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1. Non-viral chimeric antigen receptor (CAR) T cells going viral

Author

H. Balke-Want, V. Keerthi, A. Cadinanos-Garai, C. Fowler, N. Gkitsas, A.K. Brown, R. Tunuguntla, M. Abou-el-Enein, and S.A. Feldman

Subjects
cell therapy scaling, CRISPR, electroporation, gene delivery, manufacturing, non-viral CAR T cells, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Chimeric antigen receptor (CAR) T cell therapy has made significant strides in the treatment of B-cell malignancies, but its application in treating solid tumors still poses significant challenges. Particularly, the widespread use of viral vectors to deliver CAR transgenes into T cells comes with limitations, including high costs and regulatory restrictions, which hinder the translation of novel genetic engineering concepts into clinical applications. Non-viral methods, such as transposon/transposase and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems, offer promising alternatives for stable transgene insertion in CAR-T cells. These methods offer the potential to increase accessibility and efficiency in the development and delivery of CAR-T cell therapies. The main challenge in using non-viral methods, however, is their low knock-in efficiency, which leads to low transgene expression levels. In this review, we discuss recent developments in non-viral approaches for CAR-T cell production, the manufacturing requirements for clinical-grade production of non-viral CAR-T cells, and the adjustments needed in quality control for proper characterization of genomic features and evaluation of potential genotoxicity.

Published
2023
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2. Overview of T and D–T results in JET with ITER-like wall

