异源双链DNA体外错配修复功能分析模型的构建

DNA错配修复(mismatch repair, MMR)功能缺失是确认的肿瘤发病机制之一. 随着研究的深入以及临床诊断治疗的要求, 有必要从整体上对肿瘤的错配修复功能状态作出评价. 以M13mp2噬菌体及其衍生株和E. coli大肠杆菌为材料, 以lacZα为报告基因, 构建含有错配碱基的异源双链DNA分子. 提取错配修复功能完整细胞株(TK6)和错配修复功能缺陷细胞株(Lovo)的全细胞蛋白, 经大T抗原依赖性SV-40 DNA复制检测, 证实其生物学功能保持完整后与构建成功的异源双链DNA分子共同作用, 发现TK6对双碱基缺失del(2)的修复效率超过60%, 对单碱基错配G·G的修复效率超过50%; 而Lovo对双碱基缺失del(2)的修复效率低于20%, 对单碱基错配G·G的修复效率低于10%. 以异源双链DNA为待修复模板, 以细胞株TK6和Lovo分别作为MMR功能完善和缺陷表型的参照, 建立体外错配修复功能分析模型. 应用该模型检测1例具有微卫星不稳定性表型的HNPCC病人肿瘤组织, 发现其MMR功能丧失; 而检测1例微卫星稳定的散发性直肠癌病人肿瘤组织, 发现其具有MMR功能. 结果表明该模型可用于体外检测各种肿瘤细胞和/或组织的错配修复功能. 为肿瘤发病机制的研究提供了可靠的方法, 对进一步了解错配修复功能状态在各种类型肿瘤中的作用有非常重要的意义.     

The geometry of knowledge: Lewis, Becker, Carnap and the formalization of philosophy in the 1920s

On an ordinary view of the relation of philosophy of science to science, science serves only as a topic for philosophical reflection, reflection that proceeds by its own methods and according to its own standards. This ordinary view suggests a way of writing a global history of philosophy of science that finds substantially the same philosophical projects being pursued across widely divergent scientific eras. While not denying that this view is of some use regarding certain themes of and particular time periods, this essay argues that much of the epistemology and philosophy of science in the early twentieth century in a variety of projects (neo-Kantianism, logical empiricism, pragmatism, phenomenology) looked to the then current context of the exact sciences, especially geometry and physics, not merely for its topics but also for its conceptual resources and technical tools. This suggests a more variable project of philosophy of science, a deeper connection between early twentieth-century philosophy of science and its contemporary science, and a more interesting and richer history of philosophy of science than is ordinarily offered.     

Novel guanosine requirement for catalysis by the hairpin ribozyme

THERE is much interest in the development of 'designer ribozymes' to target destruction of RNAs in vitro and in vivo. Engineering of ribozymes with novel specificities requires detailed knowledge of the ribozyme-substrate interaction, and a rigorous evaluation of sequence specificity. The hairpin ribozyme catalyses an efficient and reversible site-specific cleavage reaction. We have used mutagenesis and in vitro selection strategies to show that RNA cleavage and ligation has an absolute requirement for guanosine immediately 3' to the cleavage-ligation site. This G is not required for efficient substrate binding, rather, its 2-amino group is an essential component of the active site required for catalysis.     

冷箭竹空间分布格局的研究

本文主要研究四川邛崃山系现存冷箭竹(Bachania fangiana)在残存地段上的空间分布格局;冷箭竹的空间分布格局与森林生境和生境失调的关系;冷箭竹生活史的特征及其与更新关系。     

Dental microwear texture analysis shows within-species diet variability in fossil hominins

Reconstructing the diets of extinct hominins is essential to understanding the paleobiology and evolutionary history of our lineage. Dental microwear, the study of microscopic tooth-wear resulting from use, provides direct evidence of what an individual ate in the past. Unfortunately, established methods of studying microwear are plagued with low repeatability and high observer error. Here we apply an objective, repeatable approach for studying three-dimensional microwear surface texture to extinct South African hominins. Scanning confocal microscopy together with scale-sensitive fractal analysis are used to characterize the complexity and anisotropy of microwear. Results for living primates show that this approach can distinguish among diets characterized by different fracture properties. When applied to hominins, microwear texture analysis indicates that Australopithecus africanus microwear is more anisotropic, but also more variable in anisotropy than Paranthropus robustus. This latter species has more complex microwear textures, but is also more variable in complexity than A. africanus. This suggests that A. africanus ate more tough foods and P. robustus consumed more hard and brittle items, but that both had variable and overlapping diets.     

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.     

Admixture mapping for hypertension loci with genome-scan markers

Identification of genetic variants that contribute to risk of hypertension is challenging. As a complement to linkage and candidate gene association studies, we carried out admixture mapping using genome-scan microsatellite markers among the African American participants in the US National Heart, Lung, and Blood Institute's Family Blood Pressure Program. This population was assumed to have experienced recent admixture from ancestral groups originating in Africa and Europe. We used a set of unrelated individuals from Nigeria to represent the African ancestral population and used the European Americans in the Family Blood Pressure Program to provide estimates of allele frequencies for the European ancestors. We genotyped a common set of 269 microsatellite markers in the three groups at the same laboratory. The distribution of marker location-specific African ancestry, based on multipoint analysis, was shifted upward in hypertensive cases versus normotensive controls, consistent with linkage to genes conferring susceptibility. This shift was largely due to a small number of loci, including five adjacent markers on chromosome 6q and two on chromosome 21q. These results suggest that chromosome 6q24 and 21q21 may contain genes influencing risk of hypertension in African Americans.     

Mutations in dynamin 2 cause dominant centronuclear myopathy

Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.     

Kin selection and cooperative courtship in wild turkeys

In the few species of birds in which males form display partnerships to attract females, one male secures most or all of the copulations. This leads to the question of why subordinate males help in the absence of observable reproductive benefits. Hamilton's concept of kin selection, whereby individuals can benefit indirectly by helping a relative, was a crucial breakthrough for understanding apparently altruistic systems. However in the only direct test of kin selection in coordinated display partnerships, partners were unrelated, discounting kin selection as an explanation for the evolution of cooperation. Here I show, using genetic measures of relatedness and reproductive success, that kin selection can explain the evolution of cooperative courtship in wild turkeys. Subordinate (helper) males do not themselves reproduce, but their indirect fitness as calculated by Hamilton's rule more than offsets the cost of helping. This result confirms a textbook example of kin selection that until now has been controversial and also extends recent findings of male relatedness on avian leks by quantifying the kin-selected benefits gained by non-reproducing males.