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Price JG, Idoyaga J, Salmon H, Hogstad B, Bigarella CL, Ghaffari S, Leboeuf M, Merad M
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CDKN1A regulates Langerhans cell survival and promotes T-reg cell generation upon exposure to ionizing irradiation
NATURE IMMUNOLOGY 2015 OCT; 16(10):1060-1068
Treatment with ionizing radiation (IR) can lead to the accumulation of tumor-infiltrating regulatory T cells (T-reg cells) and subsequent resistance of tumors to radiotherapy. Here we focused on the contribution of the epidermal mononuclear phagocytes Langerhans cells (LCs) to this phenomenon because of their ability to resist depletion by high-dose IR. We found that LCs resisted apoptosis and rapidly repaired DNA damage after exposure to IR. In particular, we found that the cyclin-dependent kinase inhibitor CDKN1A (p21) was overexpressed in LCs and that Cdkn1a(-/-) LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type LCs upregulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and induced an increase in T-reg cell numbers upon exposure to IR, but Cdkn1a(-/-) LCs did not. Our findings suggest a means for manipulating the resistance of LCs to IR to enhance the response of cutaneous tumors to radiotherapy.
Ewald DA, Malajian D, Krueger JG, Workman CT, Wang TJ, Tian SY, Litman T, Guttman-Yassky E, Suarez-Farinas M
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Meta-analysis derived atopic dermatitis (MADAD) transcriptome defines a robust AD signature highlighting the involvement of atherosclerosis and lipid metabolism pathways
BMC MEDICAL GENOMICS 2015 OCT 12; 8(?):? Article 60
Background: Atopic dermatitis (AD) is a common inflammatory skin disease with limited treatment options. Several microarray experiments have been conducted on lesional/LS and non-lesional/NL AD skin to develop a genomic disease phenotype. Although these experiments have shed light on disease pathology, inter-study comparisons reveal large differences in resulting sets of differentially expressed genes (DEGs), limiting the utility of direct comparisons across studies. Methods: We carried out a meta-analysis combining 4 published AD datasets to define a robust disease profile, termed meta-analysis derived AD (MADAD) transcriptome. Results: This transcriptome enriches key AD pathways more than the individual studies, and associates AD with novel pathways, such as atherosclerosis signaling (IL-37, selectin E/SELE). We identified wide lipid abnormalities and, for the first time in vivo, correlated Th2 immune activation with downregulation of key epidermal lipids (FA2H, FAR2, ELOVL3), emphasizing the role of cytokines on the barrier disruption in AD. Key AD ''classifier genes'' discriminate lesional from nonlesional skin, and may evaluate therapeutic responses. Conclusions: Our meta-analysis provides novel and powerful insights into AD disease pathology, and reinforces the concept of AD as a systemic disease.