Author

C.F. Maggi, D. Abate, N. Abid, P. Abreu, O. Adabonyan, M. Afzal, I. Ahmad, M. Akhtar, R. Albanese, S. Aleiferis, E. Alessi, P. Aleynikov, J. Alguacil, J. Alhage, M. Ali, H. Allen, M. Allinson, M. Alonzo, E. Alves, R. Ambrosino, E. Andersson Sundén, P. Andrew, M. Angelone, C. Angioni, I. Antoniou, L. Appel, C. Appelbee, C. Aramunde, M. Ariola, G. Arnoux, G. Artaserse, J.-F. Artaud, W. Arter, V. Artigues, F.J. Artola, A. Ash, O. Asztalos, D. Auld, F. Auriemma, Y. Austin, L. Avotina, J. Ayllón, E. Aymerich, A. Baciero, L. Bähner, F. Bairaktaris, I. Balboa, M. Balden, N. Balshaw, V.K. Bandaru, J. Banks, A. Banon Navarro, C. Barcellona, O. Bardsley, M. Barnes, R. Barnsley, M. Baruzzo, M. Bassan, A. Batista, P. Batistoni, L. Baumane, B. Bauvir, L. Baylor, C. Bearcroft, P. Beaumont, D. Beckett, A. Begolli, M. Beidler, N. Bekris, M. Beldishevski, E. Belli, F. Belli, S. Benkadda, J. Bentley, E. Bernard, J. Bernardo, M. Bernert, M. Berry, L. Bertalot, H. Betar, M. Beurskens, P.G. Bhat, S. Bickerton, J. Bielecki, T. Biewer, R. Bilato, P. Bílková, G. Birkenmeier, R. Bisson, J.P.S. Bizarro, P. Blatchford, A. Bleasdale, V. Bobkov, A. Boboc, A. Bock, G. Bodnar, P. Bohm, L. Bonalumi, N. Bonanomi, D. Bonfiglio, X. Bonnin, P. Bonofiglo, J. Booth, D. Borba, D. Borodin, I. Borodkina, T.O.S.J. Bosman, C. Bourdelle, M. Bowden, I. Božičević Mihalić, S.C. Bradnam, B. Breizman, S. Brezinsek, D. Brida, M. Brix, P. Brown, D. Brunetti, M. Buckley, J. Buermans, H. Bufferand, P. Buratti, A. Burckhart, A. Burgess, A. Buscarino, A. Busse, D. Butcher, G. Calabrò, L. Calacci, R. Calado, R. Canavan, B. Cannas, M. Cannon, M. Cappelli, S. Carcangiu, P. Card, A. Cardinali, S. Carli, P. Carman, D. Carnevale, B. Carvalho, I.S. Carvalho, P. Carvalho, I. Casiraghi, F.J. Casson, C. Castaldo, J.P. Catalan, N. Catarino, F. Causa, M. Cavedon, M. Cecconello, L. Ceelen, C.D. Challis, B. Chamberlain, R. Chandra, C.S. Chang, A. Chankin, B. Chapman, P. Chauhan, M. Chernyshova, A. Chiariello, G.-C. Chira, P. Chmielewski, A. Chomiczewska, L. Chone, J. Cieslik, G. Ciraolo, D. Ciric, J. Citrin, Ł. Ciupinski, R. Clarkson, M. Cleverly, P. Coates, V. Coccorese, R. Coelho, J.W. Coenen, I.H. Coffey, A. Colangeli, L. Colas, J. Collins, S. Conroy, C. Contré, N.J. Conway, D. Coombs, P. Cooper, S. Cooper, L. Cordaro, C. Corradino, Y. Corre, G. Corrigan, D. Coster, T. Craciunescu, S. Cramp, D. Craven, R. Craven, G. Croci, D. Croft, K. Crombé, T. Cronin, N. Cruz, A. Cufar, A. Cullen, A. Dal Molin, S. Dalley, P. David, A. Davies, J. Davies, S. Davies, G. Davis, K. Dawson, S. Dawson, I. Day, G. De Tommasi, J. Deane, M. Dearing, M. De Bock, J. Decker, R. Dejarnac, E. Delabie, E. de la Cal, E. de la Luna, D. Del Sarto, A. Dempsey, W. Deng, A. Dennett, G.L. Derks, G. De Temmerman, F. Devasagayam, P. de Vries, P. Devynck, A. di Siena, D. Dickinson, T. Dickson, M. Diez, P. Dinca, T. Dittmar, L. Dittrich, J. Dobrashian, T. Dochnal, A.J.H. Donné, W. Dorland, S. Dorling, S. Dormido-Canto, R. Dotse, D. Douai, S. Dowson, R. Doyle, M. Dreval, P. Drews, G. Drummond, Ph. Duckworth, H.G. Dudding, R. Dumont, P. Dumortier, D. Dunai, T. Dunatov, M. Dunne, I. Ďuran, F. Durodié, R. Dux, T. Eade, E. Eardley, J. Edwards, T. Eich, A. Eksaeva, H. El-Haroun, R.D. Ellis, G. Ellwood, C. Elsmore, S. Emery, G. Ericsson, B. Eriksson, F. Eriksson, J. Eriksson, L.G. Eriksson, S. Ertmer, G. Evans, S. Evans, E. Fable, D. Fagan, M. Faitsch, D. Fajardo Jimenez, M. Falessi, A. Fanni, T. Farmer, I. Farquhar, B. Faugeras, S. Fazinić, N. Fedorczak, K. Felker, R. Felton, H. Fernandes, D.R. Ferreira, J. Ferreira, G. Ferrò, J. Fessey, O. Février, O. Ficker, A.R. Field, A. Figueiredo, J. Figueiredo, A. Fil, N. Fil, P. Finburg, U. Fischer, G. Fishpool, L. Fittill, M. Fitzgerald, D. Flammini, J. Flanagan, S. Foley, N. Fonnesu, M. Fontana, J.M. Fontdecaba, L. Fortuna, E. Fortuna-Zalesna, M. Fortune, C. Fowler, P. Fox, O. Franklin, E. Fransson, L. Frassinetti, R. Fresa, D. Frigione, T. Fülöp, M. Furseman, S. Gabriellini, D. Gadariya, S. Gadgil, K. Gál, S. Galeani, A. Galkowski, D. Gallart, M. Gambrioli, T. Gans, J. Garcia, M. García-Muñoz, L. Garzotti, J. Gaspar, R. Gatto, P. Gaudio, D. Gear, T. Gebhart, S. Gee, M. Gelfusa, R. George, S.N. Gerasimov, R. Gerru, G. Gervasini, M. Gethins, Z. Ghani, M. Gherendi, P.-I. Gherghina, F. Ghezzi, L. Giacomelli, C. Gibson, L. Gil, M.R. Gilbert, A. Gillgren, E. Giovannozzi, C. Giroud, G. Giruzzi, J. Goff, V. Goloborodko, R. Gomes, J.-F. Gomez, B. Gonçalves, M. Goniche, J. Gonzalez-Martin, A. Goodyear, S. Gore, G. Gorini, T. Görler, N. Gotts, E. Gow, J.P. Graves, J. Green, H. Greuner, E. Grigore, F. Griph, W. Gromelski, M. Groth, C. Grove, R. Grove, N. Gupta, S. Hacquin, L. Hägg, A. Hakola, M. Halitovs, J. Hall, C.J. Ham, M. Hamed, M.R. Hardman, Y. Haresawa, G. Harrer, J.R. Harrison, D. Harting, D.R. Hatch, T. Haupt, J. Hawes, N.C. Hawkes, J. Hawkins, S. Hazael, J. Hearmon, P. Heesterman, P. Heinrich, M. Held, W. Helou, O. Hemming, S.S. Henderson, R. Henriques, R.B. Henriques, D. Hepple, J. Herfindal, G. Hermon, J.C. Hillesheim, K. Hizanidis, A. Hjalmarsson, A. Ho, J. Hobirk, O. Hoenen, C. Hogben, A. Hollingsworth, S. Hollis, E. Hollmann, M. Hölzl, M. Hook, M. Hoppe, J. Horáček, N. Horsten, A. Horton, L.D. Horton, L. Horvath, S. Hotchin, Z. Hu, Z. Huang, E. Hubenov, A. Huber, V. Huber, T. Huddleston, G.T.A. Huijsmans, Y. Husain, P. Huynh, A. Hynes, D. Iglesias, M.V. Iliasova, M. Imríšek, J. Ingleby, P. Innocente, V. Ioannou-Sougleridis, N. Isernia, I. Ivanova-Stanik, E. Ivings, S. Jachmich, T. Jackson, A.S. Jacobsen, P. Jacquet, H. Järleblad, A. Järvinen, F. Jaulmes, N. Jayasekera, F. Jenko, I. Jepu, E. Joffrin, T. Johnson, J. Johnston, C. Jones, E. Jones, G. Jones, L. Jones, T.T.C. Jones, A. Joyce, M. Juvonen, A. Kallenbach, P. Kalnina, D. Kalupin, P. Kanth, A. Kantor, A. Kappatou, O. Kardaun, J. Karhunen, E. Karsakos, Ye.O. Kazakov, V. Kazantzidis, D.L. Keeling, W. Kelly, M. Kempenaars, D. Kennedy, K. Khan, E. Khilkevich, C. Kiefer, H.