Yeshiva University

The equation of motion of a system of 864 particles interacting through a Lennard-Jones potential has been integrated for various values of the temperature and density, relative, generally, to a fluid state. The equilibrium properties have been calculated and are shown to agree very well with the corresponding properties of argon. It is concluded that, to a good approximation, the equilibrium state of argon can be described through a two-body potential.

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations. This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual. This report by the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations. Integrative analyses reveal profiles of rare and common variants in different populations. The frequencies of rare variants vary across biological pathways, and hundreds of rare, non-coding variants at conserved sites — such as changes disrupting transcription-factor motifs — can be established for each individual.

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.

The application of all-atom force fields (and explicit or implicit solvent models) to protein homology-modeling tasks such as side-chain and loop prediction remains challenging both because of the expense of the individual energy calculations and because of the difficulty of sampling the rugged all-atom energy surface. Here we address this challenge for the problem of loop prediction through the development of numerous new algorithms, with an emphasis on multiscale and hierarchical techniques. As a first step in evaluating the performance of our loop prediction algorithm, we have applied it to the problem of reconstructing loops in native structures; we also explicitly include crystal packing to provide a fair comparison with crystal structures. In brief, large numbers of loops are generated by using a dihedral angle-based buildup procedure followed by iterative cycles of clustering, side-chain optimization, and complete energy minimization of selected loop structures. We evaluate this method by using the largest test set yet used for validation of a loop prediction method, with a total of 833 loops ranging from 4 to 12 residues in length. Average/median backbone root-mean-square deviations (RMSDs) to the native structures (superimposing the body of the protein, not the loop itself) are 0.42/0.24 A for 5 residue loops, 1.00/0.44 A for 8 residue loops, and 2.47/1.83 A for 11 residue loops. Median RMSDs are substantially lower than the averages because of a small number of outliers; the causes of these failures are examined in some detail, and many can be attributed to errors in assignment of protonation states of titratable residues, omission of ligands from the simulation, and, in a few cases, probable errors in the experimentally determined structures. When these obvious problems in the data sets are filtered out, average RMSDs to the native structures improve to 0.43 A for 5 residue loops, 0.84 A for 8 residue loops, and 1.63 A for 11 residue loops. In the vast majority of cases, the method locates energy minima that are lower than or equal to that of the minimized native loop, thus indicating that sampling rarely limits prediction accuracy. The overall results are, to our knowledge, the best reported to date, and we attribute this success to the combination of an accurate all-atom energy function, efficient methods for loop buildup and side-chain optimization, and, especially for the longer loops, the hierarchical refinement protocol.

Procedures are described for the isolation of lipoproteins from human serum by precipitation with polyanions and divalent cations. A mixture of low and very low density lipoproteins can be prepared without ultracentrifugation by precipitation with heparin and either MnCl(2) alone or MgCl(2) plus sucrose. In both cases the precipitation is reversible, selective, and complete. The highly concentrated isolated lipoproteins are free of other plasma proteins as judged by immunological and electrophoretic methods. The low density and very low density lipoproteins can then be separated from each other by ultracentrifugation. The advantage of the method is that large amounts of lipoproteins can be prepared with only a single preparative ultracentrifugation. Polyanions other than heparin may also be used; when the precipitation of the low and very low density lipoproteins is achieved with dextran sulfate and MnCl(2), or sodium phosphotungstate and MgCl(2), the high density lipoproteins can subsequently be precipitated by increasing the concentrations of the reagents. These lipoproteins, containing small amounts of protein contaminants, are further purified by ultracentrifugation at d 1.22. With a single preparative ultracentrifugation, immunologically pure high density lipoproteins can be isolated from large volumes of serum.

OBJECTIVES: 1) To reassess the prevalence of migraine in the United States; 2) to assess patterns of migraine treatment in the population; and 3) to contrast current patterns of preventive treatment use with recommendations for use from an expert headache panel. METHODS: A validated self-administered headache questionnaire was mailed to 120,000 US households, representative of the US population. Migraineurs were identified according to the criteria of the second edition of the International Classification of Headache Disorders. Guidelines for preventive medication use were developed by a panel of headache experts. Criteria for consider or offer prevention were based on headache frequency and impairment. RESULTS: We assessed 162,576 individuals aged 12 years or older. The 1-year period prevalence for migraine was 11.7% (17.1% in women and 5.6% in men). Prevalence peaked in middle life and was lower in adolescents and those older than age 60 years. Of all migraineurs, 31.3% had an attack frequency of three or more per month, and 53.7% reported severe impairment or the need for bed rest. In total, 25.7% met criteria for "offer prevention," and in an additional 13.1%, prevention should be considered. Just 13.0% reported current use of daily preventive migraine medication. CONCLUSIONS: Compared with previous studies, the epidemiologic profile of migraine has remained stable in the United States during the past 15 years. More than one in four migraineurs are candidates for preventive therapy, and a substantial proportion of those who might benefit from prevention do not receive it.