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Reis T, Seva T, Thomas L, Vander Velde C, Vanlaer P, Wang J, Zenoni F, Beernaert K, Benucci L, Cimmino A, Crucy S, Fagot A, Garcia G, Gul M, Mccartin J, Rios AAO, Poyraz D, Ryckbosch D, Diblen SS, Sigamani M, Strobbe N, Tytgat M, Van Driessche W, Yazgan E, Zaganidis N, Basegmez S, Beluffi C, Bondu O, Bruno G, Castello R, Caudron A, Ceard L, Da Silveira GG, Delaere C, du Pree T, Favart D, Forthomme L, Giammanco A, Hollar J, Jafari A, Jez P, Komm M, Lemaitre V, Mertens A, Nuttens C, Perrini L, Pin A, Piotrzkowski K, Popov A, Quertenmont L, Selvaggi M, Marono MV, Beliy N, Caebergs T, Hammad GH, Alda WL, Alves GA, Brito L, Martins MC, Martins TD, Hensel C, Herrera CM, Moraes A, Pol ME, Teles PR, Das Chagas EBB, Carvalho W, Chinellato J, Custodio A, Da Costa EM, Damiao DD, Martins CD, De Souza SF, Guativa LMH, Malbouisson H, Figueiredo DM, Mundim L, Nogima H, Da Silva WLP, Santaolalla J, Santoro A, Sznajder A, Manganote EJT, Pereira AV, Ahuja S, Bernardes CA, Dogra S, Tomei TRFP, Gregores EM, Mercadante PG, Moon CS, Novaes SF, Padula SS, Abad DR, Vargas JCR, Aleksandrov A, Genchev V, Hadjiiska R, Iaydjiev P, Marinov A, Piperov S, Rodozov M, Stoykova S, Sultanov G, Vutova M, Dimitrov A, Glushkov I, Litov L, Pavlov B, Petkov P, Ahmad M, Bian JG, Chen GM, Chen HS, Chen M, Cheng T, Du R, Jiang CH, Plestina R, Romeo F, Shaheen SM, Tao J, Wang C, Wang Z, Zhang H, Asawatangtrakuldee C, Ban Y, Li Q, Liu S, Mao Y, Qian SJ, Wang D, Xu Z, Zhang F, Zhang L, Zou W, Avila C, Cabrera A, Sierra LFC, Florez C, Gomez JP, Moreno BG, Sanabria JC, Godinovic N, Lelas D, Pone D, Puljak I, Antunovic Z, Kovac M, Brigljevic V, Kadija K, Luetic J, Sudic L, Attikis A, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Rykaczewski H, Bodlak M, Finger M, Finger M, Ali A, Aly R, Aly S, Assran Y, Kamel AE, Lotfy A, Mahmoud MA, Masod R, Radi A, Calpas B, Kadastik M, Murumaa M, Raidal M, Tiko A, Veelken C, Eerola P, Voutilainen M, Harkonen J, Karimaki V, Kinnunen R, Lampen T, Lassila-Perini K, Lehti S, Linden T, Luukka P, Maenpaa T, Peltola T, Tuominen E, Tuominiemi J, Tuovinen E, Wendland L, Talvitie J, Tuuva T, Besancon M, Couderc F, Dejardin M, Denegri D, Fabbro B, Faure JL, Favaro C, Ferri F, Ganjour S, Givernaud A, Gras P, de Monchenault GH, Jarry P, Locci E, Maleles J, Rander J, Rosowsky A, Titov M, Zghiche A, Baffioni S, Beaudette F, Busson P, Cadamuro L, Chapon E, Charlot C, Dahms T, Davignon O, Filipovic N, Florent A, de Cassagnac RG, Mastrolorenzo L, Mine P, Naranjo IN, Nguyen M, Ochando C, Ortona G, Paganini P, Regnard S, Salerno R, Sauvan JB, Sirois Y, Strebler T, Yilmaz Y, Zabi A, Agram JL, Andrea J, Aubin A, Bloch D, Brom JM, Buttignol M, Chabert EC, Chanon N, Collard C, Conte E, Fontaine JC, Gele D, Goerlach U, Goetzmann C, Le Bihan AC, Merlin JA, Skovpen K, Van Hove P, Gadrat S, Beauceron S, Beaupere N, Bernet C, Boudoul G, Bouvier E, Brochet S, Montoya CAC, Chasserat J, Chierici R, Contardo D, Courbon B, Depasse P, El Mamouni H, Fan J, Fay J, Gascon S, Gouzevitch M, Ille B, Laktineh IB, Lethuillier M, Mirabito L, Pequegnot AL, Perries S, Alvarez JDR, Sabes D, Sgandurra L, Sordini V, Vander Donckt M, Verdier P, Viret S, Xiao H, Lomidze D, Autermann C, Beranek S, Edelhoff M, Feld L, Heister A, Kiesel MK, Klein K, Lipinski M, Ostapchuk A, Preuten M, Raupach F, Sammet J, Schael S, Schulte JF, Verlage T, Weber H, Wittmer B, Zhukov V, Ata M, Brodski M, Dietz-Laursonn E, Duchardt D, Endres M, Erdmann M, Erdweg S, Esch T, Fischer R, Guth A, Hebbeker T, Heidemann C, Hoepfner K, Klingebiel D, Knutzen S, Kreuzer P, Merschmeyer M, Meyer A, Millet P, Olschewski M, Padeken K, Papacz P, Pook T, Radziej M, Reithler H, Rieger M, Sonnenschein L, Teyssier D, Thuer S, Cherepanov