-T. Kim, J. Kim, S.H. Kim, D.B. King, D.J. Kinna, V.G. Kiptily, A. Kirjasuo, K.K. Kirov, A. Kirschner, T. Kiviniemi, G. Kizane, C. Klepper, A. Klix, G. Kneale, M. Knight, P. Knight, R. Knights, S. Knipe, U. Knoche, M. Knolker, M. Kocan, F. Köchl, G. Kocsis, J.T.W. Koenders, Y. Kolesnichenko, Y. Kominis, M. Kong, B. Kool, V. Korovin, S.B. Korsholm, B. Kos, D. Kos, M. Koubiti, Y. Kovtun, E. Kowalska-Strzęciwilk, K. Koziol, Y. Krasikov, A. Krasilnikov, V. Krasilnikov, M. Kresina, A. Kreter, K. Krieger, A. Krivska, U. Kruezi, I. Książek, H. Kumpulainen, B. Kurzan, S. Kwak, O.J. Kwon, B. Labit, M. Lacquaniti, A. Lagoyannis, L. Laguardia, A. Laing, V. Laksharam, N. Lam, H.T. Lambertz, B. Lane, M. Langley, E. Lascas Neto, E. Łaszyńska, K.D. Lawson, A. Lazaros, E. Lazzaro, G. Learoyd, C. Lee, K. Lee, S. Leerink, T. Leeson, X. Lefebvre, H.J. Leggate, J. Lehmann, M. Lehnen, D. Leichtle, F. Leipold, I. Lengar, M. Lennholm, E. Leon Gutierrez, L.A. Leppin, E. Lerche, A. Lescinskis, S. Lesnoj, L. Lewin, J. Lewis, J. Likonen, Ch. Linsmeier, X. Litaudon, E. Litherland-Smith, F. Liu, T. Loarer, A. Loarte, R. Lobel, B. Lomanowski, P.J. Lomas, J. Lombardo, R. Lorenzini, S. Loreti, V.P. Loschiavo, M. Loughlin, T. Lowe, C. Lowry, T. Luce, R. Lucock, T. Luda Di Cortemiglia, M. Lungaroni, C.P. Lungu, T. Lunt, V. Lutsenko, B. Lyons, J. Macdonald, E. Macusova, R. Mäenpää, H. Maier, J. Mailloux, S. Makarov, P. Manas, A. Manning, P. Mantica, M.J. Mantsinen, J. Manyer, A. Manzanares, Ph. Maquet, M. Maraschek, G. Marceca, G. Marcer, C. Marchetto, O. Marchuk, A. Mariani, G. Mariano, M. Marin, A. Marin Roldan, M. Marinelli, T. Markovič, L. Marot, C. Marren, S. Marsden, S. Marsen, J. Marsh, R. Marshall, L. Martellucci, A.J. Martin, C. Martin, R. Martone, S. Maruyama, M. Maslov, M. Mattei, G.F. Matthews, D. Matveev, E. Matveeva, A. Mauriya, F. Maviglia, M. Mayer, M.-L. Mayoral, S. Mazzi, C. Mazzotta, R. McAdams, P.J. McCarthy, P. McCullen, R. McDermott, D.C. McDonald, D. McGuckin, V. McKay, L. McNamee, A. McShee, D. Mederick, M. Medland, S. Medley, K. Meghani, A.G. Meigs, S. Meitner, S. Menmuir, K. Mergia, S. Mianowski, P. Middleton, J. Mietelski, K. Mikszuta-Michalik, D. Milanesio, E. Milani, E. Militello-Asp, F. Militello, J. Milnes, A. Milocco, S. Minucci, I. Miron, J. Mitchell, J. Mlynář, V. Moiseenko, P. Monaghan, I. Monakhov, A. Montisci, S. Moon, R. Mooney, S. Moradi, R.B. Morales, L. Morgan, F. Moro, J. Morris, T. Mrowetz, L. Msero, S. Munot, A. Muñoz-Perez, M. Muraglia, A. Murari, A. Muraro, B. N’Konga, Y.S. Na, F. Nabais, R. Naish, F. Napoli, E. Nardon, V. Naulin, M.F.F. Nave, R. Neu, S. Ng, M. Nicassio, D. Nicolai, A.H. Nielsen, S.K. Nielsen, D. Nina, C. Noble, C.R. Nobs, M. Nocente, H. Nordman, S. Nowak, H. Nyström, J. O’Callaghan, M. O’Mullane, C. O’Neill, C. Olde, H.J.C. Oliver, R. Olney, J. Ongena, G.P. Orsitto, A. Osipov, R. Otin, N. Pace, L.W. Packer, E. Pajuste, D. Palade, J. Palgrave, O. Pan, N. Panadero, T. Pandya, E. Panontin, A. Papadopoulos, G. Papadopoulos, G. Papp, V.V. Parail, A. Parsloe, K. Paschalidis, M. Passeri, A. Patel, A. Pau, G. Pautasso, R. Pavlichenko, A. Pavone, E. Pawelec, C. Paz-Soldan, A. Peacock, M. Pearce, I.J. Pearson, E. Peluso, C. Penot, K. Pepperell, A. Perdas, T. Pereira, E. Perelli Cippo, C. Perez von Thun, D. Perry, P. Petersson, G. Petravich, N. Petrella, M. Peyman, L. Pigatto, M. Pillon, S. Pinches, G. Pintsuk, C. Piron, A. Pironti, F. Pisano, R. Pitts, U. Planck, N. Platt, V. Plyusnin, M. Podesta, G. Pokol, F.M. Poli, O.G. Pompilian, M. Poradzinski, M. Porkolab, C. Porosnicu, G. Poulipoulis, A.S. Poulsen, I. Predebon, A. Previti, D. Primetzhofer, G. Provatas, G. Pucella, P. Puglia, K. Purahoo, O. Putignano, T. Pütterich, A. Quercia, G. Radulescu, V. Radulovic, R. Ragona, M. Rainford, P. Raj, M. Rasinski, D. Rasmussen, J. Rasmussen, J.J. Rasmussen, A. Raso, G. Rattá, S. Ratynskaia, R. Rayaprolu, M. Rebai, A. Redl, D. Rees, D. Réfy, R. Reichle, H. Reimerdes, B.C.G. Reman, C. Reux, S. Reynolds, D. Rigamonti, E. Righi, F.G. Rimini, J. Risner, J.F. Rivero-Rodriguez, C.M. Roach, J. Roberts, R. Robins, S. Robinson, D. Robson, S. Rode, P. Rodrigues, P. Rodriguez-Fernandez, S. Romanelli, J. Romazanov, E. Rose, C. Rose-Innes, R. Rossi, S. Rowe, D. Rowlands, C. Rowley, M. Rubel, G. Rubinacci, G. Rubino, M. Rud, J. Ruiz Ruiz, F. Ryter, S. Saarelma, A. Sahlberg, M. Salewski, A. Salmi, R. Salmon, F. Salzedas, F. Sanchez, I. Sanders, D. Sandiford, F. Sanni, O. Sauter, P. Sauvan, G. Schettini, A. Shevelev, A.A. Schekochihin, K. Schmid, B.S. Schmidt, S. Schmuck, M. Schneider, P.A. Schneider, N. Schoonheere, R. Schramm, D. Scoon, S. Scully, M. Segato, J. Seidl, L. Senni, J. Seo, G. Sergienko, M. Sertoli, S.E. Sharapov, R. Sharma, A. Shaw, R. Shaw, H. Sheikh, U. Sheikh, N. Shi, P. Shigin, D. Shiraki, G. Sias, M. Siccinio, B. Sieglin, S.A. Silburn, A. Silva, C. Silva, J. Silva, D. Silvagni, D. Simfukwe, J. Simpson, P. Sirén, A. Sirinelli, H. Sjöstrand, N. Skinner, J. Slater, T. Smart, R.D. Smirnov, N. Smith, P. Smith, T. Smith, J. Snell, L. Snoj, E.R. Solano, V. Solokha, C. Sommariva, K. Soni, M. Sos, J. Sousa, C. Sozzi, T. Spelzini, F. Spineanu, L. Spolladore, D. Spong, C. Srinivasan, G. Staebler, A. Stagni, I. Stamatelatos, M.F. Stamp, Ž. Štancar, P.A. Staniec, G. Stankūnas, M. Stead, B. Stein-Lubrano, A. Stephen, J. Stephens, P. Stevenson, C. Steventon, M. Stojanov, D.A. St-Onge, P. Strand, S. Strikwerda, C.I. Stuart, S. Sturgeon, H.J. Sun, S. Surendran, W. Suttrop, J. Svensson, J. Svoboda, R. Sweeney, G. Szepesi, M. Szoke, T. Tadić, B. Tal, T. Tala, P. Tamain, K. Tanaka, W. Tang, G. Tardini, M. Tardocchi, D. Taylor, A.S. Teimane, G. Telesca, A. Teplukhina, A. Terra, D. Terranova, N. Terranova, D. Testa, B. Thomas, V.K. Thompson, A. Thorman, A.S. Thrysoe, W. Tierens, R.A. Tinguely, A. Tipton, H. Todd, M. Tomeš, A. Tookey, P. Tsavalas, D. Tskhakaya, L.-P. Turică, A. Turner, I. Turner, M. Turner, M.M. Turner, G. Tvalashvili, A. Tykhyy, S. Tyrrell, A. Uccello, V. Udintsev, A. Vadgama, D.F. Valcarcel, A. Valentini, M. Valisa, M. Vallar, M. Valovic, M. Van Berkel, K.L. van de Plassche, M. van Rossem, D. Van Eester, J. Varela, J. Varje, T. Vasilopoulou, G. Vayakis, M. Vecsei, J. Vega, M. Veis, P. Veis, S. Ventre, M. Veranda, G. Verdoolaege, C. Verona, G. Verona Rinati, E. Veshchev, N. Vianello, E. Viezzer, L. Vignitchouk, R. Vila, R. Villari, F. Villone, P. Vincenzi, A. Vitins, Z. Vizvary, M. Vlad, I. Voldiner, U. Von Toussaint, P. Vondráček, B. Wakeling, M. Walker, R. Walker, M. Walsh, R. Walton, E. Wang, F. Warren, R. Warren, J. Waterhouse, C. Watts, T. Webster, M. Weiland, H. Weisen, M. Weiszflog, N. Wendler, A. West, M. Wheatley, S. Whetham, A. Whitehead, D. Whittaker, A. Widdowson, S. Wiesen, M. Willensdorfer, J. Williams, I. Wilson, T. Wilson, M. Wischmeier, A. Withycombe, D. Witts, A. Wojcik-Gargula, E. Wolfrum, R. Wood, R. Woodley, R. Worrall, I. Wyss, T. Xu, D. Yadykin, Y. Yakovenko, Y. Yang, V. Yanovskiy, R. Yi, I. Young, R. Young, B. Zaar, R.J. Zabolockis, L. Zakharov, P. Zanca, A. Zarins, D. Zarzoso Fernandez, K.-D. Zastrow, Y. Zayachuk, M. Zerbini, W. Zhang, B. Zimmermann, M. Zlobinski, A. Zocco, V.K. Zotta, M. Zuin, W. Zwingmann, and I. Zychor

