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Czarnowicki T, He HY, Wen HC, Hashim PW, Nia JK, Malik K, Estrada Y, Kimmel GW, Taliercio M, Krueger JG, Guttman-Yassky E
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Alopecia areata is characterized by expansion of circulating Th2/Tc2/Th22, within the skin-homing and systemic T-cell populations
ALLERGY 2018 MAR; 73(3):713-723
BackgroundCharacterizing blood profile of alopecia areata (AA) is important not only for treatment advancements, but also for possibly identifying peripheral biomarkers that will eliminate the need for scalp biopsies. We aimed to compare frequencies of skin homing (CLA(+)) vs systemic (CLA(-)) polar CD4(+) and CD8(+) and activated T-cell subsets in AA vs atopic dermatitis (AD) and control blood. MethodsFlow cytometry was used to measure IFN-, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4(+) and CD8(+) T cells. Inducible co-stimulator molecule (ICOS) and HLA-DR were used to define mid- and long-term T-cell activation. We compared peripheral blood from 32 moderate-to-severe AA adults with 43 moderate-to-severe AD patients and 30 age-matched controls. ResultsAA patients had increased CLA(+)/CLA(-) Th2 (P<.007), CLA(+) Tc2 (P=.04), and CLA(+) Th22 (P<.05) frequencies than controls. Except of CLA(-) Tc1 cells (P=.03), IFN- levels were mostly similar between AA, AD, and controls (P>.1). ICOS and HLA-DR activation were significantly higher in AA than controls (P<.05). T regulatory cells were significantly decreased in AA patients than controls (P<.01) and were correlated with activated CD8(+) T cells and with multiple cytokine subsets (P<.05). While Th2 and Tc2 clustered with disease severity, IFN- producing cells were linked with AA duration. ConclusionsAlopecia areata is accompanied by Th2/Tc2 activation in skin-homing and systemic subsets, correlating with disease severity, while IFN- is linked to disease chronicity. These data hint for a possible role of diverse T-cells subsets in disease pathogenesis and emphasize the systemic nature of AA supporting the need for systemic therapeutic strategies in severe patients.
Wagh K, Seaman MS, Zingg M, Fitzsimons T, Barouch DH, Burton DR, Connore M, Ho DD, Mascola JR, Nussenzweig MC, Ravetch J, Gautam R, Martin MA, Montefiori DC, Korber B
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Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections
PLOS PATHOGENS 2018 MAR; 14(3):? Article e1006860
There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10 mu g/ml total for bnAbs and combinations, and 5 mu g/ml for bispecifics. We used IC80 breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (similar to 98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95-97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa.
Kara EE, Bastow CR, McKenzie DR, Gregor CE, Fenix KA, Babb R, Norton TS, Zotos D, Rodda LB, Hermes JR, Bourne K, Gilchrist DS, Nibbs RJ, Alsharifi M, Vinuesa CG, Tarlinton DM, Brink R, Hill GR, Cyster JG, Comerford I, McColl SR
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Atypical chemokine receptor 4 shapes activated B cell fate
JOURNAL OF EXPERIMENTAL MEDICINE 2018 MAR; 215(3):801-813
Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.
Abel L, Fellay J, Haas DW, Schurr E, Srikrishna G, Urbanowski M, Chaturvedi N, Srinivasan S, Johnson DH, Bishai WR
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Genetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives
LANCET INFECTIOUS DISEASES 2018 MAR; 18(3):E64-E75
Tuberculosis is an ancient human disease, estimated to have originated and evolved over thousands of years alongside modern human populations. Despite considerable advances in disease control, tuberculosis remains one of the world's deadliest communicable diseases with 10 million incident cases and 1.8 million deaths in 2015 alone based on the annual WHO report, due to inadequate health service resources in less-developed regions of the world, and exacerbated by the HIV/AIDS pandemic and emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Recent findings from studies of tuberculosis infection and of patients with Mendelian predisposition to severe tuberculosis have started to reveal human loci influencing tuberculosis outcomes. In this Review, we assess the current understanding of the contribution of host genetics to disease susceptibility and to drug treatment. Despite remarkable progress in technology, only a few associated genetic variants have so far been identified, strongly indicating the need for larger global studies that investigate both common and under-represented rare variants to develop new approaches to combat the disease. Pharmacogenomic discoveries are also likely to lead to more efficient drug design and development, and ultimately safer and more effective therapies for tuberculosis.
