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1.  Medium- to long-term outcomes of botulinum toxin A for idiopathic overactive bladder 
Botulinum toxin A (BoNT-A) has become an important therapeutic tool in the management of refractory overactive bladder (OAB). Over the last decade, there have been growing numbers of patients receiving repeat injections and these outcomes have begun to be reported in large, high-quality cohorts. This article reviews the current evidence for the medium- to long-term use of BoNT-A in adults with idiopathic detrusor overactivity (IDO) receiving repeat injections. We find that medium-term outcomes are encouraging but long-term outcomes are not as extensively reported. There is high-quality evidence that efficacy following the first injection persists across multiple treatment cycles. There are no additional safety concerns from repeat injections up to six treatment cycles. However, there is a need for further data to confirm the efficacy and safety of BoNT-A beyond the follow-up period in the current literature.
PMCID: PMC5167072  PMID: 28042308
botulinum toxin; overactive bladder; detrusor overactivity; botox; onabotulinumtoxinA; Dysport; abobotulinumtoxinA
2.  Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies 
Journal of Virology  2016;90(13):6127-6139.
Although antibodies to the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein have been studied extensively for their ability to block viral infectivity, little data are currently available on nonneutralizing functions of these antibodies, such as their ability to eliminate virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 Env-specific antibodies of diverse specificities, including potent broadly neutralizing and nonneutralizing antibodies, were therefore tested for ADCC against cells infected with a lab-adapted HIV-1 isolate (HIV-1NL4-3), a primary HIV-1 isolate (HIV-1JR-FL), and a simian-human immunodeficiency virus (SHIV) adapted for pathogenic infection of rhesus macaques (SHIVAD8-EO). In accordance with the sensitivity of these viruses to neutralization, HIV-1NL4-3-infected cells were considerably more sensitive to ADCC, both in terms of the number of antibodies and magnitude of responses, than cells infected with HIV-1JR-FL or SHIVAD8-EO. ADCC activity generally correlated with antibody binding to Env on the surfaces of virus-infected cells and with viral neutralization; however, neutralization was not always predictive of ADCC, as instances of ADCC in the absence of detectable neutralization, and vice versa, were observed. These results reveal incomplete overlap in the specificities of antibodies that mediate these antiviral activities and provide insights into the relationship between ADCC and neutralization important for the development of antibody-based vaccines and therapies for combating HIV-1 infection.
IMPORTANCE This study provides fundamental insights into the relationship between antibody-dependent cell-mediated cytotoxicity (ADCC) and virus neutralization that may help to guide the development of antibody-based vaccines and immunotherapies for the prevention and treatment of HIV-1 infection.
PMCID: PMC4907221  PMID: 27122574
3.  Marker gene tethering by nucleoporins affects gene expression in plants 
Nucleus  2015;6(6):471-478.
In non-plant systems, chromatin association with the nuclear periphery affects gene expression, where interactions with nuclear envelope proteins can repress and interactions with nucleoporins can enhance transcription. In plants, both hetero- and euchromatin can localize at the nuclear periphery, but the effect of proximity to the nuclear periphery on gene expression remains largely unknown. This study explores the putative function of Seh1 and Nup50a nucleoporins on gene expression by using the Lac Operator / Lac Repressor (LacI-LacO) system adapted to Arabidopsis thaliana. We used LacO fused to the luciferase reporter gene (LacO:Luc) to investigate whether binding of the LacO:Luc transgene to nucleoporin:LacI protein fusions alters luciferase expression. Two separate nucleoporin-LacI-YFP fusions were introduced into single insert, homozygous LacO:Luc Arabidopsis plants. Homozygous plants carrying LacO:Luc and a single insert of either Seh1-LacI-YFP or Nup50a-LacI-YFP were tested for luciferase activity and compared to plants containing LacO:Luc only. Seh1-LacI-YFP increased, while Nup50a-LacI-YFP decreased luciferase activity. Seh1-LacI-YFP accumulated at the nuclear periphery as expected, while Nup50a-LacI-YFP was nucleoplasmic and was not selected for further study. Protein and RNA levels of luciferase were quantified by western blotting and RT-qPCR, respectively. Increased luciferase activity in LacO:Luc+Seh1-LacI-YFP plants was correlated with increased luciferase protein and RNA levels. This change of luciferase expression was abolished by disruption of LacI-LacO binding by treating with IPTG in young seedlings, rosette leaves and inflorescences. This study suggests that association with the nuclear periphery is involved in the regulation of gene expression in plants.
