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881.
Tyler S. Smith Benjamin Spitzbarth Jian Li Donald R. Dugger Gabi Stern-Schneider Elisabeth Sehn Susan N. Bolch J. Hugh McDowell Jeremiah Tipton Uwe Wolfrum W. Clay Smith 《Cellular and molecular life sciences : CMLS》2013,70(23):4603-4616
Arrestins are dynamic proteins that move between cell compartments triggered by stimulation of G-protein-coupled receptors. Even more dynamically in vertebrate photoreceptors, arrestin1 (Arr1) moves between the inner and outer segments according to the light conditions. Previous studies have shown that the light-driven translocation of Arr1 in rod photoreceptors is initiated by rhodopsin through a phospholipase C/protein kinase C (PKC) signaling cascade. The purpose of this study is to identify the PKC substrate that regulates the translocation of Arr1. Mass spectrometry was used to identify the primary phosphorylated proteins in extracts prepared from PKC-stimulated mouse eye cups, confirming the finding with in vitro phosphorylation assays. Our results show that Bardet–Biedl syndrome 5 (BBS5) is the principal protein phosphorylated either by phorbol ester stimulation or by light stimulation of PKC. Via immunoprecipitation of BBS5 in rod outer segments, Arr1 was pulled down; phosphorylation of BBS5 reduced this co-precipitation of Arr1. Immunofluorescence and immunoelectron microscopy showed that BBS5 principally localizes along the axonemes of rods and cones, but also in photoreceptor inner segments, and synaptic regions. Our principal findings in this study are threefold. First, we demonstrate that BBS5 is post-translationally regulated by phosphorylation via PKC, an event that is triggered by light in photoreceptor cells. Second, we find a direct interaction between BBS5 and Arr1, an interaction that is modulated by phosphorylation of BBS5. Finally, we show that BBS5 is distributed along the photoreceptor axoneme, co-localizing with Arr1 in the dark. These findings suggest a role for BBS5 in regulating light-dependent translocation of Arr1 and a model describing its role in Arr1 translocation is proposed. 相似文献
882.
In this paper we define two new properties—linear observability and L-observability—to aid the study of overspecification and unidentifiability in quasi-linear and non-linear state space time series. Various equivalence results are proved and illustrated and some general properties of observable and unobservable processes are derived. The results are often proved by using graphical methods (influence diagrams) for manipulating conditional independence statements embedded in the new definitions. © 1997 John Wiley & Sons, Ltd. 相似文献
883.
Bruno Madio Steve Peigneur Yanni K. Y. Chin Brett R. Hamilton Sónia Troeira Henriques Jennifer J. Smith Ben Cristofori-Armstrong Zoltan Dekan Berin A. Boughton Paul F. Alewood Jan Tytgat Glenn F. King Eivind A. B. Undheim 《Cellular and molecular life sciences : CMLS》2018,75(24):4511-4524
Sea anemone venoms have long been recognized as a rich source of peptides with interesting pharmacological and structural properties, but they still contain many uncharacterized bioactive compounds. Here we report the discovery, three-dimensional structure, activity, tissue localization, and putative function of a novel sea anemone peptide toxin that constitutes a new, sixth type of voltage-gated potassium channel (KV) toxin from sea anemones. Comprised of just 17 residues, κ-actitoxin-Ate1a (Ate1a) is the shortest sea anemone toxin reported to date, and it adopts a novel three-dimensional structure that we have named the Proline-Hinged Asymmetric β-hairpin (PHAB) fold. Mass spectrometry imaging and bioassays suggest that Ate1a serves a primarily predatory function by immobilising prey, and we show this is achieved through inhibition of Shaker-type KV channels. Ate1a is encoded as a multi-domain precursor protein that yields multiple identical mature peptides, which likely evolved by multiple domain duplication events in an actinioidean ancestor. Despite this ancient evolutionary history, the PHAB-encoding gene family exhibits remarkable sequence conservation in the mature peptide domains. We demonstrate that this conservation is likely due to intra-gene concerted evolution, which has to our knowledge not previously been reported for toxin genes. We propose that the concerted evolution of toxin domains provides a hitherto unrecognised way to circumvent the effects of the costly evolutionary arms race considered to drive toxin gene evolution by ensuring efficient secretion of ecologically important predatory toxins. 相似文献
884.
Albers CA Paul DS Schulze H Freson K Stephens JC Smethurst PA Jolley JD Cvejic A Kostadima M Bertone P Breuning MH Debili N Deloukas P Favier R Fiedler J Hobbs CM Huang N Hurles ME Kiddle G Krapels I Nurden P Ruivenkamp CA Sambrook JG Smith K Stemple DL Strauss G Thys C van Geet C Newbury-Ecob R Ouwehand WH Ghevaert C 《Nature genetics》2012,44(4):435-9, S1-2
885.
