Germline gain-of-function mutations in SOS1 cause Noonan syndrome

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.     

Global variation in copy number in the human genome

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.     

一种改进的规划器算法在军用软件GUI测试用例自动生成中的应用

以人工智能中智能规划方法为基础,对军用软件测试用例自动生成技术进行了研究。现有的许多规划器都不能避免组合爆炸问题的发生,而这一问题又是导致规划失败的一个重要问题,针对这一现象,以IPP规划器为例,提出目标分解法对规划器所需事实文件进行划分,并对IPP规划器应用多事实文件处理算法进行扩展,扩展后的MF-IPP规划器能够处理多个事实文档,有效避免了组合爆炸问题的发生。将该方法应用到军用主控软件GUI(Graphical User Interface)测试用例自动生成中,主要思想是首先利用规划器生成初始测试用例,其次提出解扩展的方法来完善测试用例的生成。针对测试用例生成问题进行了比对分析,结果显示,MF-IPP可以很好地防止组合爆炸问题的发生。所生成的测试用例生成时间短、覆盖率高,不仅能够很好地辅助软件测试人员进行测试用例的编写,还能应用于自动化软件测试。     

Tibetan plateau river incision inhibited by glacial stabilization of the Tsangpo gorge

A considerable amount of research has focused on how and when the Tibetan plateau formed in the wake of tectonic convergence between India and Asia. Although far less enquiry has addressed the controls on river incision into the plateau itself, widely accepted theory predicts that steep fluvial knick points (river reaches with very steep gradients) in the eastern Himalayan syntaxis at the southeastern plateau margin should erode rapidly, driving a wave of incision back into the plateau. Preservation of the plateau edge thus presents something of a conundrum that may be resolved by invoking either differential rock uplift matching erosional decay, or other mechanisms for retarding bedrock river incision in this region where high stream power excludes the potential for aridity as a simple limit to dissection of the plateau. Here we report morphologic evidence showing that Quaternary depression of the regional equilibrium line altitude, where long-term glacier mass gain equals mass loss, was sufficient to repeatedly form moraine dams on major rivers: such damming substantially impeded river incision into the southeastern edge of the Tibetan plateau through the coupled effects of upstream impoundment and interglacial aggradation. Such glacial stabilization of the resulting highly focused river incision centred on the Tsangpo gorge could further contribute to initiating and accentuating a locus of rapid exhumation, known as tectonic anaeurysm.     

川东鄂西山地紫色土发生探讨

本文研究表明,在试验区内,地质构造决定着紫色岩层的展布和紫色土的分布;老年、壮年、青年等不同地貌发育阶段则深刻影响和制约紫色土发生演化的方向.在现代成土条件下,各地类型紫色土的发育和岩石,既存在矿质元素的相对迁移和富集.也存在元素间的彼此制约关系.实质为碱金属、碱土金属在土壤剖层次间的淋溶作用.土壤淋溶系数5.90-14.960;岩石淋溶系数2.269-4.466.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

基于DEA法的虚拟企业合作伙伴效益评价应用研究

虚拟企业合作伙伴选择是虚拟企业组建过程中的重要问题，也是一个复杂的问题。从虚拟企业合作伙伴效益评价的角度出发，在AHP(层次分析)法的基础上，给出了DEA(数据包络分析)法的C^2R模型，并结合具体企业进行了实例验证，从而证明了DEA法对于虚拟企业合作伙伴选择的科学性和有效性。