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Knepp AM, Periole X, Marrink SJ, Sakmar TP, Huber T
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Rhodopsin Forms a Dimer with Cytoplasmic Helix 8 Contacts in Native Membranes
BIOCHEMISTRY 2012 MAR 6; 51(9):1819-1821
G protein-coupled receptors form dimers and higher-order oligomers in membranes, but the precise mode of receptor receptor interaction remains unknown. To probe the intradimeric proximity of helix 8 (H8), we conducted chemical cross-linking of endogenous cysteines in rhodopsin in disk membranes. We identified a Cys316-Cys316 cross-link using partial proteolysis and liquid chromatography with mass spectrometry. These results show that a symmetric dimer interface mediated by HI and H8 contacts is present in native membranes.
Chen YW, Rada PV, Butzler BP, Leibowitz SF, Hoebel BG
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CORTICOTROPIN-RELEASING FACTOR IN THE NUCLEUS ACCUMBENS SHELL INDUCES SWIM DEPRESSION, ANXIETY, AND ANHEDONIA ALONG WITH CHANGES IN LOCAL DOPAMINE/ACETYLCHOLINE BALANCE
NEUROSCIENCE 2012 MAR 29; 206(?):155-166
The nucleus accumbens shell (NAcS) has been implicated in controlling stress responses through corticotropin-releasing factor (CRF). In addition to studies indicating that CRF in the NAcS increases appetitive motivation, there is indirect evidence suggesting that NAcS CRF may also cause aversive responses and that these behaviors may be mediated through local dopamine (DA) and acetylcholine (ACh) systems. To provide a direct test of this hypothesis, we used male Sprague-Dawley rats with implanted cannulas aimed at the NAcS. Experiment 1 showed local CRF injection (10 or 50 ng/side) to increase immobility in the forced swim test and a CRF antagonist D-Phe-CRF ((12-41)) to attenuate this depressive-like behavior. In Experiment 2, injection of CRF (250 ng/side) also decreased the rats' preference for sucrose, while in Experiment 3, CRF (50 or 250 ng/side) induced anxiety-like behaviors in an elevated plus maze and open field. These same doses of CRF in Experiment 4 failed to alter the rats' locomotor activity, indicating that these behavioral changes were not caused by deficits in activity. In Experiment 5, results from in vivo microdialysis revealed that CRF in the NAcS markedly increased local extracellular ACh, while also producing a small increase in DA. These results show that NAcS CRF can generate a variety of aversive behaviors, including swim depression, anhedonia, and anxiety, in addition to approach behavior. They suggest that these behaviors may occur, in part, through enhanced activation of ACh and DA in the NAcS, respectively, supporting a role for this brain area in mediating the dual effects of stress. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
Elsasser SJ, D'Arcy S
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Towards a mechanism for histone chaperones
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2012 MAR-APR; 1819(3-4):211-221
Histone chaperones can be broadly defined as histone-binding proteins that influence chromatin dynamics in an ATP-independent manner. Their existence reflects the importance of chromatin homeostasis and the unique and unusual biochemistry of the histone proteins. Histone supply and demand at chromatin is regulated by a network of structurally and functionally diverse histone chaperones. At the core of this network is a mechanistic variability that is only beginning to be appreciated. In this review, we highlight the challenges in determining histone chaperone mechanism and discuss possible mechanisms in the context of nucleosome thermodynamics. We discuss how histone chaperones prevent promiscuous histone interactions, and consider if this activity represents the full extent of histone chaperone function in governing chromatin dynamics. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly. (C) 2011 Elsevier B.V. All rights reserved.
