Complete subunit architecture of the proteasome regulatory particle

The proteasome is the major ATP-dependent protease in eukaryotic cells, but limited structural information restricts a mechanistic understanding of its activities. The proteasome regulatory particle, consisting of the lid and base subcomplexes, recognizes and processes polyubiquitinated substrates. Here we used electron microscopy and a new heterologous expression system for the lid to delineate the complete subunit architecture of the regulatory particle from yeast. Our studies reveal the spatial arrangement of ubiquitin receptors, deubiquitinating enzymes and the protein unfolding machinery at subnanometre resolution, outlining the substrate's path to degradation. Unexpectedly, the ATPase subunits within the base unfoldase are arranged in a spiral staircase, providing insight into potential mechanisms for substrate translocation through the central pore. Large conformational rearrangements of the lid upon holoenzyme formation suggest allosteric regulation of deubiquitination. We provide a structural basis for the ability of the proteasome to degrade a diverse set of substrates and thus regulate vital cellular processes.     

交互随机系统

本书的内容报道了欧洲随机研究协会资助的“DFG．Schwerpunkt随机系统”课题中在概率论方向的网络科研人员所作的原创性工作，题为“极复杂交互随机系统”科研项目，研究目标是探索和开发无限维随机分析、统计物理、基于数学生物学的全球人口模型、金融市场的复杂模型与其它学科相关的随机模型之问的联系。     

The mass of the missing baryons in the X-ray forest of the warm-hot intergalactic medium

Recent cosmological measurements indicate that baryons comprise about four per cent of the total mass-energy density of the Universe, which is in accord with the predictions arising from studies of the production of the lightest elements. It is also in agreement with the actual number of baryons detected at early times (redshifts z > 2). Close to our own epoch (z < 2), however, the number of baryons detected add up to just over half (approximately 55 per cent) of the number seen at z > 2 (refs 6-11), meaning that about approximately 45 per cent are 'missing'. Here we report a determination of the mass-density of a previously undetected population of baryons, in the warm-hot phase of the intergalactic medium. We show that this mass density is consistent, within the uncertainties, with the mass density of the missing baryons.     

A choice-semantical approach to theoretical truth

A central topic in the logic of science concerns the proper semantic analysis of theoretical sentences, that is sentences containing theoretical terms. In this paper, we present a novel choice-semantical account of theoretical truth based on the epsilon-term definition of theoretical terms. Specifically, we develop two ways of specifying the truth conditions of theoretical statements in a choice functional semantics, each giving rise to a corresponding logic of such statements. In order to investigate the inferential strength of these logical systems, we provide a translation of each truth definition into a modal definition of theoretical truth. Based on this, we show that the stronger notion of choice-semantical truth captures more adequately our informal semantic understanding of scientific statements.     

High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease

Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% +/- 9.3%; individuals with Parkinson disease, 52.3% +/- 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.     

Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse

Vacuolar-vesicular protein sorting (Vps) factors are involved in vesicular trafficking in eukaryotic cells. We identified the missense mutation L967Q in Vps54 in the wobbler mouse, an animal model of amyotrophic lateral sclerosis, and also characterized a lethal allele, Vps54(beta-geo). Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse, indicating that Vps54 has an essential role in these processes.     

p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway

The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.