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2. SARS-CoV-2 evolution during treatment of chronic infection

Author

Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Estee Torok, M., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Abnizova, I., Aigrain, L., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Betteridge, E., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Bonfield, J., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Goodwin, S., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Liddle, J., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Makunin, A., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mccarthy, S., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Puethe, C., Quail, M., Rajan, D., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Scott, C., Seekings, P., Shirley, L., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Jansen Van, P., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., Farr, B. W., Quail, M. A., Thurston, S. A. J., Bronner, I. F., Redshaw, N. M., Lensing, S. V., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Sharrocks, K., Blane, E., Modis, Y., Leigh, K. E., Briggs, J. A. G., van Gils, M. J., Smith, K. G. C., Bradley, J. R., Doffinger, R., Ceron-Gutierrez, L., Barcenas-Morales, G., Pollock, D. D., Goldstein, R. A., Smielewska, A., Skittrall, J. P., Gouliouris, T., Goodfellow, I. G., Gkrania-Klotsas, E., Illingworth, C. J. R., Mccoy, L. E., Gupta, R. K., Medical Microbiology and Infection Prevention, AII - Infectious diseases, Collier, Dami A [0000-0001-5446-4423], Jahun, Aminu [0000-0002-4585-1701], Temperton, Nigel [0000-0002-7978-3815], Modis, Yorgo [0000-0002-6084-0429], Briggs, John AG [0000-0003-3990-6910], Goldstein, Richard A [0000-0001-5148-4672], Skittrall, Jordan P [0000-0002-8228-3758], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], McCoy, Laura E [0000-0001-9503-7946], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, viruses, Passive, Antibodies, Viral, CITIID-NIHR BioResource COVID-19 Collaboration, 2.1 Biological and endogenous factors, Viral, Aetiology, Neutralizing, Lung, Phylogeny, neutralising antibodies, Infectivity, education.field_of_study, Genome, Multidisciplinary, Alanine, biology, High-Throughput Nucleotide Sequencing, Viral Load, Spike Glycoprotein, Virus Shedding, Adenosine Monophosphate, Aged, Antibodies, Neutralizing, COVID-19, Chronic Disease, Genome, Viral, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Mutagenesis, Mutant Proteins, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Evolution, Molecular, Infectious Diseases, Pneumonia & Influenza, Antibody, Infection, Viral load, Biotechnology, Evolution, General Science & Technology, antibody escape, Convalescent plasma, 030106 microbiology, Population, evasion, Antibodies, Virus, Article, Vaccine Related, resistance, 03 medical and health sciences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Biodefense, Genetics, Viral shedding, education, COVID-19 Serotherapy, QR355, Prevention, Wild type, Molecular, Pneumonia, Virology, COVID-19 Drug Treatment, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, biology.protein, Immunization, immune suppression, mutation
Abstract

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Published
2021

3. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

Author

Collier, D. A., De Marco, A., Ferreira, I. A. T. M., Meng, B., Datir, R. P., Walls, A. C., Kemp, S. A., Bassi, J., Pinto, D., Silacci-Fregni, C., Bianchi, S., Tortorici, M. A., Bowen, J., Culap, K., Jaconi, S., Cameroni, E., Snell, G., Pizzuto, M. S., Pellanda, A. F., Garzoni, C., Riva, A., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Mccoy, L. E., Smith, K. G. C., Bradley, J. R., Temperton, N., Ceron-Gutierrez, L., Barcenas-Morales, G., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Torok, M. E., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., Hosmillo, M., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. T., Orton, R. J., Hughes, J., Vattipally, S., Ragonnet-Cronin, M., Nascimento, F. F., Jorgensen, D., Boyd, O., Geidelberg, L., Zarebski, A. E., Raghwani, J., Kraemer, M. U. G., Southgate, J., Lindsey, B. B., Freeman, T. M., Keatley, J. -P., Singer, J. B., de Oliveira Martins, L., Yeats, C. A., Abudahab, K., Taylor, B. E. W., Menegazzo, M., Danesh, J., Hogsden, W., Eldirdiri, S., Kenyon, A., Mason, J., Robinson, T. I., Holmes, A., Hartley, J. A., Curran, T., Mather, A. E., Shankar, G., Jones, R., Howe, R., Morgan, S., Wastenge, E., Chapman, M. R., Mookerjee, S., Stanley, R., Smith, W., Peto, T., Eyre, D., Crook, D., Vernet, G., Kitchen, C., Gulliver, H., Merrick, I., Guest, M., Munn, R., Bradley, D. T., Wyatt, T., Beaver, C., Foulser, L., Churcher, C. M., Brooks, E., Smith, K. S., Galai, K., Mcmanus, G. M., Bolt, F., Coll, F., Meadows, L., Attwood, S. W., Davies, A., De Lacy, E., Downing, F., Edwards, S., Scarlett, G. P., Jeremiah, S., Smith, N., Leek, D., Sridhar, S., Forrest, S., Cormie, C., Gill, H. K., Dias, J., Higginson, E. E., Maes, M., Young, J., Wantoch, M., Jamrozy, D., Lo, S., Patel, M., Hill, V., Bewshea, C. M., Ellard, S., Auckland, C., Harrison, I., Bishop, C., Chalker, V., Richter, A., Beggs, A., Best, A., Percival, B., Mirza, J., Megram, O., Mayhew, M., Crawford, L., Ashcroft, F., Moles-Garcia, E., Cumley, N., Hopes, R., Asamaphan, P., Niebel, M. O., Gunson, R. N., Bradley, A., Maclean, A., Mollett, G., Blacow, R., Bird, P., Helmer, T., Fallon, K., Tang, J., Hale, A. D., Macfarlane-Smith, L. R., Harper, K. L., Carden, H., Machin, N. W., Jackson, K. A., Ahmad, S. S. Y., George, R. P., Turtle, L., O'Toole, E., Watts, J., Breen, C., Cowell, A., Alcolea-Medina, A., Charalampous, T., Patel, A., Levett, L. J., Heaney, J., Rowan, A., Taylor, G. P., Shah, D., Atkinson, L., Lee, J. C. D., Westhorpe, A. P., Jannoo, R., Lowe, H. L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Betteridge, E., Farr, B. W., Goodwin, S., Quail, M. A., Scott, C., Shirley, L., Thurston, S. A. J., Rajan, D., Bronner, I. F., Aigrain, L., Redshaw, N. M., Lensing, S. V., Mccarthy, S., Makunin, A., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. J., Lackenby, A., Mbisa, T., Platt, S., Miah, S., Bibby, D., Manso, C., Hubb, J., Dabrera, G., Ramsay, M., Bradshaw, D., Schaefer, U., Groves, N., Gallagher, E., Lee, D., Williams, D., Ellaby, N., Hartman, H., Manesis, N., Patel, V., Ledesma, J., Twohig, K. A., Allara, E., Pearson, C., Cheng, J. K. J., Bridgewater, H. E., Frost, L. R., Taylor-Joyce, G., Brown, P. E., Tong, L., Broos, A., Mair, D., Nichols, J., Carmichael, S. N., Smollett, K. L., Nomikou, K., Aranday-Cortes, E., Johnson, N., Nickbakhsh, S., Vamos, E. E., Hughes, M., Rainbow, L., Eccles, R., Nelson, C., Whitehead, M., Gregory, R., Gemmell, M., Wierzbicki, C., Webster, H. J., Fisher, C. L., Signell, A. W., Betancor, G., Wilson, H. D., Nebbia, G., Flaviani, F., Cerda, A. C., Merrill, T. V., Wilson, R. E., Cotic, M., Bayzid, N., Thompson, T., Acheson, E., Rushton, S., O'Brien, S., Baker, D. J., Rudder, S., Aydin, A., Sang, F., Debebe, J., Francois, S., Vasylyeva, T. I., Zamudio, M. E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Bonfield, J., Puethe, C., Whitwham, A., Liddle, J., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Abnizova, I., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Quail, M., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Seekings, P., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Van, P. J., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Widaa, S., Williams, M., Wilson, M., Wright, S., Harvey, W., Virgin, H. W., Lanzavecchia, A., Piccoli, L., Doffinger, R., Wills, M., Veesler, D., Corti, D., and Gupta, R. K.

Subjects
0301 basic medicine, Male, Models, Molecular, Passive, Antibodies, Viral, Neutralization, 0302 clinical medicine, Models, Monoclonal, 80 and over, Viral, Neutralizing antibody, Neutralizing, Aged, 80 and over, Vaccines, Vaccines, Synthetic, Multidisciplinary, biology, Antibodies, Monoclonal, C500, Middle Aged, C700, Spike Glycoprotein, Vaccination, Spike Glycoprotein, Coronavirus, Female, Angiotensin-Converting Enzyme 2, Antibody, Aged, Antibodies, Neutralizing, COVID-19, COVID-19 Vaccines, HEK293 Cells, Humans, Immune Evasion, Immunization, Passive, Mutation, Neutralization Tests, SARS-CoV-2, medicine.drug_class, B100, Monoclonal antibody, Antibodies, Virus, 03 medical and health sciences, Immune system, medicine, COVID-19 Serotherapy, QR355, Synthetic, Molecular, Virology, Coronavirus, 030104 developmental biology, Immunization, biology.protein, 030217 neurology & neurosurgery
Abstract

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Published
2021

5. Asymmetric response of interfacial water to applied electric fields

Author

Haotian Shi, Alexander V. Benderskii, Stephen B. Cronin, Chayan Dutta, Bofan Zhao, Angelo Montenegro, Bingya Hou, Muhammet Mammetkuliev, and Dhritiman Bhattacharyya

Subjects
Multidisciplinary, Materials science, Field (physics), Solvation, 02 engineering and technology, Dielectric, Electron, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, Molecular physics, 0104 chemical sciences, Standard electrode potential, Electric field, Electrode, 0210 nano-technology, Polarization (electrochemistry)
Abstract

Our understanding of the dielectric response of interfacial water, which underlies the solvation properties and reaction rates at aqueous interfaces, relies on the linear response approximation: an external electric field induces a linearly proportional polarization. This implies antisymmetry with respect to the sign of the field. Atomistic simulations have suggested, however, that the polarization of interfacial water may deviate considerably from the linear response. Here we present an experimental study addressing this issue. We measured vibrational sum-frequency generation spectra of heavy water (D2O) near a monolayer graphene electrode, to study its response to an external electric field under controlled electrochemical conditions. The spectra of the OD stretch show a pronounced asymmetry for positive versus negative electrode charge. At negative charge below 5 × 1012 electrons per square centimetre, a peak of the non-hydrogen-bonded OD groups pointing towards the graphene surface is observed at a frequency of 2,700 per centimetre. At neutral or positive electrode potentials, this ‘free-OD’ peak disappears abruptly, and the spectra display broad peaks of hydrogen-bonded OD species (at 2,300–2,650 per centimetre). Miller’s rule1 connects the vibrational sum-frequency generation response to the dielectric constant. The observed deviation from the linear response for electric fields of about ±3 × 108 volts per metre calls into question the validity of treating interfacial water as a simple dielectric medium. Experimental measurements of vibrational sum-frequency generation spectra indicate that the dielectric response of water near an electrode may be strongly asymmetric, with different responses to positive and negative electrode charge.