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Vannerom D, Yonamine R, Zenoni F, Zhang F, Cornelis T, Dobur D, Fagot A, Gul M, Khvastunov I, Poyraz D, Roskas C, Salva S, Tytgat M, Verbeke W, Zaganidis N, Bakhshiansohi H, Bondu O, Brochet S, Bruno G, Caputo C, Caudron A, David P, De Visscher S, Delaere C, Delcourt M, Francois B, Giammanco A, Komm M, Krintiras G, Lemaitre V, Magitteri A, Mertens A, Musich M, Piotrzkowski K, Quertenmont L, Saggio A, Marono MV, Wertz S, Zobec J, Alda WL, Alves FL, Alves GA, Brito L, Martins MC, Hensel C, Moraes A, Pol ME, Teles PR, Das Chagas EBB, Carvalho W, Chinellato J, Coelho E, Da Costa EM, Da Silveira GG, Damiao DD, De Souza SF, Guativa LMH, Malbouisson H, De Almeida MM, Herrera CM, Mundim L, Nogima H, Rosas LJS, Santoro A, Sznajder A, Thiel M, Manganote EJT, De Araujo FTD, Pereira AV, Ahuja S, Bernardes CA, Tomei TRFP, Gregores EM, Mercadante PG, Novaes SF, Padula SS, Abad DR, Vargas JCR, Aleksandrov A, Hadjiiska R, Iaydjiev P, Misheva M, Rodozov M, Shopova M, Sultanov G, Dimitrov A, Litov L, Pavlov B, Petkov P, Fang W, Gao X, Yuan L, Ahmad M, Bian JG, Chen GM, Chen HS, Chen M, Chen Y, Jiang CH, Leggat D, Liao H, Liu Z, Romeo F, Shaheen SM, Spiezia A, Tao J, Wang C, Wang Z, Yazgan E, Zhang H, Zhang S, Zhao J, Ban Y, Chen G, Li J, Li Q, Liu S, Mao Y, Qian SJ, Wang D, Xu Z, Wang Y, Avila C, Cabrera A, Sierra LFC, Florez C, Hernandez CFG, Alvarez JDR, Delgado MAS, Courbon B, Godinovic N, Lelas D, Puljak I, Cipriano PMR, Sculac T, Antunovic Z, Kovac M, Brigljevic V, Ferencek D, Kadija K, Mesic B, Starodumov A, Susa T, Ather MW, Attikis A, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Rykaczewski H, Finger M, Finger M, Jarrin EC, El-Khateeb E, Elgammal S, Mohamed A, Dewanjee RK, Kadastik M, Perrini L, Raidal M, Tiko A, Veelken C, Eerola P, Kirschenmann H, Pekkanen J, Voutilainen M, Havukainen J, Heikkila JK, Jarvinen T, Karimaki V, Kinnunen R, Lampen T, Lassila-Perini K, Laurila S, Lehti S, Linden T, Luukka P, Siikonen H, Tuominen E, Tuominiemi J, Tuuva T, Besancon M, Couderc F, Dejardin M, Denegri D, Faure JL, Ferri F, Ganjour S, Ghosh S, Gras P, de Monchenault GH, Jarry P, Kucher I, Leloup C, Locci E, Machet M, Malcles J, Negro G, Rander J, Rosowsky A, Sahin MO, Titov M, Abdulsalam A, Amendola C, Antropov I, Baffioni S, Beaudette F, Busson P, Cadamuro L, Charlot C, de Cassagnac RG, Jo M, Lisniak S, Lobanov A, Blanco JM, Nguyen M, Ochando C, Ortona G, Paganini P, Pigard P, Salerno R, Sauvan JB, Sirois Y, Leiton AGS, Strebler T, Yilmaz Y, Zabi A, Zghiche A, Agram JL, Andrea J, Bloch D, Brom JM, Buttignol M, Chabert EC, Chanon N, Collard C, Conte E, Coubez X, Fontaine JC, Gele D, Goerlach U, Jansova M, Le Bihan AC, Tonon N, Van Hove P, Gadrat S, Beauceron S, Bernet C, Boudoul G, Chierici R, Contardo D, Depasse P, El Mamouni H, Fay J, Finco L, Gascon S, Gouzevitch M, Grenier G, Ille B, Lagarde F, Laktineh IB, Lethuillier M, Mirabito L, Pequegnot AL, Perries S, Popov A, Sordini V, Donckt MV, Viret S, Toriashvili T, Tsamalaidze Z, Autermann C, Feld L, Kiesel MK, Klein K, Lipinski M, Preuten M, Schomakers C, Schulz