced . included in the genes that were induced in a qsecdependent manner are the qsebc operon itself , flagellar genes ( flhdc , flia , flic and mota ) and the lee1 operon which encodes ler , the transcriptional activator of the other operons in the lee pathogenicity island . in addition , many genes encoding effectors that are translocated by the ttss were induced by qsec as was stxab , encoding shiga toxin . the stxab genes are late genes encoded by the bacteriophage and expressed during the lytic phase only after induction of the bacterial sos response ( neely & friedman , 1998 ) . consistent with this ( 2009 ) presumed that the induction of the qsecregulated genes was mediated by the qseb response regulator and indeed , qseb was known to bind to the promoters of qsebc and flhdc , the master regulator of the flagella regulon ( clarke & sperandio , 2005a , b ) . however , although qseb interacts with the flhdc promoter , deletion of qseb had no effect on motility and the qseb strain expressed flagella at the same level as wildtype . hence , the phenotype exhibited by the qsec mutant differs from the strain in which its cognate response regulator was deleted . it has subsequently been demonstrated that in ehec , qseb has dual regulatory functions that are dependent upon its state of phosphorylation . nonphosphorylated qseb functions to repress flhdc transcription by interacting with a site in the flhdc promoter that resides between nucleotides 300 and 650 whereas phosphoqseb induces transcription by binding to sites located between nucleotides 650 to 950 and 300 and + 50 ( hughes et al . , 2009 ) . in the absence of qseb , basal levels of flhdc expression ( i.e. qsec independent ) allow for production of flagella and motility whereas in the absence of qsec , qseb remains unphosphorylated and represses flhdc transcription . deletion of qseb also had no effect on the expression of ler or stxab , suggesting that qsecdependent regulation of these genes may be indirect . although it is generally believed that cross talk between a sensor kinase and a noncognate response regulator ( 2005 ) showed that transphosphorylation of noncognate response regulators can occur in vitro . ( 2009 ) showed that qsec was capable of activating two noncognate response regulators , kdpe and qsef , and a functional role for these response regulators was demonstrated using gene deletion mutants . deletion of kdpe reduced the expression of ler but had no effect on stxab expression or motility and deletion of qsef reduced stxab expression but had no effect on ler expression or motility . this suggests that qsecdependent regulation of ler and stxab occurs via qsecmediated activation of the kdpe and qsef response regulators , respectively . as shown in fig . 4 , activation of qsec by ai3 and/or ep results in the phosphorylation of the qseb , kdpe and qsef response regulators , each of which induces the expression of distinct sets of virulence genes . expression of qseef is stimulated by ep in a qsecdependent manner but the qsee sensor itself is also activated by catecholamine hormones . however , qsee is not activated by ai3 ( reading et al . , 2009 ) . the expression of ler is repressed in a glycolytic environment and induced under gluconeogenic conditions and this regulation is mediated by the catabolite repressor / activator protein , cra . kdpe and cra each bind to distinct sites in the ler promoter and their binding is diminished under glycolytic conditions ( njoroge & sperandio , 2012 ; ) . in addition , the interaction of kdpe and cra facilitates binding to their respective sites in the ler promoter . cra and kdpe also function coordinately to facilitate pedestal formation by ehec and regulate the expression of espfu , an effector required for the formation of ae lesions ( njoroge et al . , 2013 ) . finally , cra may also play a role in the posttranscriptional regulation of the lee4 operon . together , these results indicate that the sensing of carbon metabolites via cra integrates with qsec signaling to control the expression of ehec virulence genes . the functions of two additional lysrtype transcriptional regulators are also integrated with qsebc signaling . as shown in fig . 4 , qsea is induced by ai2 and in turn it induces the expression of qseef and also binds to the ler promoter to promote ler expression ( kendall et al . , 2010 ) . in addition , a second lysrtype transcriptional regulator designated qsed is present in a truncated form in ehec and functions to repress ler expression as deletion of this gene results in increased expression of all of the lee operons ( habdas et al . , 2010 ) . qsed expression is repressed in a qsebcdependent manner . finally , a fucose sensing system encoded by fuskr is also integrated with the qsebc cascade . fucose is generated in the gut by cleavage from mucin by commensal organisms such as bacteroides thetaiotaomicron . activation of fuskr represses the expression of ler and other fucose utilization genes , which may allow ehec to conserve energy by limiting virulence gene expression as it transits the mucus layer and also avoid competition with commensals for using fucose as a carbon source ( pacheco et al . conversely , under conditions where virulence gene expression is required and the qsebc signaling cascade is activated , qsef functions to downregulate the expression of fuskr . together , the qsebc cascade and the other signaling mechanisms that integrate with this pathway may function coordinately to allow ehecc to fine tune and optimize virulence gene expression . as shown in fig . 5 , the qsebc regulon and signaling cascade of a. actinomycetemcomitans is significantly different from that of ehec , which may reflect the different niches and virulence strategies that are used by these organisms . the a. actinomycetemcomitans genome does not code for a ttss and the organism is nonmotile and lacks the flagellar apparatus . hence , many of the qsecregulated virulence genes encoded by the lee and flagellar loci of ehec are not present in a. actinomycetemcomitans . overall , 235 genes ( > 11% of the genome ) are differentially expressed when a. actinomycetemcomitans was grown in a chemically defined medium containing ne and iron relative to cultures in the absence of signal ( weigel et al . , 2015 ) . of these , 99 genes are induced and 136 are downregulated in a qsecdependent manner . in contrast to ehec , none of the genes encoding the wellcharacterized virulence factors of a. actinomycetemcomitans , e.g. the rtx leukotoxin , cytolethal distending toxin , tad fimbriae , autotransporter epithelial cell adhesins , emaa , or the pga matrix biogenesis components were upregulated by qsebc . instead , this group includes electron transport components such as a hydrogenase complex and proteins involved in the reduction of nitrate , dmso , trimethylaminenoxide , fumarate and formate . in addition , enzymes associated with the metabolism of aspartate , fumarate , malate , oxaloacetate , pyruvate , and formate were significantly induced upon activation of qsebc in a. actinomycetemcomitans . ( 2010 ) showed that qsebc was required for a. actinomycetemcomitans virulence but the results of weigel et al . ( 2015 ) suggest that the shift in cellular metabolism and energy production that occurs upon activation of qsebc , rather than the direct regulation of virulence factors , may be the primary link between this tcs and a. actinomycetemcomitans virulence . hence , the function of qsebc in a. actinomycetemcomitans may be to prime the organism to persist in an anaerobic host environment . consistent with this , it is striking that many of the genes induced by the activation of qsebc were also identified by jorth et al . ( 2013 ) as being induced during subcutaneous growth in vivo in a mouse abscess model relative to a. actinomycetemcomitans biofilm growth in vitro . finally , the reca and recx genes are induced by qsebc , suggesting that the tcs may influence the sos response in a. actinomycetemcomitans as well as ehec . the genes of the qsebc regulon that are downregulated encode a variety of metabolic functions but a significant number of these genes are associated with iron uptake ( weigel et al . in contrast , the expression of ftnab encoding ferritin is strongly induced , indicating that activation of qsebc increases iron storage capacity and decreases highaffinity acquisition of iron . recent studies suggest that activated neutrophils , polymorphonuclear cells and macrophages release catecholamines and lactoferrin in response to inflammatory stimuli ( brown et al . , 2003 ; , 2007 , 2008 , 2009 ) and catecholamines can function as pseudosiderophores capable of extracting iron from transferrin and lactoferrin ( freestone et al . , 2000 ; anderson & armstrong , 2008 ; bearson & bearson , 2008 ; sandrini et al . , 2010 ) . hence , the inflamed subgingival pocket may be an ironreplete environment and qsebc may play a dual role of priming cellular metabolism as well as allowing a. actinomycetemcomitans to detect and exploit the production of catecholamines by host cells to facilitate the acquisition of iron from lactoferrin or other host ironbinding proteins during infection . the qsebc signal cascade of a. actinomycetemcomitans shown in fig . there is no current evidence to suggest that a. actinomycetemcomitans produces ai3 ( weigel et al . , 2015 ) , so qsec may be activated only by a combination of catecholamines and iron . in a. actinomycetemcomitans , the expression of qsebc is also induced by ai2 , which may occur via the mqsr regulator as described for e. coli k12 mg1655 by gonzalez barrios et al . in addition , a. actinomycetemcomitans does not possess genes encoding the qseef or kdpde tcs , so in contrast with ehec , qseb is the only response regulator that is currently known to be phosphorylated by qsec . similarly , a. actinomycetemcomitans also lacks genes encoding qsea , qsed and fuskr , indicating that the additional signaling pathways that integrate with the qsebc cascade in ehec do not exist in this organism . it is possible that some genes in the a. actinomycetemcomitans qsebc regulon are acted upon indirectly by transcriptional regulators other than qseb , but these additional putative regulatory proteins have not yet been identified . the initial identification of catecholamines as the activating signal for qsec rapidly led to reports that existing and/or adrenergic antagonists functioned to inhibit qsecmediated signaling and suggested that qsec may represent a novel therapeutic target . to identify more potent inhibitors , rasko et al . ( 2008 ) screened a library of 150,000 small organic molecules for candidates that were capable of reducing lacz expression of a lee1::lacz reporter . ultimately , 75 compounds were identified and one , designated led209 ( nphenyl4(3phenylthioureido)benzenesulfonamide ) was chosen for further study . led209 at a concentration of 5 pm was shown to inhibit binding of ne by qsec and to abolish a / e lesion formation on cultured epithelial cells . however , the compound did not influence ligand binding or the function of qsee ( curtis et al . , 2014 ) , indicating that it is specific for qsec . in addition , led209 did not affect the growth of ehec , which is a desirable trait because without survival pressure , it is less likely that ehec will develop resistance to the compound . although it failed to reduce ehec intestinal colonization of infant rabbits , oral administration in mice before and subsequent to intraperitoneal injection of a lethal dose of s. typhimurium resulted in increased survival and reduced recovery of viable bacteria from the spleens and livers of treated animals . similarly , led209 was shown to reduce f. tularensis virulence in a variety of in vitro and in vivo model systems ( rasko et al . , 2008 ) . ( 2014 ) to function as a prodrug and is cleaved within the bacterial cell to generate the active component , which labels cytoplasmic lysine residues 256 and 427 of qsec . substituting arg for lys or lys rendered qsec inactive , confirming their functional importance . presumably , the modification of these cytoplasmic residues alters the conformation of the periplasmic domain to prevent binding of ep or ne , but this has not yet been demonstrated experimentally . in addition , lys and lys are not conserved in the qsec proteins expressed by organisms in the family pasteurellaceae , or in serratia marsescens , pantoea ananatis or b. psittacipulmonis . indeed , in many of these organisms , the residue at position 256 is arg , suggesting that these qsec proteins may be functionally distinct from ehec and that led209 may not be active against these bacteria . led209 has also recently been conjugated with poly(amidoamine ) dendrimers ( pamam ) to successfully improve their selectivity against gramnegative bacteria and reduce the cytotoxic activity of unconjugated pamam against mammalian cells ( xue et al . , 2015 ) . dean & van hoek ( 2015 ) also conducted a small molecule screen to identify potential new therapeutics targeting qsec of francisella novicida . a screen of 420 fdaapproved drugs was conducted and three drugs , toremifene , chlorpromazine and maprotiline , were identified that inhibited qsecdependent formation of biofilms . of these , toremifine and chlorpromazine had additional undesirable activities and were subsequently excluded and maprotiline was chosen for further study . maprotiline significantly reduced the expression of virulence factor lglc encoded on the francisella pathogenicity island and rescued wax worm larvae infected with f. novicida . additional in vivo studies showed that treatment with maprotiline prolonged the time of disease onset and increased the overall survival of f. novicidainfected mice . these results suggest that the fdaapproved polycyclic antidepressant maprotiline may have additional use against francisella infections by targeting the qsec sensor . plant secondary metabolites encompass a broad range of chemical scaffolds and are known to contribute to plant defense systems against bacterial , fungal and insect infections ( langenheim , 1994 ) . ( 2012 ) screened various limonoids derived from citrus species for antibiofilm and ttssinhibitory activity of ehec and identified five compounds that reduced ehec biofilm formation , the most potent of which was isolimonic acid . this compound also reduced ehec adhesion to caco2 cells by approximately threefold without influencing cell viability . as the adherence of ehec to epithelial cells requires a variety of qsecregulated factors , vikram et al . ( 2012 ) subsequently examined the effect of isolimonic acid on the expression of flhc , ler and several other genes encoded by the lee1 and lee2 operons and showed that treatment of bacteria resulted in a 5fold to 12fold reduction of all virulence genes tested . inhibition of gene expression and biofilm formation was subsequently shown to be dependent on qsebc signaling and to also require qsea ; however , its mechanism of action remains to be determined . nonetheless , isolimonic acid likely represents a lead compound for the development of additional , more potent agents that reduce ehec virulence by targeting the qsebc signaling cascade . finally , chaudhari & kariyawasam ( 2014 ) showed that treatment of avian macrophagelike cells with purified recombinant qsec stimulated the expression of interferon , tolllike receptor4 and tolllike receptor15 and that conditioned medium from these cells reduced the expression of virulence genes of avian pathogenic e. coli o78 . this suggests that qsec may induce host innate immune factors that downregulate the expression of important e. coli virulence factors . hence , in addition to representing a viable therapeutic target , it is possible that qsec may also have utility as a potential subunit vaccine candidate . additional functional characterization of qsebc signaling in e. coli , a. actinomycetemcomitans and other organisms may highlight additional similarities and differences in this tcs and should be informative to further develop new drug candidates and therapeutic approaches to circumvent the increase in antibiotic resistance and control microbial infections .

summarythe qsebc twocomponent system ( tcs ) is associated with quorum sensing and functions as a global regulator of virulence . based on sequence similarity within the sensor domain and conservation of an acidic motif essential for signal recognition , qsebc is primarily distributed in the enterobacteriaceae and pasteurellaceae . in escherichia coli , qsec responds to autoinducer3 and/or epinephrine / norepinephrine . binding of epinephrine / norepinephrine is inhibited by adrenergic antagonists ; hence qsec functions as a bacterial adrenergic receptor . aggregatibacter actinomycetemcomitans qsec is activated by a combination of epinephrine / norepinephrine and iron , whereas only iron activates the haemophilus influenzae sensor . qsec phosphorylates qseb but there is growing evidence that qseb is activated by noncognate sensors and regulated by dephosphorylation via qsec . interestingly , the qsebc signaling cascades and regulons differ significantly . in enterohemorrhagic e. coli , qsec induces expression of a second adrenergic tcs and phosphorylates two noncognate response regulators , each of which induces specific sets of virulence genes . this signaling pathway integrates with other regulatory mechanisms mediated by transcriptional regulators qsea and qsed and a fucosesensing tcs and likely controls the level and timing of virulence gene expression . in contrast , a. actinomycetemcomitans qsec signals through qseb to regulate genes involved in anaerobic metabolism and energy production , which may prime cellular metabolism for growth in an anaerobic host niche . qsec represents a novel target for therapeutic intervention and small molecule inhibitors already show promise as broadspectrum antimicrobials . further characterization of qsebc signaling may identify additional differences in qsebc function and inform further development of new therapeutics to control microbial infections .

Toyota Motor Corp's Managing Officer and Chief Communications Officer Julie Hamp speaks to media during a news conference in Nagoya, central Japan, in this photo taken by Kyodo June 17, 2015 and released by Kyodo on June 18, 2015. TOKYO Toyota Motor Corp moved into damage control mode on Friday after its new communications chief Julie Hamp, an American and its first senior woman executive, was arrested on suspicion of illegally bringing pain killers into Japan just two months after her appointment. Toyota President Akio Toyoda apologized for the incident at a news conference and reiterated the company's belief that Hamp had no intent of breaking the law. "To me, executives and staff who are my direct reports are like my children," he said. "It's the responsibility of a parent to protect his children and, if a child causes problems, it's also a parent's responsibility to apologize." Japanese media reports, citing police investigators, said 57 addictive Oxycodone pills were found in a small parcel labeled "necklaces" that was sent from the United States and addressed to Hamp in Japan. The pills were in packets or buried at the bottom of the parcel, which also contained toy pendants and necklaces, they said. Hamp, a former General Motors Co and PepsiCo Inc executive, told police she did not think she had imported an illegal substance, a spokesman for Tokyo's Metropolitan Police Department said. A police official declined to comment on the latest media reports about the parcel. Hamp was appointed managing officer in April as part of a drive to diversify Toyota's male-dominated, mostly Japanese executive line-up. She joined Toyota's North American unit in 2012 and this month relocated to Tokyo, where she was to be based. She had been staying in a hotel, a Toyota spokeswoman said. Toyoda vowed that the automaker would maintain its policy of seeking out talent regardless of gender or nationality and expressed regret that the company had not provided enough support for an employee who was not Japanese and had come to live in Japan. Oxycodone is a prescription drug in both the United States and Japan. Bringing it into Japan requires prior approval from the government and it must be carried by the individual, a health ministry official said. Hiroaki Okamoto, a criminal defense lawyer at the Nakamura International Criminal Defense Office in Tokyo who is not involved in Hamp's case, said the large number of pills meant that, if indicted, she could face years in prison, followed by deportation. The maximum sentence for smuggling drugs with the intent to sell is life in prison, he said. Even if indicted for smuggling for personal use, it would be tough to get a suspended sentence because of the large number of pills, he said. (Additional reporting by Kiyoshi Takenaka; Editing by Edmund Klamann) ||||| Toyota Motor Corp. President Akio Toyoda adjusts his glasses as he attends a press conference in Tokyo Friday, June 19, 2015. Toyoda said he believes an American executive arrested on suspicion of importing... (Associated Press) TOKYO (AP) — Toyota Motor Corp. President Akio Toyoda said Friday he believes an American executive arrested on suspicion of importing a controlled drug into Japan had no intention of breaking the law. Julie Hamp, Toyota's head of public relations and its first senior female executive, was arrested Thursday for allegedly importing the painkiller oxycodone. She was the first foreign Toyota executive to be fully stationed in Japan, and was in the process of moving her belongings from California. At a hastily called news conference Friday, Toyoda bowed and apologized for the troubles set off by the arrest of Hamp, who was tapped as Toyota's chief communications officer in April. He said the company should have done more to help with Hamp's relocation. He declined to go into details of the police allegations, only repeating several times that the company was cooperating fully with the investigation. The drug was found by customs officials in a package Hamp sent to herself by air mail from the United States, according to police. Japanese media reports said the drugs were hidden in various parts of a jewelry box. The high-profile stumble of a media-savvy executive, so early in the game, is an embarrassment for the world's top-selling automaker. Toyota had highlighted Hamp's appointment with much fanfare as a sign that it was promoting diversity. Toyoda said he had picked Hamp, 55, because of "her character." She was an excellent leader, communicating well with Japanese employees, he said. "For me and for Toyota, she is an indispensable and precious teammate," he told reporters. "I believe that we will learn that she had no intent to violate the law." He acknowledged that her appointment had been a "big step" in a globalizing Toyota. Although Japanese Toyota officials had gone abroad to live, she was the first foreign Toyota executive to be fully stationed in Japan. It was unclear when she might be released. Japanese authorities can detain suspects without charge for up to 23 days. Japan has strict controls over drugs. Possession of marijuana, for instance, is a serious crime. Foreigners being detained for mailing or bringing in medicines they used at home is not unheard of. Such drugs may be banned in Japan or require special approval. The U.S. Embassy in Japan warns on its Internet site that Americans can be detained for bringing in prescription drugs that may perfectly legal in the U.S. Earlier this year, Oregon woman Carrie Russell, 26, was detained for 18 days in Japan over a shipment of prescription Adderall for attention-deficit disorder. The drug is commonly prescribed in the U.S. but contains amphetamines, which are outlawed in Japan. She had come to Japan to teach English and shipped in the unopened package of pills that her mother had sent from the U.S. to South Korea. U.S. Ambassador to Japan Caroline Kennedy worked for Russell's release. Japan's government has been beefing up its crackdown on drug abuse this year. About 250 cases of drug smuggling are recorded a year, according to recent government data, with about half of the cases involving foreigners including Americans. It is unclear which ones were over prescription drugs. Public relations experts say Hamp may have to resign because, even if it turns out to be an honest mistake, it's still a mistake and one that reflects lack of awareness about a country she would be expected to have some familiarity with. Before joining Toyota in 2012, Hamp worked for PepsiCo Inc. and General Motors Co. She oversaw marketing and communications for the Toyota, Lexus and Scion brands in the U.S. before her latest promotion. Toyota employees are held to a high ethical standard, and run-ins with the law, even minor misdemeanors, are rare and seen as a disgrace. Toyoda, who faced criticism for being slow in reacting to Toyota's recall crisis of several years ago, emphasized he was responding quickly to the Hamp news. "We still don't have all facts, and what I can say is limited. But I felt it's critical to tell you my thoughts in my own words," Toyoda said. ___ Follow Yuri Kageyama on Twitter at twitter.com/yurikageyama ||||| Thursday’s arrest of a high-profile Toyota Motor Corp. executive highlights the danger globetrotters can face bringing psychotropic or other medications into nations where they are banned. Julie Hamp, named Toyota’s first female managing officer in April, faces drug-smuggling charges after having oxycodone pills sent to her from the United States, said a spokesman for the Tokyo Metropolitan Police, declining to be named on policy grounds. Her arrest was front-page news in Japan, coming amid a widely publicized crackdown on the sale of mood-altering herbs that previously fell outside the nation’s strict laws against recreational drugs. Hamp denies that she imported illegal drugs, the police spokesman said. Toyota spokesman Itsuki Kurosu said in an emailed statement the company is cooperating with the investigation. Hamp, 55, “said she did not believe she had imported narcotics when she was arrested,” another police official said. By midday Friday, she had been sent to the prosecutor’s office, a third official said. In a hastily arranged news conference, Toyota President Akio Toyoda apologized for causing a stir and vowed to cooperate fully with the investigation. He said Hamp is a “very important colleague and for me and Toyota . . . we believe that the investigation will reveal that Ms. Julie Hamp had no intention to violate the law.” Toyoda said he appointed her as the head of communications mainly due to her personality and efforts to work closely with other employees, adding she has been also trying hard to adjust to Japanese culture. The parcel was sent on June 8 from the U.S. and arrived at Narita airport on June 11, the police official said. The package, labelled “necklaces,” contained several small boxes, each holding accessories and several tablets, reports said, adding police suspect there had been an attempt to hide the drug. Hamp was promoted to head of communications for the auto giant earlier this year — making her one of the company’s most senior non-Japanese executives — after previously working at Toyota’s North American division. The incident illustrates the different perceptions of drugs such as oxycodone, an opioid pain medication, which are more casually prescribed in the U.S. No matter how routine at home, the use of psychotropic drugs is strictly controlled in Japan and foreign visitors need to be careful, said Robert Dujarric, a director at the Institute of Contemporary Asian Studies of Temple University. “It’s considered by the authorities as equivalent to a friend mailing you in the U.S. with opium from Afghanistan,” Dujarric said. “Psychotropic medicines as well as prescription drugs that are legal in the U.S. are illegal in Japan,” where there’s stronger concern about addiction, he said. Earlier this year, Carrie Russell of the U.S. was detained for 18 days after her mother mailed her an amphetamine medication for attention-deficit disorder. The 26-year-old English teacher was released in March only after a personal appeal from American Ambassador Caroline Kennedy. The U.S. Embassy in Tokyo warns its citizens to check before mailing or carrying medication to Japan, or face arrest and detention. “Heroin, cocaine, MDMA, opium, cannabis, stimulant drugs including some prescription medications such as Adderall . . . are prohibited in Japan,” the embassy says on its website. “Japanese customs officials or police can detain travellers importing prohibited items. Japanese customs officials do not make on-the-spot ‘humanitarian’ exceptions for medicines that are prohibited in Japan,” it warned. Of the 13,121 individuals charged with drug crimes last year, 778, or 5.9 percent, were foreigners, according to national police data. More than 80 percent of the crimes involved methamphetamines. The same year, cases of drug smuggling rose 11 percent to 245, according to police data, which does not indicate how many cases involved prescription medicines. Japan allows individuals to bring restricted prescription drugs such as oxycodone into the country with prior approval, according to the health ministry’s website, which lists oxycodone as a “narcotic.” It is possible that illegal imports of painkillers and other drugs are increasing, and police decided to send a strong message with the arrest of Hamp, Dujarric said. “It’s either a strong message or there’s something else behind the story.”