V, Erdogan Y, Flugge G, Geenen H, Geisler M, Ahmad WH, Hoehle F, Kargoll B, Kress T, Kuessel Y, Kunsken A, Lingemann J, Nowack A, Nugent IM, Pistone C, Pooth O, Stahl A, Martin MA, Asin I, Bartosik N, Behnke O, Behrens U, Bell AJ, Borras K, Burgmeier A, Cakir A, Calligaris L, Campbell A, Choudhury S, Costanza F, Pardos CD, Dolinska G, Dooling S, Dorland T, Eckerlin G, Eckstein D, Eichhorn T, Flucke G, Gallo E, Garcia JG, Geiser A, Gizhko A, Gunnellini P, Hauk J, Hempel M, Jung H, Kalogeropoulos A, Karacheban O, Kasemann M, Katsas P, Kieseler J, Kleinwort C, Korol I, Lange W, Leonard J, Lipka K, Lobanov A, Mankel R, Marfin I, Melzer-Pellmann IA, Meyer AB, Mittag G, Mnich J, Mussgiller A, Naumann-Emme S, Nayak A, Ntomari E, Perrey H, Pitzl D, Placakyte R, Raspereza A, Cipriano PMR, Roland B, Sahin MO, Salfeld-Nebgen J, Saxena P, Schoerner-Sadenius T, Schroder M, Seitz C, Spannagel S, Trippkewitz KD, Wissing C, Blobel V, Vignali MC, Draeger AR, Erfle J, Garutti E, Goebel K, Gonzalez D, Gorner M, Haller J, Hoffmann M, Hoing RS, Junkes A, Kirschenmann H, Klanner R, Kogler R, Lapsien T, Lenz T, Marchesini I, Marconi D, Nowatschin D, Ott J, Peiffer T, Perieanu A, Pietsch N, Poehlsen J, Rathjens D, Sander C, Schettler H, Schleper P, Schlieckau E, Schmidt A, Seidel 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Swain SK, Bansal S, Beri SB, Bhatnagar V, Chawla R, Gupta R, Bhawandeep U, Kalsi AK, Kaur A, Kaur M, Kumar R, Mehta A, Mittal M, Nishu N, Singh JB, Walia G, Kumar A, Kumar A, Bhardwaj A, Choudhary BC, Garg RB, Kumar A, Malhotra S, Naimuddin M, Ranjan K, Sharma R, Sharma V, Banerjee S, Bhattacharya S, Chatterjee K, Dey S, Dutta S, Jain S, Jain S, Khurana R, Majumdar N, Modak A, Mondal K, Mukherjee S, Mukhopadhyay S, Roy A, Roy D, Chowdhury SR, Sarkar S, Sharan M, Abdulsalam A, Chudasama R, Dutta D, Jha V, Kumar V, Mohanty AK, Pant LM, Shukla P, Topkar A, Aziz T, Banerjee S, Bhowmik S, Chatterjee RM, Dewanjee RK, Dugad S, Ganguly S, Ghosh S, Guchait M, Gurtu A, Kole G, Kumar S, Mahakud B, Maity M, Majumder G, Mazumdar K, Mitra S, Mohanty GB, Panda B, Sarkar T, Sudhakar K, Sur N, Sutar B, Wickramage N, Sharma S, Bakhshiansohi H, Behnamian H, Etesami SM, Fahim A, Goldouzian R, Khakzad M, Najafabadi MM, Naseri M, Mehdiabadi SP, Hosseinabadi FR, Safarzadeh B, Zeinali M, Felcini M, Grunewald M, Abbrescia M, Calabria C, Caputo C, Chhibra SS, Colaleo A, Creanza D, Cristella L, De Filippis N, De Palma M, Fiore L, Iaselli G, Maggi G, Maggi M, Miniello G, My S, Nuzzo S, Pompili A, Pugliese G, Radogna R, Ranieri A, Selvaggi G, Sharma A, Silvestris L, Venditti R, Verwilligen P, Abbiendi G, Battilana C, 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, Montanari A, Navarria FL, Perrotta A, Rossi AM, Rovelli T, Siroli GP, Tosi N, Travaglini R, Cappello G, Chiorboli M, Costa S, Giordano F, Potenza R, Tricomi A, Tuve C, Barbagli G, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Gonzi S, Gori V, Lenzi P, Meschini M, Paoletti S, Sguazzoni G, Tropiano A, Viliani L, Benussi L, Bianco S, Fabbri F, Piccolo D, Calvelli V, Ferro F, Lo Vetere M, Robutti E, Tosi S, Dinardo ME, Fiorendi S, Gennai S, Gerosa R, Ghezzi A, Govoni P, Lucchini MT, Malvezzi S, Manzoni RA, Marzocchi B, Menasce D, Moroni L, Paganoni M, Pedrini D, Ragazzi S, Redaelli N, de Fatis TT, Buontempo S, Cavallo N, Di Guida S, Esposito M, Fabozzi F, Iorio