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91.
Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death 总被引:1,自引:0,他引:1
Baines CP Kaiser RA Purcell NH Blair NS Osinska H Hambleton MA Brunskill EW Sayen MR Gottlieb RA Dorn GW Robbins J Molkentin JD 《Nature》2005,434(7033):658-662
Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death. 相似文献
92.
Stanton H Rogerson FM East CJ Golub SB Lawlor KE Meeker CT Little CB Last K Farmer PJ Campbell IK Fourie AM Fosang AJ 《Nature》2005,434(7033):648-652
Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more 'aggrecanases' from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity. However, they are not thought to be the primary aggrecanases because ADAMTS1 null mice are not protected from experimental arthritis, and cleavage by ADAMTS8 and 9 is highly inefficient. Although ADAMTS4 and 5 are expressed in joint tissues, and are known to be efficient aggrecanases in vitro, the exact contribution of these two enzymes to cartilage pathology is unknown. Here we show that ADAMTS5 is the major aggrecanase in mouse cartilage, both in vitro and in a mouse model of inflammatory arthritis. Our data suggest that ADAMTS5 may be a suitable target for the development of new drugs designed to inhibit cartilage destruction in arthritis, although further work will be required to determine whether ADAMTS5 is also the major aggrecanase in human arthritis. 相似文献
93.
The breakdown of continuum models for mechanical contacts 总被引:5,自引:0,他引:5
Forces acting within the area of atomic contact between surfaces play a central role in friction and adhesion. Such forces are traditionally calculated using continuum contact mechanics, which is known to break down as the contact radius approaches atomic dimensions. Yet contact mechanics is being applied at ever smaller lengths, driven by interest in shrinking devices to nanometre scales, creating nanostructured materials with optimized mechanical properties, and understanding the molecular origins of macroscopic friction and adhesion. Here we use molecular simulations to test the limits of contact mechanics under ideal conditions. Our findings indicate that atomic discreteness within the bulk of the solids does not have a significant effect, but that the atomic-scale surface roughness that is always produced by discrete atoms leads to dramatic deviations from continuum theory. Contact areas and stresses may be changed by a factor of two, whereas friction and lateral contact stiffness change by an order of magnitude. These variations are likely to affect continuum predictions for many macroscopic rough surfaces, where studies show that the total contact area is broken up into many separate regions with very small mean radius. 相似文献
94.
Carbon losses from all soils across England and Wales 1978-2003 总被引:9,自引:0,他引:9
More than twice as much carbon is held in soils as in vegetation or the atmosphere, and changes in soil carbon content can have a large effect on the global carbon budget. The possibility that climate change is being reinforced by increased carbon dioxide emissions from soils owing to rising temperature is the subject of a continuing debate. But evidence for the suggested feedback mechanism has to date come solely from small-scale laboratory and field experiments and modelling studies. Here we use data from the National Soil Inventory of England and Wales obtained between 1978 and 2003 to show that carbon was lost from soils across England and Wales over the survey period at a mean rate of 0.6% yr(-1) (relative to the existing soil carbon content). We find that the relative rate of carbon loss increased with soil carbon content and was more than 2% yr(-1) in soils with carbon contents greater than 100 g kg(-1). The relationship between rate of carbon loss and carbon content is irrespective of land use, suggesting a link to climate change. Our findings indicate that losses of soil carbon in England and Wales--and by inference in other temperate regions-are likely to have been offsetting absorption of carbon by terrestrial sinks. 相似文献
95.
Farmer H McCabe N Lord CJ Tutt AN Johnson DA Richardson TB Santarosa M Dillon KJ Hickson I Knights C Martin NM Jackson SP Smith GC Ashworth A 《Nature》2005,434(7035):917-921
BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer. 相似文献
96.
97.
Vinuesa CG Cook MC Angelucci C Athanasopoulos V Rui L Hill KM Yu D Domaschenz H Whittle B Lambe T Roberts IS Copley RR Bell JI Cornall RJ Goodnow CC 《Nature》2005,435(7041):452-458
Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability. 相似文献
98.
99.
C. D. Fitch L. J. Robbins M. Jellinek J. S. Nelson 《Cellular and molecular life sciences : CMLS》1973,29(8):956-957
Zusammenfassung Intravenös verabreichte Tracerdosis von14C-Kreatin führt beim Huhn zur viermal höheren Aufnahme im Biceps femoris als im Musculus pectoralis. Dieser muskuläre Unterschied fällt fort, wenn gleichzeitig grosse Mengen nicht-radioaktiven Kreatins gegeben werden.
Supported in part by United States Public Health Service Grant Nos. NSO6807 and HEO6312. 相似文献
Supported in part by United States Public Health Service Grant Nos. NSO6807 and HEO6312. 相似文献
100.
Relationship between reward-enhancing and stereotypical effects of psychomotor stimulant drugs. 总被引:9,自引:0,他引:9
T W Robbins 《Nature》1976,264(5581):57-59