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Lanternier F, Cypowyj S, Picard C, Bustamante J, Lortholary O, Casanova JL, Puel A
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Primary immunodeficiencies underlying fungal infections
CURRENT OPINION IN PEDIATRICS 2013 DEC; 25(6):736-747
Purpose of reviewWe review the primary immunodeficiencies (PIDs) underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors.Recent findingsAn increasing number of PIDs are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia (SCN) and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of interferon- immunity underlie endemic mycoses. Inborn errors of interleukin-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis (CMC), while inborn errors of caspase recruitment domain-containing protein 9 (CARD9) immunity underlie deep dermatophytosis and invasive candidiasis.SummaryCMC, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by PIDs. Each type of infection is highly suggestive of a specific type of PID. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases.
Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, de Wit C, Kaiser FJ, Braunholz D, Medack A, Fischer M, Zimmermann ME, Tennstedt S, Graf E, Eck S, Aherrahrou Z, Nahrstaedt J, Willenborg C, Bruse P, Braenne I, Nothen MM, Hofmann P, Braund PS, Mergia E, Reinhard W, Burgdorf C, Schreiber S, Balmforth AJ, Hall AS, Bertram L, Steinhagen-Thiessen E, Li SC, Marz W, Reilly M, Kathiresan S, McPherson R, Walter U, Ott J, Samani NJ, Strom TM, Meitinger T, Hengstenberg C, Schunkert H
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Dysfunctional nitric oxide signalling increases risk of myocardial infarction
NATURE 2013 DEC 19; 504(7480):432-+
Myocardial infarction, a leading cause of death intheWesternworld(1), usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery(2). The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history(3). Nextgeneration sequencing in families with several affected individuals has revolutionized mutation identification(4). Here we report the segregation of two private, heterozygous mutations in two functionally relatedgenes, GUCY1A3 (p.Leu163Phefs*24) andCCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha 1 subunit of soluble guanylyl cyclase (alpha 1-sGC)(5), and CCT7 encodes CCT eta, a member of the tailless complex polypeptide 1 ring complex(6), which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation(7). Wedemonstratein vitro that mutations inbothGUCY1A3 and CCT7 severely reduce alpha 1-sGC as well as beta 1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxideinduced cGMP formation. Mice deficient in alpha 1-sGC protein displayed accelerated thrombus formation in themicrocirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
Chatrchyan S, Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Bergauer T, Dragicevic M, Ero J, Fabjan C, Friedl M, Fruhwirth R, Ghete VM, Hormann N, Hrubec J, Jeitler M, Kiesenhofer W, Knunz V, Krammer M, Kratschmer I, Liko D, Mikulec I, Rabady D, Rahbaran B, Rohringer C, Rohringer H, Schofbeck R, Strauss J, Taurok A, Treberer-Treberspurg W, Waltenberger W, Wulz CE, Mossolov V, Shumeiko N, Gonzalez JS, Alderweireldt S, Bansal M, Bansal S, Cornelis T, De Wolf EA, Janssen X, Knutsson A, Luyckx S, Mucibello L, Ochesanu S, Roland B, Rougny R, Staykova Z, Van Haevermaet H, Van Mechelen P, Van Remortel N, Van Spilbeeck A, Blekman F, Blyweert S, D'Hondt J, Kalogeropoulos A, Keaveney J, Lowette S, Maes M, Olbrechts A, Tavernier S, Van Doninck W, Van Mulders P, Van Onsem GP, Villella I, Caillol C, Clerbaux B, De Lentdecker G, Favart L, Gay APR, Hreus T, Leonard A, Marage PE, Mohammadi A, Pernie L, Reis T, Seva T, Thomas L, Vander Velde C, Vanlaer P, Wang J, Adler V, Beernaert K, Benucci L, Cimmino A, Costantini S, Dildick S, Garcia G, Klein B, Lellouch J, Marinov A, Mccartin J, Rios AAO, Ryckbosch D, Sigamani M, Strobbe N, Thyssen F, Tytgat M, Walsh S, Yazgan E, Zaganidis N, Basegmez S, Beluffi C, Bruno