Subjects
magnetic fusion, JET-ILW, D–T, tritium, alpha particles, fusion prediction, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

Published
2024
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3. JET machine operations in T&D-T

Author

The JET Operations Team (presented by D.B. King), E. Abdelrahman, A. Abdul Hamid, N. Abid, K. Abraham, O. Adabonyan, C. Adlam, M. Afzal, M. Akhtar, V. Aldred, S. Aldworth, S. Aleiferis, M. Ali, R. Alie, R. Allan, H. Allen, E. Alli, M. Allinson, P. Almond, J. Angus, K. Antcliffe, I. Antoniou, L. Appel, C. Appelbee, C. Aramunde, N. Archer, S. Aria, H. Arkuszynski, M. Arshad, G. Artaserse, A. Ash, C. Ashe, T. Aue, D. Auld, B. Austin, Y. Austin, C. Ayres, R.B. Morales, S. Baker, S. Bakes, I. Balboa, C. Balshaw, N. Balshaw, J. Banks, J. Banner, A. Barnard, M. Barnard, M. Baruzzo, C. Basagiannis, S. Bathe Hariyanandan, P. Batistoni, R. Baughan, P. Beaumont, D. Beckett, A. Begolli, M. Beldishevski, K. Bell, E. Belonohy, J. Bentley, J. Bernardo, M. Berry, J. Bhatt, S. Bickerton, J. Bielecki, W. Bird, D. Blackett, K. Blackman, S. Blake, P. Blatchford, A. Bleasdale, A. Boboc, J. Booth, P. Boulting, M. Bowden, C. Boyd, K. Boyd, R. Bracey, D. Brennan, A. Brett, M. Bright, M. Brix, I. Brooks, B. Brown, P. Brown, M. Brown, P. Brummitt, B. Viola, A. Buckingham, M. Buckley, J. Bumpass, M. Burford, A. Burgess, J. Burton-Sweeten, A. Busse, D. Butcher, P. Cahill, P. Camp, I. Campbell, R. Canavan, J. Cane, M. Cannon, N. Canterbury, A. Carberry, P. Card, M. Carlick, M. Carlo, P. Carman, A. Carruthers, S. Carter, I.S. Carvalho, P. Carvalho, F. Casson, D. Chalk, B. Chamberlain, P. Chauhan, A. Chow, A. Churchman, D. Ciric, M. Clark, J. Clarkson, R. Clarkson, T. Clayton, M. Cleverly, P. Coates, I. Coffey, J. Collins, S. Conroy, N.J. Conway, R. Conway, J. Cook, M. Cooke, D. Coombs, P. Cooper, S. Cooper, G. Corrigan, R. Cotterell, A. Coulson, M. Cox, S. Cox, S. Cramp, D. Craven, R. Craven, M. Crick, D. Croft, T. Cronin, Z. Cui, A. Cullen, R. Cumming, C. Cummings, A. Dal Molin, P. Dalgliesh, S. Dalley, A. Danquah, S. Davies, G. Davis, H. Dawson, K. Dawson, S. Dawson, I. Day, L. de Caires, E. de la Luna, K. Deakin, J. Deane, M. Dearing, A. Dennett, T. Dickson, J. Dobrashian, T. Dochnal, S. Dorling, D. Douai, S. Dowson, J. Drewitt, G. Drummond, P. Dumortier, R. Eade, R. Eastham, K. Eden, J. Edmond, J. Edwards, P. Edwards, H. Elamin, S. Elford, H. El-Haroun, P. Ellis, C. Elsmore, S. Emery, G. Evans, S. Evans, D. Fagan, T. Farmer, I. Farquhar, R. Felton, F. Ferner, J. Fessey, P. Finburg, G. Fishpool, L. Fittill, J. Flanagan, K. Flinders, S. Foley, M. Fontana, M. Fortune, J. Foster, C. Fowler, P. Fox, O. Franklin, R. Franklin, R. Fraser, S. French, M. Furseman, A. Gabbidon, L. Garcia, J. Garcia, M. Gardener, D. Gear, T. Gedling, S. Gee, P. Gell, R. George, S. Gerasimov, M. Gethins, Z. Ghani, L. Giacomelli, C. Gibson, V. Gilsenan, C. Giroud, R. Glen, J. Goff, C. Goodman, A. Goodyear, A. Gordon, S. Gore, S. Gosden, N. Gotts, E. Gow, W. Graham, G. Graham, M. Green, R. Gregory, R. Griffiths, T. Griffiths, F. Griph, C. Grundy, T. Grundy, D. Guard, D. Guest, C. Gurl, S. Hacquin, A. Hakola, K. Hammond, H. Harmer, P. Harper, S. Harris, D. Hart, D. Hattan, A. Haupt, J. Hawes, N. Hawkes, J. Hawkins, P. Hawkins, S. Hayes, S. Hazael, D. Heads, P. Heesterman, O. Hemming, R.B. Henriques, G. Hermon, G. Hewson, T. Hibberd, M. Hill, J. Hillesheim, I. Hirb, K. Ho, C. Hogben, A. Hollingsworth, S. Hollis, M. Hook, D. Hopley, N. Horsten, A. Horton, L.D. Horton, L. Horvath, S. Hotchin, Z. Huang, E. Hubenov, V. Huber, A. Huber, C. Huddart, T. Huddleston, T. Hunter, Y. Husain, A. Hynes, J. Ingleby, S. Ives, E. Ivings, S. Jackson, T. Jackson, P. Jacquet, N. Jayasekera, I. Jepu, D. Jezzard, E. Joffrin, R. Johnson, J. Johnston, C. Jones, E. Jones, G. Jones, L. Jones, S. Jones, T. Jones, M. Jones, A. Joyce, M. Juvonen, A. Kantor, A. Kappatou, G. Karajgikar, J. Karhunen, I. Karnowska-Paterski, E. Karsakos, G. Kaveney, G. Kay, D. Keeling, T. Keenan, R. Kelly, W. Kelly, D. Kennedy, R. Kennedy, O. Kent, K. Khan, D. King, D. Kinna, V. Kiptily, K. Kirov, G. Kneale, M. Knight, P. Knight, J. Knipe, R. Knipe, S. Knipe, P. Kochanski, D. Kos, M. Kovari, E. Kowalska-Strzęciwilk, N. Kraus, M. Kresina, B. Labit, A. Laing, V. Laksharam, N. Lam, B. Lane, C. Lane, T. Lavender, A. Lawson, K. Lawson, G. Learoyd, T. Leeson, X. Lefebvre, J. Lehmann, M. Lennholm, K. Lennon, E. Lerche, S. Lesnoj, E. Letellier, L. Lewin, J. Lewis, J. Li, G. Liddiard, E. Litherland-Smith, F. Liu, R. Lobel, J. Logan, P. Lomas, C. Long, U. Losada, C. Loveridge, T. Lowe, C. Lowry, R. Lucock, G. Lyons, J. Macdonald, P. Macheta, T. Madden, J. Maddock, C.F. Maggi, J. Mailloux, A. Manning, C. Manning, N. Mantel, A. Manzanares, S. Marsden, J. Marsh, R. Marshall, A. Martin, M. Maslov, G. Matthews, N. Mayfield, M. Mayoral, R. McAdams, L. McCafferty, P. McCullen, D. McDonald, A. McDonnell, D. McGuckin, T. McIver, V. McKay, R. McKean, L. McNamee, A. McShee, R. Meadows, D. Mederick, M. Medland, K. Meghani, A. Meigs, S. Menmuir, I. Merrigan, S. Mianowski, P. Middleton, C. Miles, J. Milnes, A. Milocco, J. Mitchell, P. Mitchell, P. Monaghan, I. Monakhov, P. Moody, R. Mooney, C. Moore, N. Mooring, L. Morgan, R. Morgan, J. Morris, O. Morton, S. Morton, P. Mulvana, S. Munot, R. Munro-Smith, K. Musgrave, R. Naish, N. Neethiraj, J. Neilson, A. Newman, S. Ng, M. Nicassio, K. Nicholls, M. Nightingale, C. Noble, R. Normington, C. Nygaard, J. O’Callaghan, R. Olney, B. O’Meara, M. O’Mullane, C. O’Neill, C. Opara, K. O’Rourke, J. Ottley, K. Otu, A. Owen, N. Pace, K. Palamartchouk, D. Paley, J. Palgrave, G. Papadopoulos, V. Parail, A. Parrott, A. Parsloe, L. Parsons, R. Parsons, A. Patel, J. Patel, A. Peacock, M. Pearce, T. Pearce, I. Pearson, J. Penzo, A. Perdas, T. Pereira, C. Perez Von Thun, D. Perry, N. Petrella, M. Peyman, N. Platt, M. Poradzinski, M. Porter, M. Porton, C. Powell, J. Pozzi, M. Price, L. Price, P. Puglia, D. Pulley, K. Purahoo, M. Rainford, A. Raj, S. Randhawa, S. Rapa, K. Ravisankar, C. Rayner, A. Read, C. Reux, S. Reynolds, V. Riccardo, L. Richiusa, D. Rigamonti, F. Rimini, J. Roberts, R. Robins, S. Robinson, T. Robinson, D. Robson, S. Romanelli, F. Rose, C. Rose-Innes, D. Rouse, S. Rowe, N. Rowland, D. Rowlands, M. Rubel, K. Sabin, R. Salmon, H. Salter, A. Sanders, E. Sanders, I. Sanders, D. Sandiford, F. Sanni, R. Sarwar, R. Sayles, C. Scaysbrook, G. Scott, D. Scraggs, S. Scully, R. Sealey, E. Searle, M. Segato, M. Sertoli, C. Shanks, R. Sharma, A. Shaw, K. Sheahan, H. Sheikh, D. Shrestha, R. Siddiqui, S. Silburn, J. Silva, D. Simfukwe, J. Simpson, M. Sinclair, A. Sips, P. Sirén, S. Skeats, N. Skinner, B. Slade, J. Slater, T. Smart, G. Smith, J. Smith, N. Smith, P. Smith, T. Smith, F. P. Smith, J. Snell, K. Snelling, K. Soare, E. Solano, A. Spelzini, C. Srinivasan, Z. Stancar, P.A. Staniec, M. Stead, R. Steadman, L. Steel, D. Steele, A. Stephen, J. Stephens, L. Stevenson, P. Stevenson, C. Steventon, L. Sticklen, M. Stojanov, S. Strikwerda, C. Stuart, G. Stubbs, N. Studd, W. Studholme, H. Sun, S. Surendran, G. Szepesi, M. Szoke, H. Tan, A. Taylor, D. Taylor, K. Taylor, A. Thingore, B. Thomas, J. Thomas, A. Thorman, A. Tilley, A. Tipton, N. Tipton, H. Todd, P. Tonner, A. Tookey, M. Towndrow, M. Tsang, E. Tsitrone, I. Turner, M. Turner, G. Tvalashvili, S. Tyrrell, A. Vadgama, D. Valcarcel, Q. Van Der Westhuizen, J. Verdon, N. Vianello, A. Vittal, Z. Vizvary, B. Wakeling, M. Walker, R. Walker, T. Wall, M. Walsh, T. Walsh, J. Walters, J. Walton, R. Walton, S. Warder, F. Warren, R. Warren, J. Waterhouse, T. Webster, G. Wells, C. Wellstood, A. West, M. Wheatley, S. Whiffin, A. Whitehead, C. Whitehead, D. Whittaker, A. Widdowson, J. Wilcox, D. Wilkins, R. Wilkins, J. Williams, M. Williams, D. Willoughby, A. Wilson, I. Wilson, T. Wilson, M. Wischmeier, P. Wise, G. Withenshaw, A. Withycombe, D. Witts, J. Witts, R. Wood, L. Woodham, C. Woodley, J. Woodley, R. Woodley, B. Woods, S. Wray, T. Xu, I. Young, R. Young, K-D. Zastrow, Y. Zayachuk, and M. Zerbini

Subjects
JET, tritium, operations, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

JET, the world’s largest operating tokamak with unique Be/W wall and tritium handling capability, completed a Deuterium-Tritium (D-T) campaign in 2021 (Maggi et al 29th Fusion Energy Conf. ) following a decade of preparatory experiments, dedicated enhancements, technical rehearsals and training (Horton et al 2016 Fusion Eng. Des. 109–111 925). Operation with tritium raises significant technical, safety and scientific challenges not encountered in standard protium or deuterium operation. This contribution describes the tritium operational requirements, pulses and technical preparations, new operating procedures, lessons learned and details on the achieved operational availability and performance. The preparation and execution of the recent JET tritium experiments benefitted from the previous experience in 1991 (Preliminary Tritium Experiment), 1997 (DTE1 campaign) and 2003 (Trace Tritium Campaigns) and consisted of the following five phases: technical rehearsals and scenario preparation, tritium commissioning, 100% tritium campaign, D-T campaign (DTE2), tritium clean-up. Following the clean-up JET resumed normal operation and is currently undertaking a further D-T campaign (DTE3).