Flaxel C, Schain MB, Hamon SC, Francis PJ
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PROSPECTIVE RANDOMIZED CONTROLLED TRIAL OF COMBINATION RANIBIZUMAB (LUCENTIS) AND BROMFENAC (XIBROM) FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION A Pilot Study
RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2012 MAR; 32(3):417-423
Purpose: To evaluate whether bromfenac eyedrops and ranibizumab intravitreal injections would provide added efficacy over ranibizumab alone. Methods: This was a single-site, multiinvestigator, prospective, open-label, interventional, Phase II study of patients with new or recurrent exudative/neovascular age-related macular degeneration. Thirty eyes were enrolled consecutively and were randomized in a ratio of 2: 1 to combination therapy with intravitreal ranibizumab and topical bromfenac, and ranibizumab alone. All patients received ranibizumab monthly therapy for 4 months then as needed monthly in accordance with standard of care. Patients receiving bromfenac self-administered 1 drop twice a day for 12 months. Patients were followed for 12 months. Results: There were no safety concerns with the combination therapy. No statistically significant differences were identified in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity or the number of injections required. However, the mean 12-month change in central macular thickness in the combination group was -81.56 mu m while in the ranibizumab group alone the change was -42.50 mu m (P = 0.03). The proportion of eyes experiencing a decrease in CMT of 50 mu m or more was also significantly higher in those receiving combination therapy (P = 0.046). Conclusion: This pilot study is the first to prospectively identify a biologic signal that may indicate combination therapy with an easily administered well-tolerated eyedrop and ranibizumab is efficacious for the treatment of neovascular age-related macular degeneration. Further studies are warranted to validate this finding. RETINA 32: 417-423, 2012
Chatrchyan S, Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, Dragicevic M, Eroe J, Fabjan C, Friedl M, Fruehwirth R, Ghete VM, Hammer J, Hoch M, Hormann N, Hrubec J, Jeitler M, Kiesenhofer W, Krammer M, Liko D, Mikulec I, Pernicka M, Rahbaran B, Rohringer C, Rohringer H, Schofbeck R, Strauss J, Taurok A, Teischinger F, Wagner P, Waltenberger W, Walzel G, Widl E, Wulz CE, Mossolov V, Shumeiko N, Gonzalez JS, Bansal S, Benucci L, Cornelis T, De Wolf EA, Janssen X, Luyckx S, Maes T, Mucibello L, Ochesanu S, Roland B, Rougny R, Selvaggi M, Van Haevermaet H, Van Mechelen R, 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 R, Van Onsem GP, Villella I, Charaf O, Clerbaux B, De Lentdecker G, Dero V, Gay APR, Hammad GH, Hreus T, Leonard A, Marage PE, Thomas L, Vander Velde C, Vanlaer P, Wickens J, Adler V, Beernaert K, Cimmino A, Costantini S, Garcia G, Grunewald M, Klein B, Lellouch J, Marinov A, Mccartin J, Rios AAO, Ryckbosch D, Strobbe N, Thyssen F, Tytgat M, Vanelderen L, Verwilligen R, Walsh S, Yazgan E, Zaganidis N, Basegmez S, Bruno G, Ceard L, De Jeneret JDF, Delaere C, du Pree T, Favart D, Forthomme L, Giammanco A, Gregoire G, Hollar J, Lemaitre V, Liao J, Militaru O, Nuttens C, Pagano D, Pin A, Piotrzkowski K, Schul N, Belly N, Caebergs T, Daubie E, Alves GA, Martin MCM, Damiao DD, Martins T, Pol ME, Souza MHG, Alda