– Toyota’s first senior female executive was arrested in Japan yesterday after customs officials allegedly found 57 Oxycodone tablets in a package mailed to her from the US. A package labeled "necklaces" was sent to Julie Hamp from the United States on June 8, and arrived in Japan on June 11, according to the Japan Times. Inside were several boxes with necklaces and pendants, and dozens of pills placed at the bottom, Reuters reports; the AP picks up local media reports that said the drugs were tucked in various parts of a jewelry box and adds that the package was sent by Hamp. According to police, Hamp "did not believe she had imported narcotics when she was arrested." Toyota is rallying around its head of public relations, expressing confidence that "the investigation will reveal that Ms. Julie Hamp had no intention to violate the law." It is unknown whether the 55-year-old has a prescription for the opiates, but transport of the drug into Japan requires a special OK from the government. Hamp faces drug smuggling charges, and a Japanese attorney tells Reuters that the large number of pills found in the parcel may make it difficult for Hamp to avoid jail time. The AP spoke to PR experts who think a resignation may be in the cards for her even if it was an innocent goof, as that would suggest a "lack of awareness about a country she would be expected to have some familiarity with." Toyota President Akio Toyoda today apologized for the arrest and compared his employees to his kids: "It's the responsibility of a parent to protect his children and, if a child causes problems, it's also a parent's responsibility to apologize."

glaucoma is the most common cause of visual impairment or visual loss worldwide , and primary open - angle glaucoma ( poag ) is the most prevalent type of glaucoma . an estimated 70 million people suffer from glaucoma , and asian ethnic minorities are more susceptible to this visual disease . poag is a chronic and aggressive optic neuropathy characterized by loss of optic nerve fibers , leading to elevated intraocular pressure ( iop ) , visual field abnormality , and occurrence of open anterior chamber angle ( http://www.lifesciencesite.com/lsj/life1101/003_21749life1101_18_26.pdf ) . the poag etiology is partly attributed to advanced age , ethnicity , and family history . iop is considered the major risk factor for poag , and an elevated iop ( > 21 mmhg ) influences both the incidence and the progression of poag ; therefore , lowering iop is the primary goal of current treatments in poag patients . timolol is a non - selective beta - adrenergic receptor antagonist that has been widely used for the treatment of elevated iop and glaucoma . timolol is actively metabolized by the drug - metabolizing enzyme cytochrome p450 2c19 ( cyp2c19 ) , improving the efficacy of medical treatment . the use of timolol in poag patients can improve retinal vascular autoregulatory function , including ocular blood flow and blood pressure , thereby reducing the loss of retinal ganglion cells and vision damage . inactive prodrugs require biotransformation into active forms , and drug metabolism is mediated by the hepatic cytochrome p450 ( cyp450 ) system . the hepatic cyp2c19 enzyme , belonging to the cyp450 superfamily , metabolizes several important drugs such as mephenytoin , antidepressants , benzodiazepines , clopidogrel , and timolol . the cyp2c191 , 2 and 3 alleles are the most common loss - of - function alleles that affect cyp2c19-mediated bioactivation of inactive drugs to active metabolites , consequently leading to poor drug pharmacodynamics and intestinal absorption . patients carrying the cyp2c191 variant have full drug - metabolizing capacity , and cyp2c192 and 3 carriers exhibit attenuation of cyp function and impaired drug response ; therefore , individual differences in drug treatment response may be attributed to cyp2c192 and 3 genetic polymorphisms ( http://www.davidpublishing.com/davidpublishing/upfile/8/14/2014/2014081408950324.pdf ) . the present study investigated the cyp2c192 and 3 genetic polymorphisms for their association with the susceptibility to poag and individual differences in drug treatment response . this case - control study was performed in accordance with the guidelines received from the local ethics committee of the affiliated hospital of beihua university . the enrolled patients provided written informed consent for the procedures and agreed to genetic analyses . the study consisted of 93 poag subjects ( male 64 , female 29 ; age range , 19~78 ; average age , 44.810.3 ; bmi , 17~31 ) and 125 controls ( male 73 , female 52 ; age range , 20~76 ; average age , 43.110.7 ; bmi , 17~31 ) , divided into 2 groups ( case and control groups ) . all patients in this study were recruited between march 2013 and may 2014 at the department of ophthalmology , the affiliated hospital of beihua university . the diagnosis of poag was based on diagnostic criteria published by the chinese medical association glaucoma branch in 2008 . the criteria for diagnosis of poag were as follows : 1 ) iop 21 mmhg ; 2 ) abnormal optic disc determined by optical coherence tomography ; 3 ) glaucomatous visual field deletion ( on the basis of mean deviation and corrected pattern standard deviation ) ; 4 ) retinal nerve fiber layer defect ; and 5 ) open anterior chamber angle . patients were excluded if they had histories of chronic obstructive pulmonary diseases , bradycardia ( heart rate < 60 beats per min ) ( bpm ) , atrioventricular heart - block , bronchial asthma , spontaneous hypoglycemia , and diabetics under medication . all patients did not use medication for 3 weeks before inclusion were excluded as well . after all subjects fasted overnight for a period of 1012 h , peripheral venous blood ( 5 ml ) was collected in ethylene diamine tetraacetic acid ( edta ) tubes and stored at 80 c . the whole - blood genomic dna isolation kit ( tiangen biotech ( beijing ) co. ltd ) an ultraviolet spectrophotometer was used to measure the concentration and purity of the dna . cyp2c192 and 3 single - nucleotide polymorphisms ( snps ) were analyzed by polymerase chain reaction - restriction fragment length polymorphism ( pcr - rlfp ) method . the pcr primers were designed by primer premier 5.0 software ( sangon biotech , shanghai , china ) and were synthesized by shanghai sangon biological engineering technology and service co. , ltd . the 50 l - pcr system consisted of 5 l 10 pcr buffer , 1 l dntp ( 10 mmol / l ) , 2 l primer compound , 0.5 l taq enzyme ( 5 u/l ) ( takara ) , and 1 l genomic dna . the amplification conditions were as follows : an initial denaturation step ( 94c for 5 min ) and 35 cycles of denaturation ( 94c for 60 s ) , followed by annealing and extension steps ( 53c for 30 s and 70c for 1 min ) . the sam i restriction digestion reaction consisted of 1 l sam i , 2.0 l 10 t buffer , 2 l 0.1% bsa , 10 l dna , and 5 l double distilled water . the bamhi restriction digestion reaction was as follows : 1 l bamh i , 2.0 l 10 k buffer , 12 l dna , and 5 l double - distilled water . the digestion products were separated on 3% agarose gels containing ethidium bromide and sequenced directly on an abi 370 automated dna sequencer ( abi systems ) . the polymorphisms of cyp2c192 and 3 were divided into 3 phenotypes according to definition of metabolic phenotype : cyp2c191/1 ( extensive metabolizers ) ; cyp2c191/2 and cyp2c191/3 ( intermediate metabolizers ) ; and cyp2c19 2/ 2 , cyp2c19 2/ 3 , and cyp2c19 3/ 3 ( poor metabolizers ) . the case group received 1 drop of 0.5% timolol without punctal occlusion , twice daily at 8 am and 6 pm . after the instillation , iop was measured on days 1 , 3 , 7 , 14 , 21 , and 28 with a perkins hand - held applanation tonometer ( perkins ) , in the sitting position . the iop daily curve was taken after measurements , and hr of patients was also recorded . patients who showed hr lower than 60 bpm after timolol treatment or lower than 20 bpm for the first - time measurement were considered as the side effect group ( se ) , and the remaining patients were considered as the non - side effect group ( nse ) . if patients had hr lower than 45 bpm or symptoms of chest stuffiness , general fatigue , or palpitations at any time during the study , they were requested to immediately stop drug use and consult a doctor . based on the effects of drug treatment and degree of iop improvement , patients were divided into 3 groups : the excellent group ( ex ) ( iop 8 mm hg ) ; the utility group ( ut ) ( 5 < iop 8 mm hg ) ; and the ineffective group ( in ) ( iop 5 mm hg ) . data analysis was performed using spss software for windows ( version 18.0 ; spss , chicago , il ) . the different genotypes of cyp2c192 and 3 polymorphisms were estimated by odds ratios ( ors ) with 95% confidence intervals ( cis ) . all tests were 2-sided , and p values less than 0.05 were considered to be statistically significant . this case - control study was performed in accordance with the guidelines received from the local ethics committee of the affiliated hospital of beihua university . the enrolled patients provided written informed consent for the procedures and agreed to genetic analyses . the study consisted of 93 poag subjects ( male 64 , female 29 ; age range , 19~78 ; average age , 44.810.3 ; bmi , 17~31 ) and 125 controls ( male 73 , female 52 ; age range , 20~76 ; average age , 43.110.7 ; bmi , 17~31 ) , divided into 2 groups ( case and control groups ) . all patients in this study were recruited between march 2013 and may 2014 at the department of ophthalmology , the affiliated hospital of beihua university . the diagnosis of poag was based on diagnostic criteria published by the chinese medical association glaucoma branch in 2008 . the criteria for diagnosis of poag were as follows : 1 ) iop 21 mmhg ; 2 ) abnormal optic disc determined by optical coherence tomography ; 3 ) glaucomatous visual field deletion ( on the basis of mean deviation and corrected pattern standard deviation ) ; 4 ) retinal nerve fiber layer defect ; and 5 ) open anterior chamber angle . patients were excluded if they had histories of chronic obstructive pulmonary diseases , bradycardia ( heart rate < 60 beats per min ) ( bpm ) , atrioventricular heart - block , bronchial asthma , spontaneous hypoglycemia , and diabetics under medication . all patients did not use medication for 3 weeks before inclusion were excluded as well . after all subjects fasted overnight for a period of 1012 h , peripheral venous blood ( 5 ml ) was collected in ethylene diamine tetraacetic acid ( edta ) tubes and stored at 80 c . the whole - blood genomic dna isolation kit ( tiangen biotech ( beijing ) co. ltd ) cyp2c192 and 3 single - nucleotide polymorphisms ( snps ) were analyzed by polymerase chain reaction - restriction fragment length polymorphism ( pcr - rlfp ) method . the pcr primers were designed by primer premier 5.0 software ( sangon biotech , shanghai , china ) and were synthesized by shanghai sangon biological engineering technology and service co. , ltd . the 50 l - pcr system consisted of 5 l 10 pcr buffer , 1 l dntp ( 10 mmol / l ) , 2 l primer compound , 0.5 l taq enzyme ( 5 u/l ) ( takara ) , and 1 l genomic dna . the amplification conditions were as follows : an initial denaturation step ( 94c for 5 min ) and 35 cycles of denaturation ( 94c for 60 s ) , followed by annealing and extension steps ( 53c for 30 s and 70c for 1 min ) . the sam i restriction digestion reaction consisted of 1 l sam i , 2.0 l 10 t buffer , 2 l 0.1% bsa , 10 l dna , and 5 l double distilled water . the bamhi restriction digestion reaction was as follows : 1 l bamh i , 2.0 l 10 k buffer , 12 l dna , and 5 l double - distilled water . the digestion products were separated on 3% agarose gels containing ethidium bromide and sequenced directly on an abi 370 automated dna sequencer ( abi systems ) . the polymorphisms of cyp2c192 and 3 were divided into 3 phenotypes according to definition of metabolic phenotype : cyp2c191/1 ( extensive metabolizers ) ; cyp2c191/2 and cyp2c191/3 ( intermediate metabolizers ) ; and cyp2c19 2/ 2 , cyp2c19 2/ 3 , and cyp2c19 3/ 3 ( poor metabolizers ) . the case group received 1 drop of 0.5% timolol without punctal occlusion , twice daily at 8 am and 6 pm . after the instillation , iop was measured on days 1 , 3 , 7 , 14 , 21 , and 28 with a perkins hand - held applanation tonometer ( perkins ) , in the sitting position . the iop daily curve was taken after measurements , and hr of patients was also recorded . patients who showed hr lower than 60 bpm after timolol treatment or lower than 20 bpm for the first - time measurement were considered as the side effect group ( se ) , and the remaining patients were considered as the non - side effect group ( nse ) . if patients had hr lower than 45 bpm or symptoms of chest stuffiness , general fatigue , or palpitations at any time during the study , they were requested to immediately stop drug use and consult a doctor . based on the effects of drug treatment and degree of iop improvement , patients were divided into 3 groups : the excellent group ( ex ) ( iop 8 mm hg ) ; the utility group ( ut ) ( 5 < iop 8 mm hg ) ; and the ineffective group ( in ) ( iop 5 mm hg ) . data analysis was performed using spss software for windows ( version 18.0 ; spss , chicago , il ) . the different genotypes of cyp2c192 and 3 polymorphisms were estimated by odds ratios ( ors ) with 95% confidence intervals ( cis ) . all tests were 2-sided , and p values less than 0.05 were considered to be statistically significant . the frequencies of cyp2c19 alleles and genotypes are shown in table 2 , and it showed that there were no statistically significant differences in frequencies of cyp2c19 alleles and genotypes between the case group and the control group ( both p>0.05 ) . the results suggest that cyp2c192 and 3 polymorphisms were not associated with susceptibility to poag . no differences in sex , age , or bmi existed between the se group and nse group ( all p>0.05 ) . however , statistically significant differences were observed in cyp2c19 metabolizer phenotypes between the se group and nse group . as seen in table 3 , the frequencies of extensive metabolizer phenotype and poor metabolizer phenotype or poor metabolizer phenotype and intermediate metabolizer phenotype were significantly different ( both p<0.05 ) , but the distributions of intermediate metabolizer phenotype and extensive metabolizer phenotype showed no statistically significant differences ( p>0.05 ) . these results suggest that the poor metabolizer phenotype slows the rate of timolol metabolism , thereby leading to ses . there were no differences in sex , age and bmi among ex group , ut group , and in group ( all p>0.05 ) . distributions of poor metabolizer phenotype and intermediate metabolizer phenotype among ex group , ut group , and in group did not show statistically significant differences ( all p>0.05 ) , while the distributions of intermediate metabolizer phenotype and extensive metabolizer phenotype and extensive metabolizer phenotype and poor metabolizer phenotype among ex group , ut group , and in group were significantly different ( all p<0.05 ) ( table 4 ) . these results revealed that extensive metabolizers rapidly metabolize timolol , contributing to low utilization ratio of the drug and poor treatment responses . the frequencies of cyp2c19 alleles and genotypes are shown in table 2 , and it showed that there were no statistically significant differences in frequencies of cyp2c19 alleles and genotypes between the case group and the control group ( both p>0.05 ) . the results suggest that cyp2c192 and 3 polymorphisms were not associated with susceptibility to poag . no differences in sex , age , or bmi existed between the se group and nse group ( all p>0.05 ) . however , statistically significant differences were observed in cyp2c19 metabolizer phenotypes between the se group and nse group . as seen in table 3 , the frequencies of extensive metabolizer phenotype and poor metabolizer phenotype or poor metabolizer phenotype and intermediate metabolizer phenotype were significantly different ( both p<0.05 ) , but the distributions of intermediate metabolizer phenotype and extensive metabolizer phenotype showed no statistically significant differences ( p>0.05 ) . these results suggest that the poor metabolizer phenotype slows the rate of timolol metabolism , thereby leading to ses . there were no differences in sex , age and bmi among ex group , ut group , and in group ( all p>0.05 ) . distributions of poor metabolizer phenotype and intermediate metabolizer phenotype among ex group , ut group , and in group did not show statistically significant differences ( all p>0.05 ) , while the distributions of intermediate metabolizer phenotype and extensive metabolizer phenotype and extensive metabolizer phenotype and poor metabolizer phenotype among ex group , ut group , and in group were significantly different ( all p<0.05 ) ( table 4 ) . these results revealed that extensive metabolizers rapidly metabolize timolol , contributing to low utilization ratio of the drug and poor treatment responses . cyp450 metabolizes almost 90% of prescribed drugs , and cyp2c19 is an important cyp450 that can also catalyze drugs by inducing oxidation reactions . our study found no association between cyp2c19 polymorphisms and susceptibility to poag , possibly because cyp2c19 affects drug metabolism , and thus is unlikely to be involved in the poag disease process . however , genetic polymorphisms play a critical role in drug responses and adverse drug reactions . a previous study suggested that drug - drug interactions are correlated with activities of cyp2c19 , but the development of poag was not linked with cyp2c19 polymorphism . we support the view that different cyp2c19 metabolizer phenotypes impact drug treatment response to timolol in patients with poag . timolol monotherapy , used for management of poag patients , lowers iop and prevents other complications and drug - related adverse events . a study conducted by frezzotti paolo observed that , despite the iop - lowering effect , 2 formulations of timolol caused varying degrees of adverse events . therefore , combination therapy for glaucoma aims to achieve minimum medication , reduced iop - lowering doses , and improved convenience and compliance for patients , leading to excellent drug effects . owing to the drug metabolic enzymes , treatment of poag using timolol is improved ; however , patients carrying different cyp2c19 phenotypes may differ in drug response . carriers of 1 or more loss - of - function cyp2c19 alleles ( so - called intermediate metabolizers ) prevent drug conversion to their active metabolites and enhance adverse outcomes ( http://circinterventions.ahajournals.org.proxy.its.virginia.edu/content/4/5/514.full ) . accordingly , we support the notion that cyp2c19 genetic variants influence clinical benefits from drug treatment by modulating availability of the active drug ; thus , treatment of poag with timolol must consider these cyp2c19 metabolizer phenotypes . according to cyp2c19 genotypes , there are 3 main phenotypes extensive metabolizers , intermediate metabolizers , and poor metabolizers that are closely correlated with drug utilization , individual response to drug treatment , and drug effects . cyp2c19 polymorphisms are chief pharmacogenetic contributors of individual differences in response to drug treatment because of the carrier status of the cyp2c19 loss - of - function allele . poor metabolizers have lower activities of cyp2c19 enzyme , and the concentration of drug significantly increases , consequently leading to drug toxicity ( http://cdn.intechopen.com/pdfs-wm/39693.pdf ) . in contrast , intermediate and extensive metabolizers exhibit higher drug metabolism and absorption , but the rapid metabolism lower drug effects in the clinic , causing administration of larger doses of the drug and severe side effects . our findings also suggest that different cyp2c19 metabolizer phenotypes , due to cyp2c192 and 3 polymorphisms , have important effects on individual responses to drug treatment and adverse drug reactions . also , we did not use different timolol dosing regimens , which may be a significant study limitation . third , the time of iop measurement and timolol use was not matched , resulting in ignoring the peak of efficacy of drug treatment . additionally , other factors like symptoms and ocular surface staining , which may provide useful information , were not analyzed in the study . finally , we only discussed cyp2c192 and 3 polymorphisms in this paper , but there are other genetic variants of cyp2c19 polymorphisms that could alter the response to timolol treatment , such as 3 , 5 , and 17 . however , we observed that different cyp2c19 metabolizer phenotypes , due to cyp2c192 and 3 polymorphisms , have important effects on individual responses to drug treatment and treatment - related side effects .