G, Castello R, Caudron A, Ceard L, Silveira G, Delaere C, du Pree T, Favart D, Forthomme L, Giammanco A, Hollar J, Jez P, Lemaitre V, Liao J, Militaru O, Nuttens C, Pagano D, Pin A, Piotrzkowski K, Popov A, Selvaggi M, Marono MV, Garcia JMV, Beliy N, Caebergs T, Daubie E, Hammad GH, Alves GA, Martins MC, Martins T, Pol ME, Souza MHG, Alda WL, Carvalho W, Chinellato J, Custodio A, Da Costa EM, Damiao DD, Martins CD, De Souza SF, Malbouisson H, Malek M, Figueiredo DM, Mundim L, Nogima H, Da Silva WLP, Santoro A, Sznajder A, Manganote EJT, Pereira AV, Bernardes CA, Dias FA, Tomei TRFP, Gregores E, Lagana C, Mercadante PG, Novaes SF, Padula SS, Genchev V, Iaydjiev P, Piperov S, Rodozov M, Sultanov G, Vutova M, Dimitrov A, Hadjiiska R, 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 X, Wang Z, Asawatangtrakuldee C, Ban Y, Guo Y, Li Q, Li W, Liu S, Mao Y, Qian SJ, Wang D, Zhang L, Zou W, Avila C, Montoya CAC, Sierra LFC, Gomez JP, Moreno BG, Sanabria JC, Godinovic N, Lelas D, Plestina R, Polic D, Puljak I, Antunovic Z, Kovac M, Brigljevic V, Kadija K, Luetic J, Mekterovic D, Morovic S, Tikvica L, Attikis A, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Finger M, Finger M, Abdelalim AA, Assran Y, Elgammal S, Kamel AE, Mahmoud MA, Radi A, Kadastik M, Muntel M, Murumaa M, Raidal M, Rebane L, Tiko A, Eerola P, Fedi G, Voutilainen M, Harkonen J, Karimaki V, Kinnunen R, Kortelainen MJ, Lampen T, Lassila-Perini K, Lehti S, Linden T, Luukka P, Maenpaa T, Peltola T, Tuominen E, Tuominiemi J, Tuovinen E, Wendland L, Tuuva T, Besancon M, Couderc F, Dejardin M, Denegri D, Fabbro B, Faure JL, Ferri F, Ganjour S, Givernaud A, Gras P, de Monchenault GH, Jarry P, Locci E, Malcles J, Millischer L, Nayak A, Rander J, Rosowsky A, Titov M, Baffioni S, Beaudette F, Benhabib L, Bluj M, Busson P, Charlot C, Daci N, Dahms T, Dalchenko M, Dobrzynski L, Florent A, de Cassagnac RG, Haguenauer M, Mine P, Mironov C, Naranjo IN, Nguyen M, Ochando C, Paganini P, Sabes D, Salerno R, Sirois Y, Veelken C, Zabi A, Agram JL, Andrea J, Bloch D, Brom JM, Chabert EC, Collard C, Conte E, Drouhin F, Fontaine JC, Gele D, Goerlach U, Goetzmann C, Juillot P, Le Bihan AC, Van Hove P, Gadrat S, Beauceron S, Beaupere N, Boudoul G, Brochet S, Chasserat J, Chierici R, Contardo D, Depasse P, El Mamouni H, Fan J, Fay J, Gascon S, Gouzevitch M, Ille B, Kurca T, Lethuillier M, Mirabito L, Perries S, Sgandurra L, Sordini V, Vander Donckt M, Verdier P, Viret S, Xiao H, Tsamalaidze Z, Autermann C, Beranek S, Bontenackels M, Calpas B, Edelhoff M, Feld L, Heracleous N, Hindrichs O, Klein K, 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, Duchardt D, Erdmann M, Fischer R, Guth A, Hebbeker T, Heidemann C, Hoepfner K, Klingebiel D, Knutzen S, Kreuzer P, Merschmeyer M, Meyer A, Olschewski M, Padeken K, Papacz P, Pieta H, Reithler H, Schmitz S, Sonnenschein L, Steggemann J, Teyssier D, Thuer S, Weber M, Cherepanov V, Erdogan Y, Flugge G, Geenen H, Geisler M, Ahmad WH, Hoehle F, Kargoll B, Kress T, Kuessel Y, Lingemann J, Nowack A, Nugent IM, Perchalla L, Pooth O, Stahl A, Asin I, Bartosik N, Behr J, Behrenhoff W, Behrens U, Bell AJ, Bergholz M, Bethani A, Borras K, Burgmeier A, Cakir A, Calligaris L, Campbell A, Choudhury S, Costanza F, Pardos CD, Dooling S, Dorland T, Eckerlin G, Eckstein D, Flucke G, Geiser A, Glushkov I, Grebenyuk A, Gunnellini P, Habib S, Hauk J, Hellwig G, Horton D, Jung H, Kasemann M, Katsas P, Kleinwort C, Kluge H, Kramer M, Krucker D, Kuznetsova E, Lange W, Leonard J, Lipka K, Lohmann W, Lutz B, Mankel R, Marfin I, Melzer-Pellmann IA, Meyer AB, Mnich J, Mussgiller A, Naumann-Emme S, Novgorodova O, Nowak F, Olzem J, Perrey H, Petrukhin A, Pitzl D, Placakyte R, Raspereza A, Cipriano PMR, Riedl C, Ron E, Sahin MO, Salfeld-Nebgen J, Schmidt R, Schoerner-Sadenius T, Sen N, Stein M, Walsh R, Wissing C, Martin MA, Blobel V, Enderle H, Erfle J, Garutti E, Gebbert U, Gorner M, Gosselink M, Haller J, Heine K, Hoing RS, Kaussen G, Kirschenmann H, Klanner R, Kogler