WL, Carvalho W, Custodio A, Da Costa EM, Martins CD, De Souza SF, Figueiredo DM, Mundim L, Nogima H, Oguri V, Da Silva WLP, Santoro A, Do Amaral SMS, Jorge LS, Sznajder A, Anjos TS, Bernardes CA, Dias FA, Tomei TRFP, Gregores EM, Lagana C, Marinho F, Mercadante PG, Novaes SF, Padula SS, Genchev V, Iaydjiev P, Piperov S, Rodozov M, Stoykova S, Sultanov G, Tcholakov V, Trayanov R, Vutova M, Dimitrov A, Hadjiiska R, Karadzhinova A, Kozhuharov V, Litov L, Pavlov B, Petkov P, Bian JG, Chen GM, Chen HS, Jiang CH, Liang D, Liang S, Meng X, Tao J, Wang 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J, Millischer L, Rander J, Rosowsky A, Shreyber I, Titov M, Baffioni S, Beaudette F, Benhabib L, Bianchini L, Bluj M, Broutin C, Busson P, Charlot C, Daci N, Dahms T, Dobrzynski L, Elgammal S, de Cassagnac RG, Haguenauer M, Mine P, Mironov C, Ochando C, Paganini P, Sabes D, Salerno R, Sirois Y, Thiebaux C, Veelken C, Zabi A, Agram JL, Andrea J, Bloch D, Bodin D, Brom JM, Cardaci M, Chabert EC, Collard C, Conte E, Drouhin F, Ferro C, Fontaine JC, Gele D, Goerlach U, Juillot P, Karim M, Le Bihan AC, Van Hove P, Fassi F, Mercier D, Baty C, Beauceron S, Beaupere N, Bedjidian M, Bondu O, Boudoul G, Boumediene D, Brun H, Chasserat J, Chierici R, Contardo D, Depasse P, El Mamouni H, Falkiewicz A, Fay J, Gascon S, Gouzevitch M, Ille B, Kurca T, Le Grand T, Lethuillier M, Mirabito L, Perries S, Sordini V, Tosi S, Tschudi Y, Verdier P, Viret S, Lomidze D, Anagnostou G, Beranek S, Edelhoff M, Feld L, Heracleous N, Hindrichs O, Jussen R, Klein K, Merz J, Ostapchuk A, Perieanu A, Raupach F, Sammet J, Schael S, Sprenger D, Weber H, Wittmer B, Zhukov V, Ata M, Caudron J, Dietz-Laursonn E, Erdmann M, Guth A, Hebbeker T, Heidemann C, Hoepfner K, Klimkovich T, Klingebiel D, Kreuzer P, Lanske D, Lingemann J, Magass C, Merschmeyer M, Meyer A, Olschewski M, Papacz P, Pieta H, Reithler H, Schmitz SA, Sonnenschein L, Steggemann J, Teyssier D, Weber M, Bontenackels M, Cherepanov V, Davids M, Flugge G, Geenen H, Geisler M, Ahmad WH, Hoehle F, Kargoll B, Kress T, Kuessel Y, Linn A, Nowack A, Perchalla L, Pooth O, Rennefeld J, Sauerland P, Stahl A, Zoeller MH, Martin MA, Behrenhoff W, Behrens U, Bergholz M, Bethani A, Borras K, Burgmeier A, Cakir A, Calligaris L, Campbell A, Castro E, Dammann D, Eckerlin G, Eckstein D, Flossdorf A, Flucke G, Geiser A, Hauk J, Jung H, Kasemann M, Katsas R, Kleinwort C, Kluge H, Knutsson A, Kramer M, Krucker D, Kuznetsova E, Lange W, Lohmann W, Lutz B, Mankel R, Marfin I, Marienfeld M, Melzer-Pellmann IA, Meyer AB, Mnich J, Mussgiller A, Naumann-Emme S, Olzem J, Petrukhin A, Pitzl D, Raspereza A, Cipriano PMR, Rosin M, Salfeld-Nebgen J, Schmidt R, Schoerner-Sadenius T, Sen N, Spiridonov A, Stein M, Tomaszewska J, Walsh R, Wissing C, Autermann C, Blobel V, Bobrovskyi S, Draeger J, Enderle H, Erfle J, Gebbert U, Gorner M, Hermanns T, Hoing RS, Kaschube K, Kaussen G, Kirschenmann H, Klanner R, Lange J, Mura B, Nowak F, Pietsch N, Sander C, Schettler H, Schleper P, Schlieckau E, Schmidt A, Schroder M, Schum T, Stadie H, Steinbruck G, Thomsen J, Barth C, Berger J, Chwalek T, De Boer W, Dierlamm A, Dirkes G, Feindt M, Gruschke J, Guthoff M, Hackstein C, Hartmann F, Heinrich M, Held H, Hoffmann KH, Honc S, Katkov I, Komaragiri JR, Kuhr T, Martschei D, Mueller S, Muller T, Niegel M, Nurnberg A, Oberst O, Oehler A, Ott