backgroundthe aim of this study was to investigate the roles of cytochrome p450 2c19 ( cyp2c19 ) polymorphisms in primary open - angle glaucoma ( poag ) susceptibility and individual responses to drug treatment.material/methodsthis case - control study consisted of 93 cases with poag and 125 controls . polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) was used to analyze cyp2c19 single - nucleotide polymorphisms ( snps ) . after timolol treatment , patients were classified into side effect ( se ) group and non - side effect ( nse ) group . according to drug treatment responses , patients were divided into 3 groups : excellent group ( ex ) ( iop 8 mm hg ) ; utility group ( ut ) ( 5 < iop 8 mm hg ) , and ineffective group ( in ) ( iop 5 mm hg ) . data analysis was performed using spss software.resultswe found no statistical differences in the alleles and genotypes frequencies of cyp2c19 between the case group and the control group ( both p>0.05 ) . frequencies of extensive metabolizer phenotype and poor metabolizer phenotype or poor metabolizer phenotype and intermediate metabolizer phenotype were significantly different between the se group and nse group ( both p<0.05 ) . the distribution of intermediate metabolizer phenotype and extensive metabolizer phenotype were significantly different among ex group , ut group , and in group ( all p<0.05).conclusionswe found no evidence that cyp2c19 polymorphisms are associated with susceptibility to poag . however , different cyp2c19 metabolizer phenotypes were identified and observed to have important effects on the individual differences in drug treatment response .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Federal Judgeship Act of 2013''. SEC. 2. CIRCUIT JUDGES FOR THE CIRCUIT COURTS OF APPEALS. (a) In General.--The President shall appoint, by and with the advice and consent of the Senate-- (1) 4 additional circuit judges for the ninth circuit court of appeals; and (2) 1 additional circuit judge for the sixth circuit court of appeals. (b) Temporary Judgeship.-- (1) In general.--The President shall appoint, by and with the advice and consent of the Senate 1 additional circuit judge for the ninth circuit court of appeals. (2) Vacancy not filled.--The first vacancy in the office of circuit judge in the ninth circuit occurring 10 years or more after the confirmation date of the circuit judge named to fill the temporary circuit judgeship created in the ninth circuit by paragraph (1) shall not be filled. (c) Tables.--In order that the table contained in section 44 of title 28, United States Code, will, with respect to each judicial circuit, reflect the changes in the total number of permanent circuit judgeships authorized as a result of subsection (a) of this section, such table is amended to read as follows: Number of ``Circuits Judges District of Columbia....................................... 11 First...................................................... 6 Second..................................................... 13 Third...................................................... 14 Fourth..................................................... 15 Fifth...................................................... 17 Sixth...................................................... 17 Seventh.................................................... 11 Eighth..................................................... 11 Ninth...................................................... 33 Tenth...................................................... 12 Eleventh................................................... 12 Federal.................................................... 12.''. SEC. 3. DISTRICT JUDGES FOR THE DISTRICT COURTS. (a) In General.--The President shall appoint, by and with the advice and consent of the Senate-- (1) 1 additional district judge for the district of Delaware; (2) 6 additional district judges for the eastern district of California; (3) 2 additional district judges for the eastern district of Texas; (4) 4 additional district judges for the western district of Texas; (5) 6 additional district judges for the district of Arizona; (6) 10 additional district judges for the central district of California; (7) 5 additional district judges for the northern district of California; (8) 2 additional district judges for the district of Colorado; (9) 2 additional district judges for the western district of Washington; (10) 1 additional district judge for the southern district of Indiana; (11) 3 additional district judges for the southern district of Florida; (12) 5 additional district judges for the middle district of Florida; (13) 1 additional district judge for the western district of New York; (14) 1 additional district judge for the northern district of Florida; (15) 1 additional district judge for the western district of Wisconsin; (16) 3 additional district judges for the southern district of California; (17) 2 additional district judges for the eastern district of New York; (18) 2 additional district judges for the district of New Jersey; (19) 1 additional district judge for the district of Idaho; (20) 2 additional district judges for the southern district of Texas; (21) 1 additional district judge for the district of Minnesota; (22) 1 additional district judge for the northern district of Georgia; (23) 1 additional district judge for the district of Nevada; (24) 1 additional district judge for the district of New Mexico; and (25) 1 additional district judge for the southern district of New York. (b) Temporary Judgeships.-- (1) In general.--The President shall appoint, by and with the advice and consent of the Senate-- (A) 1 additional district judge for the eastern district of California; (B) 1 additional district judge for the western district of Texas; (C) 4 additional district judges for the district of Arizona; (D) 2 additional district judges for the central district of California; (E) 1 additional district judge for the northern district of California; (F) 1 additional district judge for the middle district of Florida; (G) 1 additional district judge for the southern district of California; (H) 1 additional district judge for the district of New Jersey; (I) 1 additional district judge for the district of Minnesota; (J) 1 additional district judge for the western district of Missouri; (K) 1 additional district judge for the northern district of Georgia; (L) 1 additional district judge for the district of Nevada; (M) 1 additional district judge for the district of Oregon; (N) 1 additional district judge for the southern district of New York; (O) 1 additional district judge for the middle district of Tennessee; and (P) 1 additional district judge for the eastern district of Virginia. (2) Vacancies not filled.-- (A) In general.--The first vacancy in the office of district judge in each of the offices of district judge authorized by paragraph (1), except for the district of Arizona and the central district of California, occurring 10 years or more after the confirmation date of the judge named to fill the temporary district judgeship created in the applicable district by this subsection, shall not be filled. (B) Arizona.--The first 4 vacancies in the office of district judge in the district of Arizona occurring 10 years or more after the date on which judge are confirmed to fill all 4 temporary district judgeships under paragraph (1)(C), shall not be filled. (C) Central district of california.--The first 2 vacancies in the office of district judge in the central district of California occurring 10 years or more after the date on which judge are confirmed to fill both temporary district judgeships under paragraph (1)(D), shall not be filled. (c) Existing Judgeships.--The existing judgeships for the district of Kansas and the eastern district of Missouri authorized by section 203(c) of the Judicial Improvements Act of 1990 (Public Law 101-650; 28 U.S.C. 133 note) and the existing judgeships for the eastern district of Texas, the district of Arizona, the central district of California, the southern district of Florida, the northern district of Alabama, and the district of New Mexico authorized by section 312(c) of the 21st Century Department of Justice Appropriations Authorization Act (Public Law 107-273, 28 U.S.C. 133 note), as of the effective date of this Act, shall be authorized under section 133 of title 28, United States Code, and the incumbents in those offices shall hold the office under section 133 of title 28, United States Code, as amended by this Act. (d) Tables.--In order that the table contained in section 133 of title 28, United States Code, will, with respect to each judicial district, reflect the changes in the total number of permanent district judgeships authorized as a result of subsections (a) and (c) of this section, such table is amended to read as follows: Number of ``Districts Judges Alabama: Northern................................................. 8 Middle................................................... 3 Southern................................................. 3 Alaska..................................................... 3 Arizona.................................................... 19 Arkansas: Eastern.................................................. 5 Western.................................................. 3 California: Northern................................................. 19 Eastern.................................................. 12 Central.................................................. 38 Southern................................................. 16 Colorado................................................... 9 Connecticut................................................ 8 Delaware................................................... 5 District of Columbia....................................... 15 Florida: Northern................................................. 5 Middle................................................... 20 Southern................................................. 21 Georgia: Northern................................................. 12 Middle................................................... 4 Southern................................................. 3 Hawaii..................................................... 3 Idaho...................................................... 3 Illinois: Northern................................................. 22 Central.................................................. 4 Southern................................................. 4 Indiana: Northern................................................. 5 Southern................................................. 6 Iowa: Northern................................................. 2 Southern................................................. 3 Kansas..................................................... 6 Kentucky: Eastern.................................................. 5 Western.................................................. 4 Eastern and Western...................................... 1 Louisiana: Eastern.................................................. 12 Middle................................................... 3 Western.................................................. 7 Maine...................................................... 3 Maryland................................................... 10 Massachusetts.............................................. 13 Michigan: Eastern.................................................. 15 Western.................................................. 4 Minnesota.................................................. 8 Mississippi: Northern................................................. 3 Southern................................................. 6 Missouri: Eastern.................................................. 7 Western.................................................. 5 Eastern and Western...................................... 2 Montana.................................................... 3 Nebraska................................................... 3 Nevada..................................................... 8 New Hampshire.............................................. 3 New Jersey................................................. 19 New Mexico................................................. 8 New York: Northern................................................. 5 Southern................................................. 29 Eastern.................................................. 17 Western.................................................. 5 North Carolina: Eastern.................................................. 4 Middle................................................... 4 Western.................................................. 4 North Dakota............................................... 2 Ohio: Northern................................................. 11 Southern................................................. 8 Oklahoma: Northern................................................. 3 Eastern.................................................. 1 Western.................................................. 6 Northern, Eastern, and Western........................... 1 Oregon..................................................... 6 Pennsylvania: Eastern.................................................. 22 Middle................................................... 6 Western.................................................. 10 Puerto Rico................................................ 7 Rhode Island............................................... 3 South Carolina............................................. 10 South Dakota............................................... 3 Tennessee: Eastern.................................................. 5 Middle................................................... 4 Western.................................................. 5 Texas: Northern................................................. 12 Southern................................................. 21 Eastern.................................................. 10 Western.................................................. 17 Utah....................................................... 5 Vermont.................................................... 2 Virginia: Eastern.................................................. 11 Western.................................................. 4 Washington: Eastern.................................................. 4 Western.................................................. 9 West Virginia: Northern................................................. 3 Southern................................................. 5 Wisconsin: Eastern.................................................. 5 Western.................................................. 3 Wyoming.................................................... 3.''. SEC. 4. AUTHORIZATION OF APPROPRIATIONS. There are authorized to be appropriated such sums as may be necessary to carry out the provisions of this Act, including such sums as may be necessary to provide appropriate space and facilities for the judicial positions created by this Act.

Federal Judgeship Act of 2013 - Directs the President, with advice and consent of the Senate, to appoint specified additional: (1) permanent circuit judges for the sixth and ninth circuit courts of appeals and a temporary judge for the ninth circuit; and (2) permanent district judges for various judicial districts of Arizona, California, Colorado, Delaware, Florida, Georgia, Idaho, Indiana, Minnesota, Nevada, New Jersey, New Mexico, New York, Texas, Washington, and Wisconsin and temporary district judges for Arizona, California, Florida, Georgia, Minnesota, Missouri, Nevada, New Jersey, New York, Oregon, Tennessee, Texas, and Virginia.

The trend following the 2004 black-box warning about antidepressants and suicide risk was predictable — many adolescents simply stopped taking these drugs. After all, what parent wants to give potent psychiatric meds to kids if it makes them more likely to think about and even attempt suicide? Trouble is, the public response to the warning from the U.S. Food and Drug Administration might have gone too far, leaving depressed teens with less treatment. Now a University of Minnesota researcher is among the first to document the effect — not just on symptoms, but on how depressed teens did in school following the warning and whether they were prone to drug use and delinquency. “Those are all things that have lifelong consequences,” said Ezra Golberstein, a U assistant professor of public health. In the three years following the FDA warning, antidepressant use in adolescents dropped 20 to 30 percent, research has shown. There was no compensating increase in other forms of such therapy as counseling, though, meaning depressed teens simply received less treatment. Over that same time frame, Golberstein found the grade-point average of depressed teen girls dropped from a B to a B-. Depressed adolescents also became more likely to abuse illicit and prescription drugs, and to fight and steal, according to his research, which was based on more than 100,000 responses to the National ­Survey on Drug Use and Health from 2001 through 2007. Teens who weren’t depressed didn’t exhibit the same decline. Researchers were surprised to find more significant behavioral changes among girls with depression. Grades dropped for girls, not boys, in the years after the black box warning. Overall, the rate of stealing increased by 4.6 percentage points among depressed adolescents after the warning, but that trend was entirely driven by girls. It’s unclear why girls with depression were affected more after the black box warning on antidepressants. “At the end of the day for us,” Golberstein said, “it really is a mystery.” No evidence All of these trends might seem lamentable, but acceptable, if the trade-off was fewer adolescents dying by suicide. But there is no evidence of that. Earlier this summer, a study in the British Medical Journal — co-authored by a researcher from Bloomington-based HealthPartners — actually found an increase in attempted suicide by drug overdoses in the years following the black box warning. However, that study found no statistically significant change in teen ­suicides. Golberstein said his research shows the need for more caution and better communication whenever the FDA alters warnings about existing medications. His conclusions also demonstrate the need, he argued, to consider social measures such as academic performance when weighing whether to approve medications for youth or publish warnings about their usage. “These are really huge implications that have lifelong consequences,” Golberstein said. “Maybe we should be finding ways to factor that into the risk-benefit calculus more explicitly.” ||||| In 1994, when Elizabeth Wurtzel wrote “Prozac Nation,” an autobiographical account of her struggles with severe depression, which was later adapted into a feature film under the same title, her story was considered an extreme case of a troubled life. What she described then, however, was already a widespread phenomenon that has now morphed into a national malaise and beyond. Antidepressants and painkillers rank among the most commonly prescribed drugs in the United States today. In 2011, the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics published a report that identified about 11 percent of the American public as antidepressant users, a 400 percent increase since the 1980s when previous surveys were taken. Worldwide, consumption of antidepressants has been dramatically on the rise over the past decade, and there are no signs of abating. On the contrary, the pharmaceutical industry predicts ever-increasing demands in the U.S. and globally. According to the CDC report, people who take antidepressants do so not only to treat depression but also anxiety and other disorders in response to stress. In fact, about 8 percent of those taking antidepressant drugs had no current symptoms of depression at all. Women between the ages of 40 and 59 make up the largest group of antidepressant drug users – about 23 percent. Females in general are more likely to take such medications than males; whites do it in greater numbers than other ethnicities; most users stay on antidepressants for two or more years; less than half ever seek professional help in form of hospitalization or counseling. Experts have offered a wide range of explanations for the growing demand for psychotherapeutic drugs. The heightened economic struggles over the last few years have added substantially to the stress levels vast parts of the population are exposed to. In the media, pharmaceuticals of all kinds, including antidepressants, are aggressively marketed, and many insurance plans cover them. There is also suspicion that many doctors tend to over-diagnose when it comes to psychological disorders, even in cases where they appear to be temporary and mild in nature. The truth is that antidepressant drugs are not harmless and can cause a number of unpleasant side effects, among them nausea, weight gain, loss of sexual desire and erectile dysfunction, insomnia, fatigue, agitation, suicidal thoughts, and even greater anxiety. Experts recommend to switch between different types of antidepressant drugs if debilitating symptoms persist, but they also warn not to take such steps without consulting one’s physician. Generally speaking, taking medications against depression or anxiety should not always be the first measure to find relief. A health-promoting lifestyle that includes eating a balanced diet, regular exercise, and enough sleep can be very helpful in dealing with many disturbances, both of body and mind. That does not mean to underestimate their seriousness, but at least it can provide a much-needed foundation for recovery. Connect with us on Facebook, Twitter and Google+ Timi Gustafson R.D. is a registered dietitian, newspaper columnist, blogger and author of the book “The Healthy Diner – How to Eat Right and Still Have Fun”®, which is available on her blog and at amazon.com. For more articles on nutrition, health and lifestyle, visit her blog, “Food and Health with Timi Gustafson R.D.” (www.timigustafson.com). ||||| The present study aimed at investigating the possible changes of some features of loving relationships during long-term treatment of depression with both selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs), by means of a specifically designed test, the so-called “Sex, Attachment, Love” (SALT) questionnaire. The sample was composed by 192 outpatients (123 women and 69 men, mean age±SD: 41.2±10.2 years), suffering from mild or moderate depression, according to DSM-IV-TR criteria, that were selected if they were treated with one antidepressant only for at least six months and were involved in a loving relationship. The results showed that SSRIs had a significant impact on the feelings of love and attachment towards the partner especially in men, while women taking TCAs complained of more sexual side effects than men. These data were supported also by the detection of a significant interaction between drug and sex on the “Love” and “Sex” domains. The present findings, while demonstrating a dimorphic effect of antidepressants on some component of loving relationships, need to be deepened in future studies.

– People who suffer from depression but are happily in love—perhaps an odd combination—may want to think twice about popping certain antidepressants, LiveScience reports. In a new study, researchers gave two kinds of antidepressants to 192 people who were depressed but in healthy relationships for at least seven months. "Indeed, our subjects were those who could be properly considered smitten by love," says study author Hagop Akiskal. The participants—69 men and 123 women, with a mean age of 41—filled out questionnaires saying how their feelings of attraction, attachment, and love toward their partner changed after taking the drugs. What they found: Participants taking selective serotonin reuptake inhibitors (SSRIs) were more likely to be uncomfortable with "sharing their partners' thoughts and feelings," reports LiveScience, and less hopeful that their love would endure, than those taking taking the other kind—tricyclic antidepressants. Men taking SSRIs were less inclined to ask for advice or help from their partners than women taking SSRIs. Women taking tricyclic antidepressants saw more negative effects on their sex lives than men taking the same drug. "The good news is that there are a variety of agents for treating depression," says Akiskal. Meanwhile, antidepressant consumption has been rising worldwide for the past decade, reports the Seattle Post-Intelligencer in an article that looks at who is using the drugs and why. Teenagers in the US, however, are taking fewer antidepressants—perhaps too few—since an FDA warning about possible suicide risks in 2004, the Minneapolis Star Tribune reports. (But here's some good news for pregnant women taking antidepressants.)

SECTION 1. SHORT TITLE. This Act may be cited as the ``Smithsonian Facilities Authorization Act''. SEC. 2. ADDITIONAL SPACE AND RESOURCES FOR NATIONAL COLLECTIONS HELD BY THE SMITHSONIAN INSTITUTION. (a) In General.--Public Law 94-98 (20 U.S.C. 50 note; 89 Stat. 480) is amended by adding at the end the following: ``SEC. 4. ADDITIONAL SPACE AND RESOURCES FOR NATIONAL COLLECTIONS HELD BY THE SMITHSONIAN INSTITUTION. ``(a) In General.--The Board of Regents of the Smithsonian Institution may plan, design, construct, and equip additional special use storage and laboratory space at the museum support facility of the Smithsonian Institution in Suitland, Maryland, to accommodate the care, preservation, conservation, deposit, and study of national collections held in trust by the Institution. ``(b) Authorization of Appropriations.--There are authorized to be appropriated to carry out this section-- ``(1) $2,000,000 for fiscal year 2003; ``(2) $10,000,000 for fiscal year 2004; and ``(3) such sums as are necessary for each of fiscal years 2005 through 2008.''. (b) Conforming Amendment.--Section 3 of Public Law 94-98 (20 U.S.C. 50 note; 89 Stat. 480) is amended in the first sentence by striking ``the purposes of this Act.'' and inserting ``this Act (other than section 4).''. SEC. 3. PATENT OFFICE BUILDING IMPROVEMENTS. (a) Authorization of Use of Funds.-- (1) In general.--The Board of Regents of the Smithsonian Institution may plan, design, and construct improvements to the interior and exterior of the Patent Office Building (including the construction of a roof covering for the courtyard), using funds available to the Institution from nonappropriated sources. (2) Definition.--In this section, the term ``Patent Office Building'' means the building transferred to the Smithsonian Institution pursuant to Public Law 85-357. (b) Design and Specifications.--The design and specifications for any exterior alterations authorized by subsection (a) shall be-- (1) submitted by the Secretary of the Smithsonian Institution (referred to in this section as the ``Secretary'') to the Commission of Fine Arts for comments and recommendations; and (2) subject to the review and approval of the National Capital Planning Commission in accordance with section 8722 of title 40, United States Code, and section 16 of the Act of June 20, 1938 (sec. 6-641.15, D.C. Official Code). (c) Authority of Historic Preservation Agencies.-- (1) In general.--The Secretary shall-- (A) take into account the effect of the improvements authorized by subsection (a) on the historic character of the Patent Office Building; and (B) provide the Advisory Council on Historic Preservation a reasonable opportunity to comment with regard to such improvements. (2) Status of smithsonian.--In carrying out this subsection, and in carrying out other projects in the District of Columbia which are subject to the review and approval of the National Capital Planning Commission in accordance with section 16 of the Act of June 20, 1938 (sec. 6-641.15, D.C. Official Code), the Smithsonian Institution shall be deemed to be an agency for purposes of compliance with regulations promulgated by the Advisory Council on Historic Preservation pursuant to section 106 of the National Historic Preservation Act (16 U.S.C. 470f). SEC. 4. CONTRACTING AUTHORITY OF SECRETARY. (a) In General.--The Secretary of the Smithsonian Institution may-- (1) enter into multi-year contracts for the acquisition of property and services under the authority of section 304B of the Federal Property and Administrative Services Act of 1949 (41 U.S.C. 254c); and (2) enter into contracts for the acquisition of severable services for a period that begins in one fiscal year and ends in the next fiscal year under the authority of section 303L of the Federal Property and Administrative Services Act of 1949 (41 U.S.C. 253l). (b) Effective Date.--This section shall apply to contracts entered into on or after the date of the enactment of this Act. SEC. 5. VOLUNTARY SEPARATION INCENTIVE PAYMENTS. The Secretary of the Smithsonian Institution may establish a program for making voluntary separation incentive payments for employees of the Smithsonian Institution which is substantially similar to the program established under subchapter II of chapter 35 of title 5, United States Code (as added by section 1313(a) of the Homeland Security Act of 2002). SEC. 6. SENSE OF CONGRESS REGARDING JAZZ APPRECIATION MONTH. (a) Findings.--Congress finds the following: (1) On December 4, 1987, Congress approved House Concurrent Resolution 57, designating jazz as ``a rare and valuable national American treasure''. (2) Jazz has inspired some of the Nation's leading creative artists and ranks as one of the greatest cultural exports of the United States. (3) Jazz is an original American art form which has inspired dancers, choreographers, poets, novelists, filmmakers, classical composers, and musicians in many other kinds of music. (4) Jazz has become an international language that bridges cultural differences and brings people of all races, ages, and backgrounds together. (5) The jazz heritage of the United States should be appreciated as broadly as possible and should be part of the educational curriculum for children in the United States. (6) The Smithsonian Institution has played a vital role in the preservation of American culture, including art and music. (7) The Smithsonian Institution's National Museum of American History has established April as Jazz Appreciation Month to pay tribute to jazz as both a historic and living American art form. (8) The Smithsonian Institution's National Museum of American History has received great contributions toward this effort from other governmental agencies and cultural organizations. (b) Sense of Congress.--It is the sense of Congress that-- (1) the Smithsonian Institution's National Museum of American History should be commended for establishing a Jazz Appreciation Month; and (2) musicians, schools, colleges, libraries, concert halls, museums, radio and television stations, and other organizations should develop programs to explore, perpetuate, and honor jazz as a national and world treasure. Speaker of the House of Representatives. Vice President of the United States and President of the Senate.

