1,568 results on '"Coyle A"'
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2. Evaluation of freshwater prawn, <scp> Macrobrachium rosenbergii </scp> , for biological solids control in raft aquaponic systems and the protective effectiveness of root guards
- Author
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Janelle V. Hager, Joshua C. Dusci, James H. Tidwell, and Shawn D. Coyle
- Subjects
Horticulture ,Macrobrachium ,biology ,Macrobrachium rosenbergii ,Prawn ,Aquaponics ,Raft ,Aquatic Science ,biology.organism_classification ,Agronomy and Crop Science - Published
- 2021
3. Fire Can Reduce Thorn Damage by the Invasive Callery Pear Tree
- Author
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Donald L. Hagan, Brayden M. Williams, and David R. Coyle
- Subjects
Horticulture ,Pear tree ,Biology - Abstract
Callery pear (Pyrus calleryana) is an invasive tree across much of the eastern United States that can form dense thickets, and tree branches and stems are often covered in sharp thorns. Landowners and land managers attempting to manage callery pear infestations are faced with the challenge of killing and/or removing the trees while also avoiding thorn damage to equipment, which can lead to wasted time and increased costs. We evaluated fire as management tool to reduce the likelihood of equipment damage from callery pear thorns. Branches were collected in the field from callery pear trees that were killed by herbicide, and also from untreated trees, and half the branches from each group were then burned with a propane garden torch to simulate a low-intensity prescribed fire. After treatment, all branches were returned either to an old field or forest floor for 1 year, after which thorn puncture strength was evaluated and compared with freshly cut thorns. Herbicide treatment and location did not affect thorn strength, but burning reduced the likelihood that thorns would puncture a tire. Fire increased tip width, which reduced thorn sharpness. Burning also reduced wood strength, and fungi proliferated on burned thorns after 1 year in the field or forest. Both factors likely contributed to decreasing thorn strength and probability of puncture. Our results show that using prescribed fire as a management tool can weaken callery pear thorns and dull their tips, reducing the chance of equipment damage and costs associated with clearing land of this invasive species. Leaving cut callery pear trees on the ground for 1 year increased fungal colonization, which may also reduce thorn damage. Prescribed fire can be part of an effective integrated management plan for this, and possibly other, thorny invasive flora.
- Published
- 2021
4. Mapping the human genetic architecture of COVID-19
- Author
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Niemi, MEK, Karjalainen, J, Liao, RG, Neale, BM, Daly, M, Ganna, A, Pathak, GA, Andrews, SJ, Kanai, M, Veerapen, K, Fernandez-Cadenas, I, Schulte, EC, Striano, P, Marttila, M, Minica, C, Marouli, E, Karim, MA, Wendt, FR, Savage, J, Sloofman, L, Butler-Laporte, G, Kim, H-N, Kanoni, S, Okada, Y, Byun, J, Han, Y, Uddin, MJ, Smith, GD, Willer, CJ, Buxbaum, JD, Mehtonen, J, Finucane, H, Cordioli, M, Martin, AR, Zhou, W, Pasaniuc, B, Julienne, H, Aschard, H, Shi, H, Yengo, L, Polimanti, R, Ghoussaini, M, Schwartzentruber, J, Dunham, I, Chwialkowska, K, Francescatto, M, Trankiem, A, Balaconis, MK, Davis, L, Lee, S, Priest, J, Renieri, A, Sankaran, VG, van Heel, D, Deelen, P, Richards, JB, Nakanishi, T, Biesecker, L, Kerchberger, VE, Kenneth, J, Mari, F, Bernasconi, A, Ceri, S, Canakoglu, A, Wolford, B, Faucon, A, Dutta, AK, Schurmann, C, Harry, E, Birney, E, Nguyen, H, Nasir, J, Kaunisto, M, Solomonson, M, Dueker, N, Vadgama, N, Limou, S, Rahmouni, S, Mbarek, H, Darwish, D, Uddin, MM, Albertos, R, Perez-Tur, J, Li, R, Folkersen, L, Moltke, I, Koelling, N, Teumer, A, Kousathanas, A, Utrilla, A, Verdugo, RA, Zarate, R, Medina-Gomez, C, Gomez-Cabrero, D, Carnero-Montoro, E, Cadilla, CL, Moreno-Estrada, A, Garmendia, A, Moya, L, Sedaghati-Khayat, B, Boua, PR, Fave, M-J, Francioli, L, Lemacon, A, Migeotte, I, Patel, S, Varnai, R, Szentpeteri, JL, Sipeky, C, Colombo, F, von Hohenstaufen, K, Lio, P, Vallerga, C, Wang, Q, Tanigawa, Y, Im, H, Han, C, Song, H, Lim, J, Lee, Y, Kim, S, Im, S, Atanasovska, B, Ahmad, HF, Boer, C, Jansen, P, Franke, L, Kaja, E, Pasko, D, Kennis-Szilagyi, I, Kornilov, SA, Prijatelj, V, Prokic, I, Sivanadhan, I, Perumal, S, Esmaeeli, S, Pearson, NM, Auton, A, Shelton, JF, Shastri, AJ, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, O'Connell, J, Ye, C, Weldon, CH, Perera, M, O'Leary, K, Tuck, M, O'Brien, T, Meltzer, D, O'Donnell, P, Nutescu, E, Yang, G, Alarcon, C, Herrmann, S, Mazurek, S, Banagan, J, Hamidi, Z, Barbour, A, Raffat, N, Moreno, D, Friedman, P, Ferwerda, B, van de Beek, D, Brouwer, MC, Vlaar, APJ, Wiersinga, WJ, Posthuma, D, Tissink, E, Zwinderman, AHK, Uffelmann, E, van Agtmael, M, Algera, AG, van Baarle, F, Bax, D, Beudel, M, Bogaard, HJ, Bomers, M, Bonta, PI, Bos, L, Botta, M, de Brabander, J, de Bree, G, de Bruin, S, Bugiani, M, Bulle, E, Chouchane, O, Cloherty, A, Dongelmans, D, Elbers, P, Fleuren, L, Geerlings, S, Geerts, B, Geijtenbeek, T, Girbes, A, Goorhuis, B, Grobusch, MP, Hafkamp, F, Hagens, L, Hamann, J, Harris, V, Hemke, R, Hermans, SM, Heunks, L, Hollmann, M, Horn, J, Hovius, JW, de Jong, MD, Koning, R, van Mourik, N, Nellen, J, Nossent, EJ, Paulus, F, Peters, E, van der Poll, T, Preckel, B, Prins, JM, Raasveld, J, Reijnders, T, Schinkel, M, Schultz, MJ, Schuurman, A, Sigaloff, K, Smit, M, Stijnis, CS, Stilma, W, Teunissen, C, Thoral, P, Tsonas, A, van der Valk, M, Veelo, D, de Vries, H, van Vugt, M, Wouters, D, Minnaar, RP, Kromhout, A, van Uffelen, KWJ, Wolterman, RA, Roberts, G, Park, D, Ball, CA, Coignet, M, McCurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Hong, EL, Rand, K, Girshick, A, Guturu, H, Baltzell, AH, Guntz, J, Beguin, Y, Pigazzini, S, Nkambule, L, Bouysran, Y, Busson, A, Peyrassol, X, Wilkin, F, Pichon, B, Smits, G, Vandernoot, I, Goffard, J-C, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Jadot, L, Azarzar, S, Dellot, P, Gofflot, S, Claassen, S, Bertrand, A, Parzibut, G, Clarinval, M, Moermans, C, Malaise, O, El Kandoussi, K, Thonon, R, Huynen, P, Mesdagh, A, Melo, S, Jacques, N, Di Valentin, E, Giroule, F, Collignon, A, Radermecker, C, Lebrun, M, Peree, H, Latour, S, Barada, O, Sanchez, J, Josse, C, Boujemla, B, Meunier, M, Mariavelle, E, Anania, S, Gazon, H, Juszczak, D, Fadeur, M, Camby, S, Meuris, C, Thys, M, Jacques, J, Henket, M, Leonard, P, Frippiat, F, Giot, J-B, Sauvage, A-S, Von Frenckell, C, Mni, M, Wery, M, Staderoli, A, Belhaj, Y, Lambermont, B, Morrison, DR, Mooser, V, Forgetta, V, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Brassard, N, Durand, M, Schurr, E, Lepage, P, Ragoussis, J, Auld, D, Chasse, M, Kaufmann, DE, Lathrop, GM, Adra, D, Davis, LK, Cox, NJ, Below, JE, Sealock, JM, Faucon, AB, Shuey, MM, Polikowsky, HG, Petty, LE, Shaw, DM, Chen, H-H, Zhu, W, Ludwig, KU, Schroeder, J, Maj, C, Rolker, S, Noethen, MM, Fazaal, J, Keitel, V, Jensen, B-EO, Feldt, T, Kurth, I, Marx, N, Dreher, M, Pink, I, Cornberg, M, Illig, T, Lehmann, C, Schommers, P, Augustin, M, Rybniker, J, Knopp, L, Eggermann, T, Volland, S, Altmueller, J, Berger, MM, Brenner, T, Hinney, A, Witzke, O, Bals, R, Herr, C, Ludwig, N, Walter, J, Fuchsberger, C, Pattaro, C, De Grandi, A, Pramstaller, P, Emmert, D, Melotti, R, Foco, L, Mascalzoni, D, Gogele, M, Domingues, F, Hicks, A, Gignoux, CR, Wicks, SJ, Crooks, K, Barnes, KC, Daya, M, Shortt, J, Rafaels, N, Chavan, S, Goldstein, DB, Kiryluk, K, Sengupta, S, Chung, W, Reilly, MP, Khan, A, Wang, C, Povysil, G, Bhardwaj, N, Gharavi, AG, Ionita-Laza, I, Shang, N, O'Byrne, SM, Nandakumar, R, Menon, A, So, YS, Hod, E, Pendrick, D, Park, S-K, Kim, H-L, Kang, CK, Lee, H-J, Song, K-H, Yoon, KJ, Paik, N-J, Seok, W, Yoon, H, Joo, E-J, Chang, Y, Ryu, S, Park, WB, Park, JS, Park, KU, Ham, SY, Jung, J, Kim, ES, Kim, HB, Ellinghaus, D, Degenhardt, F, Caceres, M, Juzenas, S, Lenz, TL, Albillos, A, Julia, A, Heidecker, B, Garcia, F, Kurth, F, Tran, F, Hanses, F, Zoller, H, Holter, JC, Fernandez, J, Sander, LE, Rosenstiel, P, Koehler, P, de Cid, R, Asselta, R, Schreiber, S, Hehr, U, Prati, D, Baselli, G, Valenti, L, Bujanda, L, Banales, JM, Duga, S, D'Amato, M, Romero-Gomez, M, Buti, M, Invernizzi, P, Franke, A, Hov, JR, Karlsen, TH, Folseraas, T, Maya-Miles, D, Teles, A, Azuure, C, Wacker, EM, Uellendahl-Werth, F, Elabd, H, Arora, J, Lerga-Jaso, J, Wienbrandt, L, Ruehlemann, MC, Wendorff, M, Vadla, MS, Lenning, OB, Oezer, O, Myhre, R, Raychaudhuri, S, Tanck, A, Gassner, C, Hemmrich-Stanisak, G, Kaessens, J, Basso, MEF, Schulzky, M, Wittig, M, Braun, N, Wesse, T, Albrecht, W, Yi, X, Ortiz, AB, Garrido Chercoles, A, Ruiz, A, Mantovani, A, Holten, AR, Mayer, A, Cherubini, A, Protti, A, Aghemo, A, Gerussi, A, Ramirez, A, Braun, A, Barreira, A, Lleo, A, Kildal, AB, Glueck, A, Carreras Nolla, A, Latiano, A, Dyrhol-Riise, AM, Muscatello, A, Voza, A, Rando-Segura, A, Solier, A, Karina, B, Cortes, B, Mateos, B, Nafria-Jimenez, B, Schaefer, B, Bellinghausen, C, Ferrando, C, Quereda, C, Skurk, C, Thibeault, C, Spinner, CD, Lange, C, Hu, C, Cappadona, C, Bianco, C, Sancho, C, Hoff, DAL, Galimberti, D, Jimenez, D, Pestana, D, Toapanta, D, Azzolini, E, Scarpini, E, Helbig, ET, Urrechaga, E, Paraboschi, EM, Pontali, E, Reverter, E, Navas, E, Arana, E, Garcia Sanchez, F, Ceriotti, F, Malvestiti, F, Mesonero, F, Pezzoli, G, Lamorte, G, Neb, H, My, I, Hernandez, I, de Rojas, I, Galvan-Femenia, I, Heyckendorf, J, Badia, JR, Schneider, J, Goikoetxea, J, Kraft, J, Mueller, KE, Gaede, KI, Garcia-Etxebarria, K, Tonby, K, Heggelund, L, Izquierdo-Sanchez, L, Sumoy, L, Lippert, LJ, Terranova, L, Garbarino, L, Tellez, L, Roade, L, Ostadreza, M, Intxausti, M, Kogevinas, M, Gutierrez-Stampa, MA, Vehreschild, MJGT, Marquie, M, Castoldi, M, Cecconi, M, Boada, M, Seilmaier, MJ, Mazzocco, M, Rodriguez-Gandia, M, Imaz Ayo, N, Blay, N, Martinez, N, Cornely, OA, Palmieri, O, Tentorio, P, Rodrigues, PM, Espana, PP, Hoffmann, P, Bacher, P, Suwalski, P, de Pablo, R, Nieto, R, Badalamenti, S, Ciesek, S, Bombace, S, Wilfling, S, Brunak, S, Heilmann-Heimbach, S, Ripke, S, Bahmer, T, Landmesser, U, Protzer, U, Rimoldi, V, Skogen, V, Andrade, V, Moreno, V, Poller, W, Farre, X, Wang, X, Khodamoradi, Y, Karadeniz, Z, de Salazar, A, Palom, A, Garcia-Fernandez, A-E, Blanco-Grau, A, Zanella, A, Bandera, A, Nebel, A, Biondi, A, Caba Llero-Garralda, A, Gori, A, Lind, A, Fracanzani, AL, Peschuck, A, Pesenti, A, De la Horra, C, Milani, C, Paccapelo, C, Angelini, C, Cea, C, Muniz-Diaz, E, Sandoval, E, Calderon, EJ, Solligard, E, Aziz, F, Martinelli-Boneschi, F, Peyvandi, F, Blasi, F, Medrano, FJ, Rodriguez-Frias, F, Mueller, F, Grasselli, G, Costantino, G, Cardamone, G, Foti, G, Matullo, G, Kurihara, H, Afset, JE, Damas, JK, Ampuero, J, Martin, J, Erdmann, J, Bergan, J, Goerg, S, Ferrusquia-Acosta, J, Hernandez Quero, J, Delgado, J, Guerrero, JM, Risnes, K, Bettini, LR, Moreira, L, Gustad, LT, Santoro, L, Scudeller, L, Riveiro-Barciela, M, Schaefer, M, Carrabba, M, Valsecchi, MG, Hernandez-Tejero, M, Acosta-Herrera, M, D'Angio, M, Baldini, M, Cazzaniga, M, Ciccarelli, M, Bocciolone, M, Miozzo, M, Chueca, N, Montano, N, Faverio, P, Preatoni, P, Bonfanti, P, Omodei, P, Castro, P, Ferrer, R, Gualtierotti, R, Gallego-Duran, R, Morilla, R, Haider, S, Marsal, S, Aneli, S, Pelusi, S, Bosari, S, Aliberti, S, Dudman, S, Zheng, T, Pumarola, T, Gonzalez Cejudo, T, Monzani, V, Friaza, V, Peter, W, Dopazo, X, May, S, Grimsrud, MM, Gudbjartsson, DF, Stefansson, K, Sulem, P, Sveinbjornsson, G, Melsted, P, Norddahl, G, Moore, KHS, Thorsteinsdottir, U, Holm, H, Alarcon-Riquelme, ME, Bernardo, D, Martinez-Bueno, M, Rojo Rello, S, Magi, R, Milani, L, Metspalu, A, Laisk, T, Lall, K, Lepamets, M, Esko, T, Reimann, E, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Alavere, H, Metsalu, K, Puusepp, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Rivolta, C, Bochud, P-Y, Bibert, S, Boillat, N, Nussle, SG, Albrich, W, Quinodoz, M, Kamdar, D, Suh, N, Neofytos, D, Erard, V, Voide, C, Bochud, PY, Friolet, R, Vollenweider, P, Pagani, JL, Oddo, M, zu Bentrup, FM, Conen, A, Clerc, O, Marchetti, O, Guillet, A, Guyat-Jacques, C, Foucras, S, Rime, M, Chassot, J, Jaquet, M, Viollet, RM, Lannepoudenx, Y, Portopena, L, Desgranges, F, Filippidis, P, Guery, B, Haefliger, D, Kampouri, EE, Manuel, O, Munting, A, Iou-Olivgeris, MP, Regina, J, Rochat-Stettler, L, Suttels, V, Tadini, E, Tschopp, J, Van Singer, M, Viala, B, Boillat-Blanco, N, Brahier, T, Hugli, O, Meuwly, JY, Pantet, O, Bochud, M, D'Acremont, V, Younes, SE, Albrich, WC, Cerny, A, O'Mahony, L, von Mering, C, Frischknecht, M, Kleger, G-R, Filipovic, M, Kahlert, CR, Wozniak, H, Negro, TR, Pugin, J, Bouras, K, Knapp, C, Egger, T, Perret, A, Montillier, P, di Bartolomeo, C, Barda, B, Carreras, A, Mercader, JM, Guindo-Martinez, M, Torrents, D, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Gori, M, Mondelli, MU, Castelli, F, Vaghi, M, Rusconi, S, Montagnani, F, Bargagli, E, Franchi, F, Mazzei, MA, Cantarini, L, Tacconi, D, Feri, M, Scala, R, Spargi, G, Nencioni, C, Bandini, M, Caldarelli, GP, Spagnesi, M, Canaccini, A, Ognibene, A, Monforte, AD, Girardis, M, Antinori, A, Francisci, D, Schiaroli, E, Scotton, PG, Panese, S, Scaggiante, R, Della Monica, M, Capasso, M, Fiorentino, G, Castori, M, Aucella, F, Di Biagio, A, Masucci, L, Valente, S, Mandala, M, Zucchi, P, Giannattasio, F, Coviello, DA, Mussini, C, Bosio, G, Tavecchia, L, Crotti, L, Rizzi, M, La Rovere, MT, Sarzi-Braga, S, Bussotti, M, Ravaglia, S, Artuso, R, Perrella, A, Romani, D, Bergomi, P, Catena, E, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Paciosi, F, Segala, FV, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Perticaroli, V, Furini, S, Dei, S, Benetti, E, Picchiotti, N, Sanarico, M, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Bergomi, M, Zguro, K, Capitani, K, Tanfoni, M, Fallerini, C, Daga, S, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, MA, Lo Rizzo, C, Pinto, AM, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, ML, Alaverdian, D, Iuso, N, Inchingolo, G, Busani, S, Bruno, R, Vecchia, M, Belli, MA, Mantovani, S, Ludovisi, S, Quiros-Roldan, E, Antoni, MD, Zanella, I, Siano, M, Emiliozzi, A, Fabbiani, M, Rossetti, B, Zanelli, G, Bergantini, L, D'Alessandro, M, Cameli, P, Bennet, D, Anedda, F, Marcantonio, S, Scolletta, S, Guerrini, S, Conticini, E, Frediani, B, Spertilli, C, Donati, A, Guidelli, L, Corridi, M, Croci, L, Piacentini, P, Desanctis, E, Cappelli, S, Verzuri, A, Anemoli, V, Pancrazi, A, Lorubbio, M, Merlini, E, Miraglia, FG, Venturelli, S, Cossarizza, A, Vergori, A, Gabrieli, A, Riva, A, Andretta, F, Gatti, F, Parisi, SG, Baratti, S, Piscopo, C, Russo, R, Andolfo, I, Iolascon, A, Carella, M, Merla, G, Squeo, GM, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Sanguinetti, M, Giorli, A, Salerni, L, Parravicini, P, Menatti, E, Trotta, T, Coiro, G, Lena, F, Martinelli, E, Mancarella, S, Gabbi, C, Maggiolo, F, Ripamonti, D, Bachetti, T, Suardi, C, Parati, G, Botta, G, Di Domenico, P, Rancan, I, Bianchi, F, Colombo, R, van Heel, DA, Hunt, KA, Trembath, RC, Huang, QQ, Martin, HC, Mason, D, Trivedi, B, Wright, J, Finer, S, Griffiths, CJ, Akhtar, S, Anwar, M, Arciero, E, Ashraf, S, Breen, G, Chung, R, Curtis, CJ, Chowdhury, M, Colligan, G, Deloukas, P, Durham, C, Griffiths, C, Hurles, M, Hussain, S, Islam, K, Lavery, C, Lee, SH, Lerner, R, MacArthur, D, MacLaughlin, B, Martin, H, Miah, S, Newman, B, Safa, N, Tahmasebi, F, Smith, AV, Boughton, AP, Li, KW, LeFaive, J, Annis, A, Jannes, CE, Krieger, JE, Pereira, AC, Velho, M, Marques, E, Lima, IR, Tada, MT, Valino, K, McCarthy, M, Rosenberger, C, Lee, JE, Chang, D, Hammer, C, Hunkapiller, J, Mahajan, A, Pendergrass, S, Sucheston-Campbell, L, Yaspan, B, Lee, HS, Shin, E, Jang, HY, Kym, S, Kim, Y-S, Jeong, H, Kwon, KT, Kim, S-W, Kim, JY, Jang, YR, Kim, HA, Lee, JY, Choe, K-W, Kang, YM, Jee, SH, Jung, KJ, Parikh, V, Ashley, E, Wheeler, M, Rivas, M, Bustamante, C, 