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Gupta R, Kapoor N, Raleigh DP, Sakmar TP
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Nucleobindin 1 Caps Human Islet Amyloid Polypeptide Protofibrils to Prevent Amyloid Fibril Formation
JOURNAL OF MOLECULAR BIOLOGY 2012 AUG 10; 421(2-3):378-389
Many human diseases are associated with amyloid fibril deposition, including type 2 diabetes mellitus where human islet amyloid polypeptide (hIAPP) forms fibrils in the pancreas. We report here that engineered, soluble forms of the human Ca2+-binding protein nucleobindin 1 (NUCB1) prevent hIAPP fibril formation and disaggregate preexisting hIAPP fibrils. Scanning transmission electron microscopy (STEM) and atomic force microscopy indicate that NUCB1 binds to and stabilizes heterogeneous prefibrillar hIAPP species. The NUCB1-stabilized prefibrillar species were isolated by size-exclusion chromatography and analyzed by STEM, dynamic light scattering, and multi-angle light scattering. The stabilized prefibrillar species show a size range of 2-6 million Da and have other similarities to hIAPP protofibrils, but they do not progress to become mature fibrils. The effects of NUCB1 are absent in the presence of Ca2+. We postulate that the engineered forms of NUCB1 prevent hIAPP fibril formation by a mechanism where protofibril-like species are "capped" to prevent further fibril assembly and maturation. This mode of action appears to be different from other protein-based inhibitors, suggesting that NUCB1 may offer a new approach to inhibiting amyloid formation and disaggregating amyloid fibrils. (C) 2012 Elsevier Ltd. All rights reserved.
Aaltonen T, Collaboration C, Gonzalez BA, Amerio S, Amidei D, Anastassov A, Annovi A, Antos J, Apollinari G, Appel JA, Arisawa T, Artikov A, Asaadi J, Ashmanskas W, Auerbach B, Aurisano A, Azfar F, Badgett W, Bae T, Barbaro-Galtieri A, Barnes VE, Barnett BA, Barria P, Bartos P, Bauce M, Bedeschi F, Behari S, Bellettini G, Bellinger J, Benjamin D, Beretvas A, Bhatti A, Bisello D, Bizjak I, Bland KR, Blumenfeld B, Bocci A, Bodek A, Bortoletto D, Boudreau J, Boveia A, Brigliadori L, Bromberg C, Brucken E, Budagov J, Budd HS, Burkett K, Busetto G, Bussey P, Buzatu A, Calamba A, Calancha C, Camarda S, Campanelli M, Campbell M, Canelli F, Carls B, Carlsmith D, Carosi R, Carrillo S, Carron S, Casal B, Casarsa M, Castro A, Catastini P, Cauz D, Cavaliere V, Cavalli-Sforza M, Cerri A, Cerrito L, Chen YC, Chertok M, Chiarelli G, Chlachidze G, Chlebana F, Cho K, Chokheli D, Chung WH, Chung YS, Ciocci MA, Clark A, Clarke C, Compostella G, Convery ME, Conway J, Corbo M, Cordelli M, Cox CA, Cox DJ, Crescioli F, Cuevas J, Culbertson R, Dagenhart D, d'Ascenzo N, Datta M, de Barbaro P, Dell'Orso M, Demortier L, Deninno M, Devoto F, d'Errico M, Di Canto A, Di Ruzza B, Dittmann JR, D'Onofrio M, Donati S, Dong P, Dorigo M, Dorigo T, Ebina K, Elagin A, Eppig A, Erbacher R, Errede S, Ershaidat N, Eusebi R, Farrington S, Feindt M, Fernandez JP, Field R, Flanagan G, Forrest R, Frank MJ, Franklin M, Freeman JC, Funakoshi Y, Furic I, Gallinaro M, Garcia JE, Garfinkel AF, Garosi P, Gerberich H, Gerchtein E, Giagu S, Giakoumopoulou V, Giannetti P, Gibson K, Ginsburg CM, Giokaris N, Giromini P, Giurgiu G, Glagolev V, Glenzinski D, Gold M, Goldin D, Goldschmidt N, Golossanov A, Gomez G, Gomez-Ceballos G, Goncharov M, Gonzalez O, Gorelov I, Goshaw AT, Goulianos K, Grinstein S, Grosso-Pilcher C, Group RC, da Costa JG, Hahn SR, Halkiadakis E, Hamaguchi A, Han JY, Happacher F, Hara K, Hare D, Hare M, Harr RF, Hatakeyama K, Hays C, Heck M, Heinrich J, Herndon M, Hewamanage S, Hocker A, Hopkins W, Horn D, Hou S, Hughes RE, Hurwitz M, Husemann U, Hussain N, Hussein M, Huston J, Introzzi G, Iori M, Ivanov A, James E, Jang D, Jayatilaka B, Jeon EJ, Jindariani S, Jones M, Joo KK, Jun SY, Junk TR, Kamon T, Karchin PE, Kasmi A, Kato Y, Ketchum W, Keung J, Khotilovich V, Kilminster B, Kim DH, Kim HS, Kim JE, Kim MJ, Kim SB, Kim SH, Kim YK, Kim YJ, Kimura N, Kirby M, Klimenko S, Knoepfel K, Kondo K, Kong DJ, Konigsberg J, Kotwal AV, Kreps M, Kroll J, Krop D, Kruse M, Krutelyov V, Kuhr T, Kurata M, Kwang S, Laasanen AT, Lami S, Lammel S, Lancaster M, Lander RL, Lannon K, Lath A, Latino G, LeCompte T, Lee E, Lee HS, Lee JS, Lee SW, Leo S, Leone S, Lewis JD, Limosani A, Lin CJ, Lindgren M, Lipeles E, Lister A, Litvintsev DO, Liu C, Liu H, Liu Q, Liu T, Lockwitz S, Loginov A, Lucchesi D, Lueck J, Lujan P, Lukens P, Lungu G, Lys J, Lysak R, Madrak R, Maeshima K, Maestro P, Malik S, Manca G, Manousakis-Katsikakis A, Margaroli F, Marino C, Martinez M, Mastrandrea P, Matera K, Mattson ME, Mazzacane A, Mazzanti P, McFarland KS, McIntyre P, McNulty R, Mehta A, Mehtala P, Mesropian C, Miao T, Mietlicki D, Mitra A, Miyake H, Moed S, Moggi N, Mondragon MN, Moon CS, Moore R, Morello MJ, Morlock J, Fernandez PM, Mukherjee A, Muller T, Murat P, Mussini M, Nachtman J, Nagai Y, Naganoma J, Nakano I, Napier A, Nett J, Neu C, Neubauer MS, Nielsen J, Nodulman L, Noh SY, Norniella O, Oakes L, Oh SH, Oh YD, Oksuzian I, Okusawa T, Orava R, Ortolan L, Griso SP, Pagliarone C, Palencia E, Papadimitriou V, Paramonov AA, Patrick J, Pauletta G, Paulini M, Paus C, Pellett DE, Penzo A, Phillips TJ, Piacentino G, Pianori E, Pilot J, Pitts K, Plager C, Pondrom L, Poprock S, Potamianos K, Prokoshin F, Pranko A, Ptohos F, Punzi G, Rahaman A, Ramakrishnan V, Ranjan N, Redondo I, Renton P, Rescigno M, Riddick T, Rimondi F, Ristori L, Robson A, Rodrigo T, Rodriguez T, Rogers E, Rolli S, Roser R, Ruffini F, Ruiz A, Russ J, Rusu V, Safonov A, Sakumot WK, Sakurai Y, Santi L, Sato K, Saveliev V, Savoy-Navarro A, Schlabach P, Schmidt A, Schmidt EE, Schwarz T, Scodellaro L, Scribano A, Scuri F, Seidel S, Seiya Y, Semenov A, Sforza F, Shalhout SZ, Shears T, Shepard PF, Shimojima M, Shochet M, Shreyber-Tecker I, Simonenko A, Sinervo P, Sliwa K, Smith JR, Snider FD, Soha A, Sorin V, Song H, Squillacioti P, Stancari M, St Denis R, Stelzer B, Stelzer-Chilton