Smithsonian Facilities Authorization Act - (Sec. 2) Amends Federal law to authorize the Board of Regents (Board) of the Smithsonian Institution to plan, design, construct, and equip additional special use storage and laboratory space (Pod 5) at the Museum Support Facility in Suitland, Maryland, to accommodate the care, preservation, conservation, deposit, and study of national collections held in trust by the Institution. Authorize appropriations for FY 2003 through 2008. (Sec. 3) Authorizes the Board to plan, design, and construct improvements to the interior and exterior of the Patent Office Building (including the construction of a roof covering for the courtyard), using funds available to the Institution from nonappropriated sources. Requires the Secretary of the Smithsonian Institution to submit the design and specifications for any Patent Office Building exterior alterations to the Commission of Fine Arts for comments and recommendations, subject to the review and approval of the National Capital Planning Commission. Requires the Secretary to: (1) take into account the effect of such improvements on the historic character of the Patent Office Building; and (2) provide the Advisory Council on Historic Preservation a reasonable opportunity to comment on them. Deems the Smithsonian Institution to be an agency for purposes of compliance with regulations promulgated by the Advisory Council under the National Historic Preservation Act. (Sec. 4) Authorizes the Secretary, under the authority of the Federal Property and Administrative Services Act of 1949, to enter into: (1) multi-year contracts for the acquisition of property and services; and (2) contracts for the acquisition of severable services for a period that begins in one fiscal year and ends in the next fiscal year. (Sec. 5) Authorizes the Secretary to establish a program for making voluntary separation incentive payments for Smithsonian employees which is substantially similar to a specified program established under the Homeland Security Act of 2002. (Sec. 6) Declares the sense of Congress that: (1) the Smithsonian Institution's National Museum of American History should be commended for establishing a Jazz Appreciation Month; and (2) musicians, schools, colleges, libraries, concert halls, museums, radio and television stations, and other organizations should develop programs to explore, perpetuate, and honor jazz as a national and world treasure.

centenarians were once believed to be rare , but nowadays they are becoming increasingly common . in the united states , there are approximately 1020 centenarians per 100 000 population , averaging approximately 80 000 . in okinawa japan , there are approximately 50 centenarians per 100 000 population . the general consensus suggests that for a person to live to extreme old age , there has to be a series of molecular aging events working harmoniously with cellular events over time to maintain health [ 35 ] . otherwise , the end result of accumulated cellular errors due to aging can lead to acute or chronic co - morbid conditions and even cancer . up to 13% of centenarians reach the age of 100 without any age - related illness . it has also been observed that centenarians may be predisposed to a prolonged survival because there has been significant delay in the manifestation of associated disabling symptoms and/or morbidity , even in those centenarians who have reached this milestone with age - related diseases . although the factors that increase longevity are not well described , it has been suggested that new developments in medicine ; better quality and increased availability of health care ; worldwide access to healthy food ; and access to housing and genetics may contribute to increasing the life span of a population . although cancers are the second leading cause of death in the united states , only 4% of centenarians die of cancer , compared to almost 40% mortality in the middle - age group . additionally , studies have reported that centenarians have the lowest rate of cancer metastasis , which is very surprising as it is universally known that increasing age is a major risk factor for cancer development [ 1114 ] . according to perls et al , centenarians may possess some genetic advantage that prevents or delays the development of cancer . while the genetic studies and survivability of centenarians is well - documented , the literature on cancer incidence and mortality in this group is sporadic and sometimes confusing . the latter has partly been caused by patients falsifying their ages , or study designs including patients < 100 years old . what is known from reports over the last 2 decades is that most cancers have the lowest incidence in this age group . the trend seems to be that most malignancies increase and peak in the mid-80s before declining and beginning to plateau as age increases . a previous study attained the mean age of diagnosis of centenarians for the new england centenarian study , and then compared that data to the mean age of diagnosis in the surveillance epidemiology and end result ( seer ) database .the study showed that the mean age of diagnosis for centenarians with all types of cancer was 80.5 years , which is 14 years older than the mean for the entire population . surprisingly , the mean age at diagnosis for each cancer was relatively low , except pancreatic cancer , which was 104 years . this shows that the majority of centenarians do not develop cancer after age 100 . to the best of our knowledge , there is no single statistical study that has exclusively looked at the cancers of centenarians . our aim in this study was therefore to determine the most common cancers in this age group and how they affect these patients overall survival after diagnosis . the national cancer institute records 26% of cancer incidence and survival data from 17 geographical regions reporting in the surveillance epidemiology and end result ( seer ) database . patients included in this study were centenarians ( 100115 years old ) diagnosed with lung , prostate , breast , urinary ( including kidney ) , and colon / rectal cancers between 1973 and 2007 in the united states . these cancer types were identified as the 5 most common cancers in centenarians . using these criteria , demographics based on age , race , and sex were tabulated for all 5 types collectively , as well as by each individual cancer type . observed survival ( os ) was calculated for each cancer type based on sex . the kaplan - meier ( km ) method was used to calculate os at 1-month intervals for the first 40 months after diagnosis using seer*stat version 7.04 . a log rank test was performed on km survival output and a cox proportional hazard model was used to calculate hazard ratios ( hr ) . all statistical analyses were performed with 95% confidence intervals ( ci ) with significance determined at p < 0.05 . cox proportional hazard analysis was done using graphpad prism version 5.04 ( graphpad software inc , 2012 , la jolla , ca , www.graphpad.com/prism ) . a total of 1385 centenarians met our inclusion criteria , with 3.39% , 7.29% , 10.25% , 19.21% , 25.13% , and 34.73% diagnosed in 19731978 , 19791984 , 19851990 , 19911996 , 19972002 , and 20032008 , respectively ( table 1 ) . there were 879 ( 63.47% ) females and 506 ( 36.53% ) males . among races , there were 1118 ( 80.72% ) whites , 159 ( 11.48% ) blacks , and 108 ( 7.80% ) other . there were 405 ( 29.24% ) breast , 267 ( 19.28% ) colon and rectum , 254 ( 18.34% ) prostate , 247 ( 17.83% ) lung and bronchus , and 212 ( 15.31% ) urinary and kidney cancer cases ( table 2).white females were proportionally the most common demographic with breast , lung and bronchus , colon and rectal , and urinary / kidney cancers . white males were proportionally the most common demographic with prostate cancer . among white centenarians , the most common types of cancers were breast ( 351 cases , 31.40% ) , colorectal ( 216 cases , 19.32% ) , lung ( 186 cases , 16.64% ) , urinary system ( 183 cases , 16.37% ) , and prostate ( 182 cases , 16.28% ) . among the black population , the most common cancers were breast ( 43 cases , 27.04% ) , prostate ( 40 cases , 25.16% ) , lung ( 37 cases , 23.27% ) , colorectal ( 25 cases , 15.72% ) , and urinary ( 14 cases , 8.81% ) ( table 2 ) . among all male centenarians , 382 ( 75.49% ) , 61 ( 12.45% ) , and 63 ( 12.45% ) were white , black , and other , respectively . in female centenarians , 736 ( 83.73% ) , 98 ( 10.13% ) , and 45 ( 5.12% ) were white , black , and other , respectively ( table 3 ) . among supercentenarians , defined as ages 110 + , 3 were white , 2 were black , and 1 was in the other group ( tables 3 and 4 ) . notably , no cases of breast or colorectal cancer were found beyond 108 years of age ( table 4 ) . hazard proportional models showed males with colorectal cancer were associated with the greatest hazard ( hr=1.85 , p<0.0001 ) , followed by lung cancer ( hr=1.65 , p<0.0001 ) , and urinary system cancer ( hr=1.18 , p=0.0099 ) , with prostate cancer as the baseline . in females with breast cancer as the baseline , lung cancer ( hr=1.52 , p<0.0001 ) had the worst prognosis , followed by urinary system cancer ( hr=1.05 , p=0.194 ) , and colorectal cancer ( hr=0.92 , p=0.0076 ) . when comparing male and female cases ( with female as the baseline ) of lung colorectal , and urinary system cancers , hrs were 1.09 ( p=0.1485 ) , 2 ( p<0.0001 ) , and 1.12 ( p=0.0073 ) , respectively , showing that females have a significantly lower hazard ratio than males who have colorectal and urinary system cancer ( table 5 ) . as seen from the seer database , the number of centenarians diagnosed with cancer has increased since 1973 . this may reflect an increase in cancer incidence , such as that experienced in the general population , or it may simply reflect an increase in diagnosis of cancer secondary to improved methods of cancer detection since that time . contrary to the general population , it is surprising that in the centenarian population , the number of cancers detected decreased with increasing age ( tables 3 and 4 ) . this finding may be due to a genetic predisposition to evade or hinder the development of cancer in some people . according to anderson et al , centenarians may have variations that shield them from developing cancer or they might be deficient in certain genetic variations that would normally increase their chances of cancer development . another possible reason for the decrease could be that in the elderly population , less invasive tests such as biopsies are performed to confirm the presence of cancer . the most common cancers found in the centenarian population were breast , prostate , lung , colorectal , and cancers of the urinary system . there was significant variation of these cancers with race , gender , and increasing age . we found that white centenarians had a greater incidence of cancer compared to the other races . this finding may not necessarily reflect the statistics of the general population , as our study had a disproportion in the number of participants from the respective races . however , there was a trend with the ratio of females to males among the blacks and whites . however , in the remainder of cases , there were 42% females and 58% males . the most common cancers among the white population ( in descending order ) were breast cancer , followed by colorectal cancer , lung cancer , urinary system cancer , and prostate cancer . in the black population , the most common was breast followed by prostate , lung , colorectal and then cancers of the urinary system . this finding is also supported in the 10-year survey on prostate cancer incidence that was conducted by the cdc . in that study , prostate cancer had a higher incidence among the black population compared to whites and other races . in females , the most common cancer was breast cancer , followed by colorectal cancer , lung cancer , then cancers of the urinary system . in males , the most common cancer was prostate cancer followed by cancers of the urinary system , lung , colorectal , and breast cancer . the incidence of these cancers may be related to the delayed developmental course of some cancers . for instance , the high incidence of prostate cancer in centenarians may be related to the slow development of prostate cancer , resulting in a large number going undetected in the general population , but detected in the centenarian population because there are many more years in which cancer can surface . the mortality of the centenarian population varied with gender , race , and cancer type . in males , colorectal cancer had the highest mortality rate , followed by lung cancer and cancers of the urinary system . however , in females , mortality was higher with lung cancer , followed by urinary system cancer , then colorectal cancer . when comparing males to females , colorectal cancer in males had a significantly higher mortality rate ( table 5 ) . worldwide , in more developed countries , the ratio of mortality in colorectal cancer in males to females is 1.6 to 1 , while in less developed countries this ratio is 1.9 to 1 . another study also showed that long - term survival in females is greater for colorectal cancer . urinary system and lung cancer showed very similar survival rates when comparing males and females . the mortality in the centenarian population may be influenced by the fact that most cancers progress to advanced stages , making them difficult to treat . this may occur as a result of fewer options available to treat the elderly population . , surgeons frequently choose less aggressive treatment options for elderly patients , which usually leads to a worse prognosis [ 2124 ] . these patients usually have multiple co - morbidities , which may increase the incidence of post - operative complications and make surgical procedures more difficult to perform . as a result , there may be very little that could be done to improve survivability in centenarians . the 5 most common cancers seen in centenarians are breast , prostate , lung , colorectal , and urinary system cancers . there is a significant disparity in the prevalence of the different types of cancers with gender and race . the incidence of these cancers may be influenced by the slow progression of some cancers or a protective genetic advantage of some of these patients to resist or delay cancer development . mortality varies with cancer type and gender , and is influenced by the limited management options available for centenarians . invasive procedures and surgeries are more dangerous in the elderly population , as these patients usually have multiple co - morbidities . as the prevalence of centenarians increases , it is becoming increasingly important to become aware of the cancers that affect them in order to devise better prevention and treatment methods .

backgrounda centenarian is a person who attains and lives beyond the age of 100 . four percent of centenarians die from cancer . it is therefore important to understand which cancers affect them in order to devise better methods to prevent and treat them . the aim of this study was to investigate the top cancers that affect centenarians.material/methodwe identified 1385 cases with the surveillance epidemiology and end result ( seer ) database . our study included centenarians age 100115 years diagnosed with the 5 most common cancers between 1973 and 2007 in the united states . observed survival ( os ) was calculated for each cancer type . the kaplan - meier ( km ) method was used to calculate os at 1-month intervals for the first 40 months after diagnosis using seer*stat version 7.04 . a log rank test was performed on km survival output and a cox proportional hazard model was used to calculate hazard ratios . all statistical analyses were performed with 95% confidence intervals with significance determined at p<0.05 . cox proportional hazard analysis was done using graphpad prism version 5.04.resultsthere were 879 ( 63.47% ) females and 506 ( 36.53% ) males . there were 1118 ( 80.72% ) whites , 159 ( 11.48% ) blacks , and 108 ( 7.80% ) other . the top cancers were 405 ( 29.24% ) breast , 267 ( 19.28% ) colorectal , 254 ( 18.34% ) prostate , 247 ( 17.83% ) lung and bronchus , and 212 ( 15.31% ) urinary and kidney cancer cases.conclusionsas the prevalence of centenarians increases , it is becoming increasingly important to become aware of the cancers that affect them in order to better manage them .

HARWICH, England—A disagreement between two sleepy English seaside towns could make a splash across the Atlantic: by forcing a rewrite of American history. For 393 years, the southwest England town of Plymouth has been celebrated as the last port of call of the Mayflower before the ship carried the first Pilgrim settlers to what was to become the United States of America. But that is only part of the story. Plymouth's fame has come at the expense of this tiny town to the northeast of London. The reason: The Mayflower was built and originally set sail from here before making an unscheduled stop at Plymouth. Now, after nearly four centuries, Harwich wants a slice of the historical action. It is building a $3.3 million replica of the Mayflower to send back across the Atlantic. The project, spearheaded by retired oil executive Andrew March, is part of Harwich's campaign to reclaim its lost heritage by 2020, the 400th anniversary of the Mayflower's original journey. Using 400 tons of English oak and an army of young shipbuilders, Mr. March hopes to launch Harwich, pop. 15,000, onto the world stage. "We are planning to get a little bit of our share of history," says Mr. March. "Harwich was the probable birthplace of the Mayflower," he adds. Harwich, on the east coast of Britain and with a wet and windy climate, struggles to attract tourists. Currently, its biggest draw is an 800-year-old oak tree known as "Old Knobbley," inconveniently located 10 miles from the town center. But Harwich's plans are discomfiting Plymouth, equally out of the way on the southwest shoreline of the U.K. The famous ship is crucial to the town's self image: its soccer team is nicknamed "the Pilgrims." Its mascot is known as "Pilgrim Pete." Hotels, parking lots and swimming pools bear the Mayflower's name. The Mayflower steps, where the ship is said to have set sail, attracts U.S. tourists on day trips from London. Plymouth has its own ambitious anniversary campaign in the works—a party so big that it has already invited the U.S. president, whoever that happens to be in 2020. All living ex-Presidents are to be invited. So are members of the British royal family. The city recently sent a delegation to Plymouth, Mass., to discuss plans for the anniversary. Amanda Lumley, chief executive of Destination Plymouth, which aims to attract tourists to the city, was on the trip. She says there are 52 Plymouths in the world, with 24 in the U.S. "How many Harwiches are there?" Ms. Lumley asks. (According to U.S. Census data, there are three Harwiches in the U.S., all of them in Massachusetts). The face-off is the result of some planks in the Mayflower's history that have never quite been nailed down. On Sept. 6, 1620, the Mayflower "loosed from Plymouth, having been kindly entertained and courteously used by divers[e] friends there dwelling," according to a commemorative plaque on the harborside in Plymouth. But Harwich claims that the Mayflower's connection to Plymouth is an accident of circumstance and geography. Locals here contend that the Mayflower stopped in Plymouth only because the Speedwell—a smaller ship also carrying Pilgrims to the New World—sprang a leak 200 miles off the English coast, forcing it to return to Plymouth, the nearest port. Conspiracy theorists in both Plymouth and Harwich say the Speedwell's captain sabotaged his ship because he didn't think it could make it across the Atlantic. A rumor popular among Plymouth residents, but with little basis in historical fact—speculates the crew heard of Plymouth's reputation for hospitality and insisted on remaining in England. "I wouldn't blame them for coming back here, it's quite good fun when it's not raining," says Oliver Betts, 27, who lives in Plymouth. Whatever the cause, had the Speedwell not started leaking, Harwich, not Plymouth, would be remembered as the home of the Mayflower. To capitalize on this, Mr. March is employing local youngsters and using donations from benefactors to help rebuild the Mayflower. A charity—the Harwich Mayflower Project—has been set up to oversee the building of the replica and to promote Harwich's case in the U.K. and the U.S. Officials say work on the ship will begin within six months and are confident it will be finished by 2016, ready for a few trial voyages before the big crossing in 2020. Shipbuilders who will help construct the replica are already well versed in Harwich's version of history. "Plymouth was just a stop-off, that's all it was," says Miles Holdsworth, 17. By the end of 2013, Mr. March says he will have raised more than £500,000 ($770,000) to build the replica. The project receives donations from individuals, but hopes to raise most of its capital from corporate sponsors—a $75,000 donation will buy a 12-inch brass plaque embedded on the replica Mayflower's main deck, plus the chance to send staff on the 400th anniversary voyage. Mr. March points to local property records showing that the Mayflower's captain, Christopher Jones, and many crew members came from Harwich and surrounding areas. Journals written by the first settlers and reproduced online also point to the Harwich roots of Capt. Jones and the Mayflower. A plaque in Plymouth, England, listing the passengers on the Mayflower even supports the Harwich claim: "John Alden, cooper of Harwich, the first to step ashore," it states. The evidence is strong—but not strong enough to make Plymouth throw in the towel. "Well, I wasn't aware that Harwich had such a great claim to the history," says Chris Robinson, a Plymouth historian who has written extensively about his city's history. "Clearly the indications are—but there is no proof—that the Mayflower was constructed in Harwich. And Christopher Jones was a Harwich man. But the pilgrims didn't call in there. They did call into Plymouth." One thing that hasn't yet crossed the Atlantic is the hostility between the two English towns. Richard Pickering, who for 26 years has played a Pilgrim settler in Plimoth Plantation, a historical re-creation of the first settlers' community in Plymouth, Mass., says it doesn't matter where the Mayflower came from, just what it meant to America. "I have very little understanding of the Mayflower's history before it came to America," he says. ||||| Image caption The charity hopes the building of the replica will benefit Harwich A landmark step to build a replica of the ship that carried the Pilgrim Fathers to America nearly 400 years ago has taken place in Essex. The ceremony to cut the keel of a charity's £2.5m reproduction of The Mayflower was held in Harwich along with the opening of a training centre. The Harwich Mayflower Project wants the boat to be ready by 2020 - the 400th anniversary of the voyage. It is hoped the training centre will act as a "legacy" of the ship build. 'Amazing engineering' The copy of the 100ft boat will take around two years to build, with work due to start in 2016. Initial work on the site where the ship will be constructed is under way but will not be completed for some time due to the huge weight the concrete base will hold. "The engineering to go into the concrete floor is amazing," said the project's training and development manager Jeff Webber. "The ship will weigh 200 tonnes, the cradle 30 to 40 tonnes, the trailers and cranes 70 to 100 tonnes and then there is a building to go on top." People should be able to see the boat being built from a viewing gallery in an old rail shed. It will overlook the machine shop and also house some of the design and full-size template work. Mr Webber said: "Harwich has a huge maritime history but not enough to bring people here for a day out. "If we can make the Mayflower Project worth visiting, people will spend money on other things and that creates jobs." Image caption The roof had collapsed in part of the station building where the training centre is now based 'Create jobs' Sir William McAlpine, chair of the Rail Heritage Trust, also officially opened the project's £200,000 training centre at the town's train station building on Wednesday. The trust gave £100,000 towards restoring the dilapidated building, parts of which had been empty for nearly 20 years. Around 15 people are on marine, carpentry, joinery and business apprenticeships, while 300 unemployed people have attended courses at the centre since 2011. "We thought it would be a legacy of the project to create jobs instead of closing the site and making 30 to 40 redundancies once the ship is completed," said Mr Webber. The Mayflower left Plymouth to sail to America in 1620 and its links with the Devon city been well documented. However, supporters of the project have emphasised the importance of its Harwich heritage. It is believed the Mayflower was built in the Essex town in 1590 while the captain and crew for the Pilgrim Fathers voyage were also from Harwich. The charity has previously said the ship only docked at Plymouth to take extra passengers from a sabotaged vessel after setting off from Rotherhithe in London.

– You've heard of Plymouth, England, but what about Harwich? The small town is looking to finally get some recognition as the actual launch site of the Mayflower. As the argument goes, Plymouth, which has long touted itself as the Pilgrim ship's final port of call before crossing the Atlantic Ocean, was actually an unplanned stop. Harwich argues that it was actually the site where the Mayflower was built and departed from, and locals say the only reason the ship stopped in Plymouth is because another ship carrying Pilgrims (the Speedwell) started leaking and had to get to the closest port. Now, 393 years later, Harwich is elbowing its way in on the Mayflower's legacy, Barron's reports. The town intends to send a $3.3 million Mayflower replica across the Atlantic in time to celebrate the 400th anniversary of the voyage. "We are planning to get a little bit of our share of history," says the retired oil executive heading the project. The BBC reports that the two-year construction process should begin in 2016, with the transatlantic journey planned for 2020. (Quirky side note: Harwich's biggest tourist attraction right now is an 800-year-old tree called "Old Knobbley.") Needless to say, Plymouth is not happy. There are 52 Plymouths across the globe, says one tourism rep for the city who was ostensibly arguing her city is the world-renowned one: "How many Harwiches are there?" (It turns out the US has three, all in, you guessed it, Massachusetts.)

