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51.
Superoxide activates mitochondrial uncoupling proteins. 总被引:64,自引:0,他引:64
Karim S Echtay Damien Roussel Julie St-Pierre Mika B Jekabsons Susana Cadenas Jeff A Stuart James A Harper Stephen J Roebuck Alastair Morrison Susan Pickering John C Clapham Martin D Brand 《Nature》2002,415(6867):96-99
Uncoupling protein 1 (UCP1) diverts energy from ATP synthesis to thermogenesis in the mitochondria of brown adipose tissue by catalysing a regulated leak of protons across the inner membrane. The functions of its homologues, UCP2 and UCP3, in other tissues are debated. UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogenic. Mild uncoupling would, however, decrease the mitochondrial production of reactive oxygen species, which are important mediators of oxidative damage. Here we show that superoxide increases mitochondrial proton conductance through effects on UCP1, UCP2 and UCP3. Superoxide-induced uncoupling requires fatty acids and is inhibited by purine nucleotides. It correlates with the tissue expression of UCPs, appears in mitochondria from yeast expressing UCP1, and is absent in skeletal muscle mitochondria from UCP3 knockout mice. Our findings indicate that the interaction of superoxide with UCPs may be a mechanism for decreasing the concentrations of reactive oxygen species inside mitochondria. 相似文献
52.
Stephen K. McNees 《Journal of forecasting》1982,1(1):37-48
This article stresses how little is known about the quality, particularly the relative quality, of macroeconometric models. Most economists make a strict distinction between the quality of a model per se and the accuracy of solutions based on that model. While this distinction is valid, it leaves unanswered how to compare the‘validity’of conditional models. The standard test, the accuracy of ex post simulations, is not definitive when models with differing degrees of exogeneity are compared. In addition, it is extremely difficult to estimate the relative quantitative importance of conceptual problems of models, such as parameter instability across‘policy regimes’ In light of the difficulty in comparisons of conditional macroeconometric models, many model-builders and users assume that the best models are those that have been used to make the most accurate forecasts are those made with the best models. Forecasting experience indicates that forecasters using macroeconometric models have produced more accurate macroeconomic forecasts than either naive or sophisticated unconditional statistical models. It also suggests that judgementally adjusted forecasts have been more accurate than model-based forecasts generated mechanically. The influence of econometrically-based forecasts is now so pervasive that it is difficult to find examples of‘purely judgemental’forecasts. 相似文献
53.
54.
Ruiz-Lapuente P Comeron F Méndez J Canal R Smartt SJ Filippenko AV Kurucz RL Chornock R Foley RJ Stanishev V Ibata R 《Nature》2004,431(7012):1069-1072
The brightness of type Ia supernovae, and their homogeneity as a class, makes them powerful tools in cosmology, yet little is known about the progenitor systems of these explosions. They are thought to arise when a white dwarf accretes matter from a companion star, is compressed and undergoes a thermonuclear explosion. Unless the companion star is another white dwarf (in which case it should be destroyed by the mass-transfer process itself), it should survive and show distinguishing properties. Tycho's supernova is one of only two type Ia supernovae observed in our Galaxy, and so provides an opportunity to address observationally the identification of the surviving companion. Here we report a survey of the central region of its remnant, around the position of the explosion, which excludes red giants as the mass donor of the exploding white dwarf. We found a type G0-G2 star, similar to our Sun in surface temperature and luminosity (but lower surface gravity), moving at more than three times the mean velocity of the stars at that distance, which appears to be the surviving companion of the supernova. 相似文献
55.
Nitrification is a key stage in the nitrogen cycle; it enables the transformation of nitrogen into an oxidized, inorganic state. The availability of nitrates produced by this process often limits primary productivity and is an important determinant in plant community ecology and biodiversity. Chemoautotrophic prokaryotes are recognized as the main facilitators of this process, although heterotrophic nitrification by fungi may be significant under certain conditions. However, there has been neither biochemical nor ecological evidence to support nitrification by photoautotrophic plants. Here we show how certain legumes that accumulate the toxin, 3-nitropropionic acid, generate oxidized inorganic nitrogen in their shoots, which is returned to the soil in their litter. In nitrogen-fixing populations this 'new' nitrate and nitrite can be derived from the assimilation of nitrogen gas. Normally, the transformation of elemental nitrogen from the atmosphere into a fixed oxidized form (as nitrate) is represented in the nitrogen cycle as a multiphasic process involving several different organisms. We show how this can occur in a single photoautotrophic organism, representing a previously undescribed feature of this biogeochemical cycle. 相似文献
56.
