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101.
A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. 总被引:81,自引:0,他引:81
N A Thornberry H G Bull J R Calaycay K T Chapman A D Howard M J Kostura D K Miller S M Molineaux J R Weidner J Aunins 《Nature》1992,356(6372):768-774
Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target. 相似文献
102.
Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41. 总被引:5,自引:0,他引:5
During biosynthesis, class II molecules of the major histocompatibility complex are associated with a nonpolymorphic protein called invariant chain, Ii, which facilitates folding of class II molecules and their exit from the endoplasmic reticulum, interferes with their association with peptide and directs their post-Golgi transport (refs 7-9). If Ii blocks class II loading with endogenous antigens in the endoplasmic reticulum and/or directs class II molecules to the exogenous antigen-loading compartment, then the co-expression of Ii should enhance the ability of class II molecules to present exogenous antigens to T cells. But data supporting a role for Ii in class II-restricted antigen presentation are controversial. Here we show that Ii can facilitate exogenous antigen presentation for a subset of antigens. Although all known functions of Ii have been ascribed to the principal form of Ii, p31, we find that in most cases antigen presentation is facilitated only by the alternatively spliced, minor form of Ii, p41. 相似文献
103.
Female mites of the species Pyemotes tritici inject an extremely potent venom into their insect prey that causes muscle-contraction and paralysis. These mites are able to paralyse insects 150,000 times their size and their venom is effective in a broad range of insect species. A toxin (TxP-I) associated with the mite venom apparatus causes immediate muscle-contractive paralysis when injected into insects but not mice. In this report, we describe the cloning, sequencing and expression of a complementary DNA (Tox-34) encoding TxP-I. Insect cells infected with a recombinant baculovirus (vEV-Tox34) expressing Tox-34 secrete three polypeptides related to TxP-I which cause paralysis on injection. Larvae infected with vEV-Tox34 become paralysed during infection, thus reflecting the potential application of this toxin gene in insect biocontrol methods. The toxin gene expression system will also allow further exploration of the neurophysiological basis of its insect-specific effects. 相似文献
104.
Peripheral deletion of self-reactive B cells 总被引:27,自引:0,他引:27
B LYMPHOCYTES are key participants in the immune response because of their specificity, their ability to take up and present antigens to T cells, and their capacity to differentiate into antibody-secreting cells. To limit reactivity to self antigens, autospecific B cells can be functionally inactivated or deleted. Developing B cells that react with membrane antigens expressed in the bone marrow are deleted from the peripheral lymphocyte pool. It is important to ascertain the fate of B cells that recognize membrane autoantigens expressed exclusively on peripheral tissues because B cells in the peripheral lymphoid organs are phenotypically and functionally distinct from bone-marrow B cells. Here we show that in immunoglobulin-transgenic mice, B cells specific for major histocompatibility complex class I antigen can be deleted if they encounter membrane-bound antigen at a post-bone-marrow stage of development. This deletion may be necessary to prevent organ-specific autoimmunity. 相似文献
105.
106.
Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. 总被引:34,自引:0,他引:34
M McClelland K E Sanderson J Spieth S W Clifton P Latreille L Courtney S Porwollik J Ali M Dante F Du S Hou D Layman S Leonard C Nguyen K Scott A Holmes N Grewal E Mulvaney E Ryan H Sun L Florea W Miller T Stoneking M Nhan R Waterston R K Wilson 《Nature》2001,413(6858):852-856
Salmonella enterica subspecies I, serovar Typhimurium (S. typhimurium), is a leading cause of human gastroenteritis, and is used as a mouse model of human typhoid fever. The incidence of non-typhoid salmonellosis is increasing worldwide, causing millions of infections and many deaths in the human population each year. Here we sequenced the 4,857-kilobase (kb) chromosome and 94-kb virulence plasmid of S. typhimurium strain LT2. The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A (S. paratyphi A) and Klebsiella pneumoniae, and hybridization of three unsequenced genomes to a microarray of S. typhimurium LT2 genes. Lateral transfer of genes is frequent, with 11% of the S. typhimurium LT2 genes missing from S. enterica serovar Typhi (S. typhi), and 29% missing from Escherichia coli K12. The 352 gene homologues of S. typhimurium LT2 confined to subspecies I of S. enterica-containing most mammalian and bird pathogens-are useful for studies of epidemiology, host specificity and pathogenesis. Most of these homologues were previously unknown, and 50 may be exported to the periplasm or outer membrane, rendering them accessible as therapeutic or vaccine targets. 相似文献
107.
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Day CL Kaufmann DE Kiepiela P Brown JA Moodley ES Reddy S Mackey EW Miller JD Leslie AJ DePierres C Mncube Z Duraiswamy J Zhu B Eichbaum Q Altfeld M Wherry EJ Coovadia HM Goulder PJ Klenerman P Ahmed R Freeman GJ Walker BD 《Nature》2006,443(7109):350-354
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection. 相似文献
108.
109.
Eight glacial cycles from an Antarctic ice core 总被引:9,自引:0,他引:9
Augustin L Barbante C Barnes PR Barnola JM Bigler M Castellano E Cattani O Chappellaz J Dahl-Jensen D Delmonte B Dreyfus G Durand G Falourd S Fischer H Flückiger J Hansson ME Huybrechts P Jugie G Johnsen SJ Jouzel J Kaufmann P Kipfstuhl J Lambert F Lipenkov VY Littot GC Longinelli A Lorrain R Maggi V Masson-Delmotte V Miller H Mulvaney R Oerlemans J Oerter H Orombelli G Parrenin F Peel DA Petit JR Raynaud D Ritz C Ruth U Schwander J Siegenthaler U Souchez R Stauffer B Steffensen JP Stenni B 《Nature》2004,429(6992):623-628
The Antarctic Vostok ice core provided compelling evidence of the nature of climate, and of climate feedbacks, over the past 420,000 years. Marine records suggest that the amplitude of climate variability was smaller before that time, but such records are often poorly resolved. Moreover, it is not possible to infer the abundance of greenhouse gases in the atmosphere from marine records. Here we report the recovery of a deep ice core from Dome C, Antarctica, that provides a climate record for the past 740,000 years. For the four most recent glacial cycles, the data agree well with the record from Vostok. The earlier period, between 740,000 and 430,000 years ago, was characterized by less pronounced warmth in interglacial periods in Antarctica, but a higher proportion of each cycle was spent in the warm mode. The transition from glacial to interglacial conditions about 430,000 years ago (Termination V) resembles the transition into the present interglacial period in terms of the magnitude of change in temperatures and greenhouse gases, but there are significant differences in the patterns of change. The interglacial stage following Termination V was exceptionally long--28,000 years compared to, for example, the 12,000 years recorded so far in the present interglacial period. Given the similarities between this earlier warm period and today, our results may imply that without human intervention, a climate similar to the present one would extend well into the future. 相似文献
110.