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Tsumura M, Okada S, Sakai H, Yasunaga S, Ohtsubo M, Murata T, Obata H, Yasumi T, Kong XF, Abhyankar A, Heike T, Nakahata T, Nishikomori R, Al-Muhsen S, Boisson-Dupuis S, Casanova JL, AlZahrani M, Al Shehri M, ElGhazali G, Takihara Y, Kobayashi M
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Dominant-negative STAT1 SH2 domain mutations in unrelated patients with mendelian susceptibility to mycobacterial disease
HUMAN MUTATION 2012 SEP; 33(9):1377-1387
Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail segment domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant negative and result in impaired STAT1-mediated cellular responses to interferon (IFN)-alpha and IL-lambda 7. In contrast, STAT1-mediated cellular responses against IFN-alpha and IFN-lambda 1 were preserved at normal levels in patients' cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA binding, as well as for antimycobacterial immunity. Hum Mutat 33:1377-1387, 2012. (c) 2012 Wiley Periodicals, Inc.
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Lopez EL, Smith JG, Stenson K, Ulmer KA, Wagner SR, Alexander J, Chatterjee A, Eggert N, Gibbons LK, Heltsley B, Khukhunaishvili A, Kreis B, Mirman N, Kaufman GN, Patterson JR, Ryd A, Salvati E, Sun W, Teo WD, Thom J, Thompson J, Vaughan J, Weng Y, Winstrom L, Wittich P, Winn D, Abdullin S, Albrow M, Anderson J, Bauerdick LAT, Beretvas A, Berryhill J, Bhat PC, Bloch I, Burkett K, Butler JN, Chetluru V, Cheung HWK, Chlebana F, Elvira VD, Fisk I, Freeman J, Gao Y, Green D, Gutsche O, Hanlon J, Harris RM, Hirschauer J, Hooberman B, Jindariani S, Johnson M, Joshi U, Kilminster B, Klima B, Kunori S, Kwan S, Leonidopoulos C, Lincoln D, Lipton R, Lykken J, Maeshima K, Marraffino JM, Maruyama S, Mason D, McBride P, Mishra K, Mrenna S, Musienko Y, Newman-Holmes C, O'Dell V, Prokofyev O, Sexton-Kennedy E, Sharma S, Spalding WJ, Spiegel L, Tan P, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Vidal R, Whitmore J, Wu W, Yang F, Yumiceva F, Yun JC, Acosta D, Avery P, Bourilkov D, Chen M, Das S, De Gruttola M, Di Giovanni GP, Dobur D, Drozdetskiy A, Field RD, Fisher M, Fu Y, Furic IK, Gartner J, Hugon J, Kim B, Konigsberg J, Korytov A, Kropivnitskaya A, Kypreos T, Low JF, Matchev K, Milenovic P, Mitselmakher G, Muniz L, Remington R, Rinkevicius A, Sellers P, Skhirtladze N, Snowball M, Yelton J, Zakaria M, Gaultney V, Lebolo LM, Linn S, Markowitz P, Martinez G, Rodriguez JL, Adams JR, Adams T, Askew A, Bochenek J, Chen J, Diamond B, Gleyzer SV, Haas J, Hagopian S, Hagopian V, Jenkins M, Johnson KF, Prosper H, Veeraraghavan V, Weinberg M, Baarmand MM, Dorney B, Hohlmann M, Kalakhety H, Vodopiyanov I, Adams MR, Anghel IM, Apanasevich L, Bai Y, Bazterra VE, Betts RR, Bucinskaite I, Callner J, Cavanaugh R, Dragoiu C, Evdokimov O, Gauthier L, Gerber CE, Hofman DJ, Khalatyan S, Lacroix F, Malek M, O'Brien C, Silkworth C, Strom D, Varelas N, Akgun U, Albayrak EA, Bilki B, Clarida W, Duru F, Griffiths S, Merlo JP, Mermerkaya H, Mestvirishvili A, Moeller A, Nachtman J, Newsom CR, Norbeck E, Onel Y, Ozok F, Sen S, Tiras E, Wetzel J, Yetkin T, Yi K, Barnett BA, Blumenfeld B, Bolognesi S, Fehling D, Giurgiu G, Gritsan AV, Guo ZJ, Hu G, Maksimovic P, Rappoccio S, Swartz M, Whitbeck A, Baringer P, Bean A, Benelli G, Grachov O, Iii RPK, Murray M, Noonan D, Sanders S, Stringer R, Tinti G, Wood JS, Zhukova V, Barfuss AF, Bolton T, Chakaberia I, Ivanov A, Khalil S, Makouski M, Maravin Y, Shrestha S, Svintradze