To the Editor: Fisher et al. (1) state, “Little common agreement exists on the definition of the terms seizure and epilepsy,” and they propose ILAE-endorsed definitions for these terms. Although their proposed definition of “seizure” is consistent with that which has been in use throughout the field for decades, their proposed definition of epilepsy is not. Fisher and colleagues (1) propose the following definition of epilepsy: “Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.” The definition of epilepsy in Fisher's Table 1 (1) requires the occurrence of at least one epileptic seizure but not that the seizure be unprovoked. Although it may be helpful to consider diverse conditions (febrile seizure, acute symptomatic seizure, single unprovoked seizure, and epilepsy) within the context of studying the seizure disorders, it is not helpful to consider all of these conditions as epilepsy. The more restrictive definition of epilepsy (recurrent unprovoked seizures), adopted by the ILAE Commission on Epidemiology and Prognosis (2), is related to therapeutic, management, and counseling approaches and supported by epidemiologic studies of seizure disorders. Furthermore, this definition has been largely adopted in clinical practice and was instrumental in developing practice guidelines (3). The failure to clarify the concept of “enduring” is a problem with the proposed definition, and it is unclear how Fisher et al. (1) would define or make operational this term. Making operational “enduring alteration of the brain that increases the likelihood of future seizures (1)” would require a list of indicators of such an alteration. These, in turn, would have to be qualified and changed as knowledge increases. For clinical and scientific purposes, the operational criteria must be simple and robust. We suggest instead that the best way to know whether a person has an enduring alteration of the brain that increases the likelihood of future unprovoked seizures after a first seizure is the occurrence of a second unprovoked seizure. This new definition would reclassify many situations previously excluded from the term epilepsy in recent studies. Examples include a single provoked seizure secondary to a neurologic insult (e.g., stroke), a single provoked or unprovoked seizure in someone with depression or migraine, and a febrile seizure in a child with cerebral palsy, with an epileptiform EEG, or with febrile seizure recurrence. The all-inclusive definition proposed by Fisher et al. (1) is consistent with use before the emergence of the epidemiologic studies of seizure disorders and epilepsy over the past 60-year period. The exclusion of these conditions from the diagnosis of epilepsy was based on large, carefully conducted clinical and population-based studies. Most acute symptomatic seizures would be recategorized as epilepsy under the definition proposed by Fisher et al. (1). Acute symptomatic seizures have been defined as seizures in close temporal association with a transient CNS insult and presumed to be an acute manifestation of the insult. Although the risk of developing unprovoked seizure is higher in people with acute symptomatic seizures, in most, later seizures do not develop. Although the incidence of acute symptomatic seizure is similar to the incidence of epilepsy, the high early mortality and the protective effect of anticonvulsants on the development of acute symptomatic seizures dramatically distinguish this category of seizures from epilepsy. By the proposed definition (1), many children with febrile seizures, the most common convulsive disorder, would be reclassified as having epilepsy. This would be true for children with developmental delay, neurologic abnormalities, epileptiform EEG abnormalities, complex febrile seizure, and recurrent febrile seizure. Regardless of the presence of such factors, in most children with febrile seizure, later unprovoked seizures do not develop (4,5). Restricting the diagnostic labeling of epilepsy to the few who truly have recurrent unprovoked seizures would seem prudent. It is useful to study single unprovoked seizures within the context of epilepsy to better understand the underlying processes to increase the risk for the development of recurrent unprovoked seizures. Contrary to the proposed definition (1), the epidemiologic data on recurrence risks support separating single unprovoked seizure from recurrent unprovoked seizures (i.e., epilepsy). The recurrence risk is lower after a first unprovoked seizure (typically <50%) than the recurrence risk after a second unprovoked seizure for both children and adults (6,7), suggesting that the recurrence of unprovoked seizure or lack thereof delineates different entities. A major problem with the proposed definition (1), particularly for those with single seizure and with febrile seizure, is that labeling patients with only a single seizure as having epilepsy, when many will never experience another seizure, will cause unnecessary use of anticonvulsant drugs, increase stigma, and result in social and occupational limitation. This does not serve the needs of these patients and is inconsistent with epidemiologic data. The inclusion of associated conditions in the proposed definition (1) raises concerns on several levels. Although general agreement may exist that “for some people with epilepsy, behavioral disturbances such as interictal and postictal cognitive problems, can be part of the epileptic condition (1),” the definition as written seems to require these disturbances for the condition to be epilepsy. Thus a person with multiple unprovoked seizures and a likelihood of more would not have epilepsy by the definition of Fisher et al. unless one of these associated conditions also was present. This aspect of the proposal creates a new unnamed category that may be quite large—people who clearly have recurrent unprovoked seizures, but lack documentation of associated conditions. Even if the proposed behavioral component is accepted as an essential ingredient in the definition of epilepsy, it is unclear how this would be made operational. Other consequences ensue from this definition. The incidence of “epilepsy” will increase at least threefold, and the increase in prevalence will be greater, particularly in developing countries, which may provide political leverage. Undesired consequences of use of this definition will be the invalidation of prognostic studies, including those of mortality, long-term prognosis for seizure remission, and response to initial therapy. Contrary to the proposal of Fisher et al. (1), widespread acceptance of and agreement over the definitions of seizures and epilepsy are in general use in the field. We fail to see the advantages of the proposed definitions to the individual patient, to epilepsy as a condition, or to the study of epilepsy and the convulsive disorders. Maintaining a common language has been acknowledged in several ILAE Commission and Task Force reports as a prerequisite to communication and comparability of research from different groups. In addition, the medical, social, and emotional implications of epilepsy and seizures speak in favor of a separation between acute symptomatic seizures, febrile seizures, and unprovoked seizures and, for those with unprovoked seizures, between single and repeated episodes. To this end, the current definitions have been most successful. They are based on a process similar to the evidence-based approaches used for evaluating therapies and therapeutic policies. They may be subject to revision as new information comes to light, but this process should be respected. It does not appear that proposed definitions advance the field in any way.

