全文获取类型
收费全文 | 4801篇 |
免费 | 60篇 |
国内免费 | 68篇 |
出版年
2023年 | 13篇 |
2022年 | 23篇 |
2021年 | 44篇 |
2020年 | 37篇 |
2019年 | 46篇 |
2018年 | 52篇 |
2017年 | 32篇 |
2016年 | 46篇 |
2015年 | 167篇 |
2014年 | 443篇 |
2013年 | 385篇 |
2012年 | 451篇 |
2011年 | 549篇 |
2010年 | 363篇 |
2009年 | 129篇 |
2008年 | 108篇 |
2007年 | 106篇 |
2006年 | 122篇 |
2005年 | 113篇 |
2004年 | 129篇 |
2003年 | 118篇 |
2002年 | 85篇 |
2001年 | 50篇 |
2000年 | 57篇 |
1999年 | 56篇 |
1998年 | 75篇 |
1997年 | 83篇 |
1996年 | 88篇 |
1995年 | 90篇 |
1994年 | 92篇 |
1993年 | 47篇 |
1992年 | 69篇 |
1991年 | 54篇 |
1990年 | 60篇 |
1989年 | 41篇 |
1988年 | 44篇 |
1987年 | 32篇 |
1986年 | 36篇 |
1985年 | 49篇 |
1984年 | 68篇 |
1983年 | 52篇 |
1982年 | 61篇 |
1981年 | 43篇 |
1980年 | 44篇 |
1979年 | 43篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1976年 | 3篇 |
1974年 | 4篇 |
1971年 | 2篇 |
排序方式: 共有4929条查询结果,搜索用时 281 毫秒
101.
Michael Böhm 《Molecular and cellular biochemistry》1995,147(1-2):147-160
Alterations of receptor-G-protein-regulated adenylyl cyclase activity have been suggested to represent an important alteration leading to contractile dysfunction in the failing human heart. Recent experiments suggest that the 1-adrenoceptor(1AR) density and mRNA levels are reduced, while 2-adrenoceptors and stimulatory G-proteins are unchanged (mRNA and protein level). Functional assays demonstrated that the catalyst of the adenylyl cyclase is not different between failing and nonfailing myocardium. Inhibitory G-proteins are increased (pertussis toxin substrates, protein and mRNA) and correlate to the reduced inotropic effects of -adrenoceptor agonists and of CAMP-PDE inhibitors. Gi-coupled m-cholinoceptors and A1-adrenergic receptors are unchanged in density and affinity. Stimulation of these receptors resulted in an unchanged antiadrenergic effect on force of contraction. In conclusion, a downregulation of 1-AR and an increase of Gi have been observed as signal transduction alteration in failing human myocardium. These alterations are due to alterations of gene expression in the failing heart and are related to a defective regulation of force of contraction in heart failure. 相似文献
102.
Crystallization and preliminary X-ray crystallographic analysis of squalene-hopene cyclase from Alicyclobacillus acidocaldarius.
下载免费PDF全文
![点击此处可从《Protein science : a publication of the Protein Society》网站下载免费的PDF全文](/ch/ext_images/free.gif)
K. U. Wendt C. Feil A. Lenhart K. Poralla G. E. Schulz 《Protein science : a publication of the Protein Society》1997,6(3):722-724
The membrane-associated protein squalene-hopene cyclase from Alicyclobacillus acidocaldarius was overexposed in Escherichia coli and purified by ion exchange and gel permeation chromatography. Crystals of three interrelated forms were grown by vapor diffusion under identical conditions. The crystals diffract to about 2.3 A resolution, but they are unstable in the X-ray beam. An interpretable heavy-atom derivative was obtained. 相似文献
103.
Conclusion Membrane association is essential for GRK function and because of this the GRKs have evolved complex regulatory mechanisms
for associating with the membrane. Although the GRKs are highly homologous, each kinase utilizes a distinct mechanism for
associating with the membrane, which makes it unique within the family. Initially, the carboxyl terminus of the GRKs was identified
as the “membrane association domain” but recent evidence suggests that the amino terminus may also play a critical role in
localizing the kinases to the membrane (Murga et al., 1996; Pitcher et al, 1996). It is within these two domains that the
GRKs are most variable at the amino acid level. The GRKS exhibit an absolute requirement for phospholipids not only for association
with the membrane but also for activity. There are differences in preference and binding sites for the phospholipids within
the GRK family, which may reflect differential targeting of the GRKs to G protein-coupled receptors situated in different
lipid environments. There are hundreds of G protein-coupled receptors and only six known GRKs. All the GRKs appear to phosphorylate
the same receptor substrates in vitro (Sterne-Marr & Benovic, 1995; Premont et al., 1995). Receptor specificity, in a cellular 相似文献
104.
