205 results on '"Repressor Protein"'
Search Results
2. Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
-
Kousathanas, A, Pairo-Castineira, E, Rawlik, K, Stuckey, A, Odhams, C, Walker, S, Russell, C, Malinauskas, T, Wu, Y, Millar, J, Shen, X, Elliott, K, Griffiths, F, Oosthuyzen, W, Morrice, K, Keating, S, Wang, B, Rhodes, D, Klaric, L, Zechner, M, Parkinson, N, Siddiq, A, Goddard, P, Donovan, S, Maslove, D, Nichol, A, Semple, M, Zainy, T, Maleady-Crowe, F, Todd, L, Salehi, S, Knight, J, Elgar, G, Chan, G, Arumugam, P, Patch, C, Rendon, A, Bentley, D, Kingsley, C, Kosmicki, J, Horowitz, J, Baras, A, Abecasis, G, Ferreira, M, Justice, A, Mirshahi, T, Oetjens, M, Rader, D, Ritchie, M, Verma, A, Fowler, T, Shankar-Hari, M, Summers, C, Hinds, C, Horby, P, Ling, L, Mcauley, D, Montgomery, H, Openshaw, P, Elliott, P, Walsh, T, Tenesa, A, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Pathak, G, Karjalainen, J, Stevens, C, Andrews, S, Kanai, M, Cordioli, M, Polimanti, R, Pirinen, M, Harerimana, N, Veerapen, K, Wolford, B, Nguyen, H, Solomonson, M, Liao, R, Chwialkowska, K, Trankiem, A, Balaconis, M, Hayward, C, Richmond, A, Campbell, A, Morris, M, Fawns-Ritchie, C, Glessner, J, Shaw, D, Chang, X, Polikowski, H, Petty, L, Chen, H, Wanying, Z, Hakonarson, H, Porteous, D, Below, J, North, K, Mccormick, J, Timmers, P, Wilson, J, D'Mellow, K, Kerr, S, Niemi, M, Nkambul, L, von Hohenstaufen, K, Sobh, A, Eltoukhy, M, Yassen, A, Hegazy, M, Okasha, K, Eid, M, Moahmed, H, Shahin, D, El-Sherbiny, Y, Elhadidy, T, Abd Elghafar, M, El-Jawhari, J, Mohamed, A, Elnagdy, M, Samir, A, Abdel-Aziz, M, Khafaga, W, El-Lawaty, W, Torky, M, El-shanshory, M, Batini, C, Lee, P, Shrine, N, Williams, A, Tobin, M, Guyatt, A, John, C, Packer, R, Ali, A, Free, R, Wang, X, Wain, L, Hollox, E, Venn, L, Bee, C, Adams, E, Niavarani, A, Sharififard, B, Aliannejad, R, Amirsavadkouhi, A, Naderpour, Z, Tadi, H, Aleagha, A, Ahmadi, S, Moghaddam, S, Adamsara, A, Saeedi, M, Abdollahi, H, Hosseini, A, Chariyavilaskul, P, Chamnanphon, M, Suttichet, T, Shotelersuk, V, Pongpanich, M, Phokaew, C, Chetruengchai, W, Jantarabenjakul, W, Putchareon, O, Torvorapanit, P, Puthanakit, T, Suchartlikitwong, P, Hirankarn, N, Nilaratanakul, V, Sodsai, P, Brumpton, B, Hveem, K, Willer, C, Zhou, W, Rogne, T, Solligard, E, Asvold, B, Abedalthagafi, M, Alaamery, M, Alqahtani, S, Barakeh, D, Al Harthi, F, Alsolm, E, Safieh, L, Alowayn, A, Alqubaishi, F, Al Mutairi, A, Mangul, S, Alshareef, A, Sawaji, M, Almutairi, M, Aljawini, N, Albesher, N, Arabi, Y, Mahmoud, E, Khattab, A, Halawani, R, Alahmadey, Z, Albakri, J, Felemban, W, Suliman, B, Hasanato, R, Al-Awdah, L, Alghamdi, J, Alzahrani, D, Aljohani, S, Al-Afghani, H, Alrashed, M, Aldhawi, N, Albardis, H, Alkwai, S, Alswailm, M, Almalki, F, Albeladi, M, Almohammed, I, Barhoush, E, Albader, A, Massadeh, S, Almalik, A, Alotaibi, S, Alghamdi, B, Jung, J, Fawzy, M, Lee, Y, Magnus, P, Trogstad, L, Helgeland, O, Harris, J, Mangino, M, Spector, T, Duncan, E, Smieszek, S, Przychodzen, B, Polymeropoulos, C, Polymeropoulos, V, Polymeropoulos, M, Fernandez-Cadenas, I, Perez-Tur, J, Llucia-Carol, L, Cullell, N, Muino, E, Carcel-Marquez, J, Dediego, M, Iglesias, L, Planas, A, Soriano, A, Rico, V, Aguero, D, Bedini, J, Lozano, F, Domingo, C, Robles, V, Ruiz-Jaen, F, Marquez, L, Gomez, J, Coto, E, Albaiceta, G, Garcia-Clemente, M, Dalmau, D, Arranz, M, Dietl, B, Serra-Llovich, A, Soler, P, Colobran, R, Martin-Nalda, A, Martinez, A, Bernardo, D, Rojo, S, Fiz-Lopez, A, Arribas, E, de la Cal-Sabater, P, Segura, T, Gonzalez-Villa, E, Serrano-Heras, G, Marti-Fabregas, J, Jimenez-Xarrie, E, de Felipe Mimbrera, A, Masjuan, J, Garcia-Madrona, S, Dominguez-Mayoral, A, Villalonga, J, Menendez-Valladares, P, Chasman, D, Buring, J, Ridker, P, Franco, G, Sesso, H, Manson, J, Medina-Gomez, C, Uitterlinden, A, Ikram, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Ripatti, S, Ruotsalainen, S, Kaunisto, M, Nakanishi, T, Butler-Laporte, G, Forgetta, V, Morrison, D, 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, Schurr, E, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Lepage, P, Ragoussis, J, Auld, D, Brassard, N, Durand, M, Chasse, M, Kaufmann, D, Lathrop, G, Mooser, V, Richards, J, Li, R, Adra, D, Rahmouni, S, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Guntz, J, Azarzar, S, Gofflot, S, Beguin, Y, Claassen, S, Malaise, O, Huynen, P, Meuris, C, Thys, M, Jacques, J, Leonard, P, Frippiat, F, Giot, J, Sauvage, A, von Frenckell, C, Belhaj, Y, Lambermont, B, Pigazzini, S, Nkambule, L, Daya, M, Shortt, J, Rafaels, N, Wicks, S, Crooks, K, Barnes, K, Gignoux, C, Chavan, S, Laisk, T, Lall, K, Lepamets, M, Magi, R, Esko, T, Reimann, E, Milani, L, Alavere, H, Metsalu, K, Puusepp, M, Metspalu, A, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Bochud, P, Rivolta, C, Bibert, S, Quinodoz, M, Kamdar, D, Boillat, N, Nussle, S, Albrich, W, Suh, N, Neofytos, D, Erard, V, Voide, C, de Cid, R, Galvan-Femenia, I, Blay, N, Carreras, A, Cortes, B, Farre, X, Sumoy, L, Moreno, V, Mercader, J, Guindo-Martinez, M, Torrents, D, Kogevinas, M, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Renieri, A, Mari, F, Fallerini, C, Daga, S, Benetti, E, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, M, Alaverdian, D, Busani, S, Bruno, R, Vecchia, M, Belli, M, Picchiotti, N, Sanarico, M, Gori, M, Furini, S, Mantovani, S, Ludovisi, S, Mondelli, M, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Vaghi, M, Rusconi, S, Siano, M, Montagnani, F, Emiliozzi, A, Fabbiani, M, Rossetti, B, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Bandini, M, Caldarelli, G, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazzi, A, Lorubbio, M, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Cossarizza, A, Antinori, A, Vergori, A, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Gabbi, C, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, La Rovere, M, Sarzi-Braga, S, Bussotti, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Zguro, K, Capitani, K, Suardi, C, Dei, S, Parati, G, Ravaglia, S, Artuso, R, Botta, G, Di Domenico, P, Rancan, I, Perrella, A, Bianchi, F, Romani, D, Bergomi, P, Catena, E, Colombo, R, Tanfoni, M, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Segala, F, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Smith, A, Boughton, A, Li, K, Lefaive, J, Annis, A, Chittoor, G, Josyula, N, Leader, J, Carey, D, Gass, M, Cantor, M, Yadav, A, van Heel, D, Hunt, K, Mason, D, Huang, Q, Finer, S, Trivedi, B, Griffiths, C, Martin, H, Wright, J, Trembath, R, Soranzo, N, Zhao, J, Butterworth, A, Danesh, J, Di Angelantonio, E, Franke, L, Boezen, M, Deelen, P, Claringbould, A, Lopera, E, Warmerdam, R, Vonk, J, van Blokland, I, Lanting, P, Ori, A, Zollner, S, Wang, J, Beck, A, Peloso, G, Ho, Y, Sun, Y, Huffman, J, O'Donnell, C, Cho, K, Tsao, P, Gaziano, J, Nivard, M, de Geus, E, Bartels, M, Jan Hottenga, J, Weiss, S, Karlson, E, Smoller, J, Green, R, Feng, Y, Murphy, S, Meigs, J, Woolley, A, Perez, E, Li, B, Verma, S, Lucas, A, Bradford, Y, Zeberg, H, Frithiof, R, Hultstrom, M, Lipcsey, M, Tardif, N, Rooyackers, O, Grip, J, Maricic, T, Karczewski, K, Atkinson, E, Tsuo, K, Baya, N, Turley, P, Gupta, R, Callier, S, Walters, R, Palmer, D, Sarma, G, Cheng, N, Lu, W, Bryant, S, Churchhouse, C, Cusick, C, Goldstein, J, King, D, Seed, C, Finucane, H, Martin, A, Satterstrom, F, Wilson, D, Armstrong, J, Rudkin, J, Band, G, Earle, S, Lin, S, Arning, N, Crook, D, Wyllie, D, O'Connell, A, Spencer, C, Koelling, N, Caulfield, M, Scott, R, Moutsianas, L, Pasko, D, Ball, C, Hong, E, Rand, K, Girshick, A, Guturu, H, Baltzell, A, Roberts, G, Park, D, Coignet, M, Mccurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Sloofman, L, Charney, A, Beckmann, N, Schadt, E, Jordan, D, Thompson, R, Gettler, K, Abul-Husn, N, Ascolillo, S, Buxbaum, J, Chaudhary, K, Cho, J, Itan, Y, Kenny, E, Belbin, G, Sealfon, S, Sebra, R, Salib, I, Collins, B, Levy, T, Britvan, B, Keller, K, Tang, L, Peruggia, M, Hiester, L, Niblo, K, Aksentijevich, A, Labkowsky, A, Karp, A, Zlatopolsky, M, Preuss, M, Loos, R, Nadkarni, G, Do, R, Hoggart, C, Choi, S, Underwood, S, O'Reilly, P, Huckins, L, Zyndorf, M, Daly, M, Neale, B, Ganna, A, Fawkes, A, Murphy, L, Rowan, K, Ponting, C, Vitart, V, Yang, J, Bretherick, A, Hendry, S, Law, A, Baillie, J, Kousathanas A., Pairo-Castineira E., Rawlik K., Stuckey A., Odhams C. A., Walker S., Russell C. D., Malinauskas T., Wu Y., Millar J., Shen X., Elliott K. S., Griffiths F., Oosthuyzen W., Morrice K., Keating S., Wang B., Rhodes D., Klaric L., Zechner M., Parkinson N., Siddiq A., Goddard P., Donovan S., Maslove D., Nichol A., Semple M. G., Zainy T., Maleady-Crowe F., Todd L., Salehi S., Knight J., Elgar G., Chan G., Arumugam P., Patch C., Rendon A., Bentley D., Kingsley C., Kosmicki J. A., Horowitz J. E., Baras A., Abecasis G. R., Ferreira M. A. R., Justice A., Mirshahi T., Oetjens M., Rader D. J., Ritchie M. D., Verma A., Fowler T. A., Shankar-Hari M., Summers C., Hinds C., Horby P., Ling L., McAuley D., Montgomery H., Openshaw P. J. M., Elliott P., Walsh T., Tenesa A., Shelton J. F., Shastri A. J., Ye C., Weldon C. H., Filshtein-Sonmez T., Coker D., Symons A., Esparza-Gordillo J., Aslibekyan S., Auton A., Pathak G. A., Karjalainen J., Stevens C., Andrews S. J., Kanai M., Cordioli M., Polimanti R., Pirinen M., Harerimana N., Veerapen K., Wolford B., Nguyen H., Solomonson M., Liao R. G., Chwialkowska K., Trankiem A., Balaconis M. K., Hayward C., Richmond A., Campbell A., Morris M., Fawns-Ritchie C., Glessner J. T., Shaw D. M., Chang X., Polikowski H., Petty L. E., Chen H. -H., Wanying Z., Hakonarson H., Porteous D. J., Below J., North K., McCormick J. B., Timmers P. R. H. J., Wilson J. F., D'Mellow K., Kerr S. M., Niemi M. E. K., Nkambul L., von Hohenstaufen K. A., Sobh A., Eltoukhy M. M., Yassen A. M., Hegazy M. A. F., Okasha K., Eid M. A., Moahmed H. S., Shahin D., El-Sherbiny Y. M., Elhadidy T. A., Abd Elghafar M. S., El-Jawhari J. J., Mohamed A. A. S., Elnagdy M. H., Samir A., Abdel-Aziz M., Khafaga W. T., El-Lawaty W. M., Torky M. S., El-shanshory M. R., Batini C., Lee P. H., Shrine N., Williams A. T., Tobin M. D., Guyatt A. L., John C., Packer R. J., Ali A., Free R. C., Wang X., Wain L. V., Hollox E. J., Venn L. D., Bee C. E., Adams E. L., Niavarani A., Sharififard B., Aliannejad R., Amirsavadkouhi A., Naderpour Z., Tadi H. A., Aleagha A. E., Ahmadi S., Moghaddam S. B. M., Adamsara A., Saeedi M., Abdollahi H., Hosseini A., Chariyavilaskul P., Chamnanphon M., Suttichet T. B., Shotelersuk V., Pongpanich M., Phokaew C., Chetruengchai W., Jantarabenjakul W., Putchareon O., Torvorapanit P., Puthanakit T., Suchartlikitwong P., Hirankarn N., Nilaratanakul V., Sodsai P., Brumpton B. M., Hveem K., Willer C., Zhou W., Rogne T., Solligard E., Asvold B. O., Abedalthagafi M., Alaamery M., Alqahtani S., Barakeh D., Al Harthi F., Alsolm E., Safieh L. A., Alowayn A. M., Alqubaishi F., Al Mutairi A., Mangul S., Alshareef A., Sawaji M., Almutairi M., Aljawini N., Albesher N., Arabi Y. M., Mahmoud E. S., Khattab A. K., Halawani R. T., Alahmadey Z. Z., Albakri J. K., Felemban W. A., Suliman B. A., Hasanato R., Al-Awdah L., Alghamdi J., AlZahrani D., AlJohani S., Al-Afghani H., Alrashed M., AlDhawi N., AlBardis H., Alkwai S., Alswailm M., Almalki F., Albeladi M., Almohammed I., Barhoush E., Albader A., Massadeh S., AlMalik A., Alotaibi S., Alghamdi B., Jung J., Fawzy M. S., Lee Y., Magnus P., Trogstad L. -I. S., Helgeland O., Harris J. R., Mangino M., Spector T. D., Duncan E., Smieszek S. P., Przychodzen B. P., Polymeropoulos C., Polymeropoulos V., Polymeropoulos M. H., Fernandez-Cadenas I., Perez-Tur J., Llucia-Carol L., Cullell N., Muino E., Carcel-Marquez J., DeDiego M. L., Iglesias L. L., Planas A. M., Soriano A., Rico V., Aguero D., Bedini J. L., Lozano F., Domingo C., Robles V., Ruiz-Jaen F., Marquez L., Gomez J., Coto E., Albaiceta G. M., Garcia-Clemente M., Dalmau D., Arranz M. J., Dietl B., Serra-Llovich A., Soler P., Colobran R., Martin-Nalda A., Martinez A. P., Bernardo D., Rojo S., Fiz-Lopez A., Arribas E., de la Cal-Sabater P., Segura T., Gonzalez-Villa E., Serrano-Heras G., Marti-Fabregas J., Jimenez-Xarrie E., de Felipe Mimbrera A., Masjuan J., Garcia-Madrona S., Dominguez-Mayoral A., Villalonga J. M., Menendez-Valladares P., Chasman D. I., Buring J. E., Ridker P. M., Franco G., Sesso H. D., Manson J. A. E., Glessner J. R., Medina-Gomez C., Uitterlinden A. G., Ikram M. A., Kristiansson K., Koskelainen S., Perola M., Donner K., Kivinen K., Palotie A., Ripatti S., Ruotsalainen S., Kaunisto M., Nakanishi T., Butler-Laporte G., Forgetta V., Morrison D. R., 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., Schurr E., Afilalo J., Afilalo M., Oliveira M., Brenner B., Lepage P., Ragoussis J., Auld D., Brassard N., Durand M., Chasse M., Kaufmann D. E., Lathrop G. M., Mooser V., Richards J. B., Li R., Adra D., Rahmouni S., Georges M., Moutschen M., Misset B., Darcis G., Guiot J., Guntz J., Azarzar S., Gofflot S., Beguin Y., Claassen S., Malaise O., Huynen P., Meuris C., Thys M., Jacques J., Leonard P., Frippiat F., Giot J. -B., Sauvage A. -S., von Frenckell C., Belhaj Y., Lambermont B., Pigazzini S., Nkambule L., Daya M., Shortt J., Rafaels N., Wicks S. J., Crooks K., Barnes K. C., Gignoux C. R., Chavan S., Laisk T., Lall K., Lepamets M., Magi R., Esko T., Reimann E., Milani L., Alavere H., Metsalu K., Puusepp M., Metspalu A., Naaber P., Laane E., Pesukova J., Peterson P., Kisand K., Tabri J., Allos R., Hensen K., Starkopf J., Ringmets I., Tamm A., Kallaste A., Bochud P. -Y., Rivolta C., Bibert S., Quinodoz M., Kamdar D., Boillat N., Nussle S. G., Albrich W., Suh N., Neofytos D., Erard V., Voide C., de Cid R., Galvan-Femenia I., Blay N., Carreras A., Cortes B., Farre X., Sumoy L., Moreno V., Mercader J. M., Guindo-Martinez M., Torrents D., Kogevinas M., Garcia-Aymerich J., Castano-Vinyals G., Dobano C., Renieri A., Mari F., Fallerini C., Daga S., Benetti E., Baldassarri M., Fava F., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Beligni G., Tommasi A., Di Sarno L., Palmieri M., Carriero M. L., Alaverdian D., Busani S., Bruno R., Vecchia M., Belli M. A., Picchiotti N., Sanarico M., Gori M., Furini S., Mantovani S., Ludovisi S., Mondelli M. U., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Vaghi M., Rusconi S., Siano M., Montagnani F., Emiliozzi A., Fabbiani M., Rossetti B., Bargagli E., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Bandini M., Caldarelli G. P., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Pancrazzi A., Lorubbio M., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Cossarizza A., Antinori A., Vergori A., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Della Monica M., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Gabbi C., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., La Rovere M. T., Sarzi-Braga S., Bussotti M., Ceri S., Pinoli P., Raimondi F., Biscarini F., Stella A., Zguro K., Capitani K., Suardi C., Dei S., Parati G., Ravaglia S., Artuso R., Botta G., Di Domenico P., Rancan I., Perrella A., Bianchi F., Romani D., Bergomi P., Catena E., Colombo R., Tanfoni M., Vincenti A., Ferri C., Grassi D., Pessina G., Tumbarello M., Di Pietro M., Sabrina R., Luchi S., Barbieri C., Acquilini D., Andreucci E., Segala F. V., Tiseo G., Falcone M., Lista M., Poscente M., De Vivo O., Petrocelli P., Guarnaccia A., Baroni S., Smith A. V., Boughton A. P., Li K. W., LeFaive J., Annis A., Justice A. E., Chittoor G., Josyula N. S., Leader J. B., Carey D. J., Gass M. C., Cantor M. N., Yadav A., van Heel D. A., Hunt K. A., Mason D., Huang Q. Q., Finer S., Trivedi B., Griffiths C. J., Martin H. C., Wright J., Trembath R. C., Soranzo N., Zhao J. H., Butterworth A. S., Danesh J., Di Angelantonio E., Franke L., Boezen M., Deelen P., Claringbould A., Lopera E., Warmerdam R., Vonk J. M., van Blokland I., Lanting P., Ori A. P. S., Zollner S., Wang J., Beck A., Peloso G., Ho Y. -L., Sun Y. V., Huffman J. E., O'Donnell C. J., Cho K., Tsao P., Gaziano J. M., Nivard M., de Geus E., Bartels M., Jan Hottenga J., Weiss S. T., Karlson E. W., Smoller J. W., Green R. C., Feng Y. -C. A., Mercader J., Murphy S. N., Meigs J. B., Woolley A. E., Perez E. F., Rader D., Li B., Verma S. S., Lucas A., Bradford Y., Zeberg H., Frithiof R., Hultstrom M., Lipcsey M., Tardif N., Rooyackers O., Grip J., Maricic T., Karczewski K. J., Atkinson E. G., Tsuo K., Baya N., Turley P., Gupta R., Callier S., Walters R. K., Palmer D. S., Sarma G., Cheng N., Lu W., Bryant S., Churchhouse C., Cusick C., Goldstein J. I., King D., Seed C., Finucane H., Martin A. R., Satterstrom F. K., Wilson D. J., Armstrong J., Rudkin J. K., Band G., Earle S. G., Lin S. -K., Arning N., Crook D. W., Wyllie D. H., O'Connell A. M., Spencer C. C. A., Koelling N., Caulfield M. J., Scott R. H., Fowler T., Moutsianas L., Pasko D., Ball C. A., Hong E. L., Rand K., Girshick A., Guturu H., Baltzell A. H., Roberts G., Park D., Coignet M., McCurdy S., Knight S., Partha R., Rhead B., Zhang M., Berkowitz N., Gaddis M., Noto K., Ruiz L., Pavlovic M., Sloofman L. G., Charney A. W., Beckmann N. D., Schadt E. E., Jordan D. M., Thompson R. C., Gettler K., Abul-Husn N. S., Ascolillo S., Buxbaum J. D., Chaudhary K., Cho J. H., Itan Y., Kenny E. E., Belbin G. M., Sealfon S. C., Sebra R. P., Salib I., Collins B. L., Levy T., Britvan B., Keller K., Tang L., Peruggia M., Hiester L. L., Niblo K., Aksentijevich A., Labkowsky A., Karp A., Zlatopolsky M., Preuss M., Loos R. J. F., Nadkarni G. N., Do R., Hoggart C., Choi S., Underwood S. J., O'Reilly P., Huckins L. M., Zyndorf M., Daly M. J., Neale B. M., Ganna A., Fawkes A., Murphy L., Rowan K., Ponting C. P., Vitart V., Yang J., Bretherick A. D., Hendry S. C., Law A., Baillie