Conformational transition of Sec machinery inferred from bacterial SecYE structures

Over 30% of proteins are secreted across or integrated into membranes. Their newly synthesized forms contain either cleavable signal sequences or non-cleavable membrane anchor sequences, which direct them to the evolutionarily conserved Sec translocon (SecYEG in prokaryotes and Sec61, comprising alpha-, gamma- and beta-subunits, in eukaryotes). The translocon then functions as a protein-conducting channel. These processes of protein localization occur either at or after translation. In bacteria, the SecA ATPase drives post-translational translocation. The only high-resolution structure of a translocon available so far is that for SecYEbeta from the archaeon Methanococcus jannaschii, which lacks SecA. Here we present the 3.2-A-resolution crystal structure of the SecYE translocon from a SecA-containing organism, Thermus thermophilus. The structure, solved as a complex with an anti-SecY Fab fragment, revealed a 'pre-open' state of SecYE, in which several transmembrane helices are shifted, as compared to the previous SecYEbeta structure, to create a hydrophobic crack open to the cytoplasm. Fab and SecA bind to a common site at the tip of the cytoplasmic domain of SecY. Molecular dynamics and disulphide mapping analyses suggest that the pre-open state might represent a SecYE conformational transition that is inducible by SecA binding. Moreover, we identified a SecA-SecYE interface that comprises SecA residues originally buried inside the protein, indicating that both the channel and the motor components of the Sec machinery undergo cooperative conformational changes on formation of the functional complex.     

论地震灾后复兴山地运动旅游

山地运动旅游是山地旅游的重要组成部分,开发前景广阔.四川汶川大地震在一定程度上对山地运动旅游产生了负面影响,灾后重建中需要客观分析其得失.地震遗留景观为山地运动旅游的后续发展创造了新的机缘,应按照科学规划、分布实施的策略,逐步复兴山地运动旅游.     

固溶温度对0Cr32Ni7Mo3N双相不锈钢组织和耐蚀性能的影响

对0Cr32Ni7Mo3N双相不锈钢进行了1 180℃～1 220℃的固溶处理。采用XRD、OM、EDS及电化学工作站研究了固溶温度对材料的显微组织和耐蚀性能的影响。结果表明:随固溶温度的升高,γ相含量逐渐降低,Cr、Mo和Ni在两相中的分布趋于均匀;Cr和Mo在两相的分配系数K_(Cr)和K_(Mo)对材料的耐蚀性起主导作用,K_(Cr)和K_(Mo)随温度的升高逐渐减小,材料的耐蚀性下降。     

华人家族企业从家族信任到社会信任的进化

关系主义、家族信任是华人家族企业管理的基本特征.家族信任在中国民营企业创业发展的初期具有明显的积极作用.但随着企业规模的扩大,家族信任无法满足企业发展需要的.将家族信任扩展为社会信任成为一种必然.     

网络组织中合作伙伴的选择及任务协同

网络组织组建过程中的一一关键领域缺乏专业能力.传统的伙伴选择方法已不足以应付今天的挑战,在现在复杂的商务环境中,管理者需要新的思路和方法.本文通过分析传统的伙伴选择方法的缺陷讨论了一个新的联盟伙伴选择思路.     

脱硫副产物在碱化土壤改良中的应用

通过分析在不同脱硫副产物施用量下土壤理化性质的变化规律,对脱硫副产物改良碱化土壤进行理论研究,探寻改良碱化土壤的优化利用模式.采用宁夏银川和内蒙古鄂尔多斯的四种土样,每种土样分别加入4个水平(施用量分别为土样质量的0.5%、1.0%、1.5%、2.0%)的脱硫副产物,观察改良效果.结果表明:脱硫副产物能降低土壤pH和碱化度,改善土壤理化性质,从而达到改良碱化土壤的作用;碱化土壤的改良效果在一定的范围内(0～2.0%)与脱硫副产物的用量呈正相关,超过这一范围,不但不能提高改良效果,而且还会有大量的盐分累积,增加改良的难度;脱硫副产物改良碱化土壤的最佳用量范围为0.5%～1.0%.     

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.     

大跨屋盖结构风致动力响应高阶主导模态的识别

高阶模态的贡献在大跨屋盖结构风振响应分析中不能忽略.从模态空间分布和风荷载空间分布相关性强弱与模态对结构响应贡献程度的相互关系出发,提出了通过低阶主要贡献模态间接寻找风荷载强相关高阶模态的思想.在此基础上,通过对高阶模态响应方差矩阵的简化处理得到其等效矩阵.根据等效矩阵中对角线元素构造了高阶模态的模态参与系数,实现对高阶主导模态的识别,有效考虑了高阶模态的贡献.最后,通过对2008年北京奥运会网球中心屋盖结构的风振响应分析对所提出方法的有效性进行了验证.     

深水钻井隔水管段携岩规律研究

岩屑运移机理的研究对钻井作业来说至关重要,尽管前人做过许多相关工作,但仅仅停留在理论研究和物理实验的层面上。本文应用CFD软件Fluent,对岩屑在深水井隔水管段的运移规律进行研究,模拟条件更加接近实际情况,结果更加精确,可以为深水钻井井眼清洁工作提供科学参考。     

A genome-wide association study identifies three new risk loci for Kawasaki disease

We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.