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1.  The zebrafish reference genome sequence and its relationship to the human genome 
Howe, Kerstin | Clark, Matthew D. | Torroja, Carlos F. | Torrance, James | Berthelot, Camille | Muffato, Matthieu | Collins, John E. | Humphray, Sean | McLaren, Karen | Matthews, Lucy | McLaren, Stuart | Sealy, Ian | Caccamo, Mario | Churcher, Carol | Scott, Carol | Barrett, Jeffrey C. | Koch, Romke | Rauch, Gerd-Jörg | White, Simon | Chow, William | Kilian, Britt | Quintais, Leonor T. | Guerra-Assunção, José A. | Zhou, Yi | Gu, Yong | Yen, Jennifer | Vogel, Jan-Hinnerk | Eyre, Tina | Redmond, Seth | Banerjee, Ruby | Chi, Jianxiang | Fu, Beiyuan | Langley, Elizabeth | Maguire, Sean F. | Laird, Gavin K. | Lloyd, David | Kenyon, Emma | Donaldson, Sarah | Sehra, Harminder | Almeida-King, Jeff | Loveland, Jane | Trevanion, Stephen | Jones, Matt | Quail, Mike | Willey, Dave | Hunt, Adrienne | Burton, John | Sims, Sarah | McLay, Kirsten | Plumb, Bob | Davis, Joy | Clee, Chris | Oliver, Karen | Clark, Richard | Riddle, Clare | Eliott, David | Threadgold, Glen | Harden, Glenn | Ware, Darren | Mortimer, Beverly | Kerry, Giselle | Heath, Paul | Phillimore, Benjamin | Tracey, Alan | Corby, Nicole | Dunn, Matthew | Johnson, Christopher | Wood, Jonathan | Clark, Susan | Pelan, Sarah | Griffiths, Guy | Smith, Michelle | Glithero, Rebecca | Howden, Philip | Barker, Nicholas | Stevens, Christopher | Harley, Joanna | Holt, Karen | Panagiotidis, Georgios | Lovell, Jamieson | Beasley, Helen | Henderson, Carl | Gordon, Daria | Auger, Katherine | Wright, Deborah | Collins, Joanna | Raisen, Claire | Dyer, Lauren | Leung, Kenric | Robertson, Lauren | Ambridge, Kirsty | Leongamornlert, Daniel | McGuire, Sarah | Gilderthorp, Ruth | Griffiths, Coline | Manthravadi, Deepa | Nichol, Sarah | Barker, Gary | Whitehead, Siobhan | Kay, Michael | Brown, Jacqueline | Murnane, Clare | Gray, Emma | Humphries, Matthew | Sycamore, Neil | Barker, Darren | Saunders, David | Wallis, Justene | Babbage, Anne | Hammond, Sian | Mashreghi-Mohammadi, Maryam | Barr, Lucy | Martin, Sancha | Wray, Paul | Ellington, Andrew | Matthews, Nicholas | Ellwood, Matthew | Woodmansey, Rebecca | Clark, Graham | Cooper, James | Tromans, Anthony | Grafham, Darren | Skuce, Carl | Pandian, Richard | Andrews, Robert | Harrison, Elliot | Kimberley, Andrew | Garnett, Jane | Fosker, Nigel | Hall, Rebekah | Garner, Patrick | Kelly, Daniel | Bird, Christine | Palmer, Sophie | Gehring, Ines | Berger, Andrea | Dooley, Christopher M. | Ersan-Ürün, Zübeyde | Eser, Cigdem | Geiger, Horst | Geisler, Maria | Karotki, Lena | Kirn, Anette | Konantz, Judith | Konantz, Martina | Oberländer, Martina | Rudolph-Geiger, Silke | Teucke, Mathias | Osoegawa, Kazutoyo | Zhu, Baoli | Rapp, Amanda | Widaa, Sara | Langford, Cordelia | Yang, Fengtang | Carter, Nigel P. | Harrow, Jennifer | Ning, Zemin | Herrero, Javier | Searle, Steve M. J. | Enright, Anton | Geisler, Robert | Plasterk, Ronald H. A. | Lee, Charles | Westerfield, Monte | de Jong, Pieter J. | Zon, Leonard I. | Postlethwait, John H. | Nüsslein-Volhard, Christiane | Hubbard, Tim J. P. | Crollius, Hugues Roest | Rogers, Jane | Stemple, Derek L.
Nature  2013;496(7446):498-503.
Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
doi:10.1038/nature12111
PMCID: PMC3703927  PMID: 23594743
2.  CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion 
Lee, J.-M. | Ramos, E.M. | Lee, J.-H. | Gillis, T. | Mysore, J.S. | Hayden, M.R. | Warby, S.C. | Morrison, P. | Nance, M. | Ross, C.A. | Margolis, R.L. | Squitieri, F. | Orobello, S. | Di Donato, S. | Gomez-Tortosa, E. | Ayuso, C. | Suchowersky, O. | Trent, R.J.A. | McCusker, E. | Novelletto, A. | Frontali, M. | Jones, R. | Ashizawa, T. | Frank, S. | Saint-Hilaire, M.H. | Hersch, S.M. | Rosas, H.D. | Lucente, D. | Harrison, M.B. | Zanko, A. | Abramson, R.K. | Marder, K. | Sequeiros, J. | Paulsen, J.S. | Landwehrmeyer, G.B. | Myers, R.H. | MacDonald, M.E. | Gusella, J.F. | Durr, Alexandra | Rosenblatt, Adam | Frati, Luigi | Perlman, Susan | Conneally, Patrick M. | Klimek, Mary Lou | Diggin, Melissa | Hadzi, Tiffany | Duckett, Ayana | Ahmed, Anwar | Allen, Paul | Ames, David | Anderson, Christine | Anderson, Karla | Anderson, Karen | Andrews, Thomasin | Ashburner, John | Axelson, Eric | Aylward, Elizabeth | Barker, Roger A. | Barth, Katrin | Barton, Stacey | Baynes, Kathleen | Bea, Alexandra | Beall, Erik | Beg, Mirza Faisal | Beglinger, Leigh J. | Biglan, Kevin | Bjork, Kristine | Blanchard, Steve | Bockholt, Jeremy | Bommu, Sudharshan Reddy | Brossman, Bradley | Burrows, Maggie | Calhoun, Vince | Carlozzi, Noelle | Chesire, Amy | Chiu, Edmond | Chua, Phyllis | Connell, R.J. | Connor, Carmela | Corey-Bloom, Jody | Craufurd, David | Cross, Stephen | Cysique, Lucette | Santos, Rachelle Dar | Davis, Jennifer | Decolongon, Joji | DiPietro, Anna | Doucette, Nicholas | Downing, Nancy | Dudler, Ann | Dunn, Steve | Ecker, Daniel | Epping, Eric A. | Erickson, Diane | Erwin, Cheryl | Evans, Ken | Factor, Stewart A. | Farias, Sarah | Fatas, Marta | Fiedorowicz, Jess | Fullam, Ruth | Furtado, Sarah | Garde, Monica Bascunana | Gehl, Carissa | Geschwind, Michael D. | Goh, Anita | Gooblar, Jon | Goodman, Anna | Griffith, Jane | Groves, Mark | Guttman, Mark | Hamilton, Joanne | Harrington, Deborah | Harris, Greg | Heaton, Robert K. | Helmer, Karl | Henneberry, Machelle | Hershey, Tamara | Herwig, Kelly | Howard, Elizabeth | Hunter, Christine | Jankovic, Joseph | Johnson, Hans | Johnson, Arik | Jones, Kathy | Juhl, Andrew | Kim, Eun Young | Kimble, Mycah | King, Pamela | Klimek, Mary Lou | Klöppel, Stefan | Koenig, Katherine | Komiti, Angela | Kumar, Rajeev | Langbehn, Douglas | Leavitt, Blair | Leserman, Anne | Lim, Kelvin | Lipe, Hillary | Lowe, Mark | Magnotta, Vincent A. | Mallonee, William M. | Mans, Nicole | Marietta, Jacquie | Marshall, Frederick | Martin, Wayne | Mason, Sarah | Matheson, Kirsty | Matson, Wayne | Mazzoni, Pietro | McDowell, William | Miedzybrodzka, Zosia | Miller, Michael | Mills, James | Miracle, Dawn | Montross, Kelsey | Moore, David | Mori, Sasumu | Moser, David J. | Moskowitz, Carol | Newman, Emily | Nopoulos, Peg | Novak, Marianne | O'Rourke, Justin | Oakes, David | Ondo, William | Orth, Michael | Panegyres, Peter | Pease, Karen | Perlman, Susan | Perlmutter, Joel | Peterson, Asa | Phillips, Michael | Pierson, Ron | Potkin, Steve | Preston, Joy | Quaid, Kimberly | Radtke, Dawn | Rae, Daniela | Rao, Stephen | Raymond, Lynn | Reading, Sarah | Ready, Rebecca | Reece, Christine | Reilmann, Ralf | Reynolds, Norm | Richardson, Kylie | Rickards, Hugh | Ro, Eunyoe | Robinson, Robert | Rodnitzky, Robert | Rogers, Ben | Rosenblatt, Adam | Rosser, Elisabeth | Rosser, Anne | Price, Kathy | Price, Kathy | Ryan, Pat | Salmon, David | Samii, Ali | Schumacher, Jamy | Schumacher, Jessica | Sendon, Jose Luis Lópenz | Shear, Paula | Sheinberg, Alanna | Shpritz, Barnett | Siedlecki, Karen | Simpson, Sheila A. | Singer, Adam | Smith, Jim | Smith, Megan | Smith, Glenn | Snyder, Pete | Song, Allen | Sran, Satwinder | Stephan, Klaas | Stober, Janice | Sü?muth, Sigurd | Suter, Greg | Tabrizi, Sarah | Tempkin, Terry | Testa, Claudia | Thompson, Sean | Thomsen, Teri | Thumma, Kelli | Toga, Arthur | Trautmann, Sonja | Tremont, Geoff | Turner, Jessica | Uc, Ergun | Vaccarino, Anthony | van Duijn, Eric | Van Walsem, Marleen | Vik, Stacie | Vonsattel, Jean Paul | Vuletich, Elizabeth | Warner, Tom | Wasserman, Paula | Wassink, Thomas | Waterman, Elijah | Weaver, Kurt | Weir, David | Welsh, Claire | Werling-Witkoske, Chris | Wesson, Melissa | Westervelt, Holly | Weydt, Patrick | Wheelock, Vicki | Williams, Kent | Williams, Janet | Wodarski, Mary | Wojcieszek, Joanne | Wood, Jessica | Wood-Siverio, Cathy | Wu, Shuhua | Yastrubetskaya, Olga | de Yebenes, Justo Garcia | Zhao, Yong Qiang | Zimbelman, Janice | Zschiegner, Roland | Aaserud, Olaf | Abbruzzese, Giovanni | Andrews, Thomasin | Andrich, Jurgin | Antczak, Jakub | Arran, Natalie | Artiga, Maria J. Saiz | Bachoud-Lévi, Anne-Catherine | Banaszkiewicz, Krysztof | di Poggio, Monica Bandettini | Bandmann, Oliver | Barbera, Miguel A. | Barker, Roger A. | Barrero, Francisco | Barth, Katrin | Bas, Jordi | Beister, Antoine | Bentivoglio, Anna Rita | Bertini, Elisabetta | Biunno, Ida | Bjørgo, Kathrine | Bjørnevoll, Inga | Bohlen, Stefan | Bonelli, Raphael M. | Bos, Reineke | Bourne, Colin | Bradbury, Alyson | Brockie, Peter | Brown, Felicity | Bruno, Stefania | Bryl, Anna | Buck, Andrea | Burg, Sabrina | Burgunder, Jean-Marc | Burns, Peter | Burrows, Liz | Busquets, Nuria | Busse, Monica | Calopa, Matilde | Carruesco, Gemma T. | Casado, Ana Gonzalez | Catena, Judit López | Chu, Carol | Ciesielska, Anna | Clapton, Jackie | Clayton, Carole | Clenaghan, Catherine | Coelho, Miguel | Connemann, Julia | Craufurd, David | Crooks, Jenny | Cubillo, Patricia Trigo | Cubo, Esther | Curtis, Adrienne | De Michele, Giuseppe | De Nicola, A. | de Souza, Jenny | de Weert, A. Marit | de Yébenes, Justo Garcia | Dekker, M. | Descals, A. Martínez | Di Maio, Luigi | Di Pietro, Anna | Dipple, Heather | Dose, Matthias | Dumas, Eve M. | Dunnett, Stephen | Ecker, Daniel | Elifani, F. | Ellison-Rose, Lynda | Elorza, Marina D. | Eschenbach, Carolin | Evans, Carole | Fairtlough, Helen | Fannemel, Madelein | Fasano, Alfonso | Fenollar, Maria | Ferrandes, Giovanna | Ferreira, Jaoquim J. | Fillingham, Kay | Finisterra, Ana Maria | Fisher, K. | Fletcher, Amy | Foster, Jillian | Foustanos, Isabella | Frech, Fernando A. | Fullam, Robert | Fullham, Ruth | Gago, Miguel | García, RocioGarcía-Ramos | García, Socorro S. | Garrett, Carolina | Gellera, Cinzia | Gill, Paul | Ginestroni, Andrea | Golding, Charlotte | Goodman, Anna | Gørvell, Per | Grant, Janet | Griguoli, A. | Gross, Diana | Guedes, Leonor | BascuñanaGuerra, Monica | Guerra, Maria Rosalia | Guerrero, Rosa | Guia, Dolores B. | Guidubaldi, Arianna | Hallam, Caroline | Hamer, Stephanie | Hammer, Kathrin | Handley, Olivia J. | Harding, Alison | Hasholt, Lis | Hedge, Reikha | Heiberg, Arvid | Heinicke, Walburgis | Held, Christine | Hernanz, Laura Casas | Herranhof, Briggitte | Herrera, Carmen Durán | Hidding, Ute | Hiivola, Heli | Hill, Susan | Hjermind, Lena. E. | Hobson, Emma | Hoffmann, Rainer | Holl, Anna Hödl | Howard, Liz | Hunt, Sarah | Huson, Susan | Ialongo, Tamara | Idiago, Jesus Miguel R. | Illmann, Torsten | Jachinska, Katarzyna | Jacopini, Gioia | Jakobsen, Oda | Jamieson, Stuart | Jamrozik, Zygmunt | Janik, Piotr | Johns, Nicola | Jones, Lesley | Jones, Una | Jurgens, Caroline K. | Kaelin, Alain | Kalbarczyk, Anna | Kershaw, Ann | Khalil, Hanan | Kieni, Janina | Klimberg, Aneta | Koivisto, Susana P. | Koppers, Kerstin | Kosinski, Christoph Michael | Krawczyk, Malgorzata | Kremer, Berry | Krysa, Wioletta | Kwiecinski, Hubert | Lahiri, Nayana | Lambeck, Johann | Lange, Herwig | Laver, Fiona | Leenders, K.L. | Levey, Jamie | Leythaeuser, Gabriele | Lezius, Franziska | Llesoy, Joan Roig | Löhle, Matthias | López, Cristobal Diez-Aja | Lorenza, Fortuna | Loria, Giovanna | Magnet, Markus | Mandich, Paola | Marchese, Roberta | Marcinkowski, Jerzy | Mariotti, Caterina | Mariscal, Natividad | Markova, Ivana | Marquard, Ralf | Martikainen, Kirsti | Martínez, Isabel Haro | Martínez-Descals, Asuncion | Martino, T. | Mason, Sarah | McKenzie, Sue | Mechi, Claudia | Mendes, Tiago | Mestre, Tiago | Middleton, Julia | Milkereit, Eva | Miller, Joanne | Miller, Julie | Minster, Sara | Möller, Jens Carsten | Monza, Daniela | Morales, Blas | Moreau, Laura V. | Moreno, Jose L. López-Sendón | Münchau, Alexander | Murch, Ann | Nielsen, Jørgen E. | Niess, Anke | Nørremølle, Anne | Novak, Marianne | O'Donovan, Kristy | Orth, Michael | Otti, Daniela | Owen, Michael | Padieu, Helene | Paganini, Marco | Painold, Annamaria | Päivärinta, Markku | Partington-Jones, Lucy | Paterski, Laurent | Paterson, Nicole | Patino, Dawn | Patton, Michael | Peinemann, Alexander | Peppa, Nadia | Perea, Maria Fuensanta Noguera | Peterson, Maria | Piacentini, Silvia | Piano, Carla | Càrdenas, Regina Pons i | Prehn, Christian | Price, Kathleen | Probst, Daniela | Quarrell, Oliver | Quiroga, Purificacion Pin | Raab, Tina | Rakowicz, Maryla | Raman, Ashok | Raymond, Lucy | Reilmann, Ralf | Reinante, Gema | Reisinger, Karin | Retterstol, Lars | Ribaï, Pascale | Riballo, Antonio V. | Ribas, Guillermo G. | Richter, Sven | Rickards, Hugh | Rinaldi, Carlo | Rissling, Ida | Ritchie, Stuart | Rivera, Susana Vázquez | Robert, Misericordia Floriach | Roca, Elvira | Romano, Silvia | Romoli, Anna Maria | Roos, Raymond A.C. | Røren, Niini | Rose, Sarah | Rosser, Elisabeth | Rosser, Anne | Rossi, Fabiana | Rothery, Jean | Rudzinska, Monika | Ruíz, Pedro J. García | Ruíz, Belan Garzon | Russo, Cinzia Valeria | Ryglewicz, Danuta | Saft, Carston | Salvatore, Elena | Sánchez, Vicenta | Sando, Sigrid Botne | Šašinková, Pavla | Sass, Christian | Scheibl, Monika | Schiefer, Johannes | Schlangen, Christiane | Schmidt, Simone | Schöggl, Helmut | Schrenk, Caroline | Schüpbach, Michael | Schuierer, Michele | Sebastián, Ana Rojo | Selimbegovic-Turkovic, Amina | Sempolowicz, Justyna | Silva, Mark | Sitek, Emilia | Slawek, Jaroslaw | Snowden, Julie | Soleti, Francesco | Soliveri, Paola | Sollom, Andrea | Soltan, Witold | Sorbi, Sandro | Sorensen, Sven Asger | Spadaro, Maria | Städtler, Michael | Stamm, Christiane | Steiner, Tanja | Stokholm, Jette | Stokke, Bodil | Stopford, Cheryl | Storch, Alexander | Straßburger, Katrin | Stubbe, Lars | Sulek, Anna | Szczudlik, Andrzej | Tabrizi, Sarah | Taylor, Rachel | Terol, Santiago Duran-Sindreu | Thomas, Gareth | Thompson, Jennifer | Thomson, Aileen | Tidswell, Katherine | Torres, Maria M. Antequera | Toscano, Jean | Townhill, Jenny | Trautmann, Sonja | Tucci, Tecla | Tuuha, Katri | Uhrova, Tereza | Valadas, Anabela | van Hout, Monique S.E. | van Oostrom, J.C.H. | van Vugt, Jeroen P.P. | vanm, Walsem Marleen R. | Vandenberghe, Wim | Verellen-Dumoulin, Christine | Vergara, Mar Ruiz | Verstappen, C.C.P. | Verstraelen, Nichola | Viladrich, Celia Mareca | Villanueva, Clara | Wahlström, Jan | Warner, Thomas | Wehus, Raghild | Weindl, Adolf | Werner, Cornelius J. | Westmoreland, Leann | Weydt, Patrick | Wiedemann, Alexandra | Wild, Edward | Wild, Sue | Witjes-Ané, Marie-Noelle | Witkowski, Grzegorz | Wójcik, Magdalena | Wolz, Martin | Wolz, Annett | Wright, Jan | Yardumian, Pam | Yates, Shona | Yudina, Elizaveta | Zaremba, Jacek | Zaugg, Sabine W. | Zdzienicka, Elzbieta | Zielonka, Daniel | Zielonka, Euginiusz | Zinzi, Paola | Zittel, Simone | Zucker, Birgrit | Adams, John | Agarwal, Pinky | Antonijevic, Irina | Beck, Christopher | Chiu, Edmond | Churchyard, Andrew | Colcher, Amy | Corey-Bloom, Jody | Dorsey, Ray | Drazinic, Carolyn | Dubinsky, Richard | Duff, Kevin | Factor, Stewart | Foroud, Tatiana | Furtado, Sarah | Giuliano, Joe | Greenamyre, Timothy | Higgins, Don | Jankovic, Joseph | Jennings, Dana | Kang, Un Jung | Kostyk, Sandra | Kumar, Rajeev | Leavitt, Blair | LeDoux, Mark | Mallonee, William | Marshall, Frederick | Mohlo, Eric | Morgan, John | Oakes, David | Panegyres, Peter | Panisset, Michel | Perlman, Susan | Perlmutter, Joel | Quaid, Kimberly | Raymond, Lynn | Revilla, Fredy | Robertson, Suzanne | Robottom, Bradley | Sanchez-Ramos, Juan | Scott, Burton | Shannon, Kathleen | Shoulson, Ira | Singer, Carlos | Tabbal, Samer | Testa, Claudia | van, Kammen Dan | Vetter, Louise | Walker, Francis | Warner, John | Weiner, illiam | Wheelock, Vicki | Yastrubetskaya, Olga | Barton, Stacey | Broyles, Janice | Clouse, Ronda | Coleman, Allison | Davis, Robert | Decolongon, Joji | DeLaRosa, Jeanene | Deuel, Lisa | Dietrich, Susan | Dubinsky, Hilary | Eaton, Ken | Erickson, Diane | Fitzpatrick, Mary Jane | Frucht, Steven | Gartner, Maureen | Goldstein, Jody | Griffith, Jane | Hickey, Charlyne | Hunt, Victoria | Jaglin, Jeana | Klimek, Mary Lou | Lindsay, Pat | Louis, Elan | Loy, Clemet | Lucarelli, Nancy | Malarick, Keith | Martin, Amanda | McInnis, Robert | Moskowitz, Carol | Muratori, Lisa | Nucifora, Frederick | O'Neill, Christine | Palao, Alicia | Peavy, Guerry | Quesada, Monica | Schmidt, Amy | Segro, Vicki | Sperin, Elaine | Suter, Greg | Tanev, Kalo | Tempkin, Teresa | Thiede, Curtis | Wasserman, Paula | Welsh, Claire | Wesson, Melissa | Zauber, Elizabeth
Neurology  2012;78(10):690-695.