PMCID: PMC4915490  PMID: 26652762
Arabidopsis thaliana; chromatin organization; gene expression; higher plant; LacO:LacI; Nuclear pore complex; Seh1
4.  Integrative pathway genomics of lung function and airflow obstruction 
Human Molecular Genetics  2015;24(23):6836-6848.
Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.
PMCID: PMC4643644  PMID: 26395457
5.  Palaeoenvironmental drivers of vertebrate community composition in the Belly River Group (Campanian) of Alberta, Canada, with implications for dinosaur biogeography 
BMC Ecology  2016;16:52.
The Belly River Group of southern Alberta is one of the best-sampled Late Cretaceous terrestrial faunal assemblages in the world. This system provides a high-resolution biostratigraphic record of terrestrial vertebrate diversity and faunal turnover, and it has considerable potential to be a model system for testing hypotheses of dinosaur palaeoecological dynamics, including important aspects of palaeoecommunity structure, trophic interactions, and responses to environmental change. Vertebrate fossil microsites (assemblages of small bones and teeth concentrated together over a relatively short time and thought to be representative of community composition) offer an unparalleled dataset to better test these hypotheses by ameliorating problems of sample size, geography, and chronostratigraphic control that hamper other palaeoecological analyses. Here, we assembled a comprehensive relative abundance dataset of microsites sampled from the entire Belly River Group and performed a series of analyses to test the influence of environmental factors on site and taxon clustering, and assess the stability of faunal assemblages both temporally and spatially. We also test the long-held idea that populations of large dinosaur taxa were particularly sensitive to small-scale environmental gradients, such as the paralic (coastal) to alluvial (inland) regimes present within the time-equivalent depositional basin of the upper Oldman and lower Dinosaur Park Formations.
Palaeoenvironment (i.e. reconstructed environmental conditions, related to relative amount of alluvial, fluvial, and coastal influence in associated sedimentary strata) was found to be strongly associated with clustering of sites by relative-abundance faunal assemblages, particularly in relation to changes in faunal assemblage composition and marine-terrestrial environmental transitions. Palaeogeography/palaeolandscape were moderately associated to site relative abundance assemblage clustering, with depositional setting and time (i.e. vertical position within stratigraphic unit) more weakly associated. Interestingly, while vertebrate relative abundance assemblages as a whole were strongly correlated with these marine-terrestrial transitions, the dinosaur fauna does not appear to be particularly sensitive to them.
This analysis confirms that depositional setting (i.e. the sediment type/sorting and associated characteristics) has little effect on faunal assemblage composition, in contrast to the effect of changes in the broader palaeoenvironment (e.g. upper vs. lower coastal plain, etc.), with marine-terrestrial transitions driving temporal faunal dynamics within the Belly River Group. The similarity of the dinosaur faunal assemblages between the time-equivalent portions of the Dinosaur Park Formation and Oldman Formation suggests that either these palaeoenvironments are more similar than characterized in the literature, or that the dinosaurs are less sensitive to variation in palaeoenvironment than has often been suggested. A lack of sensitivity to subtle environmental gradients casts doubt on these forces acting as a driver of putative endemism of dinosaur populations in the Late Cretaceous of North America.
Electronic supplementary material
The online version of this article (doi:10.1186/s12898-016-0106-8) contains supplementary material, which is available to authorized users.
PMCID: PMC5111292  PMID: 27846871
Palaeoenvironments; Vertebrate microfossil sites; Palaeoecology; Altitudinal sensitivity; Biogeography; Dinosaurs; Faunal turnover; Latitudinal climate gradients; Belly River Group
6.  Genome-wide association study identifies 74 loci associated with educational attainment 
