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11.
Peça J Feliciano C Ting JT Wang W Wells MF Venkatraman TN Lascola CD Fu Z Feng G 《Nature》2011,472(7344):437-442
Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice. 相似文献
12.
Ricardo F. Antunes Cláudia Brandão Gonçalo Carvalho Cristina Girão Fernando A. Arosa 《Cellular and molecular life sciences : CMLS》2009,66(20):3387-3398
Red blood cells (RBC) have emerged as a novel regulatory cell type endowed with bioactivities toward activated human T cells.
Herein we show that the RBC bioactivities act on intracellular pathways initiated by T cell receptor (TCR)-dependent and -independent
stimuli, including IL-2, IL-15, and the mixture of phorbol dibutyrate and ionomycin. The RBC bioactivities preserve the antioxidant
status and are capable of rescuing activated T cells from cell death induced by serum deprivation. They are not mediated by
glycosylphosphatidylinositol-linked receptors or sialic acids, and kinetic studies revealed that they hasten the entrance
into the cell cycle. By using cyclosporine A (CsA) and rapamycin (Rapa) we show that the RBC bioactivities are calcineurin-dependent.
Thus, treatment of T cells with CsA, but not Rapa, impaired RBC bioactivities, and preincubation of RBC with CsA completely
abolished their bioactivities. We have demonstrated that RBC carry out bioactivities that are sensitive to CsA. 相似文献
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Summary Genic activity in tetraploid members of the amphibian speciesOdontophrymus americanus is reduced to that of diploid ones. Loss of ribosomal genes, a mechanism suggested by others as a means of decreasing genetic activity, could be ruled out. The diploids and the tetraploids have almost identical proportions of their genomes complementary to (28s+18s) ribosomal RNA. 相似文献
15.
Strong evidence for a genetic basis of variation in physical performance has accumulated. Considering one of the basic tenets of evolutionary physiology--that physical performance and darwinian fitness are tightly linked--one may expect phenotypes with exceptional physiological capacities to be promoted by natural selection. Why then does physical performance remain considerably variable in human and other animal populations? Our analysis of locomotor performance in the common lizard (Lacerta vivipara) demonstrates that initial endurance (running time to exhaustion measured at birth) is indeed highly heritable, but natural selection in favour of this trait can be unexpectedly weak. A manipulation of dietary conditions unravels a proximate mechanism explaining this pattern. Fully fed individuals experience a marked reversal of performance within only one month after birth: juveniles with low endurance catch up, whereas individuals with high endurance lose their advantage. In contrast, dietary restriction allows highly endurant neonates to retain their locomotor superiority as they age. Thus, the expression of a genetic predisposition to high physical performance strongly depends on the environment experienced early in life. 相似文献
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Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis 总被引:12,自引:0,他引:12
Martinez LO Jacquet S Esteve JP Rolland C Cabezón E Champagne E Pineau T Georgeaud V Walker JE Tercé F Collet X Perret B Barbaras R 《Nature》2003,421(6918):75-79
The effect of high-density lipoprotein (HDL) in protecting against atherosclerosis is usually attributed to its role in 'reverse cholesterol transport'. In this process, HDL particles mediate the efflux and the transport of cholesterol from peripheral cells to the liver for further metabolism and bile excretion. Thus, cell-surface receptors for HDL on hepatocytes are chief partners in the regulation of cholesterol homeostasis. A high-affinity HDL receptor for apolipoprotein A-I (apoA-I) was previously identified on the surface of hepatocytes. Here we show that this receptor is identical to the beta-chain of ATP synthase, a principal protein complex of the mitochondrial inner membrane. Different experimental approaches confirm this ectopic localization of components of the ATP synthase complex and the presence of ATP hydrolase activity at the hepatocyte cell surface. Receptor stimulation by apoA-I triggers the endocytosis of holo-HDL particles (protein plus lipid) by a mechanism that depends strictly on the generation of ADP. We confirm this effect on endocytosis in perfused rat liver ex vivo by using a specific inhibitor of ATP synthase. Thus, membrane-bound ATP synthase has a previously unsuspected role in modulating the concentrations of extracellular ADP and is regulated by a principal plasma apolipoprotein. 相似文献
19.
Engert JC Bérubé P Mercier J Doré C Lepage P Ge B Bouchard JP Mathieu J Melançon SB Schalling M Lander ES Morgan K Hudson TJ Richter A 《Nature genetics》2000,24(2):120-125
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis. 相似文献
20.
Gui Y Guo G Huang Y Hu X Tang A Gao S Wu R Chen C Li X Zhou L He M Li Z Sun X Jia W Chen J Yang S Zhou F Zhao X Wan S Ye R Liang C Liu Z Huang P Liu C Jiang H Wang Y Zheng H Sun L Liu X Jiang Z Feng D Chen J Wu S Zou J Zhang Z Yang R Zhao J Xu C Yin W Guan Z Ye J Zhang H Li J Kristiansen K Nickerson ML Theodorescu D Li Y Zhang X Li S Wang J Yang H Wang J Cai Z 《Nature genetics》2011,43(9):875-878
Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer. 相似文献