J, Peiffer T, Quast G, Rabbertz K, Ratnikov F, Ratnikova N, Renz M, Rocker S, Saout C, Scheurer A, Schieferdecker R, Schilling FP, Schmanau M, Schott G, Simonis HJ, Stober FM, Troendle D, Wagner-Kuhr J, Weiler T, Zeise M, Ziebarth EB, Daskalakis G, Geralis T, Kesisoglou S, Kyriakis A, Loukas D, Manolakos I, Markou A, Markou C, Mavrommatis C, Ntomari E, Gouskos L, Mertzimekis TJ, Panagiotou A, Saoulidou N, Stiliaris E, Evangelou I, Foudas C, Kokkas P, Manthos N, Papadopoulos I, Patras V, Triantis FA, Aranyi A, Bencze G, Boldizsar L, Hajdu C, Hidas P, Horvath D, Kapusi A, Krajczar K, Sikler F, Veszpremi V, Vesztergombi G, Beni N, Molnar J, Palinkas J, Szillasi Z, Karancsi J, Raics P, Trocsanyi ZL, Ujvari B, Beri SB, Bhatnagar V, Dhingra N, Gupta R, Jindal M, Kaur M, Kohli JM, Mehta MZ, Nishu N, Saini LK, Sharma A, Singh AP, Singh J, Singh SP, Ahuja S, Choudhary BC, Kumar A, Kumar A, Malhotra S, Naimuddin M, Ranjan K, Sharma V, Shivpuri RK, Banerjee S, Bhattacharya S, Dutta S, Gomber B, Jain S, Jain S, Khurana R, Sarkar S, Choudhury RK, Dutta D, Kailas S, Kumar V, Mohanty AK, Pant LM, Shukla P, Aziz T, Ganguly S, Guchait M, Gurtu A, Maity M, Majumder G, Mazumdar K, Mohanty GB, Parida B, Saha A, Sudhakar K, Wickramage 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Boccali T, Broccolo G, Castaldi R, D'Agnolo RT, Dell'Orso R, Fiori F, Foa L, Giassi A, Kraan A, Ligabue F, Lomtadze T, Martini L, Messineo A, Palla F, Palmonari F, Rizzi A, Serban AT, Spagnolo P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Barone L, Cavallari F, Del Re D, Diemoz M, Fanelli C, Grassi M, Longo E, Meridiani R, Micheli F, Nourbakhsh S, Organtini G, Pandolfi F, Paramatti R, Rahatlou S, Sigamani M, Soffi L, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Biino C, Botta C, Cartiglia N, Castello R, Costa M, Demaria N, Graziano A, Mariotti C, Maselli S, Migliore E, Monaco V, Musich M, Obertino MM, Pastrone N, Pelliccioni M, Potenza A, Romero A, Ruspa M, Sacchi R, Sola V, Solano A, Staiano A, Pereira AV, Belforte S, Cossutti F, Della Ricca G, Gobbo B, Marone M, Montanino D, Penzo A, Heo SG, Nam SK, Chang S, Chung J, Kim DH, Kim GN, Kim JE, Kong DJ, Park H, Ro SR, Son DC, Kim JY, Kim ZJ, Song S, Jo HY, Choi S, Gyun D, Hong B, Jo M, Kim H, Kim TJ, Lee KS, Moon DH, Park SK, Seo E, Sim KS, Choi M, Kang S, Kim H, Kim JH, Park C, Park IC, Park S, Ryu G, Cho Y, Choi Y, Choi YK, Goh J, Kim MS, Lee B, Lee J, Lee S, Seo H, Yu I, Bilinskas MJ, Grigelionis I, Janulis M, Castilla-Valdez H, De La Cruz-Burelo E, Heredia-de La Cruz I, Lopez-Fernandez R, Villalba RM, Martinez-Ortega J, Sanchez-Hernandez A, Villasenor-Cendejas LM, Moreno SC, Valencia FV, Ibarguen HAS, Linares EC, Pineda AM, Reyes-Santos MA, Krofcheck D, Bell AJ, Butler PH, Doesburg R, Reucroft S, Silverwood H, Ahmad M, Asghar MI, Hoorani HR, Khalid S, Khan WA, Khurshid T, Qazi S, Shah MA, Shoaib M, Brona G, Cwiok M, Dominik W, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Bialkowska H, Boimska B, Frueboes T, Gokieli R, Gorski M, Kazana M, Nawrocki K, Romanowska-Rybinska K, Szleper M, Wrochna G, Zalewski P, Almeida N, Bargassa P, David A, Faccioli P, Parracho PGF, Gallinaro M, Musella P, Nayak A, Pela J, Ribeiro PQ, Seixas J, Varela J, Vischia P, Belotelov I, Bunin P, Golutvin I, Kamenev A, Karjavin V, 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WH, Swanson J