Okbay, Aysu | Beauchamp, Jonathan P. | Fontana, Mark A. | Lee, James J. | Pers, Tune H. | Rietveld, Cornelius A. | Turley, Patrick | Chen, Guo-Bo | Emilsson, Valur | Meddens, S. Fleur W. | Oskarsson, Sven | Pickrell, Joseph K. | Thom, Kevin | Timshel, Pascal | de Vlaming, Ronald | Abdellaoui, Abdel | Ahluwalia, Tarunveer S. | Bacelis, Jonas | Baumbach, Clemens | Bjornsdottir, Gyda | Brandsma, Johannes H. | Concas, Maria Pina | Derringer, Jaime | Furlotte, Nicholas A. | Galesloot, Tessel E. | Girotto, Giorgia | Gupta, Richa | Hall, Leanne M. | Harris, Sarah E. | Hofer, Edith | Horikoshi, Momoko | Huffman, Jennifer E. | Kaasik, Kadri | Kalafati, Ioanna P. | Karlsson, Robert | Kong, Augustine | Lahti, Jari | van der Lee, Sven J. | de Leeuw, Christiaan | Lind, Penelope A. | Lindgren, Karl-Oskar | Liu, Tian | Mangino, Massimo | Marten, Jonathan | Mihailov, Evelin | Miller, Michael B. | van der Most, Peter J. | Oldmeadow, Christopher | Payton, Antony | Pervjakova, Natalia | Peyrot, Wouter J. | Qian, Yong | Raitakari, Olli | Rueedi, Rico | Salvi, Erika | Schmidt, Börge | Schraut, Katharina E. | Shi, Jianxin | Smith, Albert V. | Poot, Raymond A. | Pourcain, Beate | Teumer, Alexander | Thorleifsson, Gudmar | Verweij, Niek | Vuckovic, Dragana | Wellmann, Juergen | Westra, Harm-Jan | Yang, Jingyun | Zhao, Wei | Zhu, Zhihong | Alizadeh, Behrooz Z. | Amin, Najaf | Bakshi, Andrew | Baumeister, Sebastian E. | Biino, Ginevra | Bønnelykke, Klaus | Boyle, Patricia A. | Campbell, Harry | Cappuccio, Francesco P. | Davies, Gail | De Neve, Jan-Emmanuel | Deloukas, Panos | Demuth, Ilja | Ding, Jun | Eibich, Peter | Eisele, Lewin | Eklund, Niina | Evans68, David M. | Faul, Jessica D. | Feitosa, Mary F. | Forstner, Andreas J. | Gandin, Ilaria | Gunnarsson, Bjarni | Halldórsson, Bjarni V. | Harris, Tamara B. | Heath, Andrew C. | Hocking, Lynne J. | Holliday, Elizabeth G. | Homuth, Georg | Horan, Michael A. | Hottenga, Jouke-Jan | de Jager, Philip L. | Joshi, Peter K. | Jugessur, Astanand | Kaakinen, Marika A. | Kähönen, Mika | Kanoni, Stavroula | Keltigangas-Järvinen, Liisa | Kiemeney, Lambertus A.L.M. | Kolcic, Ivana | Koskinen, Seppo | Kraja, Aldi T. | Kroh, Martin | Kutalik, Zoltan | Latvala, Antti | Launer, Lenore J. | Lebreton, Maël P. | Levinson, Douglas F. | Lichtenstein, Paul | Lichtner, Peter | Liewald, David C.M. | Loukola, Anu | Madden, Pamela A. | Mägi, Reedik | Mäki-Opas, Tomi | Marioni, Riccardo E. | Marques-Vidal, Pedro | Meddens, Gerardus A. | McMahon, George | Meisinger, Christa | Meitinger, Thomas | Milaneschi, Yusplitri | Milani, Lili | Montgomery, Grant W. | Myhre, Ronny | Nelson, Christopher P. | Nyholt, Dale R. | Ollier, William E.R. | Palotie, Aarno | Paternoster, Lavinia | Pedersen, Nancy L. | Petrovic, Katja E. | Porteous, David J. | Räikkönen, Katri | Ring, Susan M. | Robino, Antonietta | Rostapshova, Olga | Rudan, Igor | Rustichini, Aldo | Salomaa, Veikko | Sanders, Alan R. | Sarin, Antti-Pekka | Schmidt, Helena | Scott, Rodney J. | Smith, Blair H. | Smith, Jennifer A. | Staessen, Jan A. | Steinhagen-Thiessen, Elisabeth | Strauch, Konstantin | Terracciano, Antonio | Tobin, Martin D. | Ulivi, Sheila | Vaccargiu, Simona | Quaye, Lydia | van Rooij, Frank J.A. | Venturini, Cristina | Vinkhuyzen, Anna A.E. | Völker, Uwe | Völzke, Henry | Vonk, Judith M. | Vozzi, Diego | Waage, Johannes | Ware, Erin B. | Willemsen, Gonneke | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Bisgaard, Hans | Boomsma, Dorret I. | Borecki, Ingrid B. | Bultmann, Ute | Chabris, Christopher F. | Cucca, Francesco | Cusi, Daniele | Deary, Ian J. | Dedoussis, George V. | van Duijn, Cornelia M. | Eriksson, Johan G. | Franke, Barbara | Franke, Lude | Gasparini, Paolo | Gejman, Pablo V. | Gieger, Christian | Grabe, Hans-Jörgen | Gratten, Jacob | Groenen, Patrick J.F. | Gudnason, Vilmundur | van der Harst, Pim | Hayward, Caroline | Hinds, David A. | Hoffmann, Wolfgang | Hyppönen, Elina | Iacono, William G. | Jacobsson, Bo | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Lehtimäki, Terho | Lehrer, Steven F. | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Pendleton, Neil | Penninx, Brenda W.J.H. | Perola, Markus | Pirastu, Nicola | Pirastu, Mario | Polasek, Ozren | Posthuma, Danielle | Power, Christine | Province, Michael A. | Samani, Nilesh J. | Schlessinger, David | Schmidt, Reinhold | Sørensen, Thorkild I.A. | Spector, Tim D. | Stefansson, Kari | Thorsteinsdottir, Unnur | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Tung, Joyce Y. | Uitterlinden, André G. | Vitart, Veronique | Vollenweider, Peter | Weir, David R. | Wilson, James F. | Wright, Alan F. | Conley, Dalton C. | Krueger, Robert F. | Smith, George Davey | Hofman, Albert | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Yang, Jian | Johannesson, Magnus | Visscher, Peter M. | Esko, Tõnu | Koellinger, Philipp D. | Cesarini, David | Benjamin, Daniel J.
