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1. STING-induced regulatory B cells compromise NK function in cancer immunity

Author: Sirui Li, Bhalchandra Mirlekar, Brandon M. Johnson, W. June Brickey, John A. Wrobel, Na Yang, Dingka Song, Sarah Entwistle, Xianming Tan, Meng Deng, Ya Cui, Wei Li, Benjamin G. Vincent, Michael Gale, Yuliya Pylayeva-Gupta, and Jenny P.-Y. Ting
Subjects: B-Lymphocytes, Regulatory, Multidisciplinary, Interleukins, Membrane Proteins, Immunity, Innate, Article, Killer Cells, Natural, Mice, Neoplasms, Interferon Type I, Tumor Microenvironment, Animals, Humans, Interferon Regulatory Factor-3, Immunotherapy, Nucleotides, Cyclic
Abstract: An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers(1–3). Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression(4). Although these agonists hold promise as potential cancer therapies(5), tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) are unclear(5–7). Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35 regulatory B lymphocytes in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING–IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours.
Published: 2022
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2. STING-induced regulatory B cells compromise NK function in cancer immunity

Author: Li, Sirui, primary, Mirlekar, Bhalchandra, additional, Johnson, Brandon M., additional, Brickey, W. June, additional, Wrobel, John A., additional, Yang, Na, additional, Song, Dingka, additional, Entwistle, Sarah, additional, Tan, Xianming, additional, Deng, Meng, additional, Cui, Ya, additional, Li, Wei, additional, Vincent, Benjamin G., additional, Gale, Michael, additional, Pylayeva-Gupta, Yuliya, additional, and Ting, Jenny P.-Y., additional
Published: 2022
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3. Survey of spiking in the mouse visual system reveals functional hierarchy

Author: Luke Esposito, John W. Phillips, Lydia Ng, Maggie Chvilicek, Kara Ronellenfitch, Corbett Bennett, Kael Dai, Peter A. Groblewski, John Galbraith, Jackie Swapp, Brian Hu, Ross Hytnen, Fuhui Long, Emily Gelfand, R.D. Young, India Kato, Linzy Casal, Greggory Heller, Jennifer Luviano, Xiaoxuan Jia, Ben Sutton, Michael A. Buice, Saskia E. J. de Vries, Shiella Caldejon, Sam Seid, Tamina K. Ramirez, Thuyahn Nguyen, Wayne Wakeman, Chelsea Nayan, Philip R. Nicovich, Roald Dietzman, Nicole Hancock, Colin Farrell, Carol L. Thompson, David Feng, Erika Jessett, Hongkui Zeng, Elizabeth Liang, Shawn R. Olsen, Kristen Turner, Jérôme Lecoq, Derric Williams, Katelyn Johnson, Jose Melchior, Stefan Mihalas, Hannah Choi, Sam Gale, Jennifer D. Whitesell, Ramakrishnan Iyer, Kat North, Melissa Reding, Dillan Brown, Yang Li, Kiet Ngo, Séverine Durand, Robert Howard, Amy Bernard, Anton Arkhipov, Julie A. Harris, Ali Williford, Yazan N. Billeh, Marina Garrett, Sophie Lambert, Tyler Mollenkopf, Arielle Leon, Marius Pachitariu, Michael Oliver, Nicolas Cain, Gabriel Koch Ocker, Daniel J. Denman, Justin T. Kiggins, Joshua H. Siegle, R. Clay Reid, Douglas R. Ollerenshaw, David Reid, Cliff Slaughterbeck, David Sullivan, Jed Perkins, Ruweida Ahmed, Daniel Millman, Jung Hoon Lee, Kyla Mace, Christof Koch, Andrew Cho, Nile Graddis, Timothy C. Cox, Peter Ledochowitsch, Miranda Robertson, Michelle Stoecklin, and Sarah A. Naylor
Subjects: 0301 basic medicine, Hierarchy, Retina, Multidisciplinary, Neocortex, Visual perception, genetic structures, Computer science, Direct observation, Visual task, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, medicine, Latency (engineering), Neuroscience, 030217 neurology & neurosurgery, Coding (social sciences)
Abstract: The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically1. However, direct observation of cellular-level functional interactions across this hierarchy is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory2-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area functional connectivity during visual stimulation mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas3. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.
Published: 2021
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4. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA

Author: Murtaza, Muhammed, Dawson, Sarah-Jane, Tsui, Dana W.Y., Gale, Davina, Forshew, Tim, Piskorz, Anna M., Parkinson, Christine, Chin, Suet-Feung, Kingsbury, Zoya, Wong, Alvin S.C., Marass, Francesco, Humphray, Sean, Hadfield, James, Bentley, David, Chin, Tan Min, Brenton, James D., Caldas, Carlos, and Rosenfeld, Nitzan
Subjects: Nucleotide sequencing -- Research -- Physiological aspects -- Genetic aspects, Antineoplastic agents -- Dosage and administration -- Research, DNA sequencing -- Research -- Physiological aspects -- Genetic aspects, Drug resistance -- Research -- Genetic aspects, Cancer -- Care and treatment, Blood plasma -- Physiological aspects -- Genetic aspects -- Research, Antimitotic agents -- Dosage and administration -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection (1,2). Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and [...]
Published: 2013

5. Structural basis of RNA recognition and activation by innate immune receptor RIG-I

Author: Jiang, Fuguo, Ramanathan, Anand, Miller, Matthew T., Tang, Guo-Qing, Gale, Jr., Michael, Patel, Smita S., and Marcotrigiano, Joseph
Subjects: Tretinoin -- Genetic aspects -- Health aspects, RNA -- Health aspects -- Structure, Immune recognition -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds)RNA with or without a 5' -triphosphate (ppp), by single-stranded RNA marked by a 5'-ppp (1) and by polyuridine sequences (2,3). Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer (4,5). The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5'-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the RD for RNA binding, and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within DICER and FANCM., To investigate the contributions of the individual domains of RIG-I to RNA binding, we used fluorescence anisotropy to determine the equilibrium dissociation constants ([K.sub.d]) of the protein-RNA complexes. The tightest [...]
Published: 2011
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6. 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members

Author: Daffis, Stephane, Szretter, Kristy J., Schriewer, Jill, Li, Jianqing, Youn, Soonjeon, Errett, John, Lin, Tsai-Yu, Schneller, Stewart, Zust, Roland, Dong, Hongping, Thiel, Volker, Sen, Ganes C., Fensterl, Volker, Klimstra, William B., Pierson, Theodore C., Buller, R. Mark, Gale, Jr., Michael, Shi, Pei-Yong, and Diamond, Michael S.
Subjects: Interferon, West Nile fever, Methylation, Messenger RNA, Methyltransferases, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2'-O positions of the 5' guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability (1), the function of 2'-O methylation has remained uncertain since its discovery 35 years ago (2-4). Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2'-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2'-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2'-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2'-O methylation of the 5' cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2'-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells., Most eukaryotic mRNA contains a 5' Cap 0 (7mGpppN) structure with a methyl group at the N-7 position. In higher eukaryotes, methylation of cellular mRNA occurs additionally at the 2'-O [...]
Published: 2010
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7. Early Pleistocene human occupation at the edge of the boreal zone in northwest Europe

Author: Parfitt, Simon A., Ashton, Nick M., Lewis, Simon G., Abel, Richard L., Coope, G. Russell, Field, Mike H., Gale, Rowena, Hoare, Peter G., Larkin, Nigel R., Lewis, Mark D., Karloukovski, Vassil, Maher, Barbara A., Peglar, Sylvia M., Preece, Richard C., Whittaker, John E., and Stringer, Chris B.
Subjects: Megafauna -- Research -- Environmental aspects, Taigas -- Environmental aspects -- Research
Abstract: The dispersal of early humans from Africa by 1.75 Myr ago led to a marked expansion of their range, from the island of Flores in the east to the Iberian peninsula in the west (1-5). This range encompassed tropical forest, savannah and Mediterranean habitats, but has hitherto not been demonstrated beyond 45° N. Until recently, early colonization in Europe was thought to be confined to the area south of the Pyrenees and Alps. However, evidence from Pakefield (Suffolk, UK) at ~0.7 Myr indicated that humans occupied northern European latitudes when a Mediterranean-type climate prevailed (6). This provided the basis for an 'ebb and flow' model, where human populations were thought to survive in southern refugia during cold stages, only expanding northwards during fully temperate climates (5). Here we present new evidence from Happisburgh (Norfolk, UK) demonstrating that Early Pleistocene hominins were present in northern Europe >0.78 Myr ago when they were able to survive at the southern edge of the boreal zone. This has significant implications for our understanding of early human behaviour, adaptation and survival, as well as the tempo and mode of colonization after their first dispersal out of Africa., At Happisburgh Site 3 (Fig. 1) an assemblage of 78 flint artefacts has been excavated from fluvial gravels and laminated estuarine sands and silts that fill a series of stacked, [...]
Published: 2010
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8. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Author: Saito, Takeshi, Owen, David M., Jiang, Fuguo, Marcotrigiano, Joseph, and Gale, Jr., Michael
Subjects: Hepatitis C virus -- Research -- Genetic aspects -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation, Physiological aspects, Research, Genetic aspects
Abstract: Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs) (1). Hepatitis C [...]
Published: 2008

