Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy

Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.     

Genome sequence of the Brown Norway rat yields insights into mammalian evolution

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.     

Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus

The 'Spanish' influenza pandemic of 1918-19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin (HA) and neuraminidase (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal. Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.     

Human contribution to the European heatwave of 2003

The summer of 2003 was probably the hottest in Europe since at latest ad 1500, and unusually large numbers of heat-related deaths were reported in France, Germany and Italy. It is an ill-posed question whether the 2003 heatwave was caused, in a simple deterministic sense, by a modification of the external influences on climate--for example, increasing concentrations of greenhouse gases in the atmosphere--because almost any such weather event might have occurred by chance in an unmodified climate. However, it is possible to estimate by how much human activities may have increased the risk of the occurrence of such a heatwave. Here we use this conceptual framework to estimate the contribution of human-induced increases in atmospheric concentrations of greenhouse gases and other pollutants to the risk of the occurrence of unusually high mean summer temperatures throughout a large region of continental Europe. Using a threshold for mean summer temperature that was exceeded in 2003, but in no other year since the start of the instrumental record in 1851, we estimate it is very likely (confidence level >90%) that human influence has at least doubled the risk of a heatwave exceeding this threshold magnitude.     

商业伦理的形而上学基础

考虑到形而上学和伦理的原则是人类所有理论知识与实践选择的首要而有效的方法,通过考察古代对形而上学和商业伦理的哲学反思,人自身、人的才能和商业伦理,西塞罗、亚里士多德和中世纪关于人自身的反思,训练智力和伦理美德的商业教育,从无创造、道成肉身和现代商业伦理,基督教、有限管理和现代商业伦理,现代企业的成功及商业伦理等,揭示出健康的政治经济秩序是建立在好的形而上学原则之上的.     

反物质都到哪里去了?

B介子的测量表明 ,粒子物理的标准模型无法解释为什么宇宙是由物质而不是反物质构成的     

On a family of finite moving‐average trend filters for the ends of series

A family of finite end filters is constructed using a minimum revisions criterion and based on a local dynamic model operating within the span of a given finite central filter. These end filters are equivalent to evaluating the central filter with unavailable future observations replaced by constrained optimal linear predictions. Two prediction methods are considered: best linear unbiased prediction and best linear biased prediction where the bias is time invariant. The properties of these end filters are determined. In particular, they are compared to X‐11 end filters and to the case where the central filter is evaluated with unavailable future observations predicted by global ARIMA models as in X‐11‐ARIMA or X‐12‐ARIMA. Copyright © 2002 John Wiley & Sons, Ltd.