排序方式: 共有10条查询结果,搜索用时 31 毫秒
1
1.
2.
Danielle Kamato Partha Mitra Felicity Davis Narin Osman Rebecca Chaplin Peter J. Cabot Rizwana Afroz Walter Thomas Wenhua Zheng Harveen Kaur Margaret Brimble Peter J. Little 《Cellular and molecular life sciences : CMLS》2017,74(8):1379-1390
Seven transmembrane G protein-coupled receptors (GPCRs) have gained much interest in recent years as it is the largest class among cell surface receptors. G proteins lie in the heart of GPCRs signalling and therefore can be therapeutically targeted to overcome complexities in GPCR responses and signalling. G proteins are classified into four families (Gi, Gs, G12/13 and Gq); Gq is further subdivided into four classes. Among them Gαq and Gαq/11 isoforms are most crucial and ubiquitously expressed; these isoforms are almost 88% similar at their amino acid sequence but may exhibit functional divergences. However, uncertainties often arise about Gαq and Gαq/11 inhibitors, these G proteins might also have suitability to the invention of novel-specific inhibitors for each isoforms. YM-254890 and UBO-QIC are discovered as potent inhibitors of Gαq functions and also investigated in thrombin protease-activated receptor (PAR)-1 inhibitors and platelet aggregation inhibition. The most likely G protein involved in PAR-1 stimulates responses is one of the Gαq family isoforms. In this review, we highlight the molecular structures and pharmacological responses of Gαq family which may reflect the biochemical and molecular role of Gαq and Gαq/11. The advanced understanding of Gαq and Gαq/11 role in GPCR signalling may shed light on our understanding on cell biology, cellular physiology and pathophysiology and also lead to the development of novel therapeutic agents for a number of diseases. 相似文献
3.
Todd JA Walker NM Cooper JD Smyth DJ Downes K Plagnol V Bailey R Nejentsev S Field SF Payne F Lowe CE Szeszko JS Hafler JP Zeitels L Yang JH Vella A Nutland S Stevens HE Schuilenburg H Coleman G Maisuria M Meadows W Smink LJ Healy B Burren OS Lam AA Ovington NR Allen J Adlem E Leung HT Wallace C Howson JM Guja C Ionescu-Tîrgovişte C;Genetics of Type Diabetes in Finland Simmonds MJ Heward JM Gough SC;Wellcome Trust Case Control Consortium Dunger DB Wicker LS Clayton DG 《Nature genetics》2007,39(7):857-864
The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献
4.
Jones FC Grabherr MG Chan YF Russell P Mauceli E Johnson J Swofford R Pirun M Zody MC White S Birney E Searle S Schmutz J Grimwood J Dickson MC Myers RM Miller CT Summers BR Knecht AK Brady SD Zhang H Pollen AA Howes T Amemiya C;Broad Institute Genome Sequencing Platform & Whole Genome Assembly Team Baldwin J Bloom T Jaffe DB Nicol R Wilkinson J Lander ES Di Palma F Lindblad-Toh K Kingsley DM 《Nature》2012,484(7392):55-61
Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature. 相似文献
5.
The colonization of a new habitat is a fundamental process in metapopulation biology, but it is difficult to study. The emigration of colonists from established populations might be induced by resource competition owing to high local population density. Migration distances are also important because they determine the frequency and scale of recolonization and hence the spatial scale of the metapopulation. Traditionally, these factors have been investigated with demographic approaches that are labour-intensive and are only possible in amenable species. In many cases, genetic differentiation is minimal, preventing traditional genetic approaches from identifying the source of colonists unambiguously. Here we present a bayesian approach that integrates genetic, demographic and geographic distance data. We apply the method to study the British metapopulation of grey seals, which has been growing at 6% per year over the last few decades. Our method reveals differential recruitment to three newly founded colonies and implicates density-dependent dispersal in metapopulation dynamics by using genetic data. 相似文献
6.
WF Laurance DC Useche J Rendeiro M Kalka CJ Bradshaw SP Sloan SG Laurance M Campbell K Abernethy P Alvarez V Arroyo-Rodriguez P Ashton J Benítez-Malvido A Blom KS Bobo CH Cannon M Cao R Carroll C Chapman R Coates M Cords F Danielsen B De Dijn E Dinerstein MA Donnelly D Edwards F Edwards N Farwig P Fashing PM Forget M Foster G Gale D Harris R Harrison J Hart S Karpanty WJ Kress J Krishnaswamy W Logsdon J Lovett W Magnusson F Maisels AR Marshall D McClearn D Mudappa MR Nielsen R Pearson N Pitman 《Nature》2012,489(7415):290-294
The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines. 相似文献
7.
Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA 总被引:1,自引:0,他引:1
Lindhurst MJ Parker VE Payne F Sapp JC Rudge S Harris J Witkowski AM Zhang Q Groeneveld MP Scott CE Daly A Huson SM Tosi LL Cunningham ML Darling TN Geer J Gucev Z Sutton VR Tziotzios C Dixon AK Helliwell T O'Rahilly S Savage DB Wakelam MJ Barroso I Biesecker LG Semple RK 《Nature genetics》2012,44(8):928-933
The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target. 相似文献
8.
Felicity Muth 《科学之友》2014,(12)
<正>很多雄性动物在求偶时都会给雌性送礼物。这听起来似乎太过简单,不过事实就是这样,比如雄性翠鸟在求偶时会捕鱼送给雌鸟。然而,这种送礼行为中却不乏有一些耍小聪明的动物。如果能找到一份廉价的山寨货骗雌性交配,那为什么还要费心找一份真正的礼物呢?的确,很多雄性动物都选择送没有什么价值的礼物。一些狡猾的雄性还会重复利用它们已经送出去的礼物,甚至还有些雄性会用不能吃的东西冒充食物送给雌性。 相似文献
9.
Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes 总被引:1,自引:0,他引:1
Bonnefond A Clément N Fawcett K Yengo L Vaillant E Guillaume JL Dechaume A Payne F Roussel R Czernichow S Hercberg S Hadjadj S Balkau B Marre M Lantieri O Langenberg C Bouatia-Naji N;Meta-Analysis of Glucose Insulin-Related Traits Consortium 《Nature genetics》2012,44(3):297-301
Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT(2)) increase type 2 diabetes (T2D) risk(1,2). Although the strongest association signal was highly significant (P < 1 × 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of ~1.10-1.15)(1-3). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 × 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 × 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 × 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk. 相似文献
10.
Ueda H Howson JM Esposito L Heward J Snook H Chamberlain G Rainbow DB Hunter KM Smith AN Di Genova G Herr MH Dahlman I Payne F Smyth D Lowe C Twells RC Howlett S Healy B Nutland S Rance HE Everett V Smink LJ Lam AC Cordell HJ Walker NM Bordin C Hulme J Motzo C Cucca F Hess JF Metzker ML Rogers J Gregory S Allahabadia A Nithiyananthan R Tuomilehto-Wolf E Tuomilehto J Bingley P Gillespie KM Undlien DE Rønningen KS Guja C Ionescu-Tîrgovişte C Savage DA Maxwell AP Carson DJ Patterson CC Franklyn JA 《Nature》2003,423(6939):506-511
Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction. 相似文献
1