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Hirofumi, Ikemura, Shinnosuke, Chubachi, Shotaro, Okamori, Satoshi, Terai, Hideki, Tanaka, Hiromu, Morita, Atsuho, Lee, Ho, Asakura, Takanori, Sasaki, Junichi, Morisaki, Hiroshi, Uwamino, Yoshifumi, Nanki, Kosaku, Mikami, Yohei, Tomono, Kazunori, Kato, Kazuto, Matsuda, Fumihiko, Takahashi, Meiko, Hizawa, Nobuyuki, Takeda, Yoshito, Hirata, Haruhiko, Shiroyama, Takayuki, Miyawaki, Satoru, Suzuki, Ken, Maeda, Yuichi, Nii, Takuro, Noda, Yoshimi, Niitsu, Takayuki, Adachi, Yuichi, Enomoto, Takatoshi, Amiya, Saori, Hara, Reina, Takahashi, Kunihiko, Anzai, Tatsuhiko, Hasegawa, Takanori, Ito, Satoshi, Koike, Ryuji, Endo, Akifumi, Uchimura, Yuji, Miyazaki, Yasunari, Honda, Takayuki, Tateishi, Tomoya, Tohda, Shuji, Ichimura, Naoya, Sonobe, Kazunari, Sassa, Chihiro, Nakajima, Jun, Nannya, Yasuhito, Omae, Yosuke, Takahashi, Kazuhisa, Harada, Norihiro, Hiki, Makoto, Takagi, Haruhi, Nakamura, Ai, Tagaya, Etsuko, Kawana, Masatoshi, Arimura, Ken, Ishiguro, Takashi, Takayanagi, Noboru, Isono, Taisuke, Takaku, Yotaro, Takano, Kenji, Anan, Ryusuke, Nakajima, Yukiko, Nakano, Yasushi, Nishio, Kazumi, Ueda, Soichiro, Hayashi, Reina, Tateno, Hiroki, Hase, Isano, Yoshida, Shuichi, Suzuki, Shoji, Mitamura, Keiko, Saito, Fumitake, Ueda, Tetsuya, Azuma, Masanori, Nagasaki, Tadao, Yasui, Yoshinori, Hasegawa, Yoshinori, Mutoh, Yoshikazu, Yoshiyama, Takashi, Shoko, Tomohisa, Kojima, Mitsuaki, Adachi, Tomohiro, Ishikawa, Motonao, Takahashi, Kenichiro, Watanabe, Kazuyoshi, Manabe, Tadashi, Ito, Fumimaro, Fukui, Takahiro, Funatsu, Yohei, Koh, Hidefumi, Hirai, Yoshihiro, Kawashima, Hidetoshi, Narita, Atsuya, Niwa, Kazuki, Sekikawa, Yoshiyuki, Saito, Fukuki, Yoshiya, Kazuhisa, Yoshihara, Tomoyuki, Suzuki, Yusuke, Nakayama, Sohei, Masuzawa, Keita, Nishi, Koichi, Nishitsuji, Masaru, Tani, Maiko, Inoue, Takashi, Hirano, Toshiyuki, Kobayashi, Keigo, Miyazawa, Naoki, Kimura, Yasuhiro, Sado, Reiko, Ogura, Takashi, Kitamura, Hideya, Murohashi, Kota, Nakachi, Ichiro, Baba, Rie, Arai, Daisuke, Fuke, Satoshi, Saito, Hiroshi, Kuwahara, Naota, Fujiwara, Akiko, Okada, Takenori, Baba, Tomoya, Noda, Junya, Mashimo, Shuko, Yagi, Kazuma, Shiomi, Tetsuya, Hashiguchi, Mizuha, Odani, Toshio, Mochimaru, Takao, Oyamada, Yoshitaka, Mori, Nobuaki, Izumi, Namiki, Nagata, Kaoru, Taki, Reiko, Murakami, Koji, Yamada, Mitsuhiro, Sugiura, Hisatoshi, Hayashi, Kentaro, Shimizu, Tetsuo, Gon, Yasuhiro, Fujitani, Shigeki, Tsuchida, Tomoya, Yoshida, Toru, Kagaya, Takashi, Kita, Toshiyuki, Sakagami, Satoru, Kimizuka, Yoshifumi, Kawana, Akihiko, Nakamura, Yoshihiko, Ishikura, Hiroyasu, Takata, Tohru, Kikuchi, Takahide, Taniyama, Daisuke, Nakamura, Morio, Kodama, Nobuhiro, Kaneyama, Yasunari, Maeda, Shunsuke, Nagasaki, Yoji, Okamoto, Masaki, Ishihara, Sayoko, Ito, Akihiro, Chihara, Yusuke, Takeuchi, Mayumi, Onoi, Keisuke, Hashimoto, Naozumi, Wakahara, Keiko, Ando, Akira, Masuda, Makoto, Wakabayashi, Aya, Watanabe, Hiroki, Sageshima, Hisako, Nakada, Taka-Aki, Abe, Ryuzo, Shimada, Tadanaga, Kawamura, Kodai, Ichikado, Kazuya, Nishiyama, Kenta, Yamasaki, Masaki, Hashimoto, Satoru, Kusaka, Yu, Ohba, Takehiko, Isogai, Susumu, Takada, Minoru, Kanda, Hidenori, Komase, Yuko, Sano, Fumiaki, Asano, Koichiro, Oguma, Tsuyoshi, Harada, Masahiro, Takahashi, Takeshi, Shibusawa, Takayuki, Abe, Shinji, Kono, Yuta, Togashi, Yuki, Izumo, Takehiro, Inomata, Minoru, Awano, Nobuyasu, Ogawa, Shinichi, Ogata, Tomouki, Ishihara, Shoichiro, Kanehiro, Arihiko, Ozaki, Shinji, Fuchimoto, Yasuko, Kitagawa, Yuichiro, Yoshida, Shozo, Ogura, Shinji, Nishiyama, Kei, Yoshida, Kousuke, Beppu, Satoru, Fukuyama, Satoru, Eriguchi, Yoshihiro, Yonekawa, Akiko, Inoue, Yoshiaki, Yamagata, Kunihiro, Chiba, Shigeru, Narumoto, Osamu, Nagai, Hideaki, Ooshima, Nobuharu, Motegi, Mitsuru, Sagara, Hironori, Tanaka, Akihiko, Ohta, Shin, Shibata, Yoko, Tanino, Yoshinori, Sato, Yuki, Yamada, Yuichiro, Hashino, Takuya, Shinoki, Masato, Iwagoe, Hajime, Imamura, Tomonori, Umeda, Akira, Shimada, Hisato, Endo, Mayu, Hayashi, Shinichi, Takahashi, Mai, Nakano, Shigefumi, Yatomi, Masakiyo, Maeno, Toshitaka, Ishii, Tomoo, Utsugi, Mitsuyoshi, Ono, Akihiro, Kanaoka, Kensuke, Ihara, Shoichi, Komuta, Kiyoshi, Boezen, Marike, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith. M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P. S., Obeidat, Ma’En, Hernández Cordero, Ana I., Sin, Don D., Bossé, Yohan, Joubert, Philippe, Hao, Ke, Nickle, David, Timens, Wim, van den Berge, Maarten, Feng, Yen-Chen Anne, Mercader, Josep, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Green, Robert C., Perez, Emma F., Zöllner, Sebastian, Wang, Jiongming, Beck, Andrew, Sloofman, Laura G., Ascolillo, Steven, Sebra, Robert P., Collins, Brett L., Levy, Te, Sealfon, Stuart C., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Chaudhary, Kumardeep, Belbin, Gillian M., Preuss, Michael, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., Salib, Irene, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Zyndorf, Marissa, Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Abul-Husn, Noura S., Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Loos, Ruth J. F., Nadkarni, Girish N., Do, Ron, O’Reilly, Paul, Huckins, Laura M., Ferreira, Manuel A. R., Abecasis, Goncalo R., Leader, Joseph B., Cantor, Michael N., Justice, Anne E., Carey, Dave J., Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Horowitz, Julie E., Baras, Ari, Gass, Matthew C., Yadav, Ashish, Mirshahi, Tooraj, Jan Hottenga, Jouke, Bartels, Meike, de Geus, Eco J. C., Nivard, Michel G., Verma, Anurag, Ritchie, Marylyn D., Rader, Daniel, Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Zara, Federico, Salpietro, Vincenzo, Scala, Marcello, Iacomino, Michele, Scudieri, Paolo, Bocciardi, Renata, Minetti, Carlo, Riva, Antonella, Vari, Maria Stella, Rahier, Jean-Françoi, Giorgio, Elisa, Carli, Diana, Louis, Edouad, Bulik, Cynthia M., Landén, Mikael, Brusco, Alfredo, Ferrero, Giovanni Battista, Madia, Francesca, Fundín, Bengt, Ismail, Said I., Saad, Chadi, Al-Sarraj, Yaser, Badji, Radja Messai, Al-Muftah, Wadha, Al Thani, Asma, Afifi, Nahla, Klovins, Jani, Rovite, Vita, Rescenko, Raimond, Peculis, Raiti, Ustinova, Monta, Zeberg, Hugo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Johnson, Ruth, Geschwind, Daniel H., Freimer, Nelson, Butte, Manish J., Ding, Yi, Chiu, Alec, Chang, Timothy S., Boutros, Paul, Moutsianas, Louka, Caulfield, Mark J., Scott, Richard H., Walker, Susan, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Fowler, Tom, Rendon, Augusto, Chan, Georgia, Arumugam, Prabhu, Karczewski, Konrad J., Wilson, Daniel J., Spencer, Chris A., Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikola, Turley, Patrick, Gupta, Rahul, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Churchhouse, Claire, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Daly, Mark J., Bryant, Sam, Satterstrom, F. Kyle, Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicola, Armstrong, Jacob, Rudkin, Justine K., Callier, Shawneequa, Cusick, Caroline, Soranzo, Nicole, Zhao, Jing Hua, Danesh, John, Di Angelantonio, Emanuele, Butterworth, Adam S., Sun, Yan V., Huffman, Jennifer E., Cho, Kelly, O’Donnell, Christopher J., Tsao, Phil, Gaziano, J. Michael, Peloso, Gina, Ho, Yuk-Lam, Mian, Michael, Scaggiante, Federica, Chang, Xiao, Glessner, Joseph R., Hakonarson, Hakon, Mcguigan, Peter J., Prockter Moore, Luke Stephen, Vizcaychipi, Marcela Paola, Hall, Kathryn, Campbell, Andy, Nichol, Ailstair, Ward, Geraldine, Page, Valerie Joan, Semple, Malcolm G., Adeniji, Kayode, Agranoff, Daniel, Agwuh, Ken, Ail, Dhiraj, Aldera, Erin L., Alegria, Ana, Angus, Brian, Ashish, Abdul, Atkinson, Dougal, Bari, Shahedal, Barlow, Gavin, Barnass, Stella, Barrett, Nichola, Bassford, Christopher, Basude, Sneha, Baxter, David, Beadsworth, Michael, Bernatoniene, Jolanta, Berridge, John, Best, Nicola, Bothma, Pieter, Chadwick, David, Brittain-Long, Robin, Bulteel, Naomi, Burden, Tom, Burtenshaw, Andrew, Caruth, Vikki, Chambler, Duncan, Chee, Nigel, Child, Jenny, Chukkambotla, Srikanth, Clark, Tom, Collini, Paul, Cosgrove, Catherine, Cupitt, Jason, Cutino-Moguel, Maria-Teresa, Dark, Paul, Dawson, Chri, Dervisevic, Samir, Donnison, Phil, Douthwaite, Sam, Drummond, Andrew, Durand, Ingrid, Dushianthan, Ahilanadan, Dyer, Tristan, Evans, Cariad, Eziefula, Chi, Fegan, Christopher, Finn, Adam, Fullerton, Duncan, Garg, Sanjeev, Garg, Atul, Gkrania-Klotsas, Effrossyni, Godden, Jo, Goldsmith, Arthur, Graham, Clive, Hardy, Elaine, Hartshorn, Stuart, Harvey, Daniel, Havalda, Peter, Hawcutt, Daniel B., Hobrok, Maria, Hodgson, Luke, Hormis, Anil, Jacobs, Michael, Jain, Susan, Jennings, Paul, Kaliappan, Agilan, Kasipandian, Vidya, Kegg, Stephen, Kelsey, Michael, Kendall, Jason, Kerrison, Caroline, Kerslake, Ian, Koch, Oliver, Koduri, Gouri, Koshy, George, Laha, Shondipon, Laird, Steven, Larkin, Susan, Leiner, Tama, Lillie, Patrick, Limb, Jame, Linnett, Vanessa, Little, Jeff, Lyttle, Mark, Macmahon, Michael, Macnaughton, Emily, Mankregod, Ravish, Masson, Huw, Matovu, Elijah, Mccullough, Katherine, Mcewen, Ruth, Meda, Manjula, Mills, Gary H., Minton, Jane, Ward, Karl, Mirfenderesky, Mariyam, Mohandas, Kavya, Mok, Quen, Moon, Jame, Moore, Elinoor, Morgan, Patrick, Morris, Craig, Mortimore, Katherine, Moses, Samuel, Mpenge, Mbiye, Mulla, Rohinton, Murphy, Michael, Nagel, Megan, Nagarajan, Thapa, Nelson, Mark, O’Shea, Matthew K., Otahal, Igor, Ostermann, Marlie, Pais, Mark, Panchatsharam, Selva, Papakonstantinou, Danai, Paraiso, Hassan, Patel, Brij, Pattison, Natalie, Pepperell, Justin, Peters, Mark, Phull, Mandeep, Pintus, Stefania, Pooni, Jagtur Singh, Post, Frank, Price, David, Prout, Rachel, Rae, Nikola, Reschreiter, Henrik, Reynolds, Tim, Richardson, Neil, Roberts, Mark, Roberts, Devender, Rose, Alistair, Rousseau, Guy, Ryan, Brendan, Saluja, Taranprit, Shah, Aarti, Shanmuga, Prad, Sharma, Anil, Shawcross, Anna, Sizer, Jeremy, Shankar-Hari, Manu, Smith, Richard, Snelson, Catherine, Spittle, Nick, Staines, Nikki, Stambach, Tom, Stewart, Richard, Subudhi, Pradeep, Szakmany, Tama, Tatham, Kate, Thomas, Jo, Thompson, Chri, Thompson, Robert, Tridente, Ascanio, Tupper-Carey, Darell, Twagira, Mary, Ustianowski, Andrew, Vallotton, Nick, Vincent-Smith, Lisa, Visuvanathan, Shico, Vuylsteke, Alan, Waddy, Sam, Wake, Rachel, Walden, Andrew, Welters, Ingeborg, Whitehouse, Tony, Whittaker, Paul, Whittington, Ashley, Papineni, Padmasayee, Wijesinghe, Meme, Williams, Martin, Wilson, Lawrence, Cole, Sarah, Winchester, Stephen, Wiselka, Martin, Wolverson, Adam, Wooton, Daniel G., Workman, Andrew, Yates, Bryan, Young, Peter, Beale, Rupert, Bretherick, Andrew D., Clohisey, Sara, Fourman, Max Head, Furniss, Jame, Gountouna, Elvina, Grimes, Graeme, Haley, Chri, Harrison, David, Hayward, Caroline, Keating, Sean, Klaric, Lucija, Klenerman, Paul, Law, Andy, Meynert, Alison M., Millar, Jonathan, Pairo-Castineira, Erola, Parkinson, Nichola, Ponting, Chris P., Porteous, David J., Rawlik, Konrad, Richmond, Anne, Rowan, Kathy, Russell, Clark D., Shen, Xia, Shih, Barbara, Tenesa, Albert, Vitart, Veronique, Wang, Bo, Wilson, James F., Wu, Yang, Yang, Jian, Yang, Zhijian, Zechner, Marie, Zhai, Ranran, Zheng, Chenqing, Norman, Lisa, Pius, Riinu, Drake, Thomas M., Fairfield, Cameron J., Knight, Stephen R., Mclean, Kenneth A., Murphy, Derek, Shaw, Catherine A., Dalton, Jo, Girvan, Michelle, Saviciute, Egle, Roberts, Stephanie, Harrison, Janet, Marsh, Laura, Connor, Marie, Halpin, Sophie, Jackson, Clare, Gamble, Carrol, Leeming, Gary, Law, Andrew, Wham, Murray, Hendry, Ro, Scott-Brown, Jame, Begg, Colin, Hinds, Charle, Wai Ho, Antonia Ying, Horby, Peter W., Knight, Julian, Ling, Lowell, Maslove, David, Mcauley, Danny, Montgomery, Hugh, Nichol, Alistair, Openshaw, Peter J. M., Summers, Charlotte, Walsh, Timothy, Armstrong, Lisa, Bates, Hayley, Dooks, Emma, Farquhar, Fiona, Hairsine, Brigid, Mcparland, C., Packham, Sophie, Alldis, Zoe, Astin-Chamberlain, Raine, Bibi, Fatima, Biddle, Jack, Blow, Sarah, Bolton, Matthew, Borra, Catherine, Bowles, Ruth, Burton, Maudrian, Choudhury, Yasmin, Collier, David, Cox, Amber, Easthope, Amy, Ebano, Patrizia, Fotiadis, Stavro, Gurasashvili, Jana, Halls, Rosslyn, Hartridge, Pippa, Kallon, Delordson, Kassam, Jamila, Lancoma-Malcolm, Ivone, Matharu, Maninderpal, May, Peter, Mitchelmore, Oliver, Newman, Tabitha, Patel, Mital, Pheby, Jane, Pinzuti, Irene, Prime, Zoe, Prysyazhna, Oleksandra, Shiel, Julian, Taylor, Melanie, Tierney, Carey, Wood, Suzanne, Zak, Anne, Zongo, Olivier, Forsey, Miranda, Nicholson, Anne, Riches, Joanne, Vertue, Mark, Wasson, Christopher, Finn, Stephanie, Green, Jackie, Collins, Erin, King, Bernadette, Grauslyte, Lina, Hussain, Musarat, Pogreban, Tatiana, Rosaroso, Lace, Salciute, Erika, Franke, George, Wong, Joanna, George, Aparna, Akeroyd, Louise, Bano, Shereen, Bromley, Matt, Gurr, Lucy, Lawton, Tom, Morgan, Jame, Sellick, Kirsten, Warren, Deborah, Wilkinson, Brian, Mcgowan, Janet, Ledgard, Camilla, Stacey, Amelia, Pye, Kate, Bellwood, Ruth, Bentley, Michael, Loosley, Ronda, Mcguinness, Heather, Tench, Helen, Wolf-Roberts, Rebecca, Gibson, Sian, Lyle, Amanda, Mcneela, Fiona, Radhakrishnan, Jayachandran, Hughes, Alistair, Ali, Asifa, Brady, Megan, Dale, Sam, Dance, Annalisa, Gledhill, Lisa, Greig, Jill, Hanson, Kathryn, Holdroyd, Kelly, Home, Marie, Kelly, Diane, Kitson, Ro, Matapure, Lear, Melia, Deborah, Mellor, Samantha, Nortcliffe, Tonicha, Pinnell, Jez, Robinson, Matthew, Shaw, Lisa, Shaw, Ryan, Thomis, Lesley, Wilson, Alison, Wood, Tracy, Bayo, Lee-Ann, Merwaha, Ekta, Ishaq, Tahira, Hanley, Sarah, Antcliffe, David, Banach, Dorota, Brett, Stephen, Coghlan, Phoebe, Fernandez, Ziortza, Gordon, Anthony, Rojo, Roceld, Arias, Sonia Sousa, Templeton, Maie, Jha, Rajeev, Krishnamurthy, Vinodh, Lim, Lai, Bi, Rehana, Scholefield, Barney, Ashton, Lydia, Williams, Alison, Cheyne, Claire, Saunderson, Anne, Allan, Angela, Anderson, Felicity, Kaye, Callum, Liew, Jade, Medhora, Jasmine, Scott, Teresa, Trumper, Erin, Botello, Adriana, Polgarova, Petra, Stroud, Katerina, Meaney, Eoghan, Jones, Megan, Ng, Anthony, Agrawal, Shruti, Pathan, Nazima, White, Deborah, Daubney, Esther, Elston, Kay, Parker, Robert, Reddy, Amie, Turner-Bone, Ian, Wilding, Laura, Harding, Peter, Jacob, Reni, Jones, Cathy, Denmade, Craig, Croft, Maria, White, Ian, Lim, Li, Griffin, Denise, Muchenje, Nycola, Mupudzi, Mcdonald, Partridge, Richard, Conyngham, Jo-Anna, Thomas, Rachel, Wright, Mary, Corral, Maria Alvarez, Bastion, Victoria, Clarke, Daphene, David, Beena, Kent, Harriet, Lorusso, Rachel, Lubimbi, Gamu, Murdoch, Sophie, Penacerrada, Melchizedek, Thomas, Alastair, Valentine, Jennifer, Vochin, Ana, Wulandari, Retno, Djeugam, Brice, Dawson, Joy, Garrioch, Sweyn, Tolson, Melanie, Aldridge, Jonathan, de Almeida Martins, Laura Gome, Carungcong, Jaime, Beavis, Sarah, Dale, Katie, Gascoyne, Rachel, Hawes, Joanne, Pritchard, Kelly, Stevenson, Lesley, Whileman, Amanda, Cowley, Anne, Highgate, Judith, Crawley, Rikki, Crew, Abigail, Cunningham, Mishell, Daniels, Allison, Harrison, Laura, Hope, Susan, Inweregbu, Ken, Jones, Sian, Lancaster, Nicola, Matthews, Jamie, Nicholson, Alice, Wray, Gemma, Benham, Leonie, Bradshaw, Zena, Brown, Joanna, Caswell, Melanie, Melling, Sarah, Preston, Stephen, Slawson, Nicola, Stoddard, Emma, Warden, Scott, Combes, Edward, Joefield, Teishel, Monnery, Sonja, Beech, Valerie, Trotman, Sallyanne, Hopkins, Bridget, Scriven, Jame, Thrasyvoulou, Laura, Willis, Heather, Anderson, Susan, Birch, Janine, Collins, Emma, Hammerton, Kate, O’Leary, Ryan, Abernathy, Caroline, Foster, Louise, Gratrix, Andrew, Martinson, Vicky, Parkinson, Priyai, Stones, Elizabeth, Carbral-Ortega, Llucia, Kapoor, Ritoo, Loader, David, Castle, Karen, Brandwood, Craig, Smith, Lara, Clark, Richard, Birchall, Katie, Kolakaluri, Laurel, Baines, Deborah, Sukumaran, Anila, Mapfunde, Isheunesu, Meredith, Megan, Morris, Lucy, Ryan, Lucy, Clark, Amy, Sampson, Julia, Peters, Cecilia, Dent, Martin, Langley, Margaret, Ashraf, Saima, Wei, Shuying, Andrew, Angela, Chablani, Manish, Kirkby, Amy, Netherton, Kimberley, Bates, Michelle, Dasgin, Jo, Gill, Jaspret, Nilsson, Annette, Apetri, Elena, Basikolo, Cathrine, Blackledge, Bethan, Catlow, Laura, Charles, Bethan, Doonan, Reece, Harris, Jade, Harvey, Alice, Horner, Daniel, Knowles, Karen, Lee, Stephanie, Lomas, Diane, Lyons, Chloe, Marsden, Tracy, Mclaughlan, Danielle, Mcmorrow, Liam, Pendlebury, Jessica, Perez, Jane, Poulaka, Maria, Proudfoot, Nicola, Slaughter, Melanie, Slevin, Kathryn, Thomas, Vicky, Walker, Danielle, Michael, Angiy, Collis, Matthew, Clark, Martyn, Coulding, Martina, Jude, Edward, Mccormick, Jacqueline, Mercer, Oliver, Potla, Darsh, Rehman, Hafiz, Savill, Heather, Turner, Victoria, Davey, Miriam, Golden, David, Seaman, Rebecca, Hunt, Jodie, Dearden, Joy, Dobson, Emma, Mulcahy, Michelle, Munt, Sheila, O’Connor, Grainne, Philbin, Jennifer, Rishton, Chloe, Tully, Redmond, Winnard, Sarah, Cagova, Lenka, Fofano, Adama, Garner, Lucie, Holcombe, Helen, Mepham, Sue, Mitchell, Alice Michael, Mwaura, Lucy, Praman, K., Vuylsteke, Alain, Zamikula, Julie, Bercades, Georgia, Brealey, David, Hass, Ingrid, Maccallum, Niall, Martir, Glady, Raith, Eamon, Reyes, Anna, Smyth, Deborah, Taylor, Abigail, Hughes, Rachel Anne, Thomas, Helen, Rees, Alun, Duskova, Michaela, Phipps, Janet, Brooks, Suzanne, Edwards, Michelle, Alexander, Peter, Allen, Schvearn, Bradley-Potts, Joanne, Brantwood, Craig, Egan, Jasmine, Felton, Timothy, Padden, Grace, Ward, Luke, Moss, Stuart, Glasgow, Susannah, Beesley, Kate, Board, Sarah, Kubisz-Pudelko, Agnieszka, Lewis, Alison, Perry, Je, Pippard, Lucy, Wood, Di, Buckley, Clare, Brown, Alison, Gregory, Jane, O’Connell, Susan, Smith, Tim, Belagodu, Zakaula, Fuller, Bridget, Gherman, Anca, Olufuwa, Olumide, Paramsothy, Remi, Stuart, Carmel, Oakley, Naomi, Kamundi, Charlotte, Tyl, David, Collins, Katy, Silva, Pedro, Taylor, June, King, Laura, Coates, Charlotte, Crowley, Maria, Wakefield, Phillipa, Beadle, Jane, Johnson, Laura, Sargeant, Janet, Anderson, Madeleine, Jardine, Catherine, Williams, Dewi, Parris, Victoria, Quaid, Sheena, Watson, Ekaterina, Melville, Julie, Naisbitt, Jay, Joseph, Rosane, Lazo, Maria, Walton, Olivia, Neal, Alan, Hill, Michaela, Kannan, Thogulava, Wild, Laura, Allan, Elizabeth, Darlington, Kate, Davies, Ffyon, Easton, Jack, Kumar, Sumit, Lean, Richard, Menzies, Daniel, Pugh, Richard, Qiu, Xinyi, Davies, Llino, Williams, Hannah, Scanlon, Jeremy, Davies, Gwyneth, Mackay, Callum, Lewis, Joannne, Rees, Stephanie, Coetzee, Samantha, Gales, Alistair, Raj, Meena, Sell, Craig, Langton, Helen, Watters, Malcolm, Novis, Catherine, Arbane, Gill, Bociek, Aneta, Campos, Sara, Grau, Neu, Jones, Tim