J, Teroerde M, Zhukov V, Albert A, Dietz-Laursonn E, Duchardt D, Endres M, Erdmann M, Erdweg S, Esch T, Fischer R, Guth A, Hamer M, Hebbeker T, Heidemann C, Hoepfner K, Knutzen S, Merschmeyer M, Meyer A, Millet P, Mukherjee S, Pook T, Radziej M, Reithler H, Rieger M, Scheuch F, Teyssier D, Thuer S, Flugge G, Kargoll B, Kress T, Kunsken A, Muller T, Nehrkorn A, Nowack A, Pistone C, Pooth O, Stahl A, Martin MA, Arndt T, Asawatangtrakuldee C, Beernaert K, Behnke O, Behrens U, Martinez AB, Bin Anuar AA, Borras K, Botta V, Campbell A, Connor P, Contreras-Campana C, Costanza F, Pardos CD, Eckerlin G, Eckstein D, Eichhorn T, Eren E, Gallo E, Garcia JG, Geiser A, Luyando JMG, Grohsjean A, Gunnellini P, Guthoff M, Harb A, Hauk J, Hempel M, Jung H, Kasemann M, Keaveney J, Kleinwort C, Korol I, Krucker D, Lange W, Lelek A, Lenz T, Leonard J, Lipka K, Lohmann W, Mankel R, Melzer-Pellmann IA, Meyer AB, Mittag G, Mnich J, Mussgiller A, Ntomari E, Pitzl D, Raspereza A, Savitskyi M, Saxena P, Shevchenko R, Stefaniuk N, Van Onsem GP, Walsh R, Wen Y, Wichmann K, Wissing C, Zenaiev O, Aggleton R, Bein S, Blobel V, Vignali MC, Dreyer T, Garutti E, Gonzalez D, Haller J, Hinzmann A, Hoffmann M, Karavdina A, Klanner R, Kogler R, Kovalchuk N, Kurz S, Lapsien T, Marconi D, Meyer M, Niedziela M, Nowatschin D, Pantaleo F, Peiffer T, Perieanu A, Scharf C, Schleper P, Schmidt A, Schumann S, Schwandt J, Sonneveld J, Stadie H, Steinbruck G, Stober FM, Stover M, Tholen H, Troendle D, Usai E, Vanhoefer A, Vormwald B, Akbiyik M, Barth C, Baselga M, Baur S, Butz E, Caspart R, Chwalek T, Colombo F, De Boer W, Dierlamm A, Faltermann N, Freund B, Friese R, Giffels M, Harrendorf MA, Hartmann F, Heindl SM, Husemann U, Kassel F, Kudella S, Mildner H, Mozer MU, Muller T, Plagge M, Quast G, Rabbertz K, Schroder M, Shvetsov I, Sieber G, Simonis HJ, Ulrich R, Wayand S, Weber M, Weiler T, Williamson S, Wohrmann C, Wolf R, Anagnostou G, Daskalakis G, Geralis T, Kyriakis A, Loukas D, Topsis-Giotis I, Karathanasis G, Kesisoglou S, Panagiotou A, Saoulidou N, Kousouris K, Evangelou I, Foudas C, Gianneios P, Katsoulis P, Kokkas P, Mallios S, Manthos N, Papadopoulos I, Paradas E, Strologas J, Triantis FA, Tsitsonis D, Csanad M, Filipovic N, Pasztor G, Suranyi O, Veres GI, Bencze G, Hajdu C, Horvath D, Hunyadi A, Sikler F, Veszpremi V, Beni N, Czellar S, Karancsi J, Makovec A, Molnar J, Szillasi Z, Bartok M, Raics P, Trocsanyi ZL, Ujvari B, Choudhury S, Komaragiri JR, Bahinipati S, Bhowmik S, Mal P, Mandal K, Nayak A, Sahoo DK, Sahoo N, Swain SK, Bansal S, Beri SB, Bhatnagar V, Chawla R, Dhingra N, Kaur A, Kaur M, Kaur S, Kumar R, Kumari P, Mehta A, Singh JB, Walia G, Kumar A, Shah A, Bhardwaj A, Chauhan S, Choudhary BC, Garg RB, Keshri S, Kumar A, Malhotra S, Naimuddin M, Ranjan K, Sharma R, Bhardwaj R, Bhattacharya R, Bhattacharya S, Bhawandeep U, Dey S, Dutt S, Dutta S, Ghosh S, Majumdar N, Modak A, Mondal K, Mukhopadhyay S, Nandan S, Purohit A, Roy A, Chowdhury SR, Sarkar S, Sharan M, Thakur S, Behera PK, Chudasama R, Dutta D, Jha V, Kumar V, Mohanty AK, Netrakanti PK, Pant LM, Shukla P, Topkar A, Aziz