R, Lange J, Marchesini I, Peiffer T, Pietsch N, Rathjens D, Sander C, Schettler H, Schleper P, Schlieckau E, Schmidt A, Schroder M, Schum T, Seidel M, Sibille J, Sola V, Stadie H, Steinbruck G, Thomsen J, Troendle D, Usai E, Vanelderen L, Barth C, Baus C, Berger J, Boser C, Butz E, Chwalek T, De Boer W, Descroix A, Dierlamm A, Feindt M, Guthoff M, Hartmann F, Hauth T, Held H, Hoffmann KH, Husemann U, Katkov I, Komaragiri JR, Kornmayer A, Pardo PL, Martschei D, Mozer MU, Muller T, Niegel M, Nurnberg A, Oberst O, Ott J, Quast G, Rabbertz K, Ratnikov F, Rocker S, Schilling FP, Schott G, Simonis HJ, Stober FM, Ulrich R, Wagner-Kuhr J, Wayand S, Weiler T, Zeise M, Anagnostou G, Daskalakis G, Geralis T, Kesisoglou S, Kyriakis A, Loukas D, Markou A, Markou C, Ntomari E, Topsis-giotis I, Gouskos L, Panagiotou A, Saoulidou N, Stiliaris E, Aslanoglou X, Evangelou I, Flouris G, Foudas C, Kokkas P, Manthos N, Papadopoulos I, Paradas E, Bencze G, Hajdu C, Hidas P, Horvath D, Sikler F, Veszpremi V, Vesztergombi G, Zsigmond AJ, Beni N, Czellar S, Molnar J, Palinkas J, Szillasi Z, Karancsi J, Raics P, Trocsanyi ZL, Ujvari B, Swain SK, Beri SB, Bhatnagar V, Dhingra N, Gupta R, Kaur M, Mehta MZ, Mittal M, Nishu N, Sharma A, Singh JB, Kumar A, Kumar A, Ahuja S, Bhardwaj A, Choudhary BC, Kumar A, Malhotra S, Naimuddin M, Ranjan K, Saxena P, Sharma V, Shivpuri RK, Banerjee S, Bhattacharya S, Chatterjee K, Dutta S, Gomber B, Jain S, Jain S, Khurana R, Modak A, Mukherjee S, Roy D, Sarkar S, Sharan M, Singh AP, Abdulsalam A, Dutta D, Kailas S, Kumar V, Mohanty AK, Pant LM, Shukla P, Topkar A, Aziz T, Chatterjee RM, Ganguly S, Ghosh S, Guchait M, Gurtu A, Kole G, Kumar S, Maity M, Majumder G, Mazumdar K, Mohanty GB, Parida B, Sudhakar K, Wickramage N, Banerjee S, Dugad S, Arfaei H, Bakhshiansohi H, Etesami SM, Fahim A, Jafari A, Khakzad M, Najafabadi MM, Mehdiabadi SP, Safarzadeh B, Zeinali M, Grunewald M, Abbrescia M, Barbone L, Calabria C, Chhibra SS, Colaleo A, Creanza D, De Filippis N, De Palma M, Fiore L, Iaselli G, Maggi G, Maggi M, Marangelli B, My S, Nuzzo S, Pacifico N, Pompili A, Pugliese G, Selvaggi G, Silvestris L, Singh G, Venditti R, Verwilligen P, Zito G, Abbiendi G, Benvenuti AC, Bonacorsi D, Braibant-Giacomelli S, Brigliadori L, Campanini R, Capiluppi P, Castro A, Cavallo FR, Codispoti G, Cuffiani M, Dallavalle GM, Fabbri F, Fanfani A, Fasanella D, Giacomelli P, Grandi C, Guiducci L, Marcellini S, Masetti G, Meneghelli M, Montanari A, Navarria FL, Odorici F, Perrotta A, Primavera F, Rossi AM, Rovelli T, Siroli GP, Tosi N, Travaglini R, Albergo S, Chiorboli M, Costa S, Giordano F, Potenza R, Tricomi A, Tuve C, Barbagli G, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Frosali S, Gallo E, Gonzi S, Gori V, Lenzi P, Meschini M, Paoletti S, Sguazzoni G, Tropiano A, Benussi L, Bianco S, Fabbri F, Piccolo D, Fabbricatore P, Ferretti R, Ferro F, Lo Vetere M, Musenich R, Robutti E, Tosi S, Benaglia A, Dinardo ME, Fiorendi S, Gennai S, Ghezzi A, Govoni P, Lucchini MT, Malvezzi S, Manzoni RA, Martelli A, Menasce D, Moroni L, Paganoni M, Pedrini D, Ragazzi S, Redaelli N, de Fatis TT, Buontempo S, Cavallo N, De Cosa A, Fabozzi F, Iorio AOM, Lista L, Meola S, Merola M, Paolucci P, Azzi P, Bacchetta N, Bellato M, Bisello D, Branca A, Carlin R, Checchia P, Dorigo T, Fanzago F, Galanti M, Gasparini F, Gasparini U, Giubilato P, Gozzelino A, Kanishchev K, Lacaprara S, Lazzizzera I, Margoni M, Meneguzzo AT, Passaseo M, Pazzini J, Pegoraro M, Pozzobon N, Ronchese P, Simonetto F, Torassa E, Tosi M, Vanini S, Zotto P, Zucchetta A, Zumerle G, Gabusi M, Ratti SP, Riccardi C, Vitulo P, Biasini M, Bilei GM, Fano L, Lariccia P, Mantovani G, Menichelli M, Nappi A, Romeo F, Saha A, Santocchia A, Spiezia A, Androsov K, Azzurri P, Bagliesi G, Bernardini J, Boccali T, Broccolo G, Castaldi R, Ciocci MA, D'Agnolo RT, Dell'Orso R, Fiori F, Foa L, Giassi A, Grippo MT, Kraan A, Ligabue F, Lomtadze T, Martini L, Messineo A, Moon CS, Palla F, Rizzi A, Savoy-Navarro