Volkov I Banavar JR Maritan A Hubbell SP 《Nature》2004,427(6976):696; discussion 696-696; discussion 697
The unified neutral theory of biodiversity and biogeography provides a dynamic null hypothesis for the assembly of natural communities. It is also useful for understanding the influence of speciation, extinction, dispersal and ecological drift on patterns of relative species abundance, species-area relationships and phylogeny. Clark and McLachlan argue that neutral drift is inconsistent with the palaeorecord of stability in fossil pollen assemblages of the Holocene forests of southern Canada. We show here that their analysis is based on a partial misunderstanding of neutral theory and that their data alone cannot unambiguously test its validity. 相似文献
57.
Abrescia NG Cockburn JJ Grimes JM Sutton GC Diprose JM Butcher SJ Fuller SD San Martín C Burnett RM Stuart DI Bamford DH Bamford JK 《Nature》2004,432(7013):68-74
The structure of the membrane-containing bacteriophage PRD1 has been determined by X-ray crystallography at about 4 A resolution. Here we describe the structure and location of proteins P3, P16, P30 and P31. Different structural proteins seem to have specialist roles in controlling virus assembly. The linearly extended P30 appears to nucleate the formation of the icosahedral facets (composed of trimers of the major capsid protein, P3) and acts as a molecular tape-measure, defining the size of the virus and cementing the facets together. Pentamers of P31 form the vertex base, interlocking with subunits of P3 and interacting with the membrane protein P16. The architectural similarities with adenovirus and one of the largest known virus particles PBCV-1 support the notion that the mechanism of assembly of PRD1 is scaleable and applies across the major viral lineage formed by these viruses. 相似文献
58.
Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer 总被引:29,自引:0,他引:29
Suzuki H Watkins DN Jair KW Schuebel KE Markowitz SD Chen WD Pretlow TP Yang B Akiyama Y Van Engeland M Toyota M Tokino T Hinoda Y Imai K Herman JG Baylin SB 《Nature genetics》2004,36(4):417-422
Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer. 相似文献
59.
Krakow D Robertson SP King LM Morgan T Sebald ET Bertolotto C Wachsmann-Hogiu S Acuna D Shapiro SS Takafuta T Aftimos S Kim CA Firth H Steiner CE Cormier-Daire V Superti-Furga A Bonafe L Graham JM Grix A Bacino CA Allanson J Bialer MG Lachman RS Rimoin DL Cohn DH 《Nature genetics》2004,36(4):405-410
The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein. 相似文献
60.
Thibault ST Singer MA Miyazaki WY Milash B Dompe NA Singh CM Buchholz R Demsky M Fawcett R Francis-Lang HL Ryner L Cheung LM Chong A Erickson C Fisher WW Greer K Hartouni SR Howie E Jakkula L Joo D Killpack K Laufer A Mazzotta J Smith RD Stevens LM Stuber C Tan LR Ventura R Woo A Zakrajsek I Zhao L Chen F Swimmer C Kopczynski C Duyk G Winberg ML Margolis J 《Nature genetics》2004,36(3):283-287
With the availability of complete genome sequence for Drosophila melanogaster, one of the next strategic goals for fly researchers is a complete gene knockout collection. The P-element transposon, the workhorse of D. melanogaster molecular genetics, has a pronounced nonrandom insertion spectrum. It has been estimated that 87% saturation of the approximately 13,500-gene complement of D. melanogaster might require generating and analyzing up to 150,000 insertions. We describe specific improvements to the lepidopteran transposon piggyBac and the P element that enabled us to tag and disrupt genes in D. melanogaster more efficiently. We generated over 29,000 inserts resulting in 53% gene saturation and a more diverse collection of phenotypically stronger insertional alleles. We found that piggyBac has distinct global and local gene-tagging behavior from that of P elements. Notably, piggyBac excisions from the germ line are nearly always precise, piggyBac does not share chromosomal hotspots associated with P and piggyBac is more effective at gene disruption because it lacks the P bias for insertion in 5' regulatory sequences. 相似文献