Published
2019

6. Controlling an organic synthesis robot with machine learning to search for new reactivity

Author

Jarosław M. Granda, Vincenza Dragone, Leroy Cronin, De-Liang Long, and Liva Donina

Subjects
Magnetic Resonance Spectroscopy, Time Factors, Spectrophotometry, Infrared, Decision Making, 02 engineering and technology, Chemistry Techniques, Synthetic, 010402 general chemistry, Machine learning, computer.software_genre, 01 natural sciences, Chemical synthesis, Chemical reaction, Article, Machine Learning, chemistry.chemical_compound, Reactivity (chemistry), Multidisciplinary, business.industry, Robotics, 021001 nanoscience & nanotechnology, Automation, 0104 chemical sciences, chemistry, Reagent, Robot, Organic synthesis, Indicators and Reagents, Artificial intelligence, 0210 nano-technology, business, computer
Abstract

The discovery of chemical reactions is an inherently unpredictable and time-consuming process1. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy2. Reaction prediction based on high-level quantum chemical methods is complex3, even for simple molecules. Although machine learning is powerful for data analysis4,5, its applications in chemistry are still being developed6. Inspired by strategies based on chemists’ intuition7, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert8. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions.

Published
2017

7. Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation

Author

Ciarán N. Cronin, Jeffrey H. Chen, Eric Johnson, Gretchen A. Repasky, Michele McTigue, Peter A. Wells, Mika Kontro, Tea Pemovska, Kimmo Porkka, Olli Kallioniemi, Brion W. Murray, and Krister Wennerberg

Subjects
Models, Molecular, Indazoles, Axitinib, Fusion Proteins, bcr-abl, Molecular Conformation, Angiogenesis Inhibitors, Drug resistance, Pharmacology, Biology, Crystallography, X-Ray, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Humans, Phosphorylation, Proto-Oncogene Proteins c-abl, Protein Kinase Inhibitors, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Multidisciplinary, ABL, Kinase, Ponatinib, Drug Repositioning, Imidazoles, Imatinib, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Kidney Neoplasms, 3. Good health, Leukemia, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Drug Screening Assays, Antitumor, Crystallization, Tyrosine kinase, Protein Binding, medicine.drug
Abstract

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

Published
2015

8. Design and fabrication of memory devices based on nanoscale polyoxometalate clusters

Author

Josep M. Poblet, Christoph Busche, Rasmus H. Pedersen, De-Liang Long, Nikolaj Gadegaard, Laia Vilà-Nadal, Vihar P. Georgiev, Asen Asenov, Douglas J. Paul, Haralampos N. Miras, Jun Yan, Leroy Cronin, and Muhammad M. Mirza

Subjects
Multidisciplinary, Dopant, business.industry, Chemistry, Molecular electronics, Nanotechnology, Semiconductor device, Flash memory, Flash (photography), Computer data storage, Hardware_INTEGRATEDCIRCUITS, Cluster (physics), Electronics, business
Abstract

Flash memories are essential for modern electronics; here a selenium-templated polyoxometalate is used to engineer new metal–oxide–semiconductor devices. Flash memory is becoming standard for smart phones, cameras, memory sticks and other devices. Its achievable data storage densities are ultimately limited by the minimum size of the individual data cells that can be fabricated, so molecule-based flash memory is an attractive proposition for stretching these limits. Christoph Busche and colleagues report the design, synthesis and electronic characterization of a family of metal-oxide cluster molecules that are compatible with current technology. The new materials are highly configurable at the atomic-level and show promise for implementation in practical devices. Flash memory devices—that is, non-volatile computer storage media that can be electrically erased and reprogrammed—are vital for portable electronics, but the scaling down of metal–oxide–semiconductor (MOS) flash memory to sizes of below ten nanometres per data cell presents challenges. Molecules have been proposed to replace MOS flash memory1, but they suffer from low electrical conductivity, high resistance, low device yield, and finite thermal stability, limiting their integration into current MOS technologies. Although great advances have been made in the pursuit of molecule-based flash memory2, there are a number of significant barriers to the realization of devices using conventional MOS technologies3,4,5,6,7. Here we show that core–shell polyoxometalate (POM) molecules8 can act as candidate storage nodes for MOS flash memory. Realistic, industry-standard device simulations validate our approach at the nanometre scale, where the device performance is determined mainly by the number of molecules in the storage media and not by their position. To exploit the nature of the core–shell POM clusters, we show, at both the molecular and device level, that embedding [(Se(iv)O3)2]4− as an oxidizable dopant in the cluster core allows the oxidation of the molecule to a [Se(v)2O6]2− moiety containing a {Se(v)–Se(v)} bond (where curly brackets indicate a moiety, not a molecule) and reveals a new 5+ oxidation state for selenium. This new oxidation state can be observed at the device level, resulting in a new type of memory, which we call ‘write-once-erase’. Taken together, these results show that POMs have the potential to be used as a realistic nanoscale flash memory. Also, the configuration of the doped POM core may lead to new types of electrical behaviour9,10,11. This work suggests a route to the practical integration of configurable molecules in MOS technologies as the lithographic scales approach the molecular limit12.

Published
2014

9. Publisher Correction: The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

Author

Clifford J. Woolf, Martin Aichinger, Stephen Zicha, Bruna Lenfers Turnes, Markus Seifert, Luigi Tortola, Guenther Lametschwandtner, Magdalena Paolino, Mark Joseph Tebbe, Michael Costigan, Melanie Kogler, Gerald Wirnsberger, Simon C. Robson, Keith M. Channon, Yann Pierson, Débora da Luz Scheffer, Maria Novatchkova, Ari Waisman, Guenter Weiss, Andrey V. Kozlov, Maria Serena Longhi, Alexandra Latini, Taras Kreslavsky, Shane J. F. Cronin, Alexander Jais, David Hoffmann, Lee Barrett, Sonja Reissig, Sébastien Talbot, Kai Johnsson, Manu Rangachari, Adelheid Weidinger, Alban Latremoliere, Domagoj Cikes, Shuan Rao, Josef M. Penninger, Meinrad Busslinger, Corey R. Seehus, Eileen McNeill, Nick Andrews, and Melita Ticevic

Subjects
Multidisciplinary, business.industry, Metabolite, T cell, medicine.medical_treatment, Cancer, Immunosuppression, medicine.disease_cause, medicine.disease, Autoimmunity, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Cancer research, Medicine, business
Published
2019

10. Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1

Author

Nora Cronin, David Barford, Andrew J. Thompson, Ioannis Manolaridis, Kiran Kulkarni, Ziguo Zhang, Sarah Hanrahan, Ganka Bineva, Roger B. Dodd, Satoshi Ogasawara, So Iwata, and Nicola O’Reilly

Subjects
Models, Molecular, Methanococcus, Intramembrane protease, Archaeal Proteins, Amino Acid Motifs, Molecular Sequence Data, Glutamic Acid, Plasma protein binding, Crystallography, X-Ray, Endoplasmic Reticulum, environment and public health, DNA-binding protein, Article, Substrate Specificity, Conserved sequence, Proto-Oncogene Proteins p21(ras), Mice, 03 medical and health sciences, Protein structure, Prenylation, Endopeptidases, Animals, Humans, Amino Acid Sequence, Cysteine, Peptide sequence, Conserved Sequence, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Escherichia coli Proteins, 030302 biochemistry & molecular biology, Membrane Proteins, Metalloendopeptidases, biology.organism_classification, Protein Structure, Tertiary, DNA-Binding Proteins, Biochemistry, Biocatalysis, biology.protein, Peptide Hydrolases, Signal Transduction
Abstract

CAAX proteins have essential roles in multiple signalling pathways, controlling processes such as proliferation, differentiation and carcinogenesis. The ∼120 mammalian CAAX proteins function at cellular membranes and include the Ras superfamily of small GTPases, nuclear lamins, the γ-subunit of heterotrimeric GTPases, and several protein kinases and phosphatases. The proper localization of CAAX proteins to cell membranes is orchestrated by a series of post-translational modifications of the carboxy-terminal CAAX motifs (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). These reactions involve prenylation of the cysteine residue, cleavage at the AAX tripeptide and methylation of the carboxyl-prenylated cysteine residue. The major CAAX protease activity is mediated by Rce1 (Ras and a-factor converting enzyme 1), an intramembrane protease (IMP) of the endoplasmic reticulum. Information on the architecture and proteolytic mechanism of Rce1 has been lacking. Here we report the crystal structure of a Methanococcus maripaludis homologue of Rce1, whose endopeptidase specificity for farnesylated peptides mimics that of eukaryotic Rce1. Its structure, comprising eight transmembrane α-helices, and catalytic site are distinct from those of other IMPs. The catalytic residues are located ∼10 Å into the membrane and are exposed to the cytoplasm and membrane through a conical cavity that accommodates the prenylated CAAX substrate. We propose that the farnesyl lipid binds to a site at the opening of two transmembrane α-helices, which results in the scissile bond being positioned adjacent to a glutamate-activated nucleophilic water molecule. This study suggests that Rce1 is the founding member of a novel IMP family, the glutamate IMPs.

