Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.     

A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.     

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.     

钢筋混凝土整体小开口剪力墙结构在小震作用下失效相关性的试验研究

通过对4层钢筋混凝土整体小开口剪力墙1/10缩尺模型的试验研究,基于层间位移,本文对试件在小震作用下失效相关性进行了分析,得出了整体小开口剪力墙结构在小震下的部分失效相关性规律.     

橡胶支座水平剪切弹塑性力学性能试验研究

通过对铅芯橡胶支座剪切弹塑性力学性能试验,发现铅芯橡胶支座的滞回曲线与加载时程密切相关,在同一水平应变下,水平剪切刚度随加载次数的增多有所减小,最后趋于稳定;在不同应变下,水平剪切刚度随应变的增大而减小.试验还表明铅芯橡胶支座不仅在大应变存在着小应变滞回特性,而且在小应变也存在着小应变滞回特性.     

基于BSDE的开放式基金赎回风险控制模型

目前我国开放式基金发展迅速,并已经成为基金业发展的重心,但与此同时却经常面临着大规模的赎回问题.通过借鉴国内外经验,针对开放式基金本身的管理和运作特点,综合运用系统工程、倒向随机微分方程(BSDE)的方法,以更好地配备投资组合为目标,来解决开放式基金的现金预留比例问题,从而为基金管理人规避这种由巨额赎回引起的波动性风险提供了又一种方法.最后,用现实中的数据进行了具体的算例分析.     

全彩LED显示屏在图书馆服务中的运用

介绍了LED全彩显示屏在图书馆服务中的重要作用,总结了全彩显示屏的功能特点和制作经验,并归纳出一些设计要点。     

大规模集成电路测试技术

本文主要介绍了在大规模集成电路中,必须考虑的电路测试技术的一些设计方法,同时论述了对集成电路芯片功能测试的实现以及用计算机系统对芯片测试的方法。