I, Gronberg J, Lange D, Wright D, Baden A, Boutemeur M, Calvert B, Eno SC, Gomez JA, Hadley NJ, Kellogg RG, Kirn M, Kolberg T, Lu Y, Marionneau M, Mignerey AC, Pedro K, Peterman A, Skuja A, Temple J, Tonjes MB, Tonwar SC, Twedt E, Bauer G, Bendavid J, Busza W, Butz E, Cali IA, Chan M, Dutta V, Ceballos GG, Goncharov M, Hahn KA, Kim Y, Klute M, Krajczar K, Li W, Luckey PD, Ma T, Nahn S, Paus C, Ralph D, Roland C, Roland G, Rudolph M, Stephans GSF, Stockli F, Sumorok K, Sung K, Velicanu D, Wenger EA, Wolf R, Wyslouch B, Xie S, Yang M, Yilmaz Y, Yoon AS, Zanetti M, Cooper SI, Dahmes B, De Benedetti A, Franzoni G, Gude A, Kao SC, Klapoetke K, Kubota Y, Mans J, Pastika N, Rusack R, Sasseville M, Singovsky A, Tambe N, Turkewitz J, Cremaldi LM, Kroeger R, Perera L, Rahmat R, Sanders DA, Avdeeva E, Bloom K, Bose S, Butt J, Claes DR, Dominguez A, Eads M, Keller J, Kravchenko I, Lazo-Flores J, Malbouisson H, Malik S, Snow GR, Baur U, Godshalk A, Iashvili I, Jain S, Kharchilava A, Kumar A, Shipkowski SP, Smith K, Alverson G, Barberis E, Baumgartel D, Chasco M, Haley J, Nash D, Trocino D, Wood D, Zhang J, Anastassov A, Kubik A, Mucia N, Odell N, Ofierzynski RA, Pollack B, Pozdnyakov A, Schmitt M, Stoynev S, Velasco M, Won S, Antonelli L, Berry D, Brinkerhoff A, Hildreth M, Jessop C, Karmgard DJ, Kolb J, Lannon K, Luo W, Lynch S, Marinelli N, Morse DM, Pearson T, Ruchti R, Slaunwhite J, Valls N, Wayne M, Wolf M, Bylsma B, Durkin LS, Hart A, Hill C, Hughes R, Kotov K, Ling TY, Puigh D, Rodenburg M, Vuosalo C, Williams G, Winer BL, Adam N, Berry E, Elmer P, Gerbaudo D, Halyo V, Hebda P, Hegeman J, Hunt A, Jindal P, Pegna DL, Lujan P, Marlow D, Medvedeva T, Mooney M, Olsen J, Piroue P, Quan X, Raval A, Saka H, Stickland D, Tully C, Werner JS, Zuranski A, Acosta JG, Brownson E, Huang XT, Lopez A, Mendez H, Oliveros S, Vargas JER, Zatserklyaniy A, Alagoz E, Barnes VE, Benedetti D, Bolla G, Bortoletto D, De Mattia M, Everett A, Hu Z, Jones M, Koybasi O, Kress M, Laasanen AT, Leonardo N, Maroussov V, Merkel P, Miller DH, Neumeister N, Shipsey I, Silvers D, Svyatkovskiy A, Marono MV, Yoo HD, Zablocki J, Zheng Y, Guragain S, Parashar N, Adair A, Boulahouache C, Ecklund KM, Geurts FJM, Padley BP, Redjimi R, Roberts J, Zabel J, Betchart B, Bodek A, Chung YS, Covarelli R, de Barbaro P, Demina R, Eshaq Y, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Miner DC, Vishnevskiy D, Zielinski M, Bhatti A, Ciesielski R, Demortier L, Goulianos K, Lungu G, Malik S, Mesropian C, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Lath A, Panwalkar S, Park M, Patel R, Rekovic V, Robles J, Rose K, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Cerizza G, Hollingsworth M, Spanier S, Yang ZC, York A, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, Sengupta S, Suarez I, Tatarinov A, Toback D, Akchurin N, Damgov J, Dudero PR, Jeong C, Kovitanggoon K, Lee SW, Libeiro T, Roh Y, Volobouev I, Appelt E, Florez C, Greene S, Gurrola A, Johns W, Johnston C, Kurt P, Maguire C, Melo A, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Balazs M, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Lin C, Neu C, Wood J, Yohay R, Gollapinni S, Harr R, Karchin PE, Don CKK, Lamichhane P, Sakharov A, Anderson M, Bachtis M, Belknap D, Borrello L, Carlsmith D, Cepeda M, Dasu S, Gray L, Grogg KS, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Klukas J, Lanaro A, Lazaridis C, Leonard J, Loveless R, Mohapatra A, Ojalvo I, Palmonari F, Pierro GA, Ross I, Savin A, Smith WH, Swanson J
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Measurement of the Electron Charge Asymmetry in Inclusive W Production in pp Collisions at root s=7 TeV
PHYSICAL REVIEW LETTERS 2012 SEP 11; 109(11):? Article 111806
A measurement of the electron charge asymmetry in inclusive pp -> W + X -> ev + X production at root s = 7 TeV is presented based on data recorded by the CMS detector at the LHC and corresponding to an integrated luminosity of 840 pb(-1). The electron charge asymmetry reflects the unequal production of W+ and W- bosons in pp collisions. The electron charge asymmetry is measured in bins of the absolute value of electron pseudorapidity in the range of vertical bar eta vertical bar < 2.4. The asymmetry rises from about 0.1 to 0.2 as a function of the pseudorapidity and is measured with a relative precision better than 7%. This measurement provides new stringent constraints for parton distribution functions.
Warmflash A, Arduini BL, Brivanlou AH
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The molecular circuitry underlying pluripotency in embryonic stem cells
WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2012 SEP-OCT; 4(5):443-456
Cells in the pluripotent state have the ability to self-renew indefinitely and to differentiate to all the cells of the embryo. These cells provide an in vitro window into development, including human development, as well as holding extraordinary promise for cell-based therapies in regenerative medicine. The recent demonstration that somatic cells can be reprogrammed to the pluripotent state has raised the possibility of patient and disease-specific induced pluripotent cells. In this article, we review the molecular underpinning of pluripotency. We focus on the transcriptional and signaling networks that underlie the state of pluripotency and control differentiation. In general, the action of each of the molecular components and pathways is dose and context dependent highlighting the need for a systems approach to understanding pluripotency. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1182 For further resources related to this article, please visit the WIREs website.
Aaltonen T, 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, Binkley ME, 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, Poprocki 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, Sakumoto 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, 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, Yun JC, Zanetti A, Zeng Y, Zhou C, Zucchelli S
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Search for the Standard Model Higgs Boson Decaying to a b(b)over-bar Pair in Events with No Charged Leptons and Large Missing Transverse Energy using the Full CDF Data Set
PHYSICAL REVIEW LETTERS 2012 SEP 10; 109(11):? Article 111805
We report on a search for the standard model Higgs boson produced in association with a vector boson in the full data set of proton-antiproton collisions at root s = 1.96 TeV recorded by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45 fb(-1). We consider events having no identified charged lepton, a transverse energy imbalance, and two or three jets, of which at least one is consistent with originating from the decay of a b quark. We place 95% credibility level upper limits on the production cross section times standard model branching fraction for several mass hypotheses between 90 and 150 GeV/c(2). For a Higgs boson mass of 125 GeV/c(2), the observed (expected) limit is 6.7 (3.6) times the standard model prediction.
James P, Coller BS
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Phenotyping bleeding
CURRENT OPINION IN HEMATOLOGY 2012 SEP; 19(5):406-412
Purpose of review Although recorded evidence of phenotyping bleeding disorders extends back two millennia, standardization of phenotyping has only begun in the past half century. This was spurred by the need for greater precision in diagnosing disorders in order to select proper laboratory tests and treatment, and the realization that the bleeding history provides prognostic information about the future risk of bleeding with surgery or invasive procedures. Recent findings New bleeding assessment tools (BATs) have been developed, firstly, to evaluate the relative bleeding risks associated with new anticoagulants and antiplatelet agents, secondly, to assess the efficacy of new thrombopoiesis stimulating agents in preventing hemorrhage in patients with immune thrombocytopenia, and finally, to assess complex gene-gene and gene-environment interactions. New web-based systems allow many researchers to collaborate by sharing the same electronic phenotyping infrastructure. Major issues of validation remain, but at present the data indicate that the new BATs have relatively high negative predictive value for excluding a significant bleeding disorder, but disappointingly low positive predictive values. Summary New instruments to phenotype bleeding have been developed to address a number of different important clinical and research goals. The improved standardization and opportunities for collaborative studies hold promise for maximizing diagnostic, prognostic, and scientific information.
Rao RP, Anilkumar S, McEwen BS, Chattarji S
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Glucocorticoids Protect Against the Delayed Behavioral and Cellular Effects of Acute Stress on the Amygdala
BIOLOGICAL PSYCHIATRY 2012 SEP 15; 72(6):466-475
Background: A single episode of acute immobilization stress has previously been shown to trigger a delayed onset of anxiety-like behavior and spinogenesis in the basolateral amygdala (BLA) of rats. Spurred on by a seemingly paradoxical observation in which even a modest increase in corticosterone (CORT), caused by a single vehicle injection before stress, could dampen the delayed effects of stress, we hypothesized a protective role for glucocorticoids against stress. Methods: We tested this hypothesis by analyzing how manipulations in CORT levels modulate delayed increase in anxiety-like behavior of rats on the elevated plus-maze 10 days after acute stress. We also investigated the cellular correlates of different levels of anxiety under different CORT conditions by quantifying spine density on Golgi-stained BLA principal neurons. Results: CORT in drinking water for 12 hours preceding acute stress prevented delayed increase in anxiety rather than exacerbating it. Conversely, vehicle injection failed to prevent the anxiogenic effect of stress in bilaterally adrenalectomized rats. However, when CORT was restored in adrenalectomized rats by injection, the delayed anxiogenic effect of stress was once again blocked. Finally, high and low anxiety states were accompanied by high and low levels of BLA spine density. Conclusions: Our findings suggest that the presence of elevated levels of CORT at the time of acute stress confers protection against the delayed enhancing effect of stress on BLA synaptic connectivity and anxiety-like behavior. These observations are consistent with clinical reports on the protective effects of glucocorticoids against the development of posttraumatic symptoms triggered by traumatic stress.
Chatrchyan S, Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, Dragicevic M, Ero J, Fabjan C, Friedl M, Fruhwirth R, Ghete VM, Hammer J, Hormann N, Hrubec J, Jeitler M, Kiesenhofer W, Knunz V, Krammer M, Liko D, Mikulec I, Pernicka M, Rahbaran B, Rohringer C, Rohringer H, Schofbeck R, Strauss J, Taurok A, Wagner P, Waltenberger W, Walzel G, Widl E, Wulz CE, Mossolov V, Shumeiko N, Gonzalez JS, Bansal S, Cornelis T, De Wolf EA, Janssen X, Luyckx S, Maes T, Mucibello L, Ochesanu S, Roland B, Rougny R, Selvaggi M, Staykova Z, Van Haevermaet H, Van Mechelen P, Van Remortel N, Van Spilbeeck A, Blekman F, Blyweert S, D'Hondt J, Suarez RG, Kalogeropoulos A, Maes M, Olbrechts A, Van Doninck W, Van Mulders P, Van Onsem GP, Villella I, Charaf O, Clerbaux B, De Lentdecker G, Dero V, Gay APR, Hreus T, Leonard A, Marage PE, Reis T, Thomas L, Vander Velde C, Vanlaer P, Wang J, Adler V, Beernaert K, Cimmino A, Costantini S, Garcia G, Grunewald M, Klein B, Lellouch J, Marinov A, Mccartin J, 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Borrello L, Carlsmith D, Cepeda M, Dasu S, Gray L, Grogg KS, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Klukas J, Lanaro A, Lazaridis C, Leonard J, Loveless R, Mohapatra A, Ojalvo I, Palmonari F, Pierro GA, Ross I, Savin A, Smith WH, Swanson J
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Search for high-mass resonances decaying into tau-lepton pairs in pp collisions at root s=7 TeV
PHYSICS LETTERS B 2012 SEP 17; 716(1):82-102
A search for high-mass resonances decaying into tau(+)tau(-) is performed using a data sample of pp collisions at root s = 7 TeV. The data were collected with the CMS detector at the LHC and correspond to an integrated luminosity of 4.9 fb(-1). The number of observed events is in agreement with the standard model prediction. An upper limit on the product of the resonance cross section and branching fraction into tau-lepton pairs is calculated as a function of the resonance mass. Using the sequential standard model resonance Z'(SSM) and the superstring-inspired E-6 model with resonance Z'(psi) as benchmarks, resonances with standard model couplings with masses below 1.4 and 1.1 TeV, respectively, are excluded at 95% confidence level. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.
