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Proteins governing cell death form the basis of many normal processes and contribute to the pathogenesis of many diseases when dysregulated. Here we report the cloning of a novel human CED-4-like gene, CLAN, and several of its alternatively spliced isoforms. These caspase-associated recruitment domain (CARD)-containing proteins are expressed at varying degrees in normal human tissues and may contribute to a number of intracellular processes including apoptosis, cytokine processing, and NF-κB activation. The CARD of the CLAN proteins binds a number of other CARD-containing proteins including caspase-1, BCL10, NOD2, and NAC. Once their physiologic functions are uncovered, CLAN proteins may prove to be valuable therapeutic targets. 相似文献
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Danielle C. Alcéna James J. Kobie Denise A. Kaminski Alexander F. Rosenberg Jonelle L. Mattiacio Matthew Brewer Stephen Dewhurst Carrie Dykes Xia Jin Michael C. Keefer Ignacio Sanz 《PloS one》2013,8(12)
Potent HIV-1 specific broadly neutralizing antibodies (BNA) are uncommon in HIV infected individuals, and have proven hard to elicit by vaccination. Several, isolated monoclonal BNA are polyreactive and also recognize self-antigens, suggesting a breach of immune tolerance in persons living with HIV (PLWH). Persons with systemic lupus erythematosus (SLE) often have elevated levels of autoreactive antibodies encoded by the VH4-34 heavy chain immunoglobulin gene whose protein product can be detected by the 9G4 rat monoclonal antibody. We have recently found that levels of these “9G4+” antibodies are also elevated in PLWH. However, the putative autoreactive nature of these antibodies and the relationship of such reactivities with HIV neutralization have not been investigated. We therefore examined the autoreactivity and HIV neutralization potential of 9G4+ antibodies from PLWH. Results show that 9G4+ antibodies from PLWH bound to recombinant HIV-1 envelope (Env) and neutralized viral infectivity in vitro, whereas 9G4+ antibodies from persons with SLE did not bind to Env and failed to neutralize viral infectivity. In addition, while 9G4+ antibodies from PLWH retained the canonical anti-i reactivity that mediates B cell binding, they did not display other autoreactivities common to SLE 9G4+ antibodies, such as binding to cardiolipin and DNA and had much lower reactivity with apoptotic cells. Taken together, these data indicate that the autoreactivity of 9G4+ antibodies from PLWH is distinct from that of SLE patients, and therefore, their expansion is not due to a general breakdown of B cell tolerance but is instead determined in a more disease-specific manner by self-antigens that become immunogenic in the context of, and possibly due to HIV infection. Further studies of 9G4+ B cells may shed light on the regulation of B cell tolerance and interface between the generation of specific autoreactivities and the induction of antiviral immunity in persons living with HIV. 相似文献
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The aim of this study was to investigate aging-related changes in the contribution of genetic and environmental influences to hand-grip strength in late adulthood. Subjects in this study are 152 intact twin pairs (77 monozygotic and 75 dizygotic pairs) from the National Heart, Lung, and Blood Institute Twin Study assessed repeatedly for hand-grip strength at mean ages of 63 and 73 yr. Structural equation genetic modeling was used to investigate stability and change in the genetic and environmental components of variance of hand-grip strength in late adulthood. Average decline in strength over the 10 yr of follow-up was -1.05+/-6.8 (SD) kg and was highly significant (P = 0.003). The test-retest correlation between baseline and follow-up grip strength was 0.62 (P<0.001). Bivariate genetic modeling found significant genetic and shared environmental stability in hand-grip strength over the 10 yr of follow-up, with genetic and shared environmental influences accounting for 35 and 48%, respectively, of the test-retest phenotypic correlation. We conclude from these results that stability in hand-grip strength in late adulthood is due primarily to continuity of genetic and familial influences. 相似文献
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