BACKGROUND: Genital human papillomavirus (HPV) infection is highly prevalent in sexually active young women. However, precise risk factors for HPV infection and its incidence and duration are not well known. METHODS: We followed 608 college women at six-month intervals for three years. At each visit, we collected information about lifestyle and sexual behavior and obtained cervicovaginal-lavage samples for the detection of HPV DNA by polymerase chain reaction and Southern blot hybridization. Pap smears were obtained annually. RESULTS: The cumulative 36-month incidence of HPV infection was 43 percent (95 percent confidence interval, 36 to 49 percent). An increased risk of HPV infection was significantly associated with younger age, Hispanic ethnicity, black race, an increased number of vaginal-sex partners, high frequencies of vaginal sex and alcohol consumption, anal sex, and certain characteristics of partners (regular partners having an increased number of lifetime partners and not being in school). The median duration of new infections was 8 months (95 percent confidence interval, 7 to 10 months). The persistence of HPV for > or =6 months was related to older age, types of HPV associated with cervical cancer, and infection with multiple types of HPV but not with smoking. The risk of an abnormal Pap smear increased with persistent HPV infection, particularly with high-risk types (relative risk, 37.2; 95 percent confidence interval, 14.6 to 94.8). CONCLUSIONS: The incidence of HPV infection in sexually active young college women is high. The short duration of most HPV infections in these women suggests that the associated cervical dysplasia should be managed conservatively.

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly ‘housekeeping’, whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research. A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types. FANTOM5 (standing for functional annotation of the mammalian genome 5) is the fifth major stage of a major international collaboration that aims to dissect the transcriptional regulatory networks that define every human cell type. Two Articles in this issue of Nature present some of the project's latest results. The first paper uses the FANTOM5 panel of tissue and primary cell samples to define an atlas of active, in vivo bidirectionally transcribed enhancers across the human body. These authors show that bidirectional capped RNAs are a signature feature of active enhancers and identify more than 40,000 enhancer candidates from over 800 human cell and tissue samples. The enhancer atlas is used to compare regulatory programs between different cell types and identify disease-associated regulatory SNPs, and will be a resource for studies on cell-type-specific enhancers. In the second paper, single-molecule sequencing is used to map human and mouse transcription start sites and their usage in a panel of distinct human and mouse primary cells, cell lines and tissues to produce the most comprehensive mammalian gene expression atlas to date. The data provide a plethora of insights into open reading frames and promoters across different cell types in addition to valuable annotation of mammalian cell-type-specific transcriptomes.

Wilson's lattice gauge model is presented as a canonical Hamiltonian theory. The structure of the model is reduced to the interactions of an infinite collection of coupled rigid rotators. The gauge-invariant configuration space consists of a collection of strings with quarks at their ends. The strings are lines of non-Abelian electric flux. In the strong-coupling limit the dynamics is best described in terms of these strings. Quark confinement is a result of the inability to break a string without producing a pair.

Taxol, a potent inhibitor of human HeLa and mouse fibroblast cell replication, blocked cells in the G2 and M phase of the cell cycle and stabilized cytoplasmic microtubules. The cytoplasmic microtubules of taxol-treated cells were visualized by transmission electron microscopy and indirect immunofluorescence microscopy. More than 90% of the cells treated with 10 micro M taxol for 22 hr at 37 degrees C displayed bundles of microtubules that appeared to radiate from a common site (or sites), in addition to their cytoplasmic microtubules. Untreated cells that were kept in the cold (4 degrees C) for 16 hr lost their microtubules, whereas cells that were pretreated with taxol for 22 hr at 37 degrees C continued to display their microtubules and bundles of microtubules in the cold. Taxol inhibited the migration behavior of fibroblast cells, but these cells did not lose their ability to produce mobile surface projections such as lamellipodia and filopodia.

