Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections

Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.     

白腹管鼻蝠华北与东北冬眠群内RAPD分析和亲缘关系的比较研究

用随机扩增ＤＮＡ多态（ＲＡＰＤ）方法分析白腹管鼻蝠在华北和东北两地冬眠群群内与群间个体之间的亲缘关系,探讨冬眠群的结构组成及其相互关系。结果显示：华北两个白腹管鼻蝠冬眠群内个体间遗传相似性平均分别为０８５８和０９３３,两群之间的遗传相似性平均为０８４２,群内与群间个体之间在遗传相似性方面没有明显差别;东北冬眠群内的遗传相似性平均为０６０４;华北和东北两地冬眠群间的相似性只有０５１３和０５２１。据此可认为,在同一及邻近洞中形成的白腹管鼻蝠冬眠群的组成可能是选择来自同一种群中亲缘关系较近的个体,在华北冬眠的种群和在居留地东北冬眠的种群之间的亲缘关系较远。     

Smad在TGF-β超家族信号通路中的调控作用

TGF家族蛋白在哺乳动物的器官发育及形成中起着重要作用,它们经过膜受体的介导将信号传入细胞内,其下游最主要的调控蛋白Smad在胞内通过不同的调节各种基因的表达,这些模式主要有RSmadSmad4复合物直接与DNA结合,Smad蛋白与其他DNA结合因子,Smad蛋白与非DNA结合因子间的相互作用。Smad在BMPs对成骨细胞的分化调节过程中与RasMAPKAP1通路关联,共同决定不同细胞在不同发育阶段的定向分化 。     

异丙肾上腺素对大鼠心内神经节中生长抑素(SS)影响的研究

研究异丙肾上腺对心内神经节中肽能神经递质 SS的影响 ,本文在大鼠皮下注射异丙肾上腺素 5 m g/ kg,连续三天 ,固定后取心房后壁 ,用免疫组织化学结合图像分析方法观察大鼠心内神经节中肽能递质 SS的变化。对照组大鼠心内神经节中含有 SS免疫反应 (SS- IR)阳性神经纤维和细胞 ;实验组大鼠心内神经节中 SS- IR阳性神经纤维和神经元的积分光密度均明显减低。结果说明异丙肾上腺素可降低心内神经节中 SS含量 ,提示 ,异丙肾上腺素的正性变时和变力作用可能通过降低 SS的含量来实现。     

浅山区乡镇社会-生态系统脆弱性演化与模拟——以北京平谷为例

浅山区乡镇社会-生态系统相比于平原区受地形环境等因素制约更为脆弱,在国土空间开发与保护中更需要权衡。使用显式空间脆弱性(SERV)模型,从暴露度、敏感性、适应能力3个维度构建评价体系评估平谷浅山区12个乡镇社会-生态系统脆弱性,并使用有序加权平均算法(OWA)模拟多种决策风险下脆弱性情景。研究表明：(1)平谷浅山区2007-2017年总体脆弱性呈现中度脆弱水平,局部呈现上升态势,10年间中等以上脆弱乡镇面积比重由73.09%上升到80.74%。空间上呈现"东南高,西北低"的格局。(2)处于高脆弱水平乡镇应进行严格控制,增加水土保持林面积等提高适应能力;同时注重低脆弱乡镇的高暴露风险源及时进行生态修复。(3)通过设定不同决策风险系数预测不同发展导向下区域系统脆弱性差异,在倾向于可持续发展导向下优先生态环境治理,在经济发展导向下应推动绿色基础设施建设。评价结果可满足不同决策思路下指导区域发展实践。     

Identification of two antagonists of the scavenger receptor CD36 using a high-throughput screening model

CD36, a class B scavenger receptor, is an integral membrane protein that mediates the endocytosis of modified lipoproteins. The functions of CD36 are complex and have been associated with atherosclerosis. In the current study, we developed a high-throughput screening (HTS) assay to identify small molecule antagonists by expressing human CD36 using a Bac-to-Bac baculovirus expression system in Spodoptera frugiperda (Sf9) cells. Uptake of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-labeled acetylated low-density lipoprotein (DiI-AcLDL) revealed that the IC₅₀ values for the CD36 ligands oxidatively modified LDL (Ox-LDL), Ac-LDL, and high-density lipoprotein (HDL) were 0.039, 0.019, and 0.010 μg/ml, respectively. Using the HTS assay, two novel compounds, 2016481B and 2038751B, were found to inhibit DiI-AcLDL uptake in insect cells and exhibited IC₅₀ values of 17.4 and 23.7 μM, respectively. These two novel compounds also inhibited DiI-AcLDL uptake in cultured Chinese hamster ovary (CHO) cells permanently expressing human CD36. Furthermore, these two compounds inhibited lipid accumulation in RAW 264.7 murine macrophage cells in foam cell assays. This HTS assay represents a potential method for identifying more effective macrophage scavenger receptor antagonists, which may serve as starting points for the development of novel anti-atherosclerotic agents.     

Functional analyses of vertebrate TCF proteins in C. elegans embryos

In the canonical Wnt pathway, signaling results in the stabilization and increased levels of β-catenin in responding cells. β-catenin then enters the nucleus, functioning as a coactivator for the Wnt effector, TCF/LEF protein. In the absence of Wnt signaling, TCF is complexed with corepressors, together repressing Wnt target genes. In C. elegans, Wnt signaling specifies the E blastomere to become the endoderm precursor. Activation of endoderm genes in E requires not only an increase in β-catenin level, but a concomitant decrease in the nuclear level of POP-1, the sole C. elegans TCF. A decrease in nuclear POP-1 levels requires Wnt-induced phosphorylation of POP-1 and 14-3-3 protein-mediated nuclear export. Nuclear POP-1 levels remain high in the sister cell of E, MS, where POP-1 represses the expression of endoderm genes. Here we express three vertebrate TCF proteins (human TCF4, mouse LEF1 and Xenopus TCF3) in C. elegans embryos and compare their localization, repression and activation functions to POP-1. All three TCFs are localized to the nucleus in C. elegans embryos, but none undergoes Wnt-induced nuclear export. Although unable to undergo Wnt-induced nuclear export, human TCF4, but not mouse LEF1 or Xenopus TCF3, can repress endoderm genes in MS, in a manner very similar to POP-1. This repressive activity requires that human TCF4 recognizes specific promoter sequences upstream of endoderm genes and interacts with C. elegans corepressors. Domain swapping identified two regions of POP-1 that are sufficient to confer nuclear asymmetry to human TCF4 when swapped with its corresponding domains. Despite undergoing Wnt-induced nuclear export, the human TCF4/POP-1 chimeric protein continues to function as a repressor for endoderm genes in E, a result we attribute to the inability of hTCF4 to bind to C. elegans β-catenin. Our results reveal a higher degree of species specificity among TCF proteins for coactivator interactions than for corepressor interactions, and uncover a basic difference between how POP-1 and human TCF4 steady state nuclear levels are regulated.