9. The origin of spontaneous activity in the developing auditory system

Author: Tritsch, Nicolas X., Yi, Eunyoung, Gale, Jonathan E., Glowatzki, Elisabeth, and Bergles, Dwight E.
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Nicolas X. Tritsch [1]; Eunyoung Yi [2]; Jonathan E. Gale [3]; Elisabeth Glowatzki [1, 2]; Dwight E. Bergles (corresponding author) [1, 2] Auditory perception depends on the precise conversion [...]
Published: 2007
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10. Generation of functional multipotent adult stem cells from [GPR125.sup.+] germline progenitors

Author: Seandel, Marco, James, Daylon, Shmelkov, Sergey V., Falciatori, Ilaria, Kim, Jiyeon, Chavala, Sai, Scherr, Douglas S., Zhang, Fan, Torres, Richard, Gale, Nicholas W., Yancopoulos, George D., Murphy, Andrew, Valenzuela, David M., Hobbs, Robin M., Pandolfi, Pier Paolo, and Rafii, Shahin
Subjects: Testis -- Health aspects, Stem cell research -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation, Health aspects
Abstract: Adult mammalian testis is a source of pluripotent stem cells (1). However, the lack of specific surface markers has hampered identification and tracking of the unrecognized subset of germ cells [...]
Published: 2007

11. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author: Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]
Published: 2007
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12. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis

Author: Noguera-Troise, Irene, Daly, Christopher, Papadopoulos, Nicholas J., Coetzee, Sandra, Boland, Pat, Gale, Nicholas W., Chieh Lin, Hsin, Yancopoulos, George D., and Thurston, Gavin
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Irene Noguera-Troise [1]; Christopher Daly [1]; Nicholas J. Papadopoulos [1]; Sandra Coetzee [1]; Pat Boland [1]; Nicholas W. Gale [1]; Hsin Chieh Lin [1]; George D. Yancopoulos [1]; Gavin [...]
Published: 2006
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13. Survey of spiking in the mouse visual system reveals functional hierarchy

Author: Siegle, Joshua H., primary, Jia, Xiaoxuan, additional, Durand, Séverine, additional, Gale, Sam, additional, Bennett, Corbett, additional, Graddis, Nile, additional, Heller, Greggory, additional, Ramirez, Tamina K., additional, Choi, Hannah, additional, Luviano, Jennifer A., additional, Groblewski, Peter A., additional, Ahmed, Ruweida, additional, Arkhipov, Anton, additional, Bernard, Amy, additional, Billeh, Yazan N., additional, Brown, Dillan, additional, Buice, Michael A., additional, Cain, Nicolas, additional, Caldejon, Shiella, additional, Casal, Linzy, additional, Cho, Andrew, additional, Chvilicek, Maggie, additional, Cox, Timothy C., additional, Dai, Kael, additional, Denman, Daniel J., additional, de Vries, Saskia E. J., additional, Dietzman, Roald, additional, Esposito, Luke, additional, Farrell, Colin, additional, Feng, David, additional, Galbraith, John, additional, Garrett, Marina, additional, Gelfand, Emily C., additional, Hancock, Nicole, additional, Harris, Julie A., additional, Howard, Robert, additional, Hu, Brian, additional, Hytnen, Ross, additional, Iyer, Ramakrishnan, additional, Jessett, Erika, additional, Johnson, Katelyn, additional, Kato, India, additional, Kiggins, Justin, additional, Lambert, Sophie, additional, Lecoq, Jerome, additional, Ledochowitsch, Peter, additional, Lee, Jung Hoon, additional, Leon, Arielle, additional, Li, Yang, additional, Liang, Elizabeth, additional, Long, Fuhui, additional, Mace, Kyla, additional, Melchior, Jose, additional, Millman, Daniel, additional, Mollenkopf, Tyler, additional, Nayan, Chelsea, additional, Ng, Lydia, additional, Ngo, Kiet, additional, Nguyen, Thuyahn, additional, Nicovich, Philip R., additional, North, Kat, additional, Ocker, Gabriel Koch, additional, Ollerenshaw, Doug, additional, Oliver, Michael, additional, Pachitariu, Marius, additional, Perkins, Jed, additional, Reding, Melissa, additional, Reid, David, additional, Robertson, Miranda, additional, Ronellenfitch, Kara, additional, Seid, Sam, additional, Slaughterbeck, Cliff, additional, Stoecklin, Michelle, additional, Sullivan, David, additional, Sutton, Ben, additional, Swapp, Jackie, additional, Thompson, Carol, additional, Turner, Kristen, additional, Wakeman, Wayne, additional, Whitesell, Jennifer D., additional, Williams, Derric, additional, Williford, Ali, additional, Young, Rob, additional, Zeng, Hongkui, additional, Naylor, Sarah, additional, Phillips, John W., additional, Reid, R. Clay, additional, Mihalas, Stefan, additional, Olsen, Shawn R., additional, and Koch, Christof, additional
Published: 2021
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14. Simulating micrometre-scale crystal growth from solution

Author: Piana, Stefano, Reyhani, Manijeh, and Gale, Julian D.
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Stefano Piana [1]; Manijeh Reyhani [1]; Julian D. Gale (corresponding author) [1] Understanding crystal growth is essential for controlling the crystallization used in industrial separation and purification processes. Because [...]
Published: 2005
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15. Evasion of intracellular host defence by hepatitis C virus

Author: Gale, Jr, Michael and Foy, Eileen M.
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Michael Gale, Jr [1]; Eileen M. Foy [1] Hepatitis C virus (HCV) is remarkably successful. It typically produces a persistent infection that, unless interrupted by interferon (IFN)-based therapy, will [...]
Published: 2005
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16. Averting biodiversity collapse in tropical forest protected areas

Author: Laurance, William F., Useche, Carolina D., Rendeiro, Julio, Kalka, Margareta, Bradshaw, Corey J. A., Sloan, Sean P., Laurance, Susan G., Campbell, Mason, Abernethy, Kate, Alvarez, Patricia, Arroyo-Rodriguez, Victor, Ashton, Peter, Benítez-Malvido, Julieta, Blom, Allard, Bobo, Kadiri S., Cannon, Charles H., Cao, Min, Carroll, Richard, Chapman, Colin, Coates, Rosamond, Cords, Marina, Danielsen, Finn, De Dijn, Bart, Dinerstein, Eric, Donnelly, Maureen A., Edwards, David, Edwards, Felicity, Farwig, Nina, Fashing, Peter, Forget, Pierre-Michel, Foster, Mercedes, Gale, George, Harris, David, Harrison, Rhett, Hart, John, Karpanty, Sarah, Kress, John W., Krishnaswamy, Jagdish, Logsdon, Willis, Lovett, Jon, Magnusson, William, Maisels, Fiona, Marshall, Andrew R., McClearn, Deedra, Mudappa, Divya, Nielsen, Martin R., Pearson, Richard, Pitman, Nigel, van der Ploeg, Jan, Plumptre, Andrew, Poulsen, John, Quesada, Mauricio, Rainey, Hugo, Robinson, Douglas, Roetgers, Christiane, Rovero, Francesco, Scatena, Frederick, Schulze, Christian, Sheil, Douglas, Struhsaker, Thomas, Terborgh, John, Thomas, Duncan, Timm, Robert, Urbina-Cardona, Nicolas J., Vasudevan, Karthikeyan, Wright, Joseph S., Arias, Juan Carlos G., Arroyo, Luzmila, Ashton, Mark, Auzel, Philippe, Babaasa, Dennis, Babweteera, Fred, Baker, Patrick, Banki, Olaf, Bass, Margot, Bila-Isia, Inogwabini, Blake, Stephen, Brockelman, Warren, Brokaw, Nicholas, Brühl, Carsten A., Bunyavejchewin, Sarayudh, Chao, Jung-Tai, Chave, Jerome, Chellam, Ravi, Clark, Connie J., Clavijo, José, Congdon, Robert, Corlett, Richard, Dattaraja, H. S., Dave, Chittaranjan, Davies, Glyn, de Mello Beisiegel, Beatriz, de Nazaré Paes da Silva, Rosa, Di Fiore, Anthony, Diesmos, Arvin, Dirzo, Rodolfo, Doran-Sheehy, Diane, Eaton, Mitchell, Emmons, Louise, Estrada, Alejandro, Ewango, Corneille, Fedigan, Linda, Feer, François, Fruth, Barbara, Willis, Jacalyn Giacalone, Goodale, Uromi, Goodman, Steven, Guix, Juan C., Guthiga, Paul, Haber, William, Hamer, Keith, Herbinger, Ilka, Hill, Jane, Huang, Zhongliang, Sun, I Fang, Ickes, Kalan, Itoh, Akira, Ivanauskas, Natália, Jackes, Betsy, Janovec, John, Janzen, Daniel, Jiangming, Mo, Jin, Chen, Jones, Trevor, Justiniano, Hermes, Kalko, Elisabeth, Kasangaki, Aventino, Killeen, Timothy, King, Hen-biau, Klop, Erik, Knott, Cheryl, Koné, Inza, Kudavidanage, Enoka, da Silva Ribeiro, José Lahoz, Lattke, John, Laval, Richard, Lawton, Robert, Leal, Miguel, Leighton, Mark, Lentino, Miguel, Leonel, Cristiane, Lindsell, Jeremy, Ling-Ling, Lee, Linsenmair, Eduard K., Losos, Elizabeth, Lugo, Ariel, Lwanga, Jeremiah, Mack, Andrew L., Martins, Marlucia, McGraw, Scott W., McNab, Roan, Montag, Luciano, Thompson, Jo Myers, Nabe-Nielsen, Jacob, Nakagawa, Michiko, Nepal, Sanjay, Norconk, Marilyn, Novotny, Vojtech, OʼDonnell, Sean, Opiang, Muse, Ouboter, Paul, Parker, Kenneth, Parthasarathy, N., Pisciotta, Kátia, Prawiradilaga, Dewi, Pringle, Catherine, Rajathurai, Subaraj, Reichard, Ulrich, Reinartz, Gay, Renton, Katherine, Reynolds, Glen, Reynolds, Vernon, Riley, Erin, Rödel, Mark-Oliver, Rothman, Jessica, Round, Philip, Sakai, Shoko, Sanaiotti, Tania, Savini, Tommaso, Schaab, Gertrud, Seidensticker, John, Siaka, Alhaji, Silman, Miles R., Smith, Thomas B., de Almeida, Samuel Soares, Sodhi, Navjot, Stanford, Craig, Stewart, Kristine, Stokes, Emma, Stoner, Kathryn E., Sukumar, Raman, Surbeck, Martin, Tobler, Mathias, Tscharntke, Teja, Turkalo, Andrea, Umapathy, Govindaswamy, van Weerd, Merlijn, Rivera, Jorge Vega, Venkataraman, Meena, Venn, Linda, Verea, Carlos, de Castilho, Carolina Volkmer, Waltert, Matthias, Wang, Benjamin, Watts, David, Weber, William, West, Paige, Whitacre, David, Whitney, Ken, Wilkie, David, Williams, Stephen, Wright, Debra D., Wright, Patricia, Xiankai, Lu, Yonzon, Pralad, and Zamzani, Franky
Published: 2012
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17. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

Author: Curtis, Christina, Shah, Sohrab P., Chin, Suet-Feung, Turashvili, Gulisa, Rueda, Oscar M., Dunning, Mark J., Speed, Doug, Lynch, Andy G., Samarajiwa, Shamith, Yuan, Yinyin, Gräf, Stefan, Ha, Gavin, Haffari, Gholamreza, Bashashati, Ali, Russell, Roslin, McKinney, Steven, Aparicio, Samuel, Brenton, James D., Ellis, Ian, Huntsman, David, Pinder, Sarah, Purushotham, Arnie, Murphy, Leigh, Caldas, Carlos, Bardwell, Helen, Ding, Zhihao, Jones, Linda, Liu, Bin, Papatheodorou, Irene, Sammut, Stephen J., Wishart, Gordon, Chia, Steven, Gelmon, Karen, Speers, Caroline, Watson, Peter, Blamey, Roger, Green, Andrew, Macmillan, Douglas, Rakha, Emad, Gillett, Cheryl, Grigoriadis, Anita, de Rinaldis, Emanuele, Tutt, Andy, Parisien, Michelle, Troup, Sandra, Chan, Derek, Fielding, Claire, Maia, Ana-Teresa, McGuire, Sarah, Osborne, Michelle, Sayalero, Sara M., Spiteri, Inmaculada, Hadfield, James, Bell, Lynda, Chow, Katie, Gale, Nadia, Kovalik, Maria, Ng, Ying, Prentice, Leah, Tavaré, Simon, Markowetz, Florian, Langerød, Anita, Provenzano, Elena, and Børresen-Dale, Anne-Lise
Published: 2012
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18. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding

Author: Marinari, Eliana, Mehonic, Aida, Curran, Scott, Gale, Jonathan, Duke, Thomas, and Baum, Buzz
Published: 2012
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19. Vascular-specific growth factors and blood vessel formation

Author: Yancopoulos, George D., Davis, Samuel, Gale, Nicholas W., Rudge, John S., Wiegand, Stanley J., and Holash, Jocelyn
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): George D. Yancopoulos [1]; Samuel Davis [1]; Nicholas W. Gale [1]; John S. Rudge [1]; Stanley J. Wiegand [1]; Jocelyn Holash [1] Until recently, vascular endothelial growth factor (VEGF) [...]
Published: 2000
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20. Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium

Author: Ma, Li-Jun, van der Does, Charlotte H., Borkovich, Katherine A., Coleman, Jeffrey J., Daboussi, Marie-Josée, Di Pietro, Antonio, Dufresne, Marie, Freitag, Michael, Grabherr, Manfred, Henrissat, Bernard, Houterman, Petra M., Kang, Seogchan, Shim, Won-Bo, Woloshuk, Charles, Xie, Xiaohui, Xu, Jin-Rong, Antoniw, John, Baker, Scott E., Bluhm, Burton H., Breakspear, Andrew, Brown, Daren W., Butchko, Robert A. E., Chapman, Sinead, Coulson, Richard, Coutinho, Pedro M., Danchin, Etienne G. J., Diener, Andrew, Gale, Liane R., Gardiner, Donald M., Goff, Stephen, Hammond-Kosack, Kim E., Hilburn, Karen, Hua-Van, Aurélie, Jonkers, Wilfried, Kazan, Kemal, Kodira, Chinnappa D., Koehrsen, Michael, Kumar, Lokesh, Lee, Yong-Hwan, Li, Liande, Manners, John M., Miranda-Saavedra, Diego, Mukherjee, Mala, Park, Gyungsoon, Park, Jongsun, Park, Sook-Young, Proctor, Robert H., Regev, Aviv, Ruiz-Roldan, Carmen M., Sain, Divya, Sakthikumar, Sharadha, Sykes, Sean, Schwartz, David C., Turgeon, Gillian B., Wapinski, Ilan, Yoder, Olen, Young, Sarah, Zeng, Qiandong, Zhou, Shiguo, Galagan, James, Cuomo, Christina A., Kistler, Corby H., and Rep, Martijn
Published: 2010
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21. 'Green revolution' genes encode mutant gibberellin response modulators

Author: Peng, Jinrong, Richards, Donald E., Hartley, Nigel M., Murphy, George P., Devos, Katrien, M., Flintham, John E., Beales, James, Fish, Leslie J., Worland, Anthony J., Pelica, Fatima, Sudhakar, Duraialagaraja, Christou, Paul, Snape, John W., Gale, Michael D., and Harberd, Nicholas P.
Subjects: Plant hormones -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: New wheat grain varieties grown during the 1960s and 1970s are shorter, resistant to wind and rain damage and increase grain yield. Their shortness is a response to gibberellin, the plant growth hormome, which is conferred by mutant dwarfing alleles at one of two Reduced height-1 (Rht-B1 and Rht-D1) loci. It is shown that RhtB1/D1 and maize dwarf-8 (d8) are orthologues of the Araidopsis Gibberellin Insensitive (GA1) gene, which encode proteins resembling nuclear transcription factors.
Published: 1999

22. Rewriting yeast central carbon metabolism for industrial isoprenoid production

Author: Meadows, Adam L., Hawkins, Kristy M., Tsegaye, Yoseph, Antipov, Eugene, Kim, Youngnyun, Raetz, Lauren, Dahl, Robert H., Tai, Anna, Mahatdejkul-Meadows, Tina, Xu, Lan, Zhao, Lishan, Dasika, Madhukar S., Murarka, Abhishek, Lenihan, Jacob, Eng, Diana, Leng, Joshua S., Liu, Chi-Li, Wenger, Jared W., Jiang, Hanxiao, Chao, Lily, Westfall, Patrick, Lai, Jefferson, Ganesan, Savita, Jackson, Peter, Mans, Robert, Platt, Darren, Reeves, Christopher D., Saija, Poonam R., Wichmann, Gale, Holmes, Victor F., Benjamin, Kirsten, Hill, Paul W., Gardner, Timothy S., and Tsong, Annie E.
Subjects: Biosynthesis -- Research, Carbon -- Physiological aspects, Yeasts (Fungi) -- Physiological aspects, Metabolism -- Research, Microbiological research, Terpenoids -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Adam L. Meadows [1]; Kristy M. Hawkins [1]; Yoseph Tsegaye [1]; Eugene Antipov [1]; Youngnyun Kim [1]; Lauren Raetz [1]; Robert H. Dahl [1]; Anna Tai [1]; Tina Mahatdejkul-Meadows [...]
Published: 2016
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23. Survey of spiking in the mouse visual system reveals functional hierarchy