T, Dugad S, Mahakud B, Mitra S, Mohanty GB, Sur N, Sutar B, Banerjee S, Bhattacharya S, Chatterjee S, Das P, Guchait M, Jain S, Kumar S, Maity M, Majumder G, Mazumdar K, Sarkar T, Wickramage N, Chauhan S, Dube S, Hegde V, Kapoor A, Kothekar K, Pandey S, Rane A, Sharma S, Chenarani S, Tadavani EE, Etesami SM, Khakzad M, Najafabadi MM, Naseri M, Mehdiabadi SP, Hosseinabadi FR, Safarzadeh B, Zeinali M, Felcini M, Grunewald M, Abbrescia M, Calabria C, Colaleo A, Creanza D, Cristella L, De Filippis N, De Palma M, Errico F, Fiore L, Iaselli G, Lezki S, 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, Bonacorsi D, Borgonovi L, Braibant-Giacomelli S, Campanini R, Capiluppi P, Castro A, Cavallo FR, Chhibra SS, 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, Albergo S, Costa S, Di Mattia A, Giordano F, Potenza R, Tricomi A, Tuve C, Barbagli G, Chatterjee K, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Lenzi P, Meschini M, Paoletti S, Russo L, Sguazzoni G, Strom D, Viliani L, Benussi L, Bianco S, Fabbri F, Piccolo D, Primavera F, Calvelli V, Ferro F, Ravera F, Robutti E, Tosi S, Benaglia A, Beschi A, Brianza L, Brivio F, Ciriolo V, Dinardo ME, Fiorendi S, Gennai S, Ghezzi A, Govoni P, Malberti M, Malvezzi S, Manzoni RA, Menasce D, Moroni L, Paganoni M, Pauwels K, Pedrini D, Pigazzini S, Ragazzi S, de Fatis TT, Buontempo S, Cavallo N, Di Guida S, Fabozzi F, Fienga F, Iorio AOM, Khan WA, Lista L, Meola S, Paolucci P, Sciacca C, Thyssen F, Azzi P, Benato L, Bisello D, Boletti A, Carlin R, De Oliveira ACA, Checchia P, Manzano PD, Dorigo T, Dosselli U, Gasparini F, Gozzelino A, Lacaprara S, Lujan P, Margoni M, Meneguzzo AT, Passaseo M, Pozzobon N, Ronchese P, Rossin R, Simonetto F, Torassa E, Ventura S, Zanetti M, Zotto P, Braghieri A, Magnani A, Montagna P, Ratti SP, Re V, Ressegotti M, Riccardi C, Salvini P, Vai I, Vitulo P, Solestizi LA, Biasini M, Bilei GM, Cecchi C, Ciangottini D, Fano L, Leonardi R, Manoni E, Mantovani G, Mariani V, Menichelli M, Rossi A, Santocchia A, Spiga D, Androsov K, Azzurri P, Bagliesi G, Boccali T, Borrello L, Castaldi R, Ciocci MA, Dell'Orso R, Fedi G, Giannini L, Giassi A, Grippo MT, Ligabue F, Lomtadze T, Manca E, Mandorli G, Messineo A, Palla F, Rizzi A, Savoy-Navarro A, Spagnolo P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Barone L, Cavallari F, Cipriani M, Daci N, Del Re D, Di Marco E, Diemoz M, Gelli S, Longo E, Margaroli F, Marzocchi B, Meridiani P, Organtini G, Paramatti R, Preiato F, Rahatlou S, Rovelli C, Santanastasio F, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bartosik N, Bellan R, Biino C, Cartiglia N, Cenna F, Costa M, Covarelli R, Degano A, Demaria N, Kiani B, Mariotti C, Maselli S, Migliore E, Monaco V, Monteil E, Monteno M, Obertino MM, Pacher L, Pastrone N, Pelliccioni M, Angioni GLP, Romero A, Ruspa M, Sacchi R, Shchelina K, Sola V, Solano A, Staiano A, Traczyk P, Belforte S, Casarsa M, Cossutti F, Della Ricca G, Zanetti A, Kim DH, Kim GN, Kim MS, Lee J, Lee S, Lee SW, Moon CS, Oh YD, Sekmen S, Son DC, Yang YC, Lee A, Kim H, Moon DH, Oh G, Cifuentes JAB, Goh J, Kim TJ, Cho S, Choi