Published
2024
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4. The Feeding Practices and Structure Questionnaire: development and validation of age appropriate versions for infants and toddlers

Author

E. Jansen, C. G. Russell, J. Appleton, R. Byrne, L. A. Daniels, C. Fowler, C. Rossiter, and K. M. Mallan

Subjects
Feeding practices, Structured mealtimes, Responsive feeding, Infants, Toddlers, Questionnaire, Nutritional diseases. Deficiency diseases, RC620-627, Public aspects of medicine, RA1-1270
Abstract

Abstract Background In order to measure and understand trajectories of parental feeding practices and their relationship with child eating and weight, it is desirable to perform assessment from infancy and across time, in age-appropriate ways. While many feeding practices questionnaires exist, none is presently available that enables tracking of feeding practices from infancy through childhood. The aim of the study was to develop a version of the Feeding Practices and Structure Questionnaire (FPSQ) for parents with infants and toddlers (

Published
2021
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5. Report of a Delphi exercise to inform the design of a research programme on screening for thoracic aortic disease

Author

R. G. Abbasciano, J. Barwell, R. Sayers, M. Bown, D. Milewicz, G. Cooper, G. Mariscalco, N. Wheeldon, C. Fowler, G. Owens, G. J. Murphy, and on behalf of the Aortic Dissection Awareness Day UK 2019 Working Group

Subjects
Cardiovascular surgery, Aortic dissection, Patient and public involvement, Public health, Medicine (General), R5-920
Abstract

Abstract Objectives To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design. Methods Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop. Results Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability. Conclusion A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.

Published
2020
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6. Collaborative Assessment Guide for Transition Planning

Author

National Technical Assistance Center on Transition (NTACT), M. Stoehr, M. Diehl, M. Morningstar, D. Rowe, B. K. Simmons, C. Fowler, D. Lattin, J. Vicchio, and E. Wall

Abstract

The National Technical Assistance Center on Transition: the Collaborative (NTACT:C) Collaborative Assessment Guide for Transition Planning (CAG) is intended to help students, family members, educators, vocational rehabilitation counselors, human services and health agency staff, and other partners develop a coordinated assessment approach for transition planning and service delivery. The set of resources which make up the CAG includes sections designed for students and families. It also includes a supplement to highlight the assessment requirements of the Individuals with Disabilities Education Act (IDEA, 2004) and the Rehabilitation Act of 1973 (Rehab Act), as amended by title IV of the Workforce Innovation and Opportunity Act (WIOA) as well as a supplement of Definitions referenced throughout. Finally, it includes a supplement of sample assessment tools. The assessment process for identifying post-school goals and relevant transition services for students and youth consists of six separate but interconnected processes: (1) Determining What to Assess; (2) Determining Stakeholders; (3) Selecting Appropriate Assessments; (4) Conducting Assessments; (5) Reviewing Assessment Results; and (6) Using Assessment Data.

Published
2024

7. Ozone variability and halogen oxidation within the Arctic and sub-Arctic springtime boundary layer

Author

J. B. Gilman, J. F. Burkhart, B. M. Lerner, E. J. Williams, W. C. Kuster, P. D. Goldan, P. C. Murphy, C. Warneke, C. Fowler, S. A. Montzka, B. R. Miller, L. Miller, S. J. Oltmans, T. B. Ryerson, O. R. Cooper, A. Stohl, and J. A. de Gouw

Subjects
Physics, QC1-999, Chemistry, QD1-999
Abstract

The influence of halogen oxidation on the variabilities of ozone (O3) and volatile organic compounds (VOCs) within the Arctic and sub-Arctic atmospheric boundary layer was investigated using field measurements from multiple campaigns conducted in March and April 2008 as part of the POLARCAT project. For the ship-based measurements, a high degree of correlation (r = 0.98 for 544 data points collected north of 68° N) was observed between the acetylene to benzene ratio, used as a marker for chlorine and bromine oxidation, and O3 signifying the vast influence of halogen oxidation throughout the ice-free regions of the North Atlantic. Concurrent airborne and ground-based measurements in the Alaskan Arctic substantiated this correlation and were used to demonstrate that halogen oxidation influenced O3 variability throughout the Arctic boundary layer during these springtime studies. Measurements aboard the R/V Knorr in the North Atlantic and Arctic Oceans provided a unique view of the transport of O3-poor air masses from the Arctic Basin to latitudes as far south as 52° N. FLEXPART, a Lagrangian transport model, was used to quantitatively determine the exposure of air masses encountered by the ship to first-year ice (FYI), multi-year ice (MYI), and total ICE (FYI+MYI). O3 anti-correlated with the modeled total ICE tracer (r = −0.86) indicating that up to 73% of the O3 variability measured in the Arctic marine boundary layer could be related to sea ice exposure.

Published
2010
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10. DNA-PK promotes DNA end resection at DNA double strand breaks in G0 cells

Author

Faith C Fowler, Bo-Ruei Chen, Nicholas Zolnerowich, Wei Wu, Raphael Pavani, Jacob Paiano, Chelsea Peart, Zulong Chen, André Nussenzweig, Barry P Sleckman, and Jessica K Tyler

Subjects
DNA end resection, DNA-PK, DNA double strand breaks, genome stability, mammalian cells, RPA, Medicine, Science, Biology (General), QH301-705.5
Abstract

DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs are predominately repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 murine and human cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G1 or G2 phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, which has important implications for DNA DSB repair in quiescent cells.

Published
2022
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12. LIN37-DREAM prevents DNA end resection and homologous recombination at DNA double-strand breaks in quiescent cells

Author

Bo-Ruei Chen, Yinan Wang, Anthony Tubbs, Dali Zong, Faith C Fowler, Nicholas Zolnerowich, Wei Wu, Amelia Bennett, Chun-Chin Chen, Wendy Feng, Andre Nussenzweig, Jessica K Tyler, and Barry P Sleckman

Subjects
NHEJ, HR, resection, quiescence, LIN37, DSB repair, Medicine, Science, Biology (General), QH301-705.5
Abstract

DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.

Published
2021
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16. Gene Editing/Gene Therapies: HOMOLOGY-INDEPENDENT TARGETED INSERTION (HITI) ENABLES GUIDED CAR KNOCK-IN AND EFFICIENT CLINICAL SCALE CAR-T CELL MANUFACTURING

Author

H. Balke-Want, V. Keerthi, N. Gkitsas, A. Mancini, G. Kurgan, C. Fowler, P. Xu, X. Liu, K. Asano, S. Patel, C. Fisher, A. Brown, R. Tunuguntla, E. Sotillo, C. Mackall, and S. Feldman

Subjects
Cancer Research, Transplantation, Oncology, Immunology, Immunology and Allergy, Cell Biology, Genetics (clinical)
Published
2023
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17. A review of slipped capital femoral epiphysis

Author

Emma V, Cotton, Samuel C, Fowler, and Kristopher R, Maday

Subjects
Adolescent, Humans, Pain, Hip Joint, Slipped Capital Femoral Epiphyses, Child, Arthralgia, Nurse Assisting
Abstract

Hip pain in children is common, with causes ranging from the benign to destructive. This article reviews slipped capital femoral epiphysis (SCFE), one of the most common hip pathologies in preadolescents and adolescents, which often is missed or delayed in diagnosis because of its vague, atypical presentation.