The diabetic neuropathies are heterogeneous, affecting different parts of the nervous system that present with diverse clinical manifestations. They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. DPN is a diagnosis of exclusion. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons. 1 ) Nondiabetic neuropathies may be present in patients with diabetes. 2 ) A number of treatment options exist for symptomatic diabetic neuropathy. 3 ) Up to 50% of DPN may be asymptomatic, and patients are at risk of insensate injury to their feet. As >80% of amputations follow a foot ulcer or injury, early recognition of at-risk individuals, provision of education, and appropriate foot care may result in a reduced incidence of ulceration and consequently amputation. 4 ) Autonomic neuropathy may involve every system in the body. 5 ) Autonomic neuropathy causes substantial morbidity and increased mortality, particularly if cardiovascular autonomic neuropathy (CAN) is present. Treatment should be directed at underlying pathogenesis. Effective symptomatic treatments are available for the manifestations of DPN and autonomic neuropathy. This statement is based on two recent technical reviews (1,2), to which the reader is referred for detailed discussion and relevant references to the literature. An internationally agreed simple definition of DPN for clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (3). However, the diagnosis cannot be made without a careful clinical examination of the lower limbs, as absence of symptoms should never be assumed to indicate an absence of signs. This definition conveys the important message that not all patients with peripheral nerve dysfunction have a neuropathy caused by diabetes. Confirmation can be established with …

The dielectric loss factor and dielectric permittivity of 8–16 mol% solutions of chlorobenzene, o-dichlorobenzene, and 1-chloronaphthalene in cis-decalin; 50–60 mol% mixtures of pyridine with chlorobenzene, bromobenzene, 1-chloronaphthalene, and toluene; 50–60 mol% mixtures of tetrahydrofuran with bromobenzene and 1-chloronaphthalene; the pure liquids cis-decalin, o-terphenyl, iso-propylbenzene, propylene carbonate; and two fused salt systems, 45 mol% Ca(NO3)2–KNO3 mixture and Ca(NO3)2·4H2O have been measured from 50 Hz to 1 × 105 Hz from − 196° in the vitreous state to about 30° above their respective glass transition temperatures. The Tg's of the organic glasses have been measured by DTA. With the exception of propylene carbonate, all glasses show the presence of one secondary relaxation between − 196° and their respective Tg's either as a peak or shoulder in a tanδ–temperature plot at a single frequency, or in the dielectric loss spectrum. Arrhenius plots of the frequency of maximum loss against temperature in the main relaxation region for all systems are nonlinear, with the activation energy at the lowest temperature of our measurements ranging from 55 kcal/mol to 70 kcal/mol. The Arrhenius plots in the secondary relaxation region are linear and have activation energies between 5 and 12 kcal/mol. These glasses, most of which are composed of rigid molecules, show a remarkable similarity in their dielectric behavior to amorphous polymers. The results confirm the prediction made by one of the authors that the occurence of secondary relaxations is an intrinsic property of the glassy state.

UNTIL THE 1950s THE psychological literature on bilingualism was so much more extensive than its sociological counterpart that workers in the former field have often failed to establish contact with those in the latter. Since the 1960s a very respectable sociological (or sociologically oriented) literature has developed dealing with bilingual societies. It is the purpose of this chapter to relate these two research traditions to each other by tracing the interaction between their two major constructs: bilingualism (on the part of psychologists) and diglossia (on the part of sociologists).

Two simple methods that are clinically useful for analyzing impaired memory and learning are selective reminding or restricted reminding. These new methods provide simultaneous analysis of storage, retention, and retrieval during verbal learning because they let the patient show learning by spontaneous retrieval without csnfounding by continual presentation. Because selective reminding and restricted reminding let the patient show consistent retrieval without any further presentation, they also distinguish list learning from item learning, so that impaired memory and learning can be analyzed further in terms of two stages of learning (item and list).

IMPORTANCE: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES: Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