Nature  2016;533(7604):539-542.
Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease.
PMCID: PMC4883595  PMID: 27225129
7.  British Society of Breast Radiology Annual Scientific Meeting 2016 
Azmil, Ameerah Mohd | Bansal, Gaurav Jyoti | Davies, Eleri | Wallis, Matthew | Kilburn-Toppin, Fleur | Taylor-Phillip, Sian | Buckley, Anne | Healy, Nuala | Quinn, Aine | O’Keeffe, Sylvia | Ang, Teri | Maxwell, Anthony | Lim, Yit Y. | Harkness, Elaine | Emsley, Richard | Astley, Susan | Gadde, Soujanya | Ang, Teri | Maxwell, Anthony | Lim, Yit Y. | Harkness, Elaine | Emsley, Richard | Astley, Susan | Gadde, Soujanya | Ferguson, Jennifer | Stevens, Guy | Hills, Robert | Thomas, Kate Gower | Rajan, Sabrina | Sharma, Nisha | Kishore, Ajit | O’ Dowd, John | Murphy, Claire | Lindsay, Ken | Dadayal, Guneesh | Moody, Anne Nielsen | Whitaker, Madeleine | Wolstenhulme, Stephen | Bull, Jane | Sharma, Nisha | Culpan, Anne-Marie | Roszkowski, Natalia | Grima, Alexis | Stahnke, Michaela | Rubin, Caroline | Walker, Ruth | Oeppen, Rachel | Puttagunta, Srikanth | Gray, Karen | Puri, Shama | Sharma, Nisha | Millican-Slater, Rebecca | Pascaline, Sana | Hajaj, Mohamad | Flinn, Janet | Thomson, Kim | Elsberger, Beatrix | Turnbull, Anne | Bagnall, Mark | York, Joanne | Benney, Stuart | Goyal, Amit | Topps, Ashley | Barr, Simon | Pikoulas, Panagiotis | Pritchard, Susan | Maxwell, Anthony | Greenhalgh, Sophie | Sreenivas, Muthyala | Greenhalgh, Sophie | Sreenivas, Muthyala | Greenhalgh, Sophie | Sreenivas, Muthyala | Nandhra, Anju | Sharma, Sheetal | Gulati, Archita | Razzaq, Furhan | Khan, Sana | McKillen, Jacqueline | Larkin, Rupert | Sreenivas, Muthyala | Kamat, Sachin | Goncalves, Carla | Tan, Alan | Eleti, Asha | Vidyaprakash, Nithya | McMahon, Michelle A. | Dall, Barbara J. G. | Sharma, Nisha | Majid, Faisal | Sreenivas, Muthyala | Rattehalli, Ramachadra | Gaur, Vandana | Mackenzie, Alistair | Warren, Lucy | Patel, Mishal | Halling-Brown, Mark | Wilkinson, Louise | Young, Kenneth | Tanner, James | Wallis, Matthew | Currie, Rachael | Balyes, Sharron | Wragg, Julie | Zamfir, Georgiana | Ayra, Pallavi | Marsden, Max | Butterworth, James | Sinha, Shona | Desai, Anil | Metafa, Anna | Whitaker, Madeleine | Nielsen-Moody, Anne | Wolstenhulme, Stephen | Sharma, Nisha | Bull, Jane | Ward, Laura | Heller, Samantha | Hudson, Sue | Wilkinson, Louise | Taylor, Kathryn | Xyda, Argyro | Turnbull, Anne | Allen, Steven | Orlowski, Elizabeth | York, Joanne | Downey, Kate | Sidebottom, Richard | Wallis, Matthew | Lodhi, Ahmad | Harkness, Elaine | Maxwell, Anthony | Howell, Anthony | Evans, Gareth | Gadde, Soujanya | Astley, Susan | Lim, Yit | Chen, Yan | Lepine-Williams, Elizabeth | Henderson, Steven | Litherland, Janet | Altaf, Naveed | Bury, Yvonne | Forester, Nerys | Chin, Mei Chan | Litherland, Janet | Taylor, Caroline | Skippage, Pippa | Sian, Aneet | McAvinchey, Rita | Evans, Tom | Stevens, Guy | Nisbet, Sian | Murray, Alex | Thomas, Kate Gower | Castillo, Raquel Clark | Markham, Hannah | Oeppen, Rachel | Thomas, Timothy | Jain, Anil | Molderson, Jaanilka | Wan, Joseph | Newman, Helen | Lowes, Simon | Lunt, Linsley | Sultana, Sadia | Chillal, Varun | Sreenivas, Muthyala | Dalton, Rebecca | Reeves, David | Sergeant, Jamie | Harkness, Elaine | Gadde, Soujanya | Maxwell, Anthony | Lim, Yit | Astley, Susan | Edwards, Liz | Jenkins, Kate | Stevens, Guy | Jain, Anil | Molderson, Jaanilka | Shaikh, Shaheeda | Sidebottom, Richard | O’Flynn, Elizabeth | Bombroffe, Laura | Hughes, Julie | Scurr, Erica | Wilson, Robin | Jones, Lyn | Govindarajulu, Sasirekha | Sahu, Ajay K. | Brown, Matthew | Allen, Steve | O’Flynn, Liz | deSouza, Nandita | Rahim, Rumana | Wasan, Rema | Goligher, Jane | Wijesuriya, Shalini | Morel, Juliet | Peacock, Clare | Michell, Michael | Iqbal, Asif | Evans, David | Batohi, Bhavna | Wasan, Tavleen | Phillips, Vivien | Manuel, Eden | Bowman, Gillian | Satchithananda, Keshthra | Batohi, Bhavna | Fang, Cheng | Michell, Michael | Morel, Juliet | Shah, Chirag | Wijesuriya, Shalini | Peacock, Clare | Rahim, Rumana | Wasan, Rema | Goligher, Jane | Satchithananda, Keshthra | Altaf, Naveed | Forester, Nerys | Hodkin, Leanne | Horgan, Keiran | Dodwell, David | Sharma, Nisha | Moloney, BM | Casey, M. C. | Breathnach, A. | Dwyer, R. M. | McLoughlin, R. | Sweeney, K. J. | Malone, C. | Healy, M. J. | Kerin, M. J. | Forester, Nerys | Lowes, Simon | Mitchell, Elizabeth | Twiddy, Maureen | Maxwell, Anthony | Sharma, Nisha | Dobson, Hilary | Vinnicombe, Sarah | Evans, Andrew | Grant, David | Bishop, Briony | Giggens, Roxanne | Bhuva, Shaheel | Royds, Jennifer | Camilleri, Francesca | Babu, Gauripriya | Beveridge, Carolyn | Geach, Rebecca | Klimczak, Katherine | Massey, Helen | Lyburn, Iain | Wan, Joseph | Jain, Anil | Molderson, Jaanilka | Salehi-Bird, Seema | Nishtala, Sahithi | Gunning, Liz | Changaradil, Deepthi Vinayan | Bansal, Jyoti | Davis, Joanna | Sharma, Ashwini | Del Voscovo, Elena | Etheridge, Harriet | Butler, Aisling | Fenne, David S. J. | Rubin, Gary | Burt, Helen | Ridley, Nick | Taylor, Sarah | Sreenivas, Muthyala | Seth, Subodh | Seth, Archana
Breast Cancer Research : BCR  2016;18(Suppl 1):1-20.
PMCID: PMC5123431
8.  Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression 
Molecular cancer therapeutics  2015;14(11):2452-2462.
The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA approved oncology agents and 345 investigational agents. The investigational agents library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at 9 concentrations in triplicate with an exposure time of 96 hrs using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression and microRNA expression data are publicly available at These data provide a unique resource to the cancer research community.
PMCID: PMC4636476  PMID: 26351324
Sarcoma; sarcoma cell-based screen; sarcoma microRNAs; sarcoma gene expression
10.  Iron‐ and Cobalt‐Catalyzed Synthesis of Carbene Phosphinidenes 
In the presence of stoichiometric or catalytic amounts of [M{N(SiMe3)2}2] (M=Fe, Co), N‐heterocyclic carbenes (NHCs) react with primary phosphines to give a series of carbene phosphinidenes of the type (NHC)⋅PAr. The formation of (IMe4)⋅PMes (Mes=mesityl) is also catalyzed by the phosphinidene‐bridged complex [(IMe4)2Fe(μ‐PMes)]2, which provides evidence for metal‐catalyzed phosphinidene transfer.
PMCID: PMC5064616  PMID: 26643712
catalysis; cobalt; iron; N-heterocyclic carbenes; phosphorus
11.  How neurologists are paid 
Neurology: Clinical Practice  2015;5(5):412-418.
Part 1 of this series focused on factors influencing payment for patient care services and Part 2 described compensation plans for neurologists in private practice and in academic medicine. In Part 3, we review how hospital salary support and appointments to Veterans Administration hospitals contribute to the salary structure of neurologists. We also discuss neurohospitalist care and ways neurologists can potentially increase compensation from on-call pay, telemedicine, and the use of new transitional care and complex chronic care codes. We conclude with an emphasis on the important role of neurologists as team players in a health care system that will rely on efficient coordination of care among many health care workers.
PMCID: PMC4610316  PMID: 26526185
12.  How neurologists are paid 
Neurology: Clinical Practice  2015;5(5):397-404.
Neurologists are facing yearly reductions in reimbursement for rendered services. These reductions arise from changes by Medicare, Medicaid, and third-party payers to achieve cost savings. In Part 1, we discuss reimbursement for office visits and procedures, the relative value scale, the conversion factor used by Medicare to transform work into payments, and the recently repealed sustainable growth rate. The establishment of new codes for transitional care and chronic care management may augment the salaries of neurologists who care for patients with chronic conditions. Medicare's recent elimination of payment for consultations and the bundling of nerve conduction studies have dramatically affected reimbursement. Large discrepancies remain between compensation for procedures and office visits.
PMCID: PMC4610318  PMID: 26526465
13.  How neurologists are paid 
Neurology: Clinical Practice  2015;5(5):405-411.
Part 1 of this series focused on factors influencing payment for patient care services. In Part 2, we review compensation models for nonpatient activity such as medical legal reviews, committee participation, and collaboration with the pharmaceutical industry. Compensation to neurologists in private practice is commonly in the form of guaranteed salary and bonuses. Salary for neurologists in academic medicine has changed considerably over the past 3 decades, from small departments with faculty supported by grants and volunteer faculty, to large departments with faculty split between those with research grant support and those focusing on patient care and teaching. Compensation models in academic medicine range from straight salary without bonus to straight salary with personal or shared bonus and salary based on relative value units.
PMCID: PMC4610320  PMID: 26526703
15.  Early real-world evidence of persistence on oral anticoagulants for stroke prevention in non-valvular atrial fibrillation: a cohort study in UK primary care 
BMJ Open  2016;6(9):e011471.
To examine the characteristics and persistence in patients newly initiated with oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF).
Cohort study in Clinical Practice Research Datalink.
UK primary care.
15 242 patients with NVAF newly prescribed apixaban, rivaroxaban, dabigatran or vitamin K antagonists (VKAs) between 1 December 2012 and 31 October 2014. 13 089 patients were OAC naïve.
Outcome measures
Patient characteristics and risk of non-persistence compared to apixaban using Cox regression models over the entire follow-up and using a time-partitioned approach to handle non-proportional hazards.
Among the OAC naïve patients, VKAs were most common (78.1%, n=10 218), followed by rivaroxaban (12.1%, n=1589), dabigatran (5.7%, n=741) and apixaban (4.1%, n=541). High baseline stroke risk (CHA2DS2VASc ≥2) ranged from 80.2% (dabigatran) to 88.4% (apixaban and rivaroxaban). History of stroke and bleeding was the highest among apixaban (23.7% and 31.6%) and lowest among VKA patients (15.9% and 27.5%). Across the entire follow-up period, adjusting for differences in characteristics, there was no evidence of a difference in non-persistence between VKA and apixaban (HR 0.92 (95% CI 0.68 to 1.23)). Non-persistence was higher with dabigatran (HR 1.67 (1.20 to 2.32)) and rivaroxaban (HR 1.41 (1.02 to 1.93)) than apixaban. Using the partitioned approach, non-persistence was lower with VKA (HR 0.33 (0.22 to 0.48)), and higher with dabigatran (HR 1.65 (1.08 to 2.52)) compared to apixaban in the first 2 months of follow-up. After 2 months, non-persistence was higher with VKA (HR 1.70 (1.08 to 2.66)) and dabigatran (HR 2.10 (1.30 to 3.41)). Pooling OAC naïve and experienced patients, non-persistence was also higher with rivaroxaban compared to apixaban after 2 months of follow-up (HR 1.69 (1.19 to 2.39)).