A, Serban AT, Spagnolo P, Squillacioti P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Vernieri C, Barone L, Cavallari F, Del Re D, Diemoz M, Grassi M, Longo E, Margaroli F, Meridiani P, Micheli F, Nourbakhsh S, Organtini G, Paramatti R, Rahatlou S, Rovelli C, Soffi L, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bellan R, Biino C, Cartiglia N, Casasso S, Costa M, Degano A, Demaria N, Mariotti C, Maselli S, Migliore E, Monaco V, Musich M, Obertino MM, Pastrone N, Pelliccioni M, Potenza A, Romero A, Ruspa M, Sacchi R, Solano A, Staiano A, Tamponi U, Belforte S, Candelise V, Casarsa M, Cossutti F, Della Ricca G, Gobbo B, La Licata C, Marone M, Montanino D, Penzo A, Schizzi A, Zanetti A, Chang S, Kim TY, Nam SK, Kim DH, Kim GN, Kim JE, Kong DJ, Lee S, Oh YD, Park H, Son DC, Kim JY, Kim ZJ, Song S, Choi S, Gyun D, Hong B, Jo M, Kim H, Kim TJ, Lee KS, Park SK, Roh Y, Choi M, Kim JH, Park C, Park IC, Park S, Ryu G, Choi Y, Choi YK, Goh J, Kim MS, Kwon E, Lee B, Lee J, Lee S, Seo H, Yu I, Grigelionis I, Juodagalvis A, Castilla-Valdez H, De La Cruz-Burelo E, Heredia-de La Cruz I, Lopez-Fernandez R, Martinez-Ortega J, Sanchez-Hernandez A, Villasenor-Cendejas LM, Moreno SC, Valencia FV, Ibarguen HAS, Linares EC, Pineda AM, Reyes-Santos MA, Krofcheck D, Butler PH, Doesburg R, Reucroft S, Silverwood H, Ahmad M, Asghar MI, Butt J, Hoorani HR, Khalid S, Khan WA, Khurshid T, Qazi S, Shah MA, Shoaib M, Bialkowska H, Boimska B, Frueboes T, Gorski M, Kazana M, Nawrocki K, Romanowska-Rybinska K, Szleper M, Wrochna G, Zalewski P, Brona G, Bunkowski K, Cwiok M, Dominik W, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Misiura M, Wolszczak W, Almeida N, Bargassa P, Silva CBDE, Faccioli P, Parracho PGF, Gallinaro M, Nguyen F, Antunes JR, Seixas J, Varela J, Vischia P, Afanasiev S, Bunin P, Gavrilenko M, Golutvin I, Gorbunov I, Kamenev A, Karjavin V, Konoplyanikov V, Lanev A, Malakhov A, Matveev V, Moisenz P, Palichik V, Perelygin V, Shmatov S, Skatchkov N, Smirnov V, Zarubin A, Evstyukhin S, Golovtsov V, Ivanov Y, Kim V, Levchenko P, Murzin V, Oreshkin V, Smirnov I, Sulimov V, Uvarov L, Vavilov S, Vorobyev A, Vorobyev A, Andreev Y, Dermenev A, Gninenko S, Golubev N, Kirsanov M, Krasnikov N, Pashenkov A, Tlisov D, Toropin A, Epshteyn V, Erofeeva M, Gavrilov V, Lychkovskaya N, Popov V, Safronov G, Semenov S, Spiridonov A, Stolin V, Vlasov E, Zhokin A, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Leonidov A, Mesyats G, Rusakov SV, Vinogradov A, Belyaev A, Boos E, Dudko L, Gribushin A, Khein L, Klyukhin V, Kodolova O, Lokhtin I, Markina A, Obraztsov S, Petrushanko S, Proskuryakov A, Savrin V, Snigirev A, Azhgirey I, Bayshev I, Bitioukov S, Kachanov V, Kalinin A, Konstantinov D, Krychkine V, Petrov V, Ryutin R, Sobol A, Tourtchanovitch L, Troshin S, Tyurin N, Uzunian A, Volkov A, Adzic P, Djordjevic M, Ekmedzic M, Krpic D, Milosevic J, Aguilar-Benitez M, Maestre JA, Battilana C, Calvo E, Cerrada M, Llatas MC, Colino N, De La Cruz B, Peris AD, Vazquez DD, Bedoya CF, Ramos JPF, Ferrando A, Flix J, Fouz MC, Garcia-Abia P, Lopez OG, Lopez S, Hernandez JM, Josa MI, Merino G, De Martino EN, Pelayo JP, Olmeda AQ, Redondo I, Romero L, Santaolalla J, Soares MS, Willmott C, Albajar C, de Troconiz JF, Brun H, Cuevas J, Menendez JF, Folgueras S, Caballero IG, Iglesias LL, Gomez JP, Cifuentes JAB, Cabrillo IJ, Calderon A, Chuang SH, Campderros JC, Fernandez M, Gomez G, Sanchez JG, Graziano A, Jorda C, Virto AL, Marco J, Marco R, Rivero CM, Matorras F, Sanchez FJM, Rodrigo T, Rodriguez-Marrero AY, Ruiz-Jimeno A, Scodellaro L, Vila I, Cortabitarte RV, Abbaneo D, Auffray E, Auzinger G, 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Silva P, Simon M, Sphicas P, Spiga D, Stoye M, Tsirou A, Veres GI, Vlimant JR, Wohri HK, Worm SD, Zeuner WD, Bertl W, Deiters K, Erdmann W, Gabathuler K, Horisberger R, Ingram Q, Kaestli HC, Konig S, Kotlinski D, Langenegger U, Renker D, Rohe T, Bachmair F, Bani L, Bianchini L, Bortignon P, Buchmann MA, Casal