全文获取类型
收费全文 | 10675篇 |
免费 | 1116篇 |
国内免费 | 1419篇 |
出版年
2024年 | 34篇 |
2023年 | 155篇 |
2022年 | 383篇 |
2021年 | 554篇 |
2020年 | 447篇 |
2019年 | 563篇 |
2018年 | 462篇 |
2017年 | 383篇 |
2016年 | 496篇 |
2015年 | 660篇 |
2014年 | 848篇 |
2013年 | 838篇 |
2012年 | 978篇 |
2011年 | 906篇 |
2010年 | 576篇 |
2009年 | 532篇 |
2008年 | 626篇 |
2007年 | 488篇 |
2006年 | 483篇 |
2005年 | 390篇 |
2004年 | 372篇 |
2003年 | 343篇 |
2002年 | 364篇 |
2001年 | 197篇 |
2000年 | 181篇 |
1999年 | 153篇 |
1998年 | 133篇 |
1997年 | 101篇 |
1996年 | 84篇 |
1995年 | 60篇 |
1994年 | 51篇 |
1993年 | 38篇 |
1992年 | 56篇 |
1991年 | 48篇 |
1990年 | 26篇 |
1989年 | 30篇 |
1988年 | 15篇 |
1987年 | 22篇 |
1986年 | 17篇 |
1985年 | 17篇 |
1984年 | 13篇 |
1983年 | 5篇 |
1981年 | 7篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1970年 | 5篇 |
1968年 | 8篇 |
1967年 | 6篇 |
1966年 | 7篇 |
1965年 | 5篇 |
排序方式: 共有10000条查询结果,搜索用时 171 毫秒
981.
Beta-arrestins mediate agonist-dependent desensitization and internalization of G protein-coupled receptors. Previously, we have shown that phosphorylation of beta-arrestin1 by ERKs at Ser-412 regulates its association with clathrin and its function in promoting clathrin-mediated internalization of the receptor. In this paper we report that beta-arrestin2 is also phosphorylated, predominantly at residues Thr-383 and Ser-361. Isoproterenol stimulation of the beta(2)-adrenergic receptor promotes dephosphorylation of beta-arrestin2. Mutation of beta-arrestin2 phosphorylation sites to aspartic acid decreases the association of beta-arrestin2 with clathrin, thereby reducing its ability to promote internalization of the beta(2)-adrenergic receptor. Its ability to bind and desensitize the beta(2)-adrenergic receptor is, however, unaltered. These results suggest that, analogous to beta-arrestin1, phosphorylation/dephosphorylation of beta-arrestin2 regulates clathrin-mediated internalization of the beta(2)-adrenergic receptor. In contrast to beta-arrestin1, which is phosphorylated by ERK1 and ERK2, phosphorylation of beta-arrestin2 at Thr-383 is shown to be mediated by casein kinase II. Recently, it has been reported that phosphorylation of visual arrestin at Ser-366 prevents its binding to clathrin. Thus it appears that the function of all arrestin family members in mediating internalization of G protein-coupled receptors is regulated by distinct phosphorylation/dephosphorylation mechanisms. 相似文献
982.
Banerjee K Deshpande S Zheng M Kumaraguru U Schoenberger SP Rouse BT 《Cellular immunology》2002,219(2):108-118
Herpetic stromal keratitis (HSK), resulting from ocular infection with herpes simplex virus (HSV), is thought to represent a T cell mediated immunopathologic lesion. Antigens recognized by the inflammatory T cells remain unresolved and non-TCR mediated activation of T cells (bystander activation) is considered as also involved. This report documents further evidence for the bystander activation mechanisms using three T cell transgenic RAG-/- mouse strains. Accordingly HSK occurred in PCC RAG-/-, P14 RAG-/-, and OT-1 RAG-/- mice. In none of the models could HSV specific T cell reactivity be demonstrated and animals were unprotected from lesion development by immunization prior to HSV ocular infection. The results support the role of bystander activation as a mechanism of T cell mediated immunopathology and show that CD8(+) as well as CD4(+) T cells can participate in HSK lesion development. 相似文献
983.
Li W Nadelman C Gratch NS Li W Chen M Kasahara N Woodley DT 《Experimental cell research》2002,273(2):219-228
Migration of human keratinocytes plays a critical role in the re-epithelialization of human skin wounds, the process by which the wound bed is resurfaced and closed by keratinocytes as it forms a new epidermis. While the importance of ECM components and serum factors in the regulation of keratinocytes motility is well established, the intracellular signaling mechanisms remain fragmentary. In this study, we investigated the role of protein kinase Cdelta (PKCdelta) signaling in the promotion of human keratinocyte migration by a collagen matrix and bovine pituitary extract. We found that pharmacological inhibition of the PKCdelta pathway completely blocks migration. Using a lentivirus-based vector system, which offers more than 90% gene transduction efficiency to human keratinocytes, we show that the kinase-defective mutant of PKCdelta (K376R) dramatically inhibits human keratinocyte migration. Furthermore, PKCdelta is activated in migrating human keratinocytes. These observations indicate for the first time that the PKCdelta pathway plays an important role in the control of human keratinocyte migration. 相似文献
984.