AOM, Lanza G, Lista L, Meola S, Merola M, Paolucci P, Sciacca C, Thyssen F, Azzi P, Bacchetta N, Bellato M, Bisello D, Carlin R, De Oliveira ACA, Cheechia P, Dall'Osso M, Dorigo T, Dosselli U, Fantinel S, Gasparini F, Gasparini U, Gozzelino A, Laeaprara S, Margoni M, Meneguzzo AT, Pazzini J, Pozzobon N, Ronehese P, Simonetto F, Torassa E, Tosi M, Zanetti M, Zotto P, Zucchetta A, Zumerle G, Braghieri A, Gabusi M, Magnani A, Ratti SP, Re V, Riccardi C, Salvini P, Vai I, Vitulo P, Solestizi LA, Biasini M, Bilei GM, Ciangottini D, Fano L, Lariecia P, Mantovani G, Meniehelli M, Saha A, Santocchia A, Spiezia A, Androsov K, Azzurri P, Bagliesi G, Bernardini J, Boccali T, Broccolo G, Castaldi R, Ciocci MA, Dell'Orso R, Donato S, Fedi G, Fiori F, Foa L, Giassi A, Grippo MT, Ligabue F, Lomtadze T, Martini L, Messineo A, Palla F, Rizzi A, Savoy-Navarro A, Serban AT, Spagnolo P, Squillacioti P, Tenehini R, Tonelli G, Venturi A, Verdini PG, Barone L, Cavallari F, D'imperio G, Del Re D, Diemoz M, Gelli S, Jorda C, Longo E, Margaroli F, Meridiani P, Micheli F, Organtini G, Paramatti R, Preiato F, Rahatlou S, Rovelli C, Santanastasio F, Soffi L, Traczyk P, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bellan R, Biino C, Cartiglia N, Casasso S, Costa M, Covarelli R, Degano A, Demaria N, Finco L, Kiani B, Mariotti C, Maselli S, Migliore E, Monaco V, Musich M, Obertino MM, Pacher L, Pastrone N, Pelliecioni M, Angioni GLP, 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, Schizzi A, Umer T, Zanetti A, Chang S, Kropivnitskaya A, Nam SK, Kim DH, Kim GN, Kim MS, Kong DJ, Lee S, Oh YD, Sakharov A, Son DC, Kim H, Kim TJ, Ryu MS, Song S, Choi S, Go Y, Gyun D, Hong B, Jo M, Kim H, Kim Y, Lee B, Lee K, Lee KS, Lee S, Park SK, Roh Y, Yoo HD, Choi M, Kim JH, Lee JSH, Park IC, Ryu G, Choi Y, Choi YK, Goh J, Kim D, Kwon E, Lee J, Yu I, Juodagalvis A, Vaitkus J, Ibrahim ZA, Komaragiri JR, Ali MABM, Idris FM, Abdullah WATW, Linares EC, Castilla-Valdez H, De La Cruz-Burelo E, Heredia-de La Cruz I, Hernandez-Almada A, Lopez-Fernandez R, Sanchez GR, Sanchez-Hernandez A, Moreno SC, Valencia FV, Carpinteyro S, Pedraza I, Ibarguen HAS, Pineda AM, Krofcheck D, Butler PH, Reucroft S, Ahmad A, Ahmad M, Hassan Q, Hoorani HR, Khan WA, Khurshid T, Shoaib M, Bialkowska H, Bluj M, Boimska B, Frueboes T, Gorski M, Kazana M, Nawrocki K, Romanowska-Rybinska K, Szleper M, Zalewski P, Brona G, Bunkowski K, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Misiura M, Olszewski M, Walczak M, Bargassa P, Silva CBDE, Di Francesco A, Faccioli P, Parracho PGF, Gallinaro M, Iglesias LL, Nguyen F, Antunes JR, Seixas J, Toldaiev O, Vadruccio D, Varela J, Vischia P, Afanasiev S, Bunin P, Gavrilenko M, Golutvin I, Gorbunov I, Kamenev A, Karjavin V, Konoplyanikov V, Laney A, Malakhov A, Matveev V, Moisenz P, Palichik V, Perelygin V, Shmatov S, Shulha S, Skatchkov N, Smirnov V, Toriashvili T, Zarubin A, Golovtsov V, Ivanov Y, Kim V, Kuznetsova E, Levchenko P, Murzin V, Oreshkin V, Smirnov I, Sulimov V, Uvarov L, Vavilov S, Vorobyev A, Andreev Y, Dermenev A, Gninenko S, Golubev N, Karneyeu A, Kirsanov M, Krasnikov N, Pashenkov A, Tlisov D, Toropin A, Epshteyn V, Gavrilov V, Lychkovskaya N, Popov V, Pozdnyakov I, Safronov G, Spiridonov A, Vlasov E, Zhokin A, Bylinkin A, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Leonidov A, Mesyats G, Rusakov SV, Vinogradov