Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · May 2010
Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance.
A fetus is inherently antigenic to its mother and yet is not rejected. The T regulatory (Treg) subset of CD4(+) T cells can limit immune responses and has been implicated in maternal tolerance of the fetus. Using virgin inbred mice undergoing a first syngenic pregnancy, in which only the male fetuses are antigenic, we demonstrate a maternal splenocyte proliferative response to the CD4(+) T cell restricted epitope of the male antigen (H-Y) in proportion to the fetal antigen load. ⋯ The bystander suppressive function of pregnancy-generated Tregs requires the presence of the fetal antigen, demonstrating their inherent antigen specificity. In vivo targeting of diphtheria toxin to kill Tregs leads to a lower fraction of live male offspring and a selective reduction in mass of the surviving males. Thus, Tregs generated in the context of pregnancy function in an antigen-specific manner to limit the maternal immune response to the fetus in a successful pregnancy.
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Proc. Natl. Acad. Sci. U.S.A. · May 2010
Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons.
Mammalian sweet, bitter, and umami taste is mediated by a single transduction pathway that includes a phospholipase C (PLC)beta and one cation channel, TRPM5. However, in insects such as the fruit fly, Drosophila melanogaster, it is unclear whether different tastants, such as bitter compounds, are sensed in gustatory receptor neurons (GRNs) through one or multiple ion channels, as the cation channels required in insect GRNs are unknown. Here, we set out to explore additional sensory roles for the Drosophila TRPA1 channel, which was known to function in thermosensation. ⋯ TRPA1 did not appear to be activated or inhibited directly by aristolochic acid. We found that elimination of the same PLC that leads to activation of TRPA1 in thermosensory neurons was also required in the TRPA1-expressing GRNs for avoiding aristolochic acid. Given that mammalian TRPA1 is required for responding to noxious chemicals, many of which cause pain and injury, our analysis underscores the evolutionarily conserved role for TRPA1 channels in chemical avoidance.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2010
Comment Historical ArticleCultural modernity: consensus or conundrum?
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2010
Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP.
Hypertonicity activates the transcription factor TonEBP/OREBP, resulting in increased expression of osmoprotective genes, including those responsible for accumulation of organic osmolytes and heat-shock proteins. Phosphorylation of TonEBP/OREBP contributes to its activation. Several of the kinases that are involved were previously identified, but the phosphatases were not. ⋯ SHP-1 coimmunoprecipitates with TonEBP/OREBP and vice versa, suggesting that they are physically associated in the cell. High NaCl inhibits the effect of SHP-1 on TonEBP/OREBP by increasing phosphorylation of SHP-1 on Ser591, which reduces its phosphatase activity and localization to the nucleus. Thus, TonEBP/OREBP is extensively regulated by phosphatases, including SHP-1, whose inhibition by high NaCl increases phosphorylation of TonEBP/OREBP at Y143, contributing to the nuclear localization and activation of TonEBP/OREBP.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2010
Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease.
Our previous analyses showed that allopregnanolone (APalpha) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APalpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APalpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. ⋯ APalpha reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APalpha-induced survival of neural progenitors was significantly correlated with APalpha-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Abeta, may contribute to the cognitive phenotype of AD, and that APalpha could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.