Published
2013

11. CLP1 links tRNA metabolism to progressive motor-neuron loss

Author

Reinhard Kofler, Akihiko Yoshimura, Adi Minis, Josef M. Penninger, Shane J. F. Cronin, Johannes Rainer, Justin K. Ichida, Stefan Weitzer, Markus Glatzel, Kevin Eggan, Javier Martinez, Barbara Mair, Toshikatsu Hanada, Brian J. Wainger, Michael Orthofer, Avraham Yaron, Clifford J. Woolf, Reiko Hanada, Vukoslav Komnenovic, Christian Bernreuther, Fuminori Sato, Ido Tamir, Hiromitsu Mimata, and Ruth Herbst

Subjects
Male, Small RNA, Diaphragm, TRNA processing, Mice, Transgenic, Biology, Article, Muscular Atrophy, Spinal, Mice, 03 medical and health sciences, Exon, 0302 clinical medicine, medicine, Animals, RNA Processing, Post-Transcriptional, Amyotrophic lateral sclerosis, 030304 developmental biology, Mice, Knockout, Motor Neurons, Denervation, 0303 health sciences, Muscle Denervation, Multidisciplinary, Cell Death, Respiration, Amyotrophic Lateral Sclerosis, RNA-Binding Proteins, RNA, Exons, Neuromuscular Diseases, Fibroblasts, Motor neuron, Embryo, Mammalian, medicine.disease, Molecular biology, Axons, Cell biology, Mice, Inbred C57BL, Oxidative Stress, RNA, Transfer, Tyr, Spinal Nerves, medicine.anatomical_structure, Animals, Newborn, Embryo Loss, Tyrosine, Female, Tumor Suppressor Protein p53, 030217 neurology & neurosurgery, Transcription Factors
Abstract

CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1(K/K)) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1(K/K) mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53.

Published
2013

12. Publisher Correction: Controlling an organic synthesis robot with machine learning to search for new reactivity

Author

Jarosław M. Granda, Leroy Cronin, Liva Donina, De-Liang Long, and Vincenza Dragone

Subjects
chemistry.chemical_compound, Multidisciplinary, chemistry, Computer science, business.industry, Robot, Organic synthesis, Artificial intelligence, Reactivity (psychology), business
Abstract

Change history: Owing to the misidentification of compound 22 in the original Letter, changes have been made to Fig. 5, Extended Data Fig. 2 and the main text; see accompanying Amendment.

Published
2018

13. Bibliometrics: Global gender disparities in science

Author

Blaise Cronin, Cassidy R. Sugimoto, Vincent Larivière, Yves Gingras, and Chaoqun Ni

Subjects
Male, Internationality, Multidisciplinary, Bibliometric analysis, International Cooperation, Sexism, Age Factors, Efficiency, Bibliometrics, Authorship, Research Personnel, Sex Factors, Humans, Women's Rights, Female, Sociology, Cooperative Behavior, Social science
Abstract

Cassidy R. Sugimoto and colleagues present a bibliometric analysis confirming that gender imbalances persist in research output worldwide.

Published
2013

14. Future fitness and helping in social queues

Author

Catherine Bridge, Jeremy Field, and Adam L. Cronin

Subjects
Male, Population Density, Multidisciplinary, biology, ved/biology, Reproduction, Reproduction (economics), Wasps, ved/biology.organism_classification_rank.species, Helping behavior, Stenogastrinae, Variation (game tree), biology.organism_classification, Eusociality, Social Dominance, Liostenogaster flavolineata, Workforce, Breeding pair, Animals, Female, Social Behavior, Social psychology
Abstract

Helpers in primitively eusocial and cooperatively breeding animal societies forfeit their own reproduction to rear the offspring of a queen or breeding pair, but may eventually attain breeding status themselves. Kin selection1 provides a widely accepted theoretical framework for understanding these societies, but differences in genetic relatedness do not explain a universal societal feature: the huge variation between individuals in helping effort2,3,4,5,6,7,8,9,10. An alternative explanation for this variation lies in a fundamental trade-off faced by helpers: by working harder, they increase the indirect component of their fitness, but simultaneously decrease their own future survival and fecundity2,4,8. Here, we show that individuals work less hard when they stand to lose more future fitness through working. We experimentally manipulated two components of future fitness in social queues of hover wasps (Stenogastrinae): a helper's chance of inheriting an egg-laying position, and the workforce available to rear her offspring should she inherit. After each manipulation, helpers increased or decreased their effort as appropriate to the change in expected future fitness that they experienced. Although helping provides significant indirect fitness benefits for hover wasps11, our study shows that variation in the costs associated with helping is the major determinant of helping effort.

Published
2006

15. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

Author

Carsten Schultz-Fademrecht, Dominik Wolf, Amanda M. Jamieson, Blanka Pranjic, Reinhard Hinterleitner, Stephanie Wallner, Wallace Y. Langdon, Axel Choidas, Shane J. F. Cronin, Anke Unger, Roberto Nitsch, Robert Torka, Bert Klebl, Juan Pablo Fededa, Sascha Menninger, Gottfried Baier, Magdalena Paolino, Thomas Gruber, Jan Eickhoff, Josef M. Penninger, Axel Ullrich, Fumiyo Ikeda, Iris Uribesalgo, and Stefanie Loeser

Subjects
Male, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.medical_treatment, Ubiquitin-Protein Ligases, Inmunología, Melanoma, Experimental, C-Mer Tyrosine Kinase, Receptor tyrosine kinase, Article, Mice, Immune system, Proto-Oncogene Proteins, medicine, Animals, Proto-Oncogene Proteins c-cbl, Neoplasm Metastasis, innate immunity, Adaptor Proteins, Signal Transducing, Mice, Inbred BALB C, Multidisciplinary, Innate immune system, natural killer cells, biology, c-Mer Tyrosine Kinase, Immunosurveillance, Ubiquitination, Cancer, Anticoagulants, Mammary Neoplasms, Experimental, Receptor Protein-Tyrosine Kinases, Immunotherapy, MERTK, medicine.disease, Axl Receptor Tyrosine Kinase, Ubiquitin ligase, Killer Cells, Natural, Mice, Inbred C57BL, Medicina Básica, Immunology, biology.protein, Cancer research, Female, Warfarin, Tumor metastasis, hormones, hormone substitutes, and hormone antagonists
Abstract

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies2. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology3. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a a 'pill' that awakens the innate immune system to kill cancer metastases. © 2014 Macmillan Publishers Limited. Fil: Paolino, Magdalena. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Choidas, Axel. Lead Discovery Center GmbH; Alemania Fil: Wallner, Stephanie. Medizinische Universitat Innsbruck; Austria Fil: Pranjic, Blanka. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Uribesalgo, Iris. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Loeser, Stefanie. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Jamieson, Amanda M.. University Brown; Estados Unidos Fil: Langdon, Wallace Y.. University of Western Australia; Australia Fil: Ikeda, Fumiyo. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Fededa, Juan Pablo. Institute Of Molecular Biotechnology, Vienna; Austria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Cronin, Shane J.. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Nitsch, Roberto. Institute Of Molecular Biotechnology, Vienna; Austria Fil: Schultz-Fademrecht, Carsten. Lead Discovery Center GmbH; Alemania Fil: Eickhoff, Jan. Lead Discovery Center GmbH; Alemania Fil: Menninger, Sascha. Lead Discovery Center GmbH; Alemania Fil: Unger, Anke. Lead Discovery Center GmbH; Alemania Fil: Torka, Robert. Institute for Biochemistry Max-Planck; Alemania Fil: Gruber, Thomas. Medizinische Universitat Innsbruck; Austria Fil: Hinterleitner, Reinhard. Medizinische Universitat Innsbruck; Austria Fil: Baier, Gottfried. Medizinische Universitat Innsbruck; Austria Fil: Wolf, Dominik. University Hospital Bonn; Alemania. Medical University Innsbruck; Austria Fil: Ullrich, Axel. Institute for Biochemistry Max-Planck; Alemania Fil: Klebl, Bert M.. Lead Discovery Center GmbH; Alemania Fil: Penninger, Josef M.. Institute Of Molecular Biotechnology, Vienna; Austria

