PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

基于土性相关蒙特卡罗法的争岗滑坡堆积体可靠性分析

针对澜沧江古水水电站争岗滑坡堆积体工程地质务件,在室内剪切试验、工程类比、参数反演基础上综合确定了岩土体力学参数及其统计分布规律.采用基于黏聚力c与内摩擦角φ相关抽样下的蒙特卡罗法对堆积体典型剖面进行了多种工况下的可靠性分析,预测了其未来的变形失稳特征.研究结果表明:当前堆积体B-B'剖面在正常运行工况下的破坏概率为2...     

Identity of the 19S 'prosome' particle with the large multifunctional protease complex of mammalian cells (the proteasome)

There have been many reports that eukaryotic cells contain ring-shaped 19S or 20S particles which are composed of numerous polypeptide subunits ranging in size between 25 and 35 kilodaltons. Because these particles seemed to copurify with inactive mRNA, they were assumed to function in regulating mRNA translation and hence were named 'prosomes' (for 'programmed-o-some'). A number of properties have been reported for these structures, including an association with specific RNA species or with certain heat-shock proteins and involvement in tRNA processing or aminoacyl tRNA synthesis. However, these proposed activities have not been supported by definitive evidence. During studies of the proteolytic systems in mammalian tissues, we noted many similarities between these 19S particles and the high molecular weight protease complexes that are present in most or all eukaryotic cells. This (700 kilodalton) enzyme complex, designated here as LAMP for 'large alkaline multi-functional protease', contains three distinct endoproteolytic sites which function at neutral or alkaline pH and are specific for hydrolysis of proteins, hydrophobic peptides, or basic peptides. This protease also exists in a latent form which can be activated by polylysine, fatty acids, or ATP. In this report, we show that the prosomes and these protease complexes are very similar or identical with respect to their size, polypeptide composition, immunological cross-reactivity, appearance in the electron microscope, radial symmetry of subunits, subcellular localization, and proteolytic activities. Therefore, the 'prosome' probably plays a critical role in intracellular protein breakdown, and we propose that it be renamed 'proteasome'.     

核能谱与两类转动惯量的精确表达式

用最小二乘拟合法,将稀土区的能谱实验数据,拟合不同的能谱公式,从而证明E=a〔(1+bI(I+1))~(1/2)-1〕是符合得较好的,本文还推导了与上述能谱相应的两类转动惯量,并以此与实验计算值进行比较,结果仍很满意.     

Accelerated carbonation and leaching behavior of the slag from iron and steel making industry

Ground granulated blast furnace slag(GGBFS)and steelmaking slag have been used as a raw material for cement production or as an aggregate to make concrete,which contribute aluminum,calcium,iron,and silicon oxides.The suitability of the slag for a particular application depends on its reactivity,cost,availability,and its influence on the properties of the resulting concrete.For the interest of durability studying of concrete in the presence of slag,the accelerated carbonation products and leaching behavior of the slag and Portland cement(PC)were studied.The experimental results confirmed that the slag was more resistant to carbonation compared to PC.The carbonation degree of GGBFS reduced by 17.74%;and the carbonation degrees of steelmaking slags reduced by 9.51%-11.94%.Carbonation neutralized the alkaline nature of the hydrated pastes and gave rise to the redox potential of the leachate slightly(30-77 mV).The carbonation also increased the release of most of the elements presented,except for calcium,to the aqueous environment.It is concluded that blend cements(PC plus slag)have economical advantages and better durability compared to PC.     

Genome sequence of enterohaemorrhagic Escherichia coli O157:H7

The bacterium Escherichia coli O157:H7 is a worldwide threat to public health and has been implicated in many outbreaks of haemorrhagic colitis, some of which included fatalities caused by haemolytic uraemic syndrome. Close to 75,000 cases of O157:H7 infection are now estimated to occur annually in the United States. The severity of disease, the lack of effective treatment and the potential for large-scale outbreaks from contaminated food supplies have propelled intensive research on the pathogenesis and detection of E. coli O157:H7 (ref. 4). Here we have sequenced the genome of E. coli O157:H7 to identify candidate genes responsible for pathogenesis, to develop better methods of strain detection and to advance our understanding of the evolution of E. coli, through comparison with the genome of the non-pathogenic laboratory strain E. coli K-12 (ref. 5). We find that lateral gene transfer is far more extensive than previously anticipated. In fact, 1,387 new genes encoded in strain-specific clusters of diverse sizes were found in O157:H7. These include candidate virulence factors, alternative metabolic capacities, several prophages and other new functions--all of which could be targets for surveillance.     

The stimulation of rat brain monoamine oxidase by dietary lithium chloride.

Lithium chloride administered to rats in drinking water for 30 days caused an increase of whole brain monoamine oxidase specific activity to approximately 140% of control. Carboxylesterase and formyltetrahydrofolate synthetase activities were not affected by Li+ either in vivo or in vitro.