全文获取类型
收费全文 | 495篇 |
免费 | 19篇 |
国内免费 | 14篇 |
出版年
2023年 | 12篇 |
2022年 | 7篇 |
2021年 | 13篇 |
2020年 | 20篇 |
2019年 | 23篇 |
2018年 | 34篇 |
2017年 | 24篇 |
2016年 | 14篇 |
2015年 | 14篇 |
2014年 | 112篇 |
2013年 | 42篇 |
2012年 | 13篇 |
2011年 | 30篇 |
2010年 | 20篇 |
2009年 | 16篇 |
2008年 | 29篇 |
2007年 | 12篇 |
2006年 | 14篇 |
2005年 | 9篇 |
2004年 | 11篇 |
2003年 | 9篇 |
2002年 | 4篇 |
2001年 | 6篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 5篇 |
1997年 | 2篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1983年 | 1篇 |
1979年 | 2篇 |
1976年 | 1篇 |
排序方式: 共有528条查询结果,搜索用时 15 毫秒
71.
A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs 总被引:14,自引:0,他引:14
Kotarsky K Nilsson NE Flodgren E Owman C Olde B 《Biochemical and biophysical research communications》2003,301(2):406-410
Fatty acids, which are essential nutritional components, are also involved in cardiovascular and metabolic diseases. Here we report a human cell surface receptor that we name free fatty acid receptor (FFAR), because it is specifically activated by medium to long-chain free fatty acids. The receptor belongs to the class of seven-transmembrane, G-protein coupled receptors (GPCRs) and also mediates responses to antidiabetic drugs of the thiazolidinedione type. It is expressed in skeletal muscle, heart, liver, and pancreatic beta-cells. Stimulation of FFAR increases the intracellular calcium concentration in cells expressing the receptor in a native (pancreatic beta-cell line) or in a recombinant form. In view of the nature of the activating substances, their physiological role in the body, and the tissue distribution of FFAR we suggest the term "nutrient sensing receptor" for receptors acting at the interface between dietary components and signalling molecules. 相似文献
72.
73.
The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system 总被引:20,自引:0,他引:20
Funes S Hedrick JA Vassileva G Markowitz L Abbondanzo S Golovko A Yang S Monsma FJ Gustafson EL 《Biochemical and biophysical research communications》2003,312(4):1357-1363
GPR54 is a G-protein-coupled receptor that displays a high percentage of identity in the transmembrane domains with the galanin receptors. The ligand for GPR54 has been identified as a peptide derived from the KiSS-1 gene. KiSS-1 has been shown to have anti-metastatic effects, suggesting that KiSS-1 or its receptor represents a potential therapeutic target. To further our understanding of the physiological function of this receptor, we have generated a mutant mouse line with a targeted disruption of the GPR54 receptor (GPR54 -/-). The analysis of the GPR54 mutant mice revealed developmental abnormalities of both male and female genitalia and histopathological changes in tissues which normally contain sexually dimorphic features. These data suggest a role for GPR54/KiSS-1 in normal sexual development, and indicate that study of the GPR54 mutant mice may provide valuable insights into human reproductive syndromes. 相似文献
74.
Emerging data indicate that the inflammatory cytokine TNF exerts a neuroprotective effect against brain injury. To better understand the mechanism of action of TNF on neurons we have investigated the possible activation of various MAP kinases. Exposure of neurons to TNF triggered the rapid phosphorylation of three members of the MAP kinase family, i.e., extracellular signal-regulated kinase (ERK1/2), stress-activated protein kinase/JUN N-terminal kinase (SAPK/JNK) and the p38 kinase; this activation occured with the same time course and was transient. The TNF-induced activation of ERK1/2 was specifically prevented by compound PD 98059 a specific inhibitor of the MAP kinase kinase MEK1/2. Activation of ERK1/2 was also specifically inhibited by the xanthogenic derivative D609, a specific inhibitor of phosphoinositide phospholipase C suggesting that TNFsignaling in neurons involved the acidic sphingomyelinase. 相似文献
75.
To elucidate the mechanism of root formation in tooth development, we examined the role of insulin-like growth factor I (IGF-I) on early root formation in mandibular first molar teeth from 5-day-old mice. Immunohistochemistry revealed the specific localization of the IGF-I receptor in Hertwigs epithelial root sheath (HERS) in the tooth root. The effect of IGF-I on root development, especially on HERS, was subsequently examined in vitro. The control culture showed normal development of HERS and the periodontium, resembling that in vivo. However, the presence of 100 ng/ml IGF-I resulted in elongation of HERS and increased cell proliferation in its outer layer. These effects were negated by the addition of antibodies specific for IGF-I. Thus, we propose that IGF-I is involved in early root formation by regulating the mitotic activity in the outer layer of HERS.This study was partly supported by grants to N.F. from KAKENHI (no. 13671909), to N.F. and M.J.T. from the Promotion of 2001-Multidisciplinary Research Projects in 2001–2005, and to N.F. and K.I. from Iwate Medical University—Keiryokai Research Foundation (no. 64). 相似文献
76.