Author: Joshua H, Siegle, Xiaoxuan, Jia, Séverine, Durand, Sam, Gale, Corbett, Bennett, Nile, Graddis, Greggory, Heller, Tamina K, Ramirez, Hannah, Choi, Jennifer A, Luviano, Peter A, Groblewski, Ruweida, Ahmed, Anton, Arkhipov, Amy, Bernard, Yazan N, Billeh, Dillan, Brown, Michael A, Buice, Nicolas, Cain, Shiella, Caldejon, Linzy, Casal, Andrew, Cho, Maggie, Chvilicek, Timothy C, Cox, Kael, Dai, Daniel J, Denman, Saskia E J, de Vries, Roald, Dietzman, Luke, Esposito, Colin, Farrell, David, Feng, John, Galbraith, Marina, Garrett, Emily C, Gelfand, Nicole, Hancock, Julie A, Harris, Robert, Howard, Brian, Hu, Ross, Hytnen, Ramakrishnan, Iyer, Erika, Jessett, Katelyn, Johnson, India, Kato, Justin, Kiggins, Sophie, Lambert, Jerome, Lecoq, Peter, Ledochowitsch, Jung Hoon, Lee, Arielle, Leon, Yang, Li, Elizabeth, Liang, Fuhui, Long, Kyla, Mace, Jose, Melchior, Daniel, Millman, Tyler, Mollenkopf, Chelsea, Nayan, Lydia, Ng, Kiet, Ngo, Thuyahn, Nguyen, Philip R, Nicovich, Kat, North, Gabriel Koch, Ocker, Doug, Ollerenshaw, Michael, Oliver, Marius, Pachitariu, Jed, Perkins, Melissa, Reding, David, Reid, Miranda, Robertson, Kara, Ronellenfitch, Sam, Seid, Cliff, Slaughterbeck, Michelle, Stoecklin, David, Sullivan, Ben, Sutton, Jackie, Swapp, Carol, Thompson, Kristen, Turner, Wayne, Wakeman, Jennifer D, Whitesell, Derric, Williams, Ali, Williford, Rob, Young, Hongkui, Zeng, Sarah, Naylor, John W, Phillips, R Clay, Reid, Stefan, Mihalas, Shawn R, Olsen, and Christof, Koch
Subjects: Electrophysiology, Male, Mice, Inbred C57BL, Mice, Thalamus, Action Potentials, Animals, Datasets as Topic, Photic Stimulation, Visual Cortex
Abstract: The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically
Published: 2019

24. Small self-RNA generated by RNase L amplifies antiviral innate immunity

Author: Malathi, Krishnamurthy, Dong, Beihua, Gale, Michael, Jr, and Silverman, Robert H.
Published: 2007
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25. INFLUENZA: Fatal immunity and the 1918 virus

Author: Loo, Yueh-Ming and Gale, Michael, Jr
Published: 2007

26. An intrinsic frequency limit to the cochlear amplifier

Author: Gale, Jonathan E. and Ashmore, Jonathan F.
Subjects: Cochlea -- Physiological aspects, Hearing -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: The cochlear amplifier in the inner ear determines hearing in mammals. The amplifier consists of senorimotor cells, outer hair cells, which change the passive mechanics of the cochlea. It is thought that the molecular basis of the mechanism is a voltage-sensitive motor protein. The limiting frequency at which the motor operates is shown to lie near 25 kHz, setting an upper limited to the hearing range in mammalian cochleas.
Published: 1997

27. Lymphocyte in vitro Cytotoxicity: Lymphotoxins of Several Mammalian Species

Author: WILLIAMS, TERRY W and GRANGER, GALE A
Subjects: Biomedical and Clinical Sciences, Immunology, Rare Diseases, Adenoids, Animals, Biological Products, Cats, Cricetinae, Culture Media, In Vitro Techniques, L Cells, Lectins, Lymphocytes, Mice, Spleen, Toxins, Biological, General Science & Technology
Abstract: MOUSE lymphocytes can be induced in vitro by treatment with phytohaemagglutinin (PHA), or with rabbit anti-mouse serum, and by the mixed lymphocyte reaction, to produce material(s) which is toxic to L cells1. The term lymphotoxins (previously termed lymphocyte cytotoxic factor) is applied here to the toxic factor(s). We report that lymphocytes from several animal species, including man, can be stimulated with phytohaemagglutinin in vitro to release lymphotoxin-like materials. © 1968 Nature Publishing Group.
Published: 1968

28. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras

Author: Gale, Nicholas W., Kaplan, Susan, Lowenstein, Eve J., Schlessinger, Joseph, and Bar-Sagi, Dafna
Subjects: Epidermal growth factor -- Research, Nucleotides -- Analysis, Protein binding -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Overexpression of Grb2 increases guanine-nucleotide exchange rate by working up a complex with the ligand-activated receptor. This coupling regulates tyrosine kinase that modulates Ras activity and mitogen-activated protein kinase. The ability of Grb2 to enhance Ras activity by facilitating guanine-nucleotide exchange rate is observed as a conserved mechanism that developed to advance receptor signals to Ras. Translocation can bond receptor activation to undiminished exchange factor activity, by transporting the factor to the subcellular compartment.
Published: 1993

29. Promiscuity in transgenic plants

Author: Bergelson, Joy, Purrington, Colin B., and Wichmann, Gale
Published: 1998

30. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands

Author: Holland, Sacha J., Gale, Nicholas W., Mbamalu, Geraldine, Yancopoulos, George D., Henkemeyer, Mark, and Pawson, Tony
Published: 1996

31. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author: Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, McArdle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr. , W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcus, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Janos, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charles, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Maris, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang H, Knowles J, Hlatky M, Fortmann S, Assimes TL, Quertermous T, Go A, Iribarren C, Absher D, Risch N, Meyers R, Sidney S, Ziegler A, Schillert A, Bickel C, Sinning C, Rupprecht HJ, Lackner K, Wild P, Schnabel R, Blankenberg S, Zeller T, Münzel T, Perret C, Cambien F, Tiret L, Nicaud V, Proust C, Dehghan A, Hofman A, Uitterlinden A, van Duijn C, Levy D, Whitteman J, Cupples LA, Demissie-Banjaw S, Ramachandran V, Smith A, Gudnason V, Boerwinkle E, Folsom A, Morrison A, Psaty BM, Chen IY, Rotter JI, Bis J, Volcik K, Rice K, Taylor KD, Marciante K, Smith N, Glazer N, Heckbert S, Harris T, Lumley T, Kong A, Thorleifsson G, Thorgeirsson G, Holm H, Gulcher JR, Stefansson K, Andersen K, Gretarsdottir S, Thorsteinsdottir U, Preuss M, Schreiber S, Meitinger T, König IR, Lieb W, Hengstenberg C, Schunkert H, Erdmann J, Fisher M, Grosshennig A, Medack A, Stark K, Linsel-Nitschke P, Bruse P, Aherrahrou Z, Peters A, Loley C, Willenborg C, Nahrstedt J, Freyer J, Gulde S, Doering A, Meisinger C, Wichmann HE, Klopp N, Illig T, Meinitzer A, Tomaschitz A, Halperin E, Dobnig H, Scharnagl H, Kleber M, Laaksonen R, Pilz S, Grammer TB, Stojakovic T, Renner W, März W, Böhm BO, Winkelmann BR, Winkler K, Hoffmann M, O'Donnell CJ, Voight BF, Altshuler D, Siscovick DS, Musunuru K, Peltonen L, Barbalic M, Melander O, Elosua R, Kathiresan S, Schwartz SM, Salomaa V, Guiducci C, Burtt N, Gabriel SB, Stewart AF, Wells GA, Chen L, Jarinova O, Roberts R, McPherson R, Dandona S, Pichard AD, Rader DJ, Devaney J, Lindsay JM, Kent KM, Qu L, Satler L, Burnett MS, Li M, Reilly MP, Wilensky R, Waksman R, Epstein S, Mattha W, Knouf CW, Waterworth DM, Hakonarson HH, Walker M, Mooser V, Hall AS, Balmforth AJ, Wright BJ, Nelson C, Thompson JR, Samani NJ, Braund PS, Ball SG, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Rivadeneira F, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Wang YA, Stricker B, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Uitterlinden AG, Willerson JT, van Duijn CM, Witteman JC, Vasan RS, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Parsa A, Gao X, Yang Q, Smith AV, O'Connell JR, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson A, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria, Francesco, Metter J, de Boer J, Siscovick D, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turne ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Vasan R, Felix SB, Watzinger N, Larson MG, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Stricker BH, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Arnett D, Blettner M, Friedrich N, Benjamin EJ, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic T, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Sanna S, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Uda M, Vollenweider P, Wallace C, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Abecasis GR, Lightstone L, Scott J, Navis G, Elliot P, Kooner JS., AII - Amsterdam institute for Infection and Immunity, Nephrology, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Epidemiology, Medical Microbiology & Infectious Diseases, Radiology & Nuclear Medicine, Cardiology, Internal Medicine, Clinical Genetics, Erasmus MC other, Obstetrics & Gynecology, International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Clinical Pharmacology and The Genome Centre, Queen Mary University of London (QMUL), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Center for Human Genetic Research, Massachusetts General Hospital [Boston], Program in Medical and Population Genetics, Harvard University-Massachusetts Institute of Technology (MIT), Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'An, Arora, Pankaj, Dehghan, Abba, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. 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H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliot, P, and Kooner, Js.
Subjects: novel loci, Kidney Disease, Polymorphism, Single Nucleotide/*genetics, [SDV]Life Sciences [q-bio], left ventricular wall thickness, LOCI, Genome-wide association study, Blood Pressure, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, RELEVANCE, Africa/ethnology, Cardiovascular Disease, genetics, Kidney Diseases/genetics, Stroke, genome wide association study, POPULATION, ta118, Blood pressure, hypertension, stroke, coronary artery disease, ddc:616, 0303 health sciences, education.field_of_study, Asia/ethnology, Multidisciplinary, Coronary Artery Disease/genetics, COMMON VARIANTS, Genetic Predisposition to Disease/*genetics, 3. Good health, Europe, Cardiovascular Diseases, Hypertension, Cardiology, Kidney Diseases, HEALTH, Human, medicine.medical_specialty, Asia, Population, Renal function, Polymorphism, Single Nucleotide, Europe/ethnology, Article, CLONING, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stroke/genetics, Internal medicine, medicine, Humans, Cardiovascular Diseases/*genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, 030304 developmental biology, RECEPTOR, genes, blood pressure, cardiovascular disease risk, medicine.disease, Africa, Blood Pressure/*genetics/physiology, Hypertension/genetics, Kidney disease, Genome-Wide Association Study
Abstract: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. ispartof: Nature vol:478 issue:7367 pages:103-109 ispartof: location:England status: published
Published: 2011
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32. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author: Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A., Burton, Paul R., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Taylor, Niall C., Walters, Graham R., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Nicol Ferrier, I., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Khalid Mohiuddin, M., Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Braga, Carolina A., Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bryan, Claire, Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Jilur, Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingeleif B., Howie, Bryan N., Su, Zhan, Ying Teo, Yik, Vukcevic, Damjan, Bentley, David, and Compston, Alistair
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Sergey Nejentsev [1, 57]; Joanna M. M. Howson (corresponding author) [1, 57]; Neil M. Walker [1]; Jeffrey Szeszko [1]; Sarah F. Field [1]; Helen E. Stevens [1]; Pamela Reynolds [...]
Published: 2007
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33. 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members

Author: Stewart W. Schneller, Michael S. Diamond, Volker Thiel, Jill Schriewer, R. Mark L. Buller, Ganes C. Sen, Theodore C. Pierson, Roland Züst, Soonjeon Youn, Hongping Dong, John S. Errett, Tsai-Yu Lin, Volker Fensterl, Pei Yong Shi, Michael Gale, Kristy J. Szretter, Stephane Daffis, William B. Klimstra, and Jianqing Li
Subjects: RNA Caps, Methyltransferase, viruses, RNA-binding protein, Receptor, Interferon alpha-beta, Biology, Virus Replication, Methylation, Article, Mice, 03 medical and health sciences, Interferon, medicine, Animals, Humans, Gene, Cells, Cultured, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, Messenger RNA, Multidisciplinary, Models, Genetic, 2'-O-methylation, Poxviridae, 030302 biochemistry & molecular biology, Models, Immunological, Proteins, RNA-Binding Proteins, RNA, 3T3 Cells, Methyltransferases, Fibroblasts, Virology, Immunity, Innate, Neoplasm Proteins, Coronavirus, Mice, Inbred C57BL, Survival Rate, Gene Expression Regulation, Protein Biosynthesis, RNA, Viral, Interferons, Apoptosis Regulatory Proteins, Carrier Proteins, West Nile virus, medicine.drug
Abstract: Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2'-O positions of the 5' guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability, the function of 2'-O methylation has remained uncertain since its discovery 35 years ago. Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2'-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2'-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2'-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2'-O methylation of the 5' cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2'-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.
Published: 2010
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34. Predicting crystal growth via a unified kinetic three-dimensional partition model

Author: Anderson, Michael W., primary, Gebbie-Rayet, James T., additional, Hill, Adam R., additional, Farida, Nani, additional, Attfield, Martin P., additional, Cubillas, Pablo, additional, Blatov, Vladislav A., additional, Proserpio, Davide M., additional, Akporiaye, Duncan, additional, Arstad, Bjørnar, additional, and Gale, Julian D., additional
Published: 2017
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35. The origin of spontaneous activity in the developing auditory system

Author: Eunyoung Yi, Dwight E. Bergles, Elisabeth Glowatzki, Jonathan E. Gale, and Nicolas X. Tritsch
Subjects: Auditory Pathways, Time Factors, Central nervous system, Action Potentials, Biology, Rats, Sprague-Dawley, Adenosine Triphosphate, Hearing, Hair Cells, Auditory, otorhinolaryngologic diseases, medicine, Animals, Auditory system, Inner ear, Cell Shape, Cochlea, Multidisciplinary, Anatomy, Rats, Electrophysiology, medicine.anatomical_structure, Organ of Corti, Auditory Perception, Calcium, Tonotopy, Auditory Physiology, Neuroscience
Abstract: Spontaneous activity in the developing auditory system is required for neuronal survival as well as the refinement and maintenance of tonotopic maps in the brain. However, the mechanisms responsible for initiating auditory nerve firing in the absence of sound have not been determined. Here we show that supporting cells in the developing rat cochlea spontaneously release ATP, which causes nearby inner hair cells to depolarize and release glutamate, triggering discrete bursts of action potentials in primary auditory neurons. This endogenous, ATP-mediated signalling synchronizes the output of neighbouring inner hair cells, which may help refine tonotopic maps in the brain. Spontaneous ATP-dependent signalling rapidly subsides after the onset of hearing, thereby preventing this experience-independent activity from interfering with accurate encoding of sound. These data indicate that supporting cells in the organ of Corti initiate electrical activity in auditory nerves before hearing, pointing to an essential role for peripheral, non-sensory cells in the development of central auditory pathways.
Published: 2007
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36. Small self-RNA generated by RNase L amplifies antiviral innate immunity