Yuan ZQ Feldman RI Sun M Olashaw NE Coppola D Sussman GE Shelley SA Nicosia SV Cheng JQ 《The Journal of biological chemistry》2002,277(33):29973-29982
Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV- and TNF alpha-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNF alpha-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates I kappa B kinase alpha. The phosphorylation of I kappa B kinase alpha and activation of NF kappa B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNF alpha-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFalpha -induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NF kappa B pathway. 相似文献
985.
986.
Forte TM Subbanagounder G Berliner JA Blanche PJ Clermont AO Jia Z Oda MN Krauss RM Bielicki JK 《Journal of lipid research》2002,43(3):477-485
We examined whether the putative anti-atherogenic enzymes LCAT, paraoxonase (PON), and platelet-activating factor acetylhydrolase (PAF-AH) are impaired in 8 week old atherosclerosis susceptible apolipoprotein E (apoE)(-/-) and LDL receptor (LDLr)(-/-) mice and whether plasma concentrations of bioactive oxidized phospholipids accumulate in plasma. ApoE(-/-) mice had reduced (28%) LCAT activity and elevated lysophosphatidylcholine and bioactive oxidized phospholipids (1-palmitoyl-2-oxovaleryl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine) compared with controls on the chow diet. Elevated oxidized phospholipids and reduced LCAT activity may, in part, contribute to spontaneous lesions in these mice on a chow diet. A Western diet decreased LCAT activity further (50% of controls) and PON activity was decreased 38%. The LDLr(-/-) mice showed normal LCAT activity on chow diet and little accumulation of oxidized phospholipids. On a Western diet, LDLr(-/-) mice had reduced LCAT activity (21%), but no change in PON activity. All genotypes had reduced PAF-AH activity on the Western diet. ApoE(-/-) and LDLr(-/-) mice, but not controls, had elevated plasma bioactive oxidized phospholipids on the Western diet.We conclude that impairment of LCAT activity and accumulation of oxidized phospholipids are part of an early atherogenic phenotype in these models. 相似文献
987.
Allen MP Xu M Linseman DA Pawlowski JE Bokoch GM Heidenreich KA Wierman ME 《The Journal of biological chemistry》2002,277(41):38133-38140
988.
Probing an open CFTR pore with organic anion blockers 总被引:6,自引:0,他引:6
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts Cl- current. We explored the CFTR pore by studying voltage-dependent blockade of the channel by two organic anions: glibenclamide and isethionate. To simplify the kinetic analysis, a CFTR mutant, K1250A-CFTR, was used because this mutant channel, once opened, can remain open for minutes. Dose-response relationships of both blockers follow a simple Michaelis-Menten function with K(d) values that differ by three orders of magnitude. Glibenclamide blocks CFTR from the intracellular side of the membrane with slow kinetics. Both the on and off rates of glibenclamide block are voltage dependent. Removing external Cl- increases affinity of glibenclamide due to a decrease of the off rate and an increase of the on rate, suggesting the presence of a Cl- binding site external to the glibenclamide binding site. Isethionate blocks the channel from the cytoplasmic side with fast kinetics, but has no measurable effect when applied extracellularly. Increasing the internal Cl- concentration reduces isethionate block without affecting its voltage dependence, suggesting that Cl- and isethionate compete for a binding site in the pore. The voltage dependence and external Cl- concentration dependence of isethionate block are nearly identical to those of glibenclamide block, suggesting that these two blockers may bind to a common binding site, an idea further supported by kinetic studies of blocking with glibenclamide/isethionate mixtures. By comparing the physical and chemical natures of these two blockers, we propose that CFTR channel has an asymmetric pore with a wide internal entrance and a deeply embedded blocker binding site where local charges as well as hydrophobic components determine the affinity of the blockers. 相似文献
989.
Dong LQ Ramos FJ Wick MJ Lim MA Guo Z Strong R Richardson A Liu F 《Biochemical and biophysical research communications》2002,294(1):136-144
3'-Phosphoinositide-dependent protein kinase-1 (PDK-1) phosphorylates and activates members of the protein kinase AGC family and plays a key role in receptor tyrosine kinase signaling. Here we report the cloning and characterization of a splice variant of mouse PDK-1, mPDK-1 beta. The cDNA encoding mPDK-1 beta contains two alternative start codons and translation from these start codons generates proteins that are, respectively, 27 or 51 amino acid residues shorter at the amino-terminus than the previously identified PDK-1 isolated from mouse liver (now renamed mPDK-1 alpha) [J. Biol. Chem. 274 (1999) 8117]. Analysis of mouse tissues shows that mPDK-1 beta is highly expressed in the testis and various functional regions of the brain. Expression of this isoform is increased in the brain of aged mice. Both mPDK-1 alpha and mPDK-1 beta are autophosphorylated at both serine and threonine residues in vitro and showed similar levels of tyrosine phosphorylation when co-expressed with either constitutively active Src or Fyn tyrosine kinases in cells. However, the mPDK-1 isoforms showed significant differences in their response to pervanadate- or insulin plus vanadate-stimulated tyrosine phosphorylation. Taken together, our findings suggest that the two PDK-1 isoforms may be differentially regulated in cells. The specific expression of mPDK-1 beta in mouse testis and brains of aged mice also suggests potential involvement of this kinase in regulating animal spermatogenesis and aging. 相似文献
990.