Owen, Lim, Rosario, Marotti, Martina, Whitton, Christopher, Barron, Anthony, Collins, Ciara, Kaul, Sundeep, Passmore, Heather, Prendergast, Claire, Reed, Anna, Rogers, Paula, Shokkar, Rajvinder, Woodruff, Meriel, Middleton, Hayley, Polgar, Oliver, Nolan, Claire, Thwaites, Vicky, Mahay, Kanta, Sri-Chandana, Chunda, Scherewode, Joslan, Stephenson, Lorraine, Marsh, Sarah, Bancroft, Hollie, Bellamy, Mary, Carmody, Margaret, Daglish, Jacqueline, Moore, Faye, Rhodes, Joanne, Sangombe, Mirriam, Kadiri, Salma, Ayers, Amanda, Harrison, Wendy, North, Julie, Cavazza, Anna, Cockrell, Maeve, Corcoran, Eleanor, Depante, Maria, Finney, Clare, Jerome, Ellen, Mcphail, Mark, Nayak, Monalisa, Noble, Harriet, O’Reilly, Kevin, Pappa, Evita, Saha, Rohit, Saha, Sian, Smith, John, Knighton, Abigail, Gill, Mandy, Paul, Paul, Ratnam, Valli, Shelton, Sarah, Wynter, Inez, Baptista, David, Crowe, Rebecca, Fernandes, Rita, Herdman-Grant, Rosaleen, Joseph, Anna, Loveridge, Adam, Mckenley, India, Morino, Eriko, Naranjo, Andre, Simms, Richard, Sollesta, Kathryn, Swain, Andrew, Venkatesh, Harish, Khera, Jacyntha, Fox, Jonathan, Barber, Russell, Hewitt, Claire, Hilldrith, Annette, Jackson-Lawrence, Karen, Shepardson, Sarah, Wills, Maryanne, Butler, Susan, Tavares, Silvia, Cunningham, Amy, Hindale, Julia, Arif, Sarwat, George, Linsha, Twiss, Sophie, Wright, David, Holland, Maureen, Keenan, Natalie, Lyons, Marc, Wassall, Helen, Marsh, Chri, Mahenthran, Mervin, Carter, Emma, Kong, Thoma, Adanini, Oluronke, Bhatia, Nikhil, Msiska, Maine, Mew, Louise, Mwaura, Esther, Williams, Felicity, Wren, Lynn, Sutherland, Sara-Beth, Battle, Ceri, Brinkworth, Elaine, Harford, Rachel, Murphy, Carl, Newey, Luke, Rees, Tabitha, Williams, Marie, Arnold, Sophie, Hardy, John, Houlden, Henry, Moncur, Eleanor, Tariq, Ambreen, Tucci, Arianna, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Keshet-Price, Jocelyn, Randell, Georgina, Stammers, Katie, Abdelrazik, Marwa, Bakthavatsalam, Dhanalakshmi, Elhassan, Munzir, Ganesan, Arunkumar, Haldeos, Anne, Moreno-Cuesta, Jeronimo, Purohit, Dharam, Vincent, Rachel, Xavier, Kugan, Rohit, Kumar, Alasdair, Frater, Saleem, Malik, David, Carter, Jenkins, Samuel, Lamond, Zoe, Wall, Alanna, Reynolds, Jessica, Campbell, Helen, Thompsom, Maria, Dodds, Steve, Duffy, Stacey, Butcher, Deborah, O’Sullivan, Susie, Butterworth-Cowin, Nicola, Deacon, Bethan, Hibbert, Meg, Pothecary, Carla, Tetla, Dariusz, Woodford, Christopher, Durga, Latha, Kennard-Holden, Gareth, de Gordoa, Laura Ortiz-Ruiz, Peasgood, Emily, Phillips, Claire, Skinner, Denise, Gaylard, Jane, Mullan, Dee, Newman, Julie, Davies, Ellie, Roche, Lisa, Sathe, Sonia, Brimfield, Lutece, Daly, Zoe, Pogson, David, Rose, Steve, Collins, Amy, Khaliq, Waqa, Gude, Estefania Treu, Allen, Louise, Beranova, Eva, Crisp, Nikki, Deery, Joanne, Hazelton, Tracy, Knight, Alicia, Price, Carly, Tilbey, Sorrell, Turki, Salah, Turney, Sharon, Giles, Julian, Booth, Simon, Bell, Gillian, English, Katy, Katary, Amro, Wilcox, Louise, Campbell, Rachael, Clarke, Noreen, Whiteside, Jonathan, Mascarenhas, Mairi, Donaldson, Avril, Matheson, Joanna, Barrett, Fiona, O’Hara, Marianne, O’Keefe, Laura, Bradley, Clare, Collier, Dawn, Walker, Rachel, Maynard, Victoria, Patel, Tahera, Smith, Matthew, Kazi, Aayesha, Hartley, Janice, Dykes, Joseph, Hijazi, Muhammad, Keith, Sarah, Khan, Meherunnisa, Ryan-Smith, Janet, Springle, Philippa, Thomas, Jacqueline, Truman, Nick, Saad, Samuel, Coleman, Dabheoc, Fine, Christopher, Matt, Roseanna, Gay, Bethan, Dalziel, Jack, Ali, Syamlan, Goodchild, Drew, Harling, Rhiannan, Bhatterjee, Ravi, Goddard, Wendy, Davison, Chloe, Duberly, Stephen, Hargreaves, Jeanette, Bolton, Rachel, Verlander, Mark, Williams, Alexandra, Blackman, Helen, Creagh-Brown, Ben, Donlon, Sinead, Michalak-Glinska, Natalia, Mtuwa, Sheila, Pristopan, Veronika, Salberg, Armorel, Smith, Eleanor, Stone, Sarah, Piercy, Charle, Verula, Jerik, Burda, Dorota, Montaser, Rugia, Harden, Lesley, Mayangao, Irving, Marriott, Cheryl, Bradley, Paul, Harris, Celia, Cooper, Joshua, Finch, Cheryl, Liderth, Sarah, Quinn, Alison, Waddington, Natalia, Fidler, Katy, Tagliavini, Emma, Donnelly, Kevin, Abel, Lynn, Brett, Michael, Digby, Brian, Gemmell, Lisa, Hornsby, Jame, Macgoey, Patrick, O’Neil, Pauline, Price, Richard, Rodden, Natalie, Rooney, Kevin, Sundaram, Radha, Thomson, Nicola, Flanagan, Rebecca, Hughes, Gareth, Latham, Scott, Mckenna, Emma, Anderson, Jennifer, Hull, Robert, Rhead, Kat, Branney, Debbie, Frankham, Jordan, Pitts, Sally, White, Nigel, Cristiano, Daniele, Dormand, Natalie, Farzad, Zohreh, Gummadi, Mahitha, Liyanage, Kamal, Patel, Brijesh V., Salmi, Sara, Sloane, Geraldine, Varghese, Mathew, Zborowski, Anelise C., Bean, Sarah, Burt, Karen, Spivey, Michael, Eastgate-Jackson, Christine, Filipe, Helder, Martin, Daniel, Maharajh, Amitaa, Garcia, Sara Mingo, De Neef, Mark, Lynch, Ceri, Howe, Gwenllian Sera, Singh, Jayaprakash, Turner, Keri, Ellis, Hannah, Stroud, Natalie, Cherian, Shiney, Cutler, Sean, Heron, Anne Emma, Roynon-Reed, Anna, Williams, Gemma, Richards, Owen, Cheema, Yusuf, Ahmad, Norfaizan, Barker, Joann, Bauchmuller, Kri, Bird, Sarah, Cawthron, Kay, Harrington, Kate, Jackson, Yvonne, Kibutu, Faith, Lenagh, Becky, Masuko, Shamiso, Raithatha, Ajay, Wiles, Matthew, Willson, Jayne, Newell, Helen, Lye, Alison, Nwafor, Lorenza, Jarman, Claire, Rowland-Jones, Sarah, Foote, David, Cole, Joby, Thompson, Roger, Watson, Jame, Hesseldon, Lisa, Macharia, Irene, Chetam, Luke, Smith, Jacqui, Ford, Amber, Anderson, Samantha, Birchall, Kathryn, Housley, Kay, Walker, Sara, Milner, Leanne, Hanratty, Helena, Trower, Helen, Phillips, Patrick, Oxspring, Simon, Donne, Ben, Bevan, Emily, Martin, Jane, Trodd, Dawn, Watson, Geoff, Brown, Caroline Wrey, Bunni, Lara, Jennings, Claire, Latif, Monica, Marshall, Rebecca, Subramanian, Gayathri, Bandla, Nageswar, Gellamucho, Minnie, Davies, Michelle, Thompson, Christopher, Trim, Fiona, Eapen, Beena, Ahmed, Cecilia, Baines, Balvinder, Clamp, Sarah, Colley, Julie, Haq, Risna, Hayes, Anne, Hulme, Jonathan, Hussain, Samia, Joseph, Sibet, Kumar, Rita, Maqsood, Zahira, Purewal, Manjit, Chandler, Ben, Elliott, Kerry, Mallinson, Janine, Turnbull, Alison, Dent, Kathy, Horsley, Elizabeth, Akhtar, Muhmmad Nauman, Pearson, Sandra, Potoczna, Dorota, Spencer, Sue, Blakemore, Hayley, Borislavova, Borislava, Faulkner, Beverley, Gendall, Emma, Goff, Elizabeth, Hayes, Kati, Thomas, Matt, Worner, Ruth, Smith, Kerry, Stephens, Deanna, Delgado, Carlos Castro, Dawson, Deborah, Ding, Lijun, Durrant, Georgia, Ezeobu, Obiageri, Farnell-Ward, Sarah, Harrison, Abiola, Kanu, Rebecca, Leaver, Susannah, Maccacari, Elena, Manna, Soumendu, Saluzzio, Romina Peperman, Queiroz, Joana, Samakomva, Tinashe, Sicat, Christine, Texeira, Joana, Da Gloria, Edna Fernande, Lisboa, Ana, Rawlins, John, Mathew, Jisha, Kinch, Ashley, Hurt, William Jame, Shah, Nirav, Clark, Victoria, Thanasi, Maria, Yun, Nikki, Patel, Kamal, Crickmore, Vikki, Debreceni, Gabor, Wilkins, Joy, Nicol, Liz, Burn, Iona, Hambrook, Geraldine, Manso, Katarina, Penn, Ruth, Shanmugasundaram, Pradeep, Tebbutt, Julie, Thornton, Danielle, Rostron, Anthony, Roy, Alistair, Woods, Lindsey, Cornell, Sarah, Wakinshaw, Fiona, Rogerson, Kimberley, Jarmain, Jordan, Anderson, Peter, Archer, Katie, Austin, Karen, Davis, Caroline, Durie, Alison, Kelsall, Olivia, Thrush, Jessica, Vigurs, Charlie, Wood, Hannah-Louise, Tranter, Helen, Harrison, Alison, Cowley, Nichola, Mcalindon, Michael, Digby, Stephen, Low, Emma, Morgan, Aled, Cother, Naiara, Rankin, Tobia, Clayton, Sarah, Mccurdy, Alex, Allibone, Suzanne, Mary-Genetu, Roman, Patel, Amit, Mac, Ainhi, Murphy, Anthony, Mahjoob, Parisa, Nazari, Roonak, Worsley, Lucy, Fagan, Andrew, Mohamed Ali, Inthakab Ali, Beaumont, Karen, Blunt, Mark, Coton, Zoe, Curgenven, Hollie, Elsaadany, Mohamed, Fernandes, Kay, Ally, Sameena Mohamed, Rangarajan, Harini, Sarathy, Varun, Selvanayagam, Sivarupan, Vedage, Dave, White, Matthew, Fernandez-Roman, Jaime, Hamilton, David O., Johnson, Emily, Johnston, Brian, Martinez, Maria Lopez, Mulla, Suleman, Shaw, David, Waite, Alicia A. C., Waugh, Victoria, Welters, Ingeborg D., Williams, Karen, Bemand, Thoma, Black, Ethel, Rosa, Arnold Dela, Howle, Ryan, Jhanji, Shaman, Baikady, Ravishankar Rao, Tatham, Kate Colette, Thomas, Benjamin, Halkes, Matthew, Mercer, Pauline, Thornton, Lorraine, West, Joe, Baird, Tracy, Ruddy, Jim, Reece-Anthony, Rosie, Birt, Mark, Cowton, Amanda, Kay, Andrea, Kent, Melanie, Potts, Kathryn, Wilkinson, Ami, Naylor, Suzanne, Brown, Ellen, Clark, Michele, Purvis, Sarah, Cole, Jade, Davies, Rhy, Duffin, Donna, Hill, Helen, Player, Ben, Thomas, Emma, Williams, Angharad, Beith, Claire Marie, Black, Karen, Clements, Suzanne, Morrison, Alan, Strachan, Dominic, Taylor, Margaret, Clarkson, Michelle, D’Sylva, Stuart, Norman, Kathryn, Coventry, Tina, Fowler, Susan, Mcgregor, Amanda, Brady, Ailbhe, Chan, Rebekah, Mcivor, Shane, Prady, Helena, Whittle, Helen, Mathew, Bijoy, Clapham, Melanie, Harper, Rosemary, Poultney, Una, Rice, Polly, Mutch, Rachel, Baird, Yolanda, Butler, Aaron, Chadbourn, Indra, Folkes, Linda, Fox, Heather, Gardner, Amy, Gomez, Raquel, Hobden, Gillian, King, Kirsten, Margarson, Michael, Martindale, Tim, Meadows, Emma, Raynard, Dana, Thirlwall, Yvette, Helm, David, Margalef, Jordi, Greer, Sandra, Shuker, Karen, Smuts, Sara, Duffield, Joseph, Smith, Oliver, Mallon, Lewi, Claire, Watkin, Birkinshaw, Isobel, Carter, Joseph, Howard, Kate, Ingham, Joanne, Joy, Rosie, Pearson, Harriet, Roche, Samantha, Scott, Zoe, Knights, Ellen, Price, Alicia, Thomas, Alice, Thorpe, Chri, Abraheem, Azmerelda, Bamford, Peter, Cawley, Kathryn, Dunmore, Charlie, Faulkner, Maria, Girach, Rumanah, Jeffrey, Helen, Jones, Rhianna, London, Emily, Nagra, Imrun, Nasir, Farah, Sainsbury, Hannah, Smedley, Clare, Khade, Reena, Sundar, Ashok, Tsinaslanidis, George, Behan, Teresa, Burnett, Caroline, Hatton, Jonathan, Heeney, Elaine, Mitra, Atideb, Newton, Maria, Pollard, Rachel, Stead, Rachael, Birch, Jenny, Bough, Laura, Goodsell, Josie, Tutton, Rebecca, Williams, Patricia, Williams, Sarah, Winter-Goodwin, Barbara, Auld, Fiona, Donnachie, Joanne, Edmond, Ian, Prentice, Lynn, Runciman, Nikole, Salutous, Dario, Symon, Lesley, Todd, Anne, Turner, Patricia, Short, Abigail, Sweeney, Laura, Murdoch, Euan, Senaratne, Dhaneesha, Burns, Karen, Higham, Andrew, Anderson, Taya, Hawcutt, Dan, O’Malley, Laura, Rad, Laura, Rogers, Naomi, Saunderson, Paula, Allison, Kathryn Sian, Afolabi, Deborah, Whitbread, Jennifer, Jones, Dawn, Dore, Rachael, Lankester, Liana, Nikitas, Nikita, Wells, Colin, Stowe, Bethan, Spencer, Kayleigh, Cathcart, Susanne, Duffy, Katharine, Puxty, Alex, Puxty, Kathryn, Turner, Lynne, Ireland, Jane, Semple, Gary, Barry, Peter, Hilltout, Paula, Evitts, Jayne, Tyler, Amanda, Waldron, Joanne, Irvine, Val, Shelley, Benjamin, Akinkugbe, Olugbenga, Bamford, Alasdair, Beech, Emily, Belfield, Holly, Bell, Michael, Davies, Charlene, Jones, Gareth A. L., Mchugh, Tara, Meghari, Hamza, O’Neill, Lauran, Peters, Mark J., Ray, Samiran, Tomas, Ana Luisa, Gorman, Claire, Gupta, Abhinav, Timlick, Elizabeth, Brady, Rebecca, Bonner, Stephen, Hugill, Keith, Jones, Jessica, Liggett, Steven, Bashyal, Archana, Davidson, Neil, Hutton, Paula, Mckechnie, Stuart, Wilson, Jean, Flint, Neil, Rekha, Patel, Hales, Dawn, Cruz, Carina, Gopal, Shameer, Harris, Nichola, Lake, Victoria, Metherell, Stella, Radford, Elizabeth, Clement, Ian, Patel, Bijal, Gulati, A., Hays, Carole, Webster, K., Hudson, Anne, Webster, Andrea, Stephenson, Elaine, Mccormack, Louise, Slater, Victoria, Nixon, Rachel, Hanson, Helen, Fearby, Maggie, Kelly, Sinead, Bridgett, Victoria, Robinson, Philip, Almaden-Boyle, Christine, Austin, Pauline, Cabrelli, Louise, Cole, Stephen, Casey, Matt, Chapman, Susan, Whyte, Clare, Brayne, Adam, Fisher, Emma, Hunt, Jane, Jackson, Peter, Kaye, Duncan, Love, Nichola, Parkin, Juliet, Tuckey, Victoria, van Koutrik, Lynne, Carter, Sasha, Andrew, Benedict, Findlay, Louise, Adams, Katie, Bruce, Michelle, Connolly, Karen, Duncan, Tracy, T. -Michael, Helen, Lindergard, Gabriella, Hey, Samuel, Fox, Claire, Alfonso, Jordan, Durrans, Laura Jayne, Guerin, Jacinta, Hruska, Martin, Eltayeb, Ayaa, Lamb, Thoma, Hodgkiss, Tracey, Cooper, Lisa, Rothwell, Joanne, Dennis, Catherine, Mcgregor, Alastair, Srikaran, Sinduya, Sukha, Anisha, Davies, Kim, O’Brien, Linda, Omar, Zohra, Perkins, Emma, Lewis, Tracy, Sutherland, Isobel, Brooke, Hollie, Buckley, Sarah, Suarez, Jose Cebrian, Charlesworth, Ruth, Hansson, Karen, Norris, John, Poole, Alice, Rose, Alastair, Sandhu, Rajdeep, Sloan, Brendan, Smithson, Elizabeth, Thirumaran, Muthu, Wagstaff, Veronica, Metcalfe, Alexandra, Camsooksai, Julie, Humphrey, Charlotte, Jenkins, Sarah, Wadams, Beverley, Death, Yasmin, Adams, Colene, Agasou, Anita, Arden, Tracie, Bowes, Amy, Boyle, Pauline, Beekes, Mandy, Button, Heather, Capps, Nigel, Carnahan, Mandy, Carter, Anne, Childs, Danielle, Donaldson, Denise, Hard, Kelly, Hurford, Fran, Hussain, Yasmin, Javaid, Ayesha, Jones, Jame, Jose, Sanal, Leigh, Michael, Martin, Terry, Millward, Helen, Motherwell, Nichola, Rikunenko, Rachel, Stickley, Jo, Summers, Julie, Ting, Louise, Tivenan, Helen, Tonks, Louise, Wilcox, Rebecca, Bokhari, Maria, Lucas, Rachael, Mccormick, Wendy, Ritzema, Jenny, Sanderson, Amanda, Wild, Helen, Baxter, Nicola, Henderson, Steven, Kennedy-Hay, Sophie, Mcparland, Christopher, Rooney, Laura, Sim, Malcolm, Mccreath, Gordan, Brunton, Mark, Caterson, Je, Coles, Holly, Frise, Matthew, Rai, Sabi Gurung, Keating, Liza, Tilney, Emma, Bartley, Shauna, Bhuie, Parminder, Downes, Charlotte, Holding, Kathleen, Riches, Katie, Hilton, Mary, Hayman, Mel, Subramanian, Deepak, Daniel, Priya, Zitter, Letizia, Benyon, Sarah, Marriott, Suzie, Park, Linda, Keenan, Samantha, Gordon, Elizabeth, Quinn, Helen, Baines, Kizzy, Andrew, Gillian, Barclay, Lucy, Callaghan, Marie, Clark, Sarah, Hope, Dave, Marshall, Lucy, Mcculloch, Corrienne, Briton, Kate, Singleton, Jo, Birch, Sophie, Simpson, Kerry, Craig, Jayne, Demetriou, Carrie, Eckbad, Charlotte, Hierons, Sarah, Howie, Lucy, Mitchard, Sarah, Ramos, Lidia, Serrano-Ruiz, Alfredo, White, Katie, Kelly, Fiona, Amin, Vishal, Anastasescu, Elena, Anumakonda, Vikram, Karthik, Komala, Kausar, Rizwana, Reid, Karen, Smith, Jacqueline, Imeson-Wood, Janet, Bellini, Arianna, Bryant, Jade, Mayer, Anton, Pickard, Amy, Roe, Nichola, Sowter, Jason, Howlett, Alex, Criste, Kristine, Cusack, Rebecca, Golder, Kim, Golding, Hannah, Jones, Oliver, Leggett, Samantha, Male, Michelle, Marani, Martyna, Prager, Kirsty, Williams, Toran, Roberts, Belinda, Salmon, Karen, Gondo, Prisca, Hadebe, B., Kayani, Abdul, Masunda, Bridgett, Ahmed, Ashar, Morris, Anna, Jakkula, Sriniva, Long, Kate, Whiteley, Simon, Wilby, Elizabeth, Ogg, Bethan, Moultrie, Sam, Odam, M., Bewley, Jeremy, Garland, Zoe, Grimmer, Lisa, Gumbrill, Bethany, Johnson, Rebekah, Sweet, Katie, Webster, Denise, Efford, Georgia, Bennett, Sara, Goodwin, Emma, Jackson, Matthew, Kent, Alissa, Tibke, Clare, Woodyatt, Wiesia, Zaki, Ahmed, Daniel, Amelia, Finn, Joanne, Saha, Rajnish, Bremmer, Pamela, Allan, J., Geary, T., Houston, Gordon, Meikle, A., O’Brien, P., Bell, Dina, Boyle, Rosalind, Douglas, Katie, Glass, Lynn, Lee, Emma, Lennon, Liz, Rattray, Austin, Charnock, Rob, Mcfarland, Denise, Cosgrove, Denise, Attwood, Ben, Parsons, Penny, Carmody, Siobhain, Oblak, Metod, Popescu, Monica, Thankachen, Mini, Baruah, Rosie, Morris, Sheila, Ferguson, Susie, Shepherd, Amy, Altabaibeh, Abdelhakim, Alvaro, Ana, Gilbert, Kayleigh, Ma, Louise, Mostoles, Loreta, Parmar, Chetan, Simpson, Kathryn, Jetha, Champa, Booker, Lauren, Pratley, Anezka, Cosier, Tracey, Millen, Gemma, Schumacher, Natasha, Weston, Heather, Rand, Jame, Alex, Beatrice, Bach, Benjamin, Barclay, Wendy S., Bogaert, Debby, Chand, Meera, Cooke, Graham S., Docherty, Annemarie B., Dunning, Jake, da Silva Filipe, Ana, Fletcher, Tom, Green, Christoper A., Harrison, Ewen M., Hiscox, Julian A., Ijaz, Samreen, Khoo, Saye, Lim, Wei Shen, Mentzer, Alexander J., Merson, Laura, Noursadeghi, Mahdad, Moore, Shona C., Palmarini, Massimo, Paxton, William A., Pollakis, Georgio, Price, Nichola, Rambaut, Andrew, Robertson, David L., Sancho-Shimizu, Vanessa, Scott, Janet T., de Silva, Thushan, Sigfrid, Louise, Solomon, Tom, Sriskandan, Shiranee, Stuart, David, Tedder, Richard S., Thomson, Emma C., Roger Thompson, A. A., Thwaites, Ryan S., Turtle, Lance C. W., Gupta, Rishi K., Palmieri, Carlo, Swann, Olivia V., Zambon, Maria, Dumas, Marc-Emmanuel, Griffin, Julian L., Takats, Zoltan, Chechi, Kanta, Andrikopoulos, Petro, Osagie, Anthonia, Olanipekun, Michael, Liggi, Sonia, Lewis, Matthew R., Correia, Gonçalo dos Santo, Sands, Caroline J., Takis, Panteleimon, Maslen, Lynn, Greenhalf, William, Shaw, Victoria, Mcdonald, Sarah E., Keating, Seán, Ahmed, Katie A., Armstrong, Jane A., Ashworth, Milton, Asiimwe, Innocent G., Bakshi, Siddharth, Barlow, Samantha L., Booth, Laura, Brennan, Benjamin, Bullock, Katie, Catterall, Benjamin W. A., Clark, Jordan J., Clarke, Emily A., Cooper, Louise, Cox, Helen, Davis, Christopher, Dincarslan, Oslem, Dunn, Chri, Dyer, Philip, Elliott, Angela, Evans, Anthony, Finch, Lorna, Fisher, Lewis W. S., Foster, Terry, Garcia-Dorival, Isabel, Gunning, Philip, Hartley, Catherine, Jensen, Rebecca L., Jones, Christopher B., Jones, Trevor R., Khandaker, Shadia, King, Katharine, Kiy, Robyn T., Koukorava, Chrysa, Lake, Annette, Lant, Suzannah, Latawiec, Diane, Lavelle-Langham, Lara, Lefteri, Daniella, Lett, Lauren, Livoti, Lucia A., Mancini, Maria, Mcdonald, Sarah, Mcevoy, Laurence, Mclauchlan, John, Metelmann, Soeren, Miah, Nahida S., Middleton, Joanna, Mitchell, Joyce, Murphy, Ellen G., Penrice-Randal, Rebekah, Pilgrim, Jack, Prince, Tessa, Reynolds, Will, Ridley, P. Matthew, Sales, Debby, Shaw, Victoria E., Shears, Rebecca K., Small, Benjamin, Subramaniam, Krishanthi S., Szemiel, Agnieska, Taggart, Aislynn, Tanianis-Hughes, Jolanta, Thomas, Jordan, Trochu, Erwan, van Tonder, Libby, Wilcock, Eve, Zhang, J. Eunice, Flaherty, Lisa, Maziere, Nicole, Cass, Emily, Carracedo, Alejandra Doce, Carlucci, Nicola, Holmes, Anthony, Massey, Hannah, Murphy, Lee, Wrobel, Nicola, Mccafferty, Sarah, Morrice, Kirstie, Maclean, Alan, Armstrong, Ruth, Boz, Ceilia, Brown, Adam, Coutts, Audrey, Cullum, Louise, Day, Nicky, Donnelly, Lorna, Duncan, Esther, Fawkes, Angie, Finernan, Paul, Gilchrist, Tammy, Golightly, Ailsa, Hafezi, Katarzyna, Law, Dawn, Law, Rachel, Law, Sarah, Macgillivray, Louise, Mal, Hanning, Mcmaster, Ellie, Meikle, Jen, Oosthuyzen, Wilna, Paterson, Trevor, Stenhouse, Andrew, Swets, Maaike, Szoor-McElhinney, Helen, Taneski, Filip, Wackett, Tony, Ward, Mairi, Weaver, Jane, Coyle, Judy, Gallagher, Bernadette, Lidstone-Scott, Rebecca, Hamilton, Debbie, Schon, Katherine, Furlong, Anita, Biggs, Heather, Griffiths, Fiona, Andrews, Eleanor, Brickell, Kathy, Smyth, Michelle, Murphy, Lorna, Carson, Gail, Hardwick, Hayley, Donohue, Chloe, Pérez-Tur, Jordi [0000-0002-9111-1712], Martín, Javier [0000-0002-2202-0622], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], A list of authors and their affiliations appears in the Supplementary Information, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-21-COVR-0039,GenMIS-C,Recherche 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Bocciolone, M., Miozzo, M., Chueca, N., Montano, N., Faverio, P., Preatoni, P., Bonfanti, P., Omodei, P., Castro, P., Ferrer, R., Gualtierotti, R., Gallego-Durán, R., Morilla, R., Haider, S., Marsal, S., Aneli, S., Pelusi, S., Bosari, S., Aliberti, S., Dudman, S., Zheng, T., Pumarola, T., Cejudo, T.G., Monzani, V., Friaza, V., Peter, W., Dopazo, X., May, S., Grimsrud, M.M., Gudbjartsson, D.F., Stefansson, K., Sulem, P., Sveinbjornsson, G., Melsted, P., Norddahl, G., Swerford Moore, K.H., Thorsteinsdottir, U., Holm, H., Alarcón-Riquelme, M.E., Bernardo, D., Martínez-Bueno, M., Rello, S.R., Magi, R., Milani, L., Metspalu, A., Laisk, T., Läll, K., Lepamets, M., Esko, T., Reimann, E., Naaber, P., Laane, E., Pesukova, J., Peterson, P., Kisand, K., Tabri, J., Allos, R., Hensen, K., Starkopf, J., Ringmets, I., Tamm, A., Kallaste, A., Alavere, H., Metsalu, K., Puusepp, M., Kristiansson, K., Koskelainen, S., Perola, M., Donner, K., Kivinen, K., Palotie, A., Bochud, P.Y., Boillat, N., Nussle, S.G., Albrich, W., Pagani, J.L., Zu Bentrup, F.M., Viollet, R.M., Kampouri, E.E., Meuwly, J.Y., D'Acremont, V., Younes, S.E., Albrich, W.C., O'Mahony, L., Kleger, G.R., Kahlert, C.R., Negro, T.R., Carreras, A., Galván-Femenía, I., Farré, X., Cortés, B., Mercader, J.M., Guindo-Martinez, M., Torrents, D., Garcia-Aymerich, J., Castaño-Vinyals, G., Dobaño, C., Gori, M., Mondelli, M.U., Castelli, F., Vaghi, M., Rusconi, S., Montagnani, F., Bargagli, E., Franchi, F., Mazzei, M.A., Cantarini, L., Tacconi, D., Feri, M., Scala, R., Spargi, G., Nencioni, C., Bandini, M., Caldarelli, G.P., Spagnesi, M., Canaccini, A., Ognibene, A., D'Arminio Monforte, A., Girardis, M., Antinori, A., Francisci, D., Schiaroli, E., Scotton, P.G., Panese, S., Scaggiante, R., Monica, M.D., Capasso, M., Fiorentino, G., Castori, M., Aucella, F., Di Biagio, A., Masucci, L., Valente, S., Mandalà, M., Zucchi, P., Giannattasio, F., Coviello, D.A., Mussini, C., Bosio, G., Tavecchia, L., Crotti, L., Rizzi, M., La Rovere, 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Reid, K., Imeson-Wood, J., Bellini, A., Bryant, J., Pickard, A., Roe, N., Sowter, J., Howlett, A., Criste, K., Cusack, R., Golder, K., Golding, H., Jones, O., Leggett, S., Male, M., Marani, M., Prager, K., Williams, T., Roberts, B., Salmon, K., Gondo, P., Kayani, A., Masunda, B., Ahmed, A., Morris, A., Jakkula, S., Long, K., Whiteley, S., Wilby, E., Ogg, B., Moultrie, S., Bewley, J., Garland, Z., Grimmer, L., Gumbrill, B., Sweet, K., Webster, D., Efford, G., Bennett, S., Goodwin, E., Jackson, M., Kent, A., Tibke, C., Woodyatt, W., Zaki, A., Daniel, A., Finn, J., Bremmer, P., Houston, G., O'Brien, P., Bell, D., Boyle, R., Douglas, K., Glass, L., Lee, E., Lennon, L., Rattray, A., Charnock, R., McFarland, D., Cosgrove, D., Attwood, B., Parsons, P., Carmody, S., Oblak, M., Popescu, M., Thankachen, M., Baruah, R., Morris, S., Ferguson, S., Shepherd, A., Altabaibeh, A., Alvaro, A., Gilbert, K., Ma, L., Mostoles, L., Parmar, C., Jetha, C., Booker, L., Pratley, A., Cosier, T., Millen, G., Schumacher, N., Weston, H., Rand, J., Alex, B., Bach, B., Barclay, W.S., Bogaert, D., Chand, M., Cooke, G.S., Docherty, A.B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C.A., Harrison, E.M., Hiscox, J.A., Ijaz, S., Khoo, S., Lim, W.S., Mentzer, A.J., Merson, L., Noursadeghi, M., Moore, S.C., Palmarini, M., Paxton, W.A., Pollakis, G., Price, N., Rambaut, A., Robertson, D.L., Sancho-Shimizu, V., Scott, J.T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R.S., Thomson, E.C., Roger Thompson, A.A., Thwaites, R.S., Turtle, LCW, Gupta, R.K., Palmieri, C., Swann, O.V., Zambon, M., Dumas, M.E., Griffin, J.L., Takats, Z., Chechi, K., Andrikopoulos, P., Osagie, A., Olanipekun, M., Liggi, S., Lewis, M.R., Correia, GDS, Sands, C.J., Takis, P., Maslen, L., Greenhalf, W., Shaw, V., McDonald, S.E., Ahmed, K.A., Armstrong, J.A., Ashworth, M., Asiimwe, I.G., Bakshi, S., Barlow, S.L., Booth, L., Brennan, B., Bullock, K., Catterall, BWA, Clark, J.J., Clarke, E.A., Cox, H., Dincarslan, O., Dunn, C., Dyer, P., Elliott, A., Evans, A., Finch, L., Fisher, LWS, Foster, T., Garcia-Dorival, I., Gunning, P., Hartley, C., Jensen, R.L., Jones, C.B., Jones, T.R., Khandaker, S., Kiy, R.T., Koukorava, C., Lake, A., Lant, S., Latawiec, D., Lavelle-Langham, L., Lefteri, D., Lett, L., Livoti, L.A., Mancini, M., McDonald, S., McEvoy, L., McLauchlan, J., Metelmann, S., Miah, N.S., Middleton, J., Mitchell, J., Murphy, E.G., Penrice-Randal, R., Pilgrim, J., Prince, T., Reynolds, W., Ridley, P.M., Sales, D., Shaw, V.E., Shears, R.K., Small, B., Subramaniam, K.S., Szemiel, A., Taggart, A., Tanianis-Hughes, J., Trochu, E., van Tonder, L., Wilcock, E., Zhang, J.E., Flaherty, L., Maziere, N., Cass, E., Carracedo, A.D., Carlucci, N., Holmes, A., Massey, H., Murphy, L., Wrobel, N., McCafferty, S., Morrice, K., MacLean, A., Armstrong, R., Boz, C., Coutts, A., Cullum, L., Day, N., Donnelly, L., Duncan, E., Fawkes, A., Finernan, P., Gilchrist, T., Golightly, A., Hafezi, K., Law, D., Law, R., Law, S., Macgillivray, L., Maclean, A., Mal, H., Mcmaster, E., Meikle, J., Oosthuyzen, W., Paterson, T., Stenhouse, A., Swets, M., Szoor-McElhinney, H., Taneski, F., Wackett, T., Ward, M., Weaver, J., Coyle, J., Gallagher, B., Lidstone-Scott, R., Hamilton, D., Schon, K., Furlong, A., Biggs, H., Griffiths, F., Andrews, E., Brickell, K., Smyth, M., Carson, G., Hardwick, H., Donohue, C., Neale, Benjamin M. [0000-0003-1513-6077], Apollo - University of Cambridge Repository, Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, Infectious diseases, Center of Experimental and Molecular Medicine, APH - Aging & Later Life, APH - Global Health, APH - Quality of Care, Amsterdam institute for Infection and Immunity, APH - Health Behaviors & Chronic Diseases, Global Health, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Anesthesiology, ACS - Diabetes & metabolism, APH - Digital Health, APH - Personalized Medicine, ACS - Microcirculation, Niemi, M. E. K., Liao, R. G., Neale, B. M., Pathak, G. A., Andrews, S. J., Schulte, E. C., Karim, M. A., Wendt, F. R., Kim, H. -N., Uddin, M. J., Smith, G. D., Willer, C. J., Buxbaum, J. D., Martin, A. R., Balaconis, M. K., Sankaran, V. G., Brent Richards, J., Eric Kerchberger, V., Kenneth Baillie, J., Dutta, A. K., Uddin, M. M., Perez-Tur, J., Verdugo, R. A., Zarate, R., Medina-Gomez, C., Gomez-Cabrero, D., Cadilla, C. L., Boua, P. R., Fave, M. -J., Lemacon, A., Szentpeteri, J. L., Ahmad, H. F., Kornilov, S. A., Prokic, I., Pearson, N. M., Shelton, J. F., Shastri, A. J., Weldon, C. H., Brouwer, M. C., Vlaar, A. P. J., Joost Wiersinga, W., Algera, A. G., Bogaard, H. J., Bonta, P. I., Grobusch, M. P., Hermans, S. M., Hovius, J. W., de Jong, M. D., Nossent, E. J., Prins, J. M., Schultz, M. J., Stijnis, C. S., Minnaar, R. P., van Uffelen, K. W. J., Wolterman, R. A., Ball, C. A., Mccurdy, S., Hong, E. L., Baltzell, A. H., Goffard, J. -C., Peree, H., Leonard, P., Giot, J. -B., Sauvage, A. -S., Wery, M., Morrison, D. R., Chasse, M., Kaufmann, D. E., Mark Lathrop, G., Davis, L. K., Cox, N. J., Below, J. E., Sealock, J. M., Faucon, A. B., Shuey, M. M., Polikowsky, H. G., Petty, L. E., Shaw, D. M., Chen, H. -H., Ludwig, K. U., Schroder, J., Nothen, M. M., Jensen, B. -E. O., Altmuller, J., Berger, M. M., Gogele, M., Gignoux, C. R., Wicks, S. J., Barnes, K. C., Goldstein, D. B., Reilly, M. P., Gharavi, A. G., O'Byrne, S. M., So, Y. S., Park, S. -K., Kim, H. -L., Kang, C. K., Lee, H. -J., Song, K. -H., Yoon, K. J., Paik, N. -J., Joo, E. -J., Park, W. B., Park, J. S., Park, K. U., Ham, S. Y., Kim, E. S., Kim, H. B., Caceres, M., Lenz, T. L., Julia, A., Holter, J. C., Fernandez, J., Sander, L. E., Banales, J. M., Romero-Gomez, M., Hov, J. R., Karlsen, T. H., Wacker, E. M., Elabd, H., Ruhlemann, M. C., Vadla, M. S., Lenning, O. B., Ozer, O., Kassens, J., Figuera Basso, M. E., Ortiz, A. B., Chercoles, A. G., Holten, A. R., Kildal, A. B., Gluck, A., Nolla, A. C., Dyrhol-Riise, A. M., Spinner, C. D., Hoff, D. A. L., Jimenez, D., Pestana, D., Helbig, E. T., Paraboschi, E. M., Sanchez, F. G., Hernandez, I., Galvan-Femenia, I., Badia, J. R., Muller, K. E., Gaede, K. I., Lippert, L. J., Tellez, L., Gutierrez-Stampa, M. A., Vehreschild, M. J. G. T., Marquie, M., Seilmaier, M. J., Rodriguez-Gandia, M., Ayo, N. I., Martinez, N., Cornely, O. A., Rodrigues, P. M., Espana, P. P., Garcia-Fernandez, A. -E., Fracanzani, A. L., Muniz-Diaz, E., Calderon, E. J., Solligard, E., Medrano, F. J., Muller, F., Afset, J. E., Damas, J. K., Ferrusquia-Acosta, J., Quero, J. H., Guerrero, J. M., Bettini, L. R., Gustad, L. T., Valsecchi, M. G., D'Angio, M., Gallego-Duran, R., Cejudo, T. G., Grimsrud, M. M., Gudbjartsson, D. F., Moore, K. H. S., Alarcon-Riquelme, M. E., Martinez-Bueno, M., Rello, S. R., Lall, K., Bochud, P. -Y., Nussle, S. G., Meyer zu Bentrup, F., Merlet Viollet, R., Guery, B., Hugli, O., Gonseth Nussle, S., Estoppey Younes, S., Rochat Negro, T., Mercader, J. M., Castano-Vinyals, G., Dobano, C., Mondelli, M. U., Mazzei, M. A., Caldarelli, G. P., Monforte, A. D., Scotton, P. G., Monica, M. D., Mandala, M., Coviello, D. A., La Rovere, M. T., Segala, F. V., Mencarelli, M. A., Pinto, A. M., Carriero, M. L., Ann Belli, M., Antoni, M. D., Miraglia, F. G., Parisi, S. G., Squeo, G. M., Botta, G., Hunt, K. A., Trembath, R. C., Martin, H. C., Griffiths, C. J., Curtis, C. J., Huang, Q. Q., Lee, S. H., Macarthur, D., Maclaughlin, B., Smith, A. V., Boughton, A. P., Li, K. W., Lefaive, J., Jannes, C. E., Krieger, J. E., Pereira, A. C., Lima, I. R., Tada, M. T., Mccarthy, M., Lee, J. E., Lee, H. S., Jang, H. Y., Kim, Y. -S., Kwon, K. T., Kim, S. -W., Kim, J. Y., Jang, Y. R., Kim, H., Lee, J. Y., Choe, K. -W., Kang, Y. M., Jee, S. H., Jung, K. J., Schroth, G. P., Desouza, F., Cirulli, E. T., Schiabor Barrett, K. M., Washington, N. L., Lu, J. T., Ramirez, J. M., Grzymski, J. J., Minano, J. I. E., Aguirre, L. A., Lopez-Collazo, E., Lozano-Rodriguez, R., Avendano-Ortiz, J., Arcos, V. T., Montalban-Hernandez, K. M., Quiroga, J. V., Martin-Quiros, A., Nakada, T. -A., Vonk, J. M., Ori, A. P. S., Hernandez Cordero, A. I., Sin, D. D., Bosse, Y., Feng, Y. -C. A., Weiss, S. T., Karlson, E. W., Smoller, J. W., Murphy, S. N., Meigs, J. B., Woolley, A. E., Green, R. C., Perez, E. F., Zollner, S., Sloofman, L. G., Sebra, R. P., Collins, B. L., Sealfon, S. C., Jordan, D. M., Thompson, R. C., Belbin, G. M., Underwood, S. J., Hiester, L. L., Charney, A. W., Beckmann, N. D., Schadt, E. E., Abul-Husn, N. S., Cho, J. H., Kenny, E. E., Loos, R. J. F., Nadkarni, G. N., Huckins, L. M., Ferreira, M. A. R., Abecasis, G. R., Leader, J. B., Cantor, M. N., Justice, A. E., Carey, D. J., Josyula, N. S., Kosmicki, J. A., Horowitz, J. E., Gass, M. C., Hottenga, J. J., de Geus, E. J. C., Nivard, M. G., Ritchie, M. D., Verma, S. S., Vari, M. S., Rahier, J. -F., Bulik, C. M., Landen, M., Ferrero, G. B., Fundin, B., Ismail, S. I., Badji, R. M., Hultstrom, M., Geschwind, D. H., Butte, M. J., Chang, T. S., Caulfield, M. J., Scott, R. H., Odhams, C. A., Karczewski, K. J., Wilson, D. J., Spencer, C. A., Crook, D. W., Wyllie, D. H., O'Connell, A. M., Atkinson, E. G., Walters, R. K., Palmer, D. S., Goldstein, J. I., Kyle Satterstrom, F., Earle, S. G., Lin, S. -K., Rudkin, J. K., Zhao, J. H., Butterworth, A. S., Sun, Y. V., Huffman, J. E., O'Donnell, C. J., Michael Gaziano, J., Ho, Y. -L., Glessner, J. R., Mcguigan, P. J., Moore, L. S. P., Vizcaychipi, M. P., Page, V. J., Aldera, E. L., Cutino-Moguel, M. -T., Durand, I., Hawcutt, D. B., Macmahon, M., Macnaughton, E., Mccullough, K., Mcewen, R., O'Shea, M. K., Pooni, J. S., Wooton, D. G., Bretherick, A. D., Fourman, M. H., Meynert, A. M., Ponting, C. P., Porteous, D. J., Russell, C. D., Wilson, J. F., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Shaw, C. A., Ho, A. Y. W., Horby, P. W., Mcauley, D., Openshaw, P. J. M., Semple, M. G., Mcgowan, J., Mcguinness, H., Mcneela, F., Bayo, L. -A., Arias, S. S., Conyngham, J. -A., Corral, M. A., de Almeida Martins, L. G., Mclaughlan, D., Mcmorrow, L., Mccormick, J., Mitchell, A. M., Maccallum, N., Hughes, R. A., Jones, T. O., Mcphail, M., Mckenley, I., Sutherland, S. -B., de Gordoa, L. O. -R., Gude, E. T., Macgoey, P., Mckenna, E., Patel, B. V., Zborowski, A. C., Garcia, S. M., Howe, G. S., Heron, A. E., Mills, G. H., Brown, C. W., Akhtar, M. N., Delgado, C. C., Saluzzio, R. P., Da Gloria, E. F., Hurt, W. J., Wood, H. -L., Mcalindon, M., Mccurdy, A., Ali, I. A. M., Ally, S. M., Hamilton, D. O., Lopez Martinez, M., Waite, A. A. C., Welters, I. D., Rosa, A. D., Baikady, R. R., Tatham, K. C., Beith, C. M., Mcgregor, A., Mcivor, S., Allison, K. S., Jones, G. A. L., Mchugh, T., Peters, M. J., Tomas, A. L., Mckechnie, S., Mccormack, L., Michael, H. T., Durrans, L. J., Suarez, J. C., Death, Y., Mccormick, W., Mccreath, G., Rai, S. G., Mcculloch, C., Mcfarland, D., Barclay, W. S., Cooke, G. S., Docherty, A. B., Green, C. A., Harrison, E. M., Hiscox, J. A., Lim, W. S., Mentzer, A. J., Paxton, W. A., Robertson, D. L., Scott, J. T., Tedder, R. S., Thomson, E. C., Thwaites, R. S., Gupta, R. K., Swann, O. V., Dumas, M. -E., Griffin, J. L., Lewis, M. R., dos Santos Correia, G., Sands, C. J., Mcdonald, S. E., Ahmed, K. A., Armstrong, J. A., Asiimwe, I. G., Barlow, S. L., Catterall, B. W. A., Clark, J. J., Clarke, E. A., Fisher, L. W. S., Jensen, R. L., Jones, C. B., Jones, T. R., Kiy, R. T., Livoti, L. A., Mcdonald, S., Mcevoy, L., Mclauchlan, J., Miah, N. S., Moore, S. C., Murphy, E. G., Matthew Ridley, P., Shaw, V. E., Shears, R. K., Subramaniam, K. S., Eunice Zhang, J., Carracedo, A. D., Mccafferty, S., Turtle, L. C. W., Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, HUS Helsinki and Uusimaa Hospital District, University of Helsinki, Research Programs Unit, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, and University of Zurich
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Male ,45/43 ,Autoimmunity ,Autoimmunity/genetics ,Body Mass Index ,COVID-19/genetics ,COVID-19/virology ,Critical Illness ,Female ,Genetic Loci/genetics ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Geographic Mapping ,Hospitalization ,Host-Pathogen Interactions/genetics ,Humans ,Inflammation/complications ,Information Dissemination ,Multifactorial Inheritance ,Racial Groups/genetics ,SARS-CoV-2/pathogenicity ,Smoking ,environmental risk factors ,Q1 ,631/208 ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Genetics, Genome-wide association studies, SARS-CoV-2, Viral infection ,GWAS ,Aetiology ,Lung ,QC ,0303 health sciences ,HERITABILITY ,3. Good health ,covid-19 ,Science & Technology - Other Topics ,Identification (biology) ,Infection ,Human ,631/208/205/2138 ,Settore BIO/11 - Biologia Molecolare ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Clinical Research ,Biodefense ,Genetics ,GENOME-WIDE ASSOCIATION ,Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP] ,METAANALYSIS ,1000 Multidisciplinary ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Science & Technology ,Prevention ,Racial Groups ,Pneumonia ,genetic architecture ,Human genetics ,Genetic Loci ,genetic factors ,570 Life sciences ,biology ,030217 neurology & neurosurgery ,Medizin ,Infektionsmedicin ,Genome-wide association studies ,Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Pandemic ,2.1 Biological and endogenous factors ,pandemi ,Multidisciplinary ,article ,Public Health, Global Health, Social Medicine and Epidemiology ,Racial Group ,10124 Institute of Molecular Life Sciences ,Host-Pathogen Interaction ,Multidisciplinary Sciences ,Infectious Diseases ,Host-Pathogen Interactions ,Critical Illne ,COVID-19, GWAS, genetic factors, environmental risk factors, therapy ,Infectious Medicine ,Coronavirus disease 2019 (COVID-19) ,SUSCEPTIBILITY LOCI ,General Science & Technology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Computational biology ,Biology ,Vaccine Related ,692/699/255/2514 ,Environmental risk ,Mendelian randomization ,COVID-19 Host Genetics Initiative ,QH426 ,631/326/596/4130 ,030304 developmental biology ,Inflammation ,therapy ,SARS-CoV-2 ,Human Genome ,COVID-19 ,Genetic architecture ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,Emerging Infectious Diseases ,Good Health and Well Being ,Viral infection ,3111 Biomedicine - Abstract
Niemi, Mari E. K. et al. 39 páginas, figuras y tablas. Contiene material suplementario., The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
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- 2021
5. Ofatumumab versus Teriflunomide in Multiple Sclerosis
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Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
- Subjects
Male ,MESH: Multiple Sclerosis, Relapsing-Remitting ,T-Lymphocytes ,Hydroxybutyrates ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Pharmacology ,Relapsing-Remitting ,MESH: Magnetic Resonance Imaging ,chemistry.chemical_compound ,0302 clinical medicine ,Teriflunomide ,Monoclonal ,MESH: Double-Blind Method ,030212 general & internal medicine ,Humanized ,MESH: Toluidines ,B-Lymphocytes ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,biology ,Subcutaneous ,B-Lymphocyte ,Brain ,General Medicine ,Magnetic Resonance Imaging ,MESH: Crotonates ,Crotonates ,Pyrimidine metabolism ,Disease Progression ,Female ,MESH: Disease Progression ,Antibody ,Human ,Adult ,Multiple Sclerosis ,Toluidines ,medicine.drug_class ,Injections, Subcutaneous ,Injections, Subcutaneou ,Monoclonal antibody ,Ofatumumab ,Settore MED/26 ,Antibodies, Monoclonal, Humanized ,Crotonate ,Antibodies ,Injections ,03 medical and health sciences ,MESH: Brain ,Multiple Sclerosis, Relapsing-Remitting ,Double-Blind Method ,MESH: B-Lymphocytes ,Nitriles ,medicine ,Humans ,MESH: Kaplan-Meier Estimate ,MESH: Humans ,business.industry ,Multiple sclerosis ,MESH: Injections, Subcutaneous ,MESH: Adult ,medicine.disease ,MESH: Male ,MESH: T-Lymphocytes ,T-Lymphocyte ,Multicenter study ,chemistry ,MESH: Antibodies, Monoclonal, Humanized ,biology.protein ,Human medicine ,business ,MESH: Female ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P
