Spontaneous DNA breakage in single living Escherichia coli cells

Spontaneous DNA breakage is predicted to be a frequent, inevitable consequence of DNA replication and is thought to underlie much of the genomic change that fuels cancer and evolution. Despite its importance, there has been little direct measurement of the amounts, types, sources and fates of spontaneous DNA lesions in living cells. We present a direct, sensitive flow cytometric assay in single living Escherichia coli cells for DNA lesions capable of inducing the SOS DNA damage response, and we report its use in quantification of spontaneous DNA double-strand breaks (DSBs). We report efficient detection of single chromosomal DSBs and rates of spontaneous breakage approximately 20- to 100-fold lower than predicted. In addition, we implicate DNA replication in the origin of spontaneous DSBs with the finding of fewer spontaneous DSBs in a mutant with altered DNA polymerase III. The data imply that spontaneous DSBs induce genomic changes and instability 20-100 times more potently than previously appreciated. Finally, FACS demonstrated two main cell fates after spontaneous DNA damage: viability with or without resumption of proliferation.     

Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth

17q11 microdeletions that encompass NF1 cause 5%-10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is within the NF1 microdeletion region, in six families characterized by overgrowth, learning disability, dysmorphic features and variable additional features. These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases.     

A common variant of HMGA2 is associated with adult and childhood height in the general population

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 x 10(-11), overall P = 4 x 10(-16), including the genome-wide association data). We also observed the association in children (P = 1 x 10(-6), N = 6,827) and a tall/short case-control study (P = 4 x 10(-6), N = 3,207). We estimate that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.     

Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24

Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.     

Antifungal properties of taxol and various analogues.

The antimitotic agent taxol was tested for toxicity towards fungi from different taxonomic groups and found to be particularly active against oomycete fungi. In germinating zoospore cysts of the oomycete Phytophthora capsici the mechanism of action of taxol was shown to involve inhibition of mitosis, presumably resulting from an effect on microtubules. Various taxol analogues with deleted A-ring C-13 side chain substituents were tested for toxicity towards P. capsici and Aphanomyces cochlioides to provide insight into structural features required for activity. The importance of the side chain was shown by the much lower activity as compared to taxol of analogues lacking all or part of the side chain. The effect of stereochemistry at the C-2' position on fungitoxicity towards oomycetes was similar to that reported previously on mammalian microtubule assembly.     

面向集成管理网的TMN-DCN拓扑结构设计

提出了各种网络集成管理的TMN—DCN设计方法，并举出了应用示例。TMN—DCN设备可按各个网络配置。这些设备具有网络管理功能。规模非常大的网络分配多个TMN—DCN设备。下一阶段则利用作为TMN-DCN节点的TMN-DCN设备设计TMN—DCN的布局（物理结构）。     

Structural insights into a yeast prion illuminate nucleation and strain diversity

Self-perpetuating changes in the conformations of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture and conformational conversion of amyloids remain poorly understood. Amyloid conformers of Sup35 are the molecular embodiment of the yeast prion known as [PSI], which produces heritable changes in phenotype through self-perpetuating changes in protein folding. Here we determine the nature of Sup35's cooperatively folded amyloid core, and use this information to investigate central questions in prion biology. Specific segments of the amyloid core form intermolecular contacts in a 'Head-to-Head', 'Tail-to-Tail' fashion, but the 'Central Core' is sequestered through intramolecular contacts. The Head acquires productive interactions first, and these nucleate assembly. Variations in the length of the amyloid core and the nature of intermolecular interfaces form the structural basis of distinct prion 'strains', which produce variant phenotypes in vivo. These findings resolve several problems in yeast prion biology and have broad implications for other amyloids.     

Chimpanzees are indifferent to the welfare of unrelated group members

Humans are an unusually prosocial species-we vote, give blood, recycle, give tithes and punish violators of social norms. Experimental evidence indicates that people willingly incur costs to help strangers in anonymous one-shot interactions, and that altruistic behaviour is motivated, at least in part, by empathy and concern for the welfare of others (hereafter referred to as other-regarding preferences). In contrast, cooperative behaviour in non-human primates is mainly limited to kin and reciprocating partners, and is virtually never extended to unfamiliar individuals. Here we present experimental tests of the existence of other-regarding preferences in non-human primates, and show that chimpanzees (Pan troglodytes) do not take advantage of opportunities to deliver benefits to familiar individuals at no material cost to themselves, suggesting that chimpanzee behaviour is not motivated by other-regarding preferences. Chimpanzees are among the primates most likely to demonstrate prosocial behaviours. They participate in a variety of collective activities, including territorial patrols, coalitionary aggression, cooperative hunting, food sharing and joint mate guarding. Consolation of victims of aggression and anecdotal accounts of solicitous treatment of injured individuals suggest that chimpanzees may feel empathy. Chimpanzees sometimes reject exchanges in which they receive less valuable rewards than others, which may be one element of a 'sense of fairness', but there is no evidence that they are averse to interactions in which they benefit more than others.