Caveolae are vesicular invaginations of the plasma membrane. The chief structural proteins of caveolae are the caveolins. Caveolins form a scaffold onto which many classes of signaling molecules can assemble to generate preassembled signaling complexes. In addition to concentrating these signal transducers within a distinct region of the plasma membrane, caveolin binding may functionally regulate the activation state of caveolae-associated signaling molecules. Because the responsibilities assigned to caveolae continue to increase, this review will focus on: (i) caveolin structure/function and (ii) caveolae-associated signal transduction. Studies that link caveolae to human diseases will also be considered. Molecular cloning has identified three distinct caveolin genes (1Glenney J.R. Soppet D. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10517-10521Crossref PubMed Scopus (341) Google Scholar, 2Scherer P.E. Tang Z. Chun M. Sargiacomo M. Lodish H.F. Lisanti M.P. J. Biol. 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Caveolin-1 and -2 are most abundantly expressed in adipocytes, endothelial cells, and fibroblastic cell types, whereas the expression of caveolin-3 is muscle-specific. Caveolin proteins interact with themselves to form homo- and hetero-oligomers (7Sargiacomo M. Scherer P.E. Tang Z. Kubler E. Song K.S. Sanders M.C. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9407-9411Crossref PubMed Scopus (477) Google Scholar, 8Monier S. Parton R.G. Vogel F. Behlke J. Henske A. Kurzchalia T. Mol. Biol. Cell. 1995; 6: 911-927Crossref PubMed Scopus (401) Google Scholar, 9Scherer P. Lewis R. Volonté D. Engelman J. Galbiati F. Couet J. Kohtz D. van Donselaar E. Peters P. Lisanti M.P. J. Biol. Chem. 1997; 272: 29337-29346Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar), which directly bind cholesterol (10Murata M. Peranen J. Schreiner R. Weiland F. Kurzchalia T. Simons K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10339-10343Crossref PubMed Scopus (765) Google Scholar) and require cholesterol for insertion into model lipid membranes (10Murata M. Peranen J. Schreiner R. Weiland F. Kurzchalia T. Simons K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10339-10343Crossref PubMed Scopus (765) Google Scholar, 11Li S. Song K.S. Lisanti M.P. J. Biol. Chem. 1996; 271: 568-573Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). Caveolin oligomers may also interact with glycosphingolipids (12Fra A.M. Masserini M. Palestini P. Sonnino S. Simons K. FEBS Lett. 1995; 375: 11-14Crossref PubMed Scopus (162) Google Scholar). These protein-protein and protein-lipid interactions are thought to be the driving force for caveolae formation (7Sargiacomo M. Scherer P.E. Tang Z. Kubler E. Song K.S. Sanders M.C. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9407-9411Crossref PubMed Scopus (477) Google Scholar). In addition, the caveolin gene family is structurally and functionally conserved from worms (Caenorhabditis elegans) to man (13Tang Z. Okamoto T. Boontrakulpoontawee P. Otsuka A.J. Katada T. Lisanti M.P. J. Biol. Chem. 1997; 272: 2437-2445Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), supporting the idea that caveolins play an essential role. Caveolin-1 assumes an unusual topology. A central hydrophobic domain (residues 102–134) is thought to form a hairpin-like structure within the membrane. As a consequence, both the N-terminal domain (residues 1–101) and the C-terminal domain (residues 135–178) face the cytoplasm. A 41-amino acid region of the N-terminal domain (residues 61–101) directs the formation of caveolin homo-oligomers (7Sargiacomo M. Scherer P.E. Tang Z. Kubler E. Song K.S. Sanders M.C. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9407-9411Crossref PubMed Scopus (477) Google Scholar), whereas the 44-amino acid C-terminal domain acts as a bridge to allow these homo-oligomers to interact with each other, thereby forming a caveolin-rich scaffold (14Song K. Tang Z. Li S. Lisanti M. J. Biol. Chem. 1997; 272: 4398-4403Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Recent co-immunoprecipitation and dual labeling experiments directly show that caveolin-1 and -2 form a stable hetero-oligomeric complex and are strictly co-localized (9Scherer P. Lewis R. Volonté D. Engelman J. Galbiati F. Couet J. Kohtz D. van Donselaar E. Peters P. Lisanti M.P. J. Biol. Chem. 1997; 272: 29337-29346Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar). Caveolin-2 localization corresponds to caveolae membranes as visualized by immunoelectron microscopy (9Scherer P. Lewis R. Volonté D. Engelman J. Galbiati F. Couet J. Kohtz D. van Donselaar E. Peters P. Lisanti M.P. J. Biol. Chem. 1997; 272: 29337-29346Abstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar). Thus, caveolin-2 may function as an “accessory protein” in conjunction with caveolin-1. A number of studies support the hypothesis that caveolin proteins provide a direct means for resident caveolae proteins to be sequestered within caveolae microdomains. These caveolin-interacting proteins include G-protein α subunits, Ha-Ras, Src family tyrosine kinases, endothelial NOS, 1The abbreviations used are: NOS, nitric oxide synthase; EGF-R, epidermal growth factor receptor; eNOS, endothelial NOS; PKC, protein kinase C; MAP, mitogen-activated protein; PDGF, platelet-derived growth factor; PtdIns, phosphatidylinositol; PFK-M, phosphofructokinase-M; GPI, glycosylphosphatidylinositol; GM1, II3NeuAcGgOse4Cer. EGF-R and related receptor tyrosine kinases, and protein kinase C isoforms (11Li S. Song K.S. Lisanti M.P. J. Biol. 