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- 2020
6. Identification of coagulation factor IX variants with enhanced activity through ancestral sequence reconstruction
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Fania Szlam, Christopher W. Coyle, Ernest T. Parker, Gabriela Denning, Roman M. Sniecinski, Eric A. Gaucher, Christopher B. Doering, H. Trent Spencer, Chen Michelle H, Jordan M. Shields, Kristopher A. Knight, Anatolii Purchel, Andrew Fedanov, Caelan E. Radford, and Pete Lollar
- Subjects
Drug discovery ,Genetic enhancement ,Hemorrhage ,Genetic Therapy ,Gene Therapy ,Hematology ,Computational biology ,Biology ,Coagulation Factor IX ,Hemophilia B ,Phenotype ,Factor IX ,Mice ,Coagulation ,Animals ,Blood Coagulation Tests ,Gene ,Sequence (medicine) ,Blood coagulation test - Abstract
Orthologous proteins contain sequence disparity guided by natural selection. In certain cases, species-specific protein functionality predicts pharmacological enhancement, such as greater specific activity or stability. However, immunological barriers generally preclude use of nonhuman proteins as therapeutics, and difficulty exists in the identification of individual sequence determinants among the overall sequence disparity. Ancestral sequence reconstruction (ASR) represents a platform for the prediction and resurrection of ancient gene and protein sequences. Recently, we demonstrated that ASR can be used as a platform to facilitate the identification of therapeutic protein variants with enhanced properties. Specifically, we identified coagulation factor VIII (FVIII) variants with improved specific activity, biosynthesis, stability, and resistance to anti-human FVIII antibody–based inhibition. In the current study, we resurrected a panel of ancient mammalian coagulation factor IX (FIX) variants with the goal of identifying improved pharmaceutical candidates. One variant (An96) demonstrated 12-fold greater FIX activity production than human FIX. Addition of the R338L Padua substitution further increased An96 activity, suggesting independent but additive mechanisms. after adeno-associated virus 2 (AAV2)/8-FIX gene therapy, 10-fold greater plasma FIX activity was observed in hemophilia B mice administered AAV2/8-An96–Padua as compared with AAV2/8-human FIX–Padua. Furthermore, phenotypic correction conferred by the ancestral variant was confirmed using a saphenous vein bleeding challenge and thromboelastography. Collectively, these findings validate the ASR drug discovery platform as well as identify an ancient FIX candidate for pharmaceutical development.
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- 2021
7. New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids
- Author
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Johanna Vappiani, Terezinha de Souza, Theo M. de Kok, Luke Coyle, Julio Saez-Rodriguez, Danyel Jennen, Daniel C. Sévin, D. F. Rodrigues, Seung-Wook Chung, Matteo Di Piazza, Bram Herpers, Attila Gábor, Mian Zhang, Anthony M. Lynch, Jos C. S. Kleinjans, Sofia Ferreira, Toxicogenomics, RS: GROW - R1 - Prevention, RS: FSE MaCSBio, RS: FPN MaCSBio, and RS: FHML MaCSBio
- Subjects
0301 basic medicine ,Male ,PHARMACOKINETICS ,Health, Toxicology and Mutagenesis ,Cell ,Apoptosis ,Toxicology ,Toxicogenomics and Omics Technologies ,COLORECTAL-CANCER ,Transcriptome ,0302 clinical medicine ,Intestine, Small ,E2F1 ,TISSUE DISTRIBUTION ,GENE-EXPRESSION ,Cell Cycle ,General Medicine ,Cell cycle ,STEM ,5-FU toxicity ,3. Good health ,Cell biology ,Organoids ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Antimetabolites, Antineoplastic ,Cell Survival ,Colon ,Human organoid models ,Biology ,HIGH-THROUGHPUT ,Models, Biological ,03 medical and health sciences ,Metabolomics ,Organoid ,Metabolome ,medicine ,Humans ,Transcriptomics ,MUCOSAL INJURY ,Transcription factor ,Dose-Response Relationship, Drug ,Molecular mechanisms ,IN-VITRO ,FLUOROURACIL ,MODEL ,Oxidative Stress ,030104 developmental biology - Abstract
5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03092-2.
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- 2021
8. Evaluation of brewers spent grains with different levels of exogenous enzymes on the production performance and body composition of Nile tilapia (Oreochromis niloticus) and channel catfish (Ictalurus punctatus)
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Shawn D. Coyle, Kalvin Rucker, James H. Tidwell, and Waldemar Rossi
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Ecology ,biology ,business.industry ,Aquatic Science ,biology.organism_classification ,Oreochromis ,Nile tilapia ,Animal science ,Aquaculture ,Ictalurus ,Exogenous enzymes ,Juvenile ,Composition (visual arts) ,business ,Catfish - Abstract
This study evaluated Brewers Spent Grains (BSG) and an enzyme additive (AllzymeTM; ENZ) in practical diets for juvenile (~5 g/fish) Nile tilapia (Trial 1) and channel catfish (Trial 2). Following a...
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- 2021
9. Cerebellar granule cell axons support high-dimensional representations
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Frederic Lanore, Diccon Coyle, Harsha Gurnani, R. Angus Silver, N. Alex Cayco-Gajic, Department of Neuroscience, Physiology & Pharmacology, University College of London [London] (UCL), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives & Computationnelles (LNC2), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lanore, Frédéric, École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)
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Male ,0301 basic medicine ,Cerebellum ,Population ,Purkinje cell ,Mice, Transgenic ,Biology ,Article ,Mice ,03 medical and health sciences ,Imaging, Three-Dimensional ,0302 clinical medicine ,medicine ,Animals ,Premovement neuronal activity ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,education ,education.field_of_study ,Neocortex ,Behavior, Animal ,General Neuroscience ,Granule cell ,Axons ,Associative learning ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Cerebellar cortex ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neuroscience ,Locomotion ,030217 neurology & neurosurgery - Abstract
In classical theories of cerebellar cortex, high-dimensional sensorimotor representations are used to separate neuronal activity patterns, improving associative learning and motor performance. Recent experimental studies suggest that cerebellar granule cell (GrC) population activity is low-dimensional. To examine sensorimotor representations from the point of view of downstream Purkinje cell ‘decoders’, we used three-dimensional acousto-optic lens two-photon microscopy to record from hundreds of GrC axons. Here we show that GrC axon population activity is high dimensional and distributed with little fine-scale spatial structure during spontaneous behaviors. Moreover, distinct behavioral states are represented along orthogonal dimensions in neuronal activity space. These results suggest that the cerebellar cortex supports high-dimensional representations and segregates behavioral state-dependent computations into orthogonal subspaces, as reported in the neocortex. Our findings match the predictions of cerebellar pattern separation theories and suggest that the cerebellum and neocortex use population codes with common features, despite their vastly different circuit structures. By recording from hundreds of cerebellar granule cell axons with three-dimensional two-photon calcium imaging, Lanore et al. show that population activity is high-dimensional and that quiet wakeful and active states are orthogonally arranged in neuronal activity space.
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- 2021
10. Vaccine Considerations for Multiple Sclerosis in the COVID-19 Era
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Scott D. Newsome, Anne Gocke, Patricia K. Coyle, and Megan Vignos
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Vaccines ,Innate immune system ,biology ,SARS-CoV-2 ,business.industry ,Multiple sclerosis ,COVID-19 ,Review ,General Medicine ,medicine.disease ,Acquired immune system ,Vaccination ,Immune system ,Immunology ,medicine ,biology.protein ,Alemtuzumab ,Pharmacology (medical) ,Glatiramer acetate ,Antibody ,business ,medicine.drug - Abstract
People with multiple sclerosis (MS) are at risk for infections that can result in amplification of baseline symptoms and possibly trigger clinical relapses. Vaccination can prevent infection through the activation of humoral and cellular immune responses. This is particularly pertinent in the era of emerging novel vaccines against severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19). MS disease-modifying therapies (DMTs), which affect the immune system, may impact immune responses to COVID-19 vaccines in people with MS. The objective of this article is to provide information on immune system responses to vaccinations and review previous studies of vaccine responses in people with MS to support the safety and importance of receiving currently available and emerging COVID-19 vaccines. Immunological studies have shown that coordinated interactions between T and B lymphocytes of the adaptive immune system are key to successful generation of immunological memory and production of neutralizing antibodies following recognition of vaccine antigens by innate immune cells. CD4+ T cells are essential to facilitate CD8+ T cell and B cell activation, while B cells drive and sustain T cell memory. Data suggest that some classes of DMT, including type 1 interferons and glatiramer acetate, may not significantly impair the response to vaccination. DMTs—such as sphingosine-1-phosphate receptor modulators, which sequester lymphocytes from circulation; alemtuzumab; and anti-CD20 therapies, which rely on depleting populations of immune cells—have been shown to attenuate responses to conventional vaccines. Currently, three COVID-19 vaccines have been granted emergency use authorization in the USA on the basis of promising interim findings of ongoing trials. Because analyses of these vaccines in people with MS are not available, decisions regarding COVID-19 vaccination and DMT choice should be informed by data and expert consensus, and personalized with considerations for disease burden, risk of infection, and other factors.
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- 2021
11. Herd Immunity against Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 10 Communities, Qatar
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Abdullatif Al Khal, Mohamed Ghaith Al Kuwari, Reham Awni El Kahlout, Naseer Ahmad Masoodi, Adeel A. Butt, Riyazuddin Mohammad Shaik, Anil George Thomas, Anvar Hassan Kaleeckal, Hiam Chemaitelly, Hanaa Nafady-Hego, Nourah Younes, Mohamed H. Al-Thani, Ahmed Al-Mohammed, Moza Alishaq, Huda Mohamad Al Naomi, Ali Nizar Latif, Abdul-Badi Abou-Samra, Einas Al Kuwari, Naema Hassan Abdulla Al Molawi, Jameela Ali A.A. Al Ajmi, Zaina Al Kanaani, Laith J. Abu-Raddad, Peter Coyle, Houssein H. Ayoub, Andrew Jeremijenko, Hadi M. Yassine, Hamad Eid Al Romaihi, Roberto Bertollini, Imtiaz Gillani, Hanan F. Abdul Rahim, and Nasser Ali Asad Al Ansari
- Subjects
Immunity, Herd ,Microbiology (medical) ,medicine.medical_specialty ,craft and manual workers ,Epidemiology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,030231 tropical medicine ,Population ,coronavirus ,Infectious and parasitic diseases ,RC109-216 ,medicine.disease_cause ,Herd immunity ,respiratory infections ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Internal medicine ,medicine ,Humans ,herd immunity ,Seroprevalence ,viruses ,030212 general & internal medicine ,education ,Qatar ,CMWs ,Coronavirus ,education.field_of_study ,Herd Immunity against Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 10 Communities, Qatar ,seroprevalence ,biology ,SARS-CoV-2 ,business.industry ,Research ,COVID-19 ,immunity ,infection ,zoonoses ,communities ,Infectious Diseases ,coronavirus disease ,biology.protein ,Medicine ,Antibody ,business ,severe acute respiratory syndrome coronavirus 2 - Abstract
We investigated what proportion of the population acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and whether the herd immunity threshold has been reached in 10 communities in Qatar. The study included 4,970 participants during June 21–September 9, 2020. Antibodies against SARS-CoV-2 were detected by using an electrochemiluminescence immunoassay. Seropositivity ranged from 54.9% (95% CI 50.2%–59.4%) to 83.8% (95% CI 79.1%–87.7%) across communities and showed a pooled mean of 66.1% (95% CI 61.5%–70.6%). A range of other epidemiologic measures indicated that active infection is rare, with limited if any sustainable infection transmission for clusters to occur. Only 5 infections were ever severe and 1 was critical in these young communities; infection severity rate of 0.2% (95% CI 0.1%–0.4%). Specific communities in Qatar have or nearly reached herd immunity for SARS-CoV-2 infection: 65%–70% of the population has been infected.
- Published
- 2021
12. Human-specific GAPDH qRT-PCR is an accurate and sensitive method of xenograft metastasis quantification
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Diana B Jo, Margaret L. Dahn, Krysta M. Coyle, Paola Marcato, and Cheryl A. Dean
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0301 basic medicine ,lcsh:QH426-470 ,law.invention ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,law ,Genetics ,medicine ,Mouse Lung ,lcsh:QH573-671 ,Human specific ,Molecular Biology ,Gene ,Polymerase chain reaction ,Glyceraldehyde 3-phosphate dehydrogenase ,biology ,lcsh:Cytology ,medicine.disease ,3. Good health ,lcsh:Genetics ,030104 developmental biology ,Real-time polymerase chain reaction ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Molecular Medicine ,Original Article - Abstract
Metastasis is the primary cause of cancer-related mortality. Experimental models that accurately reflect changes in metastatic burden are essential tools for developing treatments and to gain a better understanding of disease. Murine xenograft tumor models mimic the human scenario and provide a platform for metastasis analyses. An ex vivo quantitative method, gaining favor for its ease and accuracy, is quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR); however, it is currently unclear how well this method correlates with gold-standard histological analysis, and its use has required detection of overexpressed exogenous genes. We have introduced a variation of the qRT-PCR method: human-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDH) qRT-PCR, which allows quantification of metastasis in xenograft models without the requirement of overexpressed exogenous genes. This makes the method easily amenable to many xenograft models without alteration of the cancer cells. We determined that the method is able to detect a few human cells within abundant mouse lung tissue. Further, the human-specific GAPDH qRT-PCR is more sensitive and correlates with histological analysis in terms of determining relative metastatic burden, suggesting that human-specific GAPDH qRT-PCR could be used as a primary method for quantification of disseminated human cells in murine xenograft models., Graphical Abstract, We describe a quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR)-based method for quantifying metastasis in xenograft models. Human-specific glyceraldehyde 3-phosphate dehydrogenase (GAPDH) qRT-PCR allows quantification of a few disseminated human cells in murine tissue, without the requirement of overexpressed exogenous genes. The method is more sensitive and correlates with histological analysis.
- Published
- 2021
13. Real-Time SARS-CoV-2 Genotyping by High-Throughput Multiplex PCR Reveals the Epidemiology of the Variants of Concern in Qatar
- Author
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Hadi M. Yassine, Sathyavathi Sundararaju, Kin Ming Tsui, Patrick Tang, Hiam Chemaitelly, Laith J. Abu-Raddad, Stephan Lorenz, Faheem Mirza, Thabisile Xaba, Mahesh K. R. Kalikiri, Mohamed H. Al Thani, Reham A. El-Kahlout, Abdullatif Al Khal, Peter Coyle, Mohammad Rubayet Hasan, Anju Sharma, and Roberto Bertollini
- Subjects
Variants of concern (VOC) ,Microbiology (medical) ,Genotyping ,medicine.medical_specialty ,Genotype ,Coronavirus disease 2019 (COVID-19) ,Epidemiology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Infectious and parasitic diseases ,RC109-216 ,Computational biology ,Biology ,symbols.namesake ,Multiplex polymerase chain reaction ,medicine ,Humans ,Multiplex ,Qatar ,Whole genome sequencing ,Sanger sequencing ,SARS-CoV-2 ,COVID-19 ,General Medicine ,Infectious Diseases ,symbols ,Multiplex Polymerase Chain Reaction - Abstract
Complementing whole genome sequencing strategies with high-throughput multiplex RT-qPCR genotyping allows for more comprehensive and real-time tracking of SARS-CoV-2 variants of concern. During the second and third waves of COVID-19 in Qatar, PCR genotyping, combined with Sanger sequencing of un-typeable samples, was employed to describe the epidemiology of the Alpha, Beta and Delta variants. A total of 9792 nasopharyngeal PCR-positive samples collected between April-June 2021 were successfully genotyped, revealing the importation and transmission dynamics of these three variants in Qatar.