O, Stentz D, Strologas J, Strycker GL, Sudo Y, Sukhanov A, Suslov I, Takemasa K, Takeuchi Y, Tang J, Tecchio M, Teng PK, Thom J, Thome J, Thompson GA, Thomson E, Tipton P, Toback D, Tokar S, Tollefson K, Tomura T, Tonelli D, Torre S, Torretta D, Totaro P, Trovato M, Ukegawa F, Uozumi S, Varganov A, Vazquez F, Velev G, Vellidis C, Vidal M, Vila I, Vilar R, Vizan J, Vogel M, Volpi G, Wagner P, Wagner RL, Wakisaka T, Wallny R, Wang SM, Warburton A, Waters D, Wester WC, Whiteson D, Wicklund AB, Wicklund E, Wilbur S, Wick F, Williams HH, Wilson JS, Wilson P, Winer BL, Wittich P, Wolbers S, Wolfe H, Wright T, Wu X, Wu Z, Yamamoto K, Yamato D, Yang T, Yang UK, Yang YC, Yao WM, Yeh GP, Yi K, Yoh J, Yorita K, Yoshida T, Yu GB, Yu I, Yu SS, Yu JC, Zanetti A, Zeng Y, Zhou C, Zucchelli S
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Search for the standard model Higgs boson produced in association with a Z boson in 7.9 fb(-1) of p(p)over-bar collisions at root s=1.96 TeV using the CDF ll detector
PHYSICS LETTERS B 2012 AUG 29; 715(1-3):98-104
We present a search for the standard model Higgs boson produced in association with a Z boson, using up to 7.9 fb(-1) of integrated luminosity from p (p) over bar collisions collected with the CDF II detector. We utilize several novel techniques, including multivariate lepton selection, multivariate trigger parametrization, and a multi-stage signal discriminant consisting of specialized functions trained to distinguish individual backgrounds. By increasing acceptance and enhancing signal discrimination, these techniques have significantly improved the sensitivity of the analysis above what was expected from a larger dataset alone. We observe no significant evidence for a signal, and we set limits on the ZH production cross section. For a Higgs boson with mass 115 GeV/c(2), we expect (observe) a limit of 3.9 (4.8) times the standard model predicted value, at the 95% credibility level. (c) 2012 Elsevier B.V. All rights reserved.
Aaltonen T, Abazov VM, Abbott B, Acharya BS, Adams M, Adams T, Alexeev GD, Alkhazov G, Alton A, Gonzalez BA, Alverson G, Amerio S, Amidei D, Anastassov A, Annovi A, Antos J, Apollinari G, Appel JA, Arisawa T, Artikov A, Asaadi J, Ashmanskas W, Askew A, Atkins S, Auerbach B, Augsten K, Aurisano A, Avila C, Azfar F, Badaud F, Badgett W, Bae T, Bagby L, Baldin B, Bandurin DV, Banerjee S, Barbaro-Galtieri A, Barberis E, Baringer P, Barnes VE, Barnett BA, Barria P, Bartlett JF, Bartos P, Bassler U, Bauce M, Bazterra V, Bean A, Bedeschi F, Begalli M, Behari S, Bellantoni L, Bellettini G, Bellinger J, Benjamin D, Beretvas A, Beri SB, Bernardi G, Bernhard R, Bertram I, Besancon M, Beuselinck R, Bhat PC, Bhatia S, Bhatnagar V, Bhatti A, Binkley M, Bisello D, Bizjak I, Bland KR, Blazey G, Blessing S, Bloom K, Blumenfeld B, Bocci A, Bodek A, Boehnlein A, Boline D, Boos EE, Borissov G, Bortoletto D, Bose T, Boudreau J, Boveia A, Brandt A, Brandt O, Brigliadori L, Brock R, Bromberg C, Bross