Published
2022
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22. Notes from the Field: Clinical and Epidemiologic Characteristics of Mpox Cases from the Initial Phase of the Outbreak — New York City, May 19–July 15, 2022

Author

Nang Thu Thu, Kyaw, Naama, Kipperman, Karen A, Alroy, Jennifer, Baumgartner, Addie, Crawley, Eric, Peterson, Amara, Ross, Randal C, Fowler, Victoria E, Ruiz, Mindy, Leelawong, Scott, Hughes, Mirline, Juste-Tranquille, Kevin, Lovingood, Celia Deane, Joe, Michele, Chase, Amanda, Shinall, Joel, Ackelsberg, Camille, Bergeron-Parent, Brittan, Badenhop, Sally, Slavinski, Vasudha, Reddy, and Ellen H, Lee

Subjects
Health (social science), Health Information Management, Epidemiology, Health, Toxicology and Mutagenesis, Humans, New York City, General Medicine, Disease Outbreaks
Published
2022
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23. A Blueprint for Increasing Ethnic and Racial Diversity in U.S. Residency Training Programs

Author

Paris D, Butler, Jessica C, Fowler, Elana, Meer, Ilene M, Rosen, Iris M, Reyes, and Jeffrey S, Berns

Subjects
Education, Medical, Graduate, Racial Groups, Ethnicity, Humans, Internship and Residency, Hispanic or Latino, General Medicine, United States, Education
Abstract

People who identify as African Americans, Latinos, or from indigenous backgrounds, are dramatically underrepresented in the U.S. physician workforce. It is critical for academic health centers to recognize racial and ethnic diversity at the residency level and implement changes to enhance diversity among trainees.The Office of Graduate Medical Education (GME) at the University of Pennsylvania Health System (UPHS) developed a multipronged approach to enhance diversity and inclusion (DI) among residency trainees. The approach included the development of an underrepresented in medicine (UIM) professional network; UIM-focused visiting clerkship programs; holistic review implementation by selection committees; and targeted outreach to UIM candidates, overseen by an associate designated institutional official for UIM Affairs. The authors reported demographic data on residency applicants invited for interviews and matching for all programs at UPHS from 2014-2015 (baseline) to 2020-2021. They also reported data on maximum ranking number programs reached to fill their positions and the average United States Medical License Examination (USMLE) Step 1 scores of matched candidates. Finally, they discussed the implications for leaders who wish to enhance DI at academic health centers.During the baseline year (2014-2015), UIMs represented 12.1% of interviewees and 8.7% of all matched candidates into UPHS residency programs. Over the successive 6 years after incremental implementation of the approach, UIM representation steadily increased. In 2020-2021, UIMs represented 23.2% of interviewees and 26.4% of matched candidates. Programs' maximum rank number to fill and USMLE Step 1 scores of matched candidates remained relatively unchanged.The UPHS Office of GME incorporated a purposeful approach to enhance the DI of its residents. Across 6 years of implementation, UIM representation among resident matches tripled while quantitative program and candidate metrics remained unchanged. Similar efforts should be given further consideration for implementation and evaluation nationwide.

Published
2022
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25. Supplementary Data from Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

Author

Philip H. Jones, Moritz Gerstung, Benjamin A. Hall, Kourosh Saeb-Parsy, Krishnaa Mahububani, Amit Roshan, Doreen Milne, Edward Rytina, Kate Fife, Amer Durrani, David Shorthouse, Stefan C. Dentro, Jonas Koeppel, David Fernandez-Antoran, Eleanor Earp, Swee Hoe Ong, Roshan Sood, Michael W.J. Hall, Christopher Bryant, Charlotte King, and Joanna C. Fowler

Abstract

Supplementary Figures S1-S7 and Tables S1 and S2

Published
2023
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26. Data from Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

Author

Philip H. Jones, Moritz Gerstung, Benjamin A. Hall, Kourosh Saeb-Parsy, Krishnaa Mahububani, Amit Roshan, Doreen Milne, Edward Rytina, Kate Fife, Amer Durrani, David Shorthouse, Stefan C. Dentro, Jonas Koeppel, David Fernandez-Antoran, Eleanor Earp, Swee Hoe Ong, Roshan Sood, Michael W.J. Hall, Christopher Bryant, Charlotte King, and Joanna C. Fowler

Abstract

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location.Significance:Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.See related commentary by De Dominici and DeGregori, p. 227.This article is highlighted in the In This Issue feature, p. 211

Published
2023
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27. Identification of A Putative T6SS Immunity Islet in Salmonella Typhi

Author

Luke A. F. Barretto and Casey C. Fowler

Subjects
bacterial pathogenesis, Salmonella Typhi, typhoid fever, interbacterial antagonism, type VI secretion systems, T6SS, Medicine
Abstract

Typhoid fever is a major global health problem and is the result of systemic infections caused by the human-adapted bacterial pathogen Salmonella enterica serovar Typhi (S. Typhi). The pathology underlying S. Typhi infections significantly differ from infections caused by broad host range serovars of the same species, which are a common cause of gastroenteritis. Accordingly, identifying S. Typhi genetic factors that impart functionality absent from broad host range serovars offers insights into its unique biology. Here, we used an in-silico approach to explore the function of an uncharacterized 14-gene S. Typhi genomic islet. Our results indicated that this islet was specific to the S. enterica species, where it was encoded by the Typhi and Paratyphi A serovars, but was generally absent from non-typhoidal serovars. Evidence was gathered using comparative genomics and sequence analysis tools, and indicated that this islet was comprised of Type VI secretion system (T6SS) and contact-dependent growth inhibition (CDI) genes, the majority of which appeared to encode orphan immunity proteins that protected against the activities of effectors and toxins absent from the S. Typhi genome. We herein propose that this islet represents an immune system that protects S. Typhi against competing bacteria within the human gut.

Published
2020
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28. Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

Author

Emilie Abby, Stefan C. Dentro, Michael W. J. Hall, Joanna C. Fowler, Swee Hoe Ong, Roshan Sood, Albert Herms, Gabriel Piedrafita, Irina Abnizova, Christian W. Siebel, Moritz Gerstung, Benjamin A. Hall, Philip H. Jones, Dentro, Stefan C [0000-0002-0478-9729], Hall, Michael WJ [0000-0003-2904-6902], Ong, Swee Hoe [0000-0002-3629-5387], Sood, Roshan [0000-0002-1318-7025], Herms, Albert [0000-0003-2999-8196], Piedrafita, Gabriel [0000-0001-8701-1084], Gerstung, Moritz [0000-0001-6709-963X], Hall, Benjamin A [0000-0003-0355-2946], Jones, Philip H [0000-0002-5904-795X], and Apollo - University of Cambridge Repository

Subjects
45/91, 64, Esophageal Neoplasms, 631/67/1504/1477, 45, Carcinogenesis, 45/41, article, 45/23, 64/110, Middle Aged, Epithelium, 38, 631/208/514/1948, Mice, 631/532/7, Mutation, 14/63, Genetics, Animals, Humans, Receptor, Notch1, 14/19
Abstract

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

Published
2023

29. Physiological conditions leading to maternal subclinical ketosis in Holstein dairy cows can impair the offspring's postnatal growth and gut microbiome development

Author

Halfen, Jéssica, Carpinelli, Nathaly A., D. Lasso, Sergio, Michelotti, Tainara C., C. Fowler, Emily, St-Pierre, Benoit, Trevisi, Erminio, and Osorio, Johan

Abstract

This is the Supplemental Materials document for the article published in MDPI - Microorganisms by Jessica Halfen, Nathaly Ana Carpinelli, Sergio D. Lasso, Tainara Cristina Michelotti, Emily C. Fowler, Benoit St-Pierre, Erminio Trevisi, and Johan S. Osorio. Physiological conditions leading to maternal subclinical ketosis in Holstein dairy cows can impair the offspring's postnatal growth and gut microbiome development

Published
2023
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30. Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps

Author

Åsa Torinsson Naluai, Malin Östensson, Philippa C. Fowler, Sanna Abrahamsson, Björn Andersson, Stina Lassesson, Frida Jacobsson, Martin Oscarsson, Anton Bohman, Ali M. Harandi, and Mats Bende

Subjects
Multidisciplinary, Otorhinolaryngology, Oto-rino-laryngologi
Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving “Ciliated epithelial cells” were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies.

Published
2023

32. The evolutionary diversification of the Salmonella artAB toxin locus

Author

Adaobi Ojiakor, Rachel N. Gibbs, Zhe Chen, Xiang Gao, and Casey C. Fowler

Subjects
Microbiology (medical), Microbiology
Abstract

Salmonella enterica is a diverse species of bacterial pathogens comprised of >2,500 serovars with variable host ranges and virulence properties. Accumulating evidence indicates that two AB5-type toxins, typhoid toxin and ArtAB toxin, contribute to the more severe virulence properties of the Salmonella strains that encode them. It was recently discovered that there are two distinct types of artAB-like genetic elements in Salmonella: those that encode ArtAB toxins (artAB elements) and those in which the artA gene is degraded and the ArtB homolog, dubbed PltC, serves as an alternative delivery subunit for typhoid toxin (pltC elements). Here, we take a multifaceted approach to explore the evolutionary diversification of artAB-like genetic elements in Salmonella. We identify 7 subtypes of ArtAB toxins and 4 different PltC sequence groups that are distributed throughout the Salmonella genus. Both artAB and pltC are encoded within numerous diverse prophages, indicating a central role for phages in their evolutionary diversification. Genetic and structural analyses revealed features that distinguish pltC elements from artAB and identified evolutionary adaptations that enable PltC to efficiently engage typhoid toxin A subunits. For both pltC and artAB, we find that the sequences of the B subunits are especially variable, particularly amongst amino acid residues that fine tune the chemical environment of their glycan binding pockets. This study provides a framework to delineate the remarkably complex collection of Salmonella artAB/pltC-like genetic elements and provides a window into the mechanisms of evolution for AB5-type toxins.

Published
2022
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33. Change and Diversity in Neolithic Mortuary Practices on the Isle of Man

Author

C Fowler, C Crellin, and M Gamble

Subjects
Geography, media_common.quotation_subject, Ethnology, General Medicine, Diversity (politics), media_common
Abstract

While the Early Neolithic chambered tombs of the Isle of Man are well known and the Late Neolithic has been clearly defined with reference to a distinctive suite of artefacts, little is known about the Middle Neolithic. This article reports on 17 new Neolithic radiocarbon dates from cremated human remains from the Isle of Man. These identify five burials in cists as Middle Neolithic and indicate new sequences of activity at cemeteries starting in the Middle Neolithic. Each of these sites is examined in detail. The dates also spur a reconsideration of the development of Ronaldsway pottery and the integration of Grooved Ware pottery and motifs into early 3rd millennium practice on the island. The paper ends with a consideration of the changing effects of mortuary practices throughout the Neolithic on the Isle of Man and a discussion of connections with Middle and Late Neolithic activity in Ireland and Britain.

Published
2021
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36. The Space Physics Environment Data Analysis System (SPEDAS)

Author

V. Angelopoulos, P. Cruce, A. Drozdov, E. W. Grimes, N. Hatzigeorgiu, D. A. King, D. Larson, J. W. Lewis, J. M. McTiernan, D. A. Roberts, C. L. Russell, T. Hori, Y. Kasahara, A. Kumamoto, A. Matsuoka, Y. Miyashita, Y. Miyoshi, I. Shinohara, M. Teramoto, J. B. Faden, A. J. Halford, M. McCarthy, R. M. Millan, J. G. Sample, D. M. Smith, L. A. Woodger, A. Masson, A. A. Narock, K. Asamura, T. F. Chang, C.-Y. Chiang, Y. Kazama, K. Keika, S. Matsuda, T. Segawa, K. Seki, M. Shoji, S. W. Y. Tam, N. Umemura, B.-J. Wang, S.-Y. Wang, R. Redmon, J. V. Rodriguez, H. J. Singer, J. Vandegriff, S. Abe, M. Nose, A. Shinbori, Y.-M. Tanaka, S. UeNo, L. Andersson, P. Dunn, C. Fowler, J. S. Halekas, T. Hara, Y. Harada, C. O. Lee, R. Lillis, D. L. Mitchell, M. R. Argall, K. Bromund, J. L. Burch, I. J. Cohen, M. Galloy, B. Giles, A. N. Jaynes, O. Le Contel, M. Oka, T. D. Phan, B. M. Walsh, J. Westlake, F. D. Wilder, S. D. Bale, R. Livi, M. Pulupa, P. Whittlesey, A. DeWolfe, B. Harter, E. Lucas, U. Auster, J. W. Bonnell, C. M. Cully, E. Donovan, R. E. Ergun, H. U. Frey, B. Jackel, A. Keiling, H. Korth, J. P. McFadden, Y. Nishimura, F. Plaschke, P. Robert, D. L. Turner, J. M. Weygand, R. M. Candey, R. C. Johnson, T. Kovalick, M. H. Liu, R. E. McGuire, A. Breneman, K. Kersten, and P. Schroeder

Published
2019
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41. Efficacy of an Online Curriculum for Perioperative Goals of Care and Code Status Discussions: A Randomized Controlled Trial

Author

Jonathan A. Niconchuk, Angela M. Bader, Nicholas Sadovnikoff, Richard D. Urman, Matthew D. McEvoy, Elizabeth Rickerson, Leslie C Fowler, Michael T Kreger, David L. Hepner, Thomas S Kimball, Ethan Y. Brovman, and Amy Robertson

Subjects
Male, Objective structured clinical examination, media_common.quotation_subject, education, MEDLINE, Patient Care Planning, Perioperative Care, law.invention, Education, Distance, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Anesthesiology, International Classification of Diseases, 030202 anesthesiology, law, Reading (process), Humans, Medicine, Curriculum, Decision Making, Computer-Assisted, media_common, Medical education, business.industry, Internship and Residency, Rubric, Inter-rater reliability, Anesthesiology and Pain Medicine, Female, Clinical Competence, business, Decision Making, Shared, 030217 neurology & neurosurgery, Medical literature
Abstract

Background Preoperative goals of care (GOC) and code status (CS) discussions are important in achieving an in-depth understanding of the patient's care goals in the setting of a serious illness, enabling the clinician to ensure patient autonomy and shared decision making. Past studies have shown that anesthesiologists are not formally trained in leading these discussions and may lack the necessary skill set. We created an innovative online video curriculum designed to teach these skills. This curriculum was compared to a traditional method of learning from reading the medical literature. Methods In this bi-institutional randomized controlled trial at 2 major academic medical centers, 60 anesthesiology trainees were randomized to receive the educational content in 1 of 2 formats: (1) the novel video curriculum (video group) or (2) journal articles (reading group). Thirty residents were assigned to the experimental video curriculum group, and 30 were assigned to the reading group. The content incorporated into the 2 formats focused on general preoperative evaluation of patients and communication strategies pertaining to GOC and CS discussions. Residents in both groups underwent a pre- and postintervention objective structured clinical examination (OSCE) with standardized patients. Both OSCEs were scored using the same 24-point rubric. Score changes between the 2 OSCEs were examined using linear regression, and interrater reliability was assessed using weighted Cohen's kappa. Results Residents receiving the video curriculum performed significantly better overall on the OSCE encounter, with a mean score of 4.19 compared to 3.79 in the reading group. The video curriculum group also demonstrated statistically significant increased scores on 8 of 24 rubric categories when compared to the reading group. Conclusions Our novel video curriculum led to significant increases in resident performance during simulated GOC discussions and modest increases during CS discussions. Further development and refinement of this curriculum are warranted.

Published
2021
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42. Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

Author

Charlotte King, Joanna C. Fowler, Jonas Koeppel, Kourosh Saeb-Parsy, Swee Hoe Ong, Moritz Gerstung, Benjamin A. Hall, Eleanor Earp, Amer Durrani, Krishnaa Mahububani, Kate Fife, David Shorthouse, Stefan C. Dentro, Christopher J. Bryant, Sood R, Michael W. J. Hall, Philip H. Jones, Amit Roshan, Edward Rytina, Doreen Milne, David Fernandez-Antoran, Shorthouse, David [0000-0002-3207-3584], Roshan, Amit [0000-0002-2034-2759], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Hall, Benjamin [0000-0003-0355-2946], Jones, Philip [0000-0002-5904-795X], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, 0301 basic medicine, Skin Neoplasms, Mutant, Human skin, Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Ultraviolet light, Humans, Receptor, Notch1, Gene, Aged, Leg, integumentary system, Cancer, Middle Aged, Thorax, Cadherins, medicine.disease, Molecular biology, Clone Cells, Forearm, 030104 developmental biology, medicine.anatomical_structure, Oncology, Carcinoma, Basal Cell, 030220 oncology & carcinogenesis, Mutation, Carcinoma, Squamous Cell, Female, Skin cancer, Keratinocyte, FAT1
Abstract

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. Significance: Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known. See related commentary by De Dominici and DeGregori, p. 227. This article is highlighted in the In This Issue feature, p. 211

Published
2021
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43. Effect of Smartphone App-Based Education on Clinician Prescribing Habits in a Learning Health Care System: A Randomized Cluster Crossover Trial