Objective:
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
Methods:
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
Results:
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Conclusions:
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
doi:10.1212/WNL.0b013e318249f683
PMCID: PMC3306163  PMID: 22323755
3.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
RESULTS
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
CONCLUSIONS
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
doi:10.2337/db11-0415
PMCID: PMC3178302  PMID: 21873549
4.  The compact Selaginella genome identifies changes in gene content associated with the evolution of vascular plants 
Banks, Jo Ann | Nishiyama, Tomoaki | Hasebe, Mitsuyasu | Bowman, John L. | Gribskov, Michael | dePamphilis, Claude | Albert, Victor A. | Aono, Naoki | Aoyama, Tsuyoshi | Ambrose, Barbara A. | Ashton, Neil W. | Axtell, Michael J. | Barker, Elizabeth | Barker, Michael S. | Bennetzen, Jeffrey L. | Bonawitz, Nicholas D. | Chapple, Clint | Cheng, Chaoyang | Correa, Luiz Gustavo Guedes | Dacre, Michael | DeBarry, Jeremy | Dreyer, Ingo | Elias, Marek | Engstrom, Eric M. | Estelle, Mark | Feng, Liang | Finet, Cédric | Floyd, Sandra K. | Frommer, Wolf B. | Fujita, Tomomichi | Gramzow, Lydia | Gutensohn, Michael | Harholt, Jesper | Hattori, Mitsuru | Heyl, Alexander | Hirai, Tadayoshi | Hiwatashi, Yuji | Ishikawa, Masaki | Iwata, Mineko | Karol, Kenneth G. | Koehler, Barbara | Kolukisaoglu, Uener | Kubo, Minoru | Kurata, Tetsuya | Lalonde, Sylvie | Li, Kejie | Li, Ying | Litt, Amy | Lyons, Eric | Manning, Gerard | Maruyama, Takeshi | Michael, Todd P. | Mikami, Koji | Miyazaki, Saori | Morinaga, Shin-ichi | Murata, Takashi | Mueller-Roeber, Bernd | Nelson, David R. | Obara, Mari | Oguri, Yasuko | Olmstead, Richard G. | Onodera, Naoko | Petersen, Bent Larsen | Pils, Birgit | Prigge, Michael | Rensing, Stefan A. | Riaño-Pachón, Diego Mauricio | Roberts, Alison W. | Sato, Yoshikatsu | Scheller, Henrik Vibe | Schulz, Burkhard | Schulz, Christian | Shakirov, Eugene V. | Shibagaki, Nakako | Shinohara, Naoki | Shippen, Dorothy E. | Sørensen, Iben | Sotooka, Ryo | Sugimoto, Nagisa | Sugita, Mamoru | Sumikawa, Naomi | Tanurdzic, Milos | Theißen, Günter | Ulvskov, Peter | Wakazuki, Sachiko | Weng, Jing-Ke | Willats, William W.G.T. | Wipf, Daniel | Wolf, Paul G. | Yang, Lixing | Zimmer, Andreas D. | Zhu, Qihui | Mitros, Therese | Hellsten, Uffe | Loqué, Dominique | Otillar, Robert | Salamov, Asaf | Schmutz, Jeremy | Shapiro, Harris | Lindquist, Erika | Lucas, Susan | Rokhsar, Daniel | Grigoriev, Igor V.
Science (New York, N.Y.)  2011;332(6032):960-963.
Vascular plants appeared ~410 million years ago then diverged into several lineages of which only two survive: the euphyllophytes (ferns and seed plants) and the lycophytes (1). We report here the genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first non-seed vascular plant genome reported. By comparing gene content in evolutionary diverse taxa, we found that the transition from a gametophyte- to sporophyte-dominated life cycle required far fewer new genes than the transition from a non-seed vascular to a flowering plant, while secondary metabolic genes expanded extensively and in parallel in the lycophyte and angiosperm lineages. Selaginella differs in post-transcriptional gene regulation, including small RNA regulation of repetitive elements, an absence of the tasiRNA pathway and extensive RNA editing of organellar genes.
doi:10.1126/science.1203810
PMCID: PMC3166216  PMID: 21551031
5.  Nonadherent cultures of human monocytes kill Mycobacterium smegmatis, but adherent cultures do not. 
Infection and Immunity  1996;64(2):428-433.
Human peripheral blood monocytes are permissive for the growth of Mycobacterium tuberculosis, but the fate of nonpathogenic Mycobacterium smegmatis in these cells is not known. Since M. smegmatis may be used as a host with which to express and screen for M. tuberculosis genes needed for survival in monocytes, we determined whether human peripheral blood monocytes could restrict the growth of Mycobacterium smegmatis. Adherent human peripheral blood monocytes were permissive for the growth of M. smegmatis, as measured by ex vivo [3H]uracil uptake. However, human peripheral blood monocytes which were cultured nonadherently in Teflon wells were able to restrict the growth of M. smegmatis while remaining permissive for the growth of M. tuberculosis H37Ra. The loss of viability of M. smegmatis in nonadherent cells was correlated with an increase in nonspacious phagocytic vacuoles. The killing of M. smegmatis was not blocked by NG-monomethyl-L-arginine, suggesting that it was not due to the production of reactive nitrogen intermediates. Incubation of the monocytes for 1 to 7 days before infection had no effect on the fate of M. smegmatis, suggesting that adherence versus nonadherence, and not differentiation, was the key determinant for the difference in functional ability. Nonadherent human peripheral blood monocytes may be a more appropriate model than adherent cells for the study of factors employed by bacterial to survive within monocytes and for selection screening of bacterial genes needed for intracellular survival.