A, Brown D, Brown J, Brucken E, Budagov J, Bu XB, Budd HS, Buehler M, Buescher V, Bunichev V, Burdin S, Burkett K, Busetto G, Bussey P, Buszello CP, Buzatu A, Calamba A, Calancha C, Camacho-Perez E, Camarda S, Campanelli M, Campbell M, Canelli F, Carls B, Carlsmith D, Carosi R, Carrillo S, Carron S, Casal B, Casarsa M, Casey BCK, Castilla-Valdez H, Castro A, Catastini P, Caughron S, Cauz D, Cavaliere V, Cavalli-Sforza M, Cerri A, Cerrito L, Chakrabarti S, Chakraborty D, Chan KM, Chandra A, Chapon E, Chen G, Chen YC, Chertok M, Chevalier-Thery S, Chiarelli G, Chlachidze G, Chlebana F, Cho DK, Cho K, Cho SW, Choi S, Chokheli D, Choudhary B, Chung WH, Chung YS, Cihangir S, Ciocci MA, Claes D, Clark A, Clarke C, Clutter J, Compostella G, Convery ME, Conway J, Cooke M, Cooper WE, Corbo M, Corcoran M, Cordelli M, Couderc F, Cousinou MC, Cox CA, Cox DJ, Crescioli F, Croc A, Cuevas J, Culbertson R, Cutts D, Dagenhart D, d'Ascenzo N, Das A, Datta M, Davies G, de Barbaro P, de Jong SJ, De La Cruz-Burelo E, Deliot F, Dell'Orso M, Demina R, Demortier L, Deninno M, Denisov D, Denisov SP, d'Errico M, Desai S, Deterre C, DeVaughan K, Devoto F, Di Canto A, Di Ruzza B, Diehl HT, Diesburg M, Ding PF, Dittmann JR, Dominguez A, Donati S, Dong P, D'Onofrio M, Dorigo M, Dorigo T, Dubey A, Dudko LV, Duggan D, Duperrin A, Dutt S, Dyshkant A, Eads M, Ebina K, Edmunds D, Elagin A, Ellison J, Elvira VD, Enari Y, Eppig A, Erbacher R, Errede S, Ershaidat N, Eusebi R, Evans H, Evdokimov A, Evdokimov VN, Facini G, Farrington S, Feindt M, Feng L, Ferbel T, Fernandez JP, Ferrazza C, Fiedler F, Field R, Filthaut F, Fisher W, Fisk HE, Flanagan G, Forrest R, Fortner M, Fox H, Frank MJ, Franklin M, Freeman JC, Fuess S, Funakoshi Y, Gallinaro M, Garcia-Bellido A, Garcia JE, Garcia-Gonzalez JA, Garcia-Guerra GA, Garfinkel AF, Garosi P, Gavrilov V, Gay P, Geng W, Gerbaudo D, Gerber CE, Gerberich H, Gerchtein E, Gershtein Y, Giagu S, Giakoumopoulou V, Giannetti P, Gibson K, Ginsburg CM, Ginther G, Giokaris N, Giromini P, Giurgiu G, Glagolev V, Glenzinski D, Gold M, Goldin D, Goldschmidt N, Golossanov A, Golovanov G, Gomez-Ceballos G, Gomez G, Goncharov M, Gonzalez O, Gorelov I, Goshaw AT, Goulianos K, Goussiou A, Grannis PD, Greder S, Greenlee H, Grenier G, Grinstein S, Gris P, Grivaz JF, Grohsjean A, Grosso-Pilcher C, Group RC, Grunendahl S, Grunewald MW, Guillemin T, da Costa JG, Gutierrez G, Gutierrez P, Hagopian S, Hahn SR, Haley J, Halkiadakis E, Hamaguchi A, Han JY, Han L, Happacher F, Hara K, Harder K, Hare D, Hare M, Harel A, Harr RF, Hatakeyama K, Hauptman JM, Hays C, Hays J, Head T, Hebbeker T, Heck M, Hedin D, Hegab H, Heinrich J, Heinson AP, Heintz U, Hensel C, Heredia-De La Cruz I, Herndon M, Herner K, Hesketh G, Hewamanage S, Hildreth MD, Hirosky R, Hoang T, Hobbs JD, Hocker A, Hoeneisen B, Hogan J, Hohlfeld M, Hopkins W, Horn D, Hou S, Howley I, Hubacek Z, Hughes RE, Hurwitz M, Husemann U, Hussain N, Hussein M, Huston J, Hynek V, Iashvili I, Ilchenko Y, Illingworth