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排序方式: 共有217条查询结果,搜索用时 15 毫秒
51.
Kenia Pedrosa Nunes Christine S. Rigsby R. Clinton Webb 《Cellular and molecular life sciences : CMLS》2010,67(22):3823-3836
RhoA/Rho-kinase pathway plays an important role in many pathological conditions. RhoA participates in the regulation of smooth
muscle tone and activates many downstream kinases. The best characterized are the serine/threonine kinase isoforms (Rho-kinase
or ROCK), ROCKα/ROCK2 and ROCKβ/ROCK1. ROCK is necessary for diverse functions such as local blood flow, arterial/pulmonary
blood pressure, airway resistance and intestinal peristalsis. ROCK activation permits actin/myosin interactions and smooth
muscle cells contraction by maintaining the activity of myosin light-chain kinase, independently of the free cytosolic calcium
level. The sensitization of smooth muscle myofilaments to calcium has been implicated in many pathological states, such as
hypertension, diabetes, heart attack, stroke, pulmonary hypertension, erectile dysfunction, and cancer. The focus of this
review is on the involvement of RhoA/Rho-kinase in diseases. We will briefly describe the ROCK isoforms and the role of RhoA/Rho-kinase
in the vasculature, before exploring the most recent findings regarding this pathway and various diseases. 相似文献
52.
This study examined the role of Rab5a GTPase in regulating hCG-induced internalization and trafficking of the hCG-LH receptor
complex in transfected 293T cells. Coexpression of wild-type Rab5a (WT) or constitutively active Rab5a (Q79L) with LHR significantly
increased hCG-induced LHR internalization. Conversely, coexpression of dominant negative Rab5a (S34N) with LHR reduced internalization.
Confocal microscopy showed LHR colocalizing with Rab5a (WT) and Rab5a (Q79L) in punctuate structures. Coexpression of Rab5a
(WT) and Rab5a (Q79L) with LHR significantly increased colocalization of LHR in early endosomes. Conversely, dominant negative
Rab5a (S34N) decreased this colocalization. While Rab5a stimulated internalization of LHR, it significantly decreased LHR
recycling to the cell surface and increased degradation. Dominant negative Rab5a (S34N) increased LHR recycling and decreased
degradation. These results suggest that Rab5a plays a role in LHR trafficking by facilitating internalization and fusion to
early endosomes, increasing the degradation of internalized receptor resulting in a reduction in LHR recycling. 相似文献
53.
Rivas MA Beaudoin M Gardet A Stevens C Sharma Y Zhang CK Boucher G Ripke S Ellinghaus D Burtt N Fennell T Kirby A Latiano A Goyette P Green T Halfvarson J Haritunians T Korn JM Kuruvilla F Lagacé C Neale B Lo KS Schumm P Törkvist L;National Institute of Diabetes Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium 《Nature genetics》2011,43(11):1066-1073
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. 相似文献
54.
TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis 总被引:2,自引:0,他引:2
Kabashi E Valdmanis PN Dion P Spiegelman D McConkey BJ Vande Velde C Bouchard JP Lacomblez L Pochigaeva K Salachas F Pradat PF Camu W Meininger V Dupre N Rouleau GA 《Nature genetics》2008,40(5):572-574
Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis. 相似文献
55.
Park CC Ahn S Bloom JS Lin A Wang RT Wu T Sekar A Khan AH Farr CJ Lusis AJ Leahy RM Lange K Smith DJ 《Nature genetics》2008,40(4):421-429
We mapped regulatory loci for nearly all protein-coding genes in mammals using comparative genomic hybridization and expression array measurements from a panel of mouse-hamster radiation hybrid cell lines. The large number of breaks in the mouse chromosomes and the dense genotyping of the panel allowed extremely sharp mapping of loci. As the regulatory loci result from extra gene dosage, we call them copy number expression quantitative trait loci, or ceQTLs. The -2log10P support interval for the ceQTLs was <150 kb, containing an average of <2-3 genes. We identified 29,769 trans ceQTLs with -log10P > 4, including 13 hotspots each regulating >100 genes in trans. Further, this work identifies 2,761 trans ceQTLs harboring no known genes, and provides evidence for a mode of gene expression autoregulation specific to the X chromosome. 相似文献
56.
Ross MT Grafham DV Coffey AJ Scherer S McLay K Muzny D Platzer M Howell GR Burrows C Bird CP Frankish A Lovell FL Howe KL Ashurst JL Fulton RS Sudbrak R Wen G Jones MC Hurles ME Andrews TD Scott CE Searle S Ramser J Whittaker A Deadman R Carter NP Hunt SE Chen R Cree A Gunaratne P Havlak P Hodgson A Metzker ML Richards S Scott G Steffen D Sodergren E Wheeler DA Worley KC Ainscough R Ambrose KD Ansari-Lari MA Aradhya S Ashwell RI Babbage AK Bagguley CL Ballabio A Banerjee R Barker GE Barlow KF 《Nature》2005,434(7031):325-337
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence. 相似文献
57.
Sweet-Cordero A Mukherjee S Subramanian A You H Roix JJ Ladd-Acosta C Mesirov J Golub TR Jacks T 《Nature genetics》2005,37(1):48-55
Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA-mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease. 相似文献
58.
J. Gillman Christine Gilbert Isobel Spence 《Cellular and molecular life sciences : CMLS》1955,11(4):157-158
Zusammenfassung Die Entstehung von Reticulosarkom bei Ratten nach mehrmaliger Injektion von Trypanblau kann unterdrückt werden durch Entkräftung, Verabreichung anti-thyreoidaler Mittel und durch alle andern Faktoren, welche den Stoffwechsel herabsetzen. 相似文献
59.
Uncertain sinks in the shrubs 总被引:12,自引:0,他引:12
60.
Large-scale features of ocean circulation, such as deep water formation in the northern North Atlantic Ocean, are known to regulate the long-term physical uptake of CO2 from the atmosphere by moving CO2-laden surface waters into the deep ocean. But the importance of CO2 uptake into water masses that ventilate shallower ocean depths, such as subtropical mode waters of the subtropical gyres, are poorly quantified. Here we report that, between 1988 and 2001, dissolved CO2 concentrations in subtropical mode waters of the North Atlantic have increased at a rate twice that expected from these waters keeping in equilibrium with increasing atmospheric CO2. This accounts for an extra 0.4-2.8 Pg C (1 Pg = 10(15) g) over this period (that is, about 0.03-0.24 Pg C yr(-1)), equivalent to 3-10% of the current net annual ocean uptake of CO2 (ref. 3). We suggest that the lack of strong winter mixing events, to greater than 300 m in depth, in recent decades is responsible for this accumulation, which would otherwise disturb the mode water layer and liberate accumulated CO2 back to the atmosphere. However, future climate variability (which influences subtropical mode water formation) and changes in the North Atlantic Oscillation (leading to a return of deep winter mixing events) may reduce CO2 accumulation in subtropical mode waters. We therefore conclude that, although CO2 uptake by subtropical mode waters in the North Atlantic--and possibly elsewhere--does not always represent a long-term CO2 sink, the phenomenon is likely to contribute substantially to interannual variability in oceanic CO2 uptake. 相似文献