Published
2012

16. Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana

Author

C. Yordan, Bénédicte Purnelle, Kelsi Scott, S. Bray-Allen, T. Stoneking, Joseph A. Murray, B. McCullagh, A. Düsterhöft, K. Granderath, P. Vos, W. R. McCombie, Rita Aert, M. Feldpausch, Matt Cordes, M. Shekher, Joelle Kalicki, Kymberlie H. Pepin, R. Klein Lankhorst, Barbara Harris, A. Montfort, M. Cotton, J. Zhong, A. Pettett, Dmitrij Frishman, A. Brandt, S. Andrews, E. Holzer, T. Gibbons, Michael W. Bevan, S. Dose, M. Zidanic, M. Lodhi, Elena Casacuberta, D. Borkova, Thomas Pohl, K. McLay, M. Kreis, S. A. Langham, J. Cloud, Anagnostis Argiriou, L. Gnoj, B. Grymonprez, Ellson Y. Chen, K. Habermann, Michael A. Quail, David W. Johnson, M. de Haan, S. Granat, S. Johnson, S Müller-Auer, I'k. Swaby, Lucinda Fulton, C. Bielke, Joerg Hoheisel, H. Wedler, C. Berger, M. van Staveren, C. Gabel, M. Rose, P. Kötter, U. Ramsperger, G. Bothe, K.-D. Entian, N. Miller, H. Hilbert, Wilhelm Ansorge, Guido Volckaert, G. Clabauld, P. Ridley, A. Cronin, John Spieth, A. Hasegawa, K. Schutz, Joanne O. Nelson, David Bentley, S. Stocker, R. Shah, A. Johnson, J. Doggett, E. Ryan, R. Wambutt, A. Herzl, D. Dauner, R. Hiller, M. Weichselgartner, M. de la Bastide, H. Sun, Richard K. Wilson, Patrick Minx, R. Mayes, M. Van Montagu, L. Parnell, R. Preston, Johar Ali, Corinne E. Joshu, S. Aubourg, Marco A. Marra, Cindy Strong, M. Schäfer, A. Berghoff, M. D. Bargues, Rosario Liguori, Klaus F. X. Mayer, Lori Spiegel, J. Gielen, L. Bilham, P. Zaccaria, H. Van den Daele, V De Simone, A.C. Maarse, Ian Bancroft, Dan Layman, J. Hauf, A. Torres, R. De Clercq, R. Mache, Petra Brandt, R. Felber, Michael A. Rieger, K. Kemp, M. Lyne, D. Tacon, S. Till, Nicola Lennard, Leslie A. Grivell, J. Van der Schueren, S. Schnabl, D. Vitale, Hans-Werner Mewes, S. Hall, Nancy Terryn, A Perez-Perez, F. Vandenbussche, Kai Lemcke, S. Hempel, J. Hoffman, P. Ma, E. Piravandi, P. Latreille, Hui Du, Wolfgang Zimmermann, P. Francs, M. Grimm, Sindy Neumann, A. Abbott, Pere Puigdomènech, M. Kay, M. Braeken, A. Mündlein, G. Harmon, Leo Heijnen, W. Schmidt, Marc Boutry, Nadim Shohdy, J. Abu-Threideh, Patrik Scholler, F. Quigley, Marie-Adèle Rajandream, T. Greco, LaDeana W. Hillier, E. Defoor, Steffen Heber, Abdul Hameed, M. Braun, S. Rechmann, Johan Robben, L. Clark, Martin D. Watson, B. Obermaier, A. Matero, Tina Graves, F. Chefdor, B. Antonoiu, A. O'Shaughnessy, Wim G. Dirkse, I. Weltjens, D. Portatelle, Jason B. Kramer, T. H. Löhnert, M. Rodriguez, D. Vil, Robert A. Martienssen, D. Haase, O. Massenet, R. Villarroel, I. Bastiaens, P. Mooijman, N. Weber, Micheline Vandenbol, M. Scharfe, C. Schüller, George Murphy, H. Blöcker, Jane Rogers, Bob Fulton, B. Lamar, Laura Courtney, Willem J. Stiekema, Mike Dante, S. Berneiser, Vladimir Benes, E. Huang, T. Jesse, Neilay Dedhia, E. Bent, Berthold Fartmann, T. Schmidtheini, M. Fuchs, C. Geisel, Mario Müller, K. Jones, A. De Keyser, Manuel Pérez-Alonso, Elaine R. Mardis, Marleen Voet, S. Schwarz, A. Lecharny, Michel Delseny, S. Lamberth, K. Drone, P. Sheet, T. Weitzenegger, M. Sehkon, B. Reichert, Y. J. Chuang, C. Buysshaert, Javier Terol, Sander Peters, R. Cooke, Jennifer Edwards, and Molecular Biology and Microbial Food Safety (SILS, FNWI)

Subjects
Genetics, Multidisciplinary, Chromosome 4, Sequence analysis, Arabidopsis, Gene density, Biology, biology.organism_classification, Genome, Gene, Homology (biology), Caenorhabditis elegans
Abstract

The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Published
1999

17. Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana

Author

J. Craig Venter, Kelly Moffat, Mian Shen, Christopher D. Town, Gregory P. Copenhaver, Jonathan A. Eisen, Karen A. Ketchum, Susan Van Aken, Owen White, Steven L. Salzberg, Luke J. Tallon, Cheryl Bowman, Mark Raymond Adams, Todd Creasy, Samir Kaul, Daphne Preuss, Xiaoying Lin, Howard M. Goodman, Ana J. Carrera, John Gill, Terrance Shea, Hean L. Koo, Steve Rounsley, Lisa A. Cronin, Maria-Ines Benito, Claire Fujii, Catherine M. Ronning, Chris Somerville, Lowell Umayam, Mary Barnstead, Claire M. Fraser, Tanya Mason, Tamara Feldblyum, C. Robin Buell, William C. Nierman, John Lee, and Grace Pai

Subjects
Cell Nucleus, Genetics, Multidisciplinary, DNA, Plant, Sequence analysis, Centromere, Molecular Sequence Data, Arabidopsis, Chromosome Mapping, Chromosome, Sequence Analysis, DNA, Biology, Genes, Plant, biology.organism_classification, Genome, DNA sequencing, Mitochondria, Evolution, Molecular, Gene Duplication, Repeated sequence, Gene, Plant Proteins, Genomic organization
Abstract

Arabidopsis thaliana (Arabidopsis) is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA. Here we report the sequence of chromosome 2 from the Columbia ecotype in two gap-free assemblies (contigs) of 3.6 and 16 megabases (Mb). The latter represents the longest published stretch of uninterrupted DNA sequence assembled from any organism to date. Chromosome 2 represents 15% of the genome and encodes 4,037 genes, 49% of which have no predicted function. Roughly 250 tandem gene duplications were found in addition to large-scale duplications of about 0.5 and 4.5 Mb between chromosomes 2 and 1 and between chromosomes 2 and 4, respectively. Sequencing of nearly 2 Mb within the genetically defined centromere revealed a low density of recognizable genes, and a high density and diverse range of vestigial and presumably inactive mobile elements. More unexpected is what appears to be a recent insertion of a continuous stretch of 75% of the mitochondrial genome into chromosome 2.

Published
1999

18. Orbital forcing of deep-sea benthic species diversity

Author

Maureen E. Raymo and Thomas M. Cronin

Subjects
Multidisciplinary, Oceanography, Orbital forcing, Ecology, Benthic zone, Paleoclimatology, Biodiversity, Environmental science, Species diversity, Climate change, Thermohaline circulation, Glacial period
Abstract

Explanations for the temporal and spatial patterns of species biodiversity focus on stability–time1–3, disturbance–mosaic (biogenie microhabitat heterogeneity)4,5 and competition–predation (biotic interactions)6,7 hypotheses. The stability–time hypothesis holds that high species diversity in the deep sea and in the tropics reflects long-term climatic stability3. But the influence of climate change on deep-sea diversity has not been studied and recent evidence suggests that deep-sea environments undergo changes in climatically driven temperature8 and flux of nutrients9 and organic-carbon10 during glacial–interglacial cycles. Here we show that Pliocene (2.85–2.40 Myr) deep-sea North Atlantic benthic ostracod (Crustacea) species diversity is related to solar insolation changes caused by 41,000-yr cycles of Earth's obliquity (tilt). Temporal changes in diversity, as measured by the Shannon–Weiner index, H(S), correlate with independent climate indicators of benthic foraminiferal oxygen-isotope ratios (mainly ice volume11–13) and ostracod Mg:Ca ratios (bottom-water temperature8). During glacial periods, H(S) = 0.2–0.6, whereas during interglacials, H(S) = 1.2–1.6, which is three to four times as high. The control of deep-sea benthic diversity by cyclic climate change at timescales of 103–104 yr does not support the stability–time hypothesis because it shows that the deep sea is a temporally dynamic environment. Diversity oscillations reflect large-scale response of the benthic community to climatically driven changes in either thermohaline circulation, bottom temperature (or temperature-related factors) and food, and a coupling of benthic diversity to surface productivity.

Published
1997

19. CLP1 links tRNA metabolism to progressive motor neuron loss

Author

Hanada T, Weitzer S, Mair B, Bernreuther C, Wainger BJ, Ichida J, Hanada R, Orthofer M, Cronin SJ, Komnenovic V, Minis A, Sato F, Mimata H, Yoshimura A, Tamir I, Rainer J, Kofler R, Yaron A, Eggan KC, Woolf CJ, Glatzel M, Herbst R, Martinez J, and Penninger JM

Published
2013

20. Onset of submarine debris flow deposition far from original giant landslide

Author

Peter J. Talling, Lawrence A. Amy, Aggeliki Georgiopoulou, Philip Pe Weaver, C. Zühlsdorff, Ralf Schiebel, Douglas G. Masson, M. Frenz, S. Dallmeier-Tiessen, A. Akhmetzhanov, Russell B. Wynn, Sara Benetti, and Bryan T. Cronin

Subjects
Multidisciplinary, Turbidity current, Hyperconcentrated flow, Mudflow, Erosion, Landslide, Geomorphology, Sediment transport, Geology, Debris flow, Submarine landslide
Abstract

Submarine landslides can generate sediment-laden flows whose scale is impressive. Individual flow deposits have been mapped that extend for 1,500 km offshore from northwest Africa. These are the longest run-out sediment density flow deposits yet documented on Earth. This contribution analyses one of these deposits, which contains ten times the mass of sediment transported annually by all of the world's rivers. Understanding how this type of submarine flow evolves is a significant problem, because they are extremely difficult to monitor directly. Previous work has shown how progressive disintegration of landslide blocks can generate debris flow, the deposit of which extends downslope from the original landslide. We provide evidence that submarine flows can produce giant debris flow deposits that start several hundred kilometres from the original landslide, encased within deposits of a more dilute flow type called turbidity current. Very little sediment was deposited across the intervening large expanse of sea floor, where the flow was locally very erosive. Sediment deposition was finally triggered by a remarkably small but abrupt decrease in sea-floor gradient from 0.05 degrees to 0.01 degrees. This debris flow was probably generated by flow transformation from the decelerating turbidity current. The alternative is that non-channelized debris flow left almost no trace of its passage across one hundred kilometres of flat (0.2 degrees to 0.05 degrees) sea floor. Our work shows that initially well-mixed and highly erosive submarine flows can produce extensive debris flow deposits beyond subtle slope breaks located far out in the deep ocean.