Observed differential prescribing of OACs can result in channelling bias in comparative effectiveness research. Persistence patterns changed over follow-up time, but there are indications of improved persistence rates with apixaban over other OACs in the UK. A larger study with longer follow-up is needed to corroborate findings. This study is registered on (NCT02488421).
PMCID: PMC5051466  PMID: 27678530
atrial fibrillation; oral anticoagulation; discontinuation patterns
16.  Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population 
Nature genetics  2016;48(5):552-555.
Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of that risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortia and population based resources (total n>38,000), we find genomewide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in an ASD or other neuropsychiatric disorder diagnosis. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.
PMCID: PMC4986048  PMID: 26998691
18.  Crystal Structures of the M1 and M4 Muscarinic Acetylcholine Receptors 
Nature  2016;531(7594):335-340.
Muscarinic M1–M5 acetylcholine receptors are G protein-coupled receptors (GPCRs) that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here, we report the first crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures to each other, as well as the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.
PMCID: PMC4915387  PMID: 26958838
19.  Genetic evidence for causal relationships between maternal obesity-related traits and birth weight 
JAMA  2016;315(11):1129-1140.
Structured abstract
Neonates born to overweight/obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.
To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.
Design, Setting and Participants
We used Mendelian randomization to test whether maternal BMI and obesity-related traits are causally related to offspring birth weight. Mendelian randomization makes use of the fact that genotypes are randomly determined at conception and are thus not confounded by non-genetic factors. Data were analysed on 30,487 women from 18 studies. Participants were of European ancestry from population- or community-based studies located in Europe, North America or Australia and participating in the Early Growth Genetics (EGG) Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. We tested associations between a genetic score of 30 BMI-associated single nucleotide polymorphisms (SNPs) and (i) maternal BMI and (ii) birth weight, to estimate the causal relationship between BMI and birth weight. Analyses were repeated for other obesity-related traits.
Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, HDL-cholesterol level, vitamin D status and adiponectin level.
Main Outcome(s) and Measure(s)
Offspring birth weight measured by trained study personnel (n=2 studies), from medical records (n= 10 studies) or from maternal report (n=6 studies).
Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The genetic score for BMI was associated with a 2g (95%CI: 0, 3g) higher offspring birth weight per maternal BMI-raising allele (P=0.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8g (95%CI: 6, 10g) per glucose-raising allele (P=7×10−14) and −4g (95%CI: −6, −2g) per SBP-raising allele (P=1×10−5), respectively. A 1 standard deviation (1 SD ≈ 4kg/m2) genetically higher maternal BMI was associated with a 55g (95% CI: 17, 93g) higher birth weight. A 1-SD genetically higher maternal fasting glucose (≈ 0.4mmol/L) or SBP (10mmHg) were associated with a 114g (95%CI: 80, 147g) higher or −208g (95% CI: −394, −21g) lower birth weight, respectively. For BMI and fasting glucose these genetic associations were consistent with the observational associations, but for SBP, the genetic and observational associations were in opposite directions.
Conclusions and Relevance
In this Mendelian randomization study of more than 30,000 women with singleton offspring from 18 studies, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal systolic blood pressure was shown to be potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
PMCID: PMC4811305  PMID: 26978208
20.  Live-Cell Imaging of Vaccinia Virus Recombination 
PLoS Pathogens  2016;12(8):e1005824.
Recombination between co-infecting poxviruses provides an important mechanism for generating the genetic diversity that underpins evolution. However, poxviruses replicate in membrane-bound cytoplasmic structures known as factories or virosomes. These are enclosed structures that could impede DNA mixing between co-infecting viruses, and mixing would seem to be essential for this process. We hypothesize that virosome fusion events would be a prerequisite for recombination between co-infecting poxviruses, and this requirement could delay or limit viral recombination. We have engineered vaccinia virus (VACV) to express overlapping portions of mCherry fluorescent protein fused to a cro DNA-binding element. In cells also expressing an EGFP-cro fusion protein, this permits live tracking of virus DNA and genetic recombination using confocal microscopy. Our studies show that different types of recombination events exhibit different timing patterns, depending upon the relative locations of the recombining elements. Recombination between partly duplicated sequences is detected soon after post-replicative genes are expressed, as long as the reporter gene sequences are located in cis within an infecting genome. The same kinetics are also observed when the recombining elements are divided between VACV and transfected DNA. In contrast, recombination is delayed when the recombining sequences are located on different co-infecting viruses, and mature recombinants aren’t detected until well after late gene expression is well established. The delay supports the hypothesis that factories impede inter-viral recombination, but even after factories merge there remain further constraints limiting virus DNA mixing and recombinant gene assembly. This delay could be related to the continued presence of ER-derived membranes within the fused virosomes, membranes that may once have wrapped individual factories.
