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61.
Kim S Poursine-Laurent J Truscott SM Lybarger L Song YJ Yang L French AR Sunwoo JB Lemieux S Hansen TH Yokoyama WM 《Nature》2005,436(7051):709-713
Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells. 相似文献
62.
63.
Cases of convergent evolution that involve changes in the same developmental pathway, called parallelism, provide evidence that a limited number of developmental changes are available to evolve a particular phenotype. To our knowledge, in no case are the genetic changes underlying morphological convergence understood. However, morphological convergence is not generally assumed to imply developmental parallelism. Here we investigate a case of convergence of larval morphology in insects and show that the loss of particular trichomes, observed in one species of the Drosophila melanogaster species group, has independently evolved multiple times in the distantly related D. virilis species group. We present genetic and gene expression data showing that regulatory changes of the shavenbaby/ovo (svb/ovo) gene underlie all independent cases of this morphological convergence. Our results indicate that some developmental regulators might preferentially accumulate evolutionary changes and that morphological parallelism might therefore be more common than previously appreciated. 相似文献
64.
Mutations in NOTCH1 cause aortic valve disease 总被引:2,自引:0,他引:2
Garg V Muth AN Ransom JF Schluterman MK Barnes R King IN Grossfeld PD Srivastava D 《Nature》2005,437(7056):270-274
65.
The transcription factor Engrailed-2 guides retinal axons 总被引:1,自引:0,他引:1
Brunet I Weinl C Piper M Trembleau A Volovitch M Harris W Prochiantz A Holt C 《Nature》2005,438(7064):94-98
66.
Desrosiers MP Kielczewska A Loredo-Osti JC Adam SG Makrigiannis AP Lemieux S Pham T Lodoen MB Morgan K Lanier LL Vidal SM 《Nature genetics》2005,37(6):593-599
Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells. 相似文献
67.
Aubin I Adams CP Opsahl S Septier D Bishop CE Auge N Salvayre R Negre-Salvayre A Goldberg M Guénet JL Poirier C 《Nature genetics》2005,37(8):803-805
The mouse mutation fragilitas ossium (fro) leads to a syndrome of severe osteogenesis and dentinogenesis imperfecta with no detectable collagen defect. Positional cloning of the locus identified a deletion in the gene encoding neutral sphingomyelin phosphodiesterase 3 (Smpd3) that led to complete loss of enzymatic activity. Our knowledge of SMPD3 function is consistent with the pathology observed in mutant mice and provides new insight into human pathologies. 相似文献
68.
Moreira MC Klur S Watanabe M Németh AH Le Ber I Moniz JC Tranchant C Aubourg P Tazir M Schöls L Pandolfo M Schulz JB Pouget J Calvas P Shizuka-Ikeda M Shoji M Tanaka M Izatt L Shaw CE M'Zahem A Dunne E Bomont P Benhassine T Bouslam N Stevanin G Brice A Guimarães J Mendonça P Barbot C Coutinho P Sequeiros J Dürr A Warter JM Koenig M 《Nature genetics》2004,36(3):225-227
Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination. 相似文献
69.
Trocheris I 《Nature》1982,300(5894):677
Professor Georges Mathé, a prominent French cancer researcher, has questioned the competence of the physicians involved in preliminary trials of interferon in cancer treatment. Mathé also criticized the design of the trials, which have resulted in the deaths of four out of eleven patients, and asked for the resignation of the members of the scientific council set up to monitor the experiments. IPP (Institut Pasteur Production), which produces the interferon, is performing toxicity trials with a purified derivative that could be the subject of new clinical trials. 相似文献
70.
MJ Falk Q Zhang E Nakamaru-Ogiso C Kannabiran Z Fonseca-Kelly C Chakarova I Audo DS Mackay C Zeitz AD Borman M Staniszewska R Shukla L Palavalli S Mohand-Said NH Waseem S Jalali JC Perin E Place J Ostrovsky R Xiao SS Bhattacharya M Consugar AR Webster JA Sahel AT Moore EL Berson Q Liu X Gai EA Pierce 《Nature genetics》2012,44(9):1040-1045
Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss. Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis. Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA. 相似文献