A, Baskakov A, Belyaev A, Boos E, Dubinin M, Dudko L, Ershov A, Gribushin A, Klyukhin V, Kodolova O, Lokhtin I, Myagkov I, Obraztsov S, Petrushanko S, 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 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Colafranceschi S, D'Alfonso M, d'Enterria D, Dabrowski A, Daponte V, David A, De Gruttola M, De Guio F, De Roeck A, De Visscher S, Di Marco E, Dobson M, Dordevic M, Dupont-Sagorin N, Elliott-Peisert A, Eugster J, Franzoni G, Funk W, Gigi D, Gill K, Giordano D, Girone M, Glege F, Guida R, Gundacker S, Guthoff M, Hammer J, Hansen M, Harris P, Hegeman J, Innocente V, Janot P, Kortelainen MJ, Kousouris K, Krajczar K, Lecoq P, Lourenco C, Magini N, Malgeri L, Mannelli M, Marrouche J, Martelli A, Masetti L, Meijers F, Mersi S, Meschi E, Moortgat F, Morovic S, Mulders M, Nemallapudi MV, Neugebauer H, Orfanelli S, Orsini L, Pape L, Perez E, Petrilli A, Petrucciani G, Pfeiffer A, Piparo D, Racz A, Rolandi G, Rovere M, Ruan M, Sakulin H, Schafer C, Schwick C, Sharma A, Silva P, Simon M, Sphicas P, Spiga D, Steggemann J, Stieger B, Stoye M, Takahashi Y, Treille D, Tsirou A, Veres GI, Wardle N, Wohri HK, Zagozdzinska A, Zeuner WD, Bertl W, Deiters K, Erdmann W, Horisberger R, Ingram Q, Kaestli HC, 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Fereneek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Hughes E, Kaplan S, Elayavalli RK, Lath A, Panwalkar S, Park M, Salur S, Schnetzer S, Sheffield D, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Foerster M, Rose K, Spanier S, York A, Bouhali O, Hernandez AC, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Flanagan W, Gilmore J, Kamon T, Krutelyov V, Montalvo R, Mueller R, Osipenkov I, Pakhotin Y, Patel R, Perloff A, Roe J, Rose A, Safonov A, Suarez I, Tatarinov A, Ulmer KA, Akehurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Faulkner J, Kunori S, Lamichhane K, Lee SW, Libeiro T, Undleeb S, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Mao Y, Melo A, Sheldon P, Snook B, Tuo S, Velkovska J, Xu Q, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Li H, Lin C, Neu C, Wolfe E, Wood J, Xia F, Clarke C, Harr R, Karchin PE, Don CKK, Lamichhane P, Sturdy J, Belknap DA, Carlsmith D, Cepeda M, Christian A, Dasu S, Dodd L, Duric S, Friis E, Gomber B, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Ruggles T, Sarangi T, Savin A, Smith N, Smith WH, Taylor D, Woods N
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Comparison of the Z/gamma* plus jets to gamma plus jets cross sections in pp collisions at root s=8 TeV
JOURNAL OF HIGH ENERGY PHYSICS 2015 OCT 20; ?(10):? Article 128
A comparison of the differential cross sections for the processes Z/gamma* + jets and photon (gamma)+ jets is presented. The measurements are based on data collected with the CMS detector at root s = 8TeV corresponding to an integrated luminosity of 19.7 fb(-1). The differential cross sections and their ratios are presented as functions of p(T). The measurements are also shown as functions of the jet multiplicity. Differential cross sections are obtained as functions of the ratio of the Z/gamma* p(T) to the sum of all jet transverse momenta and of the ratio of the Z/gamma* p(T) to the leading jet transverse momentum. The data are corrected for detector effects and are compared to simulations based on several QCD calculations.
