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Lee JW Beebe K Nangle LA Jang J Longo-Guess CM Cook SA Davisson MT Sundberg JP Schimmel P Ackerman SL 《Nature》2006,443(7107):50-55
Misfolded proteins are associated with several pathological conditions including neurodegeneration. Although some of these abnormally folded proteins result from mutations in genes encoding disease-associated proteins (for example, repeat-expansion diseases), more general mechanisms that lead to misfolded proteins in neurons remain largely unknown. Here we demonstrate that low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. These findings demonstrate that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provide a novel mechanism underlying neurodegeneration. 相似文献
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A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase 总被引:18,自引:0,他引:18
Malek NP Sundberg H McGrew S Nakayama K Kyriakides TR Roberts JM Kyriakidis TR 《Nature》2001,413(6853):323-327
The protein p27Kip1 is an inhibitor of cell division. An increase in p27 causes proliferating cells to exit from the cell cycle, and a decrease in p27 is necessary for quiescent cells to resume division. Abnormally low amounts of p27 are associated with pathological states of excessive cell proliferation, especially cancers. In normal and tumour cells, p27 is regulated primarily at the level of translation and protein turnover. Phosphorylation of p27 on threonine 187 (T187) by cyclin-dependent kinase 2 (Cdk2) is thought to initiate the major pathway for p27 proteolysis. To critically test the importance of this pathway in vivo, we replaced the murine p27 gene with one that encoded alanine instead of threonine at position 187 (p27T187A). Here we show that cells expressing p27T187A were unable to downregulate p27 during the S and G2 phases of the cell cycle, but that this had a surprisingly modest effect on cell proliferation both in vitro and in vivo. Our efforts to explain this unexpected result led to the discovery of a second proteolytic pathway for controlling p27, one that is activated by mitogens and degrades p27 exclusively during G1. 相似文献
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Alkyl ketene dimers (AKD) have been used in the papermaking industry as reactive internal sizing agents for more than 30 years. AKD emulsions are normally stabilised by cationic starch. The advantages and disadvantages of the emulsions prepared in this way have been well documented. However, the influence of factors such as electrolytes, polyelectrolytes oligomers and pH on AKD emulsion stability has not been addressed. Polyelectrolyte oligomers often arise as impurities in cationic starch or as by-products during the cationisation of starches. The key objectives of this work have been to use starches purified by dialysis and precipitation to study (a)emulsion stabilising properties, (b) factor affecting emulsion characterisation and (c) the adsorption behaviour on AKD particles.Size exclusion chromatography (SEC) and intrinsic viscosity measurements were performed to evaluate molecular weight and MW distribution of cationic starches. NMR and Elemental analysis were conducted to characterise the degree of substitution (DS), and electrophoresis mobility was used to measure the surface charge characteristics of the emulsion particles.Within the experimental concentration ranges, the amount of the cationic starch adsorbed on the AKD particle surfaces has been shown to increase proportionally with the addition level but a high proportion remained unabsorbed. Molecular weight and charge density of cationic starch have also been observed and shown to be important. The zeta-potential of the emulsion particles was strongly dependent on the concentrations of the electrolytes added as well as pH. Excessive electrolytes and extreme pH conditions tended to reduce the zeta potential of the AKD particles. 相似文献
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Chelating agents for the binding of metal ions to macromolecules 总被引:2,自引:0,他引:2
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Ikeda F Deribe YL Skånland SS Stieglitz B Grabbe C Franz-Wachtel M van Wijk SJ Goswami P Nagy V Terzic J Tokunaga F Androulidaki A Nakagawa T Pasparakis M Iwai K Sundberg JP Schaefer L Rittinger K Macek B Dikic I 《Nature》2011,471(7340):637-641
SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo. 相似文献
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Mikaela Sundberg 《Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics》2010,41(3):273-281
While the distinction between theory and experiment is often used to discuss the place of simulation from a philosophical viewpoint, other distinctions are possible from a sociological perspective. Turkle (1995) distinguishes between cultures of calculation and cultures of simulation and relates these cultures to the distinction between modernity and postmodernity, respectively. What can we understand about contemporary simulation practices in science by looking at them from the point of view of these two computer cultures? What new questions does such an analysis raise for further studies? On the basis of two case studies, the present paper compares and discusses simulation activities in astrophysics and meteorology. It argues that simulation practices manifest aspects of both of these cultures simultaneously, but in different situations. By employing the dichotomies surface/depth, play/seriousness, and extreme/reasonable to characterize and operationalize cultures of calculation and cultures of simulation as sensitizing concepts, the analysis shows how simulation code work shifts from development to use, the importance of but also resistance towards too much visualizations, and how simulation modelers play with extreme values, yet also try to achieve reasonable results compared to observations. 相似文献
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