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Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS. 相似文献
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Zvetkova I Apedaile A Ramsahoye B Mermoud JE Crompton LA John R Feil R Brockdorff N 《Nature genetics》2005,37(11):1274-1279
Embryonic stem (ES) cells are important tools in the study of gene function and may also become important in cell therapy applications. Establishment of stable XX ES cell lines from mouse blastocysts is relatively problematic owing to frequent loss of one of the two X chromosomes. Here we show that DNA methylation is globally reduced in XX ES cell lines and that this is attributable to the presence of two active X chromosomes. Hypomethylation affects both repetitive and unique sequences, the latter including differentially methylated regions that regulate expression of parentally imprinted genes. Methylation of differentially methylated regions can be restored coincident with elimination of an X chromosome in early-passage parthenogenetic ES cells, suggesting that selection against loss of methylation may provide the basis for X-chromosome instability. Finally, we show that hypomethylation is associated with reduced levels of the de novo DNA methyltransferases Dnmt3a and Dnmt3b and that ectopic expression of these factors restores global methylation levels. 相似文献
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McKern NM Lawrence MC Streltsov VA Lou MZ Adams TE Lovrecz GO Elleman TC Richards KM Bentley JD Pilling PA Hoyne PA Cartledge KA Pham TM Lewis JL Sankovich SE Stoichevska V Da Silva E Robinson CP Frenkel MJ Sparrow LG Fernley RT Epa VC Ward CW 《Nature》2006,443(7108):218-221
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding. 相似文献
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Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells 总被引:1,自引:0,他引:1
Sensory hair cells of the mammalian organ of Corti in the inner ear do not regenerate when lost as a consequence of injury, disease, or age-related deafness. This contrasts with other vertebrates such as birds, where the death of hair cells causes surrounding supporting cells to re-enter the cell cycle and give rise to both new hair cells and supporting cells. It is not clear whether the lack of mammalian hair cell regeneration is due to an intrinsic inability of supporting cells to divide and differentiate or to an absence or blockade of regenerative signals. Here we show that post-mitotic supporting cells purified from the postnatal mouse cochlea retain the ability to divide and trans-differentiate into new hair cells in culture. Furthermore, we show that age-dependent changes in supporting cell proliferative capacity are due in part to changes in the ability to downregulate the cyclin-dependent kinase inhibitor p27(Kip1) (also known as Cdkn1b). These results indicate that postnatal mammalian supporting cells are potential targets for therapeutic manipulation. 相似文献
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Neil Ashby 《系统工程与电子技术(英文版)》1995,(4)
l'INTRo~TloNThepurposeofthisworkistoexplainhowrelativisticeffectsareaccountedforintheGlobalPositioningSystem(GPS).AlthoughclockvelocitiesaresmallandgravitationalfieldsareweakneartheEarth,theygiverisetosignificantrelativisticeffects.Theseeffectsincludesecond--orderDopplerfrequencyshiftsofclocksduetotheirrelativevelocities,gravitationalfrequencyshifts,andtheSagnaceffectduetotheEarth'srotation.Ifsucheffectsarenotaccountedforproperly,theGPSsimplywouldnotworkatallwell.Thesuccessandself--con… 相似文献
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