R, Introzzi G, Iori M, Ito AS, Ivanov A, Jabeen S, Jaffre M, James E, Jang D, Jayasinghe A, Jayatilaka B, Jeans DT, Jeon EJ, Jeong MS, Jesik R, Jiang P, Jindariani S, Johns K, Johnson E, Johnson M, Jonckheere A, Jones M, Jonsson P, Joo KK, Joshi J, Jun SY, Jung AW, Junk TR, Juste A, Kaadze K, Kajfasz E, Kamon T, Karchin PE, Karmanov D, Kasmi A, Kasper PA, Kato Y, Katsanos I, Kehoe R, Kermiche S, Ketchum W, Keung J, Khalatyan N, Khanov A, Kharchilava A, Kharzheev YN, Khotilovich V, Kilminster B, Kim DH, Kim HS, Kim JE, Kim MJ, Kim SB, Kim SH, Kim YJ, Kim YK, Kimura N, Kirby M, Kiselevich I, Klimenko S, Knoepfel K, Kohli JM, Kondo K, Kong DJ, Konigsberg J, Kotwal AV, Kozelov AV, Kraus J, Kreps M, Kroll J, Krop D, Kruse M, Krutelyov V, Kuhr T, Kulikov S, Kumar A, Kupco A, Kurata M, Kurca T, Kuzmin VA, Kwang S, Laasanen AT, Lami S, Lammel S, Lammers S, Lancaster M, Lander RL, Lannon K, Lath A, Latino G, Lebrun P, LeCompte T, Lee E, Lee HS, Lee HS, Lee JS, Lee SW, Lee SW, Lee WM, Lei X, Lellouch J, Leo S, Leone S, Lewis JD, Li D, Li H, Li L, Li QZ, Lim JK, Limosani A, Lincoln D, Lin CJ, Lindgren M, Linnemann J, Lipaev VV, Lipeles E, Lipton R, Lister A, Litvintsev DO, Liu C, Liu H, Liu H, Liu Q, Liu T, Liu Y, Lobodenko A, Lockwitz S, Loginov A, Lokajicek M, de Sa RL, Lubatti HJ, Lucchesi D, Lueck J, Lujan P, Lukens P, Luna-Garcia R, Lungu G, Lyon AL, Lysak R, Lys J, Maciel AKA, Madar R, Madrak R, Maestro P, Magana-Villalba R, Malik S, Malik S, Malyshev VL, Manca G, Manousakis-Katsikakis A, Maravin Y, Margaroli F, Marino C, Martinez M, Martinez-Ortega J, Mastrandrea P, Matera K, Mattson ME, Mazzacane A, Mazzanti P, McCarthy R, McFarland KS, McGivern CL, McIntyre P, McNulty R, Mehta A, Mehtala P, Meijer MM, Melnitchouk A, Menezes D, Mercadante PG, Merkin M, Mesropian C, Meyer A, Meyer J, Miao T, Miconi F, Mietlicki D, Mitra A, Miyake H, Moed S, Moggi N, Mondal NK, Mondragon MN, Moon CS, Moore R, Morello MJ, Morlock J, Fernandez PM, Mukherjee A, Mulhearn M, Muller T, Murat P, Mussini M, Nachtman J, Nagai Y, Naganoma J, Nagy E, Naimuddin M, Nakano I, Napier A, Narain M, Nayyar R, Neal HA, Negret JP, Nett J, Neubauer MS, Neu C, Neustroev P, Nguyen HT, Nielsen J, Nodulman L, Noh SY, Norniella O, Nunnemann T, Oakes L, Oh SH, Oh YD, Oksuzian I, Okusawa T, Orava R, Orduna J, Ortolan L, Osman N, Osta J, Padilla M, Griso SP, Pagliarone C, Pal A, Palencia E, Papadimitriou V, Paramonov AA, Parashar N, Parihar V, Park SK, Partridge R, Parua N, Patrick J, Patwa A, Pauletta G, Paulini M, Paus C, Pellett DE, Penning B, Penzo A, Perfilov M, Peters Y, Petridis K, Petrillo G, Petroff P, Phillips TJ, Piacentino G, Pianori E, Pilot J, Pitts K, Plager C, Pleier MA, Podesta-Lerma PLM, Podstavkov VM, Pondrom L, Popov AV, Poprocki S, Potamianos K, Pranko A, Prewitt M, Price D, Prokopenko N, Prokoshin F, Ptohos F, Punzi G, Qian J, Quadt A, Quinn B, Rahaman A, Ramakrishnan V, Rangel MS, Ranjan K, Ranjan N, Ratoff PN, Razumov I, Redondo I, Renkel P, Renton P, Rescigno M, Riddick T, Rimondi F, Ripp-Baudot I, Ristori L, Rizatdinova F, Robson A, Rodriguez T, Rogers E, Rolli S, Rominsky M, Roser R, Ross A, Royon C, Rubinov P, Ruchti R, Ruffini F, Ruiz A, Russ J, Rusu V, Safonov A, Sajot G, Sakumoto WK, Sakurai Y, Salcido P, Sanchez-Hernandez A, Sanders MP, Santi L, Santos AS, Sato K, Savage G, Saveliev V, Savoy-Navarro A, Sawyer L, Scanlon T, Schamberger RD, Scheglov Y, Schellman H, Schlabach P, Schlobohm S, Schmidt A, Schmidt EE, Schwanenberger C, Schwarz T, Schwienhorst R, Scodellaro L, Scribano A, Scuri F, Seidel S, Seiya Y, Sekaric J, Semenov A, Severini H, Sforza F, Shabalina E, Shalhout SZ, Shary V, Shaw S, Shchukin AA, Shears T, Shepard PF, Shimojima M, Shivpuri RK, Shochet M, Shreyber-Tecker I, Simak V, Simonenko A, Sinervo P, Skubic P, Slattery P, Sliwa K, Smirnov D, Smith JR, Smith KJ, Snider FD, Snow GR, Snow J, Snyder S, Soha A, Soldner-Rembold S, Song H, Sonnenschein L, Sorin V, Soustruznik K, Squillacioti P, St Denis R, Stancari M, Stark J, Stelzer-Chilton O, Stelzer B, Stentz D, Stoyanova DA, Strauss M, Strologas J, Strycker GL, Sudo Y, Sukhanov A, Suslov I, Suter L, Svoisky P, Takahashi M, Takemasa K, Takeuchi Y, Tang J, Tecchio M, Teng PK, Thom J, Thome J, Thompson GA, Thomson E, Titov M, Toback D, Tokar S, Tokmenin VV, Tollefson K, Tomura T, Tonelli D, Torre S, Torretta D, Totaro P, Trovato M, Tsai YT, Tschann-Grimm K, Tsybychev D, Tuchming B, Tully C, Ukegawa F, Uozumi S, Uvarov L, Uvarov S, Uzunyan S, Van Kooten R, van Leeuwen WM, Varelas N, Varganov A, Varnes EW, Vasilyev IA, Vazquez F, Velev G, Vellidis C, Verdier P, Verkheev AY, Vertogradov LS, Verzocchi M, Vesterinen M, Vidal M, Vila I, Vilanova D, Vilar R, Vizan J, Vogel M, Vokac P, Volpi G, Wagner P, Wagner RL, Wahl HD, Wakisaka T, Wallny R, Wang SM, Wang MHLS, Wang RJ, Warburton A, Warchol J, Waters D, Watts G, Wayne M, Weichert J, Welty-Rieger L, Wester WC, White A, Whiteson D, Wick F, Wicke D, Wicklund AB, Wicklund E, Wilbur S, Williams HH, Williams MRJ, Wilson GW, Wilson JS, Wilson P, Winer BL, Wittich P, Wobisch M, Wolbers S, Wolfe H, Wood DR, Wright T, Wu X, Wu Z, Wyatt TR, Xie Y, Yamada R, Yamamoto K, Yamato D, Yang S, Yang T, Yang UK, Yang WC, Yang YC, Yao WM, Yasuda T, Yatsunenko YA, Ye W, Ye Z, Yeh GP, Yi K, Yin H, Yip K, Yoh J, Yorita K, Yoshida T, Youn SW, Yu GB, Yu I, Yu JM, Yu SS, Yun JC, Zanetti A, Zeng Y, Zennamo J, Zhao T, Zhao TG, Zhou B, Zhou C, Zhu J, Zielinski M, Zieminska D, Zivkovic L, Zucchelli S
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Evidence for a Particle Produced in Association with Weak Bosons and Decaying to a Bottom-Antibottom Quark Pair in Higgs Boson Searches at the Tevatron
PHYSICAL REVIEW LETTERS 2012 AUG 14; 109(7):? Article 071804
We combine searches by the CDF and D0 Collaborations for the associated production of a Higgs boson with a W or Z boson and subsequent decay of the Higgs boson to a bottom-antibottom quark pair. The data, originating from Fermilab Tevatron p (p) over bar collisions at root s = 1.96 TeV, correspond to integrated luminosities of up to 9.7 fb(-1). The searches are conducted for a Higgs boson with mass in the range 100-150 GeV/c(2). We observe an excess of events in the data compared with the background predictions, which is most significant in the mass range between 120 and 135 GeV/c(2). The largest local significance is 3.3 standard deviations, corresponding to a global significance of 3.1 standard deviations. We interpret this as evidence for the presence of a new particle consistent with the standard model Higgs boson, which is produced in association with a weak vector boson and decays to a bottom-antibottom quark pair.
Darnell JC, Richter JD
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Cytoplasmic RNA-Binding Proteins and the Control of Complex Brain Function
COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY 2012 AUG; 4(8):? Article a012344
The formation and maintenance of neural circuits in the mammal central nervous system (CNS) require the coordinated expression of genes not just at the transcriptional level, but at the translational level as well. Recent evidence shows that regulated messenger RNA (mRNA) translation is necessary for certain forms of synaptic plasticity, the cellular basis of learning and memory. In addition, regulated translation helps guide axonal growth cones to their targets on other neurons or at the neuromuscular junction. Several neurologic syndromes have been correlated with and indeed may be caused by aberrant translation; one important example is the fragile X mental retardation syndrome. Although translation in the CNS is regulated by multiple mechanisms and factors, we focus this review on regulatory mRNA-binding proteins with particular emphasis on fragile X mental retardation protein (FMRP) and cytoplasmic polyadenylation element binding (CPEB) because they have been shown to be at the nexus of translational control and brain function in health and disease.
Lovejoy CA, Li WD, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JHJ, Sung PA, Jasin M, Rosenbluh J, Zwang Y, Weir BA, Hatton C, Ivanova E, Macconaill L, Hanna M, Hahn WC, Lue NF, Reddel RR, Jiao YC, Kinzler K, Vogelstein B, Papadopoulos N, Meeker AK
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Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway
PLOS GENETICS 2012 JUL; 8(7):? Article e1002772
The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.
Langston LD, O'Donnell M
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Subunit sharing among high- and low-fidelity DNA polymerases
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2012 JUL 31; 109(31):12268-12269
West AP, Diskin R, Nussenzweig MC, Bjorkman PJ
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Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2012 JUL 24; 109(30):E2083-E2090
A large number of anti-HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V-H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies.
Levran O, Awolesi O, Shen PH, Adelson M, Kreek MJ
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Estimating ancestral proportions in a multi-ethnic US sample: implications for studies of admixed populations
HUMAN GENOMICS 2012 JUL 5; 6(?):? Article 2
This study was designed to determine the ancestral composition of a multi-ethnic sample collected for studies of drug addictions in New York City and Las Vegas, and to examine the reliability of self-identified ethnicity and three-generation family history data. Ancestry biographical scores for seven clusters corresponding to world major geographical regions were obtained using STRUCTURE, based on genotypes of 168 ancestry informative markers (AIMs), for a sample of 1,291 African Americans (AA), European Americans (EA), and Hispanic Americans (HA) along with data from 1,051 HGDP-CEPH 'diversity panel' as a reference. Self-identified ethnicity and family history data, obtained in an interview, were accurate in identifying the individual major ancestry in the AA and the EA samples (approximately 99% and 95%, respectively) but were not useful for the HA sample and could not predict the extent of admixture in any group. The mean proportions of the combined clusters correspond!
Huang TT, Ojcius DM, Young JD, Wu YH, Ko YF, Wong TY, Wu CY, Lu CC, Lai HC
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The Anti-Tumorigenic Mushroom Agaricus blazei Murill Enhances IL-1 beta Production and Activates the NLRP3 Inflammasome in Human Macrophages
PLOS ONE 2012 JUL 23; 7(7):? Article e41383
Agaricus blazei Murill (AbM) has been reported to possess immune activity against tumors and infections through stimulation of mononuclear phagocytes. Recently, AbM extract was shown to induce the production of the pro-inflammatory cytokine, interleukin-1 beta (IL-1 beta), in human monocytes. IL-1 beta is a key pro-inflammatory cytokine produced by activated macrophages and monocytes and its secretion is strictly controlled by the inflammasome. The purpose of this study is to investigate the effect of AbM water extracts on the regulation of IL-1 beta production and activation of the NLRP3 inflammasome in human THP-1 macrophages. The NLRP3 inflammasome consists of an NLRP3 receptor, an adaptor protein called ASC, and the inflammatory protease, caspase-1. Typically, stimulation of immune cells with microbial products results in production of pro-IL-1 beta, but a second stress-related signal activates the inflammasome and caspase-1, leading to processing and secretion of IL-1 beta. Our results show that AbM enhances transcription of IL-1 beta and triggers NLRP3 inflammasome-mediated IL-1 beta secretion in human THP-1 macrophages. AbM-mediated IL-1 beta secretion was markedly reduced in macrophages deficient in NLRP3 and ASC, demonstrating that the NLRP3 inflammasome is essential for AbM-induced IL-1 beta secretion. In addition, caspase-1 was activated and involved in proteolytic cleavage and secretion of IL-1 beta in AbM-treated macrophages. AbM-mediated IL-1 beta secretion also decreased in cells treated with cathepsin B inhibitor, suggesting that AbM can induce the release of cathepsin B. Furthermore, our data show that AbM-induced inflammasome activation requires the release of ATP, binding of extracellular ATP to the purinergic receptor P2X(7), the generation of reactive oxygen species, and efflux of potassium. Taken together, these findings reveal that AbM activates the NLRP3 inflammasome via multiple mechanisms, resulting in the secretion of IL-1 beta.
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Azimuthal Anisotropy of Charged Particles at High Transverse Momenta in Pb-Pb Collisions at root S-NN=2.76 TeV
PHYSICAL REVIEW LETTERS 2012 JUL 10; 109(2):? Article 022301
The azimuthal anisotropy of charged particles in Pb-Pb collisions at root S-NN = 2.76 TeV is measured with the CMS detector at the LHC over an extended transverse momentum (p(T)) range up to approximately 60 GeV/c. The data cover both the low-p(T) region associated with hydrodynamic flow phenomena and the high-p(T) region where the anisotropies may reflect the path-length dependence of parton energy loss in the created medium. The anisotropy parameter (nu(2)) of the particles is extracted by correlating charged tracks with respect to the event-plane reconstructed by using the energy deposited in forward-angle calorimeters. For the six bins of collision centrality studied, spanning the range of 0-60% most-central events, the observed nu(2) values are found to first increase with p(T), reaching a maximum around p(T) = 3 GeV/c, and then to gradually decrease to almost zero, with the decline persisting up to at least p(T) = 40 GeV/c over the full centrality range measured.