Author Summary
Recombination plays a critical role in DNA repair and also creates the genetic diversity that underpins evolution. This has important implications for viruses, since recombination may create new pathogens with new infectious properties. It has long been known that hybrids can be recovered from cells co-infected with related viruses, some of the first artificial recombinants were produced >50 years ago from variola and rabbitpox viruses. A particular property of poxviruses is that they replicate in membrane-wrapped cytoplasmic structures called “factories”, and each of these factories develops from a single infecting particle. However, if each genome is isolated inside different factories, when and how does the DNA mix to permit recombination? To examine this question, we have developed a fluorescence-based virus recombination assay. Using live cell confocal microscopy, we have timed these reactions and observed that recombinants can be quickly formed when the recombining sequences are located on the same virus genome. However, when the gene fragments are located on different viruses, there is a significant delay (and a reduction) in recombinant gene formation. This delay supports the hypothesis that factories, and the ER-derived cell membranes that surround factories, impede recombination in poxvirus-infected cells.
PMCID: PMC4985154  PMID: 27525721
21.  Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity 
BMC Genetics  2016;17:116.
Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals.
We generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs.
We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-016-0423-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4981989  PMID: 27514831
Copy number variation; Lung function; Genome-wide association study
22.  Ontogeny reveals function and evolution of the hadrosaurid dinosaur dental battery 
Hadrosaurid dinosaurs, dominant Late Cretaceous herbivores, possessed complex dental batteries with up to 300 teeth in each jaw ramus. Despite extensive interest in the adaptive significance of the dental battery, surprisingly little is known about how the battery evolved from the ancestral dinosaurian dentition, or how it functioned in the living organism. We undertook the first comprehensive, tissue-level study of dental ontogeny in hadrosaurids using several intact maxillary and dentary batteries and compared them to sections of other archosaurs and mammals. We used these comparisons to pinpoint shifts in the ancestral reptilian pattern of tooth ontogeny that allowed hadrosaurids to form complex dental batteries.
Comparisons of hadrosaurid dental ontogeny with that of other amniotes reveals that the ability to halt normal tooth replacement and functionalize the tooth root into the occlusal surface was key to the evolution of dental batteries. The retention of older generations of teeth was driven by acceleration in the timing and rate of dental tissue formation. The hadrosaurid dental battery is a highly modified form of the typical dinosaurian gomphosis with a unique tooth-to-tooth attachment that permitted constant and perfectly timed tooth eruption along the whole battery.
We demonstrate that each battery was a highly dynamic, integrated matrix of living replacement and, remarkably, dead grinding teeth connected by a network of ligaments that permitted fine scale flexibility within the battery. The hadrosaurid dental battery, the most complex in vertebrate evolution, conforms to a surprisingly simple evolutionary model in which ancestral reptilian tissue types were redeployed in a unique manner. The hadrosaurid dental battery thus allows us to follow in great detail the development and extended life history of a particularly complex food processing system, providing novel insights into how tooth development can be altered to produce complex dentitions, the likes of which do not exist in any living vertebrate.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-016-0721-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4964017  PMID: 27465802
23.  Genome-wide association study of blood lead shows multiple associations near ALAD 
Human Molecular Genetics  2015;24(13):3871-3879.
Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993–1996 and 2002–2005 and from UK in 1991–1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10−14 for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10−6 > P > 5 × 10−8). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.
PMCID: PMC4459389  PMID: 25820613
24.  Hepatitis C Virus Infects Rhesus Macaque Hepatocytes and Simianized Mice 
Hepatology (Baltimore, Md.)  2015;62(1):57-67.
At least 170 million people are chronically infected with hepatitis C virus (HCV). Due to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small non-human primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be due to the diminished capacity of HCV to antagonize MAVS-dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks. Conclusion: Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species-specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection and vaccine development.
PMCID: PMC4482775  PMID: 25820364
Hepatitis C; hepatitis virus; animal model; host tropism
25.  A case of a pseudo colonic mass causing gastrointestinal bleeding in a patient with a left ventricular assist device 
There are many complications associated with the left ventricular assist devices (LVADs), including gastrointestinal bleeding (GIB). We present a case of a pseudo colonic mass visualized on colonoscopy during workup for GIB in an LVAD patient necessitating a right colectomy with final pathology negative for malignancy. A review of the literature in regards to the pathology, diagnosis, and treatment of this interesting condition is included.
PMCID: PMC5051059  PMID: 27722118
Colectomy; gastrointestinal bleeding; left ventricular assist device

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