S, Go Y, Gyun D, Ha S, Hong B, Jo Y, Kim Y, Lee K, Lee KS, Lee S, Lim J, Park SK, Roh Y, Almond J, Kim J, Kim JS, Lee H, Lee K, Nam K, Oh SB, Radburn-Smith BC, Seo SH, Yang UK, Yoo HD, Yu GB, Kim H, Kim JH, Lee JSH, Park IC, Choi Y, Hwang C, Lee J, Yu I, Dudenas V, Juodagalvis A, Vaitkus J, Ahmed I, Ibrahim ZA, Ali MABM, Idris FM, Abdullah WATW, Yusli MN, Zolkapli Z, Reyes-Almanza R, Ramirez-Sanchez G, Duran-Osuna MC, Castilla-Valdez H, De La Cruz-Burelo E, Heredia-De La Cruz I, Rabadan-Trejo RI, Lopez-Fernandez R, Guisao JM, Sanchez-Hernandez A, Moreno SC, Barrera CO, Valencia FV, Eysermans J, Pedraza I, Ibarguen HAS, Estrada CU, Pineda AM, Krofcheck D, Butler PH, Ahmad A, Ahmad M, Hassan Q, Hoorani HR, Saddique A, Shah MA, Shoaib M, Waqas M, Bialkowska H, Bluj M, Boimska B, Frueboes T, Gorski M, Kazana M, Nawrocki K, Szleper M, Zalewski P, Bunkowski K, Byszuk A, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Misiura M, Olszewski M, Pyskir A, Walczak M, Bargassa P, Silva CBDE, Di Francesco A, Faccioli P, Galinhas B, Gallinaro M, Hollar J, Leonardo N, Iglesias LL, Nemallapudi MV, Seixas J, Strong G, Toldaiev O, Vadruccio D, Varela J, Afanasiev S, Alexakhin V, Bunin P, Gavrilenko M, Golunov A, Golutvin I, Gorbounov N, Karjavin V, Lanev A, Malakhov A, Matveev V, Palichik V, Perelygin V, Savina M, Shmatov S, Skatchkov N, Smirnov V, Zarubin A, Ivanov Y, Kim V, Kuznetsova E, Levchenko P, Murzin V, Oreshkin V, Smirnov I, Sosnov D, 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, Stepennov A, Toms M, Vlasov E, Zhokin A, Aushev T, Bylinkin A, Chadeeva M, Markin O, Parygin P, Philippov D, Polikarpov S, Rusinov V, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Terkulov A, Baskakov A, Belyaev A, Boos E, Bunichev V, Dubinin M, Dudko L, Klyukhin V, Korneeva N, Lokhtin I, Miagkov I, Obraztsov S, Perfilov M, Petrushanko S, Savrin V, Snigirev A, Blinov V, Skovpen Y, Shtol D, Azhgirey I, Bayshev I, Bitioukov S, Elumakhov D, Godizov A, Kachanov V, Kalinin A, Konstantinov D, Mandrik P, Petrov V, Ryutin R, Sobol A, Troshin S, Tyurin N, Uzunian A, Volkov A, Adzic P, Cirkovic P, Devetak D, Dordevic M, Milosevic J, Rekovic V, Maestre JA, Bachiller I, Luna MB, Cerrada M, Colino N, De La Cruz B, Peris 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Castle J, Khalil S, Kropivnitskaya A, Majumder D, Mcbrayer W, Murray M, Royon C, Sanders S, Schmitz E, Takaki JDT, Wang Q, Ivanov A, Kaadze K, Maravin Y, Mohammadi A, Saini LK, Skhirtladze N, Rebassoo F, Wright D, Anelli C, Baden A, Baron O, Belloni A, Eno SC, Feng Y, Ferraioli C, Hadley NJ, Jabeen S, Jeng GY, Kellogg RG, Kunkle J, Mignerey AC, Ricci-Tam F, Shin YH, Skuja A, Tonwar SC, Abercrombie D, Allen B, Azzolini V, Barbieri R, Baty A, Bi R, Brandt S, Busza W, Cali IA, D'Alfonso M, Demiragli Z, Ceballos GG, Goncharov M, Hsu D, Hu M, Iiyama Y, Innocenti GM, Klute M, Kovalskyi D, Lee YJ, Levin A, Luckey PD, Maier B, Marini AC, Mcginn C, Mironov C, Narayanan S, Niu X, Paus C, Roland C, Roland G, Salfeld-Nebgen J, Stephans GSF, Tatar K, Velicanu D, Wang J, Wang TW, Wyslouch B, Benvenuti AC, Chatterjee RM, Evans