Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration

Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.     

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.     

不确定条件下纵向研发合作的投资决策研究

针对一个存在两个上游企业和两个下游企业的双层市场结构,对上下游企业实施纵向研发合作策略下的产量和利润进行了研究。并考虑了研发固有的不确定性和溢出效应的影响,从企业是否进行研发以及进行多大程度的研发两个方面,研究上下游企业实施纵向研发合作的投资决策。并在此基础上,探讨了企业研发成本分担比例和违约赔偿。     

改善供应链库存管理绩效的系统思考——以啤酒游戏为例

运用基于系统动力学的动态研究的方法,以啤酒游戏为例,从动态复杂性的视角,探讨了改善供应链库存管理绩效的影响因素和解决方案。认为"系统结构""控制策略"和"控制参数"是影响供应链库存管理绩效的3类要素,提出了调整订货周期匹配订货提前期的"结构性解决方案"、基于考虑已发出订单和在途货物量的"策略性解决方案"和基于参数控制的"操作性解决方案"。并且,通过系统仿真分析和人工试验,研究了这3类要素在集中控制和分散控制模式下对库存绩效的影响。结果表明,这3类解决方案在集中控制模式下的有效性依次递增,而在分散控制模式下的有效性依次递减。该结果展示了多级供应链库存系统的动态复杂性,以及系统思考在处理动态复杂性方面的重要性和有效性。     

γ-Aminobutyric acid (GABA) signalling in plants

The role of γ-aminobutyric acid (GABA) as a signal in animals has been documented for over 60 years. In contrast, evidence that GABA is a signal in plants has only emerged in the last 15 years, and it was not until last year that a mechanism by which this could occur was identified—a plant ‘GABA receptor’ that inhibits anion passage through the aluminium-activated malate transporter family of proteins (ALMTs). ALMTs are multigenic, expressed in different organs and present on different membranes. We propose GABA regulation of ALMT activity could function as a signal that modulates plant growth, development, and stress response. In this review, we compare and contrast the plant ‘GABA receptor’ with mammalian GABA_A receptors in terms of their molecular identity, predicted topology, mode of action, and signalling roles. We also explore the implications of the discovery that GABA modulates anion flux in plants, its role in signal transduction for the regulation of plant physiology, and predict the possibility that there are other GABA interaction sites in the N termini of ALMT proteins through in silico evolutionary coupling analysis; we also explore the potential interactions between GABA and other signalling molecules.     

1961-2014年西安市秋淋气候特征分析

利用1961-2014年8-10月西安市7个气象站逐日降水资料,采用降水强度指数分析了西安市秋淋天气气候变化特征.结果表明,20世纪90年代是近50年来西安市秋季9~10月降水量最少的阶段.1961年以来西安市共有23 a出现秋淋多雨时段,20世纪60年代至80年代中期较多,1983年和1984年出现强秋淋;20世纪80年代中期至21世纪10年代初期,只有1992年出现了1次秋淋天气;2011年以来,秋淋呈明显上升、增强趋势.1961-2014年秋淋天气过程平均降水量呈上升趋势,偏多年份主要出现在20世纪80年代初中期和21世纪.厄尔尼诺使秋季9~10月降水量减少,与秋淋天气存在明显的负相关关系.近54年西安市秋淋没有发生显著的气候突变,存在4~6 a、10 a和24 a左右的长振荡周期.     

Dual hesitant fuzzy information aggregation with Einstein t-conorm and t-norm

Dual hesitant fuzzy set (DHFS) is a new generalization of fuzzy set (FS) consisting of two parts (i.e., the membership hesitancy function and the non-membership hesitancy function), which confronts several different possible values indicating the epistemic degrees whether certainty or uncertainty. It encompasses fuzzy set (FS), intuitionistic fuzzy set (IFS), and hesitant fuzzy set (HFS) so that it can handle uncertain information more flexibly in the process of decision making. In this paper, we propose some new operations on dual hesitant fuzzy sets based on Einstein t-conorm and t-norm, study their properties and relationships and then give some dual hesitant fuzzy aggregation operators, which can be considered as the generalizations of some existing ones under fuzzy, intuitionistic fuzzy and hesitant fuzzy environments. Finally, a decision making algorithm under dual hesitant fuzzy environment is given based on the proposed aggregation operators and a numerical example is used to demonstrate the effectiveness of the method.     

Strong association of de novo copy number mutations with sporadic schizophrenia

Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively approximately 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.     

基于ADAMS.LifeMOD的人体头颈部动力学仿真与验证

基于多刚体动力学软件ADAMS和生物力学仿真软件LifeMOD,建立了一个人体头颈部三维多刚体动力学模型。该模型包括颅骨、颈椎骨、肩胛骨、躯干上段以及体现粘弹性性质的肌肉组织。采用美国海军力学实验室的前碰撞志愿者实验数据对模型进行了验证。验证结果表明,该模型具有很好的可信度,可以用来研究在碰撞条件下头颈部的动力学响应特性。