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.     

不完全市场下有违约风险的欧式期权定价

为了研究不完全市场对有违约风险欧式期权定价的影响,结合Klein的有违约风险期权处理方法和Cochrane与Saa-Requejo的不完全市场处理方法给有违约风险的欧式期权定价,得到不完全市场下有违约风险欧式期权的一般化定价公式.进一步推导出一些特定欧式期权的定价公式,并指出这些公式均为一般化定价公式的特例.结果表明定价公式结合了上述两个模型的优点,因此特别适合于给基于不可交易资产有违约风险期权定价.     

一种基于神经网络的混沌控制方法

将神经网络(NN)与内模控制(IMC)相结合,提出了一种用基于BP神经网络的内模控制进行混沌抑制的方法,该方法既具有内模控制的特点,又引入了神经网络的在线自校正机制。应用所提出的方法,针对Duffing振荡器的混沌控制问题进行了仿真研究,仿真结果验证了该方法的有效性,同时还表明该方法具有很好的鲁棒性与自适应能力。     

基于自适应神经网络的边坡位移预测

通过对边坡位移历史数据序列进行特征分析 ,计算出饱和嵌入维数和最大 Lyapunov指数 ,给出了边坡位移的最大可预报时间尺度。在此基础上 ,确定了神经网络的输入节点数 ,建立了基于自适应神经网络的边坡位移预报方法 .通过对三峡升船机高边坡和新滩滑坡实际位移数据进行预测 ,结果令人满意 .这对于建立边坡位移的实时监测 -预警系统有重要意义.     

Evolution of neoplastic cell lineages in Barrett oesophagus.

It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.     

流式在线直播视频的采集

针对由于流媒体协议的扩展性而带来的无法实时获取流媒体数据的问题,本文在深入分析流媒体传输原理的基础上,采用基于多核的包捕获技术,解决了流式在线直播视频数据的采集问题,为局域网内流式在线直播视频的实时接收和本地保存奠定了坚实的基础。     

界面反应及界面张力对Sn-Zn-Bi焊料润湿性的影响

通过合金化的方式得到了Sn-Zn-Bi三元及Sn-Zn-Bi-Nd四元无铅焊料,采用润湿平衡法测量了其润湿力和润湿时间,并对润湿后的焊料/Cu界面组织进行了分析.结果表明:Bi元素不参与焊料/Cu界面的扩散反应,但能够通过吸附作用降低界面张力,从而提高焊料在Cu基底上的润湿力;Zn元素优先向焊料/Cu界面进行扩散形成Cu5Zn8金属间化合物,且扩散层随焊料中Zn含量的提高而增长,此时固-液界面张力方向发生改变,润湿力提高,但润湿时间延长;Nd元素的作用类似于Bi,既能提高焊料的润湿力,也能够缩短润湿时间,是一种改善Sn-Zn基焊料润湿性的有效元素.     

放电电流对热阴极等离子体化学气相沉积金刚石膜影响

建立了快速沉积高品质金刚石膜的热阴极辉光放电等离子体化学气相沉积新方法. 相对于常规冷阴极辉光放电而言,热阴极辉光放电是一种新型放电形式,具有许多新的特性,其中重要一点是具有较高的放电电流(6.0～10.0 A). 较高的放电电流既是热阴极辉光放电本身的突出特点,同时对于化学气相沉积金刚石膜工艺也产生重要影响. 实验研究了放电电流于金刚石膜沉积速率、表面形貌和热导率的影响,发现由于放电电流影响辉光放电的等离子体区和阳极区,进而对金刚石膜的沉积速率和品质有很大影响. 特别是通过放电电流的提高,可以有效地提高金刚石膜的品质,这对于制备优质金刚石膜产品有重大意义.     

Cytochrome P450 2U1, a very peculiar member of the human P450s family

Cytochrome P450 2U1 (CYP2U1) exhibits several distinctive characteristics among the 57 human CYPs, such as its presence in almost all living organisms with a highly conserved sequence, its particular gene organization with only five exons, its major location in thymus and brain, and its protein sequence involving an unusually long N-terminal region containing 8 proline residues and an insert of about 20 amino acids containing 5 arginine residues after the transmembrane helix. Few substrates, including fatty acids, N-arachidonoylserotonin (AS), and some drugs, have been reported so far. However, its biological roles remain largely unknown, even though CYP2U1 mutations have been involved in some pathological situations, such as complicated forms of hereditary spastic paraplegia. These data together with its ability to hydroxylate some fatty acids and AS suggest its possible role in lipid metabolism.     

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

Background

Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.

Methods

Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.

Results

ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).

Conclusion

ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.