A, Hansen P, Hiltbrand J, Kalafut S, Kubota Y, Lesko Z, Mans J, Nourbakhsh S, Ruckstuhl N, Rusack R, Turkewitz J, Wadud MA, Acosta JG, Oliveros S, Avdeeva E, Bloom K, Claes DR, 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Malik S, Norberg S, Barker A, Barnes VE, Das S, Folgueras S, Gutay L, Jha MK, Jones M, Jung AW, Khatiwada A, Miller DH, Neumeister N, Peng CC, Qiu H, Schulte JF, Sun J, Wang F, Xiao R, Xie W, Cheng T, Parashar N, Stupak J, Chen Z, Ecklund KM, Freed S, Geurts FJM, Guilbaud M, Kilpatrick M, Li W, Michlin B, Padley BP, Roberts J, Rorie J, Shi W, Tu Z, Zabel J, Zhang A, Bodek A, de Barbaro P, Demina R, Duh YT, Ferbel T, Galanti M, Garcia-Bellido A, Han J, Hindrichs O, Khukhunaishvili A, Lo KH, Tan P, Verzetti M, Ciesielski R, Goulianos K, Mesropian C, Agapitos A, Chou JP, Gershtein Y, Espinosa TAG, Halkiadakis E, Heindl M, Hughes E, Kaplan S, Elayavalli RK, Kyriacou S, Lath A, Montalvo R, Nash K, Osherson M, Saka H, Salur S, Schnetzer S, Sheffield D, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Delannoy AG, Heideman J, Riley G, Rose K, Spanier S, Thapa K, Bouhali O, Hernandez AC, Celik A, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Gilmore J, Huang T, Kamon T, Mueller R, Pakhotin Y, Patel R, Perloff A, Pernie L, Rathjens D, Safonov A, Tatarinov A, Ulmer KA, Akchurin N, Damgov J, De Guio F, Dudero PR, Faulkner J, Gurpinar E, Kunori S, Lamichhane K, Lee SW, Libeiro T, Mengke T, Muthumuni S, Peltola T, Undleeb S, Volobouev I, Wang Z, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Melo A, Ni H, Padeken K, Sheldon P, Tuo S, Velkovska J, Xu Q, Arenton MW, Barria P, Cox B, Hirosky R, Joyce M, Ledovskoy A, Li H, Neu C, Sinthuprasith T, Wang Y, Wolfe E, Xia F, Harr R, Karchin PE, Poudyal N, Sturdy J, Thapa P, Zaleski S, Brodski M, Buchanan J, Caillol C, Dasu S, Dodd L, Duric S, Gomber B, Grothe M, Herndon M, Herve A, Hussain U, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Ruggles T, Savin A, Smith N, Smith WH, Taylor D, Woods N
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Search for pair production of excited top quarks in the lepton plus jets final state The CMS Collaboration
PHYSICS LETTERS B 2018 MAR 10; 778(?):349-370
A search is performed for the pair production of spin-3/2 excited top quarks, each decaying to a top quark and a gluon. The search uses the data collected with the CMS detector from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). Events are selected by requiring an isolated muon or electron, an imbalance in the transverse momentum, and at least six jets of which exactly two must be compatible with originating from the fragmentation of a bottom quark. No significant excess over the standard model predictions is found. A lower limit of 1.2 TeV is set at 95% confidence level on the mass of the spin-3/2 excited top quark in an extension of the Randall-Sundrum model, assuming a 100% branching fraction of its decay into a top quark and a gluon. These are the best limits to date in a search for excited top quarks and the first at 13 TeV. (c) 2018 The Author(s). Published by Elsevier B. V.
McKenna KC, Tsuji M
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Comment on "gamma delta T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations"
JOURNAL OF IMMUNOLOGY 2018 MAR 1; 200(5):1533-1533
Carey AF, Rock JM, Krieger IV, Chase MR, Fernandez-Suarez M, Gagneux S, Sacchettini JC, Ioerger TR, Fortune SM
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TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities
PLOS PATHOGENS 2018 MAR; 14(3):? Article e1006939
Once considered a phenotypically monomorphic bacterium, there is a growing body of work demonstrating heterogeneity among Mycobacterium tuberculosis (Mtb) strains in clinically relevant characteristics, including virulence and response to antibiotics. However, the genetic and molecular basis for most phenotypic differences among Mtb strains remains unknown. To investigate the basis of strain variation in Mtb, we performed genome-wide transposon mutagenesis coupled with next-generation sequencing (TnSeq) for a panel of Mtb clinical isolates and the reference strain H37Rv to compare genetic requirements for in vitro growth across these strains. We developed an analytic approach to identify quantitative differences in genetic requirements between these genetically diverse strains, which vary in genomic structure and gene content. Using this methodology, we found differences between strains in their requirements for genes involved in fundamental cellular processes, including redox homeostasis and central carbon metabolism. Among the genes with differential requirements were katG, which encodes the activator of the first-line antitubercular agent isoniazid, and glcB, which encodes malate synthase, the target of a novel small-molecule inhibitor. Differences among strains in their requirement for katG and glcB predicted differences in their response to these antimicrobial agents. Importantly, these strain-specific differences in antibiotic response could not be predicted by genetic variants identified through whole genome sequencing or by gene expression analysis. Our results provide novel insight into the basis of variation among Mtb strains and demonstrate that TnSeq is a scalable method to predict clinically important phenotypic differences among Mtb strains.
Hervera A, De Virgiliis F, Palmisano I, Zhou LM, Tantardini E, Kong GP, Hutson T, Danzi MC, Perry RB, Santos CXC, Kapustin AN, Fleck RA, Del Rio JA, Carroll T, Lemmon V, Bixby JL, Shah AM, Fainzilber M, Di Giovanni S
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Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons
NATURE CELL BIOLOGY 2018 MAR; 20(3):307-319
Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-beta 1-dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K-phosporylated (p-) Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2-PI3K-p-Akt signalling pathway.
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Search for the pair production of third-generation squarks with two-body decays to a bottom or charm quark and a neutralino in proton-proton collisions at root s=13 TeV
PHYSICS LETTERS B 2018 MAR 10; 778(?):263-291
Results are presented from a search for the pair production of third-generation squarks in proton-proton collision events with two-body decays to bottom or charm quarks and a neutralino, which produces a significant imbalance in the transverse momentum. The search is performed using a sample of proton-proton collision data at root s = 13 TeV recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 35.9fb(-1). No statistically significant excess of events is observed beyond the expected contribution from standard model processes. Exclusion limits are set in the context of simplified models of bottom or top squark pair production. Models with bottom squark masses up to 1220 GeV are excluded at 95% confidence level for light neutralinos, and models with top squark masses of 510 GeV are excluded assuming that the mass splitting between the top squark and the neutralino is small. (C) 2018 The Author. Published by Elsevier B.V.
Reznik E, Luna A, Aksoy BA, Liu EM, La K, Ostrovnaya I, Creighton CJ, Hakimi AA, Sander C
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A Landscape of Metabolic Variation across Tumor Types
CELL SYSTEMS 2018 MAR 28; 6(3):301-313.e3
Tumor metabolism is reorganized to support proliferation in the face of growth-related stress. Unlike the widespread profiling of changes to metabolic enzyme levels in cancer, comparatively less attention has been paid to the substrates/products of enzyme-catalyzed reactions, small-molecule metabolites. We developed an informatic pipeline to concurrently analyze metabolomics data from over 900 tissue samples spanning seven cancer types, revealing extensive heterogeneity in metabolic changes relative to normal tissue across cancers of different tissues of origin. Despite this heterogeneity, a number of metabolites were recurrently differentially abundant across many cancers, such as lactate and acyl-carnitine species. Through joint analysis of metabolomic data alongside clinical features of patient samples, we also identified a small number of metabolites, including several polyamines and kynurenine, which were associated with aggressive tumors across several tumor types. Our findings offer a glimpse onto common patterns of metabolic reprogramming across cancers, and the work serves as a large-scale resource accessible via a web application