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Combined results of searches for the standard model Higgs boson in pp collisions at root s=7 TeV
PHYSICS LETTERS B 2012 MAR 29; 710(1):26-48
Combined results are reported from searches for the standard model Higgs boson in proton-proton collisions at root s = 7 TeV in five Higgs boson decay modes: gamma gamma, bb, tau tau, WW, and ZZ. The explored Higgs boson mass range is 110-600 GeV. The analysed data correspond to an integrated luminosity of 4.6-4.8 fb(-1). The expected excluded mass range in the absence of the standard model Higgs boson is 118-543 GeV at 95% CL. The observed results exclude the standard model Higgs boson in the mass range 127-600 GeV at 95% CL, and in the mass range 129-525 GeV at 99% CL. An excess of events above the expected standard model background is observed at the low end of the explored mass range making the observed limits weaker than expected in the absence of a signal. The largest excess, with a local significance of 3.1 sigma, is observed for a Higgs boson mass hypothesis of 124 GeV. The global significance of observing an excess with a local significance >= 3.1 sigma anywhere in the search range 110-600 (110-145) GeV is estimated to be 1.5 sigma (2.1 sigma). More data are required to ascertain the origin of the observed excess. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.
Ascano M, Hafner M, Cekan P, Gerstberger S, Tuschl T
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Identification of RNA-protein interaction networks using PAR-CLIP
WILEY INTERDISCIPLINARY REVIEWS-RNA 2012 MAR-APR; 3(2):159-177
All mRNA molecules are subject to some degree of post-transcriptional gene regulation (PTGR) involving sequence-dependent modulation of splicing, cleavage and polyadenylation, editing, transport, stability, and translation. The recent introduction of deep-sequencing technologies enabled the development of new methods for broadly mapping interaction sites between RNA-binding proteins (RBPs) and their RNA target sites. In this article, we review crosslinking and immunoprecipitation (CLIP) methods adapted for large-scale identification of target RNA-binding sites and the respective RNA recognition elements. CLIP methods have the potential to detect hundreds of thousands of binding sites in single experiments although the separation of signal from noise can be challenging. As a consequence, each CLIP method has developed different strategies to distinguish true targets from background. We focus on photoactivatable ribonucleoside-enhanced CLIP, which relies on the intracellular incorporation of photoactivatable ribonucleoside analogs into nascent transcripts, and yields characteristic sequence changes upon crosslinking that facilitate the separation of signal from noise. The precise knowledge of the position and distribution of binding sites across mature and primary mRNA transcripts allows critical insights into cellular localization and regulatory function of the examined RBP. When coupled with other systems-wide approaches measuring transcript and protein abundance, the generation of high-resolution RBP-binding site maps across the transcriptome will broaden our understanding of PTGR and thereby lead to new strategies for therapeutic treatment of genetic diseases perturbing these processes. (C) 2011 John Wiley & Sons, Ltd.