J. K., Kousathanas, A, Pairo-Castineira, E, Rawlik, K, Stuckey, A, Odhams, C, Walker, S, Russell, C, Malinauskas, T, Wu, Y, Millar, J, Shen, X, Elliott, K, Griffiths, F, Oosthuyzen, W, Morrice, K, Keating, S, Wang, B, Rhodes, D, Klaric, L, Zechner, M, Parkinson, N, Siddiq, A, Goddard, P, Donovan, S, Maslove, D, Nichol, A, Semple, M, Zainy, T, Maleady-Crowe, F, Todd, L, Salehi, S, Knight, J, Elgar, G, Chan, G, Arumugam, P, Patch, C, Rendon, A, Bentley, D, Kingsley, C, Kosmicki, J, Horowitz, J, Baras, A, Abecasis, G, Ferreira, M, Justice, A, Mirshahi, T, Oetjens, M, Rader, D, Ritchie, M, Verma, A, Fowler, T, Shankar-Hari, M, Summers, C, Hinds, C, Horby, P, Ling, L, Mcauley, D, Montgomery, H, Openshaw, P, Elliott, P, Walsh, T, Tenesa, A, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Pathak, G, Karjalainen, J, Stevens, C, Andrews, S, Kanai, M, Cordioli, M, Polimanti, R, Pirinen, M, Harerimana, N, Veerapen, K, Wolford, B, Nguyen, H, Solomonson, M, Liao, R, Chwialkowska, K, Trankiem, A, Balaconis, M, Hayward, C, Richmond, A, Campbell, A, Morris, M, Fawns-Ritchie, C, Glessner, J, Shaw, D, Chang, X, Polikowski, H, Petty, L, Chen, H, Wanying, Z, Hakonarson, H, Porteous, D, Below, J, North, K, Mccormick, J, Timmers, P, Wilson, J, D'Mellow, K, Kerr, S, Niemi, M, Nkambul, L, von Hohenstaufen, K, Sobh, A, Eltoukhy, M, Yassen, A, Hegazy, M, Okasha, K, Eid, M, Moahmed, H, Shahin, D, El-Sherbiny, Y, Elhadidy, T, Abd Elghafar, M, El-Jawhari, J, Mohamed, A, Elnagdy, M, Samir, A, Abdel-Aziz, M, Khafaga, W, El-Lawaty, W, Torky, M, El-shanshory, M, Batini, C, Lee, P, Shrine, N, Williams, A, Tobin, M, Guyatt, A, John, C, Packer, R, Ali, A, Free, R, Wang, X, Wain, L, Hollox, E, Venn, L, Bee, C, Adams, E, Niavarani, A, Sharififard, B, Aliannejad, R, Amirsavadkouhi, A, Naderpour, Z, Tadi, H, Aleagha, A, Ahmadi, S, Moghaddam, S, Adamsara, A, Saeedi, M, Abdollahi, H, Hosseini, A, Chariyavilaskul, P, Chamnanphon, M, Suttichet, T, Shotelersuk, V, Pongpanich, M, Phokaew, C, Chetruengchai, W, Jantarabenjakul, W, Putchareon, O, Torvorapanit, P, Puthanakit, T, Suchartlikitwong, P, Hirankarn, N, Nilaratanakul, V, Sodsai, P, Brumpton, B, Hveem, K, Willer, C, Zhou, W, Rogne, T, Solligard, E, Asvold, B, Abedalthagafi, M, Alaamery, M, Alqahtani, S, Barakeh, D, Al Harthi, F, Alsolm, E, Safieh, L, Alowayn, A, Alqubaishi, F, Al Mutairi, A, Mangul, S, Alshareef, A, Sawaji, M, Almutairi, M, Aljawini, N, Albesher, N, Arabi, Y, Mahmoud, E, Khattab, A, Halawani, R, Alahmadey, Z, Albakri, J, Felemban, W, Suliman, B, Hasanato, R, Al-Awdah, L, Alghamdi, J, Alzahrani, D, Aljohani, S, Al-Afghani, H, Alrashed, M, Aldhawi, N, Albardis, H, Alkwai, S, Alswailm, M, Almalki, F, Albeladi, M, Almohammed, I, Barhoush, E, Albader, A, Massadeh, S, Almalik, A, Alotaibi, S, Alghamdi, B, Jung, J, Fawzy, M, Lee, Y, Magnus, P, Trogstad, L, Helgeland, O, Harris, J, Mangino, M, Spector, T, Duncan, E, Smieszek, S, Przychodzen, B, Polymeropoulos, C, Polymeropoulos, V, Polymeropoulos, M, Fernandez-Cadenas, I, Perez-Tur, J, Llucia-Carol, L, Cullell, N, Muino, E, Carcel-Marquez, J, Dediego, M, Iglesias, L, Planas, A, Soriano, A, Rico, V, Aguero, D, Bedini, J, Lozano, F, Domingo, C, Robles, V, Ruiz-Jaen, F, Marquez, L, Gomez, J, Coto, E, Albaiceta, G, Garcia-Clemente, M, Dalmau, D, Arranz, M, Dietl, B, Serra-Llovich, A, Soler, P, Colobran, R, Martin-Nalda, A, Martinez, A, Bernardo, D, Rojo, S, Fiz-Lopez, A, Arribas, E, de la Cal-Sabater, P, Segura, T, Gonzalez-Villa, E, Serrano-Heras, G, Marti-Fabregas, J, Jimenez-Xarrie, E, de Felipe Mimbrera, A, Masjuan, J, Garcia-Madrona, S, Dominguez-Mayoral, A, Villalonga, J, Menendez-Valladares, P, Chasman, D, Buring, J, Ridker, P, Franco, G, Sesso, H, Manson, J, Medina-Gomez, C, Uitterlinden, A, Ikram, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Ripatti, S, Ruotsalainen, S, Kaunisto, M, Nakanishi, T, Butler-Laporte, G, Forgetta, V, Morrison, D, 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, Schurr, E, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Lepage, P, Ragoussis, J, Auld, D, Brassard, N, Durand, M, Chasse, M, Kaufmann, D, Lathrop, G, Mooser, V, Richards, J, Li, R, Adra, D, Rahmouni, S, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Guntz, J, Azarzar, S, Gofflot, S, Beguin, Y, Claassen, S, Malaise, O, Huynen, P, Meuris, C, Thys, M, Jacques, J, Leonard, P, Frippiat, F, Giot, J, Sauvage, A, von Frenckell, C, Belhaj, Y, Lambermont, B, Pigazzini, S, Nkambule, L, Daya, M, Shortt, J, Rafaels, N, Wicks, S, Crooks, K, Barnes, K, Gignoux, C, Chavan, S, Laisk, T, Lall, K, Lepamets, M, Magi, R, Esko, T, Reimann, E, Milani, L, Alavere, H, Metsalu, K, Puusepp, M, Metspalu, A, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Bochud, P, Rivolta, C, Bibert, S, Quinodoz, M, Kamdar, D, Boillat, N, Nussle, S, Albrich, W, Suh, N, Neofytos, D, Erard, V, Voide, C, de Cid, R, Galvan-Femenia, I, Blay, N, Carreras, A, Cortes, B, Farre, X, Sumoy, L, Moreno, V, Mercader, J, Guindo-Martinez, M, Torrents, D, Kogevinas, M, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Renieri, A, Mari, F, Fallerini, C, Daga, S, Benetti, E, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, M, Alaverdian, D, Busani, S, Bruno, R, Vecchia, M, Belli, M, Picchiotti, N, Sanarico, M, Gori, M, Furini, S, Mantovani, S, Ludovisi, S, Mondelli, M, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Vaghi, M, Rusconi, S, Siano, M, Montagnani, F, Emiliozzi, A, Fabbiani, M, Rossetti, B, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Bandini, M, Caldarelli, G, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazzi, A, Lorubbio, M, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Cossarizza, A, Antinori, A, Vergori, A, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Gabbi, C, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, La Rovere, M, Sarzi-Braga, S, Bussotti, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Zguro, K, Capitani, K, Suardi, C, Dei, S, Parati, G, Ravaglia, S, Artuso, R, Botta, G, Di Domenico, P, Rancan, I, Perrella, A, Bianchi, F, Romani, D, Bergomi, P, Catena, E, Colombo, R, Tanfoni, M, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Segala, F, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Smith, A, Boughton, A, Li, K, Lefaive, J, Annis, A, Chittoor, G, Josyula, N, Leader, J, Carey, D, Gass, M, Cantor, M, Yadav, A, van Heel, D, Hunt, K, Mason, D, Huang, Q, Finer, S, Trivedi, B, Griffiths, C, Martin, H, Wright, J, Trembath, R, Soranzo, N, Zhao, J, Butterworth, A, Danesh, J, Di Angelantonio, E, Franke, L, Boezen, M, Deelen, P, Claringbould, A, Lopera, E, Warmerdam, R, Vonk, J, van Blokland, I, Lanting, P, Ori, A, Zollner, S, Wang, J, Beck, A, Peloso, G, Ho, Y, Sun, Y, Huffman, J, O'Donnell, C, Cho, K, Tsao, P, Gaziano, J, Nivard, M, de Geus, E, Bartels, M, Jan Hottenga, J, Weiss, S, Karlson, E, Smoller, J, Green, R, Feng, Y, Murphy, S, Meigs, J, Woolley, A, Perez, E, Li, B, Verma, S, Lucas, A, Bradford, Y, Zeberg, H, Frithiof, R, Hultstrom, M, Lipcsey, M, Tardif, N, Rooyackers, O, Grip, J, Maricic, T, Karczewski, K, Atkinson, E, Tsuo, K, Baya, N, Turley, P, Gupta, R, Callier, S, Walters, R, Palmer, D, Sarma, G, Cheng, N, Lu, W, Bryant, S, Churchhouse, C, Cusick, C, Goldstein, J, King, D, Seed, C, Finucane, H, Martin, A, Satterstrom, F, Wilson, D, Armstrong, J, Rudkin, J, Band, G, Earle, S, Lin, S, Arning, N, Crook, D, Wyllie, D, O'Connell, A, Spencer, C, Koelling, N, Caulfield, M, Scott, R, Moutsianas, L, Pasko, D, Ball, C, Hong, E, Rand, K, Girshick, A, Guturu, H, Baltzell, A, Roberts, G, Park, D, Coignet, M, Mccurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Sloofman, L, Charney, A, Beckmann, N, Schadt, E, Jordan, D, Thompson, R, Gettler, K, Abul-Husn, N, Ascolillo, S, Buxbaum, J, Chaudhary, K, Cho, J, Itan, Y, Kenny, E, Belbin, G, Sealfon, S, Sebra, R, Salib, I, Collins, B, Levy, T, Britvan, B, Keller, K, Tang, L, Peruggia, M, Hiester, L, Niblo, K, Aksentijevich, A, Labkowsky, A, Karp, A, Zlatopolsky, M, Preuss, M, Loos, R, Nadkarni, G, Do, R, Hoggart, C, Choi, S, Underwood, S, O'Reilly, P, Huckins, L, Zyndorf, M, Daly, M, Neale, B, Ganna, A, Fawkes, A, Murphy, L, Rowan, K, Ponting, C, Vitart, V, Yang, J, Bretherick, A, Hendry, S, Law, A, Baillie, J, Kousathanas A., Pairo-Castineira E., Rawlik K., Stuckey A., Odhams C. A., Walker S., Russell C. D., Malinauskas T., Wu Y., Millar J., Shen X., Elliott K. S., Griffiths F., Oosthuyzen W., Morrice K., Keating S., Wang B., Rhodes D., Klaric L., Zechner M., Parkinson N., Siddiq A., Goddard P., Donovan S., Maslove D., Nichol A., Semple M. G., Zainy T., Maleady-Crowe F., Todd L., Salehi S., Knight J., Elgar G., Chan G., Arumugam P., Patch C., Rendon A., Bentley D., Kingsley C., Kosmicki J. A., Horowitz J. E., Baras A., Abecasis G. R., Ferreira M. A. R., Justice A., Mirshahi T., Oetjens M., Rader D. J., Ritchie M. D., Verma A., Fowler T. A., Shankar-Hari M., Summers C., Hinds C., Horby P., Ling L., McAuley D., Montgomery H., Openshaw P. J. M., Elliott P., Walsh T., Tenesa A., Shelton J. F., Shastri A. J., Ye C., Weldon C. H., Filshtein-Sonmez T., Coker D., Symons A., Esparza-Gordillo J., Aslibekyan S., Auton A., Pathak G. A., Karjalainen J., Stevens C., Andrews S. J., Kanai M., Cordioli M., Polimanti R., Pirinen M., Harerimana N., Veerapen K., Wolford B., Nguyen H., Solomonson M., Liao R. G., Chwialkowska K., Trankiem A., Balaconis M. K., Hayward C., Richmond A., Campbell A., Morris M., Fawns-Ritchie C., Glessner J. T., Shaw D. M., Chang X., Polikowski H., Petty L. E., Chen H. -H., Wanying Z., Hakonarson H., Porteous D. J., Below J., North K., McCormick J. B., Timmers P. R. H. J., Wilson J. F., D'Mellow K., Kerr S. M., Niemi M. E. K., Nkambul L., von Hohenstaufen K. A., Sobh A., Eltoukhy M. M., Yassen A. M., Hegazy M. A. F., Okasha K., Eid M. A., Moahmed H. S., Shahin D., El-Sherbiny Y. M., Elhadidy T. A., Abd Elghafar M. S., El-Jawhari J. J., Mohamed A. A. S., Elnagdy M. H., Samir A., Abdel-Aziz M., Khafaga W. T., El-Lawaty W. M., Torky M. S., El-shanshory M. R., Batini C., Lee P. H., Shrine N., Williams A. T., Tobin M. D., Guyatt A. L., John C., Packer R. J., Ali A., Free R. C., Wang X., Wain L. V., Hollox E. J., Venn L. D., Bee C. E., Adams E. L., Niavarani A., Sharififard B., Aliannejad R., Amirsavadkouhi A., Naderpour Z., Tadi H. A., Aleagha A. E., Ahmadi S., Moghaddam S. B. M., Adamsara A., Saeedi M., Abdollahi H., Hosseini A., Chariyavilaskul P., Chamnanphon M., Suttichet T. B., Shotelersuk V., Pongpanich M., Phokaew C., Chetruengchai W., Jantarabenjakul W., Putchareon O., Torvorapanit P., Puthanakit T., Suchartlikitwong P., Hirankarn N., Nilaratanakul V., Sodsai P., Brumpton B. M., Hveem K., Willer C., Zhou W., Rogne T., Solligard E., Asvold B. O., Abedalthagafi M., Alaamery M., Alqahtani S., Barakeh D., Al Harthi F., Alsolm E., Safieh L. A., Alowayn A. M., Alqubaishi F., Al Mutairi A., Mangul S., Alshareef A., Sawaji M., Almutairi M., Aljawini N., Albesher N., Arabi Y. M., Mahmoud E. S., Khattab A. K., Halawani R. T., Alahmadey Z. Z., Albakri J. K., Felemban W. A., Suliman B. A., Hasanato R., Al-Awdah L., Alghamdi J., AlZahrani D., AlJohani S., Al-Afghani H., Alrashed M., AlDhawi N., AlBardis H., Alkwai S., Alswailm M., Almalki F., Albeladi M., Almohammed I., Barhoush E., Albader A., Massadeh S., AlMalik A., Alotaibi S., Alghamdi B., Jung J., Fawzy M. S., Lee Y., Magnus P., Trogstad L. -I. S., Helgeland O., Harris J. R., Mangino M., Spector T. D., Duncan E., Smieszek S. P., Przychodzen B. P., Polymeropoulos C., Polymeropoulos V., Polymeropoulos M. H., Fernandez-Cadenas I., Perez-Tur J., Llucia-Carol L., Cullell N., Muino E., Carcel-Marquez J., DeDiego M. L., Iglesias L. L., Planas A. M., Soriano A., Rico V., Aguero D., Bedini J. L., Lozano F., Domingo C., Robles V., Ruiz-Jaen F., Marquez L., Gomez J., Coto E., Albaiceta G. M., Garcia-Clemente M., Dalmau D., Arranz M. J., Dietl B., Serra-Llovich A., Soler P., Colobran R., Martin-Nalda A., Martinez A. P., Bernardo D., Rojo S., Fiz-Lopez A., Arribas E., de la Cal-Sabater P., Segura T., Gonzalez-Villa E., Serrano-Heras G., Marti-Fabregas J., Jimenez-Xarrie E., de Felipe Mimbrera A., Masjuan J., Garcia-Madrona S., Dominguez-Mayoral A., Villalonga J. M., Menendez-Valladares P., Chasman D. I., Buring J. E., Ridker P. M., Franco G., Sesso H. D., Manson J. A. E., Glessner J. R., Medina-Gomez C., Uitterlinden A. G., Ikram M. A., Kristiansson K., Koskelainen S., Perola M., Donner K., Kivinen K., Palotie A., Ripatti S., Ruotsalainen S., Kaunisto M., Nakanishi T., Butler-Laporte G., Forgetta V., Morrison D. R., 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., Schurr E., Afilalo J., Afilalo M., Oliveira M., Brenner B., Lepage P., Ragoussis J., Auld D., Brassard N., Durand M., Chasse M., Kaufmann D. E., Lathrop G. M., Mooser V., Richards J. B., Li R., Adra D., Rahmouni S., Georges M., Moutschen M., Misset B., Darcis G., Guiot J., Guntz J., Azarzar S., Gofflot S., Beguin Y., Claassen S., Malaise O., Huynen P., Meuris C., Thys M., Jacques J., Leonard P., Frippiat F., Giot J. -B., Sauvage A. -S., von Frenckell C., Belhaj Y., Lambermont B., Pigazzini S., Nkambule L., Daya M., Shortt J., Rafaels N., Wicks S. J., Crooks K., Barnes K. C., Gignoux C. R., Chavan S., Laisk T., Lall K., Lepamets M., Magi R., Esko T., Reimann E., Milani L., Alavere H., Metsalu K., Puusepp M., Metspalu A., Naaber P., Laane E., Pesukova J., Peterson P., Kisand K., Tabri J., Allos R., Hensen K., Starkopf J., Ringmets I., Tamm A., Kallaste A., Bochud P. -Y., Rivolta C., Bibert S., Quinodoz M., Kamdar D., Boillat N., Nussle S. G., Albrich W., Suh N., Neofytos D., Erard V., Voide C., de Cid R., Galvan-Femenia I., Blay N., Carreras A., Cortes B., Farre X., Sumoy L., Moreno V., Mercader J. M., Guindo-Martinez M., Torrents D., Kogevinas M., Garcia-Aymerich J., Castano-Vinyals G., Dobano C., Renieri A., Mari F., Fallerini C., Daga S., Benetti E., Baldassarri M., Fava F., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Beligni G., Tommasi A., Di Sarno L., Palmieri M., Carriero M. L., Alaverdian D., Busani S., Bruno R., Vecchia M., Belli M. A., Picchiotti N., Sanarico M., Gori M., Furini S., Mantovani S., Ludovisi S., Mondelli M. U., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Vaghi M., Rusconi S., Siano M., Montagnani F., Emiliozzi A., Fabbiani M., Rossetti B., Bargagli E., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Bandini M., Caldarelli G. P., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Pancrazzi A., Lorubbio M., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Cossarizza A., Antinori A., Vergori A., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Della Monica M., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Gabbi C., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., La Rovere M. T., Sarzi-Braga S., Bussotti M., Ceri S., Pinoli P., Raimondi F., Biscarini F., Stella A., Zguro K., Capitani K., Suardi C., Dei S., Parati G., Ravaglia S., Artuso R., Botta G., Di Domenico P., Rancan I., Perrella A., Bianchi F., Romani D., Bergomi P., Catena E., Colombo R., Tanfoni M., Vincenti A., Ferri C., Grassi D., Pessina G., Tumbarello M., Di Pietro M., Sabrina R., Luchi S., Barbieri C., Acquilini D., Andreucci E., Segala F. V., Tiseo G., Falcone M., Lista M., Poscente M., De Vivo O., Petrocelli P., Guarnaccia A., Baroni S., Smith A. V., Boughton A. P., Li K. W., LeFaive J., Annis A., Justice A. E., Chittoor G., Josyula N. S., Leader J. B., Carey D. J., Gass M. C., Cantor M. N., Yadav A., van Heel D. A., Hunt K. A., Mason D., Huang Q. Q., Finer S., Trivedi B., Griffiths C. J., Martin H. C., Wright J., Trembath R. C., Soranzo N., Zhao J. H., Butterworth A. S., Danesh J., Di Angelantonio E., Franke L., Boezen M., Deelen P., Claringbould A., Lopera E., Warmerdam R., Vonk J. M., van Blokland I., Lanting P., Ori A. P. S., Zollner S., Wang J., Beck A., Peloso G., Ho Y. -L., Sun Y. V., Huffman J. E., O'Donnell C. J., Cho K., Tsao P., Gaziano J. M., Nivard M., de Geus E., Bartels M., Jan Hottenga J., Weiss S. T., Karlson E. W., Smoller J. W., Green R. C., Feng Y. -C. A., Mercader J., Murphy S. N., Meigs J. B., Woolley A. E., Perez E. F., Rader D., Li B., Verma S. S., Lucas A., Bradford Y., Zeberg H., Frithiof R., Hultstrom M., Lipcsey M., Tardif N., Rooyackers O., Grip J., Maricic T., Karczewski K. J., Atkinson E. G., Tsuo K., Baya N., Turley P., Gupta R., Callier S., Walters R. K., Palmer D. S., Sarma G., Cheng N., Lu W., Bryant S., Churchhouse C., Cusick C., Goldstein J. I., King D., Seed C., Finucane H., Martin A. R., Satterstrom F. K., Wilson D. J., Armstrong J., Rudkin J. K., Band G., Earle S. G., Lin S. -K., Arning N., Crook D. W., Wyllie D. H., O'Connell A. M., Spencer C. C. A., Koelling N., Caulfield M. J., Scott R. H., Fowler T., Moutsianas L., Pasko D., Ball C. A., Hong E. L., Rand K., Girshick A., Guturu H., Baltzell A. H., Roberts G., Park D., Coignet M., McCurdy S., Knight S., Partha R., Rhead B., Zhang M., Berkowitz N., Gaddis M., Noto K., Ruiz L., Pavlovic M., Sloofman L. G., Charney A. W., Beckmann N. D., Schadt E. E., Jordan D. M., Thompson R. C., Gettler K., Abul-Husn N. S., Ascolillo S., Buxbaum J. D., Chaudhary K., Cho J. H., Itan Y., Kenny E. E., Belbin G. M., Sealfon S. C., Sebra R. P., Salib I., Collins B. L., Levy T., Britvan B., Keller K., Tang L., Peruggia M., Hiester L. L., Niblo K., Aksentijevich A., Labkowsky A., Karp A., Zlatopolsky M., Preuss M., Loos R. J. F., Nadkarni G. N., Do R., Hoggart C., Choi S., Underwood S. J., O'Reilly P., Huckins L. M., Zyndorf M., Daly M. J., Neale B. M., Ganna A., Fawkes A., Murphy L., Rowan K., Ponting C. P., Vitart V., Yang J., Bretherick A. D., Hendry S. C., Law A., and Baillie J. K.
- Abstract
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
- Published
- 2022
3. Towards Biopathway Modeling and Simulation
- Author
-
Matsuno, Hiroshi, Fujita, Sachie, Doi, Atsushi, Nagasaki, Masao, Miyano, Satoru, Goos, Gerhard, editor, Hartmanis, Juris, editor, van Leeuwen, Jan, editor, van der Aalst, Wil M. P., editor, and Best, Eike, editor
- Published
- 2003
- Full Text
- View/download PDF
4. An Evolutionarily Conserved Transcriptional Activator-Repressor Module Controls Expression of Genes for D-Galacturonic Acid Utilization in Aspergillus niger.
- Author
-
Jing Niu, Alazi, Ebru, Reid, Ian D., Arentshorst, Mark, Punt, Peter J., Visser, Jaap, Tsang, Adrian, and Ram, Arthur F. J.
