排序方式: 共有35条查询结果,搜索用时 16 毫秒
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Steinbusch LK Schwenk RW Ouwens DM Diamant M Glatz JF Luiken JJ 《Cellular and molecular life sciences : CMLS》2011,68(15):2525-2538
Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose
transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored
in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well
as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly
affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized
at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate
uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences
in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved
in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both
GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking
components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development
of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy. 相似文献
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Tschöp M Castañeda TR Joost HG Thöne-Reineke C Ortmann S Klaus S Hagan MM Chandler PC Oswald KD Benoit SC Seeley RJ Kinzig KP Moran TH Beck-sickinger AG Koglin N Rodgers RJ Blundell JE Ishii Y Beattie AH Holch P Allison DB Raun K Madsen K Wulff BS Stidsen CE Birringer M Kreuzer OJ Schindler M Arndt K Rudolf K Mark M Deng XY Whitcomb DC Halem H Taylor J Dong J Datta R Culler M Craney S Flora D Smiley D Heiman ML Withcomb DC 《Nature》2004,430(6996):1 p following 165; discussion 2 p following 165
Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36. 相似文献
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Singh N Ebrahimi FA Gimelbrant AA Ensminger AW Tackett MR Qi P Gribnau J Chess A 《Nature genetics》2003,33(3):339-341
Random monoallelic expression and asynchronous replication define an unusual class of autosomal mammalian genes. We show that every cell has randomly chosen either the maternal or paternal copy of each given autosome pair, such that alleles of these genes scattered across the chosen chromosome replicate earlier than the alleles on the homologous chromosome. Thus, chromosome-pair non-equivalence, rather than being limited to X-chromosome inactivation, is a fundamental property of mouse chromosomes. 相似文献
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Summary 3-H-tolbutamide was distributed in a volume exceeding the space occupied by 14-C-sucrose in islets as well as in liver, kidney, muscle, and fat. In contrast to previous reports, the findings suggest that tolbutamide is not restricted to the extracellular space of islets. 相似文献
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Epac proteins (exchange proteins directly activated by cAMP) are guanine-nucleotide-exchange factors (GEFs) for the small GTP-binding proteins Rap1 and Rap2 that are directly regulated by the second messenger cyclic AMP and function in the control of diverse cellular processes, including cell adhesion and insulin secretion. Here we report the three-dimensional structure of full-length Epac2, a 110-kDa protein that contains an amino-terminal regulatory region with two cyclic-nucleotide-binding domains and a carboxy-terminal catalytic region. The structure was solved in the absence of cAMP and shows the auto-inhibited state of Epac. The regulatory region is positioned with respect to the catalytic region by a rigid, tripartite beta-sheet-like structure we refer to as the 'switchboard' and an ionic interaction we call the 'ionic latch'. As a consequence of this arrangement, the access of Rap to the catalytic site is sterically blocked. Mutational analysis suggests a model for cAMP-induced Epac activation with rigid body movement of the regulatory region, the features of which are universally conserved in cAMP-regulated proteins. 相似文献
7.
Reverse breeding in Arabidopsis thaliana generates homozygous parental lines from a heterozygous plant 总被引:1,自引:0,他引:1
Wijnker E van Dun K de Snoo CB Lelivelt CL Keurentjes JJ Naharudin NS Ravi M Chan SW de Jong H Dirks R 《Nature genetics》2012,44(4):467-470
Traditionally, hybrid seeds are produced by crossing selected inbred lines. Here we provide a proof of concept for reverse breeding, a new approach that simplifies meiosis such that homozygous parental lines can be generated from a vigorous hybrid individual. We silenced DMC1, which encodes the meiotic recombination protein DISRUPTED MEIOTIC cDNA1, in hybrids of A. thaliana, so that non-recombined parental chromosomes segregate during meiosis. We then converted the resulting gametes into adult haploid plants, and subsequently into homozygous diploids, so that each contained half the genome of the original hybrid. From 36 homozygous lines, we selected 3 (out of 6) complementing parental pairs that allowed us to recreate the original hybrid by intercrossing. In addition, this approach resulted in a complete set of chromosome-substitution lines. Our method allows the selection of a single choice offspring from a segregating population and preservation of its heterozygous genotype by generating homozygous founder lines. 相似文献
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Rosendahl J Witt H Szmola R Bhatia E Ozsvári B Landt O Schulz HU Gress TM Pfützer R Löhr M Kovacs P Blüher M Stumvoll M Choudhuri G Hegyi P te Morsche RH Drenth JP Truninger K Macek M Puhl G Witt U Schmidt H Büning C Ockenga J Kage A Groneberg DA Nickel R Berg T Wiedenmann B Bödeker H Keim V Mössner J Teich N Sahin-Tóth M 《Nature genetics》2008,40(1):78-82
Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. 相似文献
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