the perseus cluster , a426 , is the most x - ray luminous cluster in the nearby universe , and the prototypical `` cooling core '' cluster . in these cooling core clusters the radiative cooling time of the x - ray emitting gas is considerably shorter than the age of the universe , so to maintain equilibrium the gas must flow into the center of the cluster , or another source of energy is required to re - heat the gas . since massive flows of material are not observed , the emerging solution to the energy deficit is the active galaxy that is almost always @xcite present at the center of massive clusters . shocks and ripples are clearly evident in the deep chandra image of perseus @xcite , and could provide steady heating of the center of the cluster @xcite . in perseus the agn manifests itself directly as a bright radio source known as perseus a or 3c84 , associated with the galaxy ngc1275 . 3c84 is one of the brightest compact radio sources in the sky and has been studied in some detail @xcite . in particular it is known to undergo bursts of activity @xcite that could also drive the observed shocks and sound waves through the cluster . faraday rotation measure ( rm ) observations with the very large array ( vla ) of radio galaxies embedded in clusters of galaxies have been used to elicit information about the magnetic field strength and topology associated with the hot cluster gas @xcite . these magnetic fields then play an important role in modifying the energy transport and dissipation in the center of the cluster @xcite . comparisons between the inferred cooling flow rates ( in the absence of re - heating ) and the maximum faraday rotation measure indicate a correlation , and there is some evidence that magnetic fields are enhanced at the centers of clusters @xcite . given the high density of gas at the center of the perseus cluster the faraday rotation measures towards 3c84 are expected to be well over 1000 @xcite . unfortunately such high rms , and the correspondingly large rm gradients are difficult to measure due to cancellation of the linearly polarized signal within the telescope beam ( typically 0.5for vla observations ) . another problem with obtaining polarimetric measurements of 3c84 with the vla is the high dynamic range imposed by the @xmath020 jy peak flux density at centimeter wavelengths and arcsecond resolution . in order to overcome these limitations we have used simultaneous multi - frequency observations of 3c84 at high angular resolution taken using the very long baseline array . throughout this paper we assume @xmath1 = 71 km s@xmath2 mpc@xmath2 so that 1 = 0.35 kpc at the redshift of ngc1275 ( 0.0176 ; @xcite ) . observations were centered on 4.8 ghz , 8.4 ghz , 15.1 ghz , and 22.2 ghz with the vlba on 26 october 2004 and 11 november 2004 using the vlba . in both cases , 3c84 was being used as the leakage term calibrator for observations of compact symmetric objects @xcite . six scans of typically 2 minutes duration were obtained at each frequency band . each frequency band was separated into four ifs , and these ifs were paired for the purpose of imaging the total intensity except at 22.2 ghz where all four ifs were averaged . for the purposes of determining the polarization and subsequently the rms each if was imaged separately in stokes q and u. observational parameters are presented in table 1 . amplitude calibration of the data was derived from system temperatures and antenna gains . fringe - fitting was performed with the aips task fring on 3c 84 . the leakage , or d - term solutions were determined with the aips task lpcal on 3c 84 . absolute electric vector position angle ( evpa ) calibration was determined using the evpas of j1310@xmath3322 and bl lac listed in the vla monitoring program @xcite . note that the evpas were corrected for each of the four ifs separately . we used recent deep chandra observations @xcite of the perseus cluster to model the central density profile . in fig . 1 we show the deprojected density profile and the projected temperature profile . within the central 0.8 kpc ( 2.2 ) the profile is severely affected by the nucleus so that the temperatures and densities are not representative of the properties of the intracluster medium ( icm ) . we estimate an average central density over the inner 2 kpc to be 0.3 @xmath4 . we formed total intensity images of 3c84 between 5 and 22 ghz . images of similar quality are readily available in the literature @xcite , so we do not reproduce them here . instead we provide a brief summary of source properties ( position , flux density , size , distance , etc . ) in table 2 , and we concentrate here on the polarimetry results . we formed linear polarization images at constant resolution ( see fig . 2 ) for the purpose of comparing the polarization properties of 3c84 as a function of frequency . the resolution in fig . 2 is set by the 5 ghz observations and the higher frequencies have been tapered to provide matching resolution . linear polarization is detected on november 11 from the bright jet component s1 in 3c84 at 5 , 8 , 15 and 22 ghz at a level of 0.8 to 7.5% increasing with frequency . furthermore , there is some suggestion at 8.4 ghz and above that the polarization is extended . similar results were obtained on october 26 , but the leakage calibration was not as good at this epoch , so for the remainder of the discussion we focus on the november 11 results . the detection of core polarization is less than 0.1% for all frequencies except for 22 ghz for which it is 0.2% . at this level the 14 mjy of linearly polarized flux density could well be significant . there is also some suggestion of polarization at 22 ghz in between the core and the end of the bright inner emission ( component s1 ) . in fig . 3 we present the rm image , a pixel - by - pixel fit to the polarization angle as a function of the square of the wavelength ( @xmath5 ) . since the 5 ghz observations were only weakly polarized and did not resolve s1 , we have not included them in the fit . the 8 frequencies included in the fit were : 8.114 , 8.184 , 8.421 , 8.594 , 14.906 , 14.972 , 15.269 , 15.368 , and 22.233 ghz . the 15 and 22 ghz observations were tapered to match the 8.4 ghz resolution of 1.8 @xmath6 1.3 mas@xmath7 . pixels were blanked if the statistical error in polarization angle exceeded 5 degrees at any frequency . a representative fit at the peak of the polarized flux density of s1 is shown in fig . the systematic uncertainties in the polarization angle measurements were assumed to be @xmath03 degrees . the rotation measure image ( fig . 3 ) shows a gradient of about 1000 pc@xmath2 across component s1 in the southern jet component . the statistical error in the rm determinations are @xmath060 , so it is likely that this gradient is real . it is possible that spectral effects ( see fig . 6 ) and substructure at the high frequencies cause some departures from a @xmath5 law . there is significant depolarization ( 9.5% at 15.3 ghz to 3.5% at 8.2 ghz at @xmath0 1.5 mas resolution ) in the southern hot spot . this depolarization , and that seen between 5 and 22 ghz in a larger beam , are consistent with beamwidth depolarization by the observed rm gradient . it is worth noting that the rm decreases with increasing distance from the center of the lobe , i.e. , the gradient slopes down in the direction of the edge of the lobe . this indicates that the density and/or the field strength decreases towards the edge . this situation is reminiscent of that in m87 where no polarization is detected in the bright inner few parsecs @xcite , and is most naturally explained by a radial falloff in the density . polarization is not expected from the counterjet in 3c84 , both because it is fainter , and because it is behind a denser faraday screen . the rm corrected plot of the projected magnetic field orientation of the linearly polarized flux at 15 ghz is shown in fig 5 . the intrinsic magnetic field in the southern jet component s1 appears to be predominantly perpendicular to the jet axis , as expected if the field is enhanced by compression . the polarization angle of the core is uncertain given that the rm of the core is not well determined and is likely to be well in excess of 10000 . we note that @xcite found strong circular polarization in the central parsec of 3c84 , reaching + 3% at 15 ghz . they speculate that the circular polarization may be produced by faraday conversion of linear to circular polarization . no circular polarization was detected by @xcite from the bright southern jet at 15 or 22 ghz , and the linear polarization from the central parsec was found to be less than 1% . for a refractive medium in the presence of magnetic fields the intrinsic polarization angle , @xmath8 , is observed as @xmath9 such that @xmath10 where @xmath11 is the observed wavelength . the rotation measure , rm , is related to the electron density , @xmath12 , the net line of sight magnetic field in the environment , @xmath13 , and the path length , @xmath14 , through the plasma , by the equation @xmath15 where units are in @xmath4 , @xmath16 g , and kiloparsecs . our best estimate from [ xrayobs ] for @xmath12 is 0.3 @xmath4 . we assume a path length of 2 kpc , which probes the highest density gas in the cluster , and is typical of rm scale sizes in other cooling core clusters @xcite . assuming a constant magnetic field orientation , we find a magnetic field strength of 15 @xmath16 g . this is only the component along the line - of - sight , so correcting by a factor of @xmath17 we estimate a field strength of 25 @xmath16 g . field strengths calculated with these parameters can be compared to the strength of a magnetic field that has the same pressure as a gas of the same n@xmath18 and a temperature of 5 @xmath6 10@xmath19 k using @xmath20 in the central ( @xmath21 kpc ) region of the perseus cluster we find this gives 300 @xmath16 g , so the magnetic pressure from the estimated field strength of 25 @xmath16 g is two orders of magnitude less than the thermal pressure ( @xmath22 dyn @xmath23 ) . this result is similar to that found in other cooling core clusters . a difficulty with producing the rms in 3c84 in the icm is that the observed gradient of 10% of the rm on scales of @xmath01 pc is hard to reconcile with fields organized on kpc scales . emission- and absorption - line studies have highlighted the existence of a high - velocity system ( at @xmath0 8200 km s@xmath2 ) at approximately the same position on the sky as ngc 1275 ( which has a systemic velocity of @xmath24 km s@xmath2 ) . this system is likely to be associated with a spiral galaxy falling into the perseus cluster at 3000 km s@xmath2 . recently @xcite have shown through the study of the x - ray absorption that this system is not interacting with the body of ngc 1275 and that they are separated by at least 57 kpc . can this spiral galaxy be responsible for the observed rotation measures ? the hot component of its ism is not likely to produce the observed rms , as the required density ( assuming a @xmath13 of 3 @xmath16 g , a path length of 10 kpc and a temperature of @xmath25 k ) is 0.3 @xmath4 , about two orders of magnitudes larger than one would infer from a simple pressure equilibrium argument with the neutral component of the ism , whose density and temperature were estimated by @xcite . the possibility that a very compact h ii region belonging to the high - velocity system might be responsible for the observed rms can not be completely excluded , even though the probability of finding such a region directly along our line - of - sight to the core of ngc 1275 is very small . the filamentary structure of ionized gas associated with ngc 1275 , instead , might well produce the observed rms : the h@xmath26 observations performed by @xcite showed the presence of unresolved features with size less than @xmath0230 pc and lower bound electron densities of @xmath27 @xmath4 . densities measured in the [ sii ] lines in the central kiloparsecs are 270 @xmath4 @xcite , and the optical filaments are thought to be in equipartition with the icm with pressures of @xmath28 dyn @xmath23 . comparing the central surface brightness in h@xmath29 with emission from gas at the x - ray pressure @xcite near the center of the cluster gives a depth of 0.06 pc for a temperature of 10@xmath30 k and a uniform covering fraction , @xmath31 . if the filaments are more filamentary than sheet - like , then the depth of the h@xmath29 increases in proportion to 1/@xmath31 , but it becomes difficult with a small covering factor to produce coherent rotation measures across the radio source . also , if the surface brightness of the h@xmath29 line rises close to the nucleus where it is unresolved , then this can increase the estimate of the depth . observations in the pa@xmath26 line @xcite indicate that the surface brightness does rise by one to two orders of magnitude within the inner 150 pc . this increases the above estimate for the depth of the filaments from the h@xmath29 line to at least 1 parsec . the small size of the ionized filaments could explain the 10% gradient in the rm on scales of a parsec . assuming a constant gradient we might use this to estimate a scale size for the rms of @xmath010 parsecs . assuming that the scale size along the line - of - sight is similar to that in the plane of the sky leads to an estimate for the faraday depth of @xmath010 pc . with the above density and path length ( 10 pc ) and the observed rm we obtain a lower limit for @xmath13 of 4 @xmath16 g , and hence a magnetic pressure of @xmath32 dyn @xmath23 , nearly three orders of magnitude below the thermal pressure . if the filaments are as small as 1 pc ( with a uniform covering factor , @xmath33 ) , then the field strength required to produce the observed rms is @xmath34 g , but the magnetic pressure is still less than the thermal pressure by a factor of @xmath04 . it is also possible that the radio source is interacting with the ionized gas and that the densities are enhanced at the southern edge of the expanding source , which appears reminiscent of a bow - shock . locally higher densities would further reduce the strength of the magnetic fields required to produce the observed rms . similar magnitude rms have been detected in a few other well studied radio galaxies ( e.g. , m87 , 3c120 @xcite ) , and attributed to ionized gas in close proximity to the radio emission . baum et al . ( 2005 ) have shown that there is no significant column density of more neutral gas along the line of sight to the nucleus from the lack of any strong ly@xmath26 absorption . we note that the observed decrease in fractional polarization with wavelength can be attributed to gradients in the faraday screen . we find substantial faraday rotation measures of @xmath07000 toward 3c84 . rms as large or larger than this have been suspected for some time due to the low observed polarization from this bright radio galaxy . the faraday screen is most likely to be associated with the ionized gas that also produces spectacular filaments of h@xmath26 emission in the perseus cluster . this gas may well have magnetic fields organized on small enough scales ( @xmath35 10 pc ) , to produce the observed gradient in the rm . our current measurements provide only a few very closely spaced lines - of - sight through the cluster . to establish the scale size over which the magnetic fields are organized , and to look for correlations with the cavities seen in the x - ray emission , we would like to be able to sample the rm distribution in the perseus cluster on scales out to many 10s kiloparsecs . there is fairly strong radio emission on these scales , but detecting the polarization is challenging . to determine rms in larger regions we have to have greater sensitivity to extended emission than the vlba provides . but increasing the beam size means more susceptibility to rm gradients within the beam . it also means that the flux within the central resolution element goes up ( quite dramatically when components c and s1 merge ) so the required dynamic range increases as well . errors in the leakage calibration are typically @xmath00.5% for individual antennas and will average out over an array by @xmath36 where n is the number of elements in the array ; errors are further reduced away from the image center by an additional factor of @xmath37 @xcite . these errors scale with the total intensity so that a point source of 10 jy produces a linear polarization noise floor of @xmath05 mjy / beam for the vlba and @xmath02 mjy / beam for the vla . an array like the proposed evla phase 2 with 35 antennas , excellent sensitivity , and sub - arcsecond resolution could have a good chance of detecting polarization from a larger region across 3c84 at high frequencies . the evla phase 1 currently under construction has less resolution than desired , but if the errors in the leakage terms can be reduced below 0.5% , then it might be possible for some regions where the gradient happens to be low to be measured . this will also become easier in time so long as 3c84 continues to fade at centimeter wavelengths @xcite . we are grateful to the referee , daniel homan , for insightful suggestions . gbt acknowledges support for this work from the national aeronautics and space administration through chandra award number go4 - 5134a issued by the chandra x - ray observatory center , which is operated by the smithsonian astrophysical observatory for and on behalf of the national aeronautics and space administration under contract nas8 - 03060 . neg gratefully acknowledges support from the nrao graduate summer student research assistantship . this research has made use of the nasa / ipac extragalactic database ( ned ) which is operated by the jet propulsion laboratory , caltech , under contract with nasa . the national radio astronomy observatory is a facility of the national science foundation operated under a cooperative agreement by associated universities , inc . lcccccc 3c84 & 20041026 & 4.6 & 11 & 16 & 3200 & 0.52 + & 20041026 & 5.0 & 11 & 16 & 3560 & 0.96 + & 20041026 & 8.2 & 10 & 16 & 7390 & 1.20 + & 20041026 & 8.5 & 10 & 16 & 7620 & 1.21 + & 20041026 & 14.9 & 10 & 16 & 8960 & 2.27 + & 20041026 & 15.3 & 10 & 16 & 8910 & 2.25 + & 20041026 & 22.2 & 10 & 32 & 5990 & 7.63 + 3c84 & 20041111 & 4.6 & 13 & 16 & 3120 & 0.31 + & 20041111 & 5.0 & 13 & 16 & 3520 & 0.39 + & 20041111 & 8.2 & 12 & 16 & 7430 & 0.56 + & 20041111 & 8.5 & 12 & 16 & 7600 & 0.36 + & 20041111 & 14.9 & 13 & 16 & 8750 & 1.38 + & 20041111 & 15.3 & 13 & 16 & 8750 & 1.37 + & 20041111 & 22.2 & 14 & 32 & 5940 & 1.36 +

we present very long baseline array ( vlba ) observations of the nucleus of ngc1275 , the central , dominant galaxy in the perseus cluster of galaxies . these are the first observations to resolve the linearly polarized emission from 3c84 , and from them we determine a faraday rotation measure ( rm ) ranging from 6500 to 7500 across the tip of the bright southern jet component . at 22 ghz some polarization is also detected from the central parsec of 3c84 , indicating the presence of even more extreme rms that depolarize the core at lower frequencies . the nature of the faraday screen is most consistent with being produced by magnetic fields associated with the optical filaments of ionized gas in the perseus cluster .