Estrada K Styrkarsdottir U Evangelou E Hsu YH Duncan EL Ntzani EE Oei L Albagha OM Amin N Kemp JP Koller DL Li G Liu CT Minster RL Moayyeri A Vandenput L Willner D Xiao SM Yerges-Armstrong LM Zheng HF Alonso N Eriksson J Kammerer CM Kaptoge SK Leo PJ Thorleifsson G Wilson SG Wilson JF Aalto V Alen M Aragaki AK Aspelund T Center JR Dailiana Z Duggan DJ Garcia M Garcia-Giralt N Giroux S Hallmans G Hocking LJ Husted LB Jameson KA Khusainova R Kim GS Kooperberg C Koromila T Kruk M Laaksonen M 《Nature genetics》2012,44(5):491-501
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. 相似文献
886.
Houlston RS Cheadle J Dobbins SE Tenesa A Jones AM Howarth K Spain SL Broderick P Domingo E Farrington S Prendergast JG Pittman AM Theodoratou E Smith CG Olver B Walther A Barnetson RA Churchman M Jaeger EE Penegar S Barclay E Martin L Gorman M Mager R Johnstone E Midgley R Niittymäki I Tuupanen S Colley J Idziaszczyk S;COGENT Consortium Thomas HJ Lucassen AM Evans DG Maher ER;CORGI Consortium;COIN Collaborative Group;COINB Collaborative Group Maughan T Dimas A Dermitzakis E Cazier JB 《Nature genetics》2010,42(11):973-977
Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10?1? and rs6687758, OR = 1.09, P = 2.27 × 10??, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10??), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10?1? and rs7136702, OR = 1.06, P = 4.02 × 10??) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10?1?). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered. 相似文献
887.
Jakub Bijak George Disney Allan M. Findlay Jonathan J. Forster Peter W.F. Smith Arkadiusz Winiowski 《Journal of forecasting》2019,38(5):470-487
Migration is one of the most unpredictable demographic processes. The aim of this article is to provide a blueprint for assessing various possible forecasting approaches in order to help safeguard producers and users of official migration statistics against misguided forecasts. To achieve that, we first evaluate the various existing approaches to modelling and forecasting of international migration flows. Subsequently, we present an empirical comparison of ex post performance of various forecasting methods, applied to international migration to and from the United Kingdom. The overarching goal is to assess the uncertainty of forecasts produced by using different forecasting methods, both in terms of their errors (biases) and calibration of uncertainty. The empirical assessment, comparing the results of various forecasting models against past migration estimates, confirms the intuition about weak predictability of migration, but also highlights varying levels of forecast errors for different migration streams. There is no single forecasting approach that would be well suited for different flows. We therefore recommend adopting a tailored approach to forecasts, and applying a risk management framework to their results, taking into account the levels of uncertainty of the individual flows, as well as the differences in their potential societal impact. 相似文献
888.
1. The Setting There are many countries worldwide suffering from the consequences of disasters and conflicts or wars, and they often have been inJOURNAL OF SYSTEMS SCIENCE AND SYSTEMS ENGINEERING 233 dire straits for long periods of time. The degradation of resources and utility services is a direct result of those conflicts. A concerted response from the international community to rehabilitate these countries to minimize their human tragedies is urgently needed and is growin… 相似文献
889.
In an increasingly complex and mobile society, there is a need for population estimates to be produced on a more flexible basis. Different uses of population data may require information to be output on different population bases, such as where people usually live ('usual residence') or where they are on a particular day ('population present'). This article explores many of the issues associated with defining 'the population'. Following consultation with data users, it outlines recommended population definitions that could facilitate a more flexible approach. Comparisons are made between the output bases produced from the 2001 Census and the more adaptable outputs potentially available in future if the recommended definitions were used. 相似文献
890.
Ioannidis JP Gwinn M Little J Higgins JP Bernstein JL Boffetta P Bondy M Bray MS Brenchley PE Buffler PA Casas JP Chokkalingam A Danesh J Smith GD Dolan S Duncan R Gruis NA Hartge P Hashibe M Hunter DJ Jarvelin MR Malmer B Maraganore DM Newton-Bishop JA O'Brien TR Petersen G Riboli E Salanti G Seminara D Smeeth L Taioli E Timpson N Uitterlinden AG Vineis P Wareham N Winn DM Zimmern R Khoury MJ;Human Genome Epidemiology Network the Network of Investigator Networks 《Nature genetics》2006,38(1):3-5
Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews. 相似文献