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- 2021
14. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance
- Author
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James C. Moon, Peter Kellman, Robert G. Bell, George Thornton, Yousuf Razvi, Thomas A. Treibel, Paramjit S. Jeetley, Gabriella Captur, Clare Coyle, Liza Chacko, Luke Howard, Abhishek Shetye, Anthony Wolff, Michael Jacobs, Toby Hillman, Rupert Negus, Hui Xue, Onn Min Kon, Meg Coleman, Daniel S Knight, Tushar Kotecha, Jamil Mayet, Melissa Heightman, Georgina Russell, Kavitha Vimalesvaran, Ben Ariff, Palmira Mathurdas, Niket Patel, Marianna Fontana, Donald Leith, James T Brown, Lucy E Lamb, Deepa Gopalan, Charlotte Manisty, Graham D. Cole, Iain Pierce, J. G. Goldring, Prapa Kanagaratnam, Rishi K Patel, and Kartik Kumar
- Subjects
medicine.medical_specialty ,Ejection fraction ,Myocarditis ,biology ,business.industry ,Convalescence ,media_common.quotation_subject ,Ischemia ,Infarction ,030204 cardiovascular system & hematology ,medicine.disease ,Troponin ,030218 nuclear medicine & medical imaging ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Cardiology ,biology.protein ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,media_common - Abstract
Background Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients. Methods and results One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms). Conclusions During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.
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- 2021
15. 3D spheroid models of paediatric SHH medulloblastoma mimic tumour biology, drug response and metastatic dissemination
- Author
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Franziska Linke, Sophie J Roper, Paul J. Scotting, and Beth Coyle
- Subjects
Cell Survival ,Science ,Cell Culture Techniques ,Antineoplastic Agents ,Biology ,Article ,Downregulation and upregulation ,In vivo ,Cell Line, Tumor ,Spheroids, Cellular ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,Hedgehog Proteins ,Cancer models ,Medulloblastoma ,Multidisciplinary ,Dose-Response Relationship, Drug ,Spheroid ,medicine.disease ,Prognosis ,Cell Cycle Gene ,In vitro ,Gene Expression Regulation, Neoplastic ,CNS cancer ,Cell culture ,Cancer research ,Medicine ,Stem cell - Abstract
Studying medulloblastoma, the most common malignant paediatric brain tumour, requires simple yet realistic in vitro models. In this study, we optimised a robust, reliable, three-dimensional (3D) culture method for medulloblastoma able to recapitulate the spatial conformation, cell–cell and cell–matrix interactions that exist in vivo and in patient tumours. We show that, when grown under the same stem cell enriching conditions, SHH subgroup medulloblastoma cell lines established tight, highly reproducible 3D spheroids that could be maintained for weeks in culture and formed pathophysiological oxygen gradients. 3D spheroid culture also increased resistance to standard-of-care chemotherapeutic drugs compared to 2D monolayer culture. We exemplify how this model can enhance in vitro therapeutic screening approaches through dual-inhibitor studies and continual monitoring of drug response. Next, we investigated the initial stages of metastatic dissemination using brain-specific hyaluronan hydrogel matrices. RNA sequencing revealed downregulation of cell cycle genes and upregulation of cell movement genes and key fibronectin interactions in migrating cells. Analyses of these upregulated genes in patients showed that their expression correlated with early relapse and overall poor prognosis. Our 3D spheroid model is a significant improvement over current in vitro techniques, providing the medulloblastoma research community with a well-characterised and functionally relevant culture method.
- Published
- 2021
16. Dissimilar biodiversity data sets yield congruent patterns and inference in lichens
- Author
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Jessica R. Coyle and James C. Lendemer
- Subjects
Ecology ,Yield (finance) ,Biogeography ,Botany ,Aggregate (data warehouse) ,Biodiversity ,Inference ,Plant Science ,Biology ,Lichen ,Ecology, Evolution, Behavior and Systematics ,Macroecology - Abstract
Large-scale efforts to aggregate and promote the re-use of biodiversity data are leading to novel insights into biogeography and macroecology. However, secondary analyses must account for the tradeoffs and limitations of the original studies. Studies of speciose and taxonomically complex groups often utilize morphospecies or functional subsets as proxies, potentially complicating data re-use. We evaluated whether lichen biodiversity patterns are robust to differences in sampling methodology, utilizing parallel analyses to compare species richness, regional species pool variation, species probabilities of occurrence, and correlation of those three with environmental variables in data sets that cover the same geographic region. Our analyses revealed that, although individual species distributions sometimes differed in idiosyncratic ways, inference based on the aggregated response of multiple species was generally robust across the two datasets, despite differences in observer expertise and functional and taxonomic scope. This suggests that biodiversity data assembled from disparate sources could be used to evaluate biogeographical and macroecological hypotheses in understudied groups such as lichens, particularly at larger spatial scales.
- Published
- 2021
17. Responses of Native and Non-native Bark and Ambrosia Beetles (Coleoptera: Curculionidae: Scolytinae) to Different Chemical Attractants: Insights From the USDA Forest Service Early Detection and Rapid Response Program Data Analysis
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Robert J. Rabaglia, Jess A Hartshorn, and David R. Coyle
- Subjects
Data Analysis ,0106 biological sciences ,Introduced species ,Biology ,Ambrosia beetle ,Generalist and specialist species ,Insect Control ,010603 evolutionary biology ,01 natural sciences ,Invasive species ,Animals ,Ambrosia ,United States Department of Agriculture ,Semiochemical ,Ecosystem ,Ecology ,General Medicine ,biology.organism_classification ,United States ,Coleoptera ,010602 entomology ,Insect Science ,visual_art ,Curculionidae ,North America ,Plant Bark ,visual_art.visual_art_medium ,Weevils ,Bark - Abstract
More than 60 non-native bark and ambrosia beetle species (Coleoptera: Curculionidae: Scolytinae) are established in North America and several have had severe negative impacts on ecosystems. Non-native scolytines can introduce fungi which may cause vascular wilts and compete with native fungi and lead to reductions in native species through host reduction. The Early Detection Rapid Response (EDRR) program was created by the USDA Forest Service in 2007 to detect non-native bark and ambrosia beetles and provide a baseline for tracking populations over time. This program has led to new collection records and increased communication among agencies to delimit non-native scolytine populations and perform appropriate management. Although insect responses to different lure types vary, it is unknown how different lures compare in attracting bark and ambrosia beetles. Our goal was to examine how lure combinations used in the EDRR program affect captures of bark and ambrosia beetle communities and to determine the most effective combination of lures for targeting non-native scolytines. The highest proportion of non-native scolytines was captured with ethanol, as was the greatest total number of species, and the most diverse beetle community. Traps with Ips (Coleoptera: Curculionidae) lures captured the highest proportion of native scolytines but the lowest total number of total species and was also the least diverse. Communities of scolytines differed significantly among lures, states, and years. While ethanol is an appropriate lure for generalist trapping and targeting a wide range of non-native bark and ambrosia beetles, more targeted lures are needed for monitoring certain species of non-natives.
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- 2021
18. Invasive Woody Plants and Their Effects on Arthropods in the United States: Challenges and Opportunities
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Jess A Hartshorn, David R. Coyle, and Sara Lalk
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0106 biological sciences ,Herbivore ,biology ,Ecology ,Privet ,Herbaceous plant ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,Invasive species ,Twig ,010602 entomology ,Pollinator ,Insect Science ,Arthropod ,Woody plant - Abstract
Invasive plant introductions are increasing globally, and trends in human activity suggest these increases will continue. Although we know much about interactions between invasive herbaceous plants and arthropod communities, there is a dearth of knowledge examining interactions between invasive woody plants and arthropod communities. What information does exist shows that invasive woody plant relationships with mutualists (e.g., pollinators), herbivores, twig- and stem-borers, leaf-litter and soil-dwelling arthropods, and other arthropod groups are complex and hint at multiple factors influencing effects. These relationships warrant additional attention to allow better prioritization of species for research and regulatory review. Chinese tallow tree, e.g., is renowned for its attractiveness to honeybees, whereas reduced pollinator populations are found among other invasive woody plants such as privet. The unknown driving mechanisms and interactions that create these differences represent a substantial gap in knowledge and warrant additional research. Our objectives are to review current knowledge regarding invasive woody plants and their interactions with various arthropod groups in the United States, outline future research needs, and present a call to action regarding invasive woody plant research.
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- 2021
19. Firewood Transport as a Vector of Forest Pest Dispersal in North America: A Scoping Review
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Shari L. Rodriguez, Leigh Greenwood, Angelica Solano, David R. Coyle, and Kevin J. Dodds
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0106 biological sciences ,Canada ,Forests ,Biology ,Firewood ,010603 evolutionary biology ,01 natural sciences ,Invasive species ,Trees ,Ecosystem services ,Globalization ,Animals ,Mexico ,Recreation ,Ecosystem ,Ecology ,Agroforestry ,General Medicine ,United States ,010602 entomology ,Insect Science ,Vector (epidemiology) ,North America ,Biological dispersal ,PEST analysis ,Introduced Species - Abstract
Native and nonnative insects and diseases can result in detrimental impacts to trees and forests, including the loss of economic resources and ecosystem services. Increases in globalization and changing human behaviors have created new anthropogenic pathways for long distance pest dispersal. In North America, literature suggests that once a forest or tree pest is established, the movement of firewood by the general public for recreational or home heating purposes is one of the primary pathways for its dispersal. Understanding human perceptions and behaviors is essential to inform the most effective strategies for modifying firewood and pest dispersal by humans. This scoping review seeks to assess trends and gaps in the existing literature, as well as patterns in behavior related to forest pest dispersal through firewood movement in North America. We identified 76 documents that addressed this topic to which we applied inclusion and exclusion criteria to select articles for further analysis. Twenty-five articles met the inclusion criteria and were categorized based on five identified themes: 1) insect incidence in firewood, 2) insect dispersal via firewood, 3) recreational firewood movement, 4) firewood treatments, and 5) behavior and rule compliance. The selected articles show trends that suggest that firewood movement presents a risk for forest insect dispersal, but that behavior can be modified, and compliance, monitoring, and treatments should be strengthened. This scoping review found limited research about western United States, Mexico, and Canada, various insect species and other organisms, regulation and management, awareness, and behavioral dimensions of firewood movement.
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- 2021
20. <scp>3D</scp> hydrogels reveal medulloblastoma subgroup differences and identify extracellular matrix subtypes that predict patient outcome
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Anbarasu Lourdusamy, Ian D. Kerr, Macha Aldighieri, Franziska Linke, Beth Coyle, Catherine L.R. Merry, Anna M. Grabowska, and Snow Stolnik
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3D model ,Models, Anatomic ,0301 basic medicine ,medulloblastoma ,vitronectin ,Pathology and Forensic Medicine ,Metastasis ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,laminin ,Laminin ,Cell Line, Tumor ,medicine ,metastasis ,Humans ,Cerebellar Neoplasms ,Medulloblastoma, Laminin, Vitronectin, Subtypes, Hydrogel, ECM, Metastasis, Chemoresistance, 3D model ,Medulloblastoma ,Original Paper ,ECM ,Tissue microarray ,biology ,subtypes ,Wnt signaling pathway ,chemoresistance ,Hydrogels ,medicine.disease ,Original Papers ,Extracellular Matrix ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Vitronectin ,hydrogel - Abstract
© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. Medulloblastoma (MB) is the most common malignant brain tumour in children and is subdivided into four subgroups: WNT, SHH, Group 3, and Group 4. These molecular subgroups differ in their metastasis patterns and related prognosis rates. Conventional 2D cell culture methods fail to recapitulate these clinical differences. Realistic 3D models of the cerebellum are therefore necessary to investigate subgroup-specific functional differences and their role in metastasis and chemoresistance. A major component of the brain extracellular matrix (ECM) is the glycosaminoglycan hyaluronan. MB cell lines encapsulated in hyaluronan hydrogels grew as tumour nodules, with Group 3 and Group 4 cell lines displaying clinically characteristic laminar metastatic patterns and levels of chemoresistance. The glycoproteins, laminin and vitronectin, were identified as subgroup-specific, tumour-secreted ECM factors. Gels of higher complexity, formed by incorporation of laminin or vitronectin, revealed subgroup-specific adhesion and growth patterns closely mimicking clinical phenotypes. ECM subtypes, defined by relative levels of laminin and vitronectin expression in patient tissue microarrays and gene expression data sets, were able to identify novel high-risk MB patient subgroups and predict overall survival. Our hyaluronan model system has therefore allowed us to functionally characterize the interaction between different MB subtypes and their environment. It highlights the prognostic and pathological role of specific ECM factors and enables preclinical development of subgroup-specific therapies. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
- Published
- 2020
21. Rhabdomyolysis in the Setting of Concomitant Use of Tafamidis, Atorvastatin, and Amiodarone
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Rodney H. Falk, Jessica Laird, Melissa L Coyle, and Sarah Cuddy
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0301 basic medicine ,Tafamidis ,medicine.medical_specialty ,Atorvastatin ,AST, aspartate aminotransferase ,030105 genetics & heredity ,Amiodarone ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,ALT, alanine aminotransferase ,Internal medicine ,medicine ,CK, creatinine kinase ,Diseases of the circulatory (Cardiovascular) system ,restrictive ,CYP3A4, cytochrome P-450 3A4 pathway ,ATTR, transthyretin amyloidosis ,biology ,LFT, liver function test ,business.industry ,nutritional and metabolic diseases ,Mini-Focus Issue: Heart Failure ,medicine.disease ,Transthyretin ,chemistry ,Cardiac amyloidosis ,RC666-701 ,Concomitant ,Cardiology ,biology.protein ,Creatine kinase ,Case Report: Clinical Case ,atherosclerosis ,BCRP, breast cancer receptor protein ,Cardiology and Cardiovascular Medicine ,business ,cardiomyopathy ,Rhabdomyolysis ,030217 neurology & neurosurgery ,medicine.drug - Abstract
An 85-year-old women with transthyretin cardiac amyloidosis presented with generalized weakness, elevated liver function test levels, and creatinine kinase consistent with rhabdomyolysis 1 week after starting tafamidis. She was already taking atorvastatin and amiodarone, raising the possibility of a drug–drug interaction inhibiting the breakdown and excretion of atorvastatin, causing drug-induced rhabdomyolysis. (Level of Difficulty: Intermediate.), Graphical abstract
- Published
- 2020
22. Using Plasmodium knowlesi as a model for screening Plasmodium vivax blood-stage malaria vaccine targets reveals new candidates
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Rachael Coyle, Duncan N. Ndegwa, Julian C. Rayner, Alejandro Marin-Menendez, Jessica B. Hostetler, Lisa H. Verzier, Theo Sanderson, Sophie H. Adjalley, Kioko Mwikali, Prasun Kundu, Ndegwa, Duncan N. [0000-0002-6980-9102], Marin-Menendez, Alejandro [0000-0002-4903-6392], Sanderson, Theo [0000-0003-4177-2851], Mwikali, Kioko [0000-0003-4252-0744], Verzier, Lisa H. [0000-0002-5518-8157], Coyle, Rachael [0000-0001-5838-1086], Adjalley, Sophie [0000-0001-6658-1707], Rayner, Julian C. [0000-0002-9835-1014], Apollo - University of Cambridge Repository, Ndegwa, Duncan N [0000-0002-6980-9102], Verzier, Lisa H [0000-0002-5518-8157], and Rayner, Julian C [0000-0002-9835-1014]
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Plasmodium ,Physiology ,Plasmodium vivax ,Protozoan Proteins ,Antibodies, Protozoan ,Biochemistry ,Medical Conditions ,0302 clinical medicine ,Animal Cells ,Immune Physiology ,Red Blood Cells ,Biology (General) ,Cells, Cultured ,Protozoans ,Vaccines ,0303 health sciences ,Immune System Proteins ,biology ,Malarial Parasites ,Eukaryota ,Genomics ,3. Good health ,Infectious Diseases ,Plasmodium knowlesi ,Cellular Types ,Antibody ,Research Article ,Infectious Disease Control ,QH301-705.5 ,030231 tropical medicine ,Immunology ,Antigens, Protozoan ,Microbiology ,Antibodies ,03 medical and health sciences ,Antigen ,Virology ,Parasite Groups ,Malaria Vaccines ,parasitic diseases ,Parasitic Diseases ,Malaria, Vivax ,Genetics ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Medicine and health sciences ,Blood Cells ,Biology and life sciences ,Merozoites ,Reverse vaccinology ,Organisms ,Proteins ,Cell Biology ,RC581-607 ,medicine.disease ,biology.organism_classification ,Parasitic Protozoans ,Polyclonal antibodies ,biology.protein ,Parasitology ,Immunologic diseases. Allergy ,Apicomplexa ,Malaria - Abstract
Plasmodium vivax is responsible for the majority of malaria cases outside Africa. Unlike P. falciparum, the P. vivax life-cycle includes a dormant liver stage, the hypnozoite, which can cause infection in the absence of mosquito transmission. An effective vaccine against P. vivax blood stages would limit symptoms and pathology from such recurrent infections, and therefore could play a critical role in the control of this species. Vaccine development in P. vivax, however, lags considerably behind P. falciparum, which has many identified targets with several having transitioned to Phase II testing. By contrast only one P. vivax blood-stage vaccine candidate based on the Duffy Binding Protein (PvDBP), has reached Phase Ia, in large part because the lack of a continuous in vitro culture system for P. vivax limits systematic screening of new candidates. We used the close phylogenetic relationship between P. vivax and P. knowlesi, for which an in vitro culture system in human erythrocytes exists, to test the scalability of systematic reverse vaccinology to identify and prioritise P. vivax blood-stage targets. A panel of P. vivax proteins predicted to function in erythrocyte invasion were expressed as full-length recombinant ectodomains in a mammalian expression system. Eight of these antigens were used to generate polyclonal antibodies, which were screened for their ability to recognize orthologous proteins in P. knowlesi. These antibodies were then tested for inhibition of growth and invasion of both wild type P. knowlesi and chimeric P. knowlesi lines modified using CRISPR/Cas9 to exchange P. knowlesi genes with their P. vivax orthologues. Candidates that induced antibodies that inhibited invasion to a similar level as PvDBP were identified, confirming the utility of P. knowlesi as a model for P. vivax vaccine development and prioritizing antigens for further follow up., Author summary Malaria parasites cause disease after invading human red blood cells, implying that a vaccine that interrupts this process could play a significant role in malaria control. Multiple Plasmodium parasite species can cause malaria in humans, and most malaria outside Africa is caused by Plasmodium vivax. There is currently no effective vaccine against the blood stage of any malaria parasite, and progress in P. vivax vaccine development has been particularly hampered because this parasite species cannot be cultured for prolonged periods of time in the lab. We explored whether a related species, P. knowlesi, which can be propagated in human red blood cells in vitro, can be used to screen for potential P. vivax vaccine targets. We raised antibodies against selected P. vivax proteins and tested their ability to recognize and prevent P. knowlesi parasites from invading human red blood cells, thereby identifying multiple novel vaccine candidates.
- Published
- 2021
23. Efficacy of five herbicide treatments for control of Pyrus calleryana
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James T. Vogt, Francis A. Roesch, Scott Horn, Chris Barnes, Christopher M. Crowe, Chip Bates, David R. Coyle, and David Jenkins
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0106 biological sciences ,Integrated pest management ,PEAR ,010504 meteorology & atmospheric sciences ,Triclopyr ,Plant Science ,Imazapyr ,Biology ,010603 evolutionary biology ,01 natural sciences ,Hexazinone ,chemistry.chemical_compound ,Horticulture ,chemistry ,visual_art ,Glyphosate ,Aminopyralid ,visual_art.visual_art_medium ,Bark ,0105 earth and related environmental sciences - Abstract
Callery pear (Pyrus calleryana Decne.) is rapidly spreading in the United States, gaining attention in the last two decades as a serious invasive pest. Recommended control methods include foliar, basal bark, cut stump, and hack-and-squirt application of herbicides, but there are few published studies with replicated data on efficacy. Four readily available herbicidal active ingredients and a combination of two active ingredients were tested for control efficacy against P. calleryana in old-field areas and loblolly pine (Pinus taeda L.) understory. Basal bark applications (triclopyr, triclopyr + aminopyralid), foliar applications (glyphosate, imazapyr), and a soil application (hexazinone) effectively killed P. calleryana with the exception of hexazinone at one site, where rainfall may not have been optimal. Foliar application of glyphosate provided the most consistent control. Our results demonstrate efficacy of registered herbicide formulations for P. calleryana control in two geographic locations and two habitat types. The need for development of integrated pest management programs for P. calleryana is discussed.
- Published
- 2020
24. Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity
- Author
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Chang-Jiun Wu, Ximing Tang, David H. Peng, Marcelo V. Negrao, Aik Choon Tan, Kazutaka Fukumura, Stephen G. Swisher, John V. Heymach, Jing Wang, Xin Hu, Latasha Little, Alexandre Reuben, Jianhua Zhang, Anthony San Lucas, Kenichi Suda, Jianjun Zhang, Ali Jalali, P. Andrew Futreal, Won-Chul Lee, Shawna M Hubert, Emily Roarty, Marcus Coyle, Erik P. Sulman, Ganesh Rao, Carmen Behrens, Jason T. Huse, Rebecca Thornton, Neda Kalhor, Jihye Kim, Xingzhi Song, Don L. Gibbons, Runzhe Chen, Whijae Roh, Chia Chin Wu, Chi-Wan Chow, Daniel R. Gomez, Lixia Diao, Chad Tang, Wei Lu, Jun Li, Curtis Gumbs, Nicholas McGranahan, Junya Fujimoto, J. Jack Lee, Paul Scheet, and Ignacio I. Wistuba
- Subjects
Lung Neoplasms ,lcsh:QH426-470 ,Somatic cell ,medicine.medical_treatment ,Biology ,Immune profiling ,Metastasis ,Transcriptome ,Mice ,Carcinoma, Non-Small-Cell Lung ,Exome Sequencing ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Lung cancer ,lcsh:QH301-705.5 ,Exome sequencing ,Immunosuppression Therapy ,Research ,Immunosuppression ,Genomics ,DNA Methylation ,medicine.disease ,Multiomics ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,lcsh:Genetics ,lcsh:Biology (General) ,Mutation ,Monoclonal ,Cancer research ,Gene expression ,DNA methylation - Abstract
Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
- Published
- 2020
25. Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia
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Donna L. McPhie, Hae-Young Kim, Gun-Hoo Park, Peiyan Ni, Yiren Qin, Sangmi Chung, Joseph T. Coyle, Zhicheng Shao, Derek T Le, James M. Park, Haneul Noh, Chiderah P Abani, Weihua Huang, Hualin S. Xi, Dongxin Liu, Changhong Yin, Joy S. Park, Cameron P Beaudreault, Bruce M. Cohen, Sasha Z Gonzalez, Thomas A. Lanz, and Youxin Guan
- Subjects
Adult ,Male ,0301 basic medicine ,Induced Pluripotent Stem Cells ,Gene Expression ,Glutamic Acid ,Biology ,Article ,Transcriptome ,Young Adult ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Immune system ,Interneurons ,Gene expression ,medicine ,Humans ,Induced pluripotent stem cell ,gamma-Aminobutyric Acid ,Cerebral Cortex ,Microglia ,General Neuroscience ,Middle Aged ,medicine.disease ,Coculture Techniques ,Mitochondria ,Metabolic pathway ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Schizophrenia ,Encephalitis ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.
