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排序方式: 共有63条查询结果,搜索用时 140 毫秒
41.
42.
The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer 总被引:18,自引:0,他引:18
Lipkin SM Rozek LS Rennert G Yang W Chen PC Hacia J Hunt N Shin B Fodor S Kokoris M Greenson JK Fearon E Lynch H Collins F Gruber SB 《Nature genetics》2004,36(7):694-699
Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G-->C, resulting in the amino acid substitution D132H) in approximately 1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-->C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed. 相似文献
43.
Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus 总被引:39,自引:0,他引:39
Long-term potentiation (LTP) is a widely studied model of the synaptic basis of information storage in the mammalian brain. The induction of LTP is triggered by the postsynaptic entry of calcium through the channel associated with the N-methyl-D-aspartate (NMDA) receptor, whereas its maintenance is mediated, at least in part, by presynaptic mechanisms. To explain how postsynaptic events can lead to an increase in transmitter release, we have postulated the existence of a retrograde messenger to carry information from the postsynaptic side of the synapse to recently active presynaptic terminals. Candidates for a retrograde messenger include arachidonic acid or one of its lipoxygenase metabolites. Here we report that weak activation of the perforant path, when given in the presence of arachidonic acid, leads to a slow-onset persistent increase in synaptic efficacy both in vivo and in vitro. The activity-dependent potentiation thus produced is accompanied by an increase in the release of glutamate, and is non-additive with tetanus-induced LTP. These observations indicate a role for arachidonic acid as a retrograde messenger in the later, but not the initial, stages of LTP. 相似文献
44.
Identification of receptors for neuromedin U and its role in feeding 总被引:19,自引:0,他引:19
Howard AD Wang R Pong SS Mellin TN Strack A Guan XM Zeng Z Williams DL Feighner SD Nunes CN Murphy B Stair JN Yu H Jiang Q Clements MK Tan CP McKee KK Hreniuk DL McDonald TP Lynch KR Evans JF Austin CP Caskey CT Van der Ploeg LH Liu Q 《Nature》2000,406(6791):70-74
Neuromedin U (NMU) is a neuropeptide with potent activity on smooth muscle which was isolated first from porcine spinal cord and later from other species. It is widely distributed in the gut and central nervous system. Peripheral activities of NMU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. An NMU receptor has not been molecularly identified. Here we show that the previously described orphan G-protein-coupled receptor FM-3 (ref. 15) and a newly discovered one (FM-4) are cognate receptors for NMU. FM-3, designated NMU1R, is abundantly expressed in peripheral tissues whereas FM-4, designated NMU2R, is expressed in specific regions of the brain. NMU is expressed in the ventromedial hypothalamus in the rat brain, and its level is significantly reduced following fasting. Intracerebroventricular administration of NMU markedly suppresses food intake in rats. These findings provide a molecular basis for the biochemical activities of NMU and may indicate that NMU is involved in the central control of feeding. 相似文献
45.
A novel endothelial-derived lipase that modulates HDL metabolism 总被引:31,自引:0,他引:31
Jaye M Lynch KJ Krawiec J Marchadier D Maugeais C Doan K South V Amin D Perrone M Rader DJ 《Nature genetics》1999,21(4):424-428
High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease. At least 50% of the variation in HDL cholesterol levels is genetically determined, but the genes responsible for variation in HDL levels have not been fully elucidated. Lipoprotein lipase (LPL) and hepatic lipase (HL), two members of the triacylglyerol (TG) lipase family, both influence HDL metabolism and the HL (LIPC) locus has been associated with variation in HDL cholesterol levels in humans. We describe here the cloning and in vivo functional analysis of a new member of the TG lipase family. In contrast to other family members, this new lipase is synthesized by endothelial cells in vitro and thus has been termed endothelial lipase (encoded by the LIPG gene). EL is expressed in vivo in organs including liver, lung, kidney and placenta, but not in skeletal muscle. In contrast to LPL and HL, EL has a lid of only 19 residues. EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-I. The endothelial expression, enzymatic profile and in vivo effects of EL suggest that it may have a role in lipoprotein metabolism and vascular biology. 相似文献
46.
Mossé YP Laudenslager M Longo L Cole KA Wood A Attiyeh EF Laquaglia MJ Sennett R Lynch JE Perri P Laureys G Speleman F Kim C Hou C Hakonarson H Torkamani A Schork NJ Brodeur GM Tonini GP Rappaport E Devoto M Maris JM 《Nature》2008,455(7215):930-935
Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy. 相似文献
47.
48.
Hollingworth P Harold D Sims R Gerrish A Lambert JC Carrasquillo MM Abraham R Hamshere ML Pahwa JS Moskvina V Dowzell K Jones N Stretton A Thomas C Richards A Ivanov D Widdowson C Chapman J Lovestone S Powell J Proitsi P Lupton MK Brayne C Rubinsztein DC Gill M Lawlor B Lynch A Brown KS Passmore PA Craig D McGuinness B Todd S Holmes C Mann D Smith AD Beaumont H Warden D Wilcock G Love S Kehoe PG Hooper NM Vardy ER Hardy J Mead S Fox NC Rossor M Collinge J Maier W Jessen F Rüther E Schürmann B 《Nature genetics》2011,43(5):429-435
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)). 相似文献
49.
Gehrig SM van der Poel C Sayer TA Schertzer JD Henstridge DC Church JE Lamon S Russell AP Davies KE Febbraio MA Lynch GS 《Nature》2012,484(7394):394-398
Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies. 相似文献
50.
Barouch DH Liu J Li H Maxfield LF Abbink P Lynch DM Iampietro MJ SanMiguel A Seaman MS Ferrari G Forthal DN Ourmanov I Hirsch VM Carville A Mansfield KG Stablein D Pau MG Schuitemaker H Sadoff JC Billings EA Rao M Robb ML Kim JH Marovich MA Goudsmit J Michael NL 《Nature》2012,482(7383):89-93
Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys. 相似文献