Hanna S, Beziat V, Jouanguy E, Casanova JL, Etzioni A
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A homozygous mutation of RTEL1 in a child presenting with an apparently isolated natural killer cell deficiency
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2015 OCT; 136(4):1113-1114
Czarnowicki T, Esaki H, Gonzalez J, Malajian D, Shemer A, Noda S, Talasila S, Berry A, Gray J, Becker L, Estrada Y, Xu H, Zheng XZ, Suarez-Farinas M, Krueger JG, Paller AS, Guttman-Yassky E
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Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA) 1 T(H)2/T(H)1 cell imbalance, whereas adults acquire CLA1(+) T(H)22/T(C)22 cell subsets
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2015 OCT; 136(4):941-951
Background: Identifying differences and similarities between cutaneous lymphocyte antigen (CLA)(+) polarized T-cell subsets in children versus adults with atopic dermatitis (AD) is critical for directing new treatments toward children. Objective: We sought to compare activation markers and frequencies of skin-homing (CLA(+)) versus systemic (CLA(-)) "polar'' CD4 and CD8 T-cell subsets in patients with early pediatric AD, adults with AD, and control subjects. Methods: Flow cytometry was used to measure CD69/inducible costimulator/HLA-DR frequency in memory cell subsets, as well as IFN-gamma, IL-13, IL-9, IL-17, and IL-22 cytokines, defining T(H)1/cytotoxic T(T-C) 1, T(H)2/T(C)2, TH9/T(C)9, T(H)17/T(C)17, and T(H)22/T(C)22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children less than 5 years old and 42 adults with well-characterized moderate-to-severe AD, as well as age-matched control subjects (17 children and 25 adults). Results: Selective inducible costimulator activation (P <. 001) was seen in children. CLA(+)T(H)2 T cells were markedly expanded in both children and adults with AD compared with those in control subjects, but decreases in CLA(+)T(H)1 T-cell numbers were greater in children with AD (17% vs 7.4%, P = .007). Unlike in adults, no imbalances were detected in CLA(-) T cells from pediatric patients with AD nor were there altered frequencies of T(H)22 T cells within the CLA(+) or CLA(-) compartments. adults with AD hAD increased frequencies of IL-22-producing CD4 and CD8 T cells within the skin-homing population, compared with controls (9.5% vs 4.5% and 8.6% vs 2.4%, respectively; P <. 001), as well as increased HLA-DR activation (P < .01). Conclusions: These data suggest that T(H)2 activation within skin-homing T cells might drive AD in children and that reduced counterregulation by T(H)1 T cells might contribute to excess T(H)2 activation. T(H)22 "spreading'' of AD is not seen in young children and might be influenced by immune development, disease chronicity, or recurrent skin infections.
Ye J, Yang JY, Sun YW, Zhao PZ, Gao SQ, Jung C, Qu J, Fang RX, Chua NH
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Geminivirus Activates ASYMMETRIC LEAVES 2 to Accelerate Cytoplasmic DCP2-Mediated mRNA Turnover and Weakens RNA Silencing in Arabidopsis
PLoS Pathogens 2015 OCT; 11(10):? Article e1005196
Aberrant viral RNAs produced in infected plant cells serve as templates for the synthesis of dsRNAs. The derived virus-related small interfering RNAs (siRNA) mediate cleavage of viral RNAs by post-transcriptional gene silencing (PTGS), thus blocking virus multiplication. Here, we identified ASYMMETRIC LEAVES2 (AS2) as a new component of plant P body complex which mediates mRNA decapping and degradation. We found that AS2 promotes DCP2 decapping activity, accelerates mRNA turnover rate, inhibits siRNA accumulation and functions as an endogenous suppressor of PTGS. Consistent with these findings, as2 mutant plants are resistant to virus infection whereas AS2 over-expression plants are hypersensitive. The geminivirus nuclear shuttle protein BV1 protein, which shuttles between nuclei and cytoplasm, induces AS2 expression, causes nuclear exit of AS2 to activate DCP2 decapping activity and renders infected plants more sensitive to viruses. These principles of gene induction and shuttling of induced proteins to promote mRNA decapping in the cytosol may be used by viral pathogens to weaken antiviral defenses in host plants.
McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN, Nasca C
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Mechanisms of stress in the brain
NATURE NEUROSCIENCE 2015 OCT; 18(10):1353-1363
The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.
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K, Kress M, Leonardo N, Miller DH, Neumeister N, Primavera F, Radburn-Smith BC, Shi X, Shipsey I, Silvers D, Svyatkovskiy A, Wang F, Xie W, Xu L, Zablocki J, Parashar N, Stupak J, Adair A, Akgun B, Ecklund KM, Geurts FJM, Li W, Michlin B, Padley BP, Redjimi R, Roberts J, Zabel J, Betchart B, Bodek A, de Barbaro P, Demina R, Eshaq Y, Ferbel T, Galanti M, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Hindrichs O, Khukhunaishvili A, Korjenevski S, Petrillo G, Verzetti M, Vishnevskiy D, Ciesielski R, Demortier L, Goulianos K, 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, Kaplan S, Lath A, Panwalkar S, Park M, Salur S, Schnetzer S, Sheffield D, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Rose K, Spanier S, York A, Bouhali O, Hernandez AC, Dalchenko M, De Mattia M, Dildick S, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Krutelyov V, Montalvo R, Osipenkov I, Pakhotin Y, Patel R, Perloff A, Roe J, Rose A, Safonov A, Suarez I, Tatarinov A, Ulmer KA, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Faulkner J, Kovitanggoon K, Kunori S, 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, Li H, Lin C, Neu C, Wolfe E, Wood J, Clarke C, Harr R, Karchin PE, Don CKK, Lamichhane P, Sturdy J, Belknap DA, Carlsmith D, Cepeda M, Dasu S, Dodd L, Duric S, Friis E, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Lanaro A, Lazaridis C, Levine A, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Sarangi T, Savin A, Smith WH, Taylor D, Vuosalo C, Woods N
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Search for lepton-flavour-violating decays of the Higgs boson
PHYSICS LETTERS B 2015 OCT 7; 749(?):337-362
The first direct search for lepton-flavour-violating decays of the recently discovered Higgs boson (H) is described. The search is performed in the H -> mu tau(e) and H -> mu tau(h) channels, where tau(e) and tau(h) are tau leptons reconstructed in the electronic and hadronic decay channels, respectively. The data sample used in this search was collected in pp collisions at a centre-of-mass energy of root s = 8 TeV with the CMS experiment at the CERN LHC and corresponds to an integrated luminosity of 19.7 fb(-1). The sensitivity of the search is an order of magnitude better than the existing indirect limits. A slight excess of signal events with a significance of 2.4 standard deviations is observed. The p-value of this excess at M-H = 125 GeV is 0.010. The best fit branching fraction is beta(H -> mu tau) = (0.84(-0.37)(+0.39))%. A constraint on the branching fraction, beta(H -> mu tau) < 1.51% at 95% confidence level is set. This limit is subsequently used to constrain the mu-tau Yukawa couplings to be less than 3.6 x 10(-3). (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.
Swanson MD, Boudreaux DM, Salmon L, Chugh J, Winter HC, Meagher JL, Andre S, Murphy PV, Oscarson S, Roy R, King S, Kaplan MH, Goldstein IJ, Tarbet EB, Hurst BL, Smee DF, de la Fuente C, Hoffmann HH, Xue Y, Rice CM, Schols D, Garcia JV, Stuckey JA, Gabius HJ, Al-Hashimi HM, Markovitz DM
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Engineering a Therapeutic Lectin by Uncoupling Mitogenicity from Antiviral Activity
CELL 2015 OCT 22; 163(3):746-758
A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity, while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code.
Thorek DLJ, Kramer RM, Chen Q, Jeong J, Lupu ME, Lee AM, Moynahan ME, Lowery M, Ulmert D, Zanzonico P, Deasy JO, Humm JL, Russell J
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Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 2015 OCT 1; 93(2):444-453
Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using gamma H2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360 degrees arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response. (C) 2015 Elsevier Inc. All rights reserved.