- Published
- 2020
26. Evaluation of growth, sex (male proportion; sexual dimorphism), and color segregation in four cross combinations of different strains of <scp>XX</scp> female and <scp>YY</scp> male <scp>Nile Tilapia</scp>
- Author
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Shawn D. Coyle, Noel D. Novelo, Alexander G. Kramer, and Boris Gomelsky
- Subjects
Sexual dimorphism ,Nile tilapia ,biology ,Zoology ,Aquatic Science ,biology.organism_classification ,Agronomy and Crop Science ,Crossbreed - Published
- 2020
27. Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing
- Author
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Sriram Balasubramanian, Quratulain Qureshi, Christopher Rushton, Miguel Alcaide, Nicole Thomas, Krysta M. Coyle, Bruno M. Grande, Prasath Pararajalingam, Barbara Meissner, Joseph M. Connors, Diego Villa, Ryan D. Morin, Constantine S. Tam, Randy D. Gascoyne, David W. Scott, Graham W. Slack, Christian Steidl, Nathalie A. Johnson, Timothy E. Audas, Marco A. Marra, Sarah E. Arthur, Rishu Agarwal, Andrew J. Mungall, Merrill Boyle, Sarah-Jane Dawson, and Georg Lenz
- Subjects
Adult ,Male ,0301 basic medicine ,Genotype ,Immunology ,Lymphoma, Mantle-Cell ,Biology ,medicine.disease_cause ,Biochemistry ,Genome ,Heterogeneous-Nuclear Ribonucleoproteins ,03 medical and health sciences ,Exon ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,Exome ,Exome sequencing ,Aged ,Aged, 80 and over ,Mutation ,Whole Genome Sequencing ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Lymphoma ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Mantle cell lymphoma - Abstract
Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.
- Published
- 2020
28. The pseudo-caspase FLIP(L) regulates cell fate following p53 activation
- Author
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Kirsty M. McLaughlin, Tamas Sessler, Peter Gallagher, Emma M. Kerr, Wendy L. Allen, Alexander J. McIntyre, Gemma M.A. Gregg, Vicky M. Coyle, Gerard P. Quinn, Melissa Labonte-Wilson, Nyree Crawford, Daniel B. Longley, Jamie Z. Roberts, Andrea Lees, Fiammetta Falcone, Mark Wappett, Patrick G. Johnston, Christopher McCann, Katherine McAllister, Caitriona Holohan, Laurence J. Egan, Aideen E. Ryan, Philip D Dunne, and Simon S. McDade
- Subjects
Pyridines ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Antineoplastic Agents ,Apoptosis ,Cell fate determination ,Models, Biological ,Piperazines ,TNF-Related Apoptosis-Inducing Ligand ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,Cell Line, Tumor ,Puma ,Humans ,Gene silencing ,Protein Kinase Inhibitors ,Caspase ,Caspase 8 ,Multidisciplinary ,biology ,Entinostat ,Cell Cycle ,Imidazoles ,Acetylation ,Drug Synergism ,Proto-Oncogene Proteins c-mdm2 ,Biological Sciences ,biology.organism_classification ,Cell biology ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Gene Expression Regulation ,chemistry ,Flip ,Benzamides ,biology.protein ,Mdm2 ,Tumor Suppressor Protein p53 ,Protein Binding - Abstract
p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.
- Published
- 2020
29. First molecular analysis of rabies virus in Qatar and clinical cases imported into Qatar, a case report
- Author
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Georgina Arron, Imad Ibrahim, Khaled A. Mohran, Nidal Mahmoud Younis, Marion Koopmans, Wael Goravey, Randa Abdeen, A. Aziz Mahmoud A.H. Al-Zeyara, Muneera Mohammed Saleh Alrajhi, Mazharul Islam, Reina S. Sikkema, Corine H. GeurtsvanKessel, Hamad Al-Romaihi, Elmoubashar Farag, Anne van der Linden, Robert H.G. Kohl, Peter Coyle, Bas B. Oude Munnink, Claudia M. E. Schapendonk, Richard Molenkamp, Mohammad Hamad J. Al Thani, Hisham Ziglam, and Virology
- Subjects
0301 basic medicine ,Microbiology (medical) ,Nanopore sequencing ,030106 microbiology ,Rabies virus ,General Medicine ,Biology ,medicine.disease_cause ,Genome ,Virology ,Molecular analysis ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,metagenomic sequencing ,medicine ,rabies virus ,lcsh:RC109-216 ,030212 general & internal medicine - Abstract
Identifying the origin of the rabies virus (RABV) infection may have significant implications for control measures. Here, we identified the source of a RABV infection of two Nepalese migrants in Qatar by comparing their RABV genomes with RABV genomes isolated from the brains of a RABV infected camel and fox from Qatar.
- Published
- 2020
30. TLR Stimulation Produces IFN-β as the Primary Driver of IFN Signaling in Nonlymphoid Primary Human Cells
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Stefano V Gullà, Stephen P. Berasi, Ryan Bellmore, Steven A. Greenberg, Ankur Sharma, Janet E. Buhlmann, Christine Huard, Edyta Tyminski, Christine Loreth, Anthony J. Coyle, Ryan Nistler, Katrina Meeth, and Alireza Kalbasi
- Subjects
Myxovirus Resistance Proteins ,Cell type ,Immunology ,Inflammation ,Biology ,Ligands ,Peripheral blood mononuclear cell ,medicine ,Humans ,Immunology and Allergy ,Cells, Cultured ,Interferon-alpha ,TLR9 ,Interferon-beta ,General Medicine ,TLR7 ,Gene signature ,Healthy Volunteers ,Toll-Like Receptor 3 ,Toll-Like Receptor 4 ,Toll-Like Receptor 7 ,Toll-Like Receptor 8 ,Toll-Like Receptor 9 ,TLR3 ,TLR4 ,Cancer research ,medicine.symptom ,Signal Transduction - Abstract
Several human autoimmune diseases are characterized by increased expression of type 1 IFN-stimulated genes in both the peripheral blood and tissue. The contributions of different type I IFNs to this gene signature are uncertain as the type I IFN family consists of 13 alphas and one each of β, ε, κ, and ω subtypes. We sought to investigate the contribution of various IFNs to IFN signaling in primary human cell types. We stimulated primary skin, muscle, kidney, and PBMCs from normal healthy human donors with various TLR ligands and measured the expression of type I IFN subtypes and activation of downstream signaling by quantitative PCR. We show that IFNB1 is the dominant type I IFN expressed upon TLR3 and TLR4 stimulation, and its expression profile is associated with subsequent MX1 transcription. Furthermore, using an IFN-β–specific neutralizing Ab, we show that MX1 expression is inhibited in a dose-dependent manner, suggesting that IFN-β is the primary driver of IFN-stimulated genes following TLR3 and TLR4 engagement. Stimulation with TLR7/8 and TLR9 ligands induced IFNB1 and IFNA subtypes and MX1 expression only in PBMCs and not in tissue resident cell types. Concordantly, IFN-β neutralization had no effect on MX1 expression in PBMCs potentially because of the combination of IFNB1 and IFNA expression. Combined, these data highlight the potential role for IFN-β in driving local inflammatory responses in clinically relevant human tissue types and opportunities to treat local inflammation by targeting IFN-β.
- Published
- 2020
31. Membrane Association Transforms an Inert Anti-TCRβ Fab’ Ligand into a Potent T Cell Receptor Agonist
- Author
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Nicole C. Fay, Jenny J. Lin, Michael P. Coyle, Kiera B. Wilhelm, Katherine N. Alfieri, Shalini T. Low-Nam, Jay T. Groves, and Geoff P. O’Donoghue
- Subjects
0303 health sciences ,biology ,Chemistry ,Ligand ,Phosphatase ,T-cell receptor ,Biophysics ,chemical and pharmacologic phenomena ,NFAT ,Major histocompatibility complex ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,biology.protein ,Lipid bilayer ,Receptor ,Transcription factor ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
The natural peptide-major histocompatibility complex (pMHC) ligand for T cell receptors (TCRs) is inactive from solution yet capable of activating T cells at single-molecule levels when membrane-associated. This distinctive feature stems from the mechanism of TCR activation, which is thought to involve steric phosphatase exclusion as well as direct mechanical forces. It is possible to defeat this mechanism and activate T cells with solution ligands by cross-linking pMHC or using multivalent antibodies to TCR. However, these widely used strategies activate TCRs through a nonphysiological mechanism and can produce different activation profiles than natural, monovalent, membrane-associated pMHC. Here, we introduce a strictly monovalent anti-TCRβ H57 Fab’ ligand that, when coupled to a supported lipid bilayer via DNA complementation, triggers TCRs and activates nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT) with a similar potency to pMHC in primary murine T cells. Importantly, like monovalent pMHC and unlike bivalent antibodies, monovalent Fab’-DNA triggers TCRs only when physically coupled to the membrane, and only around 100 individual Fab’:TCR interactions are necessary to stimulate early T cell activation.
- Published
- 2020
32. Characterizing tourism benefits associated with top‐predator conservation in coastal British Columbia
- Author
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Rebecca G. Martone, Theraesa A. Coyle, Bertine Stelzer, Kai M. A. Chan, and Robin Naidoo
- Subjects
0106 biological sciences ,010504 meteorology & atmospheric sciences ,Ecology ,biology ,Natural resource economics ,15. Life on land ,Aquatic Science ,010603 evolutionary biology ,01 natural sciences ,Otter ,Ecosystem services ,Geography ,Ecotourism ,biology.animal ,Revenue ,Marine ecosystem ,14. Life underwater ,Recreation ,Tourism ,0105 earth and related environmental sciences ,Nature and Landscape Conservation ,Apex predator - Abstract
Facing public concern over costs related to top‐predator reintroductions and conservation, ecosystem services such as ecotourism are often used to evoke benefits that outweigh or offset those costs. Quantifying these benefits using rigorous scientific methods can provide confidence to policymakers and other stakeholders that predators can in fact deliver positive outcomes to people living alongside them. The evaluation of these benefits is often anecdotal or qualitative, however, and empirical quantifications are rare. In coastal marine ecosystems, sea otter reintroduction is seen as a conservation success to some but a bane to others. The contribution of sea otters (Enyhdra lutris) to tourism revenue is touted as a crucial ecosystem service benefit to offset the loss of shellfish harvesting and associated revenue, but remains unquantified, weakening the favourable reception of conservation action. The potential economic benefits of sea otters associated with tourism and the extent to which benefits are realized were evaluated based on: (i) choice‐experiment surveys of tourists; and (ii) interviews with tourism operators in British Columbia. Sea otters were a strong factor in people's choices regarding wildlife viewing, and sea otters could have large benefits for local economies. Alongside socio‐economic characteristics, tourism experience influences tourists’ preferences. Tourism operators did not perceive sea otters as strongly influencing tourist choice, highlighting the gap that can occur between the perception and the reality of tourist preferences, leading to missed opportunities for the alignment of economic development with conservation actions.
- Published
- 2020
33. Spatial and temporal dynamics of Pacific capelin Mallotus catervarius in the Gulf of Alaska: implications for ecosystem-based fisheries management
- Author
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John K. Horne, Esther D. Goldstein, Mayumi L. Arimitsu, Alison L. Deary, Matthew T. Wilson, William T. Stockhausen, David W. McGowan, Kris Holderied, Olav A. Ormseth, Lauren A. Rogers, Kenneth O. Coyle, A. De Robertis, Stephani G. Zador, and John F. Piatt
- Subjects
0106 biological sciences ,010504 meteorology & atmospheric sciences ,Ecology ,biology ,Spawning habitat ,010604 marine biology & hydrobiology ,Capelin ,Aquatic Science ,biology.organism_classification ,01 natural sciences ,Fishery ,Geography ,Forage fish ,Mallotus ,Ecosystem ,Fisheries management ,Ecology, Evolution, Behavior and Systematics ,0105 earth and related environmental sciences - Abstract
Pacific capelin Mallotus catervarius are planktivorous small pelagic fish that serve an intermediate trophic role in marine food webs. Due to the lack of a directed fishery or monitoring of capelin in the Northeast Pacific, limited information is available on their distribution and abundance, and how spatio-temporal fluctuations in capelin density affect their availability as prey. To provide information on life history, spatial patterns, and population dynamics of capelin in the Gulf of Alaska (GOA), we modeled distributions of spawning habitat and larval dispersal, and synthesized spatially indexed data from multiple independent sources from 1996 to 2016. Potential capelin spawning areas were broadly distributed across the GOA. Models of larval drift show the GOA’s advective circulation patterns disperse capelin larvae over the continental shelf and upper slope, indicating potential connections between spawning areas and observed offshore distributions that are influenced by the location and timing of spawning. Spatial overlap in composite distributions of larval and age-1+ fish was used to identify core areas where capelin consistently occur and concentrate. Capelin primarily occupy shelf waters near the Kodiak Archipelago, and are patchily distributed across the GOA shelf and inshore waters. Interannual variations in abundance along with spatio-temporal differences in density indicate that the availability of capelin to predators and monitoring surveys is highly variable in the GOA. We demonstrate that the limitations of individual data series can be compensated for by integrating multiple data sources to monitor fluctuations in distributions and abundance trends of an ecologically important species across a large marine ecosystem.
- Published
- 2020
34. Prions and Prion-like assemblies in neurodegeneration and immunity: The emergence of universal mechanisms across health and disease
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Ailis O'Carroll, Joanne Coyle, and Yann Gambin
- Subjects
0301 basic medicine ,Innate immune system ,Prions ,Effector ,Neurodegeneration ,Neurodegenerative Diseases ,Cell Biology ,Disease ,Biology ,medicine.disease ,Immunity, Innate ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Health ,Immunity ,medicine ,Animals ,Humans ,Structural motif ,Neuroscience ,030217 neurology & neurosurgery ,Intracellular ,Developmental Biology - Abstract
Prion-like behaviour is an abrupt process, an "all-or-nothing" transition between a monomeric species and an "infinite" fibrillated form. Once a nucleation point is formed, the process is unstoppable as fibrils self-propagate by recruiting and converting all monomers into the amyloid fold. After the "mad cow" episode, prion diseases have made the headlines, but more and more prion-like behaviours have emerged in neurodegenerative diseases, where formation of fibrils and large conglomerates of proteins deeply disrupt the cell homeostasis. More interestingly, in the last decade, examples emerged to suggest that prion-like conversion can be used as a positive gain of function, for memory storage or structural scaffolding. More recent experiments show that we are only seeing the tip of the iceberg and that, for example, prion-like amplification is found in many pathways of the immune response. In innate immunity, receptors on the cellular surface or within the cells 'sense' danger and propagate this information as signal, through protein-protein interactions (PPIs) between 'receptor', 'adaptor' and 'effector' proteins. In innate immunity, the smallest signal of a foreign element or pathogen needs to trigger a macroscopic signal output, and it was found that adaptor polymerize to create an extreme signal amplification. Interestingly, our body uses multiple structural motifs to create large signalling platform; a few innate proteins use amyloid scaffolds but most of the polymers discovered are composed by self-assembly in helical filaments. Some of these helical assemblies even have intercellular "contamination" in a "true" prion action, as demonstrated for ASC specks and MyD88 filaments. Here, we will describe the current knowledge in neurodegenerative diseases and innate immunity and show how these two very different fields can cross-seed discoveries.
- Published
- 2020
35. Ciliate behavior: blueprints for dynamic cell biology and microscale robotics
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Scott M. Coyle
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0301 basic medicine ,Models, Molecular ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Human–computer interaction ,Blueprint ,Animals ,Humans ,Ciliophora ,Molecular Biology ,Microscale chemistry ,Ciliate ,business.industry ,Systems Biology ,Active systems ,Robotics ,Cell Biology ,Modular design ,biology.organism_classification ,Molecular machine ,030104 developmental biology ,Artificial intelligence ,business ,030217 neurology & neurosurgery ,Perspectives - Abstract
Place a drop of pond water under the microscope, and you will likely find an ocean of extraordinary and diverse single-celled organisms called ciliates. This remarkable group of single-celled organisms wield microtubules, active systems, electrical signaling, and chemical sensors to build intricate geometrical structures and perform complex behaviors that can appear indistinguishable from those of macroscopic animals. Advances in computer vision and machine learning are making it possible to completely digitize and track the dynamics of complex ciliates and mine these data for the hidden structure, patterns, and motifs that are responsible for their behaviors. By deconstructing the diversity of ciliate behaviors in the natural world, themes for organizing and controlling matter at the microscale are beginning to take hold, suggesting new modular approaches for the design of autonomous molecular machines that emulate nature’s finest examples.
- Published
- 2020
36. Quality Control Measures in Short Tandem Repeat (STR) Analysis
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Heather Miller Coyle
- Subjects
STR analysis ,Quality control ,Microsatellite ,Computational biology ,Biology - Published
- 2022
37. Statistical Confusion among Graduate Students: Sickness or Symptom?
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Boyles, Justin G., Aubrey, Doug P., Cooper, Brandon S., Cox, Jonathan G., Coyle, David R., Fisher, Ryan J., Hoffman, Justin D., and Storm, Jonathan J.
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- 2008
- Full Text
- View/download PDF
38. Evolutionary conservation of systemic and reversible amyloid aggregation
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Stephanie Vlachos, Byoungjoo Yoo, Ryan D. Morin, Lionel Pereira, Krysta M. Coyle, Richard Zapf, Timothy E. Audas, Nicholas Harden, Emma Lacroix, Sahil Chandhok, and Dane Marijan
- Subjects
0303 health sciences ,Amyloid ,Saccharomyces cerevisiae ,Biophysics ,Cell Biology ,Biology ,biology.organism_classification ,Conserved sequence ,Cell biology ,Mice ,03 medical and health sciences ,Drosophila melanogaster ,0302 clinical medicine ,Protein structure ,medicine.anatomical_structure ,medicine ,Animals ,Identification (biology) ,Nucleus ,030217 neurology & neurosurgery ,Organism ,030304 developmental biology - Abstract
In response to environmental stress, human cells have been shown to form reversible amyloid aggregates within the nucleus, termed amyloid bodies (A-bodies). These protective physiological structures share many of the biophysical characteristics associated with the pathological amyloids found in Alzheimer's and Parkinson's disease. Here, we show that A-bodies are evolutionarily conserved across the eukaryotic domain, with their detection in Drosophila melanogaster and Saccharomyces cerevisiae marking the first examples of these functional amyloids being induced outside of a cultured cell setting. The conditions triggering amyloidogenesis varied significantly among the species tested, with results indicating that A-body formation is a severe, but sublethal, stress response pathway that is tailored to the environmental norms of an organism. RNA-sequencing analyses demonstrate that the regulatory low-complexity long non-coding RNAs that drive A-body aggregation are both conserved and essential in human, mouse and chicken cells. Thus, the identification of these natural and reversible functional amyloids in a variety of evolutionarily diverse species highlights the physiological significance of this protein conformation, and will be informative in advancing our understanding of both functional and pathological amyloid aggregation events. This article has an associated First Person interview with the first author of the paper.
- Published
- 2021
39. DDRE-37. YB-1 AS A BIOMARKER FOR DRUG RESISTANCE AND TUMOUR PROGRESSION IN MEDULLOBLASTOMA
- Author
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Beth Coyle, Louisa Taylor, and Ian D. Kerr
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Medulloblastoma ,Cisplatin ,Cancer Research ,Vincristine ,biology ,business.industry ,Cancer ,Drug resistance ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,Oncology ,Tumor progression ,medicine ,biology.protein ,Cancer research ,Biomarker (medicine) ,Neurology (clinical) ,business ,medicine.drug ,P-glycoprotein - Abstract
Medulloblastoma (MB) relapse is the most significant unmet clinical challenge in childhood cancer. Recently it has become evident that MBs display altered biology at relapse, indicative of the emergence and expansion of a minor, therapy resistant cancer cell population. Thus, the examination of mechanisms underlying therapy resistance is of critical importance. Y-box binding protein 1 (YB-1) is a multi-functional oncoprotein whose elevated expression and nuclear accumulation correlate with drug resistance, metastasis and disease progression in numerous cancers, although little is known about the functional role of YB-1 in MB. Genomic analysis of large-scale publicly available patient datasets revealed YB-1 expression is significantly elevated across MB molecular subgroups and high expression correlates with poor overall survival. Immunohistochemical analysis of YB-1 localisation in patient TMAs revealed significant YB-1 nuclear accumulation, suggestive of elevated YB-1 nuclear activity in these patients. Treatment of Group 3 MB cell lines (D283MED and HDMB-03) with cisplatin and subsequent analysis by nuclear/cytoplasmic fractionation and confocal microscopy revealed significantly increased nuclear and overall YB-1 expression, indicating a role for YB-1 in cellular stress response. In support of this, ChIP analysis in D283MED and HDMB-03 cell lines confirmed YB-1 interaction with multi-drug transporter gene ABCB1, while stable YB-1 knockdown resulted in significantly reduced ABCB1 expression. Likewise, knockdown of YB-1 expression in D283MED cells results in increased susceptibility of cells to vincristine, supporting a role for YB-1 in the acquisition of drug resistance in MB cell lines. Finally, whole transcriptome sequencing of YB-1-knockdown HDMB-03 and D283MED cell lines indicated YB-1 regulation of a variety of cell death, survival and metabolic pathways. We are currently using ChIP-Seq analysis to identify targetable YB-1 downstream “hits” which drive these processes. Ultimately, we aim to identify druggable targets of YB-1 allowing us to establish more effective therapeutic options for the treatment of high-risk MB.
