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Over the last two decades the molecular and cellular mechanisms underlying T cell activation, expansion, differentiation,
and memory formation have been intensively investigated. These studies revealed that the generation of memory T cells is critically
impacted by a number of factors, including the magnitude of the inflammatory response and cytokine production, the type of
dendritic cell [DC] that presents the pathogen derived antigen, their maturation status, and the concomitant provision of
costimulation. Nevertheless, the primary stimulus leading to T cell activation is generated through the T cell receptor [TCR]
following its engagement with a peptide MHC ligand [pMHC]. The purpose of this review is to highlight classical and recent
findings on how antigen recognition, the degree of TCR stimulation, and intracellular signal transduction pathways impact
the formation of effector and memory T cells. 相似文献
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HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus 总被引:21,自引:0,他引:21
Altfeld M Allen TM Yu XG Johnston MN Agrawal D Korber BT Montefiori DC O'Connor DH Davis BT Lee PK Maier EL Harlow J Goulder PJ Brander C Rosenberg ES Walker BD 《Nature》2002,420(6914):434-439
Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development. 相似文献
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Mutations of the BRAF gene in human cancer 总被引:2,自引:0,他引:2
Davies H Bignell GR Cox C Stephens P Edkins S Clegg S Teague J Woffendin H Garnett MJ Bottomley W Davis N Dicks E Ewing R Floyd Y Gray K Hall S Hawes R Hughes J Kosmidou V Menzies A Mould C Parker A Stevens C Watt S Hooper S Wilson R Jayatilake H Gusterson BA Cooper C Shipley J Hargrave D Pritchard-Jones K Maitland N Chenevix-Trench G Riggins GJ Bigner DD Palmieri G Cossu A Flanagan A Nicholson A Ho JW Leung SY Yuen ST Weber BL Seigler HF Darrow TL Paterson H Marais R Marshall CJ Wooster R 《Nature》2002,417(6892):949-954
Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma. 相似文献
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Active zone material at the nervous system's synapses is situated next to synaptic vesicles that are docked at the presynaptic plasma membrane, and calcium channels that are anchored in the membrane. Here we use electron microscope tomography to show the arrangement and associations of structural components of this compact organelle at a model synapse, the frog's neuromuscular junction. Our findings indicate that the active zone material helps to dock the vesicles and anchor the channels, and that its architecture provides both a particular spatial relationship and a structural linkage between them. The structural linkage may include proteins that mediate the calcium-triggered exocytosis of neurotransmitter by the synaptic vesicles during synaptic transmission. 相似文献
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Kurt H. Meyer Ed. H. Fischer P. Bernfeld 《Cellular and molecular life sciences : CMLS》1946,2(9):362-363
Summary The -amylase of hog pancreas has been purified and the degree of purity controled by electrophoresis. The active substance is a protein which can dissociate in an unstable high molecular component and a thermostable component of low molecular weight. 相似文献
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Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski-/- mice. 总被引:2,自引:0,他引:2
Clemencia Colmenares Heidi A Heilstedt Lisa G Shaffer Stuart Schwartz Michael Berk Jeffrey C Murray Ed Stavnezer 《Nature genetics》2002,30(1):106-109
Experiments involving overexpression of Ski have suggested that this gene is involved in neural tube development and muscle differentiation. In agreement with these findings, Ski-/- mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass. Here we show that the penetrance and expressivity of the phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects and digit abnormalities, show increased penetrance in the C57BL6/J background. These phenotypes are interesting because they resemble some of the features observed in individuals diagnosed with 1p36 deletion syndrome, a disorder caused by monosomy of the short arm of human chromosome 1p (refs. 6-9). These similarities prompted us to re-examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. We found that human SKI is located at distal 1p36.3 and is deleted in all of the individuals tested so far who have this syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting. 相似文献
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Summary In an elliptical billiard there exists, in contrast to a circular one, an exception toPoincaré's recurrence theorem, in as much as the path of a billiard-ball that goes through a focus of the ellipse converges toward the long axis. 相似文献