Nathalie Griffon Catherine Pilon François Sautel Jean-Charles Schwartz Pierre Sokoloff 《Journal of neurochemistry》1997,68(1):1-9
Abstract: As cerebral neurons express the dopamine D1 receptor positively coupled with adenylyl cyclase, together with the D3 receptor, we have investigated in a heterologous cell expression system the relationships of cyclic AMP with D3 receptor signaling pathways. In NG108-15 cells transfected with the human D3 receptor cDNA, dopamine, quinpirole, and other dopamine receptor agonists inhibited cyclic AMP accumulation induced by forskolin. Quinpirole also increased mitogenesis, assessed by measuring [3 H]thymidine incorporation. This effect was blocked partially by genistein, a tyrosine kinase inhibitor. Forskolin enhanced by 50–75% the quinpirole-induced [3 H]thymidine incorporation. This effect was maximal with 100 n M forskolin, occurred after 6–16 h, was reproduced by cyclic AMP-permeable analogues, and was blocked by a protein kinase A inhibitor. Forskolin increased D3 receptor expression up to 135%, but only after 16 h and at concentrations of >1 µ M . Thus, in this cell line, the D3 receptor uses two distinct signaling pathways: it efficiently inhibits adenylyl cyclase and induces mitogenesis, an effect possibly involving tyrosine phosphorylation. Activation of the cyclic AMP cascade potentiates the D3 receptor-mediated mitogenic response, through phosphorylation by a cyclic AMP-dependent kinase of a yet unidentified component. Hence, transduction of the D3 receptor can involve both opposite and synergistic interactions with cyclic AMP. 相似文献
105.
Abstract: The α subunit of Gz (αz) harbors two N-terminal serine residues (at positions 16 and 27) that serve as protein kinase C-mediated phosphorylation sites. The cognate residues in the α subunit of Gt1 provide binding surfaces for the β1 subunit. We used three serine-to-alanine mutants of αz to investigate the functional importance of the two N-terminal serine residues. Wild-type or mutant αz was transiently coexpressed with different receptors and adenylyl cyclase isozymes in human embryonic kidney 293 cells, and agonist-dependent regulation of cyclic AMP accumulation was examined in a setting where all endogenous α subunits of Gi were inactivated by pertussis toxin. Replacement of one or both serine residues by alanine did not alter the ability of αz to interact with δ-opioid, dopamine D2, or adenosine A1 receptors. Its capacity to inhibit endogenous and type VI adenylyl cyclases was also unaffected. Functional release of βγ subunits from the mutant αz subunits was not impaired because they transduced βγ-mediated stimulation of type II adenylyl cyclase. Constitutively active mutants of all four αz subunits were constructed by the introduction of a Q205L mutation. The activated mutants showed differential abilities to inhibit human choriogonadotropin-mediated cyclic AMP accumulation in luteinizing hormone receptor-transfected cells. Loss of both serine residues, but not either one alone, impaired the receptor-independent inhibition of adenylyl cyclase by the GTPase-deficient mutant. Thus, replacement of the amino-terminal serine residues of αz has no apparent effect on receptor-mediated responses, but these serine residues may be essential for ensuring transition of αz into the active conformation. 相似文献
106.