Published
2007

21. The genome of the social amoeba Dictyostelium discoideum

Author

Bernard Anri Konfortov, Richard Sucgang, T. Mourier, Patrick Farbrother, Rolf Olsen, Donna M. Muzny, Brian White, Ester Rabbinowitsch, H. Loulseged, Carmen Buchrieser, Sarah Sharp, J. Song, N. Hamlin, Pascale Gaudet, Brian A. Desany, Justin A. Pachebat, Marius Felder, Kylie R. James, Karen Oliver, Adam Kuspa, Tsuneyuki Saito, Angelika A. Noegel, X. Nie, Carol Churcher, Francisco Rivero, D. Harper, Erica Sodergren, Alan T. Bankier, Arnab Pain, Takahiro Morio, Robert L. Davies, M. Quiles, Robert R. Kay, Sarah K. Kummerfeld, René Rost, R. Lindsay, Andrew J Knights, Hideko Urushihara, Ludwig Eichinger, Gernot Glöckner, Judith Hernandez, Karen Mungall, Karol Szafranski, Thomas Winckler, S. Spiegler, Christophe Anjard, Mandy Sanders, David Steffen, M. Madan Babu, Michael A. Quail, Sumio Sugano, Jun Ma, Eric M. Just, Adrian Tivey, Ian Goodhead, J. Cooper, Michael Schleicher, P. Davis, William F. Loomis, Danielle Walker, Matthias Platzer, Neil Hall, Martin Madera, Stephen F. Haydock, Mingyang Lu, Petra Fey, Paul H. Dear, Rüdiger Lehmann, Richard A. Gibbs, Yoshiaki Tanaka, A. Wardroper, Gad Shaulsky, D. Johnson, M. Thangavelu, Jeffrey G. Williams, Edward C. Cox, Rex L. Chisholm, Guokai Chen, Yuji Kohara, Matthew Berriman, André Rosenthal, Bart Barrell, Karen E Pilcher, John Woodward, Heidi Hauser, Arnaud Kerhornou, Claire Price, Ann Cronin, Lisa Hemphill, Mark Simmonds, Nathalie Bason, Qikai Xu, David L. Saunders, Budi Tunggal, N. van Driessche, George M. Weinstock, and Marie-Adèle Rajandream

Subjects
Gene Transfer, Horizontal, Proteome, Centromere, Molecular Sequence Data, Protozoan Proteins, Genomics, Genome, DNA, Ribosomal, Dictyostelium discoideum, Article, RNA, Transfer, Cell Movement, Extrachromosomal DNA, Gene Duplication, Cell Adhesion, Animals, Humans, Dictyostelium, Social Behavior, Ribosomal DNA, Gene, Conserved Sequence, Phylogeny, Repetitive Sequences, Nucleic Acid, Genetics, Base Composition, Multidisciplinary, biology, Sequence Analysis, DNA, Telomere, biology.organism_classification, Eukaryotic Cells, DNA Transposable Elements, ATP-Binding Cassette Transporters, Signal Transduction
Abstract

The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.

Published
2004

22. Activity-dependent homeostatic specification of transmitter expression in embryonic neurons

Author

Nicholas C. Spitzer, Sharon B. Sann, Laura N. Borodinsky, Cory M. Root, Xiaonan Gu, and Julia A. Cronin

Subjects
Cell signaling, Central nervous system, Action Potentials, Biology, Inhibitory postsynaptic potential, Sodium Channels, chemistry.chemical_compound, Xenopus laevis, medicine, Animals, Homeostasis, Humans, Calcium Signaling, Potassium Channels, Inwardly Rectifying, Neurotransmitter, Cells, Cultured, Neurons, Neurotransmitter Agents, Multidisciplinary, Cell Differentiation, Embryonic stem cell, Rats, medicine.anatomical_structure, Phenotype, nervous system, Biochemistry, chemistry, Gene Expression Regulation, Spinal Cord, Organ Specificity, Excitatory postsynaptic potential, Calcium, Neuron, Neuroscience, Developmental biology
Abstract

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.

Published
2003

23. The genome sequence of Schizosaccharomyces pombe (vol 415, pg 871, 2002)

Author

Wood, V, Gwilliam, R, Rajandream, MA, Lyne, M, Lyne, R, Stewart, A, Sgouros, J, Peat, N, Hayles, J, Baker, S, Basham, D, Bowman, S, Brooks, K, Brown, D, Brown, S, Chillingworth, T, Churcher, C, Collins, M, Connor, R, Cronin, A, Davis, P, Feltwell, T, Fraser, A, Gentles, S, Goble, A, Hamlin, N, Harris, D, Hidalgo, J, Hodgson, G, Holroyd, S, Hornsby, T, Howarth, S, Huckle, EJ, Hunt, S, Jagels, K, James, K, Jones, L, Jones, M, Leather, S, McDonald, S, McLean, J, Mooney, P, Moule, S, Mungall, K, Murphy, L, Niblett, D, Odell, C, Oliver, K, O'Neil, S, Pearson, D, Quail, MA, Rabbinowitsch, E, Rutherford, K, Rutter, S, Saunders, D, Seeger, K, Sharp, S, Skelton, J, Simmonds, M, Squares, R, Squares, S, Stevens, K, Taylor, K, Taylor, RG, Tivey, A, Walsh, S, Warren, T, Whitehead, S, Woodward, J, Volckaert, G, Aert, R, Robben, J, Grymonprez, B, Weltjens, I, Vanstreels, E, Rieger, M, Schafer, M, Muller-Auer, S, Gabel, C, Fuchs, M, Dusterhoft, A, Fritzc, C, Holzer, E, Moestl, D, Hilbert, H, Borzym, K, Langer, I, Beck, A, Lehrach, H, Reinhardt, R, Pohl, TM, Eger, P, Zimmermann, W, Wedler, H, Wambutt, R, Purnelle, B, Goffeau, A, Cadieu, E, Dreano, S, Gloux, S, Lelaure, V, Mottier, S, Galibert, F, Aves, SJ, Xiang, Z, Hunt, C, Moore, K, Hurst, SM, Lucas, M, Rochet, M, Gaillardin, C, Tallada, VA, Garzon, A, Thode, G, Daga, RR, Cruzado, L, Jimenez, J, Sanchez, M, del Rey, F, Benito, J, Dominguez, A, Revuelta, JL, Moreno, S, Armstrong, J, Forsburg, SL, Cerutti, L, Lowe, T, McCombie, WR, Paulsen, I, Potashkin, J, Shpakovski, GV, Ussery, D, Barrell, BG, and Nurse, P

Published
2003

24. Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13

Author

T. Hornsby, Lee Murphy, Bernard Anri Konfortov, Mandy Sanders, Zoe Christodoulou, Kathy Seeger, Michael A. Quail, Andy Barron, Louise Unwin, Tracey Chillingworth, Stephen Baker, Robert B. Smith, Chris I. Newbold, Carol Churcher, D. Johnson, P. Davis, Theresa Feltwell, S. Whitehead, John Sulston, Zahra Hance, Rebecca Atkin, Andrew J Knights, S. Squares, Neil Hall, John Woodward, R. Gwilliam, Louise Clark, Arnab Pain, S Kyes, S. Holroyd, C. Chillingworth, Matthew Berriman, Sarah Sharp, S. Bowman, Christine Burrows, D. Harper, Caroline O. Buckee, Natasha Larke, Paul H. Dear, Bart Barrell, Barbara Harris, Heidi Hauser, Karen Mungall, Sean Humphray, K. Stevens, Keith D. James, Ian Goodhead, Adrian Tivey, K. Taylor, Karen Oliver, Richard Clark, Simon Rutter, Kim Rutherford, Daniel Lawson, Alister Craig, Kay Jagels, Craig Corton, F. Dearden, David Harris, Douglas Ormond, P. Mooney, Sharon Moule, Arnaud Kerhornou, Mark Simmonds, Claire Price, Ann Cronin, Mark Maddison, Inna Cherevach, Paul Horrocks, R. Squares, J. McLean, Marie-Adèle Rajandream, Jonathon Doggett, Arlette Goble, Alexandra Line, N. Hamlin, Karen Brooks, Robert L. Davies, Ester Rabbinowitsch, and Nicola Lennard

Subjects
Genetics, Multidisciplinary, Intergenic region, Sequence analysis, parasitic diseases, Plasmodium falciparum, Genome project, Biology, biology.organism_classification, Genome, Gene, Sequence (medicine), Conserved sequence
Abstract

Since the sequencing of the first two chromosomes of the malaria parasite, Plasmodium falciparum, there has been a concerted effort to sequence and assemble the entire genome of this organism. Here we report the sequence of chromosomes 1, 3-9 and 13 of P. falciparum clone 3D7 - these chromosomes account for approximately 55% of the total genome. We describe the methods used to map, sequence and annotate these chromosomes. By comparing our assemblies with the optical map, we indicate the completeness of the resulting sequence. During annotation, we assign Gene Ontology terms to the predicted gene products, and observe clustering of some malaria-specific terms to specific chromosomes. We identify a highly conserved sequence element found in the intergenic region of internal var genes that is not associated with their telomeric counterparts.