self - amplified spontaneous emission free electron lasers ( sase fels ) @xcite are nowadays considered as a unique tool for production of intense , polarized , short - pulse radiation tunable throughout the vuv and x - ray wavelength range , with peak and average brilliance exceeding both modern synchrotron radiation and laser plasma sources by many order of magnitudes @xcite . successful operation of sase fels requires high quality ( low emittance and low energy spread ) , intense electron beams . one of the trends for sase fels is production of ultra - short radiation pulses . these can be obtained by exploiting electron bunches with an ultra - short charge concentration ( spike ) . at the flash facility at desy , hamburg @xcite , electron bunches with sharp spikes have been produced in the framework of a nonlinear bunch - compression scheme . experimental @xcite and theoretical @xcite studies of flash operation have shown that properties of ultra - short pulses are significantly influenced by collective effects , the most important of them being space - charge effects . space - charge plays an important role in the beam - formation system , in the drift space and also in a long undulator . collective effects might be crucially important for x - ray sase fels ( xfels ) as well . this article presents a description of longitudinal wake fields in xfels . in particular , our study is of importance in connection with novel schemes of radiation production , like enhanced sase schemes ( esase ) @xcite . esase proposals rely on two steps . first , the electron beam is modulated in energy by interacting with a gw - level optical laser in a modulator wiggler placed in the accelerator section . second , a dispersive section transforms the energy modulation into density modulation , eventually leading to a subfemtosecond - long spike in the beam current before the entrance in the fel undulator . the peak current of this spike can reach tens of ka without emittance worsening , because only a small charge is concentrated in the high - current region . as the electron beam undergoes the sase process , the enhanced current part should saturate faster than the rest of the bunch . alternatively , the x - ray wavelength may be reduced , for a fixed undulator length . moreover ultra - short pulses ( in the attosecond range ) are produced as a result of the presence of the short lasing spike . faster saturation of emission from the enhanced - current spike also suggests that esase schemes may be used to obtain saturation even in situations when beam parameters deteriorate with respect to design values . a detailed study of longitudinal wake fields arising after the dispersive section , in particular dominant space - charge wake fields is due in order to assess the magnitude of detrimental effects on the fel process . it is important to note that the undulator parameter @xmath3 for xfel setups obeys @xmath4 . as a result , the average longitudinal lorentz factor @xmath5 is such that @xmath6 , @xmath7 being the lorentz factor of the beam . based on @xmath8 , we will demonstrate that the presence of the undulator strongly influences the space - charge wake . in contrast to this , in @xcite , wake calculations for the lcls case are given in free - space , as if the presence of the undulator were negligible . authors of references @xcite incorrectly conclude that the fel process is basically unaffected by space - charge wakes . this paper is devoted to the calculation of impedance and longitudinal wake field in xfels , with particular attention to the lcls case , for which esase schemes have been first proposed . this means that we will restrict our attention to a very specific region of parameters , discussed in the next section [ sec : disc ] . first , the longitudinal size of the beam is much larger than the fel wavelength . second , electrons are assumed to have travelled into the undulator for a distance longer than the overtaking length . third , effects of metallic surroundings can be neglected . when the electron - beam size is larger than the radiation diffraction size calculated from a single undulator period , @xmath9 being the reduced wavelength of coherent radiation and @xmath10 the undulator period . ] , major simplifications arise . in fact , radiation from the undulator is drastically suppressed and calculations of impedance and wake function can be performed considering a non - radiating beam , and thus accounting for space - charge interactions only . then , space - charge impedance and wake function is found to reproduce the free - space case . only , the lorentz factor @xmath7 must be consistently substituted with the average longitudinal lorentz factor @xmath11 . in section [ sec : main ] we derive the electric field that will be used to calculate impedance and wake . in section [ sub : wake ] we introduce concepts of impedance and wake field . fields are calculated in section [ sec : main ] , while impedances and wakes are respectively dealt with in section [ sec : impe ] and section [ sub : resu ] . then , in section [ sec : expl ] , we apply our theory to the esase setup referring to the lcls facility . we calculate the energy chirp associated with wakes inside the undulator and between dispersive section and undulator . subsequently , the magnitude of their effect is estimated by calculating the linear energy chirp parameter @xcite . we find that the gain of the fel process is sensibly reduced , and that longitudinal wake fields constitute a reason of concern regarding the practical realization of esase schemes . conclusions end our treatment in section [ sec : conc ] . as has been said in the introduction , results of this paper can be applied to calculate effects of wake fields in planar undulators under a specific choice of parameters corresponding to an xfel system . quantities of interest are defined once the bunch and the undulator system are specified . the bunch is characterized by an rms length @xmath12 , a transverse rms dimension @xmath13 and lorentz factor @xmath7 . moreover , we define the undulator period @xmath14 , the vacuum chamber transverse dimension @xmath15 and the undulator parameter @xmath3 , where @xmath16 , @xmath17 being the negative electron charge , @xmath18 the peak undulator magnetic field on - axis , and @xmath19 the rest mass of the electron . finally , @xmath20 is the saturation length of the fel process . the bunch length @xmath12 corresponds to the reduced wavelength of the coherent field generated by the bunch , @xmath21 . this ( reduced ) wavelength is much longer than the reduced resonant wavelength @xmath22 , where @xmath23 , and @xmath24 is the already defined average longitudinal lorentz factor . this means @xmath25 . the overtaking length is defined by the quantity @xmath26 . when the bunch has travelled inside the undulator for more than @xmath27 a steady state is reached , and asymptotic expressions for the wake fields can be given . in the present study we will work with such asymptotic expressions only . this means that the saturation length of the fel process , @xmath20 , must be much longer than the overtaking length , i.e. @xmath28 . also , in this paper we will neglect the presence of the vacuum chamber . this is possible when the vacuum chamber dimension is much larger than @xmath29 , i.e. @xmath30 , a typical transverse dimension associated with the coherent field , that is verified for esase xfel setups . summing up , we will work under the following constraints : @xmath31 based on conditions in ( [ cons1 ] ) , we will develop a theory of wake fields from undulators in xfels . in particular , the first assumption greatly simplifies our consideration allowing for a long - wavelength asymptotic treatment . under the second and the third assumption we will be able to present an expression for the impedance in terms of a double convolution involving the charge density distribution and bessel functions . similarly , an analytical expression for the wake function could be given . however , it will not be necessary to explicitly calculate this expression . in fact , when discussing practical applications , we will work in the asymptotic case @xmath32 extra - condition ( [ cons2 ] ) greatly simplifies the treatment of wake fields . our results can be directly applied to realistic situations as the esase scheme analyzed in section [ sec : expl ] , where we will refer , explicitly , to the lcls case . calculation of longitudinal wake field and impedance from an fel undulator is subject to the characterization of the electric field generated at a given position ( that is the position of a test electron ) by the entire bunch . we perform an analysis in terms of harmonics , i.e. we consider sinusoidal dependence of the electric field of the kind @xmath33+c.c.$ ] , the symbol `` c.c . '' indicating complex conjugation . expressions for the field at negative values of @xmath34 can be obtained based on the property @xmath35 starting from explicit expressions for @xmath36 at @xmath37 . ] . here @xmath38 is the time , @xmath39 is the frequency , with @xmath40 the speed of light in vacuum . the complex amplitude @xmath41 can actually be considered as the representation of the electric field in the space - frequency domain , and it will be referred to as `` the field '' . we assume that particles proceed along an undulator , under the constraints discussed in section [ sec : disc ] . the transverse field @xmath42 can be treated in terms of paraxial maxwell s equations in the space - frequency domain ( see e.g. @xcite ) . from the paraxial approximation follows that the electric field envelope @xmath43}$ ] does not vary much along @xmath44 on the scale of the reduced wavelength @xmath45 . as a result , the following field equation holds : @xmath46 = \vec{g}(z , \vec{r}_\bot,\omega ) ~,\label{field1}\end{aligned}\ ] ] where the differential operator @xmath47 is defined by @xmath48 @xmath49 being the laplacian operator over transverse cartesian coordinates . ( [ field1 ] ) is maxwell s equation in paraxial approximation . the source - term vector @xmath50 is specified by the trajectory of the source electrons , and can be written in terms of the fourier transform of the transverse current density , @xmath51 , and of the charge density , @xmath52 , as @xmath53 \left(\frac{i\omega}{c^2}\vec{\bar{j}}_\bot -\vec{\nabla}_\bot \bar{\rho}\right ) ~. \label{fv}\end{aligned}\ ] ] @xmath54 and @xmath55 are regarded as given data . in this paper we will treat @xmath54 and @xmath55 as macroscopic quantities , without investigating individual electron contributions . we consider transverse and longitudinal distribution densities of the current constant through the undulator . in the time domain , we may write the charge density @xmath56 and the current density @xmath57 as @xmath58 and @xmath59 the quantity @xmath60 has the meaning of transverse electron beam distribution , while @xmath61 is the longitudinal charge density distribution . @xmath62 , @xmath63 and @xmath64 pertain a reference electron with lorentz factor @xmath7 that is injected on axis with no deflection and is guided by the undulator field only . such electron follows a trajectory specified by @xmath65 , @xmath66 and @xmath67 being the unit vectors in the horizontal and vertical directions respectively , with @xmath68 where we defined the transverse amplitude of oscillations @xmath69 . the corresponding velocity is indicated with @xmath70 : @xmath71 finally , @xmath63 is the curvilinear abscissa measured along the trajectory of the reference particle . note that , according to eq . ( [ charge ] ) and eq . ( [ curr ] ) , @xmath72 . in fact , for each particle in the beam @xmath73 . therefore we can neglect differences between the average transverse velocity of electrons @xmath74 and @xmath75 . in the space - frequency domain , ( [ charge ] ) and eq . ( [ curr ] ) transform to : @xmath76 \label{charge2tr}\ ] ] and @xmath77~ , \label{curr2tr}\ ] ] where , for simplicity , we introduced the symbol @xmath78 it should be remarked that @xmath55 and @xmath79 satisfy the continuity equation . in other words , one can find @xmath80 . we note that for a generic motion one has @xmath81 also , @xmath82 where the average longitudinal lorentz factor @xmath11 is defined as @xmath83 the approximate equality in eq . ( [ phasep ] ) follows from the fact that we are interested in wavelengths @xmath84 , where the fundamental @xmath85 is fixed imposing resonance condition between electric field and reference particle . the term in @xmath86 is of order @xmath87 , that is our accuracy , and can be neglected everywhere . with the help of eq . ( [ charge2tr ] ) and eq . ( [ curr2tr ] ) , eq . ( [ fv ] ) can be presented as ( see also @xcite ) : @xmath88 \left[\frac{i\omega}{c^2}\vec{v}_{o\bot}(z ) -\vec{\nabla}_\bot \right]{\rho_o}\left(\vec{r}_\bot - \vec{r'}_{o\bot}(z)\right ) \bar{f}(\omega ) ~.\cr & & \label{fvtf}\end{aligned}\ ] ] we find an exact solution of eq . ( [ oop ] ) without any other assumption about the parameters of the problem . a green s function for eq . ( [ oop ] ) , namely the solution corresponding to the unit point source can be written as ( see @xcite ) : @xmath89 assuming @xmath90 . when @xmath91 the paraxial approximation does not hold , and the paraxial wave equation eq . ( [ field1 ] ) should be substituted , in the space - frequency domain , by a more general helmholtz equation . yet , the radiation formation length for @xmath92 is very short with respect to the case @xmath93 , i.e. we can neglect contributions from sources located at @xmath94 . thus , after integration by parts , we obtain the solution @xmath95 + i \int_{0}^{z ' } d \bar{z}\frac { \omega } { 2 c \gamma_z^2(\bar{z } ) } \right\ } \cr&&\times \frac{1}{z - z ' } { \rho_o}\left(\vec{r'}_\bot-\vec{r'}_{\bot o}(z')\right ) \bar{f}(\omega ) \left(\frac{\vec{v}_{\bot}(z')}{c } -\frac{\vec{r}_{\bot}-\vec{r'}_{\bot}}{z - z'}\right)~. \cr & & \label{generalfin}\end{aligned}\ ] ] eq . ( [ generalfin ] ) describes the field at any position @xmath44 . note that @xmath96 depends on the difference @xmath97 . this dependence is important concerning the effect studied in this paper , as it will be seen later on . ( [ generalfin ] ) consists of two terms : one in @xmath98 and the other in @xmath99 . we will sometimes name the first term the `` current term '' @xmath100 , while the second will be indicated as the gradient term @xmath101 . with the help of eq . ( [ rhel0 ] ) , eq . ( [ vhel0 ] ) and eq . ( [ phasep ] ) we can re - write eq . ( [ generalfin ] ) as @xmath102 + \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right\ } ~. \cr & & \label{generalfin2}\end{aligned}\ ] ] a similar expression can be found for the longitudinal field . since @xmath103 , we can write the longitudinal equivalent of eq . ( [ fv ] ) as @xmath104 \left(\frac{i\omega}{c^2 } { \bar{j}}_z -\partial_z \bar{\rho}\right ) ~ , \label{fv2}\end{aligned}\ ] ] that is @xmath105 \left[-\frac{i\omega}{\bar{\gamma}_z^2 c } -\frac{\partial}{\partial z } \right]{\rho_o}\left(\vec{r}_\bot - \vec{r'}_{o\bot}(z)\right ) \bar{f}(\omega ) ~,\cr & & \label{fztf}\end{aligned}\ ] ] having used the fact that @xmath106 . it follows that the longitudinal component of the field , can be written analogously to eq . ( [ generalfin ] ) as @xmath107 + i \int_{0}^{z ' } d \bar{z}\frac { \omega } { 2 c \gamma_z^2(\bar{z } ) } \right\ } \cr & & \times \frac{1}{z - z ' } \left[-\frac{i \omega } { \bar{\gamma}_z^2 c } -\frac{\partial}{\partial z'}\right ] { \rho_o}\left(\vec{r'}_\bot-\vec{r'}_{\bot o}(z')\right ) \bar{f}(\omega)~. \cr & & \label{generalfinz}\end{aligned}\ ] ] note that the integral in eq . ( [ generalfinz ] ) is performed for @xmath108 ranging from @xmath109 up to @xmath44 exactly as the integral in eq . ( [ generalfin2 ] ) , for the same reasons . use of eq . ( [ rhel0 ] ) , eq . ( [ vhel0 ] ) and eq . ( [ phasep ] ) allow to re - write eq . ( [ generalfinz ] ) as @xmath110 + \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right\}\cr&&\times \left[-\frac{i \omega } { \bar{\gamma}_z^2 c}-\frac{k}{\gamma}\sin(k_w z')\frac{\partial}{\partial [ x'-r'_{ox}(z ' ) ] } \right]{\rho_o}\left(\vec{r'}_\bot - r_w \cos(k_w z ' ) \vec{e}_x\right ) \bar{f}(\omega ) ~. \cr & & \label{generalfinz2}\end{aligned}\ ] ] finally , integration by parts of the term in @xmath111\}$ ] gives @xmath112\cr&&\times { \rho_o}\left(\vec{r'}_\bot - r_w \cos(k_w z ' ) \vec{e}_x\right ) \bar{f}(\omega ) \exp\left\{i \omega\left[\frac{\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid^2}{2c ( z - z')}\right]+ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right\ } ~. \label{generalfinz2b}\end{aligned}\ ] ] note that , in contrast with eq . ( [ generalfin2 ] ) , we can not clearly distinguish between `` current '' and `` gradient '' terms in eq . ( [ generalfinz2b ] ) : the term in @xmath113 can be traced back to the gradient of the charge density , but the one in @xmath114 is a combination between current and gradient term . it is possible to analyze eq . ( [ generalfin2 ] ) and eq . ( [ generalfinz2b ] ) in the framework of a perturbation theory , based on expansion in the small parameter @xmath115 according to the first of conditions ( [ cons1 ] ) . this allows simplified treatment of impedance and wakes . the first step towards this direction is a presentation of of @xmath116 and @xmath117 with the help of the following expansions in plane waves : @xmath118\right\ } = \cr & & \frac{i c}{2\pi \omega } \int d\vec{k}_\bot \exp\left[-i \vec{k}_\bot \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \exp\left[\frac{i k_\bot^2 c } { 2\omega}(z'-z)\right]\label{expand1}\end{aligned}\ ] ] and @xmath119\right\ } = - \frac{i c^2}{2 \pi \omega^2}\cr & & \int d\vec{k}_\bot \vec{k}_\bot \exp\left[-i \vec{k}_\bot \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \exp\left[\frac{i k_\bot^2 c } { 2\omega}(z'-z)\right]~.\label{expand2}\end{aligned}\ ] ] we obtain @xmath120 \exp\left[\frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right]\cr&&\times { \rho_o}\left(\vec{r'}_\bot - r_w \cos(k_w z ' ) \vec{e}_x\right ) \exp\left[-i \vec{k}_\bot \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \exp\left[\frac{i k_\bot^2 c } { 2\omega}(z'-z)\right ] \label{perpexp}\end{aligned}\ ] ] and @xmath121\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right]\cr&&\times { \rho_o}\left(\vec{r'}_\bot - r_w \cos(k_w z ' ) \vec{e}_x\right ) \exp\left[-i \vec{k}_\bot \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \exp\left[\frac{i k_\bot^2 c } { 2\omega}(z'-z)\right]~. \label{longexp}\end{aligned}\ ] ] performing a change of variables @xmath122 and introducing notation @xmath123 we re - write eq . ( [ perpexp ] ) and eq . ( [ longexp ] ) as @xmath124 \exp\left[\frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right]\cr&&\times { \rho_o}\left(\vec{r'}_\bot\right ) \exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot - r_w \cos(k_w z ' ) \vec{e}_x \right)\right ] \exp\left[\frac{i \omega \theta^2}{2 c } ( z'-z)\right ] \label{perpexp2}\end{aligned}\ ] ] and @xmath125\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right]\cr&&\times { \rho_o}\left(\vec{r'}_\bot\right ) \exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot - r_w \cos(k_w z ' ) \vec{e}_x \right)\right ] \exp\left[\frac{i \omega \theta^2 } { 2 c } ( z'-z)\right]~. \label{longexp2}\end{aligned}\ ] ] note that the maximal range of angles @xmath126 is limited by the last exponential function in eq . ( [ perpexp2 ] ) and eq . ( [ longexp2 ] ) and by the fact that @xmath127 . it follows that @xmath126 can not be larger than about @xmath128 . then , the trigonometric terms inside the exponential functions in both eq . ( [ perpexp2 ] ) and eq . ( [ longexp2 ] ) are of magnitude @xmath129 . it follows that we may expand @xmath130/c\ } \simeq 1+i \omega r_w \theta_x \cos[k_w z']/c$ ] . using exponential representation for all trigonometric functions we obtain : @xmath131 \int_{0}^{z } dz ' \int d \vec{r'}_{\bot } \cr & & \times{\rho_o}\left(\vec{r'}_\bot\right ) \exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot\right)\right ] \left\{\frac{k \vec{e}_x}{2 k_w z')-\exp(-ik_w z')\right ] - \vec{\theta}\right\}\cr & & \times \left\{1+\frac{i \omega \theta_x r_w } { 2 c } \left[\exp(i k_w z')+\exp(-i k_w z')\right]\right\ } \exp\left[\frac{i \omega \theta^2 z'}{2 c } \right]\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right]~. \label{perpexp3}\end{aligned}\ ] ] and @xmath132 \int_{0}^{z } dz ' \int d \vec{r'}_{\bot } \cr&&\times { \rho_o}\left(\vec{r'}_\bot\right)\exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \left\{\frac{1}{\bar{\gamma}_z^2}- \frac{k \theta_x}{2 i \gamma}\left[\exp(i k_w z')-\exp(-ik_w z')\right]\right\}\cr & & \times \left\{1+\frac{i \omega \theta_x r_w } { 2 c } \left[\exp(i k_w z')+\exp(-i k_w z')\right]\right\}\exp\left[\frac{i \omega \theta^2 z'}{2 c } \right]\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right]~. \label{longexp3}\end{aligned}\ ] ] eq . ( [ perpexp3 ] ) and eq . ( [ longexp3 ] ) have been found exploiting the small parameter @xmath133 . in both eq . ( [ perpexp3 ] ) and eq . ( [ longexp3 ] ) products of factors within @xmath134 brackets are of the form @xmath135 $ ] , with @xmath136 , terms for @xmath137 being obtainable considering higher orders in @xmath128 in the previous expansion of the exponential of trigonometric function . note that when @xmath138 , the magnitude of @xmath126 can be estimated from the last two exponential functions in eq . ( [ perpexp3 ] ) and eq . ( [ longexp3 ] ) , giving characteristic a scale @xmath139 . for other values of @xmath140 , instead , we have a characteristic scale @xmath141 . consider first eq . ( [ perpexp3 ] ) . magnitudes of factors within @xmath134 brackets are @xmath142 and @xmath143 for the first bracket , @xmath144 and @xmath145 for the second bracket . terms of the form @xmath135 $ ] with @xmath138 can have magnitudes @xmath146 or @xmath147\cdot [ \omega \theta_x r_w/(2c)]\sim k^2 \lambdabar_r \bar{\gamma}_z/(\gamma^2 \lambdabar)$ ] , this last kind being negligible . when @xmath148 terms have magnitudes @xmath149 or @xmath150 , and both kinds have to be kept . similarly , it can be shown that all other values of @xmath140 give negligible terms . consider now eq . ( [ longexp3 ] ) . magnitudes of factors within @xmath134 brackets are @xmath114 and @xmath151 for the first bracket , @xmath144 and @xmath145 for the second bracket . terms of the form @xmath135 $ ] with @xmath138 can have magnitudes @xmath114 or @xmath152\cdot [ \omega \theta_x r_w/(2c)]\sim k^2 \lambdabar_r /(\gamma^2 \lambdabar)$ ] , this last kind being negligible . when @xmath148 terms have magnitudes @xmath153 or @xmath154 , and this last kind can be neglected . similarly , it can be shown that all other values of @xmath140 give negligible terms . altogether , we obtain the following expressions for transverse and longitudinal field : @xmath155 \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right]\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right ] \cr & & \times \left\{-\vec{\theta } + \left[\frac{k \vec{e}_x}{2i\gamma}-\frac{i \omega \theta_x r_w\vec{\theta}}{2c}\right]\exp(i k_w z')- \left[\frac{k \vec{e}_x}{2i\gamma}+\frac{i \omega \theta_x r_w\vec{\theta}}{2c}\right]\exp(-i k_w z')\right\}\cr & & \label{perpexp4}\end{aligned}\ ] ] and @xmath156\cr&&\times \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right]\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right ] \left\{\frac{1}{\bar{\gamma}_z^2}-\frac{k \theta_x}{2 \gamma i}\left[\exp(i k_w z')-\exp(-ik_w z')\right]\right\}~.\cr & & \label{longexp4}\end{aligned}\ ] ] eq . ( [ perpexp4 ] ) and eq . ( [ longexp4 ] ) are the first order result of our perturbation theory , where the small parameter @xmath133 has been exploited through the expansion of exponential functions in eq . ( [ perpexp2 ] ) and eq . ( [ longexp2 ] ) , and non - negligible terms are kept . we now go back to the space - frequency domain performing the integral in @xmath157 with the help of eq . ( [ expand1 ] ) , eq . ( [ expand2 ] ) and using also @xmath158 \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right ] \theta_x^2 \cr & & = \frac{2 c \pi \left[c(z - z')+i \omega(x - x')^2 \right]}{(z'-z)^3 } \exp\left[\frac{i \omega \left|\vec{r}_\bot - \vec{r'}_\bot \right|^2}{2c ( z - z ' ) } \right]~.\label{lastback}\end{aligned}\ ] ] finally , we obtain : for the transverse field , and @xmath160\cr & & \times \bigg\{\exp[+i k_w z]\int_{0}^{z } \frac{dz'}{z - z ' } \exp\left[i \omega\frac{\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid^2}{2c ( z - z')}\right]\left [ + \frac{k}{2 i \gamma}\frac{x - x'}{z - z'}\exp[i k_w ( z'-z)]\right ] \cr & & + \exp[-i k_w z ] \int_{0}^{z } \frac{dz'}{z - z ' } \exp\left[i \omega\frac{\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid^2}{2c ( z - z')}\right]\left [ -\frac{k}{2 i \gamma}\frac{x - x'}{z - z ' } \exp[-i k_w ( z'-z)]\right]\cr & & + \int_{0}^{z } \frac{dz'}{z - z ' } \exp\left[i \omega\frac{\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid^2}{2c ( z - z')}\right]\exp\left [ \frac{i\omega ( z'-z)}{2 c \bar{\gamma}_z^2 } \right]\frac{1}{\bar{\gamma}_z^2}\bigg\}~ \label{effz}\end{aligned}\ ] ] for the longitudinal field . here we neglected factors @xmath161 $ ] in integral terms in @xmath162 including @xmath163 $ ] , because @xmath164 . note that there exists a mathematical shortcut to obtain eq . ( [ effp ] ) and eq . ( [ effz ] ) from eq . ( [ generalfin2 ] ) and eq . ( [ generalfinz2b ] ) . in fact , if we perform a change of variables @xmath165 , we formally expand the green s function exponential @xmath166\}$ ] to the first order in @xmath167 and keep non - negligible first - harmonic terms in @xmath168 $ ] , we obtain eq . ( [ effp ] ) and eq . ( [ effz ] ) . we will regard it as a mnemonic rule , that will be useful later on . fields are calculated under conditions ( [ cons1 ] ) . in the limit for @xmath169 , as we will see in the next section [ sub : expl ] , integrals in @xmath162 depend on @xmath44 only through phase factors , i.e. a steady state solution is reached . analysis of eq . ( [ effp ] ) and eq . ( [ effz ] ) presents an interesting picture of the fields generated by the electron beam . ( [ effp ] ) and eq . ( [ effz ] ) consist of the sum of integrals in @xmath162 . some include exponential factors @xmath170 $ ] , other not . terms not including @xmath163 $ ] ( the last integrals in @xmath162 in both eq . ( [ effp ] ) and eq . ( [ effz ] ) ) oscillate , as a function of @xmath44 , on a scale @xmath171 . the field @xmath172 is given by @xmath173 $ ] . it follows that the phase velocity of terms not including @xmath163 $ ] is the same as that of the electron beam harmonic @xmath55 . we can interpret this fact by saying that this part of the field is entangled with the electron beam . it is natural to identify these terms as space - charge terms . the formation length of the space - charge field is determined by the factor @xmath174 $ ] under integral sign , and amounts to @xmath175 . similarly , the diffraction size of the space - charge field is given by @xmath29 . terms including @xmath176 $ ] are indicative of fields @xmath172 performing a cycle of oscillation on the scale of an undulator period with respect to the electron - beam harmonic @xmath55 . phase velocity of terms including @xmath177 $ ] is slower than that of the beam harmonic . these field terms have a phase velocity slower than the speed of light . phase velocity of terms including @xmath178 $ ] is faster than that of the beam harmonic . these field terms have a phase velocity faster than the speed of light . we can interpret these facts by saying that these parts of the field are not entangled with the electron beam . it is natural to identify these terms as radiation terms . the formation length of radiation field terms is determined by the factor @xmath179 $ ] under integral sign , and amounts to @xmath10 . similarly , the diffraction size of the space - charge field is given by @xmath180 . it is interesting to trace each term in eq . ( [ effp ] ) and eq . ( [ effz ] ) back to the source terms that originated them , distinguishing between gradient and current terms . considering eq . ( [ effp ] ) it can be seen that the first and the second integral are ( radiative ) current density terms . the third and the fourth term are ( radiative ) gradient terms , while the last term is a ( space charge ) gradient term . however , one can see from eq . ( [ effz ] ) that the third integral is a ( space - charge ) term originated from a mixture of gradient and current sources . thus , although the first and the second integral are ( radiative ) gradient terms , it does not make sense to separately talk about gradient and current term for the longitudinal component of the field . an interesting picture emerges , where radiation field and space - charge field are treated on equal foot , through paraxial maxwell s equation . on the one hand , as we have seen , these fields have different formation lengths , and different diffraction sizes . on the other hand , our theory allows for generic transverse sizes of the electron beam @xmath13 , that makes it possible to compare @xmath13 with both diffraction sizes , thus obtaining different regimes . as we will see , when @xmath181 , impedance and wakes are essentially dominated by the longitudinal space - charge term . it is important to remark , for future use in the next sections , that @xmath11 enters the expression of the space - charge field , and not @xmath7 . we can consider eq . ( [ effp ] ) and eq . ( [ effz ] ) as starting point for our investigations , and calculate explicit expressions for the field to be used later on in the calculation of the impedance . first , we make a change in the integration variable from @xmath108 to @xmath182 . in the limit for @xmath183 , corresponding to the second of conditions ( [ cons1 ] ) , i.e. @xmath169 , we can write for the transverse field and for the longitudinal field . we now use the fact that , for any real number @xmath186 : where @xmath188 is the n - th order modified bessel function of the second kind , @xmath189 is n - th order bessel function of the second kind and @xmath190 is the n - th order bessel function of the first kind . using eq . ( [ rele ] ) and the fact that @xmath191 , and remembering that @xmath192 ^ 2 } = \cr & & \frac{1}{4 \mid \vec{r}_{\bot}-\vec{r'}_\bot \mid^2 } \frac{d^2}{d \left[\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid\right]^2}-\frac{1 } { 4 \mid \vec{r}_{\bot}-\vec{r'}_\bot \mid^3}\frac{d}{d\left[\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid\right ] } \label{der}\end{aligned}\ ] ] we can write eq . ( [ effp2 ] ) and eq . ( [ effz2 ] ) as and note that , similarly as in eq . ( [ effp ] ) eq . ( [ effz ] ) , it is possible to recognize in eq . ( [ teffp3 ] ) and eq . ( [ teffz3 ] ) radiative and space - charge terms , as well as gradient and current terms ( for the transverse field components ) . it is possible to cross - check our expressions for the field with the help of gauss law : @xmath194 this cross - check will constitute a general cross - check of the correctness of our calculation and allow a better understanding of the interplay of different field contributions in the complicated machinery of maxwell s equation . as said before , in the present study we work in the steady state , when the bunch has travelled inside the undulator for more than @xmath195 . in this case , an explicit expression for transverse and longitudinal fields are given in eq . ( [ teffp3 ] ) and eq . ( [ teffz3 ] ) . we will demonstrate that the field @xmath196 obeys eq . ( [ gauss ] ) by separately showing that radiation field @xmath197 and space - charge field @xmath198 verify : @xmath199 relations ( [ gauss2 ] ) can be interpreted saying that the radiation field is not entangled with sources , while the space - charge field is . hence the different right hand sides . let us begin with the space - charge field . first we can write : @xmath200 \right\ } = \frac{i\omega}{c}\left(1+\frac{1}{2\bar{\gamma}_z}^2\right ) \bar{e}_{z\mathrm{sc } } \simeq \frac{i\omega}{c } \bar{e}_{z\mathrm{sc}}~ , \label{dez}\ ] ] because , in the steady state , @xmath201 depends on @xmath44 only through @xmath202 $ ] . thus , in order to verify the first of eq . ( [ gauss2 ] ) we should prove that @xmath203 from eq . ( [ teffp3 ] ) we have @xmath204 \int d \vec{r'}_{\bot } { \rho_o}\left(\vec{r'}_\bot\right ) \frac{\vec{r}_{\bot}-\vec{r'}_{\bot}}{\mid\vec{r}_{\bot}-\vec{r'}_{\bot}\mid } k_1\left ( \frac{\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid}{\bar{\gamma}_z \lambdabar } \right)~.\cr & & \label{teffp3sc}\end{aligned}\ ] ] in order to calculate the left hand side of eq . ( [ gauss2sc ] ) we can use the divergence theorem in two dimensions , to find : @xmath205 where @xmath206 indicates the dirac - delta function and derivation is understood in weak sense , we set @xmath207 . remembering @xmath208 $ ] we obtain @xmath209 \cr & & \times \bar{f}(\omega ) \exp\left[\frac{i\omega z } { v_z}\right ] ~. \label{ezbar3}\end{aligned}\ ] ] now , from eq . ( [ teffz3 ] ) we have : @xmath210 k_0\left ( \frac{\mid \vec{r}_{\bot}-\vec{r'}_\bot \mid}{\lambdabar \bar{\gamma}_z } \right ) \bar{f}(\omega ) \exp\left[\frac{i\omega z } { v_z}\right ] ~.\cr & & \label{teffz333}\end{aligned}\ ] ] substitution in the right hand side of eq . ( [ gauss2sc ] ) yields eq . ( [ ezbar3 ] ) , thus verifying eq . ( [ gauss2sc ] ) . let us now consider the radiative fields , and show that the second of eq . ( [ gauss2 ] ) is also verified . presentations in eq . ( [ teffp3 ] ) and eq . ( [ teffz3 ] ) include now many terms , and it is convenient to start with alternative presentations for the transverse and longitudinal field , namely eq . ( [ perpexp4 ] ) and eq . ( [ longexp4 ] ) . in the limit for @xmath211 the radiative part of the field is given by : @xmath212 \frac{\omega^2 \bar{f}(\omega)}{2\pi c^2 } \int d\vec{\theta } \int_{0}^{\infty } dz ' \int d \vec{r'}_{\bot } { \rho_o}\left(\vec{r'}_\bot\right ) \cr & & \times \exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot\right)\right ] \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right]\cr & & \times \left\ { \frac{k \vec{e}_x}{\gamma } \sin[k_w z']-\frac{i \omega \theta_x r_w\vec{\theta}}{c } \cos[k_w z']\right\ } \label{pexp}\end{aligned}\ ] ] and @xmath213 \int d\vec{\theta } \int_{0}^{\infty } dz ' \int d \vec{r'}_{\bot } { \rho_o}\left(\vec{r'}_\bot\right)\cr&&\times\exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right ] \theta_x \sin[k_w z']~. \label{gexp}\end{aligned}\ ] ] here we neglected factors @xmath214 $ ] because @xmath164 . we may now calculate directly @xmath215 and @xmath216 . we obtain @xmath217 \int d\vec{\theta } \int_{0}^{\infty } dz ' \int d \vec{r'}_{\bot } { \rho_o}\left(\vec{r'}_\bot\right ) \cr & & \times \exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot\right)\right ] \bigg\ { { \theta_x } \sin[k_w z']\exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right ] \cr & & -{2 \theta_x \lambdabar_w } \cos[k_w z ' ] \frac{\partial}{\partial z ' } \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right ] \bigg\ } \label{divper}\end{aligned}\ ] ] and @xmath218 \int d\vec{\theta } \int_{0}^{\infty } dz ' \int d \vec{r'}_{\bot } { \rho_o}\left(\vec{r'}_\bot\right)\cr&&\times\exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot \right)\right ] \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right]\cdot \left\{\theta_x \sin[k_w z ' ] \right\}~ , \label{divlon}\end{aligned}\ ] ] in eq . ( [ divlon ] ) we neglected an extra - term @xmath219 $ ] in parenthesis @xmath134 , because @xmath220 . we now integrate by parts the term in @xmath221 $ ] in eq . ( [ divper ] ) to obtain @xmath217 \int d\vec{\theta } \int_{0}^{\infty } dz ' \int d \vec{r'}_{\bot } { \rho_o}\left(\vec{r'}_\bot\right ) \cr & & \times \exp\left[-\frac{i \omega}{c } \vec{\theta } \cdot \left ( \vec{r}_\bot -\vec{r'}_\bot\right)\right ] \exp\left[\frac{i \omega \theta^2 ( z'-z)}{2 c } \right]\exp\left [ \frac{i\omega z'}{2 c \bar{\gamma}_z^2 } \right ] \cdot \left\ { - \theta_x \sin[k_w z']\right\}~.