Characterization of Calpain-Mediated Proteolysis of GluR1 Subunits of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionate Receptors in Rat Brain 总被引:1,自引:0,他引:1
Xiaoning Bi Jing Chen Sandeeb Dang Robert J. Wenthold Georges Tocco Michel Baudry 《Journal of neurochemistry》1997,68(4):1484-1494
Abstract: Previous results have indicated that GluR1 subunits of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are targets of calpain. In the present study, we determined the effects of calpain treatment of synaptic membranes on GluR1 subunits using western blots with antibodies directed against the C-terminal (C-Ab) and the N-terminal (N-Ab) domains of the proteins, and compared them with the effects of calcium treatment of frozen-thawed brain sections. Calpain treatment of synaptic membranes resulted in a large decrease in the GluR1 band (105 kDa) labeled with C-Ab and in the formation of a doublet band labeled with N-Ab due to the appearance of a new species of GluR1 (98 kDa). These effects were blocked almost completely by calpain inhibitors. Calpain-induced changes in GluR1 immunological properties were not associated with modifications of [3 H]AMPA or 6-cyano-7-[3 H]nitroquinoxaline-2,3-dione ([3 H]CNQX) binding. Treatment of frozen-thawed brain sections with concentrations of calcium as low as 0.2 m M resulted in a large decrease in the 105-kDa GluR1 band and in the concurrent appearance of the 98-kDa band. This treatment was associated with increased [3 H]AMPA and [3 H]CNQX binding. These results suggest that there exist several types/states of GluR1 subunits exhibiting different sensitivities to calpain. Our data also indicate the existence of additional calcium-dependent processes regulating the characteristics of receptors in intact tissues. 相似文献
107.
神经生长因子家族及其受体研究进展 总被引:9,自引:0,他引:9
过去几年在神经营养因子、受体和神经元细胞程序性死亡的研究领域中取得了几项引人注目的进展:(1)神经生长因子(NGF)基因家族的其他一些成员包括脑源性神经营养因子(BDNF)、神经营养素-3(NT-3)、神经营养素-4(NT-4)、神经营养素-5(NT-5)的发现;(2)神经生长因子三维结构及功能和进化之关系的阐明;(3)定性了两种神经生长因子受体P75^NGFR和原癌基因p140^trkA以及相关 相似文献
108.
Carlos F. de Mello Diego D. De La Vega Leandro T. Pizutti Fabiane P. Lopes Maribel A. Rubin Jaime G. Homerich Dr. Carlos R. Melo Joana E. Somer Diogo O. Souza Moacir Wajner 《Neurochemical research》1995,20(12):1437-1441
The effect ofl-pyroglutamic acid, a metabolite that accumulates in pyroglutamic aciduria, on different neurochemical parameters was investigated in adult male Wistar rats. Glutamate binding, adenylate cyclase activity and G protein coupling to adenylate cyclase were assayed in the presence of the acid.l-pyroglutamic acid decreased Na+-dependent and Na+-independent glutamate binding Basal and GMP-PNP stimulated adenylate cyclase activity were not affected by the acid. Furthermore, rats received unilateral intrastriatal injections of 10–300 nmol of bufferedl-pyroglutamic acid. Vehicle (0.25 M Tris-Cl, pH 7.35–7.4) was injected into the contralateral striatum. Neurotoxic damage was assessed seven days after the injection by histological examination and by weighing both cerebral hemispheres. No difference in histology or weight could be identified between hemispheres. These results suggest that, although capable of interfering with glutamate binding, pyroglutamate did not cause a major lesion in the present model of neurotoxicity. 相似文献
109.
Valerie Brecx Aleksandra Misicka Patricia Verheyden Dirk Tourwé George van Binst 《Letters in Peptide Science》1995,2(3-4):165-168
Summary A new cis-peptide bond mimetic, -benzyl-o-aminomethylphenylacetic acid, was synthesized and incorporated in a homodetic somatostatin analogue. Biological binding tests and 2D NMR conformational analysis indicate that the configuration of the bridge-unit asymmetric center and the orientation of the benzyl side chain play a key role in the biological activity of this type of somatostatin analogues. 相似文献
110.
Interaction of Gila monster venom with secretin receptors in rat pancreatic membranes 总被引:1,自引:0,他引:1
L. Gillet P. Robberecht M. Waelbroeck J.C. Camus P. De Neef W. König J. Christophe 《Peptides》1984,5(2):407-409
The stimulatory effect of Gila monster venom on adenylate cyclase activity in rat pancreatic membranes was compared to that of porcine secretin and porcine VIP. The maximal effect exerted by the venom was identical to that of VIP but significantly lower than that of secretin. The effect of Gila monster venom could, however, be attributed to its interaction with secretin receptors rather than with VIP receptors, at variance with its previously described action on guinea pig pancreatic acini. Adenylate cyclase activation by both Gila monster venom and secretin in rat pancreatic membranes was, indeed: (1) dose-dependently inhibited by two secretin fragments secretin-(4-27) and secretin-(7-27), and (2) more severely depressed than VIP stimulation, after pretreating pancreatic membranes with dithiothreitol (DTT). 相似文献