PMCID: PMC173781  PMID: 8550187
9.  Orthopaedics in the Tropics 
British Medical Journal  1961;2(5248):383-384.
Images
PMCID: PMC1969219
10.  Late Lactation 
British Medical Journal  1960;1(5182):1365.
PMCID: PMC1967584
11.  Stillbirth Rates in “Non-White” Women 
British Medical Journal  1957;1(5033):1472.
PMCID: PMC1973401  PMID: 13436828
13.  Transplantation and inflammation: implications for the modification of chemokine function 
Immunology  2014;143(2):138-145.
Oxidative stress is a major and recurring cause of damage during inflammation, especially following organ transplantation. Initial ischaemia–reperfusion injury causes the production of many reactive oxygen and nitrogen species, and subsequent recruitment and activation of inflammatory cells can lead to further oxidative stress. This stress is well known to cause damage at the cellular level, for example by induction of senescence leading to the production of a characteristic senescence-associated secretory phenotype. Chemokines are an important component of the senescence-associated secretory phenotype, recruiting further leucocytes and reinforcing the stress and senescence responses. As well as inducing the production of proteins, including chemokines, oxidative stress can alter proteins themselves, both directly and by induction of enzymes capable of modification. These alterations can lead to important modifications to their biological activity and also alter detection by some antibodies, potentially limiting the biological relevance of some immunochemical and proteomic biomarkers. Peroxynitrite, a reactive nitrogen species generated during inflammation and ischaemia, can cause such modifications by nitrating chemokines. Matrix metalloproteinases, released by many stressed cells, can cleave chemokines, altering function, while peptidylarginine deiminases can inactivate certain chemokines by citrullination. This review discusses the relationship between inflammation and post-translational modification, focusing on the functional modulation of transplant-relevant pro-inflammatory chemokines.
doi:10.1111/imm.12332
PMCID: PMC4172130  PMID: 24912917
chemokines; inflammation; post-translational modification; stress
15.  Population Declines of Mountain Coqui (Eleutherodactylus portoricensis) in the Cordillera Central of Puerto Rico 
The Mountain Coqui (Eleutherodactylus portoricensis) is a frog endemic to montane rainforests in the Cordillera Central and Luquillo Mountains of Puerto Rico. Classified as endangered by the IUCN Red List and as vulnerable by the Department of Natural and Environmental Resources of Puerto Rico, this species has undergone considerable decline in the Luquillo Mountains. To evaluate the population status of E. portoricensis across its entire range, we conducted ~87 hours of surveys at 18 historical localities and 25 additional localities that we considered suitable for this species. We generated occupancy models to estimate the probability of occurrence at surveyed sites and to identify geographic and climatic factors affecting site occupancy. We also constructed a suitability map to visualize population status in relation to the presence of land cover at elevations where the species has been documented, and determined the dates when populations were last detected at historical localities. Eleutherodactylus portoricensis was detected at 14 of 43 localities, including 10 of 18 historical localities, but it was not detected at any localities west of Aibonito (western Cordillera Central). Occupancy models estimated the probability of occurrence for localities in the western Cordillera Central as zero. Site occupancy was positively associated with montane cloud forest, and negatively associated with the western Cordillera Central, maximum temperature, and precipitation seasonality. The suitability map suggests that declines have occurred despite the presence of suitable habitat. We suggest upgrading the extinction risk of E. portoricensis and potentially developing a captive breeding program for this species.
PMCID: PMC4326090
Mountain Coqui; Eleutherodactylus portoricensis; population status; decline; extirpation; Puerto Rico; Cordillera Central
16.  Bicuspid Aortic Cusp Fusion Morphology Alters Aortic 3D Outflow Patterns, Wall Shear Stress and Expression of Aortopathy 
Circulation  2013;129(6):673-682.
Background:
Aortic 3D blood flow was analyzed to investigate altered ascending aorta (AAo) hemodynamics in bicuspid aortic valve (BAV) patients and its association with differences in cusp fusion patterns (right-left, RL versus right-noncoronary, RN) and expression of aortopathy.
Methods and Results:
4D flow MRI measured in vivo 3D blood flow in the aorta of 75 subjects: BAV patients with aortic dilatation stratified by leaflet fusion pattern (n=15 RL-BAV, mid AAo diameter=39.9±4.4mm; n=15 RN-BAV, 39.6±7.2mm); aorta size controls with tricuspid aortic valves (n=30, 41.1±4.4mm); healthy volunteers (n=15, 24.9±3.0mm). Aortopathy type (0-3), systolic flow angle, flow displacement, and regional wall shear stress (WSS) were determined for all subjects. Eccentric outflow jet patterns in BAV patients resulted in elevated regional WSS (p<0.0125) at the right-anterior walls for RL-BAV and right-posterior walls for RN-BAV compared to aorta size controls. Dilatation of the aortic root only (type 1) or involving the entire AAo and arch (type 3) was found in the majority of RN-BAV patients (87%) but was mostly absent for RL-BAV (87% type 2). Differences in aortopathy type between RL-BAV and RN-BAV were associated with altered flow displacement in the proximal and mid AAo for type 1 (42-81% decrease versus type 2) and distal AAo for type 3 (33-39% increase versus type 2).