The maturation of Borna disease virus (BDV) glycoprotein GP was studied in regard to intracellular compartmentalization, compartmentalization signal-domains, proteolytic processing, and packaging into virus particles. Our data show that BDV-GP is (i) predominantly located in the endoplasmic reticulum (ER), (ii) partially exists in the ER already as cleaved subunits GP-N and GP-C, (iii) is directed to the ER/cis-Golgi region by its transmembrane and/or cytoplasmic domains in CD8-BDV-GP hybrid constructs and (iv) is incorporated in the virus particles as authentic BDV glycoprotein exclusively in the cleaved form decorated with N-glycans of the complex type. Downregulation of BDV-glycoproteins on the cell surface, their limited proteolytic processing, and protection of antigenic epitopes on the viral glycoproteins by host-identical N-glycans are different strategies for persistent virus infections. 相似文献
77.
Role of GPR40 in fatty acid action on the beta cell line INS-1E 总被引:7,自引:0,他引:7
Shapiro H Shachar S Sekler I Hershfinkel M Walker MD 《Biochemical and biophysical research communications》2005,335(1):97-104
GPR40 is a G protein-coupled receptor expressed preferentially in beta cells, that has been implicated in mediating free fatty acid-stimulated insulin release. GPR40 RNAi impaired the ability of palmitic acid (PA) to increase both insulin secretion and intracellular calcium ([Ca2+]i). The PA-dependent [Ca2+]i increase was attenuated by inhibitors of Galphaq, PLC, and SERCA. Thus GPR40 activates the Galphaq pathway, leading to release of Ca2+ from the ER. Yet the GPR40-dependent [Ca2+]i rise was dependent on extracellular Ca2+ and elevated glucose, and was blocked by inhibition of L-type calcium channels (LTCC) or opening of the K(ATP) channel; this suggests that GPR40 promotes Ca2+ influx through up-regulation of LTCC pre-activated by glucose and membrane depolarization. Taken together, the data indicate that GPR40 mediates the increase in [Ca2+]i and insulin secretion through the Galphaq-PLC pathway, resulting in release of Ca2+ from the ER and leading to up-regulation of Ca2+ influx via LTCC. 相似文献
78.
The effect of ANG II on pHi, [Ca2+]i and cell volume was investigated in T84 cells, a cell line originated from colon epithelium, using the probes BCECF-AM, Fluo
4-AM and acridine orange, respectively. The recovery rate of pHi via the Na+/H+ exchanger was examined in the first 2 min following the acidification of pHi with a NH4Cl pulse. In the control situation, the pHi recovery rate was 0.118 ± 0.001 (n = 52) pH units/min and ANG II (10−12 M or 10−9 M) increased this value (by 106% or 32%, respectively) but ANG II (10−7 M) decreased it to 47%. The control [Ca2+]i was 99 ± 4 (n = 45) nM and ANG II increased this value in a dose-dependent manner. The ANG II effects on cell volume were minor and late
and should not interfere in the measurements of pHi recovery and [Ca2+]i. To document the signaling pathways in the hormonal effects we used: Staurosporine (a PKC inhibitor), W13 (a calcium-dependent
calmodulin antagonist), H89 (a PKA inhibitor) or Econazole (an inhibitor of cytochrome P450 epoxygenase). Our results indicate
that the biphasic effect of ANG II on Na+/H+ exchanger is a cAMP-independent mechanism and is the result of: 1) stimulation of the exchanger by PKC signaling pathway
activation (at 10−12 – 10−7 M ANG II) and by increases of [Ca2+]i in the lower range (at 10−12 M ANG II) and 2) inhibition of the exchanger at high [Ca2+]i levels (at 10−9 – 10−7 M ANG II) through cytochrome P450 epoxygenase-dependent metabolites of the arachidonic acid signaling pathway. 相似文献
79.
The intermediate chain of dynein forms a tight subcomplex with dimeric light chains LC8 and Tctex-1, and together they constitute the cargo attachment complex. There is considerable interest in identifying the role of these light chains in the assembly of the two copies of the intermediate chain. The N-terminal domain of the intermediate chain, IC1-289, contains the binding sites for the light chains, and is a highly disordered monomer but gains helical structure upon binding to light chains LC8 and Tctex-1. To provide insights into the structural and dynamic changes that occur in the intermediate chain upon light chains binding, we have used NMR spectroscopy to compare the properties of two distinct sub-domains of IC1-289: IC84-143 which is the light chains binding domain, and IC198-237, which contains a predicted coiled coil necessary for the increase in ordered structure upon light chain binding. Neither construct has stable secondary structure when probed by circular dichroism and amide chemical shift dispersion. Specific residues of IC84-143 involved in binding to the light chains were identified by their increase in resonance line broadening and the corresponding large intensity reduction in 1H-15N HSQC spectra. Interestingly, IC84-143 shows no sign of structure formation after binding to either LC8 or Tctex-1 or to both. IC198-237, on the other hand, contains a population of a nascent helix at low temperature as identified by heteronuclear NMR relaxation measurements, secondary chemical shifts, and sequential amide-amide connectivities. These data are consistent with a model for light chain binding coupled to intermediate chain dimerization through forming a coiled coil distant from the binding site. 相似文献
80.