\cr & & \label{divper2}\end{aligned}\ ] ] obviously @xmath222 , and also the second of eq . ( [ gauss2 ] ) is satisfied . the knowledge of the electric field at the position of any test particle inside the beam , that has been derived in section ( [ sec : main ] ) , allows to derive wake function and impedance related with the system under study . let us briefly review here concepts of longitudinal impedance and wake function , that will be used later on . the longitudinal impedance of a system , @xmath223 , can be given as the fourier transform of the wake function @xmath224 : @xmath225~,\cr & & g_o = \frac{1}{(-e ) } \int_{-\infty}^{\infty } d \vec{r } ' \cdot ~\vec{e}^{o}(\delta s , \vec{r'}(t ) , t)| _ { t = z'/(\beta_z c)}~. \label{impe}\end{aligned}\ ] ] here the integral in the expression for @xmath226 is a line integral calculated along the trajectory of a test particle . in fact , @xmath227 indicates the time - domain electric field generated by a source particle acting on the test particle at longitudinal distance @xmath228 from the source . in the calculation of @xmath227 we assume that effects from the vacuum chamber are negligible , i.e. @xmath229 , that is the third of conditions ( [ cons1 ] ) . @xmath227 is integrated along the test particle trajectory , and divided by the electron charge @xmath17 , so that @xmath230 is the energy ( gained , or lost ) by the test particle due to the action of the source . in agreement with @xcite we take the test particle behind the source for positive values of @xmath228 . according to the given definition of wake function , one should integrate the field over the entire trajectory . however , there is no principle difficulty in considering only part of the trajectory , let us say , up to longitudinal position @xmath44 . mathematically , this means that the line integral for @xmath226 should be performed up to the trajectory point of the test electron corresponding to longitudinal position @xmath44 . in this way , @xmath231 . note that eq . ( [ impe ] ) is automatically dependent on a particular source electron , and a particular test electron . in order to formulate this statement in a mathematical way , we may introduce test and source particle initial transverse position @xmath232 and @xmath233 and write @xmath234 , where we neglect differences in energy between the two particles . following our previous work @xcite , we will slightly modify the concepts of wake and impedance by substituting test and source particles with disks of total charge ( -e ) , longitudinally separated by a distance @xmath228 . this amounts to an integration over the transverse particle distribution in @xmath235 and @xmath236 , that makes our definitions independent of @xmath232 and @xmath233 . we thus obtain @xmath237 in eq . ( [ gred ] ) we used the fact that @xmath238 is independent of the longitudinal position . with the redefinition in eq . ( [ gred ] ) we can further consider the impedance @xmath239 proceeding as in ( [ impe ] ) for the definition of @xmath223 , but fourier substituting @xmath224 with @xmath240 . note that by definition of @xmath239 we have @xmath241 where @xmath242 accounts for the fact that test and source disks have total charge ( -e ) , while @xmath243 , @xmath244 being the already defined fourier transform of the longitudinal bunch - profile . here the volume @xmath245 is a cylinder of base a including the undulator up to position @xmath246 . the integration in @xmath108 is performed from @xmath109 to @xmath44 , because we will be interested in impedance and wakes generated inside the undulator , and we will assume that the undulator begins at position @xmath247 . according to eq . ( [ defzz ] ) , the expressions for the longitudinal impedance associated with @xmath248 and @xmath249 , @xmath250 and @xmath251 are given by @xmath252 \cr & & \times \int d\vec{r'}_\bot \bar{f}^*(\omega ) \rho_o^*[\vec{r'}_\bot- r_w \cos(k_w z ) ] \vec{v}_{o\bot}(z')\cdot \vec{\bar{e}}_\bot(z',\omega,\vec{r'}_\bot ) \cr z_z & = & \frac{1}{|\bar{f}(\omega)|^2 } \int_0^z dz ' \exp\left[-\frac{i s_o(z')}{v_o}\right ] \cr & & \times \int d\vec{r'}_\bot \bar{f}^*(\omega ) \rho_o^*[\vec{r'}_\bot- r_w \cos(k_w z)\vec{e}_x ] c { \bar{e}}_z(z',\omega,\vec{r'}_\bot ) ~.\cr & & \label{imped0}\end{aligned}\ ] ] when we calculated the field , we saw that the dependence of the source transverse charge density @xmath238 on the electron motion @xmath253 had to be accounted for . we will show that , in the calculation of the impedance , the dependence of the test transverse charge density @xmath238 on @xmath254 must also be accounted for . with the help of a change of variables we rewrite eq . ( [ imped0 ] ) as a sum @xmath255 : calculations can be drastically simplified , because transverse radiative gradient terms in @xmath257 cancel with longitudinal radiative terms in @xmath258 . it is easier to show this facts with the help of eq . ( [ effp ] ) and eq . ( [ effz ] ) , rather than using explicit expressions eq . ( [ teffp3 ] ) and eq . ( [ teffz3 ] ) . first , with the help of eq . ( [ effp ] ) and eq . ( [ effz ] ) , we write down the part of the impedance from the radiative transverse field , @xmath259 and from the radiative longitudinal field , @xmath260 . in principle , in order to dispose of the oscillating terms in @xmath261 , we may use the same mathematical shortcut that can be exploited to obtain eq . ( [ effp ] ) and eq . ( [ effz ] ) from eq . ( [ generalfin2 ] ) and eq . ( [ generalfinz2b ] ) . in fact , we may formally expand the green s function exponential @xmath262\}$ ] to the first order in @xmath167 and keep non - negligible first - harmonic terms in @xmath168 $ ] . however , @xmath263 is multiplied by @xmath264 in the expression for the impedance @xmath257 . since @xmath264 oscillates with period @xmath10 , we can neglect the oscillatory contributions in @xmath265 in the expression of @xmath266 , because they would give oscillatory contributions that average to zero after integration in @xmath162 . we therefore obtain : for the transverse field . on the contrary , the longitudinal velocity @xmath268 is a sum of a constant term , whose magnitude is about @xmath40 and a negligible oscillates with period @xmath269 . as a result , the oscillatory contributions in @xmath270 in the expression of @xmath271 must be kept , and an expansion of the exponential in the green s function must be performed , leading to partial cancellation can be exploited between the last two terms of eq . ( [ effpr ] ) and eq . ( [ effzr ] ) . note that the longitudinal radiative impedance is completely cancelled , and one obtains performing the integrals in @xmath274 with the help of eq . ( [ rele ] ) or , equivalently , calculating @xmath275 with the help of the transverse radiative current terms in eq . ( [ teffp3 ] ) we finally obtain @xmath276 + k_o\left[\frac{-\sqrt{2}i\mid \vec{r'}_{\bot}-\vec{r''}_\bot \mid } { \sqrt{\lambdabar\lambdabar_w}}\right ] \bigg\}~. \label{zradfin}\end{aligned}\ ] ] let us now consider the space - charge part of the impedance . one finds that the space - charge term in @xmath257 , i.e. @xmath277 , averages to zero , as can directly be seen by inspecting the last term in @xmath278 $ ] of eq . ( [ teffp3 ] ) . in fact , such term is independent of @xmath44 . now , according to eq . ( [ imped ] ) , in order to obtain the correspondent impedance contribution , this term must be multiplied by @xmath98 ( i.e. by @xmath168 $ ] ) and integrated in @xmath162 for a saturation length . it follows that , during the integration process in @xmath162 , one integrates a fast varying function of @xmath44 on the scale of @xmath10 . as a result , we obtain a negligible effective impedance contribution over many undulator periods , and we can neglect the transverse space - charge contribution in the calculation of wake and impedance . the total space - charge part of the impedance coincides with the longitudinal space - charge impedance . it can be shown that oscillatory contributions in @xmath279 in the expression of @xmath280 are of higher order in @xmath87 and they can thus be neglected . as a result we obtain @xmath281 we thus reach the conclusion that only longitudinal space - charge terms and transverse radiative terms enter the expression for the impedance that can now be calculated in integral from for any transverse beam - distribution under conditions ( [ cons1 ] ) . finally , we obtain the total impedance @xmath282 . the real part @xmath283 is given by @xmath284 the imaginary part @xmath285 , instead , amounts to @xmath286 having used the fact that @xmath287 $ ] . before proceeding with the analysis of the wake , it is interesting to derive asymptotic limits of eq . ( [ zr ] ) and eq . ( [ ir ] ) in the case for @xmath289 . bessel functions in eq . ( [ zr ] ) and eq . ( [ ir ] ) can be expanded for small argument values . in particular , using @xmath290 for @xmath291 , and recalling that @xmath238 is normalized to @xmath292 , the real part of the impedance becomes @xmath293 independently of the choice of @xmath238 . subsequently , we use @xmath294 and @xmath295 $ ] , @xmath296 being the euler gamma constant in the imaginary part of the impedance , eq . ( [ ir ] ) . we obtain @xmath297 where @xmath298 @xmath299 is the only model - part of the impedance . in particular , assuming a gaussian transverse profile : @xmath300 ~\label{rhoog}\end{aligned}\ ] ] we obtain @xmath301 \exp\left[-\frac{r^{''2}_\bot}{2\sigma_\bot^2}\right ] \ln\left(\frac{\left|\vec{r'}_\bot -\vec{r''}_\bot\right|}{2\lambdabar \gamma}\right ) \cr & = & \frac{2 z \gamma_e}{c \lambdabar \gamma^2}+ \frac{2 z } { c \lambdabar { \gamma}^2 } \ln\left(\frac{\sigma_\bot}{{\gamma } \lambdabar}\right ) ~.\cr & & \label{zifree2}\end{aligned}\ ] ] also , @xmath299 , is logarithmically divergent on @xmath13 . this is , in fact , the free - space impedance . the renormalized impedance$ ] ) , it would be impossible to recover eq . ( [ irr2 ] ) and eq . ( [ renim ] ) . in other words , the renormalization process would fail . this underlines the fact that , although slow - wave radiative contributions have no realization in the far zone , they are of fundamental importance in the calculation of the impedance . ] , i.e. the difference of eq . ( [ irr2 ] ) with the free - space impedance is independent of @xmath13 and constitute a result valid for any value of @xmath3 . here we underline the fact that in the limit for @xmath302 the difference between the impedance of an electron beam moving through a magnetic system and the free - space impedance is independent of the electron beam model . it is finite , and can thus be applied in a one - dimensional approximation whereby the electron bunch is modelled by a line density . this one - dimensional approach was first proposed in the time - domain to study coherent synchrotron radiation ( csr ) in @xcite and is currently used in csr codes . also in this case , the renormalized wake is obtained by subtracting the free - space wake ( as is natural , because the wake is the fourier transform of the impedance , i.e. its time - domain counterpart ) . the renormalization procedure used here and introduced in @xcite has to be seen as a mathematical algorithm to deal with calculation of self - forces of a moving charged line . such calculation is problematic due to incompleteness of electromagnetic theory , yielding to divergence . such divergence is cancelled by subtracting the longitudinal force that would be present in a straight - line motion from the force calculated on a curved trajectory . the finite difference can be entirely ascribed to curvature . analytical and numerical studies can be found in literature , treating longitudinal impedance and wake from an undulator setup in the case of a line density distribution of electrons ( see e.g. @xcite , @xcite and @xcite ) . reference @xcite deals with the one - dimensional renormalized wake of an electron beam with a gaussian longitudinal profile @xmath303~ , \label{fs}\end{aligned}\ ] ] @xmath304 being the number of electrons in the beam . in particular , in reference @xcite , the following expression for the energy gained or lost by a particle at position @xmath44 down the beamline and position @xmath305 within the bunch in this paper differs for a sign with respect to that in @xcite . ] was obtained : @xmath306 where @xmath307 , @xmath308 is the bunch length parameter @xmath309 and @xmath310 is given by @xmath311 \left[\ln(p ) + g(k)\right ] + f(x)~ , \label{gggg}\end{aligned}\ ] ] with @xmath312x \exp\left[-\frac{x^2}{2}\right ] \cr & & - \sqrt{\frac{\pi}{8 } } \bigg\{1+\mathrm{erf}\left[\frac{x}{\sqrt{2}}\right ] - x\exp\left[-\frac{x^2}{2}\right ] \cr & & \times \int_0^x dx ' \exp\left[\frac{(x')^2}{2}\right ] \left[1+\mathrm{erf}\left[\frac{x'}{\sqrt{2}}\right ] \right]\bigg\}~.\label{fxdef}\end{aligned}\ ] ] moreover , in the limit for @xmath313 , @xmath314 , while in the limit for @xmath4 , @xmath315 . for arbitrary values of @xmath3 , @xmath316 was presented in @xcite as a plot , using numerical integration techniques . now @xmath316 can be expressed fully analytically : @xmath317}{k^2/2}~. \label{gofk}\end{aligned}\ ] ] eq . ( [ enlo ] ) was already been independently cross - checked , with the help of the code @xmath318 , in @xcite . in this paper we underline the correctness of eq . ( [ enlo ] ) . reference @xcite deals with the renormalized impedance in the case of a line density distribution . such impedance is presented in eq . ( 26 ) of @xcite in the asymptotic case for @xmath319 . when @xmath320 and @xmath321 only the first term of eq . ( [ irr2 ] ) survives , and the total renormalized impedance @xmath322 reads : @xmath323 eq . ( [ renim ] ) is in agreement with reference @xcite , where the impedance per unit length is given in our expression is the result of different definition of impedance . ] . in general , the real part of the impedance can always be cross - checked with the energy conservation law , that requires : @xmath325 where the energy spectrum of the radiation , @xmath326 , is defined as the integral over all angles of the total energy emitted per unit frequency per unit solid angle @xmath327 : @xmath328 it is easy to verify eq . ( [ poy ] ) in the case @xmath324 . in this case , the electron beam transverse size is much smaller than the radiation diffraction size , and a filament - beam model can be used . our theory has been developed for any value of the undulator parameter @xmath3 , and in the long - wavelength asymptote , i.e. for @xmath329 . in this case it is possible to give a simple mathematical description of the radiation energy spectrum . based on this expression we will then verify eq . ( [ poy ] ) . in order to calculate the energy spectrum according to eq . ( [ espec ] ) we must first calculate @xmath116 in the far zone . we can specify `` how near '' @xmath34 is to the resonant frequency @xmath330 by introducing a detuning parameter @xmath331 , defined as @xmath332 , where @xmath333 . then , the field generated by a filament - beam is well - known and is given , in paraxial approximation ( see e.g. eq . ( 13 ) of @xcite ) , by : @xmath334 \frac{i \omega |\bar{f}(\omega)|}{c^2 z } \int_{-l_w/2}^{l_w/2 } dz'\left\{\frac{k}{2 i \gamma}\left[\exp\left(2 i k_w z'\right)-1\right]\vec{e}_x + \vec{\theta}\exp\left(i k_w z'\right)\right\ } \cr & & \times \exp\left[i \left(c + { \omega \theta^2 \over{2 c } } \right ) z ' - { k\theta_x\over{\gamma}}{\omega\over{k_w c}}\cos(k_w z ' ) - { k^2\over{8\gamma^2 } } { \omega\over{k_w c } } \sin(2 k_w z ' ) \right ] ~.\label{undurad2}\end{aligned}\ ] ] as first proposed in @xcite one may use the anger - jacobi expansion @xmath335 = \sum_{p=-\infty}^{\infty } j_p(a ) \exp\left[ip\psi\right]$ ] , where @xmath336 indicates the bessel function of the first kind of order @xmath140 , to write the integral in eq . ( [ undurad2 ] ) in a different way : @xmath334 \frac{i \omega |\bar{f}(\omega)|}{c^2 z } \sum_{m , n=-\infty}^\infty j_m(u ) j_n(v ) \exp\left[\frac{i \pi n}{2}\right ] \cr & & \times \int_{-l_w/2}^{l_w/2 } dz'\exp\left[i \left(c + { \omega \theta^2 \over{2 c } } \right ) z'\right ] \left\{\frac{k}{2 i \gamma } \left[\exp\left(2 i k_w z'\right)-1\right]\vec{e}_x + \vec{\theta}\exp\left(i k_w z'\right)\right\ } \cr & & \times \exp\left[i ( n+2 m ) k_w z'\right ] ~,\label{undurad3}\end{aligned}\ ] ] where @xmath337 and @xmath338 . there is no simple result valid at the same time for arbitrary @xmath3 values and arbitrary detuning . however , there are asymptotes for @xmath329 and arbitrary @xmath3 , or @xmath313 and arbitrary detuning . we will first assume @xmath313 and arbitrary values for @xmath339 , i.e. @xmath340 , we always have @xmath341 , but not viceversa . thus , here we are considering @xmath341 , but arbitrary value for @xmath339 . ] . consider the case @xmath341 , @xmath342 being the number of undulator periods , @xmath343 and @xmath313 . because of these assumptions , both @xmath344 and @xmath345 ( here @xmath346 or for @xmath347 and @xmath348 . it follows that @xmath349 \left\{\vec{e}_x- \vec{\theta}\frac { \theta_x \omega } { k_w c}\right\ } \cr & & \times \int_{-l_w/2}^{l_w/2 } dz'\exp\left[i \left(c + { \omega \theta^2 \over{2 c } } \right ) z'\right ] \cr & = & - \frac{\omega |\bar{f}(\omega)| k l_w}{2 c^2 z \gamma } \exp\left[i\frac{\omega \theta^2 z}{2c}\right ] \left\{\left[1-\frac { \theta_x^2 \omega } { k_w c}\right]\vec{e}_x + \left[\frac { \theta_x \theta_y \omega } { k_w c}\right]\vec{e}_y\right\}\cr & & \times \mathrm{sinc}\left[\frac{l_w}{4}\left(c + { \omega \theta^2 \over{2 c } } \right ) \right ] ~. \label{undurad4}\end{aligned}\ ] ] note that since both @xmath344 and @xmath345 , the anger - jacobi expansion is not really necessary here , and we might have derived eq . ( [ undurad4 ] ) , based on @xmath313 and @xmath350 , directly from eq . ( [ undurad2 ] ) by directly expanding in taylor series the exponential function of trigonometric arguments . the total energy emitted per unit frequency per unit solid angle @xmath313 and @xmath341 is @xmath351 ^ 2 + \left[\frac { \theta_x \theta_y \omega } { k_w c}\right]^2\right\ } \mathrm{sinc}^2\left[\frac{l_w}{4}\left(c + { \omega \theta^2 \over{2 c } } \right ) \right ] \cr & & \label{dwdodw}\end{aligned}\ ] ] in agreement with @xcite . substituting eq . ( [ dwdodw ] ) in eq . ( [ espec ] ) and using the fact that @xmath352 and @xmath353/(\pi a ) \longrightarrow \delta(x)$ ] for @xmath354 we obtain @xmath355~ , \label{dwdw}\end{aligned}\ ] ] also eq . ( [ dwdw ] ) is valid for @xmath356 and @xmath350 , and is in agreement with @xcite ( where the energy spectrum was first calculated ) and , @xcite and @xcite . in the limit for @xmath357 we write @xmath358 eq . ( [ dwdwlim ] ) is at the left hand side of eq . ( [ poy ] ) and has been calculated for @xmath356 and @xmath357 . the right hand side can be written using the real part of eq . ( [ zrr ] ) , that is valid for arbitrary @xmath3 values and @xmath25 , and calculating the impedance along an undulator of length @xmath359 . we obtain : @xmath360 thus verifying eq . ( [ poy ] ) and energy conservation . agreement between the asymptote of eq . ( [ dwdw ] ) for @xmath357 and eq . ( [ zrr ] ) is due to the fact that eq . ( [ zrr ] ) is valid for arbitrary values of @xmath3 . however , eq . ( [ dwdwlim ] ) can also be calculated from eq . ( [ undurad2 ] ) under the only assumption @xmath25 , i.e. eq . ( [ dwdwlim ] ) is not only valid for @xmath361 , but for any value of @xmath3 . more generally , we can say that in the long wavelength asymptote ( @xmath25 ) it is sufficient to account for the first harmonic only , independently of the value of @xmath3 . as we already discussed , radiation field and space - charge field exhibit different formation lengths and different transverse scales , namely @xmath180 and @xmath363 . the same transverse scales are also present in eq . ( [ zr ] ) and eq . ( [ ir ] ) . the first two terms in @xmath364 and @xmath365 in eq . ( [ ir ] ) , as well as the entire real part of the impedance , are linked to the presence of transverse current density and to radiation field . the last term in eq . ( [ ir ] ) instead , is due to the presence of longitudinal space - charge field , a combination of current and gradient terms . the corresponding bessel functions yield different characteristic transverse scales . bessel functions related with the radiation field are linked with a transverse size @xmath366 . those related with the longitudinal space - charge field are linked with a transverse size @xmath367 . since @xmath25 , it follows that the characteristic transverse size related with the radiation field contribution is much smaller than that related with the space - charge field contribution , @xmath368 . by inspection of eq . ( [ zr ] ) and eq . ( [ ir ] ) one can see that the value of @xmath369 is limited by @xmath13 , because of the presence of the exponential functions under the integration sign . therefore , assuming constant total charge of the beam , when the electron beam transverse size @xmath13 increases beyond @xmath180 the radiation contribution is suppressed with respect to the space - charge one . summing up , when condition ( [ cons2 ] ) is valid together with ( [ cons1 ] ) , i.e. @xmath370 , we may neglect the real part of the impedance @xmath283 and approximate the total impedance with @xmath371 this means that , in the limit @xmath372 , the only field to be accounted for when calculating impedance ( and wake ) , is the effective longitudinal space - charge field . results obtained in section [ sub : aslarg ] , namely eq . ( [ zapprox ] ) , mean that in the limit @xmath373 radiation is suppressed , so that the beam can be considered as non - radiating , and only space - charge impedance is present . such impedance amounts to the free - space impedance , where @xmath7 is consistently substituted with @xmath11 . ( [ zapprox ] ) gives the correct impedance at position @xmath44 inside the undulator , as an asymptotic limit for @xmath370 of our general theory . our results are in contrast with @xcite . authors of @xcite first noted , correctly , that the presence of a finite transverse dimension of the beam @xmath13 suppresses radiation in the far zone . thus , the real part of the renormalized impedance in eq . ( [ renim ] ) ( valid in the one - dimensional limit of a pencil beam ) can be generalized to the case when a finite transverse dimension of the beam @xmath13 is present , by multiplying it by an exponentially suppressing factor . however , they extended such understanding to the imaginary part as well , that is incorrect . this led them to obtain the following expression for the renormalized undulator impedance accounting for a finite @xmath13 ( see eq . ( 2 ) of reference @xcite ) : @xmath374 = \left[- \frac{k^2 \pi z}{4 c \lambdabar \gamma^2 } - i \frac{k^2 z}{2 c \lambdabar \gamma^2 } \ln\left({\frac{\lambdabar}{\lambdabar_r}}\right)\right]\exp\left[- \frac{2\omega}{c } k_w \sigma_\bot^2 \right],\cr & & \label{renim2}\end{aligned}\ ] ] the explicit expression for @xmath322 being given by eq . ( [ renim ] ) . ( [ renim2 ] ) is not derived , in @xcite , as the asymptotic result from a complete theory . it is the outcome of an analogy with the fact that radiation in the far zone is suppressed when a finite transverse electron beam size @xmath13 is considered . however , the imaginary part of @xmath322 results as a combination ( a difference , actually ) of two logarithmic contributions , that can be respectively ascribed to space - charge and radiative field ( see section [ sub : smalll ] ) and present different characteristic transverse scales ( @xmath29 and @xmath375 ) as a consequence of different field formation - lengths . @xmath322 is calculated in the limit for @xmath324 . only in this limit the dependence on @xmath13 in the imaginary part of @xmath322 is cancelled as a result of the combination of the before - mentioned logarithmic contributions . for finite transverse size @xmath13 such compensation does not take place at all . for example , for the esase scheme at lcls ( see section [ sec : expl ] ) , one has @xmath376 m , @xmath377 m and @xmath378 m . as a result , @xmath13 is small with respect to @xmath29 , but large with respect to @xmath375 . the incorrectness of eq . ( [ renim2 ] ) ( i.e. eq . ( 2 ) of @xcite ) follows from these observations . authors of reference @xcite conclude that the impedance in eq . ( [ renim2 ] ) , that is related with curved trajectory , is suppressed . thus , the space - charge induced , free - space impedance ( eq . ( 5 ) in @xcite ) is finally considered when calculating the energy spread inside the undulator . this result is counterintuitive . according to it , when the electron beam does not radiate ( @xmath379 ) , the presence of the undulator does not influence the impedance , independently of the value of the undulator parameter @xmath3 . however , its incorrectness was not trivial to prove , because it relies on an apparently correct analogy between real and imaginary part of the impedance . only developing a complete theory the presence of two separate logarithmic dependencies can be spotted thus , in eq . ( [ zapprox ] ) we saw , as an asymptotic case of our theory , that only space - charge impedance is relevant for @xmath379 , but we additionally demonstrated that @xmath7 must be consistently substituted with @xmath11 . our conclusion is that when @xmath380 the presence of the undulator strongly influences the longitudinal impedance , whether the beam radiates or not ( i.e. independently of the transverse size @xmath13 ) . as discussed in the previous sections , our derivations hold under conditions ( [ cons1 ] ) and drastically simplify under condition ( [ cons2 ] ) , i.e. for @xmath362 . in fact , as we have seen before , when condition ( [ cons2 ] ) holds transverse contributions to impedance and wake are negligible . in the following we will consider the case when both ( [ cons1 ] ) and ( [ cons2 ] ) are satisfied , that is the case for esase schemes at lcls , as we will see in section [ sec : expl ] . we will consider a transverse longitudinal profile , as specified in eq . ( [ rhoog ] ) , and a longitudinal bunch profile , specified by eq . ( [ fs ] ) . note that the @xmath382 bunch length @xmath12 is connected to the @xmath382 bunch duration @xmath383 by @xmath384 , so that , in terms of time and frequency we have when @xmath379 , an expression for the wake can be found by fourier - transforming the impedance given in eq . ( [ zapprox ] ) ) hold , we should fourier - transform both eq . ( [ zr ] ) and eq . ( [ ir ] ) . ] . as already noted , eq . ( [ zapprox ] ) is mathematically identical to the free - space expression where only @xmath7 has been substituted by @xmath11 . here we will present only the final result for the wake function . for mathematical details regarding wake calculations , we refer the interested reader to a previous work of us @xcite . that paper dealt with a different subject , namely wake fields and impedances for electron beams accelerated through ultra - high field gradients . however , in @xcite , we also analyzed the steady - state ( @xmath386 ) , free - space case of gaussian transverse and longitudinal distribution for the beam , the antisymmetric part of the longitudinal wake function @xmath387 ( always defined , as in eq . ( [ gred ] ) , from a source disk to a test disk separated of @xmath228 ) is dominant with respect to the symmetric part . in this paper we will only analyze this part , that will be used later on to discuss the feasibility of esase schemes . ] . we find has been substituted with @xmath11 . ] that the antisymmetric part of the wake @xmath387 is given by @xmath388 , where @xmath389 \mathrm{erfc}\left[\frac{|\delta\xi|}{2}\right]\right\}~. \label{asym4b}\end{aligned}\ ] ] here we defined @xmath390 , @xmath391 and @xmath392 . a plot of the universal function @xmath393 , that is the symmetric part of the wake in units of @xmath394 , as a function of @xmath395 is given in fig . [ ga ] . plot of the universal function @xmath393 as a function of @xmath395 . , width=453 ] the energy change of a single particle at position @xmath305 within the bunch due to the reactive part of the wake , averaged over transverse coordinates is given by the convolution @xmath396 . an explicit expression for @xmath397 , with @xmath398 , as a function of @xmath399 : @xmath400~.\label{elossa2}\end{aligned}\ ] ] note that eq . ( [ elossa2 ] ) is a function of @xmath401 but also depends parametrically on @xmath402 , and may be presented as @xmath403 where we indicated the parametric dependence of @xmath402 after the semicolon and plot of f in eq . ( [ elossaker ] ) as a function of @xmath404 for different values of @xmath402.,width=453 ] @xmath405~.\label{elossaker}\end{aligned}\ ] ] a plot of @xmath406 is given as a function of @xmath404 in fig . [ fseta ] for different values of @xmath402 . we can now give a practical example of application of our work . namely , we calculate the impact of longitudinal wake fields in esase schemes @xcite . here we propose an analysis on a set of parameters referring to the lcls @xcite setup considered in @xcite . similar calculations may be performed on other parameter sets like those for the european xfel @xcite . we consider a beam with normalized emittance after the dispersive section @xmath407 mm mrad ( like in fig . 3 of @xcite ) . we take the average betatron function in the focusing lattice @xmath408 m , and @xmath409 . this gives a transverse beam size @xmath410 m . the longitudinal size of the bunch is @xmath411 nm . the maximal current is about the alfven current @xmath412 ka ; in fact , @xmath413 . finally , the undulator has a period @xmath414 m , @xmath415 , and the vacuum chamber dimension is @xmath416 mm . we consider a wavelength @xmath417 nm . we can neglect the vacuum chamber influence ( see section [ sec : disc ] ) , because @xmath418 m , as @xmath419 , and @xmath420 mm . the overtaking length is @xmath421 m. the saturation length is about @xmath422 m. thus @xmath423 , according to the definition in section [ sub : resu ] and we can use our asymptotic expression . moreover @xmath424 . from fig . [ fseta ] ( or from direct calculations ) one can see that the maximal value assumed by @xmath425 for @xmath426 is about @xmath427 . it follows that the energy - chirp peak - to - peak is given by ( see eq . ( [ elossa2 ] ) or eq . ( [ elossa3 ] ) ) : @xmath428 in contrast to this , estimations in @xcite indicate `` a swing in energy of @xmath429 mev '' . the reason for this large discrepancy is due to the fact that in reference @xcite , where it is correctly recognized that the `` most significant cause for concern is the longitudinal space charge forces '' , the lorentz factor @xmath7 is incorrectly used in place of @xmath11 . in fact , as it is clearly stated in that reference : `` while this expression has been derived for beam lines containing only drift sections and focusing elements , we apply it _ without modification _ to the present case where the electron beam is passing through the undulator and oscillates almost rigidly with a deviation of less than @xmath430 m '' . in addition to this , it should be noted that energy chirp is also accumulated in the free - space between the dispersive section and the undulator , worsening the situation even more . in the lcls case @xcite , the dispersive section is a dogleg located about @xmath431 m from the undulator . one should account for the energy chirp accumulated in this region too , and sum it to that in eq . ( [ elossamax ] ) . to this extent , reference @xcite can be used . the overtaking length is now @xmath432 m , so that @xmath433 and our asymptotic expression for the wake are still valid with some accuracy . using the same procedure as for the wake inside the undulator ( but considering @xmath7 instead of @xmath11 ) , we obtain an extra energy chirp of about @xmath434 mev . the sum of contributions from the straight section after the dogleg and from the undulator amounts to about @xmath435 mev . although the energy chirp is non - linear , in order to estimate the magnitude of the effect we can use the linear energy chirp parameter @xmath436 defined in @xcite . the effect of linear energy chirp starts to play a significant role on the fel gain when @xmath437 . intuitively , this means that the relative energy change becomes comparable with the fel parameter on the scale of the coherence length . the chirp parameter is defined as @xmath438 , @xmath439 being the one - dimensional @xmath440-parameter in fel theory defined as ( see @xcite ) : @xmath441^{1/3 } \label{rho1ddef } ~,\end{aligned}\ ] ] where @xmath442 is the beam current density and the coupling factor @xmath443 , for a planar undulator , is given by @xmath444 , where @xmath445 . for esase schemes at lcls @xmath446 ka , and we have @xmath447 . using an estimated peak - to - peak chirp of @xmath435 mev we obtain @xmath448 . thus , the saturation length is significantly modified @xcite . this is a reason of concern , because esase schemes are based on the assumption that the nominal saturation length of about @xmath449 m is shortened to about @xmath435 m , that is only @xmath450 less . the effect described here is fundamental , in the sense that it can not be avoided by fine tuning of the setup parameters . finally , it should be noted that in this paper we did not account for the symmetric part of the wake , related with transition undulator radiation . this part constitutes only a correction to our calculations , as the space - charge wake accumulates along the longitudinal axis , being proportional to @xmath451 . we did not include it in this article , because the space - charge wake alone is enough to raise concern . numerical estimations presented in this paper indicate that effects of energy chirp induces by space - charge longitudinal wake pose a serious threat to the operation of esase schemes at lcls . in this paper we presented a theory of wake fields in an xfel system , with particular emphasis to esase schemes @xcite . we worked with specific constraints on parameters , that are fulfilled in xfel setups ( see section [ sec : disc ] ) . namely , we neglected the influence of the vacuum chamber and we assumed that the saturation length is long with respect to the overtaking length . our results are valid for arbitrary values of the undulator parameter @xmath3 and in the long wavelength asymptotic , i.e. @xmath25 , @xmath452 being the reduced wavelength of the fundamental harmonic . note that , for any fel setup , the lasing part of the bunch is always much longer than @xmath452 so that condition @xmath25 is very natural . it follows that our results are of practical importance not only in relation with esase schemes , but for any fel setup . we derived expressions for the steady state impedance , that is composed of a radiative and a space - charge part . radiation field and space - charge field are characterized by different formation lengths : the undulator period @xmath10 and the overtaking length @xmath175 , respectively . as a result , the steady state radiative part of the impedance can be applied for any undulator system ( with @xmath352 ) , whereas the steady state space - charge part of the impedance can be used only assuming that the saturation length is long with respect to the overtaking length , which limits its practical region of applicability . non - steady state results for the space - charge part of the impedance can be obtained applying methods presented in @xcite and @xcite . after having dealt with a generic expression for the steady - state impedance , we specialized our theory to the case when the transverse beam size @xmath379 . major simplifications arise in this case : in particular , space - charge contributions to impedance and wake dominate with respect to radiative contributions . in this particular condition , that is practically fulfilled for esase xfel setups , we showed that the ( antisymmetric ) wake can be given in terms of an asymptotic expression for the wake generated by a beam in uniform motion along the longitudinal axis ( see @xcite ) , provided that the lorentz factor @xmath7 is consistently substituted with the average longitudinal lorentz factor @xmath11 . final expressions are presented in the case of a planar undulator . however , there are no specific effects related with such choice , and our work may be straightforwardly extended to the case of a helical undulator as well . we applied our theory to calculate the effects of longitudinal wake fields on esase schemes . our conclusion is that longitudinal wake fields pose a threat to the practical realization of esase schemes . this finding is in contrast with estimations in literature , where no important detrimental effect is foreseen . the reason for this contrast is an incorrect application , in literature , of expressions that are valid for beam lines containing drift sections and focusing elements to describe the case of xfel undulators , where the longitudinal lorentz factor is sensibly different . we thank martin dohlus ( desy ) for many useful discussions , massimo altarelli and jochen schneider ( desy ) for their interest in this work . a.m. kondratenko and e. l. saldin , part . accelerators 10 , 207 ( 1980 ) ya . s. derbenev . , a.m. kondrarenko and e. saldin , nucl . instr . and methods 193 , 415 ( 1982 ) j.b . murphy and c. pellegrini , nucl . instr . and meth . res . a 237 , 159 ( 1985 ) v. ayvazyan et al . , phys . rev . lett 88 , 104802 ( 2002 ) v. ayvazyan et al . , 20 , 149 ( 2002 ) v. ayvazyan et al . phys . j.d . 37 , 297 ( 2006 ) w. ackermann et al . , nature photonics 1 , 336 ( 2007 ) j. arthur et al . linac coherent light source ( lcls ) . conceptual design report , slac - r593 , stanford ( 2002 ) ( see also http://www-ssrl.slac.stanford.edu/lcls/cdr ) m. altarelli et al . ( eds . ) , xfel : the european x - ray free - electron laser . technical design report , desy 2006 - 097 , desy , hamburg ( 2006 ) ( see also http://xfel.desy.de ) m. dohlus et al . nucl . instr . and meth . res . a 530 , 217 ( 2004 ) e. saldin , e. schneidmiller and m. yurkov , nucl . instr . and meth . res . a 562 , 472 ( 2006 ) a. zholents and w. fawley , phys 92 , 22 224801 - 1 ( 2004 ) a. zholents , w.m . fawley , p. emma , z. huang , g. stupakov and s. reiche , proceedings of the 2004 fel conference , trieste , p. 582 ( 2004 ) a. zholents and g. penn , phys . stab 8 , 050704 ( 2005 ) s. krinsky and z. huang , phys . rev . beams 6 , 050702 ( 2003 ) e. l. saldin , e. a. schneidmiller , and m. v. yurkov phys . beams 9 , 050702 ( 2006 ) g. geloni , e. saldin , e. schneidmiller and m. yurkov , opt . commun ( 2007 ) doi:10.1016/j.optcom.2007.03.051 and desy 06 - 127 ( 2006 ) g. geloni , e. saldin , e. schneidmiller and m. yurkov , `` undulator radiation in a waveguide '' , desy 07 - 031 ( 2007 ) , submitted to nucl . instrum . and methods in phys . a g. geloni , e. saldin , e. schneidmiller and m. yurkov , `` theory of nonlinear harmonic generation in free - electron lasers with helical wigglers '' , desy 07 - 058 ( 2007 ) , submitted to nucl . instrum . and methods in phys . a b. zotter and s. kheifets , `` impedances and wakes in high - energy particle accelerators '' , world scientific , singapore , 1997 g. geloni , e. saldin , e. schneidmiller and m. yurkov , `` longitudinal wake field for an electron beam accelerated through a ultra - high field gradient '' , desy 06 - 222 , accepted for publication in nucl . instrum . and meth . a e. saldin , e. schneidmiller and m. yurkov , nucl . instrum and meth . in phys . res . a 398 , 373 ( 1997 ) p.a.m . dirac , proc . ( london ) a 167 , 148 ( 1938 ) e. saldin , e. schneidmiller and m. yurkov , nucl . instrum and meth . in phys . res . a 417 , 158 ( 1998 ) m. dohlus , a. kabel and t. limberg , nucl . instr . and meth . res . a 445 , 84 ( 2000 ) j. wu , t. raubenheimer and g. stupakov , phys . rev . st ab 6 , 040701 ( 2003 ) d. alferov , y. bashmakov and e. bessonov , sov . phys . - tech . 18 , 1336 ( 1974 ) a. amir , i. boscolo and l. elias , phys a 32 , 5 , 2864 ( 1985 ) r. bonifacio , c. pellegrini and l. narducci , opt . 50 , 373 ( 1984 ) r. a. bosch , phys . rev . beams 10 , 050701 ( 2007 )