Published
2002

25. Adaptive visual metamorphosis in a deep-sea hydrothermal vent crab

Author

Thomas W. Cronin, Elizabeth E. Taylor, Tara L. Markley, Ana I. Dittel, Gina Perovich, Charles E. Epifanio, and Robert N. Jinks

Subjects
Hot Temperature, genetic structures, Light, Mesopelagic zone, Brachyura, media_common.quotation_subject, Oceans and Seas, Environment, Eye, Deep sea, Bathyal zone, Animals, Metamorphosis, Ocular Physiological Phenomena, Vision, Ocular, media_common, Larva, Multidisciplinary, biology, Ecology, fungi, Metamorphosis, Biological, equipment and supplies, biology.organism_classification, Plankton, Crustacean, Adaptation, Physiological, Steam, Habitat, sense organs, Retinal Pigments, geographic locations, Hydrothermal vent
Abstract

Hydrothermal vents along the mid-ocean ridges host ephemeral ecosystems of diverse endemic fauna including several crustacean species, some of which undergo planktonic development as larvae up to 1,000 m above and 100 km away from the vents. Little is known about the role of vision in the life history of vent fauna. Here we report that planktonic zoea larvae of the vent crab Bythograea thermydron possess image-forming compound eyes with a visual pigment sensitive to the blue light of mesopelagic waters. As they metamorphose and begin to descend to and settle at the vents, they lose their image-forming optics and develop high-sensitivity naked-retina eyes. The spectral absorbance of the visual pigment in these eyes shifts towards longer wavelengths from larva to postlarva to adult. This progressive visual metamorphosis trades imaging for increased sensitivity, and changes spectral sensitivity from the blue wavelengths of the larval environment towards the dim, longer wavelengths produced in the deeper bathypelagic vent environment of the adults. As hydrothermal vents produce light, vision may supplement thermal and chemical senses to orient postlarval settlement at vent sites.

Published
2002

26. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2)

Author

John Woodward, Keith F. Chater, David L. Saunders, Kim Rutherford, Karen Oliver, T. Hornsby, Nicholas R. Thomson, L. Larke, Carton W. Chen, Ana Cerdeño-Tárraga, Simon Rutter, Andreas Wietzorrek, H. M. Kieser, Arlette Goble, Ann Cronin, Lee Murphy, Sarah Sharp, D. Harper, Michael A. Quail, R. Squares, Alex Bateman, Bart Barrell, Andrew G. Fraser, S. Howarth, Tobias Kieser, Susan O'Neil, Kathy Seeger, Julian Parkhill, S. Squares, David A. Hopwood, Govind Chandra, Mark O. Collins, Stephen D. Bentley, K. Taylor, Marie-Adèle Rajandream, Steve D.M. Brown, Keith D. James, Ester Rabbinowitsch, T. Warren, J. Hidalgo, Chih-Hung Huang, David Harris, and Gregory L. Challis

Subjects
Whole genome sequencing, Genetics, Multidisciplinary, biology, Corynebacterium diphtheriae, Streptomyces coelicolor, Molecular Sequence Data, Genomics, Genome project, Mycobacterium tuberculosis, Chromosomes, Bacterial, biology.organism_classification, Genome, Synteny, Streptomyces, Bacterial Proteins, Genes, Bacterial, Genes, Duplicate, Multigene Family, Protein Isoforms, Gene, Genome, Bacterial, Regulator gene
Abstract

Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.

Published
2002

27. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18

Author

Mark Simmonds, S. Leather, Matthew T. G. Holden, Torben Larsen, Julian Parkhill, Tran Tinh Hien, S. Holroyd, Stephen D. Bentley, Kim Rutherford, Nicholas J. White, Nicholas R. Thomson, Tracey Chillingworth, Stephen Baker, Carol Churcher, Karen Mungall, Bart Barrell, John Wain, K. Stevens, Michael A. Quail, Phillippa L. Connerton, Christopher M. Parry, L. Dowd, Kay Jagels, Keith D. James, Robert L. Davies, N. Hamlin, P. Davis, Ashraful Haque, D. Basham, Theresa Feltwell, Karen Brooks, Derek Pickard, Jeremy Farrar, Gordon Dougan, Anders Krogh, Peadar O'Gaora, A. Cronin, Jason Skelton, Sally Whitehead, Sharon Moule, and Mohammed Sebaihia

Subjects
Salmonella bongori, DNA, Bacterial, Salmonella typhimurium, Salmonella, Pseudogene, Molecular Sequence Data, Virulence, medicine.disease_cause, Salmonella typhi, Genome, Microbiology, Plasmid, Drug Resistance, Multiple, Bacterial, medicine, Escherichia coli, Humans, Serotyping, Genetics, Recombination, Genetic, Multidisciplinary, Bacterial disease, biology, Chromosome Mapping, Sequence Analysis, DNA, Chromosomes, Bacterial, biology.organism_classification, Mutagenesis, Insertional, Gene Deletion, Genome, Bacterial, Plasmids
Abstract

Salmonella enterica serovar Typhi (S. typhi) is the aetiological agent of typhoid fever, a serious invasive bacterial disease of humans with an annual global burden of approximately 16 million cases, leading to 600,000 fatalities. Many S. enterica serovars actively invade the mucosal surface of the intestine but are normally contained in healthy individuals by the local immune defence mechanisms. However, S. typhi has evolved the ability to spread to the deeper tissues of humans, including liver, spleen and bone marrow. Here we have sequenced the 4,809,037-base pair (bp) genome of a S. typhi (CT18) that is resistant to multiple drugs, revealing the presence of hundreds of insertions and deletions compared with the Escherichia coli genome, ranging in size from single genes to large islands. Notably, the genome sequence identifies over two hundred pseudogenes, several corresponding to genes that are known to contribute to virulence in Salmonella typhimurium. This genetic degradation may contribute to the human-restricted host range for S. typhi. CT18 harbours a 218,150-bp multiple-drug-resistance incH1 plasmid (pHCM1), and a 106,516-bp cryptic plasmid (pHCM2), which shows recent common ancestry with a virulence plasmid of Yersinia pestis.

Published
2001

28. Sensory adaptation. Tunable colour vision in a mantis shrimp

Author

T W, Cronin, R L, Caldwell, and J, Marshall

Subjects
Light, Decapoda, Animals, Adaptation, Physiological, Color Perception
Abstract

Systems of colour vision are normally identical in all members of a species, but a single design may not be adequate for species living in a diverse range of light environments. Here we show that in the mantis shrimp Haptosquilla trispinosa, which occupies a range of depths in the ocean, long-wavelength colour receptors are individually tuned to the local light environment. The spectral sensitivity of specific classes of photoreceptor is adjusted by filters that vary between individuals.

Published
2001

29. Desperately seeking silicon

Author

Cronin B. Vining

Subjects
Multidisciplinary, Work (electrical), Silicon, chemistry, business.industry, Thermoelectric effect, chemistry.chemical_element, Nanotechnology, Electricity, business, nobody, Engineering physics
Abstract

Using silicon as a 'thermoelectric' material to convert heat into electricity would be a technological leap forward. But silicon conducts heat so well that nobody thought that could work — until now.

Published
2008

30. Thermopower to the people

Author

Cronin B. Vining

Subjects
Physics, Multidisciplinary, Electricity generation, Condensed matter physics, Spins, Seebeck coefficient, Voltage
Abstract

The larger-than-expected thermally generated voltage seen in a layered-oxide material — which may prove useful in power generation or cooling — is now attributed to the spins of moving charges.

Published
2003

31. Semiconductors are cool

Author

Cronin B. Vining

Subjects
Multidisciplinary, Materials science, business.industry, Transistor, Vacuum tube, New materials, Nanotechnology, law.invention, Bit (horse), Semiconductor, law, Thermocouple, Optoelectronics, business
Abstract

In the 1950s there were hopes that semiconductor thermocouples would replace mechanical refrigerators, just as semiconductor transistors supplanted vacuum tubes. New materials may bring that goal a bit closer.

Published
2001

32. Tunable colour vision in a mantis shrimp

Author

Roy L. Caldwell, Justin Marshall, and Thomas W. Cronin

Subjects
Sensory Adaptation, Multidisciplinary, genetic structures, biology, Color vision, Ecology, Range (biology), fungi, Colour Vision, Adaptation (eye), biology.organism_classification, Crustacean, Mantis shrimp, Spectral sensitivity, Biological system
Abstract

Systems of colour vision are normally identical in all members of a species, but a single design may not be adequate for species living in a diverse range of light environments. Here we show that in the mantis shrimp Haptosquilla trispinosa, which occupies a range of depths in the ocean, long-wavelength colour receptors are individually tuned to the local light environment. The spectral sensitivity of specific classes of photoreceptor is adjusted by filters that vary between individuals.

Published
2001

34. Erratum: Arctic hydrology during global warming at the Palaeocene/Eocene thermal maximum

Author

David Smith, Steve Clemens, Kozo Takahashi, Jérôme Gattacceca, Itsuki Suto, Jens Matthiessen, Matt O'Regan, Domenico Rio, Kristen St. John, Thomas W. Cronin, Brice R. Rea, Martin Jakobsson, Matthew Huber, John S. King, R.W. Jordan, Nikolai Pedentchouk, Heiko Pälike, David McInroy, Henk Brinkhuis, Theodore C. Moore, Nahysa C. Martinez, Jan Backman, Kathryn Moran, Stefan Schouten, Frédérique Eynaud, Nalân Koç, Masanobu Yamamoto, Appy Sluijs, Jonaotaro Onodera, Mahito Watanabe, Tatsuhiko Sakamoto, Mark Pagani, Noritoshi Suzuki, Michael A. Kaminski, Ruediger Stein, Gerald R. Dickens, and Jaap S. Sinninghe Damsté

Subjects
Multidisciplinary, Hydrology (agriculture), 010504 meteorology & atmospheric sciences, Arctic, Climatology, Global warming, Carbon isotope excursion, 010502 geochemistry & geophysics, 01 natural sciences, Geology, 0105 earth and related environmental sciences
Published
2006

35. Erratum: corrigendum: The genome sequence of Schizosaccharomyces pombe

Author

K. Taylor, David W. Ussery, Ruth Taylor, H. Wedler, P. Davis, Theresa Feltwell, Stéphane Dréano, Judith A. Potashkin, Guido Volckaert, Wolfgang Zimmermann, R. Gwilliam, K. Borzym, Valerie Lelaure, Francis Galibert, David Harris, Johan Robben, K. Stevens, Todd M. Lowe, K. Oliver, S. Squares, R. Connor, T. Hornsby, T. Warren, Karen Mungall, Mark O. Collins, D. Basham, David L. Saunders, Rafael R. Daga, S. M. Hurst, Ester Rabbinowitsch, Kay Jagels, Carol Churcher, Sarah Sharp, S. McDonald, Claude Gaillardin, D. Pearson, A. Düsterhöft, Paul Nurse, Stéphanie Mottier, R. Wambutt, Valerie Wood, Richard Reinhardt, A. Stewart, Sergio Moreno, Thomas M. Pohl, J. Benito, Ann Cronin, N. Hamlin, Andrés Garzón, Sharon Moule, W. R. McCombie, John Woodward, J. Sgouros, S. Gentles, P. Eger, André Goffeau, L. Cerutti, S. Holroyd, Kathy Seeger, Karen Brooks, J. McLean, Victor A. Tallada, Cherryl Hunt, Sarah E. Hunt, G. Thode, Mark Simmonds, Z. Xiang, S. Leather, I. Langer, Kim Rutherford, D. Moestl, Geoffrey M. Hodgson, Rita Aert, Kylie R. James, Edouard Cadieu, S. Walsh, C. Odell, Ian T. Paulsen, Hans Lehrach, L. Cruzado, Stéphanie Gloux, Michael A. Quail, Miguel del Nogal Sánchez, Karen Moore, S. Muller-Auer, D. Niblett, P. Mooney, E. Vanstreels, Elizabeth J. Huckle, José L. Revuelta, Tracey Chillingworth, Stephen Baker, I. Weltjens, Susan O'Neil, Angel Domínguez, G. V. Shpakovski, N. Peat, F. del Rey, M. Lyne, Adrian Tivey, B. Grymonprez, E. Holzer, Alfred Beck, Marie-Adèle Rajandream, Michael A. Rieger, Steve D.M. Brown, Bart Barrell, Rachel Lyne, Bénédicte Purnelle, M. Schafer, Simon Rutter, S. Howarth, M. Fuchs, Matthew Jones, Stephen J. Aves, John Armstrong, Lee Murphy, Audrey Fraser, C. Gabel, Jason Skelton, Arlette Goble, H. Hilbert, C. Fritzc, Susan L. Forsburg, Sharen Bowman, Juan Jimenez, S. Whitehead, Derek J. Brown, M. Rochet, R. Squares, Jacqueline Hayles, M. Lucas, J. Hidalgo, and L. Jones

Subjects
Whole genome sequencing, Genetics, Multidisciplinary, Schizosaccharomyces pombe, Biology, Line (text file), biology.organism_classification
Abstract

Nature 415, 871–880 (2002). In this Article, the author Andreas Dusterhoft was mistakenly omitted: his name and affiliation (footnote 6) should have been inserted between M. Fuchs and C. Fritzc in the author list. In addition, the name of L. Cerutti (in the last line of the author list) was misspelled.

Published
2003

36. Alanine enantiomers in the Murchison meteorite

Author

John R. Cronin and Sandra Pizzarello

Subjects
Alanine, Murchison meteorite, Multidisciplinary, Meteorite, Chemistry, Environmental chemistry, Enantiomer, Astrobiology
Abstract

Engel and Macko 1 have reported that alanine indigenous to the Murchison meteorite has an l-enantiomer excess of about 33%. Furthermore, they reported very similar δ15nitrogen values for l-alanine and d-alanine; these values are quite high in comparison with those of terrestrial amino acids. On this basis, they argued that contamination of the meteorite by terrestrial l-alanine can be ruled out because, if it contributed to the l-enantiomer excess, the lower 15N content of terrestrial l-alanine would significantly lower the δ15N value that they observed for l-alanine.

Published
1998

37. A retina with at least ten spectral types of photoreceptors in a mantis shrimp

Author

Thomas W. Cronin and N. Justin Marshall

Subjects
Retina, Multidisciplinary, genetic structures, business.industry, SUPERFAMILY, Gonodactyloidea, Biology, Stellar classification, biology.organism_classification, eye diseases, Mantis shrimp, medicine.anatomical_structure, Optics, Ommatidium, Pseudosquilla ciliata, medicine, sense organs, Mantis, business
Abstract

STOMATOPOD crustaceans, commonly named mantis shrimps, have compound eyes of unique design. A central band composed of six parallel rows of ommatidia separates two peripheral ommatidial groups, and all three regions view the same area of visual space1–3. In the central bands of members of the stomatopod superfamily Gonodactyloidea, four of the ommatidial rows are built of tiers of photoreceptors; in two of these rows, the photoreceptors themselves contain coloured filters4. Such a design could in principle produce many spectral classes of photoreceptors using only a single visual pigment4,5. We measured the absorption spectra of the coloured filters and the visual pigments in frozen sections of retinae of a typical species, Pseudosquilla ciliata, using end-on microspectrophotometry. The retina contains not one, but as many as ten visual pigments, each in a distinct photoreceptor class, having maximum absorbances at wavelengths from 400 to 539 nm. Because of the unique anatomy of stomatopod eyes, ten or more spectral types of photoreceptors exist in this species.

Published
1989

38. Unusual luminescence behaviour of terbium phosphate glasses

Author

David J. Cronin, Wolfgang Haller, and Douglas H. Blackburn

Subjects
Multidisciplinary, Quenching (fluorescence), Materials science, chemistry.chemical_element, Terbium, Green-light, Phosphate, Photochemistry, Phosphate glass, chemistry.chemical_compound, chemistry, Naked eye, Europium, Luminescence
Abstract

While preparing a terbium-containing phosphate glass, an intense emission of green light was observed when the melt was poured into a metal mould. This emission was easily visible to the naked eye and was only observed on quenching of the melts. To our knowledge this phenomenon, termed ‘cooling-induced luminescence (CIL)’, has not previously been reported. Experimental evidence suggests that the CIL may be related to a thermally induced shift in the oxidation-reduction balance in the melt. A similar phenomenon was also observed with europium phosphate melts.

Published
1982

39. Aliphatic amines in the Murchison meteorite

Author

George U. Yuen, Gregory Jungclaus, John R. Cronin, and Carleton B. Moore

Subjects
chemistry.chemical_classification, Murchison meteorite, Multidisciplinary, Primary (chemistry), Meteorite, Chemistry, chemistry.chemical_element, Organic chemistry, Compounds of carbon, Gas chromatography, Carbon, Amino acid
Abstract

The paper reports on the determination of aliphatic amines in water extracts of the Murchison meteorite. The amines were analyzed by gas chromatography both as the free amines and as 2,4-dinitrophenyl (DNP) derivatives. The results give evidence for the presence of all of the possible primary aliphatic monoamines (eight) with fewer than five carbon atoms. Two of the seven possible secondary or tertiary aliphatic monoamines were identified. The identified primary amines total 80 nmol per g meteorite, and seem to be chemically or physically trapped in the meteorite. Similarities between the water-extractable amines and amino acids suggest that (1) a simple carbon compound, methane, for example, is the precursor of meteorite amines and amino acids, and (2) both amines and amino acids are extracted from the meteorite both as such and in the form of acid-hydrolyzable derivative or precursor species.

Published
1976

40. Molecular evidence for dual origin of mangabeys among Old World monkeys

Author

Vincent M. Sarich and John E. Cronin

Subjects
Papionini, Multidisciplinary, Old World, biology, Transferrin, Haplorhini, Old World monkey, biology.organism_classification, Biological Evolution, Epitopes, Monophyly, Species Specificity, Genus, Evolutionary biology, biology.animal, Animals, Primate, Mangabey, Mandrillus, Serum Albumin
Abstract

THE morphological similarities among the various mangabey species have been uniformly judged by primate systematists to warrant their association in a single genus (Cercocebus) of Old World monkeys. These similarities are not, however, reflected in their macromolecules. We find that the two groups of mangabeys are, by Old World monkey standards, so different at the protein level as to force the conclusion that the genus is not a natural that is, monophyletic, group.

Published
1976

41. On the reported optical activity of amino acids in the Murchison meteorite

Author

Jeffrey L. Bada, John R. Cronin, James G. Lawless, J. Oró, Spencer Steinberg, Keith A. Kvenvolden, Ming-shan Ho, and Stanley L. Miller

Subjects
Murchison meteorite, chemistry.chemical_classification, chemistry.chemical_compound, Multidisciplinary, Methionine, chemistry, Meteorite, Carbonaceous chondrite, Organic chemistry, Phenylalanine, Threonine, Tyrosine, Amino acid
Abstract

It is shown that the explanation of terrestrial contamination of the Murchison meteorite is consistent with the analysis of extracts from the meteorite reported by Engel and Nagy (EN) (1982) and is much more probable than their suggestion that the excess of L-enantiomers for several protein amino acids is due to asymmetric synthesis or decomposition. The low abundance of serine and threonine reported by EN may be due to their decomposition during the derivatization procedure, and the absence of methionine, tyrosine, and phenylalanine can be attributed to various causes. The amount of contamination in EN's extracts are estimated from a mass balance of the amino acid enantiomers, and it is found that the amino acids in the HCl could be due entirely to contamination while in the water extract the amount of contamination ranges from about 40 to 97 percent, depending on the amino acid. The argument that contaminants were preferentially extracted by EN's procedure cannot account for the failure to detect methionine, tyrosine, and phenylalanine.