Author: Beihua Dong, Krishnamurthy Malathi, Michael Gale, and Robert H. Silverman
Subjects: Transcriptional Activation, Small RNA, RNase P, Endoribonuclease, Article, Mice, Endoribonucleases, Cardiovirus Infections, Animals, Encephalomyocarditis virus, Promoter Regions, Genetic, RNase H, RNA, Double-Stranded, Oligoribonucleotides, Multidisciplinary, biology, Adenine Nucleotides, RNA, Interferon-beta, Fibroblasts, Non-coding RNA, Virology, Immunity, Innate, Cell biology, RNase MRP, biology.protein, Ribonuclease L, Signal Transduction
Abstract: RNA molecules in virus-infected cells trigger interferon production and initiate antiviral innate immunity. Small RNA cleavage products from 'self' RNA generated by the antiviral endoribonuclease RNase L have now been found to initiate and amplify antiviral responses. This points to RNase L activation as a possible strategy for antiviral therapy. RNA molecules in virus-infected cells trigger interferon production and initiate antiviral innate immunity. This paper shows that small RNA cleavage products from 'self' RNA, generated by the antiviral endonuclease RNas L, can initiate and amplify antiviral responses. Antiviral innate immunity is initiated in response to RNA molecules that are produced in virus-infected cells1. These RNAs activate signalling cascades that activate the genes that encode α- and β-interferon (IFN). Signalling occurs through the interaction of the RNAs with either of two pathogen recognition receptors, retinoic acid-inducible gene-I (RIG-I, also known as DDX58) and melanoma differentiation associated gene-5 (MDA5, also known as IFIH1), which contain amino-terminal caspase activation and recruitment domains (CARD) and carboxy-terminal DExD/H Box RNA helicase motifs2,3,4,5. RIG-I and MDA5 interact with another CARD protein, interferon-β promotor stimulator protein-1 (IPS-1, also known as MAVS, VISA and Cardif), in the mitochondrial membrane, which relays the signal through the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor (NF)-κB to the IFN-β gene6,7,8,9,10. Although the signalling pathway is well understood, the origin of the RNA molecules that initiate these processes is not. Here we show that activation of the antiviral endoribonuclease, RNase L11, by 2′,5′-linked oligoadenylate (2-5A)12 produces small RNA cleavage products from self-RNA that initiate IFN production. Accordingly, mouse embryonic fibroblasts lacking RNase L were resistant to the induction of IFN-β expression in response to 2-5A, dsRNA or viral infection. Single-stranded regions of RNA are cleaved 3′ of UpUp and UpAp sequences by RNase L during viral infections, resulting in small, often duplex, RNAs13,14. We show that small self-RNAs produced by the action of RNase L on cellular RNA induce IFN-β expression and that the signalling involves RIG-I, MDA5 and IPS-1. Mice lacking RNase L produce significantly less IFN-β during viral infections than infected wild-type mice. Furthermore, activation of RNase L with 2-5A in vivo induced the expression of IFN-β in wild-type but not RNase L-deficient mice. Our results indicate that RNase L has an essential role in the innate antiviral immune response that relieves the requirement for direct sensing of non-self RNA.
Published: 2007
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37. Rewriting yeast central carbon metabolism for industrial isoprenoid production

Author: Madhukar S. Dasika, Paul W. Hill, Savita Ganesan, Robert Mans, Kirsten R. Benjamin, Eugene Antipov, Jacob R. Lenihan, Diana Eng, Lan Xu, Hanxiao Jiang, Annie Ening Tsong, Abhishek Murarka, Lishan Zhao, Robert H. Dahl, Jefferson Lai, Lily Chao, Lauren Raetz, Kristy Michelle Hawkins, Poonam R. Saija, Yoseph Tsegaye, Chi-Li Liu, Christopher D. Reeves, Darren Platt, Gale Wichmann, Youngnyun Kim, Jared W. Wenger, Tina Mahatdejkul-Meadows, Joshua S. Leng, Victor F. Holmes, Adam L. Meadows, Patrick J. Westfall, Timothy S. Gardner, Peter K. Jackson, and Anna Tai
Subjects: 0106 biological sciences, 0301 basic medicine, Farnesene, Industrial production, Saccharomyces cerevisiae, 01 natural sciences, Metabolic engineering, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, Bioreactors, Cytosol, Biosynthesis, Acetyl Coenzyme A, 010608 biotechnology, Bioreactor, Multidisciplinary, biology, Terpenes, Metabolism, Carbon Dioxide, biology.organism_classification, Yeast, Carbon, Biosynthetic Pathways, Oxygen, 030104 developmental biology, chemistry, Biochemistry, Metabolic Engineering, Fermentation, Carbohydrate Metabolism, Oxidation-Reduction, Sesquiterpenes
Abstract: Yeast central carbon metabolism has been engineered to achieve a more efficient isoprenoid biosynthesis pathway, an advance that brings commodity-scale production of such compounds a step closer. These authors have re-engineered the central carbon metabolism of Saccharomyces cerevisiae to improve redox balance and eliminate carbon and energy waste associated with acetyl-CoA biosynthesis. The resulting strains can produce the acetyl-CoA-based hydrocarbon β-farnesene—an important precursor to many fragrances, fuels and therapeutics—in greater quantities than the starting yeast strain while consuming less oxygen. Cultures can be grown effectively in 200,000-litre industrial bioreactors. This system points the way towards a platform for high-productivity, feedstock-efficient production for all isoprenoids and other acetyl-CoA-derived compounds. A bio-based economy has the potential to provide sustainable substitutes for petroleum-based products and new chemical building blocks for advanced materials. We previously engineered Saccharomyces cerevisiae for industrial production of the isoprenoid artemisinic acid for use in antimalarial treatments1. Adapting these strains for biosynthesis of other isoprenoids such as β-farnesene (C15H24), a plant sesquiterpene with versatile industrial applications2,3,4,5, is straightforward. However, S. cerevisiae uses a chemically inefficient pathway for isoprenoid biosynthesis, resulting in yield and productivity limitations incompatible with commodity-scale production. Here we use four non-native metabolic reactions to rewire central carbon metabolism in S. cerevisiae, enabling biosynthesis of cytosolic acetyl coenzyme A (acetyl-CoA, the two-carbon isoprenoid precursor) with a reduced ATP requirement, reduced loss of carbon to CO2-emitting reactions, and improved pathway redox balance. We show that strains with rewired central metabolism can devote an identical quantity of sugar to farnesene production as control strains, yet produce 25% more farnesene with that sugar while requiring 75% less oxygen. These changes lower feedstock costs and dramatically increase productivity in industrial fermentations which are by necessity oxygen-constrained6. Despite altering key regulatory nodes, engineered strains grow robustly under taxing industrial conditions, maintaining stable yield for two weeks in broth that reaches >15% farnesene by volume. This illustrates that rewiring yeast central metabolism is a viable strategy for cost-effective, large-scale production of acetyl-CoA-derived molecules.
Published: 2015

38. Whole-genome sequencing of patients with rare diseases in a national health system

Author: Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V. V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B. A., Saleem, Moin A., Smith, Kenneth G. C., Stark, Hannah, Tan, Rhea Y. Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Kingston, Nathalie, Walker, Neil, Bradley, John R., Ashford, Sofie, Penkett, Christopher J., Freson, Kathleen, Stirrups, Kathleen E., Raymond, F. Lucy, and Ouwehand, Willem H.
Abstract: Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBAand MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Published: 2020
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39. Vascular-specific growth factors and blood vessel formation

Author: George D. Yancopoulos, Nicholas W. Gale, Jocelyn Holash, Samuel Davis, John S. Rudge, and Stanley J. Wiegand
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, Angiogenesis, medicine.medical_treatment, Ischemia, Neovascularization, Physiologic, Ephrin-B2, Endothelial Growth Factors, Biology, Bioinformatics, Models, Biological, TIE1, Receptors, TIE, Angiopoietin-2, Angiopoietin, chemistry.chemical_compound, Internal medicine, medicine, Animals, Receptors, Growth Factor, Lymphokines, Multidisciplinary, Neovascularization, Pathologic, Vascular Endothelial Growth Factors, Growth factor, Membrane Proteins, Proteins, Receptor Protein-Tyrosine Kinases, medicine.disease, Vascular endothelial growth factor, Vascular endothelial growth factor A, Receptors, Vascular Endothelial Growth Factor, medicine.anatomical_structure, Endocrinology, chemistry, Blood vessel
Abstract: A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
Published: 2000
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40. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands

Author: Tony Pawson, Sacha J. Holland, Mark Henkemeyer, Geraldine Mbamalu, Nicholas W. Gale, and George D. Yancopoulos
Subjects: Receptor, EphB2, Recombinant Fusion Proteins, Molecular Sequence Data, Ephrin-B2, Biology, Ligands, EPH receptor B2, Receptor tyrosine kinase, Mice, chemistry.chemical_compound, EPH receptor A3, Proto-Oncogene Proteins, Tumor Cells, Cultured, Animals, Ephrin, Amino Acid Sequence, Phosphorylation, ets-Domain Protein Elk-1, Multidisciplinary, Cell Membrane, Erythropoietin-producing hepatocellular (Eph) receptor, Membrane Proteins, Receptor Protein-Tyrosine Kinases, Tyrosine phosphorylation, EPH receptor A2, Coculture Techniques, Rats, Cell biology, DNA-Binding Proteins, chemistry, Biochemistry, COS Cells, biology.protein, Tyrosine, Signal Transduction, Transcription Factors, Proto-oncogene tyrosine-protein kinase Src
Abstract: RECEPTOR tyrosine kinases of the EPH class have been implicated in the control of axon guidance and fascieulation1–7, in regulating cell migration8, and in defining compartments in the developing embryo9–11. Efficient activation of EPH receptors generally requires that their ligands be anchored to the cell surface, either through a transmembrane (TM) region or a glycosyl phosphatidylinositol (GPI) group12. These observations have suggested that EPH receptors can transduce signals initiated by direct cell–cell interaction. Genetic analysis of Nuk, a murine EPH receptor that binds TM ligands, has raised the possibility that these ligands might themselves have a signalling function6. Consistent with this, the three known TM ligands have a highly conserved cytoplasmic region, with multiple potential sites for tyrosine phosphorylation12–17. Here we show that challenging cells that express the TM ligands Elk-L or Htk-L with the clustered ectodomain of Nuk induces phosphorylation of the ligands on tyrosine, a process that can be mimicked both in vitro and in vivo by an activated Src tyrosine kinase. Co-culture of cells expressing a TM ligand with cells expressing Nuk leads to tyrosine phosphorylation of both the ligand and Nuk. These results suggest that the TM ligands are associated with a tyrosine kinase, and are inducibly phosphorylated upon binding Nuk, in a fashion reminiscent of cytokine receptors18. Furthermore, we show that TM ligands, as well as Nuk, are phosphorylated on tyrosine in mouse embryos, indicating that this is a physiological process. EPH receptors and their TM ligands therefore mediate bidirectional cell signalling.
Published: 1996
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41. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding

Author: Thomas Duke, Buzz Baum, Aida Mehonic, Eliana Marinari, Scott Curran, and Jonathan E. Gale
Subjects: Male, Programmed cell death, Cell signaling, Cell Survival, Cell, Morphogenesis, Cell Growth Process, Nanotechnology, Apoptosis, Cell Count, Cell Communication, Cell Growth Processes, Biology, Models, Biological, Article, Neoplasms, medicine, Animals, Stochastic Processes, Multidisciplinary, Cell Death, Delamination, Epithelial Cells, Notum, Cell biology, medicine.anatomical_structure, Drosophila melanogaster, Female, Developmental biology
Abstract: The development and maintenance of an epithelium requires finely balanced rates of growth and cell death. However, the mechanical and biochemical mechanisms that ensure proper feedback control of tissue growth, which when deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as a model system to identify a novel process of crowding-induced cell delamination that balances growth to ensure the development of well-ordered cell packing. In crowded regions of the tissue, a proportion of cells undergo a serial loss of cell-cell junctions and a progressive loss of apical area, before being squeezed out by their neighbours. This path of delamination is recapitulated by a simple computational model of epithelial mechanics, in which stochastic cell loss relieves overcrowding as the system tends towards equilibrium. We show that this process of delamination is mechanistically distinct from apoptosis-mediated cell extrusion and precedes the first signs of cell death. Overall, this analysis reveals a simple mechanism that buffers epithelia against variations in growth. Because live-cell delamination constitutes a mechanistic link between epithelial hyperplasia and cell invasion, this is likely to have important implications for our understanding of the early stages of cancer development.
Published: 2011

42. Estimation of 1 (+)-arginine in protein hydrolysates by the use of 1 (+)-arginine decarboxylase

Author: E F, GALE
Subjects: Carboxy-Lyases, Protein Hydrolysates, Humans, Arginine, Aged
Published: 2010

43. Action of tyrocidin and detergents in liberating aminoacids from bacterial cells

Author: E. Shirley Taylor and E. F. Gale
Subjects: chemistry.chemical_classification, Multidisciplinary, Chromatography, Lysine decarboxylase, Bacteria, Lysine, Detergents, complex mixtures, Amino acid, Suspension (chemistry), chemistry.chemical_compound, Enzyme, Adsorption, chemistry, Anti-Infective Agents, Casein, Carbon dioxide, bacteria, Organic chemistry, Amino Acids
Abstract: THE estimation of amino-acids by the amino-acid decarboxylase technique1 provides a means for the investigation of the amino-acid content of the internal environment of bacterial cells. If 1 ml. of a thick washed suspension of S. faecalis cells grown in casein digest medium is placed along with 1·5 ml. phosphate buffer pH 6·0 in the main cup of a Warburg manometer and 0·5 ml. lysine decarboxylase preparation tipped in from a side-bulb in the usual way, there is a small output of carbon dioxide of magnitude depending upon the degree of washing of the cells and corresponding to the amount of lysine carried down with and adsorbed on the surface of the cells (see curve labelled'intact cells'). If a further aliquot of cell suspension is treated in such a way as to disintegrate the cells, either by mechanical shaking with glass beads2 or by immersion in a boiling water bath for 10 min., before the addition of the enzyme, the amount of lysine assayed increases markedly (curve labelled 'boiled cells'). The difference in the quantities of lysine measured with the intact cells and with the disintegrated cells corresponds to the lysine liberated from the internal environment by disruption of the cell-wall, through which the enzyme cannot pass. Investigation of the amount of such lysine contained in the internal environment of the cells shows that its concentration depends upon that existing in the external environment, the ratio of the internal to external concentration varying from 2–3 for external concentrations of the order 0·02 M to approximately 20 for external concentrations of the order 0·001 M.
Published: 2010

44. Correlation between penicillin resistance and assimilation affinity in Staphylococcus aureus

Author: Ernest Frederick Gale
Subjects: Staphylococcus aureus, Multidisciplinary, Chemistry, Penicillin Resistance, Staphylococcus, Cell, Assimilation (biology), Metabolism, Glutamic acid, Penicillins, Staphylococcal Infections, medicine.disease_cause, Microbiology, Glutamine, Penicillin, medicine.anatomical_structure, Biochemistry, medicine, Protein biosynthesis, Humans, medicine.drug
Abstract: GRAM-POSITIVE cocci possess the ability to assimilate certain amino-acids and to concentrate them in the free state within the internal environment1,2. The level of free amino-acid attained within the cell is determined by the balance between the rate at which the amino-acid is assimilated from the external environment and the rate at which it is metabolized within the cell3. If the assimilation process is impaired, then the level of free amino-acid within the cell will fall as metabolism continues; conversely, if the internal metabolism is inhibited, then the level will rise to a saturation value. Studies on the assimilation and concentration of glutamic acid by Gram-positive cocci have shown that the Migration across the cell-wall requires energy which can be supplied by glycolysis1, and that the free amino-acid in the internal environment acts as a Source of glutamic acid for protein synthesis in the growing cell4, and also undergoes some other form of metabolism which is inhibited by triphenylmethane dyes3. When the cells are grown in penicillin, the assimilatory processes become impaired, with the result that glutamic acid and glutamine can no longer be assimilated from the external environment, and, since the internal metabolic processes are not affected, the level of free glutamic acid within the cell falls until protein synthesis, and consequently growth, can no longer take place5,6.
Published: 2010

45. Early Pleistocene human occupation at the edge of the boreal zone in northwest Europe

Author: Nigel R. Larkin, Vassil Karloukovski, G. Russell Coope, Michael H. Field, Richard L. Abel, Simon A. Parfitt, Rowena Gale, Peter G. Hoare, Simon G. Lewis, Nick Ashton, Chris Stringer, Mark Lewis, Sylvia M. Peglar, Barbara A. Maher, John E. Whittaker, and Richard C. Preece
Subjects: Geologic Sediments, Technology, Early Pleistocene, Pleistocene, Survival, Range (biology), Climate, Population, Environment, Paleontology, Magnetics, Rivers, Peninsula, Animals, Humans, education, Ecosystem, History, Ancient, geography, education.field_of_study, Multidisciplinary, geography.geographical_feature_category, Geography, Fossils, Temperature, Hominidae, Emigration and Immigration, Archaeology, Adaptation, Physiological, United Kingdom, Interglacial, Biological dispersal, Seasons, Quaternary
Abstract: Early humans colonized Eurasia fairly swiftly after they left Africa more than 1.8 million years ago, occupying tropical and Mediterranean habitats from Flores in the east to present-day Spain in the west. The prevailing view from sparse fossil and archaeological evidence has been that humans were still largely adapted to warm climates, and penetrated more than 45° north only in exceptionally warm intervals. New findings of artefacts, fauna and flora from a river deposit in Norfolk, UK, dating back more than 780,000 years, will change that perception. Excavations at the eroding coastal site of Happisburgh uncovered 78 flint artefacts, including flint tools, from what was a forest habitat in a climate resembling that of southern Britain today. This suggests that humans were capable of living in northern Europe in cooler intervals much earlier than was thought. Hominins colonized Eurasia fairly swiftly after they left Africa around 1.75 million years ago, although it had been thought that they did not penetrate beyond 45° N except in very warm intervals. Now, however, artefacts, fauna and flora dating back more 0.78 million years have been found in a river deposit in Norfolk, England. The findings show that humans were capable of penetrating northern Europe in cooler intervals, and will prompt a re-evaluation of the adaptations and abilities of humans at this early date. The dispersal of early humans from Africa by 1.75 Myr ago led to a marked expansion of their range, from the island of Flores in the east to the Iberian peninsula in the west1,2,3,4,5. This range encompassed tropical forest, savannah and Mediterranean habitats, but has hitherto not been demonstrated beyond 45° N. Until recently, early colonization in Europe was thought to be confined to the area south of the Pyrenees and Alps. However, evidence from Pakefield (Suffolk, UK) at ∼0.7 Myr indicated that humans occupied northern European latitudes when a Mediterranean-type climate prevailed6. This provided the basis for an ‘ebb and flow’ model, where human populations were thought to survive in southern refugia during cold stages, only expanding northwards during fully temperate climates5. Here we present new evidence from Happisburgh (Norfolk, UK) demonstrating that Early Pleistocene hominins were present in northern Europe >0.78 Myr ago when they were able to survive at the southern edge of the boreal zone. This has significant implications for our understanding of early human behaviour, adaptation and survival, as well as the tempo and mode of colonization after their first dispersal out of Africa.
Published: 2009

