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Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells 总被引:41,自引:0,他引:41
Mandelboim O Lieberman N Lev M Paul L Arnon TI Bushkin Y Davis DM Strominger JL Yewdell JW Porgador A 《Nature》2001,409(6823):1055-1060
Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined. NKp46 is thought to be the main activating receptor for human NK cells. Here we show that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein. 相似文献
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Dibbens LM Tarpey PS Hynes K Bayly MA Scheffer IE Smith R Bomar J Sutton E Vandeleur L Shoubridge C Edkins S Turner SJ Stevens C O'Meara S Tofts C Barthorpe S Buck G Cole J Halliday K Jones D Lee R Madison M Mironenko T Varian J West S Widaa S Wray P Teague J Dicks E Butler A Menzies A Jenkinson A Shepherd R Gusella JF Afawi Z Mazarib A Neufeld MY Kivity S Lev D Lerman-Sagie T Korczyn AD Derry CP Sutherland GR Friend K Shaw M Corbett M Kim HG Geschwind DH Thomas P Haan E Ryan S McKee S 《Nature genetics》2008,40(6):776-781
Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation. 相似文献
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The last deglaciation was abruptly interrupted by a millennial-scale reversal to glacial conditions, the Younger Dryas cold event. This cold interval has been connected to a decrease in the rate of North Atlantic Deep Water formation and to a resulting weakening of the meridional overturning circulation owing to surface water freshening. In contrast, an earlier input of fresh water (meltwater pulse 1a), whose origin is disputed, apparently did not lead to a reduction of the meridional overturning circulation. Here we analyse an ensemble of simulations of the drainage chronology of the North American ice sheet in order to identify the geographical release points of freshwater forcing during deglaciation. According to the simulations with our calibrated glacial systems model, the North American ice sheet contributed about half the fresh water of meltwater pulse 1a. During the onset of the Younger Dryas, we find that the largest combined meltwater/iceberg discharge was directed into the Arctic Ocean. Given that the only drainage outlet from the Arctic Ocean was via the Fram Strait into the Greenland-Iceland-Norwegian seas, where North Atlantic Deep Water is formed today, we hypothesize that it was this Arctic freshwater flux that triggered the Younger Dryas cold reversal. 相似文献
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McMurray HR Sampson ER Compitello G Kinsey C Newman L Smith B Chen SR Klebanov L Salzman P Yakovlev A Land H 《Nature》2008,453(7198):1112-1116
Understanding the molecular underpinnings of cancer is of critical importance to the development of targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features and induce complex changes in gene expression patterns. Genes critical to this multifaceted cellular phenotype have therefore only been identified after signalling pathway analysis or on an ad hoc basis. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signalling circuitry suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 out of 24 'cooperation response genes' were found to contribute to tumour formation in gene perturbation experiments. In contrast, only 1 in 14 perturbations of the genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations. 相似文献