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21.
beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass 总被引:22,自引:0,他引:22
Kulkarni RN Holzenberger M Shih DQ Ozcan U Stoffel M Magnuson MA Kahn CR 《Nature genetics》2002,31(1):111-115
Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function. 相似文献
22.
Mechanical properties and low cycle fatigue are two factors that must be considered in developin gnew type steel for shock absorption. Process capability and process control are significant factors in achieving the purpose of research and development programs. Often-used evaluation methods failed to measure processyield and process centering ; so this paper uses Taguchi loss function as basis to establish an evaluation methodand the steps for assessing the quality of mechanical properties and process control of an iron and steel manu-facturer. The establishment of this method can serve the research and development and manufacturing industry and lay a foundation in enhancing its process control ability to select better manufacturing processes that are more reliable than decision making by using the other commonly used methods. 相似文献
23.
Four new fossil species of the family Ommatidae from the Yixian Formation of western Liaoning, China are described. Two of them belong to tribe Brochocoleini: Brochocoleus sulcatus sp. nov. and Brochocoleus angustus sp. nov. The other two refer to tribe Ommatini: Cionocoleus planiusculus sp. nov. and Cionocoleus cervicalis sp. nov. The diagnosis of Brochocoleus and Cionocoleus, respectively, are revised. A preliminary analysis of geographical distribution suggests a possible migration pathway of the genus Brochocoleus. The relationship between the genus Cionocoleus and the extant family Crowsoniellidae is briefly discussed. 相似文献
24.
Distal residues in the oxygen binding site of haemoglobin studied by protein engineering 总被引:4,自引:0,他引:4
K Nagai B Luisi D Shih G Miyazaki K Imai C Poyart A De Young L Kwiatkowsky R W Noble S H Lin 《Nature》1987,329(6142):858-860
The geometries of the Fe-O2 and Fe-CO bonds in myoglobin and haemoglobin differ significantly from those in free porphyrin model compounds. It has been suggested that steric hindrance by Val-E11 and His-E7 and a hydrogen bond between His-E7 and oxygen affect the geometry and electronic state of the Fe-ligand bond, and that these interactions may be important in controlling oxygen affinity. We have produced mutant haemoglobins in E. coli having Val(67 beta)E11 replaced by Ala, Met, Leu or Ile and His(58 beta)E7 by Gln, Val or Gly. We have studied the effect of these mutations on the equilibrium and kinetics of ligand binding. The conformation of the new side chains and their effect on the protein structure have been examined by X-ray crystallography, and the vibrational properties of the Fe-CO bond observed by resonance Raman spectroscopy. We found that the steric hindrance of ligand binding by the E11 residue and the polarity of the E7 residue in the beta subunit are critical for fine-tuning ligand affinity. 相似文献
25.
Wang SH Shih YL Ko WC Wei YH Shih CM 《Cellular and molecular life sciences : CMLS》2008,65(22):3640-3652
The cytotoxicity of cadmium (Cd) induced autophagy and apoptosis in MES-13 cells was determined by flow cytometry. Autophagy
was also assessed by formation of autophagosomes and processing of LC3. Pharmacological inhibition of autophagy resulted in
increased of cell viability, suggesting autophagy plays a role in cell death in Cd-treated mesangial cells. Cd also induced
a rapid elevation in cytosolic calcium ([Ca2+]i ), and modulation of [Ca2+]i via treatment with IP
3R inhibitor or knockdown of calcineurin resulted in a change in the proportion of cell death, suggesting that the release
of calcium from the ER plays a crucial role in Cd-induced cell death. Inhibition of Cd-induced ERK activation by PD 98059
suppressed Cd-induced autophagy, and BAPTA-AM eliminated activation of ERK. BAPTA-AM also inhibited Cd-induced mitochondrial
depolarization and activation of caspases. These findings demonstrated that Cd induces both autophagy and apoptosis through
elevation of [Ca2+]i, followed by Ca2+-ERK and Ca2+-mitochondria-caspase signaling pathways.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 05 July 2008; received after revision 25 August 2008; accepted 17 September 2008 相似文献
26.
T-cell co-stimulation through B7RP-1 and ICOS 总被引:65,自引:0,他引:65
Yoshinaga SK Whoriskey JS Khare SD Sarmiento U Guo J Horan T Shih G Zhang M Coccia MA Kohno T Tafuri-Bladt A Brankow D Campbell P Chang D Chiu L Dai T Duncan G Elliott GS Hui A McCabe SM Scully S Shahinian A Shaklee CL Van G Mak TW Senaldi G 《Nature》1999,402(6763):827-832
T-cell activation requires co-stimulation through receptors such as CD28 and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine costimulatory receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-I do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response. 相似文献
27.
Northcott PA Shih DJ Peacock J Garzia L Morrissy AS Zichner T Stütz AM Korshunov A Reimand J Schumacher SE Beroukhim R Ellison DW Marshall CR Lionel AC Mack S Dubuc A Yao Y Ramaswamy V Luu B Rolider A Cavalli FM Wang X Remke M Wu X Chiu RY Chu A Chuah E Corbett RD Hoad GR Jackman SD Li Y Lo A Mungall KL Nip KM Qian JQ Raymond AG Thiessen NT Varhol RJ Birol I Moore RA Mungall AJ Holt R Kawauchi D Roussel MF Kool M Jones DT Witt H Fernandez-L A Kenney AM Wechsler-Reya RJ Dirks P Aviv T 《Nature》2012,488(7409):49-56
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. 相似文献
28.
Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2 总被引:1,自引:0,他引:1
CA Doege K Inoue T Yamashita DB Rhee S Travis R Fujita P Guarnieri G Bhagat WB Vanti A Shih RL Levine S Nik EI Chen A Abeliovich 《Nature》2012,488(7413):652-655
29.
30.
Résumé On a développé und méthode simple pour déteminer sans chromatographie en colonne le testostérone du plasma. La purification a été faite par préextraction avec l'hexane. Un antisérum contre le testostérone a été produit chez des lapins inoculés avec des conjugués de testostérone-3-oxine et d'albumine de sérum bovin. 相似文献