in this article we derive longitudinal impedance and wake function for an undulator setup with arbitrary undulator parameter , taking into account a finite transverse size of the electron bunch . earlier studies considered a line density - distribution of electrons instead . we focus our attention on the long - wavelength asymptote ( compared with resonance wavelength ) , at large distance of the electron bunch from the undulator entrance compared to the overtaking length , and for large vacuum - chamber size compared to the typical transverse size of the field . these restrictions define a parameter region of interest for practical applications . we calculate a closed expression for impedance and wake function that may be evaluated numerically in the most general case . such expression allows us to derive an analytical solution for a gaussian transverse and longitudinal bunch shape . finally , we study the feasibility of current - enhanced sase schemes ( esase ) recently proposed for lcls , that fall well - within our approximations . numerical estimations presented in this paper indicate that impedance - induced energy spread is sufficient to seriously degrade the fel performance . our conclusion is in contrast with results in literature , where wake calculations for the lcls case are given in free - space , as if the presence of the undulator were negligible . * deutsches elektronen - synchrotron * * + * desy 07 - 087 june 2007 @xmath0 @xmath1 * longitudinal impedance and wake from xfel undulators . impact on current - enhanced sase schemes * @xmath2 gianluca geloni , evgeni saldin , evgeni schneidmiller and mikhail yurkov _ + deutsches elektronen - synchrotron desy , hamburg _ @xmath1 @xmath1 @xmath1 issn 0418 - 9833 @xmath1 * notkestrasse 85 - 22607 hamburg * longitudinal impedance , longitudinal wake - function , x - ray free - electron laser ( xfel ) , enhanched sase schemes 41.60.ap , 41.60.-m , 41.20.-q