- Published
- 2021
40. Protective antigenic sites identified in respiratory syncytial virus fusion protein reveals importance of p27 domain
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Laura Klenow, Juanjie Tang, Youri Lee, Surender Khurana, Hana Golding, Supriya Ravichandran, Elizabeth M. Coyle, and Jeehyun Lee
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Medicine (General) ,viruses ,Respiratory Syncytial Virus Infections ,Biology ,QH426-470 ,Antibodies, Viral ,Virus ,Epitope ,Article ,Mice ,Immune system ,R5-920 ,Antigen ,vaccine ,Genetics ,Respiratory Syncytial Virus Vaccines ,Animals ,Antibody-dependent cell-mediated cytotoxicity ,epitope ,Mice, Inbred BALB C ,F protein ,virus diseases ,RSV ,Articles ,respiratory system ,neutralization ,Virology ,Fusion protein ,Antibodies, Neutralizing ,Microbiology, Virology & Host Pathogen Interaction ,Respiratory Syncytial Virus, Human ,biology.protein ,Molecular Medicine ,Antibody ,Viral load ,Viral Fusion Proteins - Abstract
Respiratory syncytial virus (RSV) vaccines primarily focused on surface fusion (F) protein are under development. Therefore, to identify RSV‐F protective epitopes, we evaluated 14 antigenic sites recognized following primary human RSV infection. BALB/c mice were vaccinated with F peptides, F proteins, or RSV‐A2, followed by rA2‐Line19F challenge. F peptides generated binding antibodies with minimal in vitro neutralization titers. However, several F peptides (including Site II) reduced lung viral loads and lung pathology scores in animals, suggesting partial protection from RSV disease. Interestingly, animals vaccinated with peptides (aa 101–121 and 110–136) spanning the F‐p27 sequence, which is only present in unprocessed F0 protein, showed control of viral loads with significantly reduced pathology compared with mock‐vaccinated controls. Furthermore, we observed F‐p27 expression on the surface of RSV‐infected cells as well as lungs from RSV‐infected mice. The anti‐p27 antibodies demonstrated antibody‐dependent cellular cytotoxicity (ADCC) of RSV‐infected A549 cells. These findings suggest that p27‐mediated immune response may play a role in control of RSV disease in vivo, and F‐p27 should be considered for inclusion in an effective RSV vaccine., This study identifies possible protective linear antigenic sites on the RSV F protein in a mouse RSV challenge model for development of RSV vaccine. We show that F‐p27 peptide control viral loads and reduced RSV disease in vivo. Therefore, F‐p27 should be included in an effective RSV vaccine.
- Published
- 2021
41. Competing at the Cybathlon Championship for Athletes With Disabilities: Long-Term Motor Imagery Brain-Computer Interface Training of a Tetraplegic Cybathlete
- Author
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Karl McCreadie, Jacqui Stow, Attila Korik, Niall McShane, Jacinta McElligott, Damien Coyle, Naomi du Bois, Áine Carroll, and Massoud Khodadadzadeh
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medicine.medical_specialty ,Physical medicine and rehabilitation ,Motor imagery ,biology ,Athletes ,medicine ,Training (meteorology) ,Championship ,biology.organism_classification ,Psychology ,Term (time) ,Brain–computer interface - Abstract
Background: The brain-computer interface (BCI) race at the Cybathlon championship for athletes with disabilities challenges teams (BCI researchers, developers and pilots with spinal cord injury) to control an avatar on a virtual racetrack without movement. Here we describe the training regime and results of the Ulster University BCI Team pilot who is tetraplegic and has trained to use an electroencephalography (EEG)-based BCI intermittently over 10 years, to compete in three Cybathlon events. Methods: A multi-class, multiple binary classifier framework was used to decode three kinesthetically imagined movements (motor imagery) (left (L) and right (R) arm and feet (F)) as well as relax state (X). Three games paradigms were used for training i.e., NeuroSensi, Triad, and Cybathlon: BrainDriver. An evaluation of the pilot’s performance is presented for two Cybathlon competition training periods – spanning 20 sessions over 5 weeks prior to the 2019 competition, and 25 sessions over 5 weeks in the run up to the 2020 competition.Results: Having participated in BCI training in 2009 and competed in Cybathlon 2016, the experienced pilot achieved high two-class accuracy on all class pairs when training began in 2019 (decoding accuracy >90%, resulting in efficient NeuroSensi and Triad game control). The BrainDriver performance (i.e., Cybathlon race completion time) improved significantly during the training period, leading up to the competition day, ranging from 274s - 156s (255±24s to 191±14s mean±std), over 17 days (10 sessions) in 2019, and from 230s - 168s (214±14s to 181±4s), over 18 days (13 sessions) in 2020. However, on both competition occasions, towards the race date, the performance deteriorated significantly.Conclusions: The training regime and framework applied were highly effective in achieving competitive race completion times. The BCI framework did not cope with significant deviation in electroencephalography (EEG) observed in the sessions occurring shortly before and during the race day. Stress, arousal level and fatigue, associated with the competition challenge and performance pressure resulting in cognitive state changes, were likely contributing factors to the nonstationary effects that resulted in the BCI and pilot achieving suboptimal performance on race day. Trial registration: not registered
- Published
- 2021
42. Real-Time SARS-CoV-2 Genotyping by High-Throughput Multiplex PCR Reveals the Epidemiology of the Variants of Concern in Qatar
- Author
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Reham A. El-Kahlout, Laith J. Abu-Raddad, Mohammad Rubayet Hasan, Hadi M. Yassine, Mahesh K. R. Kalikiri, Kin Ming Tsui, Abdullatif Al Khal, Peter Coyle, Stephan Lorenz, Faheem Mirza, Mohamed H. Al Thani, Sathyavathi Sundararaju, Hiam Chemaitelly, Anju Sharma, Patrick Tang, and Roberto Bertollini
- Subjects
Whole genome sequencing ,Sanger sequencing ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Computational biology ,Biology ,symbols.namesake ,Multiplex polymerase chain reaction ,Epidemiology ,medicine ,symbols ,Multiplex ,Genotyping - Abstract
Complementing whole genome sequencing strategies with high-throughput multiplex RT-qPCR genotyping allows for more comprehensive and real-time tracking of SARS-CoV-2 variants of concern. During the second and third waves of COVID-19 in Qatar, PCR genotyping, combined with Sanger sequencing of un-typeable samples, was employed to describe the epidemiology of the Alpha, Beta and Delta variants. A total of 9792 nasopharyngeal PCR-positive samples collected between April-June 2021 were successfully genotyped, revealing the importation and transmission dynamics of these three variants in Qatar.
- Published
- 2021
43. Epidemiology Profile of Viral Meningitis Infections Among Patients in Qatar (2015–2018)
- Author
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Peter Coyle, Hadi M. Yassine, Muna Al Maslamani, Nadin Younes, Asmaa A. Al Thani, Gheyath K. Nasrallah, Joanne Daghfal Nader, Shilu Mathew, Hebah A. Al Khatib, and Khalid Al Ansari
- Subjects
0301 basic medicine ,Serotype ,medicine.medical_specialty ,Medicine (General) ,viruses ,viral meningitis ,clinical outcome ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,Internal medicine ,medicine ,Viral meningitis ,030212 general & internal medicine ,Original Research ,Molecular epidemiology ,biology ,business.industry ,enterovirus ,Varicella zoster virus ,General Medicine ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,genotyping ,Parechovirus ,Etiology ,Medicine ,Enterovirus ,epidemiology ,business ,Meningitis - Abstract
Background:Little is known about the etiology of meningitis in the MENA region, including Qatar. Viral agents are considered the major cause for meningitis worldwide. Here, we present primary data about the etiology and clinical and demographic characteristics of viral meningitis (VM) in Qatar between 2015 and 2018.Methods:We retrospectively collected data from Hamad Medical Corporation (HMC), which provides about 80% of healthcare services in Qatar. Data were collected for the period between 2015 and 2018. During this time period, 6,705 specimens were collected from patients with suspected meningitis attending HMC and primary healthcare centers. These specimens were tested for a panel of viruses using the “FTD Viral meningitis” multiplex real-time PCR kit that detects Adenovirus (ADV), Human herpesvirus 1&2 (HSV1 and HSV2), Epstein–Barr virus (EBV), Enteroviruses (EV), Cytomegalovirus (CMV), Varicella zoster virus (VZV), and Parechovirus (PV).Results:Only 10.9% (732/6,705) of all suspected meningitis cases were caused by viral agents. 60.9% of the reported cases were males, compared to 39.1% in females. Most of the infections (73.9%) were reported in children younger than 10 years of age. EV were identified as the main causative agent (68.7%), followed by EBV (7.5%) and ADV (6.8%). Other viral agents including VZV, PV, HSV-1, and HSV-2 were also detected with a lower frequency. Confirmed VM were more prevalent among Qatari subjects compared to other nationalities. We observed no specific seasonality of viral agents, but a slight rise was recorded during the spring seasons (March to June). Fever (59.4%, 435/732) and acute central nervous system (CNS) infection (15.6%, 114/732) were initial symptoms of most cases.Conclusion:This is the first report about the molecular epidemiology of VM in Qatar. In line with the international records, our data showed that EV is responsible for 68.7% of Qatar's VM cases. Further studies are needed to genotype and serotype the identified viruses.
- Published
- 2021
- Full Text
- View/download PDF
44. Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine
- Author
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Staffan Schmidt, Joseph T. Coyle, Micaela Galante, Glenn Dallérac, Kevin C. F. Fone, Silvia Sacchi, Grégoire Levasseur, Jan Kehr, David J. G. Watson, Brigitte Potier, Xia Li, Pierre Lecouflet, Alain M. Gardier, Loredano Pollegioni, Thu Ha Pham, Rachel Asselot, Angelo Contarino, Pascal Fossat, Jean-Pierre Mothet, Millan Mark, Andrey Besedin, Ginetta Collo, Thomas Freret, Jean-Michel Rivet, Nadege Morisot, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Lumière, Matière et Interfaces (LuMIn), CentraleSupélec-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), University of Nottingham, UK (UON), Pronexus Analytical AB, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches SERVIER (IRS), Harvard Medical School [Boston] (HMS), McLean Hospital [Belmont, Ma.], Università degli Studi di Brescia = University of Brescia (UniBs), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, The Protein Factory 2.0, Dipartimento di Biotecnologie e Scienze della Vita, Laboratoire de Neuropharmacologie, Centre de Recherche en Epidémiologie et Santé des Populations, School of Life Sciences, Queen's Medical Centre, Centre for Thérapeutique Innovation in Neuropsychiatry, Department of Psychiatry, Harvard Medical School, USA, Laboratory for Psychiatric and Molecular Neuroscience, Università degli Studi di Brescia [Brescia], The ProFactory 2.0, Dipartimento di Biotecnologie e Scienze della Vita, Universitá degli Studi dell’Insubria, and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,serine racemase knockout mice ,D1- and D2-type receptors ,NMDA receptors ,d-serine ,schizophrenia ,Dopamine ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Racemases and Epimerases ,Glutamic Acid ,Prefrontal Cortex ,Biology ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,Receptors, Dopamine ,Mice ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Neuromodulation ,Serine ,medicine ,Animals ,Prefrontal cortex ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,Dopaminergic ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,Long-term potentiation ,D-serine ,Schizophrenia ,Serine racemase knockout mice ,Biological Sciences ,medicine.anatomical_structure ,Synaptic plasticity ,NMDA receptor ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
International audience; Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d -serine is implicated in the dopamine–glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d -serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D 1 and D 3 receptors. Using in vivo microdialysis, we show that D 1 and D 3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d -serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d -serine is required for the potentiation of cognition by D 3 R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d -serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine–glutamate cross-talk.
- Published
- 2021
45. Analytic comparison between three high-throughput commercial SARS-CoV-2 antibody assays reveals minor discrepancies in a high-incidence population
- Author
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Andrew Jeremijenko, Soha R. Dargham, Mohamed H. Al-Thani, Laith J. Abu-Raddad, Hiam Chemaitelly, Farah Shurrab, Zaina Al Kanaani, Abdullatif Al Khal, Hadi M. Yassine, Hamad Eid Al Romaihi, Duaa W. Al-Sadeq, Riyazuddin Mohammad Shaik, Mohamed Ghaith Al Kuwari, Gheyath K. Nasrallah, Hanan F. Abdul Rahim, Hadeel Al-Jighefee, Roberto Bertollini, Hamda Qotba, Patrick Tang, Anvar Hassan Kaleeckal, Einas Al Kuwari, Asmaa Althani, Ali Nizar Latif, and Peter Coyle
- Subjects
0301 basic medicine ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Epidemiology ,assays ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Science ,030106 microbiology ,Population ,Antibodies, Viral ,Gastroenterology ,Sensitivity and Specificity ,Article ,Serology ,COVID-19 Serological Testing ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,antibody ,medicine ,Seroprevalence ,Humans ,030212 general & internal medicine ,education ,SARS‑CoV‑2 ,education.field_of_study ,Multidisciplinary ,biology ,business.industry ,SARS-CoV-2 ,Incidence (epidemiology) ,Incidence ,COVID-19 ,Viral infection ,Immunoglobulin G ,biology.protein ,Infectious diseases ,Medicine ,Antibody ,business - Abstract
Performance of three automated commercial serological IgG-based assays was investigated for assessing SARS-CoV-2 “ever” (past or current) infection in a population-based sample in a high exposure setting. PCR and serological testing was performed on 394 individuals. SARS-CoV-2-IgG seroprevalence was 42.9% (95% CI 38.1–47.8%), 40.6% (95% CI 35.9–45.5%), and 42.4% (95% CI 37.6–47.3%) using the CL-900i, VidasIII, and Elecsys assays, respectively. Between the three assays, overall, positive, and negative percent agreements ranged between 93.2–95.7%, 89.3–92.8%, and 93.8–97.8%, respectively; Cohen’s kappa statistic ranged from 0.86 to 0.91; and 35 specimens (8.9%) showed discordant results. Among all individuals, 12.5% (95% CI 9.6–16.1%) had current infection, as assessed by PCR. Of these, only 34.7% (95% CI 22.9–48.7%) were seropositive by at least one assay. A total of 216 individuals (54.8%; 95% CI 49.9–59.7%) had evidence of ever infection using antibody testing and/or PCR during or prior to this study. Of these, only 78.2%, 74.1%, and 77.3% were seropositive in the CL-900i, VidasIII, and Elecsys assays, respectively. All three assays had comparable performance and excellent agreement, but missed at least 20% of individuals with past or current infection. Commercial antibody assays can substantially underestimate ever infection, more so when infection rates are high.
- Published
- 2021
46. Haplotype analysis for Irish ancestry
- Author
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Robert Whiting and Heather Miller Coyle
- Subjects
Biology ,DNA dragnet ,Y chromosome ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Pathology and Forensic Medicine ,Analytical Chemistry ,Irish ,familial search ,lcsh:K5000-5582 ,Physical and Theoretical Chemistry ,Sexual assault ,Genetics ,forensic genetics ,lcsh:Public aspects of medicine ,Haplotype ,lcsh:RA1-1270 ,Original Articles ,DNA ,language.human_language ,Forensic science ,Psychiatry and Mental health ,haplotype analysis ,Anthropology ,language ,lcsh:Criminal law and procedure ,Forensic sciences ,Bloodstain pattern analysis ,Forensic genetics ,Research Article - Abstract
Forensic haplotype analysis of the male Y chromosome is currently used to establish the number of male donors in sexual assaults, the number of male bleeders in blood pattern analysis, and for ancestry correlation to genetic founder populations in biogeographic studies. In forensic laboratory applications, its primary use is for DNA profile generation with trace amounts of male DNA in the presence of excess female DNA (e.g. spermatozoa identification, male component of fingernail scrapings). Our study supports the potential use of the Y chromosome in a “dragnet” approach (most haplotypes are unique) similar to that described by Kayser in 2017 for solving a cold case sex assault and homicide in The Netherlands. Our study also researched the potential for the identification of an ancestral Irish genetic “footprint” linked to surname O’Brien and identified multiple founder group origins in Ireland and England as well as three samples with the Dal Riata (a Gaelic overkingdom) ancestral haplotype. This study indicates correlation to ancestral Irish ancestry by haplotype but not conclusively to the O’Brien surname.
- Published
- 2019
47. Abiotic and Biotic Factors Affecting Loblolly Pine Health in the Southeastern United States
- Author
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Kier D. Klepzig, Lawrence A. Morris, William J. Otrosina, Kamal J.K. Gandhi, John T. Nowak, Brittany F. Barnes, William D. Smith, David R. Coyle, and Frank H. Koch
- Subjects
0106 biological sciences ,Abiotic component ,Biotic component ,Ecology ,biology ,Ecological Modeling ,Forestry ,biology.organism_classification ,complex mixtures ,010603 evolutionary biology ,01 natural sciences ,Loblolly pine ,Environmental science ,Heterobasidion ,010606 plant biology & botany - Abstract
Southern pine forests are important fiber and wood sources, and critical to local, regional, and national economies in the United States. Recently, certain areas of southern pine forests, especially those dominated by loblolly pine (Pinus taeda), have been reported to exhibit abnormally high levels of tree dieback and mortality. However, causal agents either have not been well defined or are controversial in their impacts on tree health. We assessed various abiotic (e.g., slope, aspect, soil characteristics) and biotic (e.g., tree species, stand characteristics, presence of root fungi) factors in 37 healthy (asymptomatic) and unhealthy (symptomatic) sites to elucidate specific factors affecting loblolly pine health in Alabama and Georgia. Soil nutrient content did not differ statistically between healthy and unhealthy sites, but manganese contents were slightly greater, and nitrogen and carbon contents were slightly lower in healthy sites. Unhealthy sites did have a higher silt content than did healthy sites. Pine stems and basal area were greater on unhealthy than on healthy sites, whereas opposite trends were observed for the incidence of stem cankers and mechanical damage. An increased incidence of the root fungal pathogen Heterobasidion irregulare, the causal agent of Heterobasidion root disease, was found on unhealthy sites, but incidence of Leptographium spp. did not differ between the two site types. Thus, soil attributes, stand structure, and management history seem to be the most critical factors affecting loblolly pine health, at least at the local level. Further, some of these factors may be improved through appropriate silvicultural techniques, emphasizing the importance of silviculture in maintaining pine health throughout the southern region.
- Published
- 2019
48. Social network analysis reveals specialized trade in an Endangered songbird
- Author
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L. Ovalle, Brian Coyle, Kathryn M. Rodríguez-Clark, J. Morales-Campos, Ada Sánchez-Mercado, Lisandro Morán, M. Á. Arvelo, Arlene Cardozo-Urdaneta, and Michael J. Braun
- Subjects
0106 biological sciences ,Red Siskin ,Ecology ,biology ,Corruption ,010604 marine biology & hydrobiology ,media_common.quotation_subject ,Law enforcement ,Social network analysis (criminology) ,Endangered species ,Context (language use) ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,Intermediary ,Development economics ,Spite ,Business ,Nature and Landscape Conservation ,media_common - Abstract
Unsustainable harvest is one of the most important threats to biodiversity, and birds are highly impacted, but avian markets remain poorly understood. When species value and corruption/criminality are high, the “parallel trafficking” hypothesis predicts that illegal animal items will move through networks used for other illicit products. Alternatively, when particular demands, logistical skills or access limits trade, “specialized trafficking” hypotheses predict that few, expert actors will control markets. Here, we use social network analysis of trade in an Endangered songbird, the Red Siskin Spinus cucullatus, originating in Venezuela, to examine the generality of the parallel trafficking hypothesis in a setting where corruption/criminality and species value are high. In spite of these circumstances, of 2575 Red Siskin (RS) records compiled from 2010 to 2017, we found just six reports consistent with parallel trafficking. Instead, we discovered an independent network of 15 actor types, and a trade structure consistent with specialized trafficking. Just two intermediary types (national vendors to intermediaries and to consumers) and one consumer type (national breeders) had the highest exposure to the flow of birds, and the most trade connectivity. Use of wild‐caught over captive‐bred birds was high (67% of records), as was use of natural‐phenotype birds over hybrid or mutant‐phenotype birds (65% of records). Geographically, Spain and Venezuela had the highest exposure to the flow of birds, but Brazil and Colombia had the most direct connections with other countries. The unexpected lack of evidence for parallel trafficking suggests that combined flows of illicit products are not inevitable, even in adverse settings. In a context where law enforcement may not be feasible, our results suggest that it may be possible to reduce unsustainable harvest using breeder connectivity in informational campaigns to stimulate peer‐to‐peer interactions and accelerate behavior change.
- Published
- 2019
49. Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics
- Author
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Jeehyun Lee, Andrew B. Ward, Juanjie Tang, Laura Klenow, Kazuyo Takeda, Surender Khurana, Hannah L. Turner, Elizabeth M. Coyle, Hana Golding, Jody Manischewitz, and Katie L. Winarski
- Subjects
0301 basic medicine ,Chemokine ,medicine.drug_class ,Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,Virus Replication ,Monoclonal antibody ,Virus ,Madin Darby Canine Kidney Cells ,Mice ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Orthomyxoviridae Infections ,In vivo ,medicine ,Animals ,Antibody-dependent enhancement ,Lung ,Mice, Inbred BALB C ,Binding Sites ,Multidisciplinary ,biology ,Chemistry ,Influenza A Virus, H3N2 Subtype ,Virion ,Antibodies, Monoclonal ,Biological Sciences ,Viral Load ,Virus Internalization ,Virology ,Endocytosis ,030104 developmental biology ,Viral replication ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Female ,Antibody ,Viral load ,Protein Binding - Abstract
Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles' entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus-receptor interaction.
- Published
- 2019
50. Connectivity between spawning and nursery areas for Pacific cod (Gadus macrocephalus) in the Gulf of Alaska
- Author
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Georgina A. Gibson, Sarah Hinckley, Miriam J. Doyle, William T. Stockhausen, Carolina Parada, Albert J. Hermann, Kenneth O. Coyle, Carol Ladd, André E. Punt, Thomas P. Hurst, and Benjamin J. Laurel
- Subjects
0106 biological sciences ,geography ,geography.geographical_feature_category ,010504 meteorology & atmospheric sciences ,biology ,010604 marine biology & hydrobiology ,Pacific cod ,Model system ,Oceanography ,biology.organism_classification ,01 natural sciences ,Early life ,symbols.namesake ,Ocean gyre ,symbols ,Biological dispersal ,Gadus ,Sound (geography) ,Lagrangian ,0105 earth and related environmental sciences - Abstract
We present the results of a study of the connectivity between Pacific cod spawning and nursery areas, and settlement of Pacific cod in the Gulf of Alaska. This work was conducted to address the hypothesis that spatial and temporal patterns of recruitment are related to variability in connectivity between spawning and nursery areas. To examine this hypothesis, we developed a Lagrangian, biophysical, individual-based model of Pacific cod early life history and dispersal using the Dispersal Model for Early Life Stages (DisMELS) framework. This model is driven by currents and scalars such as temperature from a version of the Regional Oceanographic Model System (ROMS) developed for the Gulf of Alaska. Results of our study show connectivity patterns predicted by the model that agree with our understanding (based on genetic analyses) that there is a high degree of localized retention in Pacific cod. The results indicate that the Shumagin Islands and Prince William Sound regions may serve as important collectors of Pacific cod recruits from upstream spawning areas. We also find correlations between individual-based model outputs and several large-scale climate indicators that appear to show settlement in several important nursery areas, and recruitment overall, are positively affected by slower gyre circulation in the Gulf of Alaska. We hypothesize that this is due to enhancement of retention, settlement in the Shumagin Island region, and reduction of transport of young cod out of the Gulf of Alaska to the southwest.
- Published
- 2019
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