排序方式: 共有43条查询结果,搜索用时 31 毫秒
1.
Gandin V Miluzio A Barbieri AM Beugnet A Kiyokawa H Marchisio PC Biffo S 《Nature》2008,455(7213):684-688
Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6(+/-) cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6(+/-) mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6(+/-) cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals. 相似文献
2.
The Ni samples were electroformed from additive-free(AF) and saccharin-containing(SC) sulfamate solutions, respectively. In situ backscattered electron(BSE) imaging, electron backscatter diffraction(EBSD), and electron-probe microanalysis(EPMA) were used to investigate the effect of annealing on the deformation behaviors of the AF and SC samples. The results indicate that columnar grains of the as-deposited AF sample had an approximated average width of 3 μm and an approximated aspect ratio of 8. The average width of columnar grains of the as-deposited SC sample was reduced to approximately 400 nm by the addition of saccharin to the electrolyte. A few very-large grains distributed in the matrix of the SC sample after annealing. No direct evidence indicated that S segregated at the grain boundaries before or after annealing. The average value of the total elongations of the SC samples decreased from 16% to 6% after annealing, whereas that of the AF samples increased from 18% to 50%. The dislocation recovery in grain-boundary areas of the annealed AF sample was reduced, which contributed to the appearance of microvoids at the triple junctions. The incompatibility deformation between very-large grains and fine grains contributed to the brittle fracture behavior of the annealed SC Ni. 相似文献
3.
4.
5.
Lens-specific aquaporin-0 (AQP0) functions as a specific water pore and forms the thin junctions between fibre cells. Here we describe a 1.9 A resolution structure of junctional AQP0, determined by electron crystallography of double-layered two-dimensional crystals. Comparison of junctional and non-junctional AQP0 structures shows that junction formation depends on a conformational switch in an extracellular loop, which may result from cleavage of the cytoplasmic amino and carboxy termini. In the centre of the water pathway, the closed pore in junctional AQP0 retains only three water molecules, which are too widely spaced to form hydrogen bonds with each other. Packing interactions between AQP0 tetramers in the crystalline array are mediated by lipid molecules, which assume preferred conformations. We were therefore able to build an atomic model for the lipid bilayer surrounding the AQP0 tetramers, and we describe lipid-protein interactions. 相似文献
6.
Magnetic flux emerges from the solar surface as dark filaments connecting small sunspots with opposite polarities. The regions around the dark filaments are often bright in X-rays and are associated with jets. This implies plasma heating and acceleration, which are important for coronal heating. Previous two-dimensional simulations of such regions showed that magnetic reconnection between the coronal magnetic field and the emerging flux produced X-ray jets and flares, but left unresolved the origin of filamentary structure and the intermittent nature of the heating. Here we report three-dimensional simulations of emerging flux showing that the filamentary structure arises spontaneously from the magnetic Rayleigh-Taylor instability, contrary to the previous view that the dark filaments are isolated bundles of magnetic field that rise from the photosphere carrying the dense gas. As a result of the magnetic Rayleigh-Taylor instability, thin current sheets are formed in the emerging flux, and magnetic reconnection occurs between emerging flux and the pre-existing coronal field in a spatially intermittent way. This explains naturally the intermittent nature of coronal heating and the patchy brightenings in solar flares. 相似文献
7.
Hoshino K Sugiyama T Matsumoto M Tanaka T Saito M Hemmi H Ohara O Akira S Kaisho T 《Nature》2006,440(7086):949-953
The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation. TLRs 7 and 9 can recognize nucleic acids and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (IFN-alpha) (refs 7, 8). TLR7/9-mediated dendritic cell activation is critical for antiviral immunity but also contributes to the pathogenesis of systemic lupus erythematosus, a disease in which serum IFN-alpha levels are elevated owing to plasmacytoid dendritic cell activation. TLR7/9-induced IFN-alpha induction depends on a molecular complex that contains a TLR adaptor, MyD88, and IFN regulatory factor 7 (IRF-7) (refs 10-14), but the underlying molecular mechanisms are as yet unknown. Here we show that IkappaB kinase-alpha (IKK-alpha) is critically involved in TLR7/9-induced IFN-alpha production. TLR7/9-induced IFN-alpha production was severely impaired in IKK-alpha-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-alpha inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-alpha associated with and phosphorylated IRF-7. Our results identify a role for IKK-alpha in TLR7/9 signalling, and highlight IKK-alpha as a potential target for manipulating TLR-induced IFN-alpha production. 相似文献
8.
Boyd PW Law CS Wong CS Nojiri Y Tsuda A Levasseur M Takeda S Rivkin R Harrison PJ Strzepek R Gower J McKay M Abraham E Arychuk M Barwell-Clarke J Crawford W Crawford D Hale M Harada K Johnson K Kiyosawa H Kudo I Marchetti A Miller W Needoba J Nishioka J Ogawa H Page J Robert M Saito H Sastri A Sherry N Soutar T Sutherland N Taira Y Whitney F Wong SK Yoshimura T 《Nature》2004,428(6982):549-553
Iron supply has a key role in stimulating phytoplankton blooms in high-nitrate low-chlorophyll oceanic waters. However, the fate of the carbon fixed by these blooms, and how efficiently it is exported into the ocean's interior, remains largely unknown. Here we report on the decline and fate of an iron-stimulated diatom bloom in the Gulf of Alaska. The bloom terminated on day 18, following the depletion of iron and then silicic acid, after which mixed-layer particulate organic carbon (POC) concentrations declined over six days. Increased particulate silica export via sinking diatoms was recorded in sediment traps at depths between 50 and 125 m from day 21, yet increased POC export was not evident until day 24. Only a small proportion of the mixed-layer POC was intercepted by the traps, with more than half of the mixed-layer POC deficit attributable to bacterial remineralization and mesozooplankton grazing. The depletion of silicic acid and the inefficient transfer of iron-increased POC below the permanent thermocline have major implications both for the biogeochemical interpretation of times of greater iron supply in the geological past, and also for proposed geo-engineering schemes to increase oceanic carbon sequestration. 相似文献
9.
Nakayama M Abiru N Moriyama H Babaya N Liu E Miao D Yu L Wegmann DR Hutton JC Elliott JF Eisenbarth GS 《Nature》2005,435(7039):220-223
A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens. 相似文献
10.
Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 总被引:25,自引:0,他引:25
Yamamoto M Sato S Hemmi H Sanjo H Uematsu S Kaisho T Hoshino K Takeuchi O Kobayashi M Fujita T Takeda K Akira S 《Nature》2002,420(6913):324-329
Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4. 相似文献