- Subjects
- *
GENE expression , *TRANSCRIPTION factors , *MONOMERS , *POLYMERS , *GALACTURONIC acid - Abstract
The expression of genes encoding extracellular polymer-degrading enzymes and the metabolic pathways required for carbon utilization in fungi are tightly controlled. The control is mediated by transcription factors that are activated by the presence of specific inducers, which are often monomers or monomeric derivatives of the polymers. A D-galacturonic acid-specific transcription factor named GaaR was recently identified and shown to be an activator for the expression of genes involved in galacturonic acid utilization in Botrytis cinerea and Aspergillus niger. Using a forward genetic screen, we isolated A. niger mutants that constitutively express GaaR-controlled genes. Reasoning that mutations in the gaaR gene would lead to a constitutively activated transcription factor, the gaaR gene in 11 of the constitutive mutants was sequenced, but no mutations in gaaR were found. Full genome sequencing of five constitutive mutants revealed allelic mutations in one particular gene encoding a previously uncharacterized protein (NRRL3_08194). The protein encoded by NRRL3_08194 shows homology to the repressor of the quinate utilization pathway identified previously in Neurospora crassa (qa-1S) and Aspergillus nidulans (QutR). Deletion of NRRL3_08194 in combination with RNA-seq analysis showed that the NRRL3_08194 deletion mutant constitutively expresses genes involved in galacturonic acid utilization. Interestingly, NRRL3_08194 is located next to gaaR (NRRL3_08195) in the genome. The homology to the quinate repressor, the chromosomal clustering, and the constitutive phenotype of the isolated mutants suggest that NRRL3_08194 is likely to encode a repressor, which we name GaaX. The GaaR-GaaX module and its chromosomal organization is conserved among ascomycetes filamentous fungi, resembling the quinate utilization activator-repressor module in amino acid sequence and chromosomal organization. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
5. Whole genome sequencing reveals host factors underlying critical Covid-19
- Author
-
Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C. A., Walker, S., Russell, C. D., Malinauskas, T., Wu, Y., Millar, J., Shen, X., Elliott, K. S., Griffiths, F., Oosthuyzen, W., Morrice, K., Keating, S., Wang, B., Rhodes, D., Klaric, L., Zechner, M., Parkinson, N., Siddiq, A., Goddard, P., Donovan, S., Maslove, D., Nichol, A., Semple, M. G., Zainy, T., Maleady-Crowe, F., Todd, L., Salehi, S., Knight, J., Elgar, G., Chan, G., Arumugam, P., Patch, C., Rendon, A., Bentley, D., Kingsley, C., Kosmicki, J. A., Horowitz, J. E., Baras, A., Abecasis, G. R., Ferreira, M. A. R., Justice, A., Mirshahi, T., Oetjens, M., Rader, D. J., Ritchie, M. D., Verma, A., Fowler, T. A., Shankar-Hari, M., Summers, C., Hinds, C., Horby, P., Mcauley, D., Montgomery, H., Openshaw, P. J. M., Elliott, P., Walsh, T., Tenesa, A., Fawkes, A., Murphy, L., Rowan, K., Ponting, C. P., Vitart, V., Wilson, J. F., Yang, J., Bretherick, A. D., Scott, R. H., Hendry, S. C., Moutsianas, L., Law, A., Caulfield, M. J., Baillie, J. K., Begg, C., Ling, L., Pereira, A. C., Aravindan, L., Armstrong, R., Biggs, H., Boz, C., Brown, A., Clark, R., Coutts, A., Coyle, J., Cullum, L., Das, S., Day, N., Donnelly, L., Duncan, E., Finernan, P., Fourman, M. H., Furlong, A., Furniss, J., Gallagher, B., Gilchrist, T., Golightly, A., Hafezi, K., Hamilton, D., Hendry, R., Law, D., Law, R., Law, S., Lidstone-Scott, R., Macgillivray, L., Maclean, A., Mal, H., Mccafferty, S., Mcmaster, E., Meikle, J., Moore, S. C., Murphy, S., Hellen, M., Zheng, C., Chen, J., Paterson, T., Schon, K., Stenhouse, A., Das, M., Swets, M., Szoor-McElhinney, H., Taneski, F., Turtle, L., Wackett, T., Ward, M., Weaver, J., Wrobel, N., Arbane, G., Bociek, A., Campos, S., Grau, N., Jones, T. O., Lim, R., Marotti, M., Ostermann, M., Whitton, C., Alldis, Z., Astin-Chamberlain, R., Bibi, F., Biddle, J., Blow, S., Bolton, M., Borra, C., Bowles, R., Burton, M., Choudhury, Y., Collier, D., Cox, A., Easthope, A., Ebano, P., Fotiadis, S., Gurasashvili, J., Halls, R., Hartridge, P., Kallon, D., Kassam, J., Lancoma-Malcolm, I., Matharu, M., May, P., Mitchelmore, O., Newman, T., Patel, M., Pheby, J., Pinzuti, I., Prime, Z., Prysyazhna, O., Shiel, J., Taylor, M., Tierney, C., Wood, S., Zak, A., Zongo, O., Bonner, S., Hugill, K., Jones, J., Liggett, S., Headlam, E., Bandla, N., Gellamucho, M., Davies, M., Thompson, C., Abdelrazik, M., Bakthavatsalam, D., Elhassan, M., Ganesan, A., Haldeos, A., Moreno-Cuesta, J., Purohit, D., Vincent, R., Xavier, K., Kumar, R., Frater, Alessia, Saleem, M., Carter, D., Jenkins, S., Lamond, Z., Wall, A., Fernandez-Roman, J., Hamilton, D. O., Johnson, E., Johnston, B., Martinez Guzman, Maria Loreto, Mulla, S., Shaw, D., Waite, A. A. C., Waugh, V., Welters, I. D., Williams, K., Cavazza, A., Cockrell, M., Corcoran, E., Depante, M., Finney, C., Jerome, E., Mcphail, M., Nayak, M., Noble, H., O'Reilly, K., Pappa, E., Saha, R., Saha, S., Smith, Jenovia Amisti, Knighton, A., Antcliffe, D., Banach, D., Brett, S., Coghlan, P., Fernandez, Z., Gordon, A., Rojo, R., Arias, S. S., Templeton, M., Meredith, M., Morris, L., Ryan, L., Clark, A., Sampson, J., Peters, C., Dent, M., Langley, M., Ashraf, Sana, Wei, S., Andrew, A., Bashyal, A., Davidson, N., Hutton, P., Mckechnie, S., Wilson, J., Baptista, D., Crowe, R., Fernandes, R., Herdman-Grant, R., Joseph, A., O'Connor, D., Allen, M., Loveridge, A., Mckenley, I., Morino, E., Naranjo, A., Simms, R., Sollesta, K., Swain, A., Venkatesh, H., Khera, J., Fox, J., Andrew, G., Barclay, L., Callaghan, M., Campbell, R., Clark, S., Hope, D., Marshall, L., Mcculloch, C., Briton, K., Singleton, J., Birch, S., Brimfield, L., Daly, Z., Pogson, D., Rose, S., Nown, A., Battle, C., Brinkworth, E., Harford, R., Murphy, C., Newey, L., Rees, T., Williams, M., Arnold, S., Polgarova, P., Stroud, K., Meaney, E., Jones, M., Ng, A., Agrawal, S., Pathan, N., White, D., Daubney, E., Elston, K., Grauslyte, L., Hussain, M., Phull, M., Pogreban, T., Rosaroso, L., Salciute, E., Franke, G., Wong, J., George, A., de Gordoa, L. O. -R., Peasgood, E., Phillips, C., Bates, M., Dasgin, J., Gill, J., Nilsson, A., Scriven, J., Collins, A., Khaliq, W., Gude, E. T., Delgado, C. C., Dawson, D., Ding, L., Durrant, G., Ezeobu, O., Farnell-Ward, S., Harrison, A., Kanu, R., Leaver, S., Maccacari, E., Manna, S., Saluzzio, R. P., Queiroz, J., Samakomva, T., Sicat, C., Texeira, J., Da Gloria, E. F., Lisboa, A., Rawlins, J., Mathew, J., Kinch, A., Hurt, W. J., Shah, N., Clark, V., Thanasi, M., Yun, N., Patel, K., Bennett, S., Goodwin, E., Jackson, M., Kent, A., Tibke, C., Woodyatt, W., Zaki, A., Abraheem, A., Bamford, P., Cawley, K., Dunmore, C., Faulkner, M., Girach, R., Jeffrey, H., Jones, R., London, E., Nagra, I., Nasir, F., Sainsbury, H., Smedley, C., Patel, T., Smith, M., Chukkambotla, S., Kazi, A., Hartley, J., Dykes, J., Hijazi, M., Keith, S., Khan, M., Ryan-Smith, J., Springle, P., Thomas, J., Truman, N., Saad, S., Coleman, D., Fine, C., Matt, R., Gay, B., Dalziel, J., Ali, S., Goodchild, D., Harling, R., Bhatterjee, R., Goddard, W., Davison, C., Duberly, S., Hargreaves, J., Bolton, R., Davey, M., Golden, D., Seaman, R., Cherian, S., Cutler, S., Heron, A. E., Roynon-Reed, A., Szakmany, T., Williams, G., Richards, O., Cheema, Y., Brooke, H., Buckley, S., Suarez, J. C., Charlesworth, R., Hansson, K., Norris, J., Poole, A., Rose, A., Sandhu, R., Sloan, B., Smithson, E., Thirumaran, M., Wagstaff, V., Metcalfe, A., Brunton, M., Caterson, J., Coles, H., Frise, M., Rai, S. G., Jacques, N., Keating, L., Tilney, E., Bartley, S., Bhuie, P., Gibson, S., Lyle, A., Mcneela, F., Radhakrishnan, J., Hughes, A., Yates, B., Reynolds, J., Campbell, H., Thompsom, M., Dodds, S., Duffy, S., Greer, S., Shuker, K., Tridente, A., Khade, R., Sundar, A., Tsinaslanidis, G., Birkinshaw, I., Carter, J., Howard, K., Ingham, J., Joy, R., Pearson, H., Roche, S., Scott, Z., Bancroft, H., Bellamy, M., Carmody, M., Daglish, J., Moore, F., Rhodes, J., Sangombe, M., Kadiri, S., Croft, M., White, I., Frost, V., Aquino, M., Jha, R., Krishnamurthy, V., Lim, L., Combes, E., Joefield, T., Monnery, S., Beech, V., Trotman, S., Christine, Almaden-Boyle, Austin, P., Cabrelli, L., Cole, S., Casey, M., Chapman, S., Whyte, C., Baird, Y., Butler, A., Chadbourn, I., Folkes, L., Fox, H., Gardner, A., Gomez, R., Hobden, G., Hodgson, L., King, K., Margarson, M., Martindale, T., Meadows, E., Raynard, D., Thirlwall, Y., Helm, D., Margalef, J., Criste, K., Cusack, R., Golder, K., Golding, H., Jones, O., Leggett, S., Male, M., Marani, M., Prager, K., Williams, T., Roberts, B., Salmon, K., Anderson, P., Archer, K., Austin, K., Davis, C., Durie, A., Kelsall, O., Thrush, J., Vigurs, C., Wild, L., Wood, H. -L., Tranter, H., Cowley, N., Mcalindon, M., Burtenshaw, A., Digby, S., Low, E., Morgan, A., Cother, N., Rankin, T., Clayton, S., Mccurdy, A., Ahmed, C., Baines, B., Clamp, S., Colley, J., Haq, R., Hayes, A., Hulme, J., Hussain, S., Joseph, S., Maqsood, Z., Purewal, M., Benham, L., Bradshaw, Z., Brown, J., Caswell, M., Cupitt, J., Melling, S., Preston, S., Slawson, N., Stoddard, E., Warden, S., Deacon, B., Lynch, C., Pothecary, C., Roche, L., Howe, G. S., Singh, Jaywant, Turner, K., Ellis, H., Stroud, N., Hunt, J., Dearden, J., Dobson, E., Drummond, A., Mulcahy, M., Munt, S., O'Connor, G., Philbin, J., Rishton, C., Tully, R., Winnard, S., Cathcart, S., Duffy, K., Puxty, A., Puxty, K., Turner, L., Ireland, J., Semple, G., Long, K., Whiteley, S., Wilby, E., Ogg, B., Cowton, A., Kay, Abigail, Kent, M., Potts, K., Wilkinson, A., Campbell, S., Brown, E., Melville, J., Naisbitt, J., Joseph, R., Lazo, M., Walton, O., Neal, A., Alexander, P., Allen, S., Bradley-Potts, J., Brantwood, C., Egan, J., Felton, T., Padden, G., Ward, L., Moss, S., Glasgow, S., Abel, L., Brett, M., Digby, B., Gemmell, L., Hornsby, J., Macgoey, P., O'Neil, P., Price, R., Rodden, N., Rooney, K., Sundaram, R., Thomson, N., Hopkins, B., Thrasyvoulou, L., Willis, H., Clark, M., Coulding, M., Jude, E., Mccormick, J., Mercer, O., Potla, D., Rehman, H., Savill, H., Turner, V., Downes, C., Holding, K., Riches, K., Hilton, M., Hayman, M., Subramanian, D., Daniel, P., Adanini, O., Bhatia, N., Msiska, M., Collins, R., Clement, I., Patel, B., Gulati, A., Hays, C., Webster, K., Hudson, A., Webster, A., Stephenson, E., Mccormack, L., Slater, V., Nixon, R., Hanson, H., Fearby, M., Kelly, S., Bridgett, V., Robinson, P., Camsooksai, J., Humphrey, C., Reschreiter, H., Wadams, B., Death, Y., Bastion, V., Clarke, D., David, B., Kent, H., Lorusso, Riccardo, Lubimbi, G., Murdoch, S., Penacerrada, M., Thomas, A., Valentine, J., Vochin, A., Wulandari, R., Djeugam, B., Bell, G., English, K., Katary, A., Wilcox, L., Bruce, M., Connolly, K., Duncan, T., Michael, H. T., Lindergard, G., Hey, S., Fox, C., Alfonso, J., Durrans, L. J., Guerin, J., Blackledge, B., Harris, J., Hruska, M., Eltayeb, A., Lamb, T., Hodgkiss, T., Cooper, L., Rothwell, J., Allan, A., Anderson, F., Kaye, C., Liew, J., Medhora, J., Scott, T., Trumper, E., Botello, A., Lankester, L., Nikitas, N., Wells, C., Stowe, B., Spencer, K., Brandwood, C., Smith, L., Birchall, K., Kolakaluri, L., Baines, D., Sukumaran, A., Apetri, E., Basikolo, C., Catlow, L., Charles, B., Dark, P., Doonan, R., Harvey, A., Horner, D., Knowles, K., Lee, S., Lomas, D., Lyons, C., Marsden, T., Mclaughlan, D., Mcmorrow, L., Pendlebury, J., Perez, J., Poulaka, M., Proudfoot, N., Slaughter, M., Slevin, K., Thomas, V., Walker, D., Michael, A., Collis, M., Cosier, T., Millen, G., Richardson, N., Schumacher, N., Weston, H., Rand, J., Baxter, N., Henderson, S., Kennedy-Hay, S., Mcparland, C., Rooney, L., Sim, M., Mccreath, G., Akeroyd, L., Bano, S., Bromley, M., Gurr, L., Lawton, T., Morgan, J., Sellick, K., Warren, D., Wilkinson, B., Mcgowan, J., Ledgard, C., Stacey, A., Pye, K., Bellwood, R., Bentley, M., Bewley, J., Garland, Z., Grimmer, L., Gumbrill, B., Johnson, R., Sweet, K., Webster, D., Efford, G., Convery, K., Fottrell-Gould, D., Hudig, L., Keshet-Price, J., Randell, G., Stammers, K., Bokhari, M., Linnett, V., Lucas, R., Mccormick, W., Ritzema, J., Sanderson, A., Wild, H., Rostron, A., Roy, A., Woods, L., Cornell, S., Wakinshaw, F., Rogerson, K., Jarmain, J., Parker, R., Reddy, A., Turner-Bone, I., Harding, P., Abernathy, C., Foster, L., Gratrix, A., Martinson, V., Parkinson, P., Stones, E., Carbral-Ortega, L., Bercades, G., Brealey, D., Hass, I., Maccallum, N., Martir, G., Raith, E., Reyes, A., Smyth, D., Zitter, L., Benyon, S., Marriott, S., Park, L., Keenan, S., Gordon, E., Quinn, H., Baines, K., Cagova, L., Fofano, A., Garner, L., Holcombe, H., Mepham, S., Mitchell, A. M., Mwaura, L., Praman, K., Vuylsteke, A., Zamikula, J., Purewal, B., Rivers, V., Bell, S., Blakemore, H., Borislavova, B., Faulkner, B., Gendall, E., Goff, E., Hayes, K., Thomas, M., Worner, R., Smith, K., Stephens, D., Mew, L., Mwaura, E., Stewart, R., Williams, F., Wren, L., Sutherland, S. -B., Bevan, E., Martin, J., Trodd, D., Watson, G., Brown, C. W., Akinkugbe, O., Bamford, A., Beech, E., Belfield, H., Bell, M., Davies, C., Jones, G. A. L., Mchugh, T., Meghari, H., O'Neill, L., Peters, M. J., Ray, S., Tomas, A. L., Burn, I., Hambrook, G., Manso, K., Penn, R., Shanmugasundaram, P., Tebbutt, J., Thornton, D., Cole, J., Davies, R., Duffin, D., Hill, H., Player, B., Thomas, E., Williams, A., Griffin, D., Muchenje, N., Mupudzi, M., Partridge, R., Conyngham, J. -A., Thomas, R., Wright, M., Corral, M. A., Jacob, R., Jones, C., Denmade, C., Beavis, S., Dale, K., Gascoyne, R., Hawes, J., Pritchard, K., Stevenson, L., Whileman, A., Doble, P., Hutter, J., Pawley, C., Shovelton, C., Vaida, M., Butcher, D., O'Sullivan, S., Butterworth-Cowin, N., Ahmad, N., Barker, J., Bauchmuller, K., Bird, S., Cawthron, K., Harrington, K., Jackson, Y., Kibutu, F., Lenagh, B., Masuko, S., Mills, G. H., Raithatha, A., Wiles, M., Willson, J., Newell, H., Lye, A., Nwafor, L., Jarman, C., Rowland-Jones, S., Foote, D., Thompson, R., Watson, J., Hesseldon, L., Macharia, I., Chetam, L., Ford, A., Anderson, S., Housley, K., Milner, L., Hanratty, H., Trower, H., Phillips, P., Oxspring, S., Donne, B., Jardine, C., Williams, D., Hay, A., Flanagan, R., Hughes, G., Latham, S., Mckenna, E., Anderson, J., Hull, R., Rhead, K., Cruz, C., Pattison, N., Charnock, R., Mcfarland, D., Cosgrove, D., Ahmed, A., Morris, A., Jakkula, S., Nune, A., Ali, Amjad, Brady, M., Dale, S., Dance, A., Gledhill, L., Greig, J., Hanson, K., Holdroyd, K., Home, M., Kelly, D., Kitson, R., Matapure, L., Melia, D., Mellor, S., Nortcliffe, T., Pinnell, J., Robinson, M., Shaw, L., Shaw, R., Thomis, L., Wilson, A., Wood, T., Bayo, L. -A., Merwaha, E., Ishaq, T., Hanley, S., Hibbert, M., Tetla, D., Woodford, C., Durga, L., Kennard-Holden, G., Branney, D., Frankham, J., Pitts, S., White, N., Laha, S., Verlander, M., Altabaibeh, A., Alvaro, A., Gilbert, K., Ma, L., Mostoles, L., Parmar, C., Simpson, K., Jetha, C., Booker, L., Pratley, A., Adams, C., Agasou, A., Arden, T., Bowes, A., Boyle, P., Beekes, M., Button, H., Capps, N., Carnahan, M., Carter, A., Childs, D., Donaldson, D., Hard, K., Hurford, F., Hussain, Y., Javaid, A., Jose, S., Leigh, M., Martin, T., Millward, H., Motherwell, N., Rikunenko, R., Stickley, J., Summers, J., Ting, L., Tivenan, H., Tonks, L., Wilcox, R., Skinner, D., Gaylard, J., Mullan, D., Newman, J., Holland, M., Keenan, N., Lyons, M., Wassall, H., Marsh, C., Mahenthran, M., Carter, E., Kong, T., Blackman, H., Creagh-Brown, B., Donlon, S., Michalak-Glinska, N., Mtuwa, S., Pristopan, V., Salberg, A., Smith, E., Stone, S., Piercy, C., Verula, J., Burda, D., Montaser, R., Harden, L., Mayangao, I., Marriott, C., Bradley, P., Harris, C., Andrews, E., Birch, J., Collins, E., Hammerton, K., O'Leary, R., Purvis, S., Barber, R., Hewitt, C., Hilldrith, A., Jackson-Lawrence, K., Shepardson, S., Wills, M., Butler, S., Tavares, S., Cunningham, A., Hindale, J., Arif, S., Bean, S., Burt, K., Spivey, M., Demetriou, C., Eckbad, C., Hierons, S., Howie, L., Mitchard, S., Ramos, L., Serrano-Ruiz, A., White, K., Kelly, F., Cristiano, D., Dormand, N., Farzad, Z., Gummadi, M., Liyanage, K., Salmi, S., Sloane, G., Thwaites, V., Varghese, M., Zborowski, A. C., Allan, J., Geary, T., Houston, G., Meikle, A., O'Brien, P., Forsey, M., Kaliappan, A., Nicholson, A., Riches, J., Vertue, M., Allan, E., Darlington, K., Davies, F., Easton, J., Kumar, S., Lean, R., Menzies, D., Pugh, R., Qiu, X., Davies, L., Williams, John Harford, Scanlon, J., Davies, G., Mackay, C., Lewis, J., Rees, S., Oblak, M., Popescu, M., Thankachen, M., Higham, A., Craig, J., Baruah, R., Morris, S., Ferguson, S., Shepherd, A., Moore, L. S. P., Vizcaychipi, M. P., de Almeida Martins, L. G., Carungcong, J., Ali, I. A. M., Beaumont, K., Blunt, M., Coton, Z., Curgenven, H., Elsaadany, M., Fernandes, K., Ally, S. M., Rangarajan, H., Sarathy, V., Selvanayagam, S., Vedage, D., White, M., Gill, M., Paul, P., Ratnam, V., Shelton, S., Wynter, I., Carmody, S., Page, V. J., Beith, C. M., Black, K., Clements, S., Morrison, A., Strachan, D., Clarkson, M., D'Sylva, S., Norman, K., Auld, F., Donnachie, J., Edmond, I., Prentice, L., Runciman, N., Salutous, D., Symon, L., Todd, A., Turner, P., Short, A., Sweeney, L., Murdoch, E., Senaratne, D., Hill, M., Kannan, T., Crawley, R., Crew, A., Cunningham, M., Daniels, A., Harrison, L., Hope, S., Inweregbu, K., Jones, S., Lancaster, N., Matthews, J., Wray, G., Langton, H., Prout, R., Watters, M., Novis, C., Barron, A., Collins, C., Kaul, S., Passmore, H., Prendergast, C., Reed, A., Rogers, P., Shokkar, R., Woodruff, M., Middleton, H., Polgar, O., Nolan, C., Mahay, K., Hormis, A., Maynard, V., Graham, C., Walker, R., Knights, E., Price, A., Thorpe, C., Behan, T., Burnett, C., Hatton, J., Heeney, E., Mitra, A., Newton, M., Pollard, R., Stead, R., Amin, V., Anastasescu, E., Anumakonda, V., Karthik, K., Kausar, R., Reid, K., Imeson-Wood, J., Crickmore, V., Debreceni, G., Wilkins, J., Nicol, L., Reece-Anthony, R., Birt, M., Ghosh, A., Williams, E., Allen, L., Beranova, E., Crisp, N., Deery, J., Hazelton, T., Knight, A., Price, C., Tilbey, S., Turki, S., Turney, S., Cooper, J., Finch, C., Liderth, S., Quinn, A., Waddington, N., Coventry, T., Fowler, S., Macmahon, M., Mcgregor, A., Cowley, A., Highgate, J., Gregory, J., O'Connell, S., Smith, T., Barberis, Lorenzo, Gopal, S., Harris, N., Lake, V., Metherell, S., Radford, E., Daniel, A., Finn, J., Donnison, P., Trim, F., Eapen, B., Bough, L., Goodsell, J., Tutton, R., Williams, P., Williams, S., Winter-Goodwin, B., Brickell, K., Smyth, M., Coetzee, S., Gales, A., Raj, M., Sell, C., Hilltout, P., Evitts, J., Tyler, A., Waldron, J., Beesley, K., Board, S., Kubisz-Pudelko, A., Lewis, A., Perry, J., Pippard, L., Wood, Dawn, Buckley, C., Barry, P., Flint, N., Rekha, P., Hales, D., Bunni, L., Jennings, C., Latif, Marco, Marshall, R., Subramanian, G., Mcguigan, P. J., Wasson, C., Finn, Stephen Edward, Green, J., King, B., Campbell, A., Smuts, S., Duffield, J., Smith, O., Mallon, L., Watkins, C., Botfield, L., Butler, J., Dexter, C., Fletcher, J., Garg, A., Kuravi, A., Ranga, P., Virgilio, E., Belagodu, Z., Fuller, B., Gherman, A., Olufuwa, O., Paramsothy, R., Stuart, C., Oakley, N., Kamundi, C., Tyl, D., Collins, K., Silva, P., Taylor, J., King, L., Coates, C., Crowley, M., Wakefield, P., Beadle, J., Johnson, L., Sargeant, J., Anderson, M., Brady, A., Chan, R., Little, J., Mcivor, S., Prady, H., Whittle, H., Mathew, B., Attwood, B., Parsons, P., Ward, G., Bremmer, P., Joe, W., Tracy, B., Jim, R., Davies, E., Sathe, S., Dennis, C., Parris, V., Srikaran, S., Sukha, A., Clarke, N., Whiteside, J., Mascarenhas, M., Donaldson, A., Matheson, J., Barrett, F., O'Hara, M., Okeefe, L., Bradley, C., Eastgate-Jackson, C., Filipe, H., Martin, D., Maharajh, A., Garcia, S. M., Pakou, G., De Neef, M., Dent, K., Horsley, E., Akhtar, M. N., Pearson, S., Potoczna, D., Spencer, S., Clapham, M., Harper, R., Poultney, U., Rice, P., Mutch, R., Armstrong, L., Bates, H., Dooks, E., Farquhar, F., Hairsine, B., Packham, S., Bi, R., Scholefield, B., Ashton, L., George, L., Twiss, S., Wright, D., Chablani, M., Kirkby, A., Netherton, K., Davies, K., O'Brien, L., Omar, Z., Otahal, I., Perkins, E., Lewis, T., Sutherland, I., Burns, K., Chandler, B., Elliott, K., Mallinson, J., Turnbull, A., Gondo, P., Hadebe, B., Kayani, A., Masunda, B., Anderson, T., Hawcutt, D., O'Malley, L., Rad, L., Rogers, N., Saunderson, P., Allison, K. S., Afolabi, D., Whitbread, J., Jones, D., Dore, R., Halkes, M., Mercer, P., Thornton, L., Dawson, J., Garrioch, S., Tolson, M., Aldridge, J., Kapoor, R., Loader, D., Castle, K., Humphreys, S., Tampsett, R., Mackintosh, K., Ayers, A., Harrison, W., North, J., Allibone, S., Genetu, R., Kasipandian, V., Patel, A., Mac, A., Murphy, A., Mahjoob, P., Nazari, R., Worsley, L., Fagan, A., Bemand, T., Black, E., Rosa, A. D., Howle, R., Jhanji, S., Baikady, R. R., Tatham, K. C., Thomas, B., Bell, D., Boyle, R., Douglas, K., Glass, L., Lee, E., Lennon, L., Rattray, A., Taylor, Anita, Hughes, R. A., Thomas, H., Rees, A., Duskova, M., Phipps, J., Brooks, S., Edwards, M., Quaid, S., Watson, E., Brayne, A., Fisher, E., Jackson, P., Kaye, D., Love, N., Parkin, J., Tuckey, V., van Koutrik, L., Carter, S., Andrew, B., Findlay, L., Adams, K., Service, J., Cheyne, C., Saunderson, A., Moultrie, S., Odam, M., Hall, K., Mapfunde, I., Willis, C., Lyon, A., Sri-Chandana, C., Scherewode, J., Stephenson, L., Marsh, S., Hardy, J., Houlden, H., Moncur, E., Tariq, A., Tucci, Domenico Antonio, Hobrok, M., Loosley, R., Mcguinness, H., Tench, H., Wolf-Roberts, R., Irvine, V., Shelley, B., Gorman, C., Gupta, A., Timlick, E., Brady, R., Milligan, B., Bellini, A., Bryant, J., Mayer, A., Pickard, A., Roe, N., Sowter, J., Howlett, A., Fidler, K., Tagliavini, E., Donnelly, K., Shelton, J. F., Shastri, A. J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Pathak, G. A., Karjalainen, J., Stevens, C., Andrews, S. J., Kanai, M., Cordioli, M., Polimanti, R., Pirinen, M., Harerimana, N., Veerapen, K., Wolford, B., Nguyen, H., Solomonson, M., Liao, R. G., Chwialkowska, K., Trankiem, A., Balaconis, M. K., Hayward, C., Richmond, A., Morris, M., Fawns-Ritchie, C., Glessner, J. T., Shaw, D. M., Chang, X., Polikowski, H., Petty, L. E., Chen, H. -H., Wanying, Z., Porteous, D. J., Below, J., North, K., Mccormick, J. B., Timmers, P. H. J., D'Mellow, K., Kerr, S. M., Niemi, M. E. K., Nkambul, L., von Hohenstaufen, K. A., Sobh, A., Eltoukhy, M. M., Yassen, A. M., Hegazy, M. A. F., Okasha, K., Eid, M. A., Moahmed, H. S., Shahin, D., El-Sherbiny, Y. M., Elhadidy, T. A., Abd Elghafar, M. S., El-Jawhari, J. J., Mohamed, A. A. S., Elnagdy, M. H., Samir, A., Abdel-Aziz, M., Khafaga, W. T., El-Lawaty, W. A., Torky, M. S., El-shanshory, M. R., Batini, C., Lee, P. H., Shrine, N., Williams, A. T., Tobin, M. D., Guyatt, A. L., John, C., Packer, R. J., Free, R. C., Wang, X., Wain, L. V., Hollox, E. J., Venn, L. D., Bee, C. E., Adams, Mary Elizabeth, Niavarani, A., Sharififard, B., Aliannejad, R., Amirsavadkouhi, A., Naderpour, Z., Tadi, H. A., Aleagha, A. E., Ahmadi, S., Moghaddam, S. B. M., Adamsara, A., Saeedi, M., Abdollahi, H., Hosseini, A., Chariyavilaskul, P., Chamnanphon, M., Suttichet, T. B., Shotelersuk, V., Pongpanich, M., Phokaew, C., Chetruengchai, W., Jantarabenjakul, W., Putchareon, O., Torvorapanit, P., Puthanakit, T., Suchartlikitwong, P., Hirankarn, N., Nilaratanakul, V., Sodsai, P., Brumpton, B. M., Hveem, K., Willer, C., Zhou, W., Rogne, T., Solligard, E., Asvold, B. O., Abedalthagafi, M., Alaamery, M., Alqahtani, S., Barakeh, D., Harthi, F. A., Alsolm, E., Safieh, L. A., Alowayn, A. M., Alqubaishi, F., Mutairi, A. A., Mangul, S., Alshareef, A., Sawaji, M., Almutairi, M., Aljawini, N., Albesher, N., Arabi, Y. M., Mahmoud, E. S., Khattab, A. K., Halawani, R. T., Alahmadey, Z. Z., Albakri, J. K., Felemban, W. A., Suliman, B. A., Hasanato, R., Al-Awdah, L., Alghamdi, J., Alzahrani, D., Aljohani, S., Al-Afghani, H., Alrashed, M., Aldhawi, N., Albardis, H., Alkwai, S., Alswailm, M., Almalki, F., Albeladi, M., Almohammed, I., Barhoush, E., Albader, A., Massadeh, S., Almalik, A., Alotaibi, S., Alghamdi, B., Jung, J., Fawzy, M. S., Lee, Y., Magnus, P., Trogstad, L. -I. S., Helgeland, O., Harris, J. R., Mangino, M., Spector, T. D., Smieszek, S. P., Przychodzen, B. P., Polymeropoulos, C., Polymeropoulos, V., Polymeropoulos, M. H., Fernandez-Cadenas, I., Perez-Tur, J., Llucia-Carol, L., Cullell, N., Muino, E., Carcel-Marquez, J., Dediego, M. L., Iglesias, L. L., Planas, A. M., Soriano, A., Rico, V., Aguero, D., Bedini, J. L., Lozano, F., Domingo, C., Robles, V., Ruiz-Jaen, F., Marquez, L., Gomez, J., Coto, E., Albaiceta, G. M., Garcia-Clemente, M., Dalmau, D., Arranz, M. J., Dietl, B., Serra-Llovich, A., Soler, P., Colobran, R., Martin-Nalda, A., Martinez, A. P., Bernardo, D., Rojo, S., Fiz-Lopez, A., Arribas, E., de la Cal-Sabater, P., Segura, T., Gonzalez-Villa, E., Serrano-Heras, G., Marti-Fabregas, J., Jimenez-Xarrie, E., Mimbrera, A. F., Masjuan, J., Garcia-Madrona, S., Dominguez-Mayoral, A., Villalonga, J. M., Menendez-Valladares, P., Chasman, D. I., Buring, J. E., Ridker, P. M., Franco, G., Sesso, H. D., Manson, J. E., Glessner, J. R., Hakonarson, H., Medina-Gomez, C., Uitterlinden, A. G., Ikram, M. A., Kristiansson, K., Koskelainen, S., Perola, M., Donner, K., Kivinen, K., Palotie, A., Ripatti, S., Ruotsalainen, S., Kaunisto, M., Nakanishi, T., Butler-Laporte, G., Forgetta, V., Morrison, D. R., 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., Schurr, E., Afilalo, J., Afilalo, M., Oliveira, M., Brenner, B., Lepage, P., Ragoussis, J., Auld, D., Brassard, N., Durand, M., Chasse, M., Kaufmann, D. E., Lathrop, G. M., Mooser, V., Richards, J. B., Li, R., Adra, D., Rahmouni, S., Georges, M., Moutschen, M., Misset, B., Darcis, G., Guiot, J., Guntz, J., Azarzar, S., Gofflot, S., Beguin, Y., Claassen, S., Malaise, O., Huynen, P., Meuris, C., Thys, M., Jacques, J., Leonar, P., Frippiat, F., Giot, J. -B., Sauvage, A. -S., von Frenckell, C., Belhaj, Y., Lambermont, B., Pigazzini, S., Daya, M., Shortt, J., Rafaels, N., Wicks, S. J., Crooks, K., Barnes, K. C., Gignoux, C. R., Chavan, S., Laisk, T., Lall, K., Lepamets, M., Magi, R., Esko, T., Reimann, E., Milani, Luca, Alavere, H., Metsalu, K., Puusepp, M., Metspalu, A., Naaber, P., Laane, E., Pesukova, J., Peterson, P., Kisand, K., Tabri, J., Allos, R., Hensen, K., Starkopf, J., Ringmets, I., Tamm, A., Kallaste, A., Bochud, P. -Y., Rivolta, C., Bibert, S., Quinodoz, M., Kamdar, D., Boillat, N., Nussle, S. G., Albrich, W., Suh, N., Neofytos, D., Erard, V., Voide, C., de Cid, R., Galvan-Femenia, I., Blay, N., Carreras, A., Cortes, B., Farre, X., Sumoy, L., Moreno, V., Mercader, J. M., Guindo-Martinez, M., Torrents, D., Kogevinas, M., Garcia-Aymerich, J., Castano-Vinyals, G., Dobano, C., Renieri, A., Mari, F., Fallerini, C., Daga, S., Benetti, E., Baldassarri, M., Fava, F., Frullanti, E., Valentino, Francesca, Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Mencarelli, Marta, Rizzo, C. L., Pinto, A. M., Beligni, G., Tommasi, A., Sarno, L. D., Palmieri, Marco, Carriero, M. L., Alaverdian, D., Busani, S., Bruno, R., Vecchia, M., Belli, M. A., Picchiotti, N., Sanarico, M., Gori, Mario, Furini, S., Mantovani, Susanna, Ludovisi, S., Mondelli, M. U., Castelli, F., Quiros-Roldan, E., Antoni, M. D., Zanella, I., Vaghi, M., Rusconi, S., Siano, M., Montagnani, F., Emiliozzi, A., Fabbiani, M., Rossetti, Barbara, Bargagli, E., Bergantini, L., D'Alessandro, Michele, Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, Francesca, Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, Andrea, Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Bandini, M., Caldarelli, G. P., Piacentini, P., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Pancrazzi, A., Lorubbio, M., Monforte, A. D., Miraglia, F. G., Girardis, M., Venturelli, S., Cossarizza, A., Antinori, Armando, Vergori, A., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Baratti, S., Monica, M. D., Piscopo, C., Capasso, Monica, Russo, R., Andolfo, I., Iolascon, A., Fiorentino, Giuseppe, Carella, M., Castori, M., Merla, G., Squeo, G. M., Aucella, F., Raggi, P., Marciano, C., Perna, Raffaella, Bassetti, M., Biagio, A. D., Sanguinetti, Maurizio, Masucci, Luca, Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, Francesco, Coviello, D. A., Mussini, C., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Gabbi, Chiara, Rizzi, M., Maggiolo, F., Ripamonti, D., Bachetti, T., Rovere, M. T. L., Sarzi-Braga, S., Bussotti, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Zguro, K., Capitani, K., Suardi, C., Dei, S., Parati, G., Ravaglia, S., Artuso, R., Botta, Giovanni, Di Domenico, Pasqualina, Rancan, I., Perrella, A., Bianchi, F., Romani, D., Bergomi, P., Catena, E., Colombo, R., Tanfoni, M., Vincenti, A., Ferri, C., Grassi, D., Pessina, Gloria, Tumbarello, Mario, Di Pietro, Maria Luisa, Sabrina, R., Luchi, S., Barbieri, Cristiano, Acquilini, D., Andreucci, E., Segala, F. V., Tiseo, G., Falcone, M., Lista, Maddalena, Poscente, M., De Vivo, O., Petrocelli, Paolo, Guarnaccia, A., Baroni, S., Smith, A. V., Boughton, A. P., K. W., Li, Lefaive, J., Annis, A., Chittoor, G., Josyula, N. S., Leader, J. B., Carey, D. J., Gass, M. C., Cantor, M. N., Yadav, A., van Heel, D. A., Hunt, K. A., Mason, D., Huang, Q. Q., Finer, S., Trivedi, B., Griffiths, C. J., Martin, H. C., Wright, J., Trembath, R. C., Soranzo, N., Zhao, J. H., Butterworth, A. S., Danesh, J., Di Angelantonio, E., Franke, L., Boezen, M., Deelen, P., Claringbould, A., Lopera, E., Warmerdam, R., Vonk, J. M., van Blokland, I., Lanting, P., Ori, A. P. S., Zollner, S., Wang, J., Beck, A., Peloso, G., Y. -L., Ho, Sun, Y. V., Huffman, J. E., O'Donnell, C. J., Cho, K., Tsao, P., Gaziano, J. M., Nivard, M., de Geus, E., Bartels, M., Hottenga, J. J., Weiss, S. T., Karlson, E. W., Smoller, J. W., Green, R. C., Feng, Y. -C. A., Mercader, J., Murphy, S. N., Meigs, J. B., Woolley, A. E., Perez, E. F., Rader, D., Li, B., Verma, S. S., Lucas, A., Bradford, Y., Zeberg, H., Frithiof, R., Hultstrom, M., Lipcsey, M., Tardif, N., Rooyackers, O., Grip, J., Maricic, T., Karczewski, K. J., Atkinson, E. G., Tsuo, K., Baya, N., Turley, P., Gupta, R., Callier, S., Walters, R. K., Palmer, D. S., Sarma, G., Cheng, N., Lu, W., Bryant, S., Churchhouse, C., Cusick, C., Goldstein, J. I., King, D., Seed, C., Finucane, H., Martin, A. R., Satterstrom, F. K., Wilson, D. J., Armstrong, J., Rudkin, J. K., Band, G., Earle, S. G., Lin, S. -K., Arning, N., Crook, D. W., Wyllie, D. H., O'Connell, A. M., Spencer, C. C. A., Koelling, N., Fowler, T., Pasko, D., Ball, C. A., Hong, E. L., Rand, K., Girshick, A., Guturu, H., Baltzell, A. H., Roberts, G., Park, D., Coignet, M., Mccurdy, S., Knight, S., Partha, R., Rhead, B., Zhang, M., Berkowitz, N., Gaddis, M., Noto, K., Ruiz, L., Pavlovic, M., Sloofman, L. G., Charney, A. W., Beckmann, N. D., Schadt, E. E., Jordan, D. M., Thompson, R. C., Gettler, K., Abul-Husn, N. S., Ascolillo, S., Buxbaum, J. D., Chaudhary, K., Cho, J. H., Itan, Y., Kenny, E. E., Belbin, G. M., Sealfon, S. C., Sebra, R. P., Salib, I., Collins, B. L., Levy, T., Britvan, B., Keller, K., Tang, L., Peruggia, M., Hiester, L. L., Niblo, K., Aksentijevich, A., Labkowsky, A., Karp, A., Zlatopolsky, M., Preuss, M., Loos, R. J. F., Nadkarni, G. N., Do, R., Hoggart, C., Choi, S., Underwood, S. J., O'Reilly, P., Huckins, L. M., Zyndorf, M., Daly, M. J., Neale, B. M., Ganna, A., Kousathanas, A, Pairo-Castineira, E, Rawlik, K, Stuckey, A, Odhams, C, Walker, S, Russell, C, Malinauskas, T, Wu, Y, Millar, J, Shen, X, Elliott, K, Griffiths, F, Oosthuyzen, W, Morrice, K, Keating, S, Wang, B, Rhodes, D, Klaric, L, Zechner, M, Parkinson, N, Siddiq, A, Goddard, P, Donovan, S, Maslove, D, Nichol, A, Semple, M, Zainy, T, Maleady-Crowe, F, Todd, L, Salehi, S, Knight, J, Elgar, G, Chan, G, Arumugam, P, Patch, C, Rendon, A, Bentley, D, Kingsley, C, Kosmicki, J, Horowitz, J, Baras, A, Abecasis, G, Ferreira, M, Justice, A, Mirshahi, T, Oetjens, M, Rader, D, Ritchie, M, Verma, A, Fowler, T, Shankar-Hari, M, Summers, C, Hinds, C, Horby, P, Ling, L, Mcauley, D, Montgomery, H, Openshaw, P, Elliott, P, Walsh, T, Tenesa, A, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Pathak, G, Karjalainen, J, Stevens, C, Andrews, S, Kanai, M, Cordioli, M, Polimanti, R, Pirinen, M, Harerimana, N, Veerapen, K, Wolford, B, Nguyen, H, Solomonson, M, Liao, R, Chwialkowska, K, Trankiem, A, Balaconis, M, Hayward, C, Richmond, A, Campbell, A, Morris, M, Fawns-Ritchie, C, Glessner, J, Shaw, D, Chang, X, Polikowski, H, Petty, L, Chen, H, Wanying, Z, Hakonarson, H, Porteous, D, Below, J, North, K, Mccormick, J, Timmers, P, Wilson, J, D'Mellow, K, Kerr, S, Niemi, M, Nkambul, L, von Hohenstaufen, K, Sobh, A, Eltoukhy, M, Yassen, A, Hegazy, M, Okasha, K, Eid, M, Moahmed, H, Shahin, D, El-Sherbiny, Y, Elhadidy, T, Abd Elghafar, M, El-Jawhari, J, Mohamed, A, Elnagdy, M, Samir, A, Abdel-Aziz, M, Khafaga, W, El-Lawaty, W, Torky, M, El-shanshory, M, Batini, C, Lee, P, Shrine, N, Williams, A, Tobin, M, Guyatt, A, John, C, Packer, R, Ali, A, Free, R, Wang, X, Wain, L, Hollox, E, Venn, L, Bee, C, Adams, E, Niavarani, A, Sharififard, B, Aliannejad, R, Amirsavadkouhi, A, Naderpour, Z, Tadi, H, Aleagha, A, Ahmadi, S, Moghaddam, S, Adamsara, A, Saeedi, M, Abdollahi, H, Hosseini, A, Chariyavilaskul, P, Chamnanphon, M, Suttichet, T, Shotelersuk, V, Pongpanich, M, Phokaew, C, Chetruengchai, W, Jantarabenjakul, W, Putchareon, O, Torvorapanit, P, Puthanakit, T, Suchartlikitwong, P, Hirankarn, N, Nilaratanakul, V, Sodsai, P, Brumpton, B, Hveem, K, Willer, C, Zhou, W, Rogne, T, Solligard, E, Asvold, B, Abedalthagafi, M, Alaamery, M, Alqahtani, S, Barakeh, D, Al Harthi, F, Alsolm, E, Safieh, L, Alowayn, A, Alqubaishi, F, Al Mutairi, A, Mangul, S, Alshareef, A, Sawaji, M, Almutairi, M, Aljawini, N, Albesher, N, Arabi, Y, Mahmoud, E, Khattab, A, Halawani, R, Alahmadey, Z, Albakri, J, Felemban, W, Suliman, B, Hasanato, R, Al-Awdah, L, Alghamdi, J, Alzahrani, D, Aljohani, S, Al-Afghani, H, Alrashed, M, Aldhawi, N, Albardis, H, Alkwai, S, Alswailm, M, Almalki, F, Albeladi, M, Almohammed, I, Barhoush, E, Albader, A, Massadeh, S, Almalik, A, Alotaibi, S, Alghamdi, B, Jung, J, Fawzy, M, Lee, Y, Magnus, P, Trogstad, L, Helgeland, O, Harris, J, Mangino, M, Spector, T, Duncan, E, Smieszek, S, Przychodzen, B, Polymeropoulos, C, Polymeropoulos, V, Polymeropoulos, M, Fernandez-Cadenas, I, Perez-Tur, J, Llucia-Carol, L, Cullell, N, Muino, E, Carcel-Marquez, J, Dediego, M, Iglesias, L, Planas, A, Soriano, A, Rico, V, Aguero, D, Bedini, J, Lozano, F, Domingo, C, Robles, V, Ruiz-Jaen, F, Marquez, L, Gomez, J, Coto, E, Albaiceta, G, Garcia-Clemente, M, Dalmau, D, Arranz, M, Dietl, B, Serra-Llovich, A, Soler, P, Colobran, R, Martin-Nalda, A, Martinez, A, Bernardo, D, Rojo, S, Fiz-Lopez, A, Arribas, E, de la Cal-Sabater, P, Segura, T, Gonzalez-Villa, E, Serrano-Heras, G, Marti-Fabregas, J, Jimenez-Xarrie, E, de Felipe Mimbrera, A, Masjuan, J, Garcia-Madrona, S, Dominguez-Mayoral, A, Villalonga, J, Menendez-Valladares, P, Chasman, D, Buring, J, Ridker, P, Franco, G, Sesso, H, Manson, J, Medina-Gomez, C, Uitterlinden, A, Ikram, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Ripatti, S, Ruotsalainen, S, Kaunisto, M, Nakanishi, T, Butler-Laporte, G, Forgetta, V, Morrison, D, 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, Schurr, E, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Lepage, P, Ragoussis, J, Auld, D, Brassard, N, Durand, M, Chasse, M, Kaufmann, D, Lathrop, G, Mooser, V, Richards, J, Li, R, Adra, D, Rahmouni, S, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Guntz, J, Azarzar, S, Gofflot, S, Beguin, Y, Claassen, S, Malaise, O, Huynen, P, Meuris, C, Thys, M, Jacques, J, Leonard, P, Frippiat, F, Giot, J, Sauvage, A, von Frenckell, C, Belhaj, Y, Lambermont, B, Pigazzini, S, Nkambule, L, Daya, M, Shortt, J, Rafaels, N, Wicks, S, Crooks, K, Barnes, K, Gignoux, C, Chavan, S, Laisk, T, Lall, K, Lepamets, M, Magi, R, Esko, T, Reimann, E, Milani, L, Alavere, H, Metsalu, K, Puusepp, M, Metspalu, A, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Bochud, P, Rivolta, C, Bibert, S, Quinodoz, M, Kamdar, D, Boillat, N, Nussle, S, Albrich, W, Suh, N, Neofytos, D, Erard, V, Voide, C, de Cid, R, Galvan-Femenia, I, Blay, N, Carreras, A, Cortes, B, Farre, X, Sumoy, L, Moreno, V, Mercader, J, Guindo-Martinez, M, Torrents, D, Kogevinas, M, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Renieri, A, Mari, F, Fallerini, C, Daga, S, Benetti, E, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, M, Alaverdian, D, Busani, S, Bruno, R, Vecchia, M, Belli, M, Picchiotti, N, Sanarico, M, Gori, M, Furini, S, Mantovani, S, Ludovisi, S, Mondelli, M, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Vaghi, M, Rusconi, S, Siano, M, Montagnani, F, Emiliozzi, A, Fabbiani, M, Rossetti, B, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Bandini, M, Caldarelli, G, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazzi, A, Lorubbio, M, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Cossarizza, A, Antinori, A, Vergori, A, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Gabbi, C, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, La Rovere, M, Sarzi-Braga, S, Bussotti, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Zguro, K, Capitani, K, Suardi, C, Dei, S, Parati, G, Ravaglia, S, Artuso, R, Botta, G, Di Domenico, P, Rancan, I, Perrella, A, Bianchi, F, Romani, D, Bergomi, P, Catena, E, Colombo, R, Tanfoni, M, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Segala, F, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Smith, A, Boughton, A, Li, K, Lefaive, J, Annis, A, Chittoor, G, Josyula, N, Leader, J, Carey, D, Gass, M, Cantor, M, Yadav, A, van Heel, D, Hunt, K, Mason, D, Huang, Q, Finer, S, Trivedi, B, Griffiths, C, Martin, H, Wright, J, Trembath, R, Soranzo, N, Zhao, J, Butterworth, A, Danesh, J, Di Angelantonio, E, Franke, L, Boezen, M, Deelen, P, Claringbould, A, Lopera, E, Warmerdam, R, Vonk, J, van Blokland, I, Lanting, P, Ori, A, Zollner, S, Wang, J, Beck, A, Peloso, G, Ho, Y, Sun, Y, Huffman, J, O'Donnell, C, Cho, K, Tsao, P, Gaziano, J, Nivard, M, de Geus, E, Bartels, M, Jan Hottenga, J, Weiss, S, Karlson, E, Smoller, J, Green, R, Feng, Y, Murphy, S, Meigs, J, Woolley, A, Perez, E, Li, B, Verma, S, Lucas, A, Bradford, Y, Zeberg, H, Frithiof, R, Hultstrom, M, Lipcsey, M, Tardif, N, Rooyackers, O, Grip, J, Maricic, T, Karczewski, K, Atkinson, E, Tsuo, K, Baya, N, Turley, P, Gupta, R, Callier, S, Walters, R, Palmer, D, Sarma, G, Cheng, N, Lu, W, Bryant, S, Churchhouse, C, Cusick, C, Goldstein, J, King, D, Seed, C, Finucane, H, Martin, A, Satterstrom, F, Wilson, D, Armstrong, J, Rudkin, J, Band, G, Earle, S, Lin, S, Arning, N, Crook, D, Wyllie, D, O'Connell, A, Spencer, C, Koelling, N, Caulfield, M, Scott, R, Moutsianas, L, Pasko, D, Ball, C, Hong, E, Rand, K, Girshick, A, Guturu, H, Baltzell, A, Roberts, G, Park, D, Coignet, M, Mccurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Sloofman, L, Charney, A, Beckmann, N, Schadt, E, Jordan, D, Thompson, R, Gettler, K, Abul-Husn, N, Ascolillo, S, Buxbaum, J, Chaudhary, K, Cho, J, Itan, Y, Kenny, E, Belbin, G, Sealfon, S, Sebra, R, Salib, I, Collins, B, Levy, T, Britvan, B, Keller, K, Tang, L, Peruggia, M, Hiester, L, Niblo, K, Aksentijevich, A, Labkowsky, A, Karp, A, Zlatopolsky, M, Preuss, M, Loos, R, Nadkarni, G, Do, R, Hoggart, C, Choi, S, Underwood, S, O'Reilly, P, Huckins, L, Zyndorf, M, Daly, M, Neale, B, Ganna, A, Fawkes, A, Murphy, L, Rowan, K, Ponting, C, Vitart, V, Yang, J, Bretherick, A, Hendry, S, Law, A, Baillie, J, Kousathanas, Athanasios [0000-0001-6265-6521], Pairo-Castineira, Erola [0000-0002-2423-3090], Rawlik, Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Malinauskas, Tomas [0000-0002-4847-5529], Wu, Yang [0000-0002-0128-7280], Shen, Xia [0000-0003-4390-1979], Elliott, Katherine S [0000-0002-8125-797X], Keating, Sean [0000-0001-8552-5604], Wang, Bo [0000-0002-1580-797X], Klaric, Lucija [0000-0003-3105-8929], Parkinson, Nick [0000-0001-6336-5654], Nichol, Alistair [0000-0002-4689-1238], Semple, Malcolm G [0000-0001-9700-0418], Salehi, Shahla [0000-0002-5058-7706], Knight, Julian [0000-0002-0377-5536], Elgar, Greg [0000-0001-7323-1596], Patch, Christine [0000-0002-4191-0663], Baras, Aris [0000-0002-6830-3396], Abecasis, Goncalo R [0000-0003-1509-1825], Ferreira, Manuel AR [0000-0001-9059-1825], Rader, Daniel J [0000-0002-9245-9876], Ritchie, Marylyn D [0000-0002-1208-1720], Shankar-Hari, Manu [0000-0002-5338-2538], Summers, Charlotte [0000-0002-7269-2873], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Elliott, Paul [0000-0002-7511-5684], Tenesa, Albert [0000-0003-4884-4475], Murphy, Lee [0000-0001-6467-7449], Rowan, Kathy [0000-0001-8217-5602], Ponting, Chris P [0000-0003-0202-7816], Vitart, Veronique [0000-0002-4991-3797], Wilson, James F [0000-0001-5751-9178], Yang, Jian [0000-0003-2001-2474], Bretherick, Andrew D [0000-0001-9258-3140], Hendry, Sara Clohisey [0000-0001-7489-9846], Moutsianas, Loukas [0000-0001-5453-345X], Law, Andy [0000-0003-1868-2364], Caulfield, Mark J [0000-0001-9295-3594], Baillie, J Kenneth [0000-0001-5258-793X], Apollo - University of Cambridge Repository, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, UK Research and Innovation, Internal Medicine, Epidemiology, Center of Experimental and Molecular Medicine, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, 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), APH - Methodology, APH - Mental Health, Biological Psychology, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Department of Health & Social Care (UK), Medical Research Council (UK), Roslin Institute, Pérez-Tur, Jordi, Institute for Molecular Medicine Finland, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Faculty Common Matters (Faculty of Social Sciences), Data Science Genetic Epidemiology Lab, CAMM - Research Program for Clinical and Molecular Metabolism, investigators, GenOMICC, investigators, 23andMe, and Initiative, COVID-19 Human Genetics
- Subjects
Genome-wide association studies ,PATHWAY ,Fucosyltransferase ,Lectins ,Receptors ,Genetics research ,TOOL ,Phospholipid Transfer Proteins ,Genome ,Multidisciplinary ,C-Type ,ATP-Binding Cassette Transporters ,Cell Adhesion Molecules ,Critical Care ,E-Selectin ,Factor VIII ,Fucosyltransferases ,Genome-Wide Association Study ,Humans ,Interleukin-10 Receptor beta Subunit ,Lectins, C-Type ,Mucin-1 ,Nerve Tissue Proteins ,Receptors, Cell Surface ,Repressor Proteins ,SARS-CoV-2 ,COVID-19 ,Critical Illness ,Genome, Human ,Host-Pathogen Interactions ,Whole Genome Sequencing ,1184 Genetics, developmental biology, physiology ,ASSOCIATION ,GenOMICC investigators ,COVID-19/genetics ,Host-Pathogen Interactions/genetics ,Multidisciplinary Sciences ,Host-Pathogen Interaction ,Cell Surface ,Science & Technology - Other Topics ,Infectious diseases ,Critical Illne ,Human ,Respiratory distress syndrome ,General Science & Technology ,ATP-Binding Cassette Transporter ,DENDRITIC CELLS ,23andMe investigators ,Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA ,Phospholipid Transfer Protein ,SDG 3 - Good Health and Well-being ,LINKAGE ,Science & Technology ,SARS-CoV-2/pathogenicity ,Repressor Protein ,SIGNAL ,ONTOLOGY ,COVID-19 Human Genetics Initiative ,Critical Illness/mortality ,Cell Adhesion Molecule ,Nerve Tissue Protein ,Genome, Human/genetics - Abstract
34 páginas, 3 figuras, 1 tabla., Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease., GenOMICC was funded by the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council (MRC), UKRI, Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (J.K.B., 223164/Z/21/Z) a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_ PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. WGS was performed by Illumina Article at Illumina Laboratory Services and was overseen by Genomics England. We would like to thank all at Genomics England who have contributed to the sequencing, clinical and genomic data analysis. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref. MC_PC_20029). A.D.B. would like to acknowledge funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z) and the Edinburgh Clinical Academic Track (ECAT) programme. We thank the research participants and employees of 23andMe for making this work possible. Genomics England and the 100,000 Genomes Project were funded by the National Institute for Health Research, the Wellcome Trust, the MRC, Cancer Research UK, the DHSC and NHS England. We are grateful for the support from S. Hill and the team in NHS England and the 13 Genomic Medicine Centres that delivered the 100,000 Genomes Project, which provided most of the control genome sequences for this study. We thank the participants in the 100,000 Genomes Project, who made this study possible, and the Genomics England Participant Panel for their strategic advice, involvement and engagement. We acknowledge NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre, who provided life-course longitudinal clinical data on the participants. This work forms part of the portfolio of research of the National Institute for Health Research Barts Biomedical Research Centre. Mark Caulfield is an NIHR Senior Investigator. This study owes a great deal to the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. Additional replication was conducted using the UK Biobank Resource (project 26041). The Penn Medicine BioBank is funded by a gift from the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award number UL1TR001878; and the Perelman School of Medicine at the University of Pennsylvania. We thank the AncestryDNA customers who voluntarily contributed information in the COVID-19 survey. HRS (dbGaP accession: phs000428.v1.p1): HRS was supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 22 August 2021 (GTEx Analysis Release v.8 (dbGaP Accession phs000424.v8.p2). We thank the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available at https://www.covid19hg.org/acknowledgements. The views expressed are those of the authors and not necessarily those of the DHSC, NHS, Department for International Development (DID), NIHR, MRC, Wellcome Trust or Public Health England.
- Published
- 2022
6. Clinical-Pathological Evaluation and Prognostic Analysis of 228 Merkel Cell Carcinomas Focusing on Tumor-Infiltrating Lymphocytes, MCPYV Infection and ALK Expression
- Author
-
Federica Santoro, Francesca Maletta, Renato Parente, Jessica Fissore, Cristian Tampieri, Leonardo Santoro, Nadia Birocco, Franco Picciotto, Pietro Quaglino, Marco Volante, Sofia Asioli, Rebecca Senetta, Mauro Papotti, Santoro, Federica, Maletta, Francesca, Parente, Renato, Fissore, Jessica, Tampieri, Cristian, Santoro, Leonardo, Birocco, Nadia, Picciotto, Franco, Quaglino, Pietro, Volante, Marco, Asioli, Sofia, Senetta, Rebecca, and Papotti, Mauro
- Subjects
Skin Neoplasms ,INSM1 expression ,Prognosi ,Endocrinology, Diabetes and Metabolism ,Tumor-infiltrating lymphocyte ,Polyomavirus Infection ,Tumor-infiltrating lymphocytes ,Pathology and Forensic Medicine ,Lymphocytes, Tumor-Infiltrating ,Endocrinology ,Merkel cell carcinoma ,Humans ,Lymphocytes ,Tumor-Infiltrating ,Polyomavirus Infections ,ALK expression ,Merkel cell polyomavirus ,Prognosis ,Receptor Protein-Tyrosine Kinases ,Repressor Proteins ,Carcinoma, Merkel Cell ,Carcinoma ,General Medicine ,Repressor Protein ,Receptor Protein-Tyrosine Kinase ,Merkel Cell ,Merkel cell polyomaviru ,Human - Abstract
Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series.
- Published
- 2022
7. HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations
- Author
-
Naama Hirsch, Idit Dahan, Eva D'haene, Matan Avni, Sarah Vergult, Marta Vidal-García, Pamela Magini, Claudio Graziano, Giulia Severi, Elena Bonora, Anna Maria Nardone, Francesco Brancati, Alberto Fernández-Jaén, Olson J. Rory, Benedikt Hallgrímsson, Ramon Y. Birnbaum, Hirsch, Naama, Dahan, Idit, D'haene, Eva, Avni, Matan, Vergult, Sarah, Vidal-García, Marta, Magini, Pamela, Graziano, Claudio, Severi, Giulia, Bonora, Elena, Nardone, Anna Maria, Brancati, Francesco, Fernández-Jaén, Alberto, Rory, Olson J, Hallgrímsson, Benedikt, and Birnbaum, Ramon Y
- Subjects
Craniosynostose ,Animal ,Twist-Related Protein 1 ,Repressor Protein ,TRANSLOCATION ,Mice ,Polydactyly ,Phenotype ,Gene Expression Regulation ,Histone Deacetylase ,Medicine and Health Sciences ,Genetics ,Genetics (clinical) ,Human ,Nuclear Protein ,TISSUE-SPECIFIC ENHANCERS - Abstract
Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as cis-regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the histone deacetylase 9 (HDAC9) protein-coding sequence are associated with disruption of TWIST1 regulatory elements that reside within the HDAC9 sequence. Based on SVs within the HDAC9‐TWIST1 locus, we defined the 3′-HDAC9 sequence as a critical TWIST1 regulatory region, encompassing craniofacial TWIST1 enhancers and CTCF sites. Deletions of either Twist1 enhancers (eTw5-7Δ/Δ) or CTCF site (CTCF-5Δ/Δ) within the Hdac9 protein-coding sequence led to decreased Twist1 expression and altered anterior/posterior limb expression patterns of SHH pathway genes. This decreased Twist1 expression results in a smaller sized and asymmetric skull and polydactyly that resembles Twist1+/− mouse phenotype. Chromatin conformation analysis revealed that the Twist1 promoter interacts with Hdac9 sequences that encompass Twist1 enhancers and a CTCF site, and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entire Hdac9 sequence (Hdac9INV/+) in mice that does not disrupt Hdac9 expression but repositions Twist1 regulatory elements showed decreased Twist1 expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidates essential components of TWIST1 transcriptional machinery that reside within the HDAC9 sequence. It suggests that SVs encompassing protein-coding sequences could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene.
- Published
- 2022
8. Investigations of the oligometric state of the 42 kDa repressor isoform from the streptomcyes temperate bacteriophage φC31
- Author
-
Jumel, K., Wilson, S. E., Smith, M. C. M., Harding, S. E., Kremer, F., editor, Lagaly, G., editor, and Behlke, J., editor
- Published
- 1995
- Full Text
- View/download PDF
9. Glucocorticoid-Induced Death of Immune Cells: Mechanisms of Action
- Author
-
Montague, J. W., Cidlowski, J. A., Capron, A., editor, Compans, R. W., editor, Cooper, M., editor, Koprowski, H., editor, McConnell, I., editor, Melchers, F., editor, Oldstone, M., editor, Olsnes, S., editor, Potter, M., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, Kroemer, Guido, editor, and Martinez-A., Carlos, editor
- Published
- 1995
- Full Text
- View/download PDF
10. Mechanisms of Translational Initiation and Repression in Prokaryotes
- Author
-
Draper, David E., Nierhaus, Knud H., editor, Franceschi, François, editor, Subramanian, Alap R., editor, Erdmann, Volker A., editor, and Wittmann-Liebold, Brigitte, editor
- Published
- 1993
- Full Text
- View/download PDF
11. The Helix-Turn-Helix Motif and the Cro Repressor
- Author
-
Anderson, Wayne F., Bayley, P. M., editor, and Taylor, William R., editor
- Published
- 1992
- Full Text
- View/download PDF
12. Control of transcription
- Author
-
Adams, Roger L. P., Knowler, John T., Leader, David P., Adams, Roger L. P., Knowler, John T., and Leader, David P.
- Published
- 1992
- Full Text
- View/download PDF
13. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia
- Author
-
Di Giacomo, D, La Starza, R, Gorello, P, Pellanera, F, Kalender Atak, Z, De Keersmaecker, K, Pierini, V, Harrison, C, Arniani, S, Moretti, M, Testoni, N, De Santis, G, Roti, G, Matteucci, C, Bassan, R, Vandenberghe, P, Aerts, S, Cools, J, Bornhauser, B, Bourquin, J, Piazza, R, Mecucci, C, Di Giacomo D., La Starza R., Gorello P., Pellanera F., Kalender Atak Z., De Keersmaecker K., Pierini V., Harrison C. J., Arniani S., Moretti M., Testoni N., De Santis G., Roti G., Matteucci C., Bassan R., Vandenberghe P., Aerts S., Cools J., Bornhauser B., Bourquin J. -P., Piazza R., Mecucci C., Di Giacomo, D, La Starza, R, Gorello, P, Pellanera, F, Kalender Atak, Z, De Keersmaecker, K, Pierini, V, Harrison, C, Arniani, S, Moretti, M, Testoni, N, De Santis, G, Roti, G, Matteucci, C, Bassan, R, Vandenberghe, P, Aerts, S, Cools, J, Bornhauser, B, Bourquin, J, Piazza, R, Mecucci, C, Di Giacomo D., La Starza R., Gorello P., Pellanera F., Kalender Atak Z., De Keersmaecker K., Pierini V., Harrison C. J., Arniani S., Moretti M., Testoni N., De Santis G., Roti G., Matteucci C., Bassan R., Vandenberghe P., Aerts S., Cools J., Bornhauser B., Bourquin J. -P., Piazza R., and Mecucci C.
- Abstract
Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.
- Published
- 2021
14. Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy
- Author
-
Anna Maria Lena, E. Logli, Cristina Has, Marco D'Agostino, May El Hachem, Angelo Giuseppe Condorelli, Giovanna Zambruno, Alessandra Magenta, Eleonora Candi, Andrea Diociaiuti, Libenzio Adrian Conti, Elisa Marzuolo, Elena Dellambra, Valentina Cianfanelli, Logli, Elena, Marzuolo, Elisa, D'Agostino, Marco, Conti, Libenzio Adrian, Lena, Anna Maria, Diociaiuti, Andrea, Dellambra, Elena, Has, Cristina, Cianfanelli, Valentina, Zambruno, Giovanna, El Hachem, May, Magenta, Alessandra, Candi, Eleonora, and Condorelli, Angelo Giuseppe
- Subjects
Senescence ,Keratinocytes ,Proteasome Endopeptidase Complex ,Keratin 14 ,Mutant ,Biology ,Epidermolysis bullosa simplex ,Pregnancy ,Keratin ,Genetics ,medicine ,Humans ,Molecular Biology ,Genetics (clinical) ,Cardiomyopathie ,chemistry.chemical_classification ,integumentary system ,Epidermis (botany) ,General Medicine ,Repressor Protein ,medicine.disease ,Cell biology ,Repressor Proteins ,medicine.anatomical_structure ,chemistry ,Proteasome ,Epidermolysis Bullosa Simplex ,Mutation ,Skin Abnormalities ,Keratins ,Female ,Keratinocyte ,Cardiomyopathies ,Human - Abstract
Epidermolysis bullosa simplex (EBS) with cardiomyopathy (EBS-KLHL24) is an EBS subtype caused by dominantly inherited, gain-of-function mutations in the gene encoding for the ubiquitin-ligase KLHL24, which addresses specific proteins to proteasomal degradation. EBS-KLHL24 patients are born with extensive denuded skin areas and skin fragility. Whilst skin fragility rapidly ameliorates, atrophy and scarring develop over time, accompanied by life-threatening cardiomyopathy. To date, pathogenetic mechanisms underlying such a unique disease phenotype are not fully characterized. The basal keratin 14 (K14) has been indicated as a KLHL24 substrate in keratinocytes. However, EBS-KLHL24 pathobiology cannot be determined by the mutation-enhanced disruption of K14 alone, as K14 is similarly expressed in foetal and postnatal epidermis and its protein levels are preserved both in vivo and in vitro disease models. In this study, we focused on foetal keratins as additional KLHL24 substrates. We showed that K7, K8, K17 and K18 protein levels are markedly reduced via proteasome degradation in normal foetal keratinocytes transduced with the mutant KLHL24 protein (ΔN28-KLHL24) as compared to control cells expressing the wild-type form. In addition, heat stress led to keratin network defects and decreased resilience in ΔN28-KLHL24 cells. The KLHL24-mediated degradation of foetal keratins could contribute to congenital skin defects in EBS-KLHL24. Furthermore, we observed that primary keratinocytes from EBS-KLHL24 patients undergo accelerated clonal conversion with reduced colony forming efficiency (CFE) and early replicative senescence. Finally, our findings pointed out a reduced CFE in ΔN28-KLHL24-transduced foetal keratinocytes as compared to controls, suggesting that mutant KLHL24 contributes to patients’ keratinocyte clonogenicity impairment.
- Published
- 2021
15. Mechanisms of Ribosomal Protein Translational Autoregulation
- Author
-
Draper, David E., McCarthy, John E. G., editor, and Tuite, Mick F., editor
- Published
- 1990
- Full Text
- View/download PDF
16. A cryptic long-chain 3-ketoacyl-ACP synthase in the Pseudomonas putida F1 unsaturated fatty acid synthesis pathway
- Author
-
Yu-Ling Liao, Lujie Liang, John E. Cronan, Bo Chen, Haihong Wang, Jin-Cheng Ma, Huijuan Dong, Yu-Lu Song, and Qunyi Chen
- Subjects
0301 basic medicine ,ACP, acyl carrier protein ,Operon ,Auxotrophy ,SFA, saturated fatty acid ,Repressor ,Biochemistry ,03 medical and health sciences ,3-Oxoacyl-(Acyl-Carrier-Protein) Synthase ,3-ketoacyl-ACP synthase ,UFA, unsaturated fatty acid ,Molecular Biology ,Unsaturated fatty acid ,fatty acid oxidation ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Pseudomonas putida ,Genetic Complementation Test ,repressor protein ,Cell Biology ,biology.organism_classification ,Complementation ,Acyl carrier protein ,030104 developmental biology ,fatty acid metabolism ,regulator ,Saturated fatty acid ,biology.protein ,Fatty Acids, Unsaturated ,fatty acid synthase (FAS) ,Research Article - Abstract
The Pseudomonas putida F1 genome contains five genes annotated as encoding 3-ketoacyl-acyl carrier protein (ACP) synthases. Four are annotated as encoding FabF (3-ketoacyl-ACP synthase II) proteins, and the fifth is annotated as encoding a FabB (3-ketoacyl-ACP synthase I) protein. Expression of one of the FabF proteins, FabF2, is cryptic in the native host and becomes physiologically important only when the repressor controlling fabF2 transcription is inactivated. When derepressed, FabF2 can functionally replace FabB, and when expressed from a foreign promoter, had weak FabF activity. Complementation of Escherichia coli fabB and fabF mutant strains with high expression showed that P. putida fabF1 restored E. coli fabF function, whereas fabB restored E. coli fabB function and fabF2 restored the functions of both E. coli fabF and fabB. The P. putida ΔfabF1 deletion strain was almost entirely defective in synthesis of cis-vaccenic acid, whereas the ΔfabB strain is an unsaturated fatty acid (UFA) auxotroph that accumulated high levels of spontaneous suppressors in the absence of UFA supplementation. This was due to increased expression of fabF2 that bypasses loss of fabB because of the inactivation of the regulator, Pput_2425, encoded in the same operon as fabF2. Spontaneous suppressor accumulation was decreased by high levels of UFA supplementation, whereas competition by the P. putida β-oxidation pathway gave increased accumulation. The ΔfabB ΔfabF2 strain is a stable UFA auxotroph indicating that suppressor accumulation requires FabF2 function. However, at low concentrations of UFA supplementation, the ΔfabF2 ΔPput_2425 double-mutant strain still accumulated suppressors at low UFA concentrations.
- Published
- 2021
17. A eutherian-specific microRNA controls the translation of Satb2 in a model of cortical differentiation
- Author
-
Silvia Giulia Galfrè, Manuela Helmer-Citterich, Milena Rizzo, Robert Vignali, Laura Poliseno, Irene Appolloni, Keagan Dunville, Francesco Morandin, Paolo Malatesta, Manuella Martins, Andrea Marranci, Marco Pietrosanto, Luca Pandolfini, Marco Terrigno, Federico Cremisi, Alberto Mercatanti, Martins, Manuella, Galfrè, Silvia, Terrigno, Marco, Pandolfini, Luca, Appolloni, Irene, Dunville, Keagan, Marranci, Andrea, Rizzo, Milena, Mercatanti, Alberto, Poliseno, Laura, Morandin, Francesco, Pietrosanto, Marco, Helmer-Citterich, Manuela, Malatesta, Paolo, Vignali, Robert, and Cremisi, Federico
- Subjects
0301 basic medicine ,Transcription Factor ,Biochemistry ,corpus callosum ,neural stem cell ,Mice ,Settore BIO/06 - Anatomia Comparata e Citologia ,0302 clinical medicine ,RNA interference ,developmental timing ,3' Untranslated Regions ,neural stem cells ,Cerebral Cortex ,cell fate ,biology ,microRNA ,Settore BIO/11 ,Eutheria ,Matrix Attachment Region Binding Protein ,Gene Expression Regulation, Developmental ,Translation (biology) ,Cell Differentiation ,Neural stem cell ,Cell biology ,mammalian evolution ,Corticogenesis ,cortex ,Human ,in vitro corticogenesi ,Neurogenesis ,3' Untranslated Region ,Cell fate determination ,post-transcriptional control ,Article ,Cell Line ,03 medical and health sciences ,SATB2 ,cell identity ,cortical layering ,in vitro corticogenesis ,miR-catch ,Genetics ,Animals ,Humans ,Progenitor cell ,Post-transcriptional regulation ,Animal ,Tumor Suppressor Proteins ,Matrix Attachment Region Binding Proteins ,Cell Biology ,Repressor Protein ,Repressor Proteins ,MicroRNAs ,030104 developmental biology ,Cell fate ,biology.protein ,Neurogenesi ,in vitro corticogenesis ,TBR1 ,030217 neurology & neurosurgery ,Transcription Factors ,Developmental Biology - Abstract
Summary Cerebral cortical development is controlled by key transcription factors that specify the neuronal identities in the different layers. The mechanisms controlling their expression in distinct cells are only partially known. We investigated the expression and stability of Tbr1, Bcl11b, Fezf2, Satb2, and Cux1 mRNAs in single developing mouse cortical cells. We observe that Satb2 mRNA appears much earlier than its protein and in a set of cells broader than expected, suggesting an initial inhibition of its translation, subsequently released during development. Mechanistically, Satb2 3′UTR modulates protein translation of GFP reporters during mouse corticogenesis. We select miR-541, a eutherian-specific miRNA, and miR-92a/b as the best candidates responsible for SATB2 inhibition, being strongly expressed in early and reduced in late progenitor cells. Their inactivation triggers robust and premature SATB2 translation in both mouse and human cortical cells. Our findings indicate RNA interference as a major mechanism in timing cortical cell identities., Graphical abstract, Highlights • mRNAs for key transcription factors are differentially stable during corticogenesis • miRNAs show a dynamic profile of expression in a model of mouse corticogenesis • miR-541 and miR-92a/b bind Satb2 3′UTR and prevent SATB2 translation • Antagonizing mir-541 and miR-92a/b anticipates SATB2 protein production, In this article, Cremisi and colleagues show that post-transcriptional mechanisms are involved in controlling key functional aspects of SATB2-expressing cortical neurons. They show that mir-541, a eutherian-specific miRNA, delays SATB2 protein production in an in vitro model of cortical cell differentiation. These results may explain the heterochronic shift of SATB2 appearance in the eutherian compared with the metatherian cortex.
- Published
- 2021
18. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia
- Author
-
Jan Cools, Martina Moretti, Peter Vandenberghe, Paolo Gorello, Giovanni Roti, Renato Bassan, Giovanna De Santis, Rocco Piazza, Nicoletta Testoni, Fabrizia Pellanera, Roberta La Starza, Jean-Pierre Bourquin, Cristina Mecucci, Kim De Keersmaecker, Zeynep Kalender Atak, Christine J. Harrison, Valentina Pierini, Beat Bornhauser, Danika Di Giacomo, Caterina Matteucci, Silvia Arniani, Stein Aerts, Di Giacomo, D, La Starza, R, Gorello, P, Pellanera, F, Kalender Atak, Z, De Keersmaecker, K, Pierini, V, Harrison, C, Arniani, S, Moretti, M, Testoni, N, De Santis, G, Roti, G, Matteucci, C, Bassan, R, Vandenberghe, P, Aerts, S, Cools, J, Bornhauser, B, Bourquin, J, Piazza, R, Mecucci, C, University of Zurich, Mecucci, Cristina, Di Giacomo D., La Starza R., Gorello P., Pellanera F., Kalender Atak Z., De Keersmaecker K., Pierini V., Harrison C.J., Arniani S., Moretti M., Testoni N., De Santis G., Roti G., Matteucci C., Bassan R., Vandenberghe P., Aerts S., Cools J., Bornhauser B., Bourquin J.-P., Piazza R., and Mecucci C.
- Subjects
Adult ,Male ,Myeloid ,1303 Biochemistry ,Adolescent ,BCL11B ,Immunology ,2720 Hematology ,Chromosomal translocation ,610 Medicine & health ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Biochemistry ,Translocation, Genetic ,Fusion gene ,1307 Cell Biology ,hemic and lymphatic diseases ,Acute lymphocytic leukemia ,medicine ,Biomarkers, Tumor ,Humans ,Child ,Aged ,Chromosomes, Human, Pair 14 ,Acute leukemia ,2403 Immunology ,Tumor Suppressor Protein ,Gene Expression Regulation, Leukemic ,Tumor Suppressor Proteins ,Gene Expression Profiling ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Repressor Protein ,medicine.disease ,Repressor Proteins ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Fusion transcript ,10036 Medical Clinic ,Child, Preschool ,Cancer research ,Female ,Human - Abstract
Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.
- Published
- 2021
19. Thiazolidinedione 'magic Bullets' Simultaneously Targeting PPARγand HDACs: Design, Synthesis, and Investigations of their in Vitro and in Vivo Antitumor Effects
- Author
-
Neha Upadhyay, Jessica D. Hess, Antonio Laghezza, Fulvio Loiodice, Alessandra Lo Bianco, Renato J. Aguilera, Franz-Josef Meyer-Almes, Ramaa C S, Kalpana Tilekar, Antonio Lavecchia, Markus Schweipert, Tilekar, K., Hess, J. D., Upadhyay, N., Bianco, A. L., Schweipert, M., Laghezza, A., Loiodice, F., Meyer-Almes, F. -J., Aguilera, R. J., Lavecchia, A., and Ramaa, C. S.
- Subjects
Transcriptional Activation ,medicine.drug_class ,Mice, SCID ,01 natural sciences ,Antineoplastic Agent ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Cell Cycle Checkpoint ,In vivo ,Histone Deacetylase ,Cell Line, Tumor ,Drug Discovery ,Transplantation, Heterologou ,medicine ,Cytotoxic T cell ,Thiazolidinedione ,IC50 ,030304 developmental biology ,0303 health sciences ,Chemistry ,Animal ,Rational design ,Binding Site ,Apoptosi ,Repressor Protein ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,PPAR gamma ,010404 medicinal & biomolecular chemistry ,Apoptosis ,Drug Design ,Cancer research ,Molecular Medicine ,DNA fragmentation ,Neoplasm ,Drug Screening Assays, Antitumor ,Human - Abstract
Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγ agonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγ and HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγ EC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.
- Published
- 2021
20. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
- Author
-
Wang T., Hoekzema K., Vecchio D., Wu H., Sulovari A., Coe B. P., Gillentine M. A., Wilfert A. B., Perez-Jurado L. A., Kvarnung M., Sleyp Y., Earl R. K., Rosenfeld J. A., Geisheker M. R., Han L., Du B., Barnett C., Thompson E., Shaw M., Carroll R., Friend K., Catford R., Palmer E. E., Zou X., Ou J., Li H., Guo H., Gerdts J., Avola E., Calabrese G., Elia M., Greco D., Lindstrand A., Nordgren A., Anderlid B. -M., Vandeweyer G., Van Dijck A., Van der Aa N., McKenna B., Hancarova M., Bendova S., Havlovicova M., Malerba G., Bernardina B. D., Muglia P., van Haeringen A., Hoffer M. J. V., Franke B., Cappuccio G., Delatycki M., Lockhart P. J., Manning M. A., Liu P., Scheffer I. E., Brunetti Pierri N., Rommelse N., Amaral D. G., Santen G. W. E., Trabetti E., Sedlacek Z., Michaelson J. J., Pierce K., Courchesne E., Kooy R. F., Acampado J., Ace A. J., Amatya A., Astrovskaya I., Bashar A., Brooks E., Butler M. E., Cartner L. A., Chin W., Chung W. K., Daniels A. M., Feliciano P., Fleisch C., Ganesan S., Jensen W., Lash A. E., Marini R., Myers V. J., O'Connor E., Rigby C., Robertson B. E., Shah N., Shah S., Singer E., Snyder L. A. G., Stephens A. N., Tjernagel J., Vernoia B. M., Volfovsky N., White L. C., Hsieh A., Shen Y., Zhou X., Turner T. N., Bahl E., Thomas T. R., Brueggeman L., Koomar T., Michael R. J., O'Roak B. J., Barnard R. A., Gibbs R. A., Muzny D., Sabo A., Ahmed K. L. B., Eichler E. E., Siegel M., Abbeduto L., Hilscher B. A., Li D., Smith K., Thompson S., Albright C., Butter E. M., Eldred S., Hanna N., Jones M., Coury D. L., Scherr J., Pifher T., Roby E., Dennis B., Higgins L., Brown M., Alessandri M., Gutierrez A., Hale M. N., Herbert L. M., Schneider H. L., David G., Annett R. D., Sarver D. E., Arriaga I., Camba A., Gulsrud A. C., Haley M., McCracken J. T., Sandhu S., Tafolla M., Yang W. S., Carpenter L. A., Bradley C. C., Gwynette F., Manning P., Shaffer R., Thomas C., Bernier R. A., Fox E. A., Gerdts J. A., Pepper M., Ho T., Cho D., Piven J., Lechniak H., Soorya L. V., Gordon R., Wainer A., Yeh L., Ochoa-Lubinoff C., Russo N., Berry-Kravis E., Booker S., Erickson C. A., Prock L. M., Pawlowski K. G., Matthews E. T., Brewster S. J., Hojlo M. A., Abada E., Lamarche E., Murali S. C., Harvey W. T., Kaplan H. E., Pierce K. L., DeMarco L., Horner S., Pandey J., Plate S., Sahin M., Riley K. D., Carmody E., Constantini J., Esler A., Fatemi A., Hutter H., Landa R. J., McKenzie A. P., Neely J., Singh V., Van Metre B., Wodka E. L., Fombonne E. J., Huang-Storms L. Y., Pacheco L. D., Mastel S. A., Coppola L. A., Francis S., Jarrett A., Jacob S., Lillie N., Gunderson J., Istephanous D., Simon L., Wasserberg O., Rachubinski A. L., Rosenberg C. R., Kanne S. M., Shocklee A. D., Takahashi N., Bridwell S. L., Klimczac R. L., Mahurin M. A., Cotrell H. E., Grant C. A., Hunter S. G., Martin C. L., Taylor C. M., Walsh L. K., Dent K. A., Mason A., Sziklay A., Smith C. J., Nordenskjold M., Romano C., Peeters H., Gecz J., Xia K., SPARK Consortium, Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., Kvarnung, M., Sleyp, Y., Earl, R. K., Rosenfeld, J. A., Geisheker, M. R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E. E., Zou, X., Ou, J., Li, H., Guo, H., Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B. -M., Vandeweyer, G., Van Dijck, A., Van der Aa, N., Mckenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B. D., Muglia, P., van Haeringen, A., Hoffer, M. J. V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P. J., Manning, M. A., Liu, P., Scheffer, I. E., Brunetti Pierri, N., Rommelse, N., Amaral, D. G., Santen, G. W. E., Trabetti, E., Sedlacek, Z., Michaelson, J. J., Pierce, K., Courchesne, E., Kooy, R. F., Acampado, J., Ace, A. J., Amatya, A., Astrovskaya, I., Bashar, A., Brooks, E., Butler, M. E., Cartner, L. A., Chin, W., Chung, W. K., Daniels, A. M., Feliciano, P., Fleisch, C., Ganesan, S., Jensen, W., Lash, A. E., Marini, R., Myers, V. J., O'Connor, E., Rigby, C., Robertson, B. E., Shah, N., Shah, S., Singer, E., Snyder, L. A. G., Stephens, A. N., Tjernagel, J., Vernoia, B. M., Volfovsky, N., White, L. C., Hsieh, A., Shen, Y., Zhou, X., Turner, T. N., Bahl, E., Thomas, T. R., Brueggeman, L., Koomar, T., Michael, R. J., O'Roak, B. J., Barnard, R. A., Gibbs, R. A., Muzny, D., Sabo, A., Ahmed, K. L. B., Eichler, E. E., Siegel, M., Abbeduto, L., Hilscher, B. A., Li, D., Smith, K., Thompson, S., Albright, C., Butter, E. M., Eldred, S., Hanna, N., Jones, M., Coury, D. L., Scherr, J., Pifher, T., Roby, E., Dennis, B., Higgins, L., Brown, M., Alessandri, M., Gutierrez, A., Hale, M. N., Herbert, L. M., Schneider, H. L., David, G., Annett, R. D., Sarver, D. E., Arriaga, I., Camba, A., Gulsrud, A. C., Haley, M., Mccracken, J. T., Sandhu, S., Tafolla, M., Yang, W. S., Carpenter, L. A., Bradley, C. C., Gwynette, F., Manning, P., Shaffer, R., Thomas, C., Bernier, R. A., Fox, E. A., Gerdts, J. A., Pepper, M., Ho, T., Cho, D., Piven, J., Lechniak, H., Soorya, L. V., Gordon, R., Wainer, A., Yeh, L., Ochoa-Lubinoff, C., Russo, N., Berry-Kravis, E., Booker, S., Erickson, C. A., Prock, L. M., Pawlowski, K. G., Matthews, E. T., Brewster, S. J., Hojlo, M. A., Abada, E., Lamarche, E., Murali, S. C., Harvey, W. T., Kaplan, H. E., Pierce, K. L., Demarco, L., Horner, S., Pandey, J., Plate, S., Sahin, M., Riley, K. D., Carmody, E., Constantini, J., Esler, A., Fatemi, A., Hutter, H., Landa, R. J., Mckenzie, A. P., Neely, J., Singh, V., Van Metre, B., Wodka, E. L., Fombonne, E. J., Huang-Storms, L. Y., Pacheco, L. D., Mastel, S. A., Coppola, L. A., Francis, S., Jarrett, A., Jacob, S., Lillie, N., Gunderson, J., Istephanous, D., Simon, L., Wasserberg, O., Rachubinski, A. L., Rosenberg, C. R., Kanne, S. M., Shocklee, A. D., Takahashi, N., Bridwell, S. L., Klimczac, R. L., Mahurin, M. A., Cotrell, H. E., Grant, C. A., Hunter, S. G., Martin, C. L., Taylor, C. M., Walsh, L. K., Dent, K. A., Mason, A., Sziklay, A., Smith, C. J., Nordenskjold, M., Romano, C., Peeters, H., Gecz, J., and Xia, K.
- Subjects
0301 basic medicine ,Male ,CCCTC-Binding Factor ,Transcription Factor ,Basic Helix-Loop-Helix Transcription Factor ,DNA Mutational Analysis ,General Physics and Astronomy ,RNA-Binding Protein ,Heterogeneous-Nuclear Ribonucleoprotein U ,VARIANTS ,medicine.disease_cause ,Cohort Studies ,0302 clinical medicine ,Neurodevelopmental Disorder ,Basic Helix-Loop-Helix Transcription Factors ,SPARK Consortium ,2.1 Biological and endogenous factors ,Copy-number variation ,Aetiology ,lcsh:Science ,GABRG2 ,Genetics ,Mutation ,Multidisciplinary ,biology ,Neurodevelopmental disorders ,RNA-Binding Proteins ,High-Throughput Nucleotide Sequencing ,Autism spectrum disorders ,Multidisciplinary Sciences ,DNA-Binding Proteins ,Science & Technology - Other Topics ,Female ,Case-Control Studie ,Engineering sciences. Technology ,Human ,Science ,DNA-Binding Protein ,Genetic Association Studie ,COPY-NUMBER VARIATION ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,Article ,KCNQ3 Potassium Channel ,DNA Mutational Analysi ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,AUTISM ,Gene ,Genetic Association Studies ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Science & Technology ,DISABILITY ,Prevention ,Case-control study ,General Chemistry ,Repressor Protein ,medicine.disease ,FRAMEWORK ,Repressor Proteins ,DE-NOVO MUTATION ,030104 developmental biology ,CTCF ,Neurodevelopmental Disorders ,Case-Control Studies ,biology.protein ,Next-generation sequencing ,Autism ,lcsh:Q ,Cohort Studie ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF, For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.
- Published
- 2020
21. High incidence of multiple antibiotic resistant cells in cultures of in enterohemorrhagic Escherichia coli O157:H7.
- Author
-
Carone, Benjamin R., Xu, Tao, Murphy, Kenan C., and Marinus, Martin G.
- Subjects
- *
BETA lactam antibiotics , *DRUG resistance in bacteria , *CELL culture , *GENETIC mutation , *GENE frequency , *DRUG tolerance , *ESCHERICHIA coli - Abstract
Highlights: [•] marR gene mutations occur at a higher frequency in Escherichia coli O157:H7 than E. coli K-12. [•] rpsL, rpsE and rpoB mutations occur at the same frequency in both E. coli strains. [•] E. coli O157:H7 marR mutant strains can become tolerant to beta-lactam antibiotics. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
22. Protein environment: a crucial triggering factor in Josephin domain aggregation : the role of 2,2,2-trifluoroethanol
- Author
-
Paolo Tortora, Gianvito Grasso, Salvador Ventura, Marco Agostino Deriu, Susanna Navarro, Cristina Visentin, Maria Elena Regonesi, Visentin, C, Navarro, S, Grasso, G, Regonesi, M, Deriu, M, Tortora, P, and Ventura, S
- Subjects
0301 basic medicine ,Secondary ,Circular dichroism ,Molecular dynamic ,Protein Conformation ,Molecular Conformation ,Protein aggregation ,Josephin domain ,01 natural sciences ,Protein Structure, Secondary ,lcsh:Chemistry ,Molecular dynamics ,chemistry.chemical_compound ,Protein structure ,Ataxin-3 ,lcsh:QH301-705.5 ,Spectroscopy ,Amyloid aggregation ,Protein Stability ,Circular Dichroism ,General Medicine ,Computer Science Applications ,2,2,2-trifluoroethanol ,Protein-cosolvent interaction ,Amyloid ,Humans ,Molecular Dynamics Simulation ,Peptides ,Protein Aggregates ,Protein Domains ,Protein Structure, Tertiary ,Repressor Proteins ,Trifluoroethanol ,2,2,2-Trifluoroethanol ,Peptide ,Spinocerebellar ataxia ,Human ,Protein Structure ,Protein Domain ,Protein domain ,010402 general chemistry ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Organic Chemistry ,Repressor Protein ,medicine.disease ,molecular dynamics ,0104 chemical sciences ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,2-trifluoroethanol ,Biophysics ,Protein Aggregate ,Tertiary - Abstract
The protein ataxin-3 contains a polyglutamine stretch that triggers amyloid aggregation when it is expanded beyond a critical threshold. This results in the onset of the spinocerebellar ataxia type 3. The protein consists of the globular N-terminal Josephin domain and a disordered C-terminal tail where the polyglutamine stretch is located. Expanded ataxin-3 aggregates via a two-stage mechanism: first, Josephin domain self-association, then polyQ fibrillation. This highlights the intrinsic amyloidogenic potential of Josephin domain. Therefore, much effort has been put into investigating its aggregation mechanism(s). A key issue regards the conformational requirements for triggering amyloid aggregation, as it is believed that, generally, misfolding should precede aggregation. Here, we have assayed the effect of 2,2,2-trifluoroethanol, a co-solvent capable of stabilizing secondary structures, especially &alpha, helices. By combining biophysical methods and molecular dynamics, we demonstrated that both secondary and tertiary JD structures are virtually unchanged in the presence of up to 5% 2,2,2-trifluoroethanol. Despite the preservation of JD structure, 1% of 2,2,2-trifluoroethanol suffices to exacerbate the intrinsic aggregation propensity of this domain, by slightly decreasing its conformational stability. These results indicate that in the case of JD, conformational fluctuations might suffice to promote a transition towards an aggregated state without the need for extensive unfolding, and highlights the important role played by the environment on the aggregation of this globular domain.
- Published
- 2020
23. miR-622 is a novel potential biomarker of breast carcinoma and impairs motility of breast cancer cells through targeting NUAK1 kinase
- Author
-
Mario Capasso, Raffaela Mariarosaria Mariniello, Anna Elisa De Stefano, Paola Lucia Chiara Iervolino, Francesca Maria Orlandella, Mariarosaria Incoronato, Rosa Giannatiempo, Francesco Messina, Peppino Mirabelli, Vito Alessandro Lasorsa, Giuliana Salvatore, Andrea Soricelli, Maria Rongo, Marco Salvatore, Orlandella, F. M., Mariniello, R. M., Mirabelli, P., De Stefano, A. E., Iervolino, P. L. C., Lasorsa, V. A., Capasso, M., Giannatiempo, R., Rongo, M., Incoronato, M., Messina, F., Salvatore, M., Soricelli, A., and Salvatore, G.
- Subjects
Cancer Research ,Prognosi ,3' Untranslated Region ,Protein Kinase ,NUAK1 ,Motility ,Down-Regulation ,Context (language use) ,Breast Neoplasms ,Article ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,MCF-7 Cell ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,microRNA ,Biomarkers, Tumor ,Medicine ,Humans ,skin and connective tissue diseases ,3' Untranslated Regions ,030304 developmental biology ,Cancer ,0303 health sciences ,Kinase ,business.industry ,MicroRNA ,Repressor Protein ,medicine.disease ,Prognosis ,Repressor Proteins ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,MCF-7 Cells ,Female ,Breast carcinoma ,business ,Protein Kinases ,Breast Neoplasm ,Human - Abstract
Background Aberrant expression of microRNAs (miR) has been proposed as non-invasive biomarkers for breast cancers. The aim of this study was to analyse the miR-622 level in the plasma and in tissues of breast cancer patients and to explore the role of miR-622 and its target, the NUAK1 kinase, in this context. Methods miR-622 expression was analysed in plasma and in tissues samples of breast cancer patients by q-RT-PCR. Bioinformatics programs, luciferase assay, public dataset analysis and functional experiments were used to uncover the role of miR-622 and its target in breast cancer cells. Results miR-622 is downregulated in plasma and in tissues of breast cancer patients respect to healthy controls and its downregulation is significantly associated with advanced grade and high Ki67 level. Modulation of miR-622 affects the motility phenotype of breast cancer cells. NUAK1 kinase is a functional target of miR-622, it is associated with poor clinical outcomes of breast cancer patients and is inversely correlated with miR-622 level. Conclusions miR-622/NUAK1 axis is deregulated in breast cancer patients and affects the motility phenotype of breast cancer cells. Importantly, miR-622 and NUAK1 hold promises as biomarkers and as targets for breast cancers.
- Published
- 2020
24. Repressor Protein
- Author
-
Gooch, Jan W. and Gooch, Jan W., editor
- Published
- 2011
- Full Text
- View/download PDF
25. A Hydrogel Sensing Pathological Urate Concentrations.
- Author
-
Geraths, Christian, Christen, Erik H., and Weber, Wilfried
- Abstract
Metabolite-responsive hydrogels that detect pathological metabolite concentrations and react by releasing a therapeutic stimulus hold high promises in treating metabolic diseases. In this study, a hydrogel is described that discriminates between physiological and pathological concentrations of urate, the causative agent of gouty arthritis. The hydrogel is synthesized by coupling a dimeric variant of the Deinococcus radiodurans-derived urate repressor HucR to linear polyacrylamide. The protein-grafted polymer is crosslinked to form a hydrogel by a multimeric hucO DNA sequence [ hucO] n specifically binding HucR. At elevated urate concentrations, HucR dissociates from [ hucO] n thereby weakening the hydrogel structure and resulting in its dissolution. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
26. Clostridium difficile: trend in an Italian Tertiary Care Hospital during fifteen years, 2002-2016
- Author
-
Masucci, Luca, Nicolotti, Nicola, Graffeo, Rosalia, Tamburrano, Andrea, Archibusacci, Carola M., Nagel, Domenico, Quaranta, Gianluca, Eisendle, Klau, Primus, Sandra, Romano, Lucio, Mazzella, Patrizia, Posteraro, Brunella, Cammarota, Giovanni, Sanguinetti, Maurizio, Masucci, Luca (ORCID:0000-0002-8358-6726), Posteraro, Brunella (ORCID:0000-0002-1663-7546), Cammarota, Giovanni (ORCID:0000-0002-3626-6148), Sanguinetti, Maurizio (ORCID:0000-0002-9780-7059), Masucci, Luca, Nicolotti, Nicola, Graffeo, Rosalia, Tamburrano, Andrea, Archibusacci, Carola M., Nagel, Domenico, Quaranta, Gianluca, Eisendle, Klau, Primus, Sandra, Romano, Lucio, Mazzella, Patrizia, Posteraro, Brunella, Cammarota, Giovanni, Sanguinetti, Maurizio, Masucci, Luca (ORCID:0000-0002-8358-6726), Posteraro, Brunella (ORCID:0000-0002-1663-7546), Cammarota, Giovanni (ORCID:0000-0002-3626-6148), and Sanguinetti, Maurizio (ORCID:0000-0002-9780-7059)
- Abstract
No abstract
- Published
- 2019
27. Cellular repressor of E1A-stimulated genes regulates vascular endothelial cell migration by The ILK/AKT/mTOR/VEGF165 signaling pathway
- Author
-
Zhang, Huimin, Han, Yaling, Tao, Jie, Liu, Shaowei, Yan, Chenghui, and Li, Shaohua
- Subjects
- *
GENETIC regulation , *ENDOTHELIUM , *CELL migration , *VASCULAR endothelial growth factors , *CELLULAR signal transduction , *WOUND healing - Abstract
Abstract: The migration of vascular endothelial cells plays a critical role in a variety of vascular physiological and pathological processes, such as embryonic development, angiogenesis, wound healing, re-endothelialization, and vascular remodeling. This study clarified the role and mechanism of a new vascular homeostasis regulator, Cellular repressor of E1A-stimulated genes (CREG), in the migration of primary human umbilical vein endothelial cells (HUVECs). A wound healing assay and transwell migration model showed that upregulation of CREG expression induced HUVEC migration and it was positively correlated with the expression of vascular endothelial growth factor. Furthermore, wild type integrin-linked kinase reversed the poor mobility of CREG knock-down HUVECs; in contrast, kinase-dead integrin-linked kinase weakened the migration of HUVECs. We also studied the effect of CREG on HUVEC migration by the addition of an mTOR inhibitor, recombinant vascular endothelial growth factor165, neutralizing antibody of vascular endothelial growth factor165 and AKT siRNA, and we concluded that CREG induces endothelial cell migration by activating the integrin-linked kinase/AKT/mTOR/VEGF165 signaling pathway. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
28. Pattern of expression of the CREG gene and CREG protein in the mouse embryo.
- Author
-
Guitang Yang, Yaling Han, Xiaoxiang Tian, Jie Tao, Mingyu Sun, Jian Kang, and Chenghui Yan
- Abstract
The cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein that inhibits cell proliferation and/or enhances differentiation. CREG is widely expressed in adult tissues such as the brain, heart, lungs, liver, intestines and kidneys in mice. We investigated the level of CREG expression during mouse embryogenesis and its distribution at 18.5 days post coitus (dpc) using immunohistochemical staining with diaminobenzidine, western blotting and reverse transcription-polymerase chain reaction. CREG expression was first detected in mouse embryos at 4.5 dpc. It was expressed at almost all stages up to 18.5 dpc. The level of CREG was found to increase gradually and was highest at 18.5 dpc. Western blotting showed that the CREG protein was expressed at higher levels in the brain, heart, intestines and kidneys than in the lungs and liver at 18.5 dpc. In 9.5 dpc embryos, CREG was expressed only in the endothelial cells of blood vessels, after the vascular lumen had formed. With advanced differentiation, vascular smooth muscle cells developed in the embryonic vascular structures; the expression of smooth muscle α-actin protein and CREG were positive and increased gradually in 10.5 dpc embryonic vessels. CREG expression in the embryonic blood vessels peaked at 15.5 dpc and was reduced slightly at 18.5 dpc. These results indicate that CREG is expressed during mouse embryogenesis and might participate in the differentiation of these organs during embryogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
29. Structure of FocB – a member of a family of transcription factors regulating fimbrial adhesin expression in uropathogenic Escherichia coli.
- Author
-
Hultdin, Ulrika W., Lindberg, Stina, Grundström, Christin, Huang, Shenghua, Uhlin, Bernt Eric, and Sauer-Eriksson, A. Elisabeth
- Subjects
- *
ESCHERICHIA coli , *PILI (Microbiology) , *TRANSCRIPTION factors , *CRYSTALLOGRAPHY , *DNA-binding proteins - Abstract
In uropathogenic Escherichia coli, UPEC, different types of fimbriae are expressed to mediate interactions with host tissue. FocB belongs to the PapB family of transcription factors involved in the regulation of fimbriae gene clusters. Recent findings suggest that members from this family of proteins may form homomeric or heteromeric complexes and exert both positive and negative effects on the transcription of fimbriae genes. To elucidate the detailed function of FocB, we have determined its crystal structure at 1.4 Å resolution. FocB is an all α-helical protein with a helix-turn-helix motif. Interestingly, conserved residues important for DNA-binding are located not in the postulated recognition helix of the motif, but in the preceding helix. Results from protein–DNA-binding studies suggest that FocB interacts with the minor groove of its cognate DNA target, which is indicative of a DNA interaction that is unusual for this motif. FocB crystallizes in the form of dimers. Packing interactions in the crystals give two plausible dimerization interfaces. Conserved residues, known to be important for protein oligomerization, are present at both interfaces, suggesting that both sites could play a role in a functional FocB protein. Structured digital abstract • : focB (uniprotkb: ) and focB (uniprotkb: ) bind ( ) by x-ray crystallography ( ) [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
30. Cellular repressor of E1A-stimulated genes inhibits human vascular smooth muscle cell apoptosis via blocking P38/JNK MAP kinase activation
- Author
-
Han, Yaling, Wu, Guangzhe, Deng, Jie, Tao, Jie, Guo, Liang, Tian, Xiaoxiang, Kang, Jian, Zhang, Xiaolin, and Yan, Chenghui
- Subjects
- *
GENETIC repressors , *VASCULAR smooth muscle , *MUSCLE cells , *APOPTOSIS , *ENZYME regulation , *JNK mitogen-activated protein kinases , *MITOGEN-activated protein kinases , *CELLULAR signal transduction - Abstract
Abstract: Vascular smooth muscle cell (VSMC) apoptosis accelerates atherosclerosis and promotes restenosis following vascular injury. The current study examined the effects of cellular repressor of E1A-stimulated genes (CREG), a novel glycoprotein inhibiting transcription activation, on the regulation of VSMC apoptosis. Serum starvation or treatment of human VSMCs with apoptosis inducers (STS or VP-16) significantly reduced CREG expression and caused caspase-3 activation. CREG downregulation and caspase-3 activation were inversely related, suggesting that reduced CREG expression may contribute to VSMC apoptosis. Both loss-of-function (CREG-DW produced by retroviruses expressing CREG shRNAs) and gain-of-function (CREG-UP produced by retroviral infection with vector pLNCX-CREG) studies were performed to confirm this hypothesis. CREG-DW significantly increased VSMC apoptosis, whereas CREG-UP significantly reduced apoptosis. Moreover, p38 and JNK mitogen-activated protein kinases were significantly upregulated in CREG-DW and significantly reduced in CREG-UP VSMCs. More importantly, CREG-DW-induced VSMC apoptosis was blocked by the p38-specific inhibitor SB203580 or by overexpression of a dominant-negative P38α (p38α AGF). Balloon injury-induced vascular caspase-3 activation was significantly inhibited by treatment with recombinant CREG protein. These results demonstrated for the first time that CREG plays a key role in modulating VSMC apoptosis through the p38 and JNK signal transduction pathways, both in vitro and in situ. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
31. CREG inhibits migration of human vascular smooth muscle cells by mediating IGF-II endocytosis
- Author
-
Han, Yaling, Cui, Jifu, Tao, Jie, Guo, Liang, Guo, Peng, Sun, Mingyu, Kang, Jian, Zhang, Xiaolin, Yan, Chenghui, and Li, Shaohua
- Subjects
- *
MUSCLE cells , *ENDOCYTOSIS , *HYPERPLASIA , *VASCULAR diseases , *IMMUNOGLOBULINS , *CELL migration , *PHENOTYPES - Abstract
Abstract: We previously determined that the cellular repressor of E1A-stimulated genes, (CREG) plays a role in the maintenance of the mature phenotype of vascular smooth muscle cells (SMCs). This study aimed to identify the role of CREG in modulating the migration of SMCs. Recombinant virus-mediated CREG expression inhibited the cellular migration of cultured SMCs associated with down-regulated activity of matrix metalloproteinase-9 (MMP-9). In contrast, CREG knockdown via the retroviral transfer of short hairpin RNAs promoted cellular migration. Enzyme-linked immunosorbent assay and endocytosis analysis revealed that CREG knockdown attenuated the internalization and increased secretion of insulin-like growth factor (IGF)-II. Western blot analysis demonstrated that both phosphoinositide 3-kinase (PI3K) and phosphatase Akt were enhanced in CREG knockdown SMCs. Furthermore, the effect of CREG knockdown on SMC migration was abrogated in a dose-dependent manner by the addition of either IGF-II neutralizing antibody or the PI3K inhibitor, LY294002. These results indicate that the CREG knockdown-mediated increase in IGF-II secretion promoted cellular migration in SMCs via the PI3K/Akt signal pathway. Additionally, blockage of IGF-II binding to the mannose-6-phosphate/IGF-II receptor (M6P/IGF2R) by IGF2R antibody or recombinant IGF2R fragment attenuated the endocytosis of IGF-II in cells overexpressing CREG. This indicates that M6P/IGF2R is involved in the regulation of CREG-mediated IGF-II endocytosis. In summary, these data demonstrate for the first time that CREG plays a critical role in the inhibition of SMC migration, as well as maintaining SMCs in a mature phenotype. These results may provide a new therapeutic target for vascular disease associated with neointimal hyperplasia. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
32. Regulation of translation via mRNA structure in prokaryotes and eukaryotes
- Author
-
Kozak, Marilyn
- Subjects
- *
MESSENGER RNA , *NUCLEIC acids , *MICROORGANISMS , *PROKARYOTES - Abstract
Abstract: The mechanism of initiation of translation differs between prokaryotes and eukaryotes, and the strategies used for regulation differ accordingly. Translation in prokaryotes is usually regulated by blocking access to the initiation site. This is accomplished via base-paired structures (within the mRNA itself, or between the mRNA and a small trans-acting RNA) or via mRNA-binding proteins. Classic examples of each mechanism are described. The polycistronic structure of mRNAs is an important aspect of translational control in prokaryotes, but polycistronic mRNAs are not usable (and usually not produced) in eukaryotes. Four structural elements in eukaryotic mRNAs are important for regulating translation: (i) the m7G cap; (ii) sequences flanking the AUG start codon; (iii) the position of the AUG codon relative to the 5′ end of the mRNA; and (iv) secondary structure within the mRNA leader sequence. The scanning model provides a framework for understanding these effects. The scanning mechanism also explains how small open reading frames near the 5′ end of the mRNA can down-regulate translation. This constraint is sometimes abrogated by changing the structure of the mRNA, sometimes with clinical consequences. Examples are described. Some mistaken ideas about regulation of translation that have found their way into textbooks are pointed out and corrected. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
33. Human interleukin-1α gene expression is regulated by Sp1 and a transcriptional repressor
- Author
-
McDowell, Tarra L., Symons, Julian A., and Duff, Gordon W.
- Subjects
- *
INTERLEUKIN-1 , *CHLORAMPHENICOL , *GENE expression , *ACUTE phase proteins - Abstract
Abstract: The regulation of the human IL-1α gene was studied using a series of 5′ deletion promoter chloramphenicol acetyltransferase (CAT) reporter constructs. The IL-1α promoter from −967 to +64 produced no significant expression of CAT. Progressive 5′ deletion indicated the presence of a repressor binding site between −477 and −305 bp as deletion in this region resulted in CAT expression. Electrophoretic mobility shift assay (EMSA) analysis confirmed that protein(s) bound to this region and DNaseI footprinting localized the binding site to between −448 and −435. Deletion of the IL-1α promoter to −42 resulted in reduced CAT expression suggesting the presence of a positive regulatory element in this region. EMSA experiments using IL-1α promoter DNA from −163 to +64 demonstrated protein binding to this region and DNaseI footprinting demonstrated protection between −59 and −40. Transcriptional activity of the IL-1α promoter was also tested using an in vitro transcription assay. Reactions using −163, −100 and −52 promoter templates all produced a correctly sized transcript but deletion to −42 resulted in no transcript production. Analysis of the promoter indicated that a potential Sp1 binding site existed in the region from −52 to −45. An EMSA using an anti-Sp1 antibody indicated that Sp1 specifically bound to the −52 to +64 region. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
34. Mutational analysis of the bglH catabolite-responsive element (cre) in Lactobacillus plantarum
- Author
-
Marasco, Rosangela, Muscariello, Lidia, Rigano, Manuela, and Sacco, Margherita
- Subjects
- *
LACTOBACILLUS plantarum , *METABOLISM , *GENETIC repressors - Abstract
Catabolite repression of the Lactobacillus plantarum bglH gene is mediated by the catabolite control protein A (CcpA). Here we show that the binding site for the protein is a catabolite-responsive element (cre) sequence overlapping the start site of transcription. Two single and one double base substitutions in the cre sequence caused derepression of a plasmid-borne bglH–cat transcriptional fusion in L. plantarum cells grown on glucose. Analysis of the single mutations indicates that the G and C nucleotide residues in positions 2 and 13, respectively, of the 14-bp cre sequence are required for catabolite repression. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
35. Phenotypic features of epidermolysis bullosa simplex due to klhl24 mutations in 3 italian cases
- Author
-
Marco Tartaglia, Daniele Castiglia, Angelo Giuseppe Condorelli, Sabina Barresi, Ettore Capoluongo, Andrea Diociaiuti, Giulietta Scuvera, Cristina Has, May El Hachem, Vittoria Proto, Renata Boldrini, El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, Ettore Domenico, Proto, V., Scuvera, G., Has, C., Tartaglia, M., and Castiglia, D.
- Subjects
Male ,Prognosi ,DNA Mutational Analysis ,Dermatology ,Gene mutation ,medicine.disease_cause ,DNA Mutational Analysi ,Epidermolysis bullosa simplex ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Child ,NAIL DYSTROPHY ,Exome sequencing ,Skin ,Genetics ,Mutation ,Wound Healing ,business.industry ,Infant, Newborn ,General Medicine ,Skin atrophy ,Repressor Protein ,Prognosis ,medicine.disease ,Phenotype ,Repressor Proteins ,Italy ,RL1-803 ,Epidermolysis Bullosa Simplex ,Female ,business ,Human - Abstract
No abstract
- Published
- 2019
36. Novel markers in pediatric-type follicular lymphoma
- Author
-
Elena Sabattini, Stefania Pittaluga, Manuel Rodriguez-Justo, Stefano Pileri, Hasan Rizvi, Teresa Marafioti, Claudio Agostinelli, Sabine Pomplun, Ian Proctor, Alan G. Ramsay, Stephen Daw, Elaine S. Jaffe, Ayse U. Akarca, Leticia Quintanilla-Martinez, David C. Linch, Agostinelli C., Akarca A.U., Ramsay A., Rizvi H., Rodriguez-Justo M., Pomplun S., Proctor I., Sabattini E., Linch D., Daw S., Pittaluga S., Pileri S.A., Jaffe E.S., Quintanilla-Martinez L., and Marafioti T.
- Subjects
0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Pediatric-type follicular lymphoma ,Lymphoma, B-Cell ,Adolescent ,Differential diagnosi ,Follicular lymphoma ,Blastoid ,Immunoglobulin light chain ,Pathology and Forensic Medicine ,Immunophenotyping ,Diagnosis, Differential ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Humans ,music ,Child ,Molecular Biology ,Lymphoma, Follicular ,music.instrument ,FOXP-1 ,biology ,medicine.diagnostic_test ,Germinal center ,Forkhead Transcription Factors ,Cell Biology ,General Medicine ,Forkhead Transcription Factor ,Repressor Protein ,biology.organism_classification ,BCL6 ,medicine.disease ,Follicular hyperplasia ,Immunohistochemistry ,Repressor Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,Stathmin ,Original Article ,Differential diagnosis ,Fluorescence in situ hybridization ,Human - Abstract
The aim of this study was to review the histopathological, phenotypic, and molecular characteristics of pediatric-type follicular lymphoma (PTFL) and to assess the diagnostic value of novel immunohistochemical markers in distinguishing PTFL from follicular hyperplasia (FH). A total of 13 nodal PTFLs were investigated using immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR and were compared with a further 20 reactive lymph nodes showing FH. Morphologically, PTFL cases exhibited a follicular growth pattern with irregular lymphoid follicles in which the germinal centers were composed of numerous blastoid cells showing a starry-sky appearance. Immunohistochemistry highlighted preserved CD10 (13/13) and BCL6 (13/13) staining, CD20 (13/13) positivity, a K light chain predominance (7/13), and partial BCL2 expression in 6/13 cases (using antibodies 124, E17, and SP66). The germinal center (GC)–associated markers stathmin and LLT-1 were positive in most of the cases (12/13 and 12/13, respectively). Interestingly, FOXP-1 was uniformly positive in PTFL (12/13 cases) in contrast to reactive GCs in FH, where only a few isolated positive cells were observed. FISH revealed no evidence ofBCL2,BCL6, orMYCrearrangements in the examined cases. By PCR, clonal immunoglobulin gene rearrangements were detected in 100% of the tested PTFL cases. Our study confirmed the unique morphological and immunophenotypic features of PTFL and suggests that FOXP-1 can represent a novel useful diagnostic marker in the differential diagnosis between PTFL and FH.
- Published
- 2019
37. New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies
- Author
-
Alan J. Robinson, Daniele Ghezzi, Isabella Moroni, Costanza Lamperti, Federica Invernizzi, Eleonora Lamantea, Massimo Zeviani, Andrea Legati, Alessia Nasca, Aurelio Reyes, Valeria Tiranti, Barbara Garavaglia, Anna Ardissone, Reyes Tellez, Aurelio [0000-0003-2876-2202], Robinson, Alan [0000-0001-9943-0059], Apollo - University of Cambridge Repository, Legati, A, Reyes, A, Nasca, A, Invernizzi, F, Lamantea, E, Tiranti, V, Garavaglia, B, Lamperti, C, Ardissone, A, Moroni, I, Robinson, A, Ghezzi, D, and Zeviani, M
- Subjects
Male ,0301 basic medicine ,Mitochondrial Diseases ,Next Generation Sequencing ,Gene Expression ,Biochemistry ,Cohort Studies ,0302 clinical medicine ,Mitochondrial Disease ,Exome ,Child ,Exome sequencing ,Genetics ,Electron Transport Chain Complex Protein ,Homozygote ,High-Throughput Nucleotide Sequencing ,Penetrance ,Mitochondrial ,Mitochondrial disorder ,Mitochondria ,Child, Preschool ,Female ,Human ,E4F1 ,Mitochondrial disorders ,Whole Exome sequencing ,Adolescent ,Amino Acid Sequence ,DNA, Mitochondrial ,Electron Transport ,Electron Transport Chain Complex Proteins ,Heterozygote ,Humans ,Infant ,Molecular Sequence Data ,Repressor Proteins ,Sequence Alignment ,Young Adult ,Mutation ,Mitochondrial DNA ,Nuclear gene ,Ubiquitin-Protein Ligases ,Mitochondrial disease ,Biophysics ,Biology ,DNA sequencing ,03 medical and health sciences ,Genetic linkage ,medicine ,Preschool ,DNA ,Cell Biology ,Repressor Protein ,medicine.disease ,030104 developmental biology ,Biophysic ,Cohort Studie ,030217 neurology & neurosurgery - Abstract
Next Generation Sequencing (NGS) technologies are revolutionizing the diagnostic screening for rare disease entities, including primary mitochondrial disorders, particularly those caused by nuclear gene defects. NGS approaches are able to identify the causative gene defects in small families and even single individuals, unsuitable for investigation by traditional linkage analysis. These technologies are contributing to fill the gap between mitochondrial disease cases defined on the basis of clinical, neuroimaging and biochemical readouts, which still outnumber by approximately 50% the cases for which a molecular-genetic diagnosis is attained. We have been using a combined, two-step strategy, based on targeted genes panel as a first NGS screening, followed by whole exome sequencing (WES) in still unsolved cases, to analyze a large cohort of subjects, that failed to show mutations in mtDNA and in ad hoc sets of specific nuclear genes, sequenced by the Sanger's method. Not only this approach has allowed us to reach molecular diagnosis in a significant fraction (20%) of these difficult cases, but it has also revealed unexpected and conceptually new findings. These include the possibility of marked variable penetrance of recessive mutations, the identification of large-scale DNA rearrangements, which explain spuriously heterozygous cases, and the association of mutations in known genes with unusual, previously unreported clinical phenotypes. Importantly, WES on selected cases has unraveled the presence of pathogenic mutations in genes encoding non-mitochondrial proteins (e.g. the transcription factor E4F1), an observation that further expands the intricate genetics of mitochondrial disease and suggests a new area of investigation in mitochondrial medicine. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
- Published
- 2016
38. Prominent and elongated coccyx, a new manifestation of KBG syndrome associated with novel mutation in ANKRD11
- Author
-
De Bernardi, M. L., Ivanovski, I., Caraffi, S. G., Maini, I., Street, M. E., Bayat, A., Zollino, Marcella, Lepri, F. R., Gnazzo, M., Errichiello, E., Superti-Furga, A., Garavelli, L., Zollino M. (ORCID:0000-0003-4871-9519), De Bernardi, M. L., Ivanovski, I., Caraffi, S. G., Maini, I., Street, M. E., Bayat, A., Zollino, Marcella, Lepri, F. R., Gnazzo, M., Errichiello, E., Superti-Furga, A., Garavelli, L., and Zollino M. (ORCID:0000-0003-4871-9519)
- Abstract
KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon–intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.
- Published
- 2018
39. Dissecting the Wolf–Hirschhorn syndrome phenotype: WHSC1 is a neurodevelopmental gene contributing to growth delay, intellectual disability, and to the facial dysmorphism
- Author
-
Zollino, Marcella, Doronzio, P. N., Zollino M. (ORCID:0000-0003-4871-9519), Zollino, Marcella, Doronzio, P. N., and Zollino M. (ORCID:0000-0003-4871-9519)
- Abstract
N/A
- Published
- 2018
40. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations
- Author
-
Lee, E., Le, T., Zhu, Y., Elakis, G., Turner, A., Lo, W., Venselaar, H., Verrenkamp, C. -A., Snow, N., Mowat, D., Kirk, E. P., Sachdev, R., Smith, J., Brown, N. J., Wallis, M., Barnett, C., Mckenzie, F., Freckmann, M. -L., Collins, F., Chopra, M., Gregersen, N., Hayes, I., Rajagopalan, S., Tan, T. Y., Stark, Z., Savarirayan, R., Yeung, A., Ades, L., Gattas, M., Gibson, K., Gabbett, M., Amor, D. J., Lattanzi, Wanda, Boyd, S., Haan, E., Gianoutsos, M., Cox, T. C., Buckley, M. F., Roscioli, T., Lattanzi W. (ORCID:0000-0003-3092-4936), Lee, E., Le, T., Zhu, Y., Elakis, G., Turner, A., Lo, W., Venselaar, H., Verrenkamp, C. -A., Snow, N., Mowat, D., Kirk, E. P., Sachdev, R., Smith, J., Brown, N. J., Wallis, M., Barnett, C., Mckenzie, F., Freckmann, M. -L., Collins, F., Chopra, M., Gregersen, N., Hayes, I., Rajagopalan, S., Tan, T. Y., Stark, Z., Savarirayan, R., Yeung, A., Ades, L., Gattas, M., Gibson, K., Gabbett, M., Amor, D. J., Lattanzi, Wanda, Boyd, S., Haan, E., Gianoutsos, M., Cox, T. C., Buckley, M. F., Roscioli, T., and Lattanzi W. (ORCID:0000-0003-3092-4936)
- Abstract
Purpose: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods: A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.
