Parameters for reliable results in genetic association studies in common disease.

It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.     

Action of diphenylhydantoin on chromosomes

The effect of diphenyl hydantoin, (DPH) a nonbarbituate anticonvulsant drug, on chromosomes and fertility was tested in cultured human lymphocytes, mouse fertility, and rat maternal marrow chromosomes and fetal development. Whole human blood from 5 male and 5 female subjects was cultured for 68 hours with phytohemagglutinin, then incubated for 2 hours in isotonic salts with .05-.3 mg per ml DPH, .02 mcg per ml colchicine, or .4 mg per ml sodium diethylbarbiturate. The mean number of metaphases per 1000 stimulated cells was 10.0 in controls, 40.3 with colchicine, 27.9 with diethylbarbiturate, and 30.5 with .25 mg DPH per ml. Both diphenylbarbiturate and DPH produced linear dose effect curves. These results were demonstrated not to be due to urea, since there were no differences in urea content, with a 2 hour urease micromethod. Mouse fertility was totally inhibited in 6 virgin mice given .1mg DPH daily for 10 days compared to 41 pups both of 6 control mice. In 6 pregnant rats given 25 mg DPH per 100 gm/orally 4 times daily for 2 days on gestation Days 7 and 8, there were 5 rats with all fetuses resorbed and 1 rat with 3 living and several resorptions. 6 controls had 6-14 normal fetuses each. 50 metaphase plates from each rat's femoral marrow and each fetus were examined 2 hous after injecting .3 mg colchicine per 100 gm. 30% of the metaphase cells from treated females and fetuses showed strongly contracted chromosomes and reduced number os "pulverized" chromosomes. These phenomena may have been due to inhibition by DPH of folic acid metabolism which is involved in purine synthesis.     

Measurement of the conductance of single conjugated molecules

Electrical conduction through molecules depends critically on the delocalization of the molecular electronic orbitals and their connection to the metallic contacts. Thiolated (- SH) conjugated organic molecules are therefore considered good candidates for molecular conductors: in such molecules, the orbitals are delocalized throughout the molecular backbone, with substantial weight on the sulphur-metal bonds. However, their relatively small size, typically approximately 1 nm, calls for innovative approaches to realize a functioning single-molecule device. Here we report an approach for contacting a single molecule, and use it to study the effect of localizing groups within a conjugated molecule on the electrical conduction. Our method is based on synthesizing a dimer structure, consisting of two colloidal gold particles connected by a dithiolated short organic molecule, and electrostatically trapping it between two metal electrodes. We study the electrical conduction through three short organic molecules: 4,4'-biphenyldithiol (BPD), a fully conjugated molecule; bis-(4-mercaptophenyl)-ether (BPE), in which the conjugation is broken at the centre by an oxygen atom; and 1,4-benzenedimethanethiol (BDMT), in which the conjugation is broken near the contacts by a methylene group. We find that the oxygen in BPE and the methylene groups in BDMT both suppress the electrical conduction relative to that in BPD.     

重复元件介导的重组是新嵌合基因形成的一个重要机制

先前的研究提示重复元件在产生新的嵌合基因中具有机制性的作用,这与经典的外显子洗牌模型是一致的,它依赖于非同源重组。而近期一些关于染色体异常的研究结果显示,异位的同源重组可能对于产生新基因也非常重要。本项研究通过对8种果蝇的年轻基因进行筛选和分析,从中识别出了17个重复片段,它们是在最近1200万年中通过异位重组形成的。它们中的大多数已具有功能,并进化出多样的表达类型和嵌合结构。这些结果证实,重复元件介导的非等位同源重组在产生新嵌合基因中起到重要作用。     

船用柴油机磨损模式识别方法

在总结船用柴油机磨损形式的磨粒分析基础上,分析了模糊逻辑方法进行模式识别的不足,提出了在船用柴油机磨损模式识别中采用基于灰色关联分析的模式识别方法,建立了相应模式识别专家系统,并验证了识别结果的可靠性。     

NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity

Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K⁺, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease.