全文获取类型
收费全文 | 268篇 |
免费 | 28篇 |
专业分类
296篇 |
出版年
2024年 | 1篇 |
2023年 | 1篇 |
2022年 | 5篇 |
2021年 | 5篇 |
2020年 | 4篇 |
2019年 | 3篇 |
2018年 | 6篇 |
2017年 | 2篇 |
2016年 | 5篇 |
2015年 | 14篇 |
2014年 | 12篇 |
2013年 | 14篇 |
2012年 | 21篇 |
2011年 | 15篇 |
2010年 | 17篇 |
2009年 | 6篇 |
2008年 | 8篇 |
2007年 | 15篇 |
2006年 | 18篇 |
2005年 | 12篇 |
2004年 | 9篇 |
2003年 | 14篇 |
2002年 | 8篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 9篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 7篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有296条查询结果,搜索用时 0 毫秒
251.
beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Usui I Imamura T Huang J Satoh H Shenoy SK Lefkowitz RJ Hupfeld CJ Olefsky JM 《Molecular and cellular biology》2004,24(20):8929-8937
beta-arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR signaling. In the present study, we determined whether beta-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation. Overexpression of wild-type (WT) beta-arrestin-1 attenuated insulin-induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1. When endogenous beta-arrestin-1 was knocked down by transfection of beta-arrestin-1 small interfering RNA, insulin-induced IRS-1 degradation was enhanced. Insulin stimulated the association of IRS-1 and Mdm2, an E3 ubiquitin ligase, and this association was inhibited to overexpression of WT beta-arrestin-1, which led by decreased ubiquitin content of IRS-1, suggesting that both beta-arrestin-1 and IRS-1 competitively bind to Mdm2. In summary, we have found the following: (i) beta-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) beta-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on beta-arrestin and the amino terminus of beta-arrestin-1 are required for this effect of beta-arrestin on IRS-1 degradation; and (iv) inhibition of beta-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance. 相似文献
252.
253.
Recombinant subunit IV mutants which identify the regions essential for restoration of bc(1) activity to the three-subunit core complex of Rhodobacter sphaeroides were generated and characterized. Four C-terminal truncated mutants: IV(1-109), IV(1-85), IV(1-76), and IV(1-40) had 100, 0, 0, and 0% of reconstitutive activity of the wild-type IV, indicating that residues 86-109 are essential. IV(1-109) is associated with the core complex in the same manner as the wild-type IV while mutants IV(1-85), IV(1-76), and IV(1-40) do not associate with the core complex, indicating that subunit IV requires its transmembrane helix region (residues 86-109) for assembly into the bc(1) complex. Since GST-IV(86-109) fusion protein has little reconstitutive activity, some region(s) in residues 1-85 are required for bc(1) activity restoration after subunit IV is incorporated into the complex through the transmembrane helix, presumably by interaction with cytochrome b in the core complex. The interacting regions are identified as residues 41-53 and 77-85, since mutants IV(21-109), IV(41-109), IV(54-109), and IV(77-109) had 95, 98, 53, and 53% of the reconstitutive activity of the wild-type IV. These two interacting regions are on the cytoplasmic side of the chromatophore membrane and closed to the DE loop and helix G of cytochrome b, respectively. 相似文献
254.
Kitamura T Garofalo RP Kamijo A Hammond DK Oka JA Caflisch CR Shenoy M Casola A Weigel PH Goldblum RM 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(10):5029-5034
Binding and transport of polymeric Igs (pIgA and IgM) across epithelia is mediated by the polymeric Ig receptor (pIgR), which is expressed on the basolateral surface of secretory epithelial cells. Although an Fc receptor for IgA (FcalphaR) has been identified on myeloid cells and some cultured mesangial cells, the expression of an FcalphaR on epithelial cells has not been described. In this study, binding of IgA to a human epithelial line, HT-29/19A, with features of differentiated colonic epithelial cells, was examined. Radiolabeled monomeric IgA (mIgA) showed a dose-dependent, saturable, and cation-independent binding to confluent monolayers of HT-29/19A cells. Excess of unlabeled mIgA, but not IgG or IgM, competed for the mIgA binding, indicating that the binding was IgA isotype-specific and was not mediated by the pIgR. The lack of competition by asialoorosomucoid and the lack of requirement for divalent cations excluded the possibility that IgA binding to HT-29/19A cells was due to the asialoglycoprotein receptor or beta-1, 4-galactosyltransferase, previously described on HT-29 cells. Moreover, the FcalphaR (CD89) protein and message were undetectable in HT-29/19A cells. FACS analysis of IgA binding demonstrated two discrete populations of HT-29/19 cells, which bound different amounts of mIgA. IgA binding to other colon carcinoma cell lines was also demonstrated by FACS analysis, suggesting that an IgA receptor, distinct from the pIgR, asialoglycoprotein receptor, galactosyltransferase, and CD89 is constitutively expressed on cultured human enterocytes. The function of this novel IgA receptor in mucosal immunity remains to be elucidated. 相似文献
255.