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Pierro GA, Ross I, Savin A, Smith WH, Swanson J
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Search for the Standard Model Higgs Boson in the Decay Channel H -> ZZ -> 4l in pp Collisions at root s=7 TeV
PHYSICAL REVIEW LETTERS 2012 MAR 13; 108(11):? Article 111804
A search for a Higgs boson in the four-lepton decay channel H -> ZZ, with each Z boson decaying to an electron or muon pair, is reported. The search covers Higgs boson mass hypotheses in the range of 110 < m(H) < 600 GeV. The analysis uses data corresponding to an integrated luminosity of 4.7 fb(-1) recorded by the CMS detector in pp collisions at root s = 7 TeV from the LHC. Seventy-two events are observed with four-lepton invariant mass m(4l) > 100 GeV (with 13 below 160 GeV), while 67.1 +/- 6.0 (9.5 +/- 1.3) events are expected from background. The four-lepton mass distribution is consistent with the expectation of standard model background production of ZZ pairs. Upper limits at 95% confidence level exclude the standard model Higgs boson in the ranges of 134-158 GeV, 180-305 GeV, and 340-465 GeV. Small excesses of events are observed around masses of 119, 126, and 320 GeV, making the observed limits weaker than expected in the absence of a signal.
Bowles NP, Hill MN, Bhagat SM, Karatsoreos IN, Hillard CJ, McEwen BS
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CHRONIC, NONINVASIVE GLUCOCORTICOID ADMINISTRATION SUPPRESSES LIMBIC ENDOCANNABINOID SIGNALING IN MICE
NEUROSCIENCE 2012 MAR 1; 204(?):83-89
Limbic endocannabinoid signaling is known to be sensitive to chronic stress; however, studies investigating the impact of prolonged exposure to glucocorticoid hormones have been limited by the concurrent exposure to the stress of daily injections. The present study was designed to examine the effects of a noninvasive approach to alter plasma corticosterone (CORT) on the endocannabinoid system. More precisely, we explored the effects of a 4-week exposure to CORT dissolved in the drinking water of mice (100 mu g/ml) and measured cannabinoid CB1 receptor binding, endocannabinoid content, activity of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH), and mRNA expression of both the CB1 receptor and FAAH in both the hippocampus and amygdala. Our data demonstrate that CORT decreases CB1 receptor binding site density in both the hippocampus and amygdala and also reduced anandamide (AEA) content and increased FAAH activity within both structures. These changes in both CB1 receptor binding and FAAH activity were not accompanied by changes in mRNA expression of either the CB1 receptor or FAAH in either brain region. Interestingly, our CORT delivery regimen significantly increased 2-AG concentrations within the hippocampus, but not the amygdala. Collectively, these data demonstrate that the confounder of injection stress is sufficient to conceal the ability of protracted exposure to glucocorticoids to reduce CB1 receptor density and augment AEA metabolism within limbic structures. This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
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I, Savin A, Smith WH, Swanson J
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Search for the standard model Higgs boson in the H -> ZZ -> 2l2v channel in pp collisions at root s=7 TeV
JOURNAL OF HIGH ENERGY PHYSICS 2012 MAR; ?(3):? Article 040
A search for the standard model Higgs boson in the H -> ZZ -> 2l2v decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 fb(-1). No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440GeV range is excluded at 95% confidence level.
Aitchison JD, Rout MP
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The Yeast Nuclear Pore Complex and Transport Through It
GENETICS 2012 MAR; 190(3):855-883
Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell's genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or "Nups"), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC's role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins.