Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.     

Have national trends in fertility between 1986 and 2006 occurred evenly across England and Wales?

During the past 20 years fertility patterns within England and Wales have changed considerably. The total fertility rate experienced a prolonged decline during the 1990s and hit a record low in 2001. Since then the level of fertility has increased fairly rapidly. Over the two decades, fertility has been constantly increasing at ages above 30, and as a consequence the mean age of motherhood has been rising. This article explores fertility trends within statistical regions and local authorities to improve our understanding of changes in fertility at the subnational level between 1986 and 2006.     

JWA参与调控细胞分化的结构和功能研究

为阐明新基因JWA的结构特征、表达调节规律和生物学功能,通过基因重组和测序,确定了大鼠JWA同源基因和人JWA基因621bp的启动子序列;用RT-PCR法,分析了培养细胞株和原代白血病细胞经药物处理后JWAmRNA的表达情况,发现TPA处理后JWAmRNA水平在肿瘤细胞株与非肿瘤细胞株中呈反向变化;用维甲酸治疗前的M3型白血病人骨髓白细胞,其JWA基因对多种诱导分化剂处理不敏感;而用维甲酸治疗10d后再用诱导分化剂处理,则JWA基因的转录水平均被下调,提示M3型白血病细胞在ATRA作用下的分化可能是启动JWA信号转导通路的前提,而JWA基因的表达下调是否为白血病细胞进一步分化及4HPR,As     

JWA参与调控细胞分化的结构和功能

为阐明新基因JWA的结构特征、表达调节规律和生物学功能,通过基因重组和测序,确定了大鼠JWA同源基因和人JWA基因621bp的启动子序列;用RT－PCR法,分析了培养细胞株和原代白血病细胞经药物处理后JWA mRNA的表达情况,发现TPA处理后JWAmRNA水平在肿瘤细胞株与非肿瘤细胞株中呈反向变化：用维甲酸治疗前的M3型白血病人骨髓白细胞,其JWA基因对多种诱导分化剂处理不敏感;而用维甲酸治疗10d后再用诱导分化剂处理,则JWA基因的转录水平均被下调,提示M3型白血病细胞在ATRA作用下的分化可能是启动JWA信号转导通路的前提。而JWA基因的表达下调是否为白血病细胞进一步分化及4HPR,As2O3和TPA等诱导细胞凋亡所必需,值得进一步探讨。JWA基因在不同种属中保持较为稳定的序列特征,说明该基因在生物进化中可能较保守并可能具有相近的生物学功能。     

欧陆科学哲学的两条路径（英文）

如果你戴上我称为"欧陆式眼镜"的东西,运用欧陆哲学的视角来审视诸如探究、发现、实验、理论和确证等传统的科学哲学问题,某些事物就会以颇为不同的方式呈现,你就会看到新的事物,一切事物会彼此相关并以不同的方式与背景相关。透过欧陆式眼镜的凝视,让你倾向于关注两种事物:第一,那些妨碍你看得更清晰的事物;第二,事物"如何"显现,而非事物是"什么"。该隐喻有某种严重的缺陷,但仍是有用的,因为它提示了审视科学的传统视角与欧陆视角之间的巨大差异。它也能被用于发展"科研平台"这个观念,即科学不仅仅是一组活动,不仅仅是在某种程度上允许我们将之封闭的一组工具、实践和借此形成的知识,而是由诸线条的流动之网构成的,这些线条顺利地与紧密地整合入我们的世界并且塑造了世界的轮廓。我在本文中讨论了欧陆科学哲学的两条可能路径。一条涉及的是"解构性的重演",即对我们继承下来的科学概念(包括传统的分析性概念与海德格尔的"科学不思"的概念)的探究;另一条涉及的是可被称为"回归田野研究"的东西,即仔细地审视科学实践。接受这两条路径,将让欧陆科学哲学唤醒一大片重要的探究领域。忽略这些探究的领域,科学哲学将自食其果。     

Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity

Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs.     

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.