Kuhnle G Spencer JP Schroeter H Shenoy B Debnam ES Srai SK Rice-Evans C Hahn U 《Biochemical and biophysical research communications》2000,277(2):507-512
There is considerable interest in the bioavailability of polyphenols and their bioactivity in vivo. We have studied the absorption and metabolism of catechin and epicatechin in the small intestine and the comparative transfer across the jejunum and ileum. Perfusion of isolated jejunum with the flavanols resulted in glucuronidation ( approximately 45%), O-methylation: 3'-O-Methyl- and 4'-O-methyl- ( approximately 30%), and O-methyl-glucuronidation ( approximately 20% of total flavanols identified) during transfer across the enterocytes to the serosal side. This demonstrates the activity of catechol-O-methyl transferases in the metabolism of flavanols and suggests that these metabolites and conjugates are likely to enter the portal vein. In contrast, in the case of the ileum, the majority of the flavanols appeared on the serosal side unmetabolised and the total percentage of flavanols transferred was higher than that in the jejunum ( approximately fivefold). 相似文献
256.
Ojamaa K Kenessey A Shenoy R Klein I 《American journal of physiology. Endocrinology and metabolism》2000,279(6):E1319-E1324
In a rat model of acute myocardial infarction (MI) produced by coronary artery ligation, thyroid hormone metabolism was altered with significant reductions (54%) in serum triiodo-L-thyronine (T(3)), the cellular active hormone metabolite. T(3) has profound effects on the heart; therefore, rats were treated with T(3) after acute MI for 2 or 3 wk, at either replacement or elevated doses, to determine whether cardiac function and gene expression could be normalized. Acute MI resulted in a 50% (P < 0.001) decrease in percent ejection fraction (%EF) with a 32-35% increase (P < 0.01) in compensatory left ventricle (LV) hypertrophy. Treatment of the MI animals with either replacement or elevated doses of T(3) significantly increased %EF to 64 and 73% of control, respectively. Expression levels of several T(3)-responsive genes were altered in the hypertrophied LV after MI, including significant decreases in alpha-myosin heavy chain (MHC), sarcoplasmic reticulum calcium-activated ATPase (SERCA2), and Kv1.5 mRNA, whereas beta-MHC and phospholamban (PLB) mRNA were significantly increased. Normalization of serum T(3) did not restore expression of all T(3)-regulated genes, indicating altered T(3) responsiveness in the postinfarcted myocardium. Although beta-MHC and Kv1.5 mRNA content was returned to control levels, alpha-MHC and SERCA2 were unresponsive to T(3) at replacement doses, and only at higher doses of T(3) was alpha-MHC mRNA returned to control values. The present study showed that acute MI in the rat was associated with a fall in serum T(3) levels, LV dysfunction, and altered expression of T(3)-responsive genes and that T(3) treatment significantly improved cardiac function, with normalization of some, but not all, of the changes in gene expression. 相似文献
257.
258.