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Chem. 1995; 270: 15693-15701Abstract Full Text Full Text PDF PubMed Scopus (559) Google Scholar). Mutational or pharmacological activation of Gsα prevents its co-fractionation with caveolin-1 and blocks its direct interaction with caveolin-1 in vitro, indicating that the inactive GDP-bound form of Gsα preferentially interacts with caveolin-1. G-protein binding activity is located within a 41-amino acid region of the cytoplasmic N-terminal domain of caveolin-1 (residues 61–101). A polypeptide derived from this region of caveolin-1 (residues 82–101) effectively suppresses the basal GTPase activity of purified G-proteins by inhibiting GDP/GTP exchange. In contrast, the analogous region of caveolin-2 possesses GTPase-activating protein activity with regard to heterotrimeric G-proteins (3Scherer P.E. Okamoto T. Chun M. Nishimoto I. Lodish H.F. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 131-135Crossref PubMed Scopus (492) Google Scholar). However, both of these activities (GDI and GAP) actively hold or place G-proteins in the inactiveGDP-liganded conformation (3Scherer P.E. Okamoto T. Chun M. Nishimoto I. Lodish H.F. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 131-135Crossref PubMed Scopus (492) Google Scholar). Ha-Ras and Src family tyrosine kinases also directly interact with caveolin-1 (20Li S. Couet J. Lisanti M.P. J. Biol. Chem. 1996; 271: 29182-29190Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar, 23Song K.S. Li S. Okamoto T. Quilliam L. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1996; 271: 9690-9697Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar). Using a detergent-free procedure and a polyhistidine-tagged form of caveolin-1 for affinity purification of caveolin-rich membranes, G-proteins, Src family kinases, and Ha-Ras were all found to co-fractionate and co-elute with caveolin-1. Wild-type Ha-Ras also interacted with recombinant caveolin-1 in vitro. Ras binding activity was localized to a 41-amino acid membrane-proximal region (61–101) of the cytosolic N-terminal domain of caveolin-1, i.e. the same caveolin-1 region responsible for interacting with G-protein α subunits. Reconstituted caveolin-rich membranes interacted with a soluble recombinant form of wild-type Ha-Ras but failed to interact with mutationally activated soluble Ha-Ras (G12V) (23Song K.S. Li S. Okamoto T. Quilliam L. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1996; 271: 9690-9697Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar). Thus, a single amino acid change (G12V) that constitutively activates Ras prevents this interaction. Recombinant overexpression of caveolin in intact cells was sufficient to functionally recruit a non-farnesylated mutant of Ras (C186S) onto membranes (23Song K.S. Li S. Okamoto T. Quilliam L. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1996; 271: 9690-9697Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar). This is consistent with the hypothesis that direct interaction with caveolin-1 promotes the sequestration of inactive Ha-Ras within caveolae microdomains. Caveolin-1 interacts with wild-type Src (c-Src) but does not form a stable complex with mutationally activated Src (v-Src) (20Li S. Couet J. Lisanti M.P. J. Biol. Chem. 1996; 271: 29182-29190Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar). Thus, caveolin prefers the inactive conformation of Gα subunits, Ha-Ras and c-Src. Deletion mutagenesis indicates that the Src-interacting domain of caveolin is located within residues 61–101. A caveolin peptide derived from this region (residues 82–101) functionally suppressed the autoactivation of purified recombinant c-Src tyrosine kinase and a related Src family kinase, Fyn. Co-expression of caveolin-1 with c-Src shows that caveolin-1 dramatically suppresses the tyrosine kinase activity of c-Src. Thus, it appears that caveolin-1 functionally interacts with wild-type c-Src via caveolin residues 82–101. Several independent co-immunoprecipitation and domain-mapping studies demonstrate that eNOS interacts directly with caveolin-1 residues 82–101 (30Ju H. Zou R. Venema V.J. Venema R.C. J. Biol. Chem. 1997; 272: 18522-18525Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 34Michel T. Feron O. J. Clin. Invest. 1997; 100: 2146-2152Crossref PubMed Scopus (846) Google Scholar, 36Garcı́a-Cardeña G. Fan R. Stern D.F. Liu J. Sessa W.C. J. Biol. Chem. 1996; 271: 27237-27240Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar, 37Venema V. Ju H. Zou R. Venema R. J. Biol. Chem. 1997; 272: 28187-28190Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 38Garcia-Cardena G. Martasek P. Siler-Masters B.S. Skidd P.M. Couet J. Li S. Lisanti M.P. Sessa W.C. J. Biol. Chem. 1997; 272: 25437-25440Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). In support of these data, recombinant co-expression of caveolin-1 with eNOS can inhibit NOS activity in vivo (38Garcia-Cardena G. Martasek P. Siler-Masters B.S. Skidd P.M. Couet J. Li S. Lisanti M.P. Sessa W.C. J. Biol. Chem. 1997; 272: 25437-25440Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). Caveolin has also been shown