B, Chanon N, Deisher A, Dissertori G, Dittmar M, Donega M, Dunser M, Eller P, Freudenreich K, Grab C, Hits D, Lecomte P, Lustermann W, Mangano B, Marini AC, del Arbol PMR, Meister D, Mohr N, Moortgat F, Nageli C, Nef P, Nessi-Tedaldi F, Pandolfi F, Pape L, Pauss F, Peruzzi M, Quittnat M, Ronga FJ, Rossini M, Sala L, Sanchez AK, Starodumov A, Stieger B, Takahashi M, Tauscher L, Thea A, Theofilatos K, Treille D, Urscheler C, Wallny R, Weber HA, Amsler C, Chiochia V, Favaro C, Rikova MI, Kilminster B, Mejias BM, Robmann P, Snoek H, Taroni S, Verzetti M, Yang Y, Cardaci M, Chen KH, Ferro C, Kuo CM, Li SW, Lin W, Lu YJ, Volpe R, Yu SS, Bartalini P, Chang P, Chang YH, Chang YW, Chao Y, 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Flowers K, Geffert P, George C, Golf F, Incandela J, Justus C, Kovalskyi D, Krutelyov V, Villalba RM, Mccoll N, Pavlunin V, Richman J, Rossin R, Stuart D, To W, West C, Apresyan A, Bornheim A, Bunn J, Chen Y, Di Marco E, Duarte J, Kcira D, Ma Y, Mott A, Newman HB, Pena C, Rogan C, Spiropulu M, Timciuc V, Veverka J, Wilkinson R, Xie S, Zhu RY, Azzolini V, Calamba A, Carroll R, Ferguson T, Iiyama Y, Jang DW, Liu YF, Paulini M, Russ J, Vogel H, Vorobiev I, Cumalat JP, Drell BR, Ford WT, Gaz A, Lopez EL, Nauenberg U, Smith JG, Stenson K, Ulmer KA, Wagner SR, Alexander J, Chatterjee A, Eggert N, Gibbons LK, Hopkins W, Khukhunaishvili A, Kreis B, Mirman N, Nicolas Kaufman G, Patterson JR, Ryd A, Salvati E, Sun W, Teo WD, Thom J, Thompson J, Tucker J, Weng Y, Winstrom L, Wittich P, Winn D, Abdullin S, Albrow M, Anderson J, Apollinari G, Bauerdick LAT, Beretvas A, Berryhill J, Bhat PC, Burkett K, Butler JN, Chetluru V, Cheung HWK, Chlebana F, Cihangir S, Elvira VD, Fisk I, Freeman J, Gao Y, Gottschalk E, Gray L, Green D, Gutsche O, Hare D, Harris RM, Hirschauer J, Hooberman B, Jindariani S, Johnson M, Joshi U, Kaadze K, Klima B, Kunori S, Kwan S, Linacre J, Lincoln D, Lipton R, Lykken J, Maeshima K, Marraffino JM, Outschoorn VIM, Maruyama S, Mason D, McBride P, Mishra K, Mrenna S, Musienko Y, Newman-Holmes C, O'Dell V, Prokofyev O, Ratnikova N, Sexton-Kennedy E, Sharma S, Spalding WJ, Spiegel L, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Vidal R, Whitmore J, Wu W, Yang F, Yun JC, Acosta D, Avery P, Bourilkov D, Chen M, Cheng T, Das S, De Gruttola M, Di Giovanni GP, Dobur D, Drozdetskiy A, Field RD, Fisher M, Fu Y, Furic IK, 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, Skhirtladze N, Snowball M, Yelton J, Zakaria M, Gaultney V, Hewamanage S, Linn S, Markowitz P, Martinez G, Rodriguez JL, Adams T, Askew A, Bochenek J, Chen J, Diamond B, Haas J, Hagopian S, Hagopian V, Johnson KF, Prosper H, Veeraraghavan V, Weinberg M, Baarmand MM, Dorney B, Hohlmann M, Kalakhety H, Yumiceva F, Adams MR, Apanasevich L, Bazterra VE, Betts RR, Bucinskaite I, Callner J, Cavanaugh R, Evdokimov O, Gauthier L, Gerber CE, Hofman DJ, Khalatyan S, Kurt P, Lacroix F, Moon DH, O'Brien C, Silkworth C, Strom D, Turner P, Varelas N, Akgun U, Albayrak EA, Bilki B, Clarida W, Dilsiz K, Duru F, Griffiths S, Merlo JP, Mermerkaya H, Mestvirishvili A, Moeller A, Nachtman J, Newsom CR, Ogul H, Onel Y, Ozok F, Sen S, Tan P, Tiras E, Wetzel J, Yetkin T, Yi K, Barnett BA, Blumenfeld B, Bolognesi S, Giurgiu G, Gritsan AV, Hu G, Maksimovic P, Martin C, Swartz M, Whitbeck A, Baringer P, Bean A, Benelli G, Kenny RP, Murray M, Noonan D, Sanders S, Stringer R, Wood JS, Barfuss AF, Chakaberia I, Ivanov A, Khalil S, Makouski M, Maravin Y, Saini LK, Shrestha S, Svintradze I, Gronberg J, Lange D, Rebassoo F, Wright D, Baden A, Calvert B, Eno SC, Gomez JA, Hadley NJ, Kellogg RG, Kolberg T, Lu Y, Marionneau M, Mignerey AC, Pedro K, Peterman A, Skuja A, Temple J, Tonjes MB, Tonwar SC, Apyan A, Bauer G, Busza W, Cali IA, Chan M, Di Matteo L, Dutta V, Ceballos GG, Goncharov M, Gulhan D, Kim Y, Klute M, Lai YS, Levin A, Luckey PD, Ma T, Nahn S, Paus C, Ralph D, Roland C, Roland G, Stephans GSF, Stockli F, Sumorok K, Velicanu D, Wolf R, Wyslouch B, Yang M, Yilmaz Y, Yoon AS, Zanetti M, Zhukova V, Dahmes B, De Benedetti A, Gude A, Haupt J, Kao SC, Klapoetke K, Kubota Y, Mans J, Pastika N, Rusack R, Sasseville M, Singovsky A, Tambe N, Turkewitz J, Acosta JG, Cremaldi LM, Kroeger R, Oliveros S, Perera L, Rahmat R, Sanders DA, Summers D, Avdeeva E, Bloom K, Bose S, Claes DR, Dominguez A, Eads M, Suarez RG, Keller J, Kravchenko I, Lazo-Flores J, Malik S, Meier F, Snow GR, Dolen J, Godshalk A, Iashvili I, Jain S, Kharchilava A, Kumar A, Rappoccio S, Wan Z, Alverson G, Barberis E, Baumgartel D, Chasco M, Haley J, Massironi A, Nash D, Orimoto T, Trocino D, Wood D, Zhang J, Anastassov A, Hahn KA, Kubik A, Lusito L, Mucia N, Odell N, Pollack B, Pozdnyakov A, Schmitt M, Stoynev S, Sung K, Velasco M, Won S, Berry D, Brinkerhoff A, Chan KM, Hildreth M, Jessop C, Karmgard DJ, Kolb J, Lannon K, Luo W, Lynch S, Marinelli N, Morse DM, Pearson T, Planer M, Ruchti R, Slaunwhite J, Valls N, Wayne M, Wolf M, Antonelli L, Bylsma B, Durkin LS, Hill C, Hughes R, Kotov K, Ling TY, Puigh D, Rodenburg M, Smith G, Vuosalo C, Winer BL, Wolfe H, Berry E, Elmer P, Halyo V, Hebda P, Hegeman J, Hunt A, Jindal P, Koay SA, Lujan P, Marlow D, Medvedeva T, Mooney M, Olsen J, Piroue P, Quan X, Raval A, Saka H, Stickland D, Tully C, Werner JS, Zenz SC, Zuranski A, Brownson E, Lopez A, Mendez H, Vargas JER, Alagoz E, Benedetti D, Bolla G, Bortoletto D, De Mattia M, Everett A, Hu Z, Jones M, Jung K, Koybasi O, Kress M, Leonardo N, Pegna DL, Maroussov V, Merkel P, Miller DH, Neumeister N, Shipsey I, Silvers D, Svyatkovskiy A, Wang F, Xie W, Xu L, Yoo HD, Zablocki J, Zheng Y, Parashar N, Adair A, Akgun B, Ecklund KM, Geurts FJM, Li W, Michlin B, Padley BP, Redjimi R, Roberts J, Zabel J, Betchart B, Bodek A, Covarelli R, de Barbaro P, Demina R, Eshaq Y, Ferbel T, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Miner DC, Petrillo G, 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, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Cerizza G, Hollingsworth M, Rose K, Spanier S, Yang ZC, York A, Bouhali O, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, Suarez I, Tatarinov A, Toback D, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Kovitanggoon K, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Lin C, Neu C, Wood J, Gollapinni S, Harr R, Karchin PE, Don CKK, Lamichhane P, Sakharov A, Belknap DA, Borrello L, Carlsmith D, Cepeda M, Dasu S, Duric S, Friis E, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Klukas J, Lanaro A, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Sarangi T, Savin A, Smith WH, Swanson J
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Jet and underlying event properties as a function of charged-particle multiplicity in proton-proton collisions at root s=7 TeV
EUROPEAN PHYSICAL JOURNAL C 2013 DEC 11; 73(12):? Article 2674
Characteristics of multi-particle production in proton-proton collisions at root s = 7 TeV are studied as a function of the charged-particle multiplicity, N (ch). The produced particles are separated into two classes: those belonging to jets and those belonging to the underlying event. Charged particles are measured with pseudorapidity |eta|< 2.4 and transverse momentum p (T)> 0.25 GeV/c. Jets are reconstructed from charged-particles only and required to have p (T)> 5 GeV/c. The distributions of jet p (T), average p (T) of charged particles belonging to the underlying event or to jets, jet rates, and jet shapes are presented as functions of N (ch) and compared to the predictions of the pythia and herwig event generators. Predictions without multi-parton interactions fail completely to describe the N (ch)-dependence observed in the data. For increasing N (ch), pythia systematically predicts higher jet rates and harder p (T) spectra than seen in the data, whereas herwig shows the opposite trends. At the highest multiplicity, the data-model agreement is worse for most observables, indicating the need for further tuning and/or new model ingredients.