Bipasha Bose Sudheer P Shenoy Sudhakar Konda Pralhad Wangikar 《Cell biology international》2012,36(11):1013-1020
hESC (human embryonic stem cells), when differentiated into pancreatic β ILC (islet‐like clusters), have enormous potential for the cell transplantation therapy for Type 1 diabetes. We have developed a five‐step protocol in which the EBs (embryoid bodies) were first differentiated into definitive endoderm and subsequently into pancreatic lineage followed by formation of functional endocrine β islets, which were finally matured efficiently under 3D conditions. The conventional cytokines activin A and RA (retinoic acid) were used initially to obtain definitive endoderm. In the last step, ILC were further matured under 3D conditions using amino acid rich media (CMRL media) supplemented with anti‐hyperglycaemic hormone‐Glp1 (glucagon‐like peptide 1) analogue Liraglutide with prolonged t½ and Exendin 4. The differentiated islet‐like 3D clusters expressed bonafide mature and functional β‐cell markers‐PDX1 (pancreatic and duodenal homoeobox‐1), C‐peptide, insulin and MafA. Insulin synthesis de novo was confirmed by C‐peptide ELISA of culture supernatant in response to varying concentrations of glucose as well as agonist and antagonist of functional 3D β islet cells in vitro. Our results indicate the presence of almost 65% of insulin producing cells in 3D clusters. The cells were also found to ameliorate hyperglycaemia in STZ (streptozotocin) induced diabetic NOD/SCID (non‐obese diabetic/severe combined immunodeficiency) mouse up to 96 days of transplantation. This protocol provides a basis for 3D in vitro generation of long‐term in vivo functionally viable islets from hESC. 相似文献
259.
Kapur NK Shenoy C Yunis AA Mohammad NN Wilson S Paruchuri V Mackey EE Qiao X Shah A Esposito ML Karas RH Jaffe IZ 《PloS one》2012,7(4):e34344
Background
Human studies of therapeutic angiogenesis, stem-cell, and progenitor-cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied.Methodology/Principal Findings
We measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients undergoing elective percutaneous coronary intervention. Compared to baseline values, sFLT1 and PlGF levels increased by 2629±313% and 253±54%, respectively, within 30 minutes of UFH therapy (p<0.01 for both; n = 8). VEGF levels decreased by 93.2±5% in patients treated with UFH (p<0.01 versus baseline). No change in sEng levels were observed after UFH therapy. No changes in sFLT1, PlGF, VEGF, or sEng levels were observed in any patients receiving bivalirudin (n = 8). To further explore the direct effect of anticoagulation on circulating angiogenic peptides, adult, male wild-type mice received venous injections of clinically dosed UFH or bivalirudin. Compared to saline controls, sFLT1 and PlGF levels increased by >500% (p<0.01, for both) and VEGF levels increased by 221±101% (p<0.05) 30 minutes after UFH treatment. Bivalirudin had no effect on peptide levels. To study the cellular origin of peptides after anticoagulant therapy, human coronary endothelial cells were treated with UFH and demonstrated increased sFLT1 and PlGF levels (ANOVA p<0.01 for both) with reduced VEGF levels (ANOVA p<0.05). Bivalirudin had no effect on peptide levels in vitro.Conclusions/Significance
Circulating levels of sFLT1, PlGF, and VEGF are significantly altered by UFH, while bivalirudin therapy has no effect. These findings may have significant implications for clinical studies of therapeutic angiogenesis, stem-cell and progenitor-cell therapy. 相似文献260.
As many articles in this issue of IEEE Pulse demonstrate, interfacing directly with the brain presents several fundamental challenges. These challenges reside at multiple levels and span many disciplines, ranging from the need to understand brain states at the level of neural circuits to creating technological innovations to facilitate new therapeutic options. The goal of our multiuniversity research team, composed of researchers from Stanford University, Brown University, the University of California at San Francisco (UCSF), and the University College London (UCL), is to substantially elevate the fundamental understanding of brain information processing and its relationship with sensation, behavior, and injury. Our team was assembled to provide expertise ranging from neuroscience to neuroengineering and to neurological and psychiatric clinical guidance, all of which are critical to the overarching research goal. By employing a suite of innovative experimental, computational, and theoretical approaches, the Defense Advanced Research Projects Agency (DARPA) Reorganization and Plasticity to Accelerate Injury Recovery (REPAIR) team has set its sights on learning how the brain and its microcircuitry react (e.g., to sudden physiological changes) and what can be done to encourage recovery from such (reversible) injury. In this article, we summarize some of the team's technical goals, approaches, and early illustrative results. 相似文献