to interact with other NOS isoforms (37Venema V. Ju H. Zou R. Venema R. J. Biol. Chem. 1997; 272: 28187-28190Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 38Garcia-Cardena G. Martasek P. Siler-Masters B.S. Skidd P.M. Couet J. Li S. Lisanti M.P. Sessa W.C. J. Biol. Chem. 1997; 272: 25437-25440Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). In summary, a short cytosolic domain derived from the N-terminal region of caveolin-1: (i) is required to form multivalent homo-oligomers of caveolin; (ii) mediates the interaction of caveolin-1 with Gα subunits, Ha-Ras, Src family tyrosine kinases, and eNOS; (iii) a peptide encoding this region can functionally inactivate the enzymatic activity of G-protein, Src family kinases, and eNOS but does not affect the activity of Ha-Ras; and (iv) it is membrane-proximal, suggesting that this caveolin domain may be involved in other potential protein-protein interactions. As a consequence, this caveolin-derived protein domain has been termed the caveolin scaffolding domain (Fig. 1). What is the mechanism by which the caveolin scaffolding domain recognizes this diverse group of signal transducers? Perhaps the caveolin scaffolding domain recognizes a common sequence motif within caveolin-binding signaling molecules. To investigate this possibility, we have used the caveolin scaffolding domain as a receptor to select caveolin-binding peptide ligandsfrom random peptide sequences displayed at the surface of bacteriophage. Two related caveolin-binding motifs (ΦXΦXXXXΦ and ΦXXXXΦXXΦ, where Φ is aromatic amino acid Trp, Phe, or Tyr) were elucidated, and these motifs exist within most caveolae-associated proteins (31Couet J. Li S. Okamoto T. Ikezu T. Lisanti M.P. J. Biol. Chem. 1997; 272: 6525-6533Abstract Full Text Full Text PDF PubMed Scopus (805) Google Scholar). Thus, caveolin-binding motifs mediate the interaction of caveolin-binding proteins with the scaffolding domain of caveolin. These caveolin-binding motifs are present within most Gα subunits and the kinase domains of many distinct families of tyrosine and serine/threonine protein kinases (Src family kinases; PKCα; MAP kinase; EGF-R; insulin receptor; and PDGF receptor). As many known caveolae or caveolin-associated proteins contain caveolin-binding motifs (see Table II in Ref. 31Couet J. Li S. Okamoto T. Ikezu T. Lisanti M.P. J. Biol. Chem. 1997; 272: 6525-6533Abstract Full Text Full Text PDF PubMed Scopus (805) Google Scholar), this may be a general mechanism for caveolin-mediated sequestration and inactivation of a diverse group of signaling molecules within caveolae membranes for regulated activation by receptor ligands. Thus, the caveolin scaffolding domain may function like other modular protein domains (Src homology-2, Src homology-3, Pleckstrin homology, WW, and others) to generate preassembled membrane-bound oligomeric complexes that contain signaling molecules and cytoskeletal elements. In essence, caveolin may act as molecular “Velcro” to nucleate the formation of signal transduction complexes, holding these molecules in the off state (Fig. 1). Additional molecular mapping studies have identified functional caveolin-binding sequence motifs within the catalytic region of G-protein α-subunits and the kinase domains of EGF-R and PKC (32Couet J. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1997; 272: 30429-30438Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). Interaction of the caveolin scaffolding domain with these caveolin-binding sequence motifs inhibits the kinase activity of EGF-R and PKC, suggesting that caveolin may indeed function as a general kinase inhibitor (32Couet J. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1997; 272: 30429-30438Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, 39Oka N. Yamamoto M. Schwencke C. Kawabe J. Ebina T. Ohno S. Couet J. Lisanti M.P. Ishikawa Y. J. Biol. Chem. 1997; 272: 33416-33421Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). eNOS contains a well conserved predicted caveolin-binding motif (FSAAPFSGW) within its catalytic domain (31Couet J. Li S. Okamoto T. Ikezu T. Lisanti M.P. J. Biol. Chem. 1997; 272: 6525-6533Abstract Full Text Full Text PDF PubMed Scopus (805) Google Scholar, 38Garcia-Cardena G. Martasek P. Siler-Masters B.S. Skidd P.M. Couet J. Li S. Lisanti M.P. Sessa W.C. J. Biol. Chem. 1997; 272: 25437-25440Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). Does this represent a functional caveolin-binding motif? Two independent lines of evidence suggest that this region binds to caveolin-1 directly. First, caveolin competes with calmodulin for binding at this site (30Ju H. Zou R. Venema V.J. Venema R.C. J. Biol. Chem. 1997; 272: 18522-18525Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 40Michel J. Feron O. Sacks D. Michel T. J. Biol. Chem. 1997; 272: 15583-15586Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 41Michel J. Feron O. Sase K. Prabhakar P. Michel T. J. Biol. Chem. 1997; 272: 25907-25912Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). This may have functional significance, as calmodulin binding activates eNOS activity, whereas caveolin binding represses eNOS activity (30Ju H. Zou R. Venema V.J. Venema R.C. J. Biol. Chem. 1997; 272: 18522-18525Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 40Michel J. Feron O. Sacks D. Michel T. J. Biol. Chem. 1997; 272: 15583-15586Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar,41Michel J. Feron O. Sase K. Prabhakar P. Michel T. J. Biol. Chem. 1997; 272: 25907-25912Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). This suggests that caveolin-1 and calmodulin have a reciprocal relationship with respect to eNOS functioning (40Michel J. Feron O. Sacks D. Michel T. J. Biol. Chem. 1997; 272: 15583-15586Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 41Michel J. Feron O. Sase K. Prabhakar P. Michel T. J. Biol. Chem. 1997; 272: 25907-25912Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar).Second, Sessa and colleagues (38Garcia-Cardena G. Martasek P. Siler-Masters B.S. Skidd P.M. Couet J. Li S. Lisanti M.P. Sessa W.C. J. Biol. Chem. 1997; 272: 25437-25440Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar) have performed site-directed mutagenesis to modify the predicted caveolin-binding motif (fromFSAAPFSGW to ASAAPASGA) within eNOS. It is known from in vitro studies that aromatic residues (Trp, Phe, or Tyr) are required for the proper recognition of the caveolin-binding motif (31Couet J. Li S. Okamoto T. Ikezu T. Lisanti M.P. J. Biol. Chem. 1997; 272: 6525-6533Abstract Full Text Full Text PDF PubMed Scopus (805) Google Scholar). In their work, Sessa and colleagues (38Garcia-Cardena G. Martasek P. Siler-Masters B.S. Skidd P.M. Couet J. Li S. Lisanti M.P. Sessa W.C. J. Biol. Chem. 1997; 272: 25437-25440Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar) show that mutation of the caveolin-binding motif within eNOS blocks the ability of caveolin-1 to inhibit eNOS activity in vivo. These findings provide the first demonstration that a caveolin-binding motif is relevant and functional in vivo. Direct interaction of caveolin with signaling molecules leads to their inactivation (18Li S. Okamoto T. Chun M. Sargiacomo M. Casanova J.E. Hansen S.H. Nishimoto I. Lisanti M.P. J. Biol. Chem. 1995; 270: 15693-15701Abstract Full Text Full Text PDF PubMed Scopus (559) Google Scholar). Since many signaling molecules can cause cellular transformation when constitutively activated, it is reasonable to speculate that caveolin may possess transformation suppressor activity. Consistent with this hypothesis, both caveolae and caveolin are most abundantly expressed in terminally differentiated cells: adipocytes, endothelial cells, and muscle cells. In addition, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes such as v-abl and Ha-ras (G12V); caveolae are absent from these cell lines (42Koleske A.J. Baltimore D. Lisanti M.P. Proc. Natl. Acad. Sci . U. S. A. 1995; 92: 1381-1385Crossref PubMed Scopus (472) Google Scholar). The potential “transformation suppressor” activity of caveolin-1 has recently been evaluated by using inducible expression in oncogenically transformed cells. Induction of caveolin-1 expression in v-Abl- and Ha-Ras (G12V)-transformed NIH 3T3 cells abrogated the anchorage-independent growth of these cells in soft agar and resulted in the de novo formation of caveolae (43Engelman J.A. Wykoff C.C. Yasuhara S. Song K.S. Okamoto T. Lisanti M.P. J. Biol. 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Literature on the contributions of social cognitive and emotion processes to children's social competence is reviewed and interpreted in the context of an integrated model of emotion processes and cognition in social information processing. Neurophysiological and functional evidence for the centrality of emotion processes in personal-social decision making is reviewed. Crick and Dodge's model is presented as a cognitive model of social decision making, and a revised model is proposed into which emotion processes are integrated. Hypotheses derived from the proposed model are described.

Recent attempts have been made to assess the relative merits of the free volume and entropy theories of viscous flow in glass-forming liquids by accurate measurement of viscosity over wide temperature ranges, and subsequent comparison with the equations derived from these theories. In the author's view, this effort is misguided. The theories are crude and qualitative, and such tests are too stringent. It is better to make qualitative or semiquantitative comparison of a wide variety of physical phenomena; judged by this criterion, the entropy theory appears more successful. It is conjectured that further progress can be made by accepting the crude, naive character of any model we are likely to find tractable for the foreseeable future, and recognizing both the values and limitations of such models. A picture of the flow process in viscous liquids is proposed, in an attempt to answer certain questions about the molecular steps in flow either answered unsuccessfully or ignored by present theories, in the hope that it will lead a model closer to molecular reality but still sufficiently tractable to allow some range of predictive value. The model is based on the idea that in “viscous” liquids (shear relaxation time ≥10−9 sec) flow is dominated by potential barriers high compared to thermal energies, while at higher temperature, this will no longer be true. Certain concepts borrowed from the continuum theory of lattice defects are joined to a qualitative description of viscous flow due to Orowan, to provide a picture which leads to some qualitative predictions about flow and relaxation in the liquid and glassy states.