- Published
- 2018
41. A Molecular Dynamics Study of the Repressor/Operator(OR1,OR3) Complexes from Bacteriophage 434.
- Author
-
David, Laurent and Field, Martin
- Abstract
We have performed three molecular dynamics simulations using the CHARMM molecular modeling program to study the repressor protein from bacteriophage 434 complexed with DNA operators of two different sequences. Two approaches to the modeling of the solvent were used. In the first method, applied to the R1-69/OR1 truncated complex, water molecules were included explicitly in conjunction with a stochastic boundary force to solvate the complex. In the second approach, used for simulations of the R1-69/OR1 and the R1-69/OR3 complexes, the solvent was omitted and implicitly represented by using a distance-dependent dielectric constant and a scaling of the charges on the exposed residues. The simulation with the model which explicitly includes the solvent serves as a validation of the simulations using a simpler solvent representation. In our discussion of the results we focus upon the important interactions between the DNA binding motif of the 434 repressor (motif helix turn helix) and the operators and how the structures of the complexes change with time. [ABSTRACT FROM AUTHOR]
- Published
- 1996
- Full Text
- View/download PDF
42. HDAC8 Loss of Function and SHOX Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype
- Author
-
Severi G., Bonora E., Perri A., Scarano E., Mazzanti L., Isidori F., Zuntini R., Menabo S., Graziano C., Severi G., Bonora E., Perri A., Scarano E., Mazzanti L., Isidori F., Zuntini R., Menabo S., and Graziano C.
- Subjects
Haploinsufficiency ,Osteochondrodysplasias ,Whole Exome Sequencing ,Histone Deacetylases ,Brachydactyly-mental retardation syndrome ,Short Stature Homeobox Protein ,Growth Disorder ,Histone Deacetylase ,De Lange Syndrome ,Exome Sequencing ,Humans ,Osteochondrodysplasia ,Child ,Frameshift Mutation ,Growth Disorders ,Comparative Genomic Hybridization ,Repressor Protein ,Dual molecular diagnosi ,Pedigree ,Repressor Proteins ,Phenotype ,HDAC8 ,Female ,Gene Deletion ,SHOX ,Human - Abstract
We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis.
- Published
- 2018
43. Purification and Characterization of Antibodies in Single-Chain Format against the E6 Oncoprotein of Human Papillomavirus Type 16
- Author
-
Elisabetta Affabris, Zulema A. Percario, P. Di Bonito, F. Verachi, Carla Amici, Luigi Accardi, Verachi, F., Percario, Z., Di Bonito, P., Affabris, E., Amici, C., and Accardi, L.
- Subjects
0301 basic medicine ,Uterine Cervical Neoplasm ,Article Subject ,Immunology and Microbiology (all) ,Carcinogenesis ,lcsh:Medicine ,Uterine Cervical Neoplasms ,Immunofluorescence ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Intrabody ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Affinity chromatography ,law ,Cell Line, Tumor ,medicine ,Humans ,Single-Chain Antibodie ,Papillomavirus Infection ,Carcinogenesi ,Human papillomavirus 16 ,Biochemistry, Genetics and Molecular Biology (all) ,General Immunology and Microbiology ,biology ,medicine.diagnostic_test ,Chemistry ,lcsh:R ,Papillomavirus Infections ,General Medicine ,Oncogene Proteins, Viral ,Repressor Protein ,Molecular biology ,Repressor Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Recombinant DNA ,Female ,Antibody ,Single-Chain Antibodies ,Human ,Research Article - Abstract
In Human Papillomaviruses- (HPV-) associated carcinogenesis, continuous expression of the E6 oncoprotein supports its value as a potential target for the development of diagnostics and therapeutics for HPV cancer. We previously reported that the I7 single-chain antibody fragment (scFv) specific for HPV16 E6, expressed as an intrabody by retroviral system, could inhibit significantly the growth of cervical cancer cells in vitro and was even able to reduce tumor development in experimental HPV-related cancer models. Nevertheless, for the development of therapeutic tools to be employed in humans, it is important to achieve maximum safety guarantee, which can be provided by the protein format. In the current study, two anti-16E6 scFvs derived from I7 were expressed in E. coli and purified in soluble form by affinity chromatography. Specificity, sensitivity and stability in physiologic environment of the purified scFvs were demonstrated by binding studies using recombinant 16E6 as an antigen. The scFvs functionality was confirmed by immunofluorescence in cervical cancer cells, where the scFvs were able to recognize the nuclear E6. Furthermore, an antiproliferative activity of the scFvI7nuc delivered in protein format to HPV16-positive cell lines was observed. Our results demonstrate that functional anti-16E6 scFvs can be produced in E. coli, suggesting that such purified antibodies could be used in the diagnosis and treatment of HPV-induced malignancies.
- Published
- 2018
44. The interferon-stimulated gene TRIM22: A double-edged sword in HIV-1 infection
- Author
-
Guido Poli, Elisa Vicenzi, Vicenzi, Elisa, and Poli, Guido
- Subjects
0301 basic medicine ,Transcription, Genetic ,Sp1 Transcription Factor ,Endocrinology, Diabetes and Metabolism ,Immunology ,HIV Infections ,Biology ,TRIM22 ,Virus Replication ,General Biochemistry, Genetics and Molecular Biology ,Minor Histocompatibility Antigens ,Tripartite Motif Proteins ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,medicine ,Immunology and Allergy ,Humans ,HIV Infection ,Epigenetics ,Promoter Regions, Genetic ,Sp1 transcription factor ,Innate immune system ,Biochemistry, Genetics and Molecular Biology (all) ,Interferon-stimulated gene ,Restriction factor ,Repressor Protein ,Virology ,HIV transcription ,Immunity, Innate ,Minor Histocompatibility Antigen ,Host-Pathogen Interaction ,Repressor Proteins ,Chronic infection ,030104 developmental biology ,Proviral latency ,Viral replication ,Tripartite Motif Protein ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,HIV-1 ,medicine.drug ,Human - Abstract
Infection of target cells by the human immunodeficiency virus type-1 (HIV-1) is hampered by constitutively expressed host cell proteins preventing or curtailing virus replication and therefore defined as "restriction factors". Among them, members of the tripartite motif (TRIM) family have emerged as important players endowed with both antiviral effects and modulatory capacity of the innate immune response. TRIM5α and TRIM19 (i.e. promyelocytic leukemia, PML) are among the best-characterized family members; however, in this review we will focus on the potential role of another family member, i.e. TRIM22, a factor strongly induced by interferon stimulation, in HIV infection in vivo and in vitro in the context of its broader antiviral effects. We will also focus on the potential role of TRIM22 in HIV-1-infected individuals speculating on its dual role in controlling virus replication and more complex role in chronic infection. At the molecular levels, we will review the evidence in favor of a relevant role of TRIM22 as epigenetic inhibitor of HIV-1 transcription acting by preventing the binding of the host cell transcription factor Sp1 to the viral promoter. These evidences suggest that TRIM22 should be considered a potential new player in either the establishment or maintenance of HIV-1 reservoirs of latently infected cells unaffected by combination antiretroviral therapy.
- Published
- 2018
45. The landscape of epilepsy-related GATOR1 variants
- Author
-
Johannes R. Lemke, Pia Zacher, Thomas Dorn, Laura Hernandez-Hernandez, Natasha E. Schoeler, Stéphanie Baulac, Sara Baldassari, Anne de Saint Martin, Eleni Panagiotakaki, Anne Fabienne Lepine, Markus Wolff, Arnaud Biraben, Renske Oegema, Edouard Hirsch, Anna Jansen, Charles Deckers, Nienke E. Verbeek, Fabienne Picard, Georg Dorfmüller, Sarah Ferrand-Sorbets, Barbora Benova, Francesca Bisulli, Inga Talvik, Kristin Lindstrom, Tilman Polster, Douglas R. Nordli, Tommaso Pippucci, Eva H. Brilstra, Shifteh Sattar, Erik H. Niks, Marie Line Jacquemont, Kees P.J. Braun, Karen Müller-Schlüter, Sanjay M. Sisodiya, Sarah Weckhuysen, Lysa Boissé Lomax, Sophie Julia, Brigitte Ricard-Mousnier, Mathilde Chipaux, Laura Licchetta, Gaetan Lesca, Bianca Berghuis, S. Krithika, Jamel Chelly, Renzo Guerrini, Hélène Catenoix, Annapurna Poduri, Melanie Jennesson, Pasquale Striano, Rikke S. Møller, Antonio Gambardella, Guillaume Achaz, Peter Uldall, Fabrice Bartolomei, Giuseppe d'Orsi, Laurence Faivre, Floor E. Jansen, An Sofie Schoonjans, Kevin Rostasy, Thomas Becher, Pavel Krsek, Julien Thevenon, Marjan J. A. van Kempen, Guido Rubboli, Cécile Marchal, Meral Balci, Boudewijn Gunning, Ilona Krey, Julitta de Bellescize, Veronique Darmency, Christopher J. Yuskaitis, Daniëlle de Jong, Giovanni Crichiutti, Paolo Tinuper, Katrien Stouffs, Valentin Sander, Anne-Sophie Lebre, Thomas Cloppenborg, Valerio Conti, Gabrielle Rudolf, Courtney Kiss, Eveline Hagebeuk, Caroline Nava, Eric LeGuern, Ilse Wegner, Christian Brandt, Martin Zenker, Simona Balestrini, Picard, Fabienne, Baldassari S., Picard F., Verbeek N.E., van Kempen M., Brilstra E.H., Lesca G., Conti V., Guerrini R., Bisulli F., Licchetta L., Pippucci T., Tinuper P., Hirsch E., de Saint Martin A., Chelly J., Rudolf G., Chipaux M., Ferrand-Sorbets S., Dorfmuller G., Sisodiya S., Balestrini S., Schoeler N., Hernandez-Hernandez L., Krithika S., Oegema R., Hagebeuk E., Gunning B., Deckers C., Berghuis B., Wegner I., Niks E., Jansen F.E., Braun K., de Jong D., Rubboli G., Talvik I., Sander V., Uldall P., Jacquemont M.-L., Nava C., Leguern E., Julia S., Gambardella A., d'Orsi G., Crichiutti G., Faivre L., Darmency V., Benova B., Krsek P., Biraben A., Lebre A.-S., Jennesson M., Sattar S., Marchal C., Nordli D.R., Lindstrom K., Striano P., Lomax L.B., Kiss C., Bartolomei F., Lepine A.F., Schoonjans A.-S., Stouffs K., Jansen A., Panagiotakaki E., Ricard-Mousnier B., Thevenon J., de Bellescize J., Catenoix H., Dorn T., Zenker M., Muller-Schluter K., Brandt C., Krey I., Polster T., Wolff M., Balci M., Rostasy K., Achaz G., Zacher P., Becher T., Cloppenborg T., Yuskaitis C.J., Weckhuysen S., Poduri A., Lemke J.R., Moller R.S., Baulac S., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Service de Génétique [HCL Groupement Hospitalier Est], Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Children's Hospital A. Meyer, Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze], Danish Epilepsy Centre, Denmark and Aarhus University, Aarhus, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Université de Bourgogne (UB), Service de Neurophysiologie Clinique (CHU Dijon), CHU Pontchaillou [Rennes], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Institute of Human Genetics, University Hospital Magdeburg, Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
- Subjects
Male ,0301 basic medicine ,Proband ,DEPDC5 ,SUDEP ,030105 genetics & heredity ,Bioinformatics ,Loss of Function Mutation/genetics ,Epilepsy ,INDEL Mutation ,Loss of Function Mutation ,mTORC1 pathway ,Genetics(clinical) ,Child ,Genetics (clinical) ,Multiprotein Complexes/genetics ,Brugada Syndrome ,DNA Copy Number Variation ,Brugada syndrome ,INDEL Mutation/genetics ,GTPase-Activating Proteins ,NPRL3 ,Seizure ,Phenotype ,Pedigree ,3. Good health ,Brugada Syndrome/genetics ,Child, Preschool ,Female ,Human ,Signal Transduction ,DNA Copy Number Variations ,Adolescent ,Seizures/complications ,Mechanistic Target of Rapamycin Complex 1/genetics ,DNA Copy Number Variations/genetics ,Mechanistic Target of Rapamycin Complex 1 ,Tumor Suppressor Proteins/genetics ,Article ,Focal cortical dysplasia ,03 medical and health sciences ,Seizures ,GTPase-Activating Proteins/genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic focal epilepsy ,Epilepsy/complications ,Repressor Proteins/genetics ,business.industry ,GTPase-Activating Protein ,Tumor Suppressor Proteins ,Infant, Newborn ,Correction ,Infant ,Repressor Protein ,Cortical dysplasia ,medicine.disease ,ddc:616.8 ,Repressor Proteins ,030104 developmental biology ,Frontal lobe seizures ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Multiprotein Complexes ,Multiprotein Complexe ,Signal Transduction/genetics ,Human medicine ,business - Abstract
Purpose:\ud \ud To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway.\ud \ud Methods:\ud \ud We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.\ud \ud Results:\ud \ud The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.\ud \ud Conclusion:\ud \ud Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
- Published
- 2018
46. ZNF224 is a transcriptional repressor of AXL in chronic myeloid leukemia cells
- Author
-
Patrick Auberger, Elena Cesaro, Paola Costanzo, Giancarlo Blasio, Federica Fiorentino, Gaetano Sodaro, Sodaro, Gaetano, Blasio, Giancarlo, Fiorentino, Federica, Auberger, Patrick, Costanzo, Paola, and Cesaro, Elena
- Subjects
0301 basic medicine ,Receptor Protein-Tyrosine Kinases ,Repressor ,Biochemistry ,Receptor tyrosine kinase ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Transcription factor ,Proto-Oncogene Protein ,biology ,business.industry ,Myeloid leukemia ,Axl ,Imatinib ,General Medicine ,Repressor Protein ,medicine.disease ,Axl Receptor Tyrosine Kinase ,Repressor Proteins ,Receptor Protein-Tyrosine Kinase ,030104 developmental biology ,030220 oncology & carcinogenesis ,Imatinib-resistance ,Mutation ,biology.protein ,Cancer research ,business ,ZNF224 ,Transcription ,Chronic myelogenous leukemia ,medicine.drug ,Human ,Protein Binding - Abstract
ZNF224 is a KRAB-zinc finger transcription factor that exerts a key tumor suppressive role in chronic myelogenous leukemia. In this study, we identify the receptor tyrosine kinase Axl as a novel target of ZNF224 transcriptional repression activity. Axl overexpression is found in many types of cancer and is frequently associated with drug resistance. Interestingly, we also found that sensitivity to imatinib can be partly restored in imatinib-resistant chronic myelogenous leukemia cells by ZNF224 overexpression and the resulting suppression of Axl expression. These results, in accordance with our previous findings, support the role of ZNF224 in imatinib responsiveness and shed new insights into potential therapeutic use of ZNF224 in imatinib-resistant chronic myelogenous leukemia.
- Published
- 2018
47. The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export
- Author
-
Vohhodina, Jekaterina, Barros, Eliana M, Savage, Abigail L, Liberante, Fabio G, Manti, Lorenzo, Bankhead, Peter, Cosgrove, Nicola, Madden, Angelina F, Harkin, D Paul, Savage, Kienan I, Vohhodina, Jekaterina, Barros, Eliana M., Savage, Abigail L., Liberante, Fabio G., Manti, Lorenzo, Bankhead, Peter, Cosgrove, Nicola, Madden, Angelina F., Harkin, D Paul, and Savage, Kienan I.
- Subjects
Transcription Factor ,DNA-Binding Protein ,RNA Splicing ,Transcription Factors/genetics ,Active Transport, Cell Nucleus ,Ataxia Telangiectasia Mutated Proteins ,Genome Integrity, Repair and Replication ,Tumor Suppressor Proteins/genetics ,Ataxia Telangiectasia Mutated Protein ,SDG 3 - Good Health and Well-being ,HEK293 Cell ,Ataxia Telangiectasia Mutated Proteins/genetics ,Cell Line, Tumor ,Genetics ,Humans ,In Situ Hybridization, Fluorescence ,Repressor Proteins/genetics ,Tumor Suppressor Protein ,Active Transport, Cell Nucleu ,Gene Expression Profiling ,Tumor Suppressor Proteins ,Repressor Protein ,DNA-Binding Proteins ,Repressor Proteins ,HEK293 Cells ,Microscopy, Fluorescence ,Mutation ,RNA Interference ,Gene Expression Profiling/methods ,DNA-Binding Proteins/genetics ,Active Transport, Cell Nucleus/genetics ,Human ,DNA Damage ,Transcription Factors - Abstract
mRNA splicing and export plays a key role in the regulation of gene expression, with recent evidence suggesting an additional layer of regulation of gene expression and cellular function through the selective splicing and export of genes within specific pathways. Here we describe a role for the RNA processing factors THRAP3 and BCLAF1 in the regulation of the cellular DNA damage response (DDR) pathway, a key pathway involved in the maintenance of genomic stability and the prevention of oncogenic transformation. We show that loss of THRAP3 and/or BCLAF1 leads to sensitivity to DNA damaging agents, defective DNA repair and genomic instability. Additionally, we demonstrate that this phenotype can be at least partially explained by the role of THRAP3 and BCLAF1 in the selective mRNA splicing and export of transcripts encoding key DDR proteins, including the ATM kinase. Moreover, we show that cancer associated mutations within THRAP3 result in deregulated processing of THRAP3/BCLAF1-regulated transcripts and consequently defective DNA repair. Taken together, these results suggest that THRAP3 and BCLAF1 mutant tumors may be promising targets for DNA damaging chemotherapy.
- Published
- 2017
48. A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response
- Author
-
Amin-Wetzel, Niko, Saunders, Reuben A, Kamphuis, Maarten J, Rato, Claudia, Preissler, Steffen, Harding, Heather P, Ron, David, Preissler, Steffen [0000-0001-7936-9836], Harding, Heather [0000-0002-7359-7974], Ron, David [0000-0002-3014-5636], and Apollo - University of Cambridge Repository
- Subjects
Protein Folding ,genetic structures ,Protein Dimerization ,Membrane Proteins ,Repressor Protein ,HSP40 Heat-Shock Proteins ,Protein Serine-Threonine Kinases ,Endoplasmic Reticulum ,Stress ,Allosteric Regulation ,Cricetinae ,Endoribonucleases ,Fluorescence Resonance Energy Transfer ,Unfolded Protein Response ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,Endoplasmic Reticulum Chaperone BiP ,Biological Feedback ,Heat-Shock Proteins ,Molecular Chaperones - Abstract
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.
- Published
- 2017
49. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes
- Author
-
Elise Valkanas, Hon-Yin Brian Chung, Peter Farndon, Patricia M. Zerfas, Oliver Bartsch, Martin Zenker, Jeroen Bakkers, Alexander Hoischen, Feliciano J. Ramos, Eva Bermejo-Sánchez, Haigen Huang, Gijs van Haaften, Lynne A. Wolfe, Taylor Davis, Eduarda Morgana da Silva, Han G. Brunner, W. K. Jacyk, Bruno Dallapiccola, Laura Mazzanti, Cathy A. Stevens, Mieke M. van Haelst, Hanka Venselaar, Cornelius F. Boerkoel, Francesco Brancati, Cynthia J. Tifft, May Christine V. Malicdan, Nathalie Roche, Bert B.A. de Vries, Victor Evangelista de Faria Ferraz, Chyi-Chia Richard Lee, Brian P. Brooks, Farahnaz Sabbagh-Kermani, Federico Tessadori, Denny Schanze, Barbara N. Pusey, Ariana Kariminejad, Valerie Maduro, Janice Lee, Giovanna Zambruno, Shuo Lin, Cédric Le Caignec, Thomas C. Markello, Maria Tsokos, Shannon Marchegiani, Fabiana Martins, William A. Gahl, Anneke T. Vulto-van Silfhout, Other departments, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, Van Haaften, Gij, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-Van Silfhout, Anneke T., Wolfe, Lynne A., Tifft, Cynthia J., Zerfas, Patricia M., Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G., Lee, Chyi-Chia R., Ferraz, Victor, Da Silva, Eduarda Morgana, Stevens, Cathy A., Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P., Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J., Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K., Mazzanti, Laura, Brunner, Han G., Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V., Boerkoel, Cornelius F., Gahl, William A., De Vries, Bert B.A., Van Haelst, Mieke M., Zenker, Martin, Markello, Thomas C., and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
Models, Molecular ,Candidate gene ,Hirsutism ,Protein Conformation ,HeLa Cell ,medicine.disease_cause ,Transcriptome ,Twist transcription factor ,Models ,Genetics(clinical) ,Exome ,Eye Abnormalities ,Non-U.S. Gov't ,Genetics (clinical) ,Zebrafish ,Genetics ,Mutation ,Microscopy ,Macrostomia ,Setleis syndrome ,Hypertelorism ,Research Support, Non-U.S. Gov't ,Hypertrichosi ,Eyelid Disease ,GENÉTICA ,Phenotype ,Eyelid Diseases ,Abnormalities ,Multiple ,Sequence Analysis ,Human ,Chromatin Immunoprecipitation ,Molecular Sequence Data ,Mutation, Missense ,Hypertrichosis ,Amino Acid Sequence ,Animals ,Base Sequence ,HeLa Cells ,Humans ,Electron ,Missense ,Repressor Proteins ,DNA ,Skin Abnormalities ,Twist Transcription Factor ,Molecular ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Biology ,Research Support ,Article ,Frameshift mutation ,Genetic ,Ablepharon macrostomia syndrome ,Skin Abnormalitie ,medicine ,Journal Article ,Abnormalities, Multiple ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Animal ,Twist-Related Protein 1 ,Sequence Analysis, DNA ,Repressor Protein ,medicine.disease ,Eye Abnormalitie ,Microscopy, Electron ,sense organs ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - Abstract
Contains fulltext : 153827.pdf (Publisher’s version ) (Open Access) Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
- Published
- 2015
50. Oculo-facio-cardio-dental (OFCD) syndrome: The first Italian case of BCOR and co-occurring OTC gene deletion
- Author
-
Barbara Lombardo, C. Fabbricatore, I. Caliendo, Lucio Pastore, C Di Stefano, F. Gallo, C. Munno, Di Stefano, C, Lombardo, Barbara, Fabbricatore, C., Munno, C., Caliendo, I., Gallo, F., and Pastore, Lucio
- Subjects
Oculo-facio-cardio-dental syndrome ,DNA Mutational Analysis ,Biology ,Cataract ,Microphthalmo ,DNA Mutational Analysi ,chemistry.chemical_compound ,Genetic ,Proto-Oncogene Proteins ,OFCD SYNDROME ,Genetics ,medicine ,Humans ,Microphthalmos ,Abnormalities, Multiple ,BCOR ,Gene ,Ornithine Carbamoyltransferase ,Sequence Deletion ,Proto-Oncogene Protein ,Comparative Genomic Hybridization ,Medicine (all) ,Heart Septal Defects ,Genetic disorder ,General Medicine ,Repressor Protein ,Ornithine ,Oculo facio cardio dental ,BCL6 ,medicine.disease ,Repressor Proteins ,OTC ,Real-time polymerase chain reaction ,chemistry ,Child, Preschool ,A-CGH ,Heart Septal Defect ,Female ,Human ,Comparative genomic hybridization - Abstract
Oculo-facio-cardio-dental (OFCD) syndrome is a rare genetic disorder affecting ocular, facial, dental and cardiac systems. The syndrome is an X-linked dominant trait and it might be lethal in males. This syndrome is usually caused by mutations in the BCL6 interacting co-repressor gene (BCOR). We described a female child with mild phenotype of oculo-facio-cardio-dental syndrome. Array-comparative genomic hybridization (a-CGH) analysis revealed a de novo heterozygous deletion in the Xp11.4 region of approximately 2.3 Mb, involving BCOR and ornithine carbamoyl-transferase (OTC) genes. The deletion observed was subsequently confirmed by real time PCR. In this study we report a first case with co-occurrence of BCOR and OTC genes completely deleted in OFCD syndrome.
- Published
- 2015
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.