Kost RG, Lee LM, Yessis J, Wesley RA, Henderson DK, Coller BS
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Assessing Participant-Centered Outcomes to Improve Clinical Research
NEW ENGLAND JOURNAL OF MEDICINE 2013 DEC 5; 369(23):2179-2181
Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, Minder JL, Mercan F, Wang E, Eckersley-Maslin MA, Campbell AE, Kawaoka S, Shareef S, Zhu Z, Kendall J, Muhar M, Haslinger C, Yu M, Roeder RG, Wigler MH, Blobel GA, Zuber J, Spector DL, Young RA, Vakoc CR
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Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation
GENES & DEVELOPMENT 2013 DEC 15; 27(24):2648-2662
Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in similar to 3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.
Xiao HX, Liu L, Zhu QY, Tan ZW, Yu WB, Tang X, Zhan DW, Du YH, Wang HB, Liu D, Li ZX, Yuen KY, Ho DD, Gao GF, Chen ZW
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A Replicating Modified Vaccinia Tiantan Strain Expressing an Avian-Derived Influenza H5N1 Hemagglutinin Induce Broadly Neutralizing Antibodies and Cross-Clade Protective Immunity in Mice
PLOS ONE 2013 DEC 17; 8(12):? Article e83274
To combat the possibility of a zoonotic H5N1 pandemic in a timely fashion, it is necessary to develop a vaccine that would confer protection against homologous and heterologous human H5N1 influenza viruses. Using a replicating modified vaccinia virus Tian Tan strain (MVTT) as a vaccine vector, we constructed MVTTHA-QH and MVTTHA-AH, which expresses the H5 gene of a goose-derived Qinghai strain A/Bar-headed Goose/Qinghai/1/2005 or human-derived Anhui Strain A/Anhui/1/2005. The immunogenicity profiles of both vaccine candidates were evaluated. Vaccination with MVTTHA-QH induced a significant level of neutralizing antibodies (Nabs) against a homologous strain and a wide range of H5N1 pseudoviruses (clades 1, 2.1, 2.2, 2.3.2, and 2.3.4). Neutralization tests (NT) and Haemagglutination inhibition (HI) antibodies inhibit the live autologous virus as well as a homologous A/Xingjiang/1/2006 and a heterologous A/Vietnam/1194/2004, representing two human isolates from clade 2.2 and clade 1, respectively. Importantly, mice vaccinated with intranasal MVTTHA-QH were completely protected from challenge with lethal dosages of A/Bar-headed Goose/Qinghai/1/2005 and the A/Viet Nam/1194/2004, respectively, but not control mice that received a mock MVTTS vaccine. However, MVTTHA-AH induced much lower levels of NT against its autologous strain. Our results suggest that it is feasible to use the H5 gene from A/Bar-headed Goose/Qinghai/1/2005 to construct an effective vaccine, when using MVTT as a vector, to prevent infections against homologous and genetically divergent human H5N1 influenza viruses.
Shahbazi MN, Megias D, Epifano C, Akhmanova A, Gundersen GG, Fuchs E, Perez-Moreno M
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CLASP2 interacts with p120-catenin and governs microtubule dynamics at adherens junctions
JOURNAL OF CELL BIOLOGY 2013 DEC 23; 203(6):1043-1061
Classical cadherins and their connections with microtubules (MTs) are emerging as important determinants of cell adhesion. However, the functional relevance of such interactions and the molecular players that contribute to tissue architecture are still emerging. In this paper, we report that the MT plus end-binding protein CLASP2 localizes to adherens junctions (AJs) via direct interaction with p120-catenin (p120) in primary basal mouse keratinocytes. Reductions in the levels of p120 or CLASP2 decreased the localization of the other protein to cell-cell contacts and altered AJ dynamics and stability. These features were accompanied by decreased MT density and altered MT dynamics at intercellular junction sites. Interestingly, CLASP2 was enriched at the cortex of basal progenitor keratinocytes, in close localization to p120. Our findings suggest the existence of a new mechanism of MT targeting to AJs with potential functional implications in the maintenance of proper cell-cell adhesion in epidermal stem cells.
