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51.
R. Shringarpure T. Grune K.J.A. Davies 《Cellular and molecular life sciences : CMLS》2001,58(10):1442-1450
The generation of reactive oxygen species is an inevitable aspect of aerobic life. In addition to being exposed to free radicals in the environment, aerobic organisms must also deal with oxygen radicals generated as byproducts of a number of physiological mechanisms - for example, by the mitochondrial and endoplasmic reticulum electron transport chains, and by cells of the immune system. Although most organisms are equipped with several lines of defense against oxidative stress, these defensive mechanisms are not 100% effective, and oxidatively modified forms of proteins accumulate during aging, and in many pathological conditions.?Oxidatively modified proteins can form large aggregates due to covalent cross-linking or increased surface hydrophobicity. Unless repaired or removed from cells, these oxidized proteins are often toxic and can threaten cell viability. Mammalian cells exhibit only limited direct repair mechanisms, and oxidatively damaged proteins appear to undergo selective proteolysis, primarily by the major cytosolic proteinase, the proteasome. Interestingly, it appears that the 20S 'core' proteasome conducts the recognition and elimination of oxidized proteins in an ATP-independent and ubiquitin-independent pathway. Received 31 May 2001; accepted 26 June 2001 相似文献
52.
什么东西都不能从黑洞里逃脱。可是斯蒂芬·霍金出色地证明:黑洞并非真正是黑的,相反,它们因热而发光。那末这种热能怎么可能从那条单向通道里往外流源呢?答案全然同它所解释的现象一样奇特:黑洞辐射的热量不是用从黑洞流出来的通常能量来偿付,而是由流入黑洞的负能量来补偿。这难道是个数学花招?不对。负能量是确实存在的。问题在于:相当大的负能量的生成和利用会损害一些最神圣的自然法则,比如说热力学第二定律。梦想制造众动机或作逆时间旅行这些反常的非自然情景是容易的。对于物理学家来说,这些都是吓人的观念。但是大自然似… 相似文献
53.
A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse 总被引:37,自引:0,他引:37
Nolan PM Peters J Strivens M Rogers D Hagan J Spurr N Gray IC Vizor L Brooker D Whitehill E Washbourne R Hough T Greenaway S Hewitt M Liu X McCormack S Pickford K Selley R Wells C Tymowska-Lalanne Z Roby P Glenister P Thornton C Thaung C Stevenson JA Arkell R Mburu P Hardisty R Kiernan A Erven A Steel KP Voegeling S Guenet JL Nickols C Sadri R Nasse M Isaacs A Davies K Browne M Fisher EM Martin J Rastan S Brown SD Hunter J 《Nature genetics》2000,25(4):440-443
As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics. 相似文献
54.
Zhiheng Huang Hua Xiong Zhiyong Wu Paul Conway Hugh Davies Alan Dinsdale Yunfei En Qingfeng Zeng 《科学通报(英文版)》2014,59(15):1696-1708
Semiconductor technology and packaging is advancing rapidly toward system integration where the packaging is co-designed and co-manufactured along with the wafer fabrication. However, materials issues, in par- ticular the mesoscale microstructure, have to date been excluded from the integrated product design cycle of electronic packaging due to the myriad of materials used and the complex nature of the material phenomena that require a multiphysics approach to describe. In the context of the materials genome initiative, we present an overview of a series of studies that aim to establish the linkages between the material microstructure and its responses by considering the multiple perspectives of the various mul- tiphysics fields. The microstructure was predicted using thermodynamic calculations, sharp interface kinetic models, phase field, and phase field crystal modeling techniques. Based on the predicted mesoscale microstruc- ture, linear elastic mechanical analyses and electromigra- tion simulations on the ultrafine interconnects were performed. The microstructural index extracted by a method based on singular value decomposition exhibits a monotonous decrease with an increase in the interconnect size. An artificial neural network-based fitting revealed a nonlinear relationship between the microstructure index and the average yon Mises stress in the ultrafine interconnects. Future work to address the randomness of microstructure and the resulting scatter in the reliability is discussed in this study. 相似文献
55.
The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. 总被引:18,自引:0,他引:18
One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T-P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1. Pin1 specifically isomerizes pS/T-P bonds and regulates the function of mitotic phosphoproteins. Here we show that Pin1 binds to only one pT-P motif in tau and copurifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease. 相似文献
56.
Genzel R Tacconi LJ Eisenhauer F Schreiber NM Cimatti A Daddi E Bouché N Davies R Lehnert MD Lutz D Nesvadba N Verma A Abuter R Shapiro K Sternberg A Renzini A Kong X Arimoto N Mignoli M 《Nature》2006,442(7104):786-789
Observations and theoretical simulations have established a framework for galaxy formation and evolution in the young Universe. Galaxies formed as baryonic gas cooled at the centres of collapsing dark-matter haloes; mergers of haloes and galaxies then led to the hierarchical build-up of galaxy mass. It remains unclear, however, over what timescales galaxies were assembled and when and how bulges and disks--the primary components of present-day galaxies--were formed. It is also puzzling that the most massive galaxies were more abundant and were forming stars more rapidly at early epochs than expected from models. Here we report high-angular-resolution observations of a representative luminous star-forming galaxy when the Universe was only 20% of its current age. A large and massive rotating protodisk is channelling gas towards a growing central stellar bulge hosting an accreting massive black hole. The high surface densities of gas, the high rate of star formation and the moderately young stellar ages suggest rapid assembly, fragmentation and conversion to stars of an initially very gas-rich protodisk, with no obvious evidence for a major merger. 相似文献
57.
Visual Models in Analogical Problem Solving 总被引:1,自引:0,他引:1
Visual analogy is believed to be important in human problem solving. Yet, there are few computational models of visual analogy.
In this paper, we present a preliminary computational model of visual analogy in problem solving. The model is instantiated
in a computer program, called Galatea, which uses a language for representing and transferring visual information called Privlan.
We describe how the computational model can account for a small slice of a cognitive-historical analysis of Maxwell’s reasoning
about electromagnetism. 相似文献
58.
Antibiotic resistance in microbes 总被引:31,自引:0,他引:31
The treatment of infectious disease is compromised by the development of antibiotic-resistant strains of microbial pathogens. A variety of biochemical processes are involved that may keep antibiotics out of the cell, alter the target of the drug, or disable the antibiotic. Studies have shown that resistance determinants arise by either of two genetic mechanisms: mutation and acquisition. Antibiotic resistance genes can be disseminated among bacterial populations by several processes, but principally by conjugation. Thus the overall problem of antibiotic resistance is one of genetic ecology and a better understanding of the contributing parameters is necessary to devise rational approaches to reduce the development and spread of antibiotic resistance and so avoid a critical situation in therapy--a return to a pre-antibiotic era. 相似文献
59.
Colour categories in a stone-age tribe 总被引:5,自引:0,他引:5
60.