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31.
de Castro RO Zhang J Groves JR Barbu EA Siraganian RP 《The Journal of biological chemistry》2012,287(11):8194-8204
Activation of the high affinity IgE-binding receptor (FcεRI) results in the tyrosine phosphorylation of two conserved tyrosines located close to the COOH terminus of the protein-tyrosine kinase Syk. Synthetic peptides representing the last 10 amino acids of the tail of Syk with these two tyrosines either nonphosphorylated or phosphorylated were used to precipitate proteins from mast cell lysates. Proteins specifically precipitated by the phosphorylated peptide were identified by mass spectrometry. These included the adaptor proteins SLP-76, Nck-1, Grb2, and Grb2-related adaptor downstream of Shc (GADS) and the protein phosphatases SHIP-1 and TULA-2 (also known as UBASH3B or STS-1). The presence of these in the precipitates was further confirmed by immunoblotting. Using the peptides as probes in far Western blots showed direct binding of the phosphorylated peptide to Nck-1 and SHIP-1. Immunoprecipitations suggested that there were complexes of these proteins associated with Syk especially after receptor activation; in these complexes are Nck, SHIP-1, SLP-76, Grb2, and TULA-2 (UBASH3B or STS-1). The decreased expression of TULA-2 by treatment of mast cells with siRNA increased the FcεRI-induced tyrosine phosphorylation of the activation loop tyrosines of Syk and the phosphorylation of phospholipase C-γ2. There was parallel enhancement of the receptor-induced degranulation and activation of nuclear factor for T cells or nuclear factor κB, indicating that TULA-2, like SHIP-1, functions as a negative regulator of FcεRI signaling in mast cells. Therefore, once phosphorylated, the terminal tyrosines of Syk bind complexes of proteins that are positive and negative regulators of signaling in mast cells. 相似文献
32.
mtDNA diversity in rhesus monkeys reveals overestimates of divergence time and paraphyly with neighboring species 总被引:4,自引:0,他引:4
Reconstructions of the human-African great ape phylogeny by using
mitochondrial DNA (mtDNA) have been subject to considerable debate. One
confounding factor may be the lack of data on intraspecific variation. To
test this hypothesis, we examined the effect of intraspecific mtDNA
diversity on the phylogenetic reconstruction of another Plio- Pleistocene
radiation of higher primates, the fascicularis group of macaque (Macaca)
monkey species. Fifteen endonucleases were used to identify 10 haplotypes
of 40-47 restriction sites in M. mulatta, which were compared with similar
data for the other members of this species group. Interpopulational,
intraspecific mtDNA diversity was large (0.5%- 4.5%), and estimates of
divergence time and branching order incorporating this variation were
substantially different from those based on single representatives of each
species. We conclude that intraspecific mtDNA diversity is substantial in
at least some primate species. Consequently, without prior information on
the extent of genetic diversity within a particular species, intraspecific
variation must be assessed and accounted for when reconstructing primate
phylogenies. Further, we question the reliability of hominoid mtDNA
phylogenies, based as they are on one or a few representatives of each
species, in an already depauperate superfamily of primates.
相似文献
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Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development 总被引:3,自引:0,他引:3
Raft S Koundakjian EJ Quinones H Jayasena CS Goodrich LV Johnson JE Segil N Groves AK 《Development (Cambridge, England)》2007,134(24):4405-4415
Temporal and spatial coordination of multiple cell fate decisions is essential for proper organogenesis. Here, we define gene interactions that transform the neurogenic epithelium of the developing inner ear into specialized mechanosensory receptors. By Cre-loxP fate mapping, we show that vestibular sensory hair cells derive from a previously neurogenic region of the inner ear. The related bHLH genes Ngn1 (Neurog1) and Math1 (Atoh1) are required, respectively, for neural and sensory epithelial development in this system. Our analysis of mouse mutants indicates that a mutual antagonism between Ngn1 and Math1 regulates the transition from neurogenesis to sensory cell production during ear development. Furthermore, we provide evidence that the transition to sensory cell production involves distinct autoregulatory behaviors of Ngn1 (negative) and Math1 (positive). We propose that Ngn1, as well as promoting neurogenesis, maintains an uncommitted progenitor cell population through Notch-mediated lateral inhibition, and Math1 irreversibly commits these progenitors to a hair-cell fate. 相似文献
35.
Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals 总被引:7,自引:0,他引:7 下载免费PDF全文
Freathy RM Weedon MN Bennett A Hypponen E Relton CL Knight B Shields B Parnell KS Groves CJ Ring SM Pembrey ME Ben-Shlomo Y Strachan DP Power C Jarvelin MR McCarthy MI Davey Smith G Hattersley AT Frayling TM 《American journal of human genetics》2007,80(6):1150-1161
The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation. 相似文献
36.
A miniaturised parallel-plate shearing apparatus for the measurement of cell adhesion 总被引:2,自引:0,他引:2
The design and construction of a miniaturised shearing apparatus is described. Cultures (24 h) of an established epithelial cell line (BEB) were exposed to flow conditions in the shearing chamber at 37 degrees C, and subsequently glass coverslip cultures were prepared for photography. The critical shear radius (CSR) was determined by densitometry from a negative film and the minimum distraction force (MDF) at the CSR calculated using predetermined viscosity values of the flow medium. The mean calculated MDF of BEB cells ranged from 1.04-1.36 Nm-2, and was independent of the culture inoculation density (9 to 37 X 10(4) cells cm-2) and the time (5-20 min) of exposure to shearing conditions. The MDF was increased to 3.3 Nm-2 by a 30 min exposure of cultures to concanavalin A (50 micrograms ml-1), and this effect was abolished by treating with mannose (0.05 M). The results demonstrated that the radial flow chamber principle is applicable to the measurement of cell to substratum adhesion of cultured mammalian cells. 相似文献
37.
Three new proteins have now been isolated from goat milk obtained after colchicine is infused into the mammary gland. Two of the proteins are proline-rich, and a third is a very acidic phosphoprotein. One of the proline-rich proteins is related compositionally to a sheep colostrum proline-rich protein, which has been shown to have a regulatory effect on the immune response (Janusz, M., Stavoscik, K., Zimecki, M., Wieczorek, Z., and Lisowski, J. (1981) Biochem. J. 199, 9-15). Other aspects of colchicine-treated milks are described. 相似文献
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There is a need for safe medications that can effectively support recovery by treating symptoms of protracted abstinence that may precipitate relapse in alcoholics, e.g. craving and disturbances in sleep and mood. This proof-of-concept study reports on the effectiveness of gabapentin 1200 mg for attenuating these symptoms in a non-treatment-seeking sample of cue-reactive, alcohol-dependent individuals. Subjects were 33 paid volunteers with current Diagnostic and Statistical Manual of Mental Disorders-IV alcohol dependence and a strength of craving rating 1 SD or greater for alcohol than water cues. Subjects were randomly assigned to gabapentin or placebo for 1 week and then participated in a within-subjects trial where each was exposed to standardized sets of pleasant, neutral and unpleasant visual stimuli followed by alcohol or water cues. Gabapentin was associated with significantly greater reductions than placebo on several measures of subjective craving for alcohol as well as for affectively evoked craving. Gabapentin was also associated with significant improvement on several measures of sleep quality. Side effects were minimal, and gabapentin effects were not found to resemble any major classes of abused drugs. Results suggest that gabapentin may be effective for treating the protracted abstinence phase in alcohol dependence and that a randomized clinical trial would be an appropriate next step. The study also suggests the value of cue-reactivity studies as proof-of-concept screens for potential antirelapse drugs. 相似文献