Conclusions:
The presence and type of BAV fusion was associated with changes in regional WSS distribution, systolic flow eccentricity, and expression of BAV aortopathy. Hemodynamic markers suggest a physiologic mechanism by which valve morphology phenotype can influence phenotypes of BAV aortopathy.
doi:10.1161/CIRCULATIONAHA.113.003026
PMCID: PMC3946057  PMID: 24345403
MRI; Bicuspid Aortic Valve; Wall Shear Stress; Hemodynamics; Aortic Disease; 4D flow MRI
17.  Investigation of Inter-Slice Magnetization Transfer Effects as a New Method for MTR Imaging of the Human Brain 
PLoS ONE  2015;10(2):e0117101.
We present a new method for magnetization transfer (MT) ratio imaging in the brain that requires no separate saturation pulse. Interslice MT effects that are inherent to multi-slice balanced steady-state free precession (bSSFP) imaging were controlled via an interslice delay time to generate MT-weighted (0 s delay) and reference images (5–8 s delay) for MT ratio (MTR) imaging of the brain. The effects of varying flip angle and phase encoding (PE) order were investigated experimentally in normal, healthy subjects. Values of up to ∼50% and ∼40% were observed for white and gray matter MTR. Centric PE showed larger MTR, higher SNR, and better contrast between white and gray matter than linear PE. Simulations of a two-pool model of MT agreed well with in vivo MTR values. Simulations were also used to investigate the effects of varying acquisition parameters, and the effects of varying flip angle, PE steps, and interslice delay are discussed. Lastly, we demonstrated reduced banding with a non-balanced SSFP-FID sequence and showed preliminary results of interslice MTR imaging of meningioma.
doi:10.1371/journal.pone.0117101
PMCID: PMC4321840  PMID: 25664938
18.  Structural and Biochemical Studies of a Moderately Thermophilic Exonuclease I from Methylocaldum szegediense 
PLoS ONE  2015;10(2):e0117470.
A novel exonuclease, designated as MszExo I, was cloned from Methylocaldum szegediense, a moderately thermophilic methanotroph. It specifically digests single-stranded DNA in the 3ʹ to 5ʹ direction. The protein is composed of 479 amino acids, and it shares 47% sequence identity with E. coli Exo I. The crystal structure of MszExo I was determined to a resolution of 2.2 Å and it aligns well with that of E. coli Exo I. Comparative studies revealed that MszExo I and E. coli Exo I have similar metal ion binding affinity and similar activity at mesophilic temperatures (25–47°C). However, the optimum working temperature of MszExo I is 10°C higher, and the melting temperature is more than 4°C higher as evaluated by both thermal inactivation assays and DSC measurements. More importantly, two thermal transitions during unfolding of MszExo I were monitored by DSC while only one transition was found in E. coli Exo I. Further analyses showed that magnesium ions not only confer structural stability, but also affect the unfolding of MszExo I. MszExo I is the first reported enzyme in the DNA repair systems of moderately thermophilic bacteria, which are predicted to have more efficient DNA repair systems than mesophilic ones.
doi:10.1371/journal.pone.0117470
PMCID: PMC4319927  PMID: 25658953
19.  Linked Clinical Trials – The Development of New Clinical Learning Studies in Parkinson’s Disease Using Screening of Multiple Prospective New Treatments 
Journal of Parkinson's disease  2013;3(3):231-239.
Finding new therapies for Parkinson’s disease (PD) is a slow process. We assembled an international committee of experts to examine drugs potentially suitable for repurposing to modify PD progression. This committee evaluated multiple drugs currently used, or being developed, in other therapeutic areas, as well as considering several natural, non-pharmaceutical compounds. The committee prioritized which of these putative treatments were most suited to move immediately into pilot clinical trials. Aspects considered included known modes of action, safety, blood-brain-barrier penetration, preclinical data in animal models of PD and the possibility to monitor target engagement in the brain. Of the 26 potential interventions, 10 were considered worth moving forward into small, parallel ‘learning’ clinical trials in PD patients. These trials could be funded in a multitude of ways through support from industry, research grants and directed philanthropic donations. The committee-based approach to select the candidate compounds might help rapidly identify new potential PD treatment strategies for use in clinical trials.
doi:10.3233/JPD-139000
PMCID: PMC4318242  PMID: 24018336
Drug repositioning; disease modification; neuroprotection

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