46. Generation of functional multipotent adult stem cells from GPR125+ germline progenitors

Author: Jiyeon Kim, Pier Paolo Pandolfi, Sergey V. Shmelkov, Daylon James, Nicholas W. Gale, David M. Valenzuela, Sai H. Chavala, George D. Yancopoulos, Richard Torres, Shahin Rafii, Robin M. Hobbs, Ilaria Falciatori, Fan Zhang, Douglas S. Scherr, Andrew J. Murphy, and Marco Seandel
Subjects: Male, Adult Germline Stem Cells, Aging, Cellular differentiation, Biology, Article, Cell Line, Receptors, G-Protein-Coupled, Mice, Testis, Animals, Regeneration, Progenitor cell, Induced pluripotent stem cell, Busulfan, Multidisciplinary, Gene Expression Profiling, Multipotent Stem Cells, Myocardium, Cell Differentiation, Spermatogonia, Cell biology, Mice, Inbred C57BL, Adult Stem Cells, Cell culture, Multipotent Stem Cell, Immunology, Blood Vessels, Stem cell, Adult stem cell
Abstract: Adult mammalian testis is a source of pluripotent stem cells1. However, the lack of specific surface markers has hampered identification and tracking of the unrecognized subset of germ cells that gives rise to multipotent cells2. Although embryonic-like cells can be derived from adult testis cultures after only several weeks in vitro1, it is not known whether adult self-renewing spermatogonia in long-term culture can generate such stem cells as well. Here, we show that highly proliferative adult spermatogonial progenitor cells (SPCs) can be efficiently obtained by cultivation on mitotically inactivated testicular feeders containing CD34+ stromal cells. SPCs exhibit testicular repopulating activity in vivo and maintain the ability in long-term culture to give rise to multi-potent adult spermatogonial-derived stem cells (MASCs). Furthermore, both SPCs and MASCs express GPR125, an orphan adhesion-type G-protein-coupled receptor. In knock-in mice bearing a GPR125–β-galactosidase (LacZ) fusion protein under control of the native Gpr125 promoter (GPR125–LacZ), expression in the testis was detected exclusively in spermatogonia and not in differentiated germ cells. Primary GPR125–LacZ SPC lines retained GPR125 expression, underwent clonal expansion, maintained the phenotype of germline stem cells, and reconstituted spermatogenesis in busulphan-treated mice. Long-term cultures of GPR125+ SPCs (GSPCs) also converted into GPR125+ MASC colonies. GPR125+MASCs generated derivatives of the three germ layers and contributed to chimaeric embryos, with concomitant downregulation of GPR125 during differentiation into GPR125− cells. MASCs also differentiated into contractile cardiac tissue in vitro and formed functional blood vessels in vivo. Molecular book marking by GPR125 in the adult mouse and, ultimately, in the human testis could enrich for a population of SPCs for derivation of GPR125+ MASCs, which may be employed for genetic manipulation, tissue regeneration and revascularization of ischaemic organs.
Published: 2007

47. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis

Author: Hsin Chieh Lin, Irene Noguera-Troise, Christopher Daly, George D. Yancopoulos, Gavin Thurston, Pat Boland, Nicholas W. Gale, Sandra Coetzee, and Nicholas J. Papadopoulos
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, Angiogenesis, medicine.medical_treatment, Notch signaling pathway, Biology, Adenoviridae, Neovascularization, chemistry.chemical_compound, Mice, Genes, Reporter, Internal medicine, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, education, education.field_of_study, Multidisciplinary, Delta-like ligand 4, Neovascularization, Pathologic, Receptors, Notch, Growth factor, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Cell Hypoxia, Blockade, Rats, Vascular endothelial growth factor, Endocrinology, Cytokine, chemistry, Gene Expression Regulation, Cancer research, medicine.symptom, Signal Transduction
Abstract: Tumour growth requires accompanying expansion of the host vasculature, with tumour progression often correlated with vascular density. Vascular endothelial growth factor (VEGF) is the best-characterized inducer of tumour angiogenesis. We report that VEGF dynamically regulates tumour endothelial expression of Delta-like ligand 4 (Dll4), which was previously shown to be absolutely required for normal embryonic vascular development. To define Dll4 function in tumour angiogenesis, we manipulated this pathway in murine tumour models using several approaches. Here we show that blockade resulted in markedly increased tumour vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was non-productive—as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumour growth—even for tumours resistant to anti-VEGF therapy. Thus, VEGF-induced Dll4 acts as a negative regulator of tumour angiogenesis; its blockade results in a striking uncoupling of tumour growth from vessel density, presenting a novel therapeutic approach even for tumours resistant to anti-VEGF therapies. VEGF, or vascular endothelial growth factor, is the best-characterized inducer of tumour angiogenesis, and the blockade of VEGF has become an important tool in cancer therapy. But VEGF blockade is not effective against all tumours, so the search for alternative approaches continues. Two groups this week report that one such alternative could be blockade of Dll4, Delta-like ligand 4. This transmembrane molecule is part of the Notch signalling pathway. It was known to be essential for normal development of blood vessels in the embryo: the new work shows that it is also required for tumour angiogenesis. It may be a viable — and potentially well tolerated — alternative in patients with solid tumours that are resistant to anti-VEGF therapy. One of two papers showing that inhibition of Dll4-mediated Notch signalling inhibits tumour growth by deregulation of tumour angiogenesis.
Published: 2006

48. Evasion of intracellular host defence by hepatitis C virus

Author: Eileen Foy and Michael Gale
Subjects: Multidisciplinary, biology, Effector, Hepatitis C virus, Hepacivirus, Alpha interferon, medicine.disease_cause, biology.organism_classification, Virology, Hepatitis C, Virus, Host-Parasite Interactions, Viral replication, Immunity, Immunology, medicine, Animals, Humans, Viral disease, Interferons, Signal Transduction
Abstract: Viral infection of mammalian cells rapidly triggers intracellular signalling events leading to interferon alpha/beta production and a cellular antiviral state. This 'host response' is our first line of immune defence against infection as it imposes several barriers to viral replication and spread. Hepatitis C virus (HCV) evades the host response through a complex combination of processes that include signalling interference, effector modulation and continual viral genetic variation. These evasion strategies support persistent infection and the spread of HCV. Defining the molecular mechanisms by which HCV regulates the host response is of crucial importance and may reveal targets for novel therapeutic strategies.
Published: 2005

49. Simulating micrometre-scale crystal growth from solution

Author: Stefano Piana, Julian D. Gale, and Manijeh M. Reyhani
Subjects: Supersaturation, Multidisciplinary, Chemistry, Monte Carlo method, Crystal growth, law.invention, Crystal, law, Chemical physics, Physical chemistry, Particle, Nanometre, Kinetic Monte Carlo, Crystallization
Abstract: Understanding crystal growth is essential for controlling the crystallization used in industrial separation and purification processes. Because solids interact through their surfaces, crystal shape can influence both chemical and physical properties. The thermodynamic morphology can readily be predicted, but most particle shapes are actually controlled by the kinetics of the atomic growth processes through which assembly occurs. Here we study the urea-solvent interface at the nanometre scale and report kinetic Monte Carlo simulations of the micrometre-scale three-dimensional growth of urea crystals. These simulations accurately reproduce experimentally observed crystal growth. Unlike previous models of crystal growth, no assumption is made that the morphology can be constructed from the results for independently growing surfaces or from an a priori specification of surface defect concentration. This approach offers insights into the role of the solvent, the degree of supersaturation, and the contribution that extended defects (such as screw dislocations) make to crystal growth. It also connects observations made at the nanometre scale, through in situ atomic force microscopy, with those made at the macroscopic level. If extended to include additives, the technique could lead to the computer-aided design of crystals.
Published: 2005

50. Fatal immunity and the 1918 virus

Author: Yueh Ming Loo and Michael Gale
Subjects: Multidisciplinary, Innate immune system, viruses, First line, Limiting, Biology, medicine.disease_cause, Virology, Virus, Viral replication, Immunity, Influenza A virus, medicine, Viral disease
Abstract: Innate immune defences are our first line of protection against infection by viruses and are essential in limiting viral disease. But their reaction to the 1918 influenza virus could have been deadly.
Published: 2007
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