Hill MN, Bierer LM, Makotkine I, Golier JA, Galea S, McEwen BS, Hillard CJ, Yehuda R
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Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the world trade center attacks
PSYCHONEUROENDOCRINOLOGY 2013 DEC; 38(12):2952-2961
Endocannabinoid (eCB) signaling has been identified as a modulator of adaptation to stress, and is integral to basal and stress-induced glucocorticoid regulation. Furthermore, interactions between eCBs and glucocorticoids have been shown to be necessary for the regulation of emotional memories, suggesting that eCB function may relate to the development of post-traumatic stress disorder (PTSD). To examine this, plasma eCBs were measured in a sample (n = 46) drawn from a population-based cohort selected for physical proximity to the World Trade Center (WTC) at the time of the 9/11 attacks. Participants received a structured diagnostic interview and were grouped according to whether they met diagnostic criteria for PTSD (no PTSD, n = 22; lifetime diagnosis of PTSD = 24). eCB content (2-arachidonoylglycerol (2-AG) and anandamide (AEA)) and cortisol were measured from 8 a.m. plasma samples. Circulating 2-AG content was significantly reduced among individuals meeting diagnostic criteria for PTSD. The effect of reduced 2-AG content in PTSD remained significant after controlling for the stress of exposure to the WTC collapse, gender, depression and alcohol abuse. There were no significant group differences for AEA or cortisol levels; however, across the whole sample AEA levels positively correlated with circulating cortisol, and AEA levels exhibited a negative relationship with the degree of intrusive symptoms within the PTSD sample. This report shows that PTSD is associated with a reduction in circulating levels of the eCB 2-AG. Given the role of 2-AG in the regulation of the stress response, these data support the hypothesis that deficient eCB signaling may be a component of the glucocorticoid dysregulation associated with PTSD. The negative association between AEA levels and intrusive symptoms is consistent with animal data indicating that reductions in AEA promote retention of aversive emotional memories. Future work will aim to replicate these findings and extend their relevance to clinical pathophysiology, as well as to neuroendocrine and molecular markers of PTSD. (C) 2013 Elsevier Ltd. All rights reserved.
Faria NA, Miragaia M, de Lencastre H
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Massive Dissemination of Methicillin Resistant Staphylococcus aureus in Bloodstream Infections in a High MRSA Prevalence Country: Establishment and Diversification of EMRSA-15
MICROBIAL DRUG RESISTANCE 2013 DEC 1; 19(6):483-490
Portugal is the European country with the highest prevalence of methicillin resistant Staphylococcus aureus (MRSA), in which EMRSA-15 (ST22-IVh) has been the dominant clone since soon after its introduction in Portuguese hospitals in 2001. In this study, we intend to not only, assess the evolution of the invasive MRSA in Portuguese hospitals, but also to evaluate the invasive methicillin susceptible S. aureus (MSSA) population and the relationship between both populations. In the current study, two major MRSA clones were identified: EMRSA-15 that has been dominant for more than 10 years and accounts for 75% of the MRSA isolates, and ST105-II, a clone related with the New York/Japan clone (ST5-II). In contrast, among MSSA, several clonal backgrounds were identified. Despite of the massive predominance of EMRSA-15 in the last decade, an increase in spa diversity has been observed in the last few years, which suggests a recent and local diversification of this clone. Interestingly, MRSA and MSSA populations with related clonal backgrounds appear to have increased as a result of the dissemination of MRSA to the community environment.
Chatrchyan S, Khachatryan V, Sirunyan A, Tumasyan A, Adam W, Bergauer T, Dragicevic M, Ero J, Fabjan C, Friedl M, Fruhwirth R, Ghete VM, Hormann N, Hrubec J, Jeitler M, Kiesenhofer W, Knunz V, Krammer M, Kratschmer I, Liko D, Mikulec I, Rabady D, Rahbaran B, Rohringer C, Rohringer H, Schofbeck R, Strauss J, Taurok A, Treberer-Treberspurg W, Waltenberger W, Wulz CE, Mossolov V, Shumeiko N, Suarez Gonzalez J, Alderweireldt S, Bansal M, Bansal S, Cornelis T, De Wolf EA, Janssen X, Knutsson A, Luyckx S, Mucibello L, Ochesanu S, Roland B, Rougny R, Staykova Z, Van Haevermaet H, Van Mechelen P, Van Remortel N, Van Spilbeeck A, Blekman F, Blyweert S, D'Hondt J, Kalogeropoulos A, Keaveney J, Lowette S, Maes M, Olbrechts A, Tavernier S, Van Doninck W, Van Mulders P, Van Onsem GP, Villella I, Caillol C, Clerbaux B, De Lentdecker G, Favart L, Gay APR, Hreus T, Leonard A, Marage PE, Mohammadi A, Pernis L, Reis T, Seva T, Thomas L, Vander Velde C, Vanlaer P, Wang J, Adler V, Beernaert K, Benucci L, 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Search for top-squark pair production in the single-lepton final state in pp collisions at
EUROPEAN PHYSICAL JOURNAL C 2013 DEC 21; 73(12):?
This paper presents a search for the pair production of top squarks in events with a single isolated electron or muon, jets, large missing transverse momentum, and large transverse mass. The data sample corresponds to an integrated luminosity of 19.5 fb(-1) of pp collisions collected in 2012 by the CMS experiment at the LHC at a center-of-mass energy of . No significant excess in data is observed above the expectation from standard model processes. The results are interpreted in the context of supersymmetric models with pair production of top squarks that decay either to a top quark and a neutralino or to a bottom quark and a chargino. For small mass values of the lightest supersymmetric particle, top-squark mass values up to around 650 GeV are excluded.