Negri A, Li JH, Naini S, Coller BS, Filizola M
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Structure-based virtual screening of small-molecule antagonists of platelet integrin alpha IIb beta 3 that do not prime the receptor to bind ligand
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 2012 SEP; 26(9):1005-1015
Integrin alpha IIb beta 3 has emerged as an important therapeutic target for thrombotic vascular diseases owing to its pivotal role in mediating platelet aggregation through interaction with adhesive ligands. In the search for effective anti-thrombotic agents that can be administered orally without inducing the high-affinity ligand binding state, we recently discovered via high-throughput screening of 33,264 compounds a novel, alpha IIb beta 3-selective inhibitor (RUC-1) of adenosine-5'-diphosphate (ADP) -induced platelet aggregation that exhibits a different chemical scaffold and mode of binding with respect to classical Arg-Gly-Asp (RGD)-mimicking alpha IIb beta 3 antagonists. Most importantly, RUC-1 and its higher-affinity derivative, RUC-2, do not induce major conformational changes in the protein beta 3 subunit or prime the receptor to bind ligand. To identify additional alpha IIb beta 3-selective chemotypes that inhibit platelet aggregation through similar mechanisms, we screened in silico over 2.5 million commercially available, 'lead-like' small molecules based on complementarity to the predicted binding mode of RUC-2 into the RUC-1-alpha IIb beta 3 crystal structure. This first reported structure-based virtual screening application to the alpha IIb beta 3 integrin led to the identification of 2 alpha IIb beta 3-selective antagonists out of 4 tested, which compares favorably with the 0.003 % "hit rate" of our previous high-throughput chemical screening study. The newly identified compounds, like RUC-1 and RUC-2, showed specificity for alpha IIb beta 3 compared to alpha V beta 3 and did not prime the receptor to bind ligand. They thus may hold promise as alpha IIb beta 3 antagonist therapeutic scaffolds.
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Pierro GA, Ross I, Savin A, Smith WH, Swanson J
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Measurement of the underlying event in the Drell-Yan process in proton-proton collisions at root s=7 TeV
EUROPEAN PHYSICAL JOURNAL C 2012 SEP; 72(9):? Article 2080
A measurement of the underlying event (UE) activity in proton-proton collisions at a center-of-mass energy of 7 TeV is performed using Drell-Yan events in a data sample corresponding to an integrated luminosity of 2.2 fb(-1), collected by the CMS experiment at the LHC. The activity measured in the muonic final state (q (q) over bar -> mu(+) mu(-)) is corrected to the particle level and compared with the predictions of various Monte Carlo generators and hadronization models. The dependence of the UE activity on the dimuon invariant mass is well described by PYTHIA and HERWIG++ tunes derived from the leading jet/track approach, illustrating the universality of the UE activity. The UE activity is observed to be independent of the dimuon invariant mass in the region above 40 GeV/c(2), while a slow increase is observed with increasing transverse momentum of the dimuon system. The dependence of the UE activity on the transverse momentum of the dimuon system is accurately described by MADGRAPH, which simulates multiple hard emissions.