Author

Matthew D, McEvoy, Mary Lynn, Dear, Reagan, Buie, David A, Edwards, Tyler W, Barrett, Brian, Allen, Amy C, Robertson, Leslie C, Fowler, Cassandra, Hennessy, Bonnie M, Miller, Kim V, Garvey, Robert P, Bland, Geoffrey M, Fleming, Don, Moore, Todd W, Rice, Gordon R, Bernard, Christopher J, Lindsell, and Irving, Zamora

Subjects
Analgesics, Opioid, Habits, Cross-Over Studies, Humans, General Medicine, Prospective Studies, Practice Patterns, Physicians', Mobile Applications
Abstract

Effective methods for engaging clinicians in continuing education for learning-based practice improvement remain unknown.To determine whether a smartphone-based app using spaced education with retrieval practice is an effective method to increase evidence-based practice.A prospective, unblinded, single-center, crossover randomized clinical trial was conducted at a single academic medical center from January 6 to April 24, 2020. Vanderbilt University Medical Center clinicians prescribing intravenous fluids were invited to participate in this study.All clinicians received two 4-week education modules: 1 on prescribing intravenous fluids and 1 on prescribing opioid and nonopioid medications (counterbalancing measure), over a 12-week period. The order of delivery was randomized 1:1 such that 1 group received the fluid management module first, followed by the pain management module after a 4-week break, and the other group received the pain management module first, followed by the fluid management module after a 4-week break.The primary outcome was evidence-based clinician prescribing behavior concerning intravenous fluids in the inpatient setting and pain medication prescribing on discharge from the hospital.A total of 354 participants were enrolled and randomized, with 177 in group 1 (fluid then pain management education) and 177 in group 2 (pain management then fluid education). During the overall study period, 16 868 questions were sent to 349 learners, with 11 783 (70.0%) being opened: 10 885 (92.4%) of those opened were answered and 7175 (65.9%) of those answered were answered correctly. The differences between groups changed significantly over time, indicated by the significant interaction between educational intervention and time (P = .002). Briefly, at baseline evidence-concordant IV fluid ordered 7.2% less frequently in group 1 than group 2 (95% CI, -19.2% to 4.9%). This was reversed after training at 4% higher (95% CI, -8.2% to 16.0%) in group 1 than group 2, a more than doubling in the odds of evidence-concordant ordering (OR, 2.56, 95% CI, 0.80-8.21). Postintervention, all gains had been reversed with less frequent ordering in group 1 than group 2 (-9.5%, 95% CI, -21.6% to 2.7%). There was no measurable change in opioid prescribing behaviors at any time point.In this randomized clinical trial, use of smartphone app learning modules resulted in statistically significant short-term improvement in some prescribing behaviors. However, this effect was not sustained over the long-term. Additional research is needed to understand how to sustain improvements in care delivery as a result of continuous professional development at the institutional level.ClinicalTrials.gov Identifier: NCT03771482.

Published
2022

44. Prevalence of SARS-CoV-2 antibodies during phased access to vaccination: results from a population-based survey in New York City, September 2020-March 2021

Author

Jannae C. Parrott, Ariana Maleki Annibale, Sukhminder Osahan, Karen Alroy, Jo-Anne Caton, Claudia Chernov, Sarah Dumas, Randal C. Fowler, Gabriella Hermosi, Yusyin Hsin, Sharon Perlman, Jing Wu, Scott Hughes, L. Hannah Gould, and Anne Schuster

Subjects
Adult, Infectious Diseases, COVID-19 Vaccines, Epidemiology, SARS-CoV-2, Vaccination, Prevalence, COVID-19, Humans, New York City, Antibodies, Viral
Abstract

Repeated serosurveys are an important tool for understanding trends in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. During 1 September 2020–20 March 2021, the NYC Health Department conducted a population-based SARS-CoV-2 antibody prevalence survey of 2096 NYC adults who either provided a blood specimen or self-reported the results of a previous antibody test. The serosurvey, the second in a series of surveys conducted by the NYC Health Department, aimed to estimate SARS-CoV-2 antibody prevalence across the city and for different groups at higher risk for adverse health outcomes. Weighted citywide prevalence was 23.5% overall (95% confidence interval (CI) 20.1–27.4) and increased from 19.2% (95% CI 14.7–24.6) before coronavirus disease 2019 vaccines were available to 31.3% (95% CI 24.5–39.0) during the early phases of vaccine roll-out. We found no differences in antibody prevalence by age, race/ethnicity, borough, education, marital status, sex, health insurance coverage, self-reported general health or neighbourhood poverty. These results show an overall increase in population-level seropositivity in NYC following the introduction of SARS-CoV-2 vaccines and highlight the importance of repeated serosurveys in understanding the pandemic's progression.

Published
2022

46. Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium

Author

Swee Hoe Ong, Joanna C. Fowler, Charlotte King, Michael W. J. Hall, Moritz Gerstung, Bartomeu Colom, Philip H. Jones, Gabriel Piedrafita, Sood R, Agnieszka Wabik, Stefan C. Dentro, Maria P. Alcolea, Inigo Martincorena, Benjamin A. Hall, and Albert Herms

Subjects
0303 health sciences, Mutation, Transgene, Mutant, Clone (cell biology), Biology, medicine.disease_cause, Deep sequencing, Epithelium, 3. Good health, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Genetics, medicine, Progenitor cell, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

Published
2020
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48. Molecular Insights into the Assembly and Functional Diversification of Typhoid Toxin

Author

Xiaoyu Liu, Zhe Chen, Xuyao Jiao, Xukai Jiang, Jicheng Qiu, Fuping You, Hongan Long, Hongzhi Cao, Casey C. Fowler, and Xiang Gao

Subjects
bacterial pathogenesis, glycobiology, AB5 toxins, Virology, bacterial infections and mycoses, Salmonella Typhi, complex mixtures, Microbiology, Research Article, typhoid fever, bacterial toxins
Abstract

Typhoid toxin is an A2B5 protein toxin and an important virulence factor for the human-adapted bacterial pathogen Salmonella enterica serovar Typhi, the causative agent of typhoid fever. Typhoid toxin contains two enzymatic subunits, PltA and CdtB, which dock onto a pentameric delivery platform composed of the protein PltB. It was recently reported that the same enzymatic subunits can assemble with a different delivery platform composed of the protein PltC, forming a distinct version of typhoid toxin. However, the differences in structure and receptor specificity between the PltC and PltB typhoid toxins remain unknown. Here, we determined atomic-level structures of the pentameric PltC subunit, the fully assembled PltC typhoid toxin, and the PltC pentamers in complex with glycan receptors. Biochemical and structural analyses indicate that PltB and PltC are unable to form heteromeric delivery complexes due to electrostatic repulsion at the subunit interface and thus form separate toxins only. We further observed that, despite low sequence similarity between PltB and PltC, they interact with PltA in a similar manner but that PltC exhibits stronger electrostatic interactions with PltA, enabling it to outcompete PltB in toxin assembly. The ligand-bound atomic structures of PltC show an additional glycan binding site not found in PltB and glycan array analysis indicates that PltB and PltC exhibit significant differences in glycan binding specificity. Collectively, this study offers atomic-level insights into how S. Typhi produces two distinct versions of typhoid toxin, thereby generating functional diversity in this key virulence factor.

Published
2022
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49. Somatic Mutation: What Shapes the Mutational Landscape of Normal Epithelia?

Author

Joanna C. Fowler and Philip H. Jones

Subjects
Oncology, Carcinogenesis, Neoplasms, Mutation, Humans, Epithelium, Article, Clone Cells
Abstract

Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the stem cell niche and persist to acquire further genome alterations. After a transient expansion, mutant stem cells must revert to homeostatic behavior so normal tissue architecture is maintained. Some positively selected mutants may promote cancer development, whereas others inhibit carcinogenesis. Factors that shape the mutational landscape include wild-type and mutant stem cell dynamics, competition for the niche, and environmental exposures. Understanding these processes may give new insight into the basis of cancer risk and opportunities for cancer prevention. Significance: Recent advances in sequencing have found somatic mutations in all epithelial tissues studied to date. Here we review how the mutational landscape of normal epithelia is shaped by clonal competition within the stem cell niche combined with environmental exposures. Some of the selected mutant genes are oncogenic, whereas others may be inhibitory of transformation. Discoveries in this area leave many open questions, such as the definition of cancer driver genes, the mechanisms by which tissues constrain a high proportion of oncogenic mutant cells, and whether clonal fitness can be modulated to decrease cancer risk.

Published
2022

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