Published
1983

42. Perception of apparent motion by commissurotomy patients

Author

J. J. Myers, A. Cronin-Golomb, and Vilayanur S. Ramachandran

Subjects
Multidisciplinary, Eye Movements, media_common.quotation_subject, Illusion, Motion Perception, Geodesy, Corpus Callosum, Meridian (perimetry, visual field), Perception, Forebrain Commissures, Humans, Visual Pathways, Commissurotomy, Geology, media_common
Abstract

When two spatially separated light spots are flashed in rapid succession, the spot will appear to move between the two locations—an illusion called apparent motion1,2. We have presented this display to callosum-sectioned human patients and found that they could correctly report the temporal order of a simple apparent motion sequence presented across the vertical meridian. Hence, the forebrain commissures are not required for this function.

Published
1986

43. Unusual stable isotope ratios in amino acid and carboxylic acid extracts from the Murchison meteorite

Author

R. V. Krishnamurthy, Samuel Epstein, George U. Yuen, Sandra Pizzarello, and John R. Cronin

Subjects
Murchison meteorite, Nitrogen, Carboxylic acid, Interstellar cloud, Inorganic chemistry, Origin of Life, Carboxylic Acids, Astrobiology, Isotopes, Chondrite, Abiogenesis, Amino Acids, chemistry.chemical_classification, Carbon Isotopes, Multidisciplinary, Evolution, Chemical, Nitrogen Isotopes, Stable isotope ratio, Temperature, Meteoroids, Hydrogen-Ion Concentration, Deuterium, Carbon, chemistry, Meteorite, Carbonaceous chondrite, Hydrogen
Abstract

Much effort has been directed to analyses of organic compounds in carbonaceous chondrites because of their implications for organic chemical evolution and the origin of life. We have determined the isotopic composition of hydrogen, nitrogen and carbon in amino acid and monocarboxylic acid extracts from the Murchison meteorite. The unusually high D/H and 15N/14N ratios in the amino acid fraction (delta D = 1,370% after correction for isotope exchange; delta 15N = 90) are uniquely characteristic of known interstellar organic materials. The delta D value of the monocarboxylic acid fraction is lower (377%), but still consistent with an interstellar origin. These results confirm the extraterrestrial origin of both classes of compound, and provide the first evidence suggesting a direct relationship between the massive organo-synthesis occurring in interstellar clouds and the presence of pre-biotic compounds in primitive planetary bodies. The isotope data also bear on the historical problem of distinguishing indigenous material from terrestrial contaminants.

Published
1987

44. Pygmy chimpanzee as a possible prototype for the common ancestor of humans, chimpanzees and gorillas

Author

Vincent M. Sarich, Adrienne L. Zihlman, John E. Cronin, and Douglas L. Cramer

Subjects
Multidisciplinary, Gorilla gorilla, biology, Phylogenetic tree, Pan troglodytes, Range (biology), Cephalometry, Fossils, Zoology, Troglodytes, biology.organism_classification, Common ancestry, Biological Evolution, Pan paniscus, DNA annealing, Amino acid analysis, Animals, Humans, Ancestor
Abstract

A CONVINCING theory of human origins must clarify man's relationships with living primates and with the ancestral forms known only through fossils. Phylogenetic relationships have previously been determined mainly by anatomical similarities, but now, biochemical similarities provide independent criteria for evolutionary relationships. Albumin and transferrin immunology, immunodifrusion, DNA annealing and amino acid analysis all indicate that chimpanzees, gorillas and humans share a substantial common ancestry, and that the Asiatic apes (gibbons and orangutans) diverged earlier from this lineage1–3. These findings directly conflict with the more widely held view that all the great apes diverged from a common ancestor long after the ‘Origin’ of the evolutionary line leading to modern humans4. The molecular data consistently suggest a much more recent origin of the man–chimpanzee–gorilla separation than was previously imagined, namely, in the range of 4–6 M yr ago3,5. These data show that, although the two chimpanzee species (Pan paniscus and P. troglodytes) are biochemically distinct, they are more closely related to each other than either is to humans or gorillas6,7. The chimpanzees speciated, then, after the initial three-way split. We therefore, here contend that, among living species, the pygmy chimpanzee (P. paniscus) offers us the best prototype of the prehominid ancestor. Biochemical, morphological, behavioural and palaeontological data support this proposition and argue for a relatively recent and accelerated divergence of the hominid from the pongid line.

Published
1978

45. Percutaneous absorption of nicotinic acid and ethyl nicotinate in human skin

Author

Richard B. Stoughton and Etain Cronin

Subjects
Multidisciplinary, Chemistry, Skin Absorption, Skin physiology, Nicotinic Acids, Human skin, Pharmacology, Niacin, Ethyl nicotinate, Nicotinic agonist, Skin Physiological Phenomena, Percutaneous absorption, Humans, Skin
Abstract

THIS communication concerns the vast difference in percutaneous absorption through human skin of two related substances, nicotinic acid and ethyl nicotinate.

Published
1962

46. Amino acids and bolide impacts

Author

John R. Cronin

Subjects
chemistry.chemical_classification, Multidisciplinary, chemistry, Bolide, Amino acid, Astrobiology, Geological Phenomena
Published
1989

47. Relation of Nucleotides and Nucleosides to Proliferation-Promoting Factors Produced by Ultra-Violet Irradiated Yeast Cells

Author

Thomas Mary Walsh, Elton S. Cook, Cornelius W. Kreke, and Ann Gertrude Cronin

Subjects
chemistry.chemical_classification, Multidisciplinary, biology, Chemistry, Yeast, Cofactor, chemistry.chemical_compound, Biotin, Biochemistry, Adenine nucleotide, Casein, biology.protein, Nucleotide, Irradiation, Hormone
Abstract

RECENT reports by Loofbourow1 on the role of adenine nucleotides in wound hormone preparations from ultra-violet treated yeast cells prompt us to give a preliminary account of some of our experiments which bear upon the problem.

Published
1943

48. Proliferation-promoting Activities of Extracts from Ultra-violet Injured Yeast Cells and of Bios Components

Author

Elton S. Cook and Ann Gertrude Cronin

Subjects
Multidisciplinary, Biochemistry, Response to injury, Normal growth, Vitamin b complex, Ultra violet, Biology, Ultraviolet radiation, Yeast, Hormone
Abstract

NUMEROUS papers from these laboratories have dealt with the production of proliferation-promoting factors ('intercellular wound hormones') by cells subjected to various injuring agents. It seems warranted to believe that these substances are produced by living, injured cells as a response to injury and are not simply dead-cell disintegration products1. The question of the nature of these materials is of great interest. It might be assumed that they are merely normal growth substances produced or released in greater quantities under the conditions of injury, or it is possible that they represent specific 'injury substances'. Two lines of inquiry have been undertaken to answer the question: (1) chemical and spectrographic studies, which suggest a nucleic acid-like nature for the wound hormones and which definitely show that substances of this type are produced in greater quantity as a result of injury2 ; (2) comparative growth studies, on the wound hormone preparations and known growth substances. The present note is concerned with the latter.

Published
1942

50. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England

Author

Daniel Mair, Adrian Signell, Daniel Laydon, Nadua Bayzid, Clare M McCann, Flavia Flaviani, Thomas Connor, Samir Bhatt, Catherine Moore, Dr Benjamin Lindsey, Malte Pinckert, Jane Masoli, Rachel Blacow, Jacqui Prieto, Ian Harrison, Scott Thurston, Lance Turtle, Thushan De Silva, Gregory Young, Natalie Groves, Andrew Nelson, Angie Lackenby, Lily Geidelberg, Mili Estee Torok, Brendan Payne, Katy Gaythorpe, Sonia Goncalves, Ewan Harrison, Andrew Rambaut, Angela Beckett, David Partridge, Swapnil Mishra, Dimitris Grammatopoulos, Judith Breuer, Jenna Nichols, Erik Volz, Sharon Glaysher, Harry David Wilson, Jack Lee, Marta Gallis, Christophe Fraser, Susan Hopkins, Patrick McClure, Derrick Crook, Juan Ledesma, Theocharis Tsoleridis, Natasha Palmalux, Matthew Dorman, Helen Lowe, Kordo Saeed, Oliver Ratmann, Darren Smith, Gilberto Betancor Quintana, Alan McNally, Matthew Bashton, Steven Rudder, Dennis Wang, Joseph Chappell, Elias Allara, Volz, Erik [0000-0001-6268-8937], Mishra, Swapnil [0000-0002-8759-5902], Geidelberg, Lily [0000-0002-8057-1844], Laydon, Daniel J [0000-0003-4270-3321], Jackson, Ben [0000-0002-9981-0649], Gaythorpe, Katy [0000-0003-3734-9081], Kwiatkowski, Dominic P [0000-0002-5023-0176], Flaxman, Seth [0000-0002-2477-4217], Gandy, Axel [0000-0002-6777-0451], Rambaut, Andrew [0000-0003-4337-3707], Ferguson, Neil M [0000-0002-1154-8093], Apollo - University of Cambridge Repository, Medical Research Council, Bill & Melinda Gates Foundation, and Medical Research Council (MRC)

Subjects
The COVID-19 Genomics UK (COG-UK) consortium, Adult, 0301 basic medicine, Time Factors, Adolescent, General Science & Technology, Lineage (evolution), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Basic Reproduction Number, Population genetics, Genome, Viral, Biology, law.invention, Evolution, Molecular, Young Adult, 03 medical and health sciences, Age Distribution, 0302 clinical medicine, law, Phylogenetics, Humans, 030212 general & internal medicine, Child, Phylogeny, Aged, Aged, 80 and over, COVID-19 Genomics UK (COG-UK) consortium, Science & Technology, Multidisciplinary, Generation time, SARS-CoV-2, Infant, Newborn, COVID-19, Infant, Middle Aged, Transmissibility (vibration), 3. Good health, Multidisciplinary Sciences, 030104 developmental biology, Transmission (mechanics), England, Evolutionary biology, Child, Preschool, Spike Glycoprotein, Coronavirus, Science & Technology - Other Topics, Basic reproduction number
Abstract

The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England1, was first identified in the UK in late summer to early autumn 20202. Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number.

Published
2021

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