A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.     

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia

Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.     

无线网络的移动管理：数据的复制和应用

在无线通讯系统中，网络通过从数据库中查找用户信息来跟踪用户，这样就需要把用户信息事先存储在大量的数据库中。本书讨论了有关在数据库中复制用户信息并更新的若干问题。     

尾矿库溃坝灾害防控现状及发展

尾矿库溃坝灾害应急响应时间短、潜在威胁巨大,往往造成惨重人员伤亡与巨额财产损失.近些年尾矿库安全事故发生数量的总体下降趋势充分体现出现代化技术及安全管理方面的进步,然而重大事故发生频次却不减反增,2015年巴西Samarco铁矿与2014年加拿大Mount Polley重大溃坝事故及其惨重后果,再次为尾矿库安全敲响警钟.我国现存尾矿库8869座,含"头顶库"1425座,安全形势复杂.本文在收集大量相关领域文献的基础上,聚焦尾矿库溃坝灾害防控体系中的安全监测、灾害预警与应急准备、安全管理与标准规范这三大方面核心内容,分别综述对比国内外现状及前沿进展,探讨分析我国当前所面临的问题并尝试提出改进建议,为尾矿库防灾减灾理论研究与技术革新提供参考.结果表明:(1)我国尾矿库安全监测标准更高,但仪器耐久性、可靠度与实用性不足,专用监测器件与新技术的研发应用势在必行;(2)灾害预警方法单一且可信度不高,而信息技术融合应用成为发展趋势;(3)应急管理与预警决策需以充分的科学论证为基础,当前研究在试验手段与计算方法上存在局限;(4)我国拥有完善的安全管理标准规范体系,但在安全等别划分、全生命周期管理、主体变更、事故总结等方面相对欠缺.     

Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice

Glycogen synthase kinase-3beta (GSK-3beta) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer's disease. As such, a thorough understanding of GSK-3beta function will have a broad impact on human biology and therapeutics. Because GSK-3beta interacts with many different pathways, its specific developmental roles remain unclear. We have discovered a genetic requirement for GSK-3beta in midline development. Homozygous null mice display cleft palate, incomplete fusion of the ribs at the midline and bifid sternum as well as delayed sternal ossification. Using a chemically regulated allele of GSK-3beta (ref. 6), we have defined requirements for GSK-3beta activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK-3beta produces GSK-3beta fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimaeric protein. In the absence of drug, GSK-3beta(FRB)*(/FRB)* mutants appear phenotypically identical to GSK-3beta-/- mutants. In the presence of drug, GSK-3betaFRB* is rapidly stabilized, restoring protein levels and activity. Using this system, mutant phenotypes were rescued by restoring endogenous GSK-3beta activity during two distinct periods in gestation. This technology provides a powerful tool for defining windows of protein function during development.