全文获取类型
收费全文 | 517篇 |
免费 | 30篇 |
国内免费 | 1篇 |
专业分类
548篇 |
出版年
2023年 | 4篇 |
2022年 | 5篇 |
2021年 | 7篇 |
2019年 | 5篇 |
2018年 | 6篇 |
2017年 | 11篇 |
2016年 | 14篇 |
2015年 | 18篇 |
2014年 | 28篇 |
2013年 | 37篇 |
2012年 | 35篇 |
2011年 | 28篇 |
2010年 | 16篇 |
2009年 | 24篇 |
2008年 | 17篇 |
2007年 | 24篇 |
2006年 | 33篇 |
2005年 | 16篇 |
2004年 | 15篇 |
2003年 | 13篇 |
2002年 | 8篇 |
2001年 | 16篇 |
2000年 | 12篇 |
1999年 | 6篇 |
1998年 | 11篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1992年 | 7篇 |
1991年 | 10篇 |
1990年 | 8篇 |
1989年 | 10篇 |
1988年 | 4篇 |
1987年 | 6篇 |
1986年 | 10篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1979年 | 8篇 |
1978年 | 2篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1975年 | 7篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1971年 | 4篇 |
1969年 | 3篇 |
1967年 | 2篇 |
排序方式: 共有548条查询结果,搜索用时 15 毫秒
181.
Characterization of ATP-stimulated guanylate cyclase activation in rat lung membranes 总被引:6,自引:0,他引:6
C H Chang K P Kohse B Chang M Hirata B Jiang J E Douglas F Murad 《Biochimica et biophysica acta》1990,1052(1):159-165
Many of the effects of ANP are mediated through the elevation of cellular cGMP levels by the activation of particulate guanylate cyclase. While the stimulation of this enzyme is receptor-mediated, the molecular mechanism of activation remains unknown. In this study we present evidence that ATP as well as its analogues adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S) and adenylylimidophosphate (AMPPNP) activates guanylate cyclase from rat lung membranes and markedly potentiates the effect of ANP on the enzyme. The order of potency is ATP gamma S greater than ATP greater than AMPPNP. The enzyme activation by adenine nucleotide and ANP together is much more than the sum of the individual activations, suggesting that ATP may be the physiological component essential for the ANP-stimulated guanylate cyclase activation. The ATP gamma S-stimulated guanylate cyclase activity diminishes in the presence of various kinds of detergents, suggesting either that the conformation of an ATP binding site in guanylate cyclase is altered by detergents or that protein-protein interaction may be involved in the activation of guanylate cyclase by ATP. Guanylate cyclase from rat lung membranes is poorly activated by ANP and/or ATP gamma S after removing the cytosolic and weakly membrane-associated proteins or factors by centrifugation. Pre-incubation of the membranes with ATP gamma S retains enzyme activation after membrane washing. These results suggest either that ATP gamma S stabilizes the conformation of nucleotide binding site in guanylate cyclase from denaturation by membrane washing, or that the stimulatory effect of ATP on guanylate cyclase activity may be mediated by accessory proteins or non-protein cofactors which are lost during membrane washing, but remain bound to membranes by ATP gamma S pretreatment. 相似文献
182.
N omega-nitro-L-arginine: a potent inhibitor of the L-arginine-dependent soluble guanylate cyclase activation pathway in LLC-PK1 cells 总被引:1,自引:0,他引:1
Oxytocin increased cyclic GMP levels in LLC-PK1 porcine kidney epithelial cells through activation of soluble guanylate cyclase. NG-Monomethyl-L-arginine and N omega-nitro-L-arginine inhibited oxytocin (10 microM) induced cyclic GMP accumulation with IC50 values of 2.3 microM and 140 nM, respectively, and the inhibition was prevented with L-arginine. Both inhibitors at 100 microM lowered the basal levels of cyclic GMP, but did not affect those induced by 1 microM sodium nitroprusside and 100 nM atrial natriuretic factor. These data support our hypothesis that an endothelium-derived relaxing factor-like substance is formed as the endogenous activator of soluble guanylate cyclase in an L-arginine-dependent fashion in various cell types. N omega-Nitro-L-arginine is 16 times more potent than NG-monomethyl-L-arginine as a specific inhibitor of this pathway in LLC-PK1 cells. 相似文献
183.
The tumor-suppressing activity of angiostatin protein resides within kringles 1 to 3. 总被引:8,自引:0,他引:8
N J MacDonald A C Murad W E Fogler Y Lu B K Sim 《Biochemical and biophysical research communications》1999,264(2):469-477
Angiostatin protein, which comprises the first four kringle domains of plasminogen, is an endogenous inhibitor of angiogenesis that inhibits the growth of experimental primary and metastatic tumors. Truncation of Angiostatin K1-4 to K1-3 retained the activity of Angiostatin. We recombinantly expressed full-length human Angiostatin protein corresponding to the first four kringle domains of human plasminogen and a truncated form of the Angiostatin protein, kringles 1-3. Purified recombinant Angiostatin K1-3 and K1-4 proteins inhibited the formation of experimental B16-BL6 lung metastases by greater than 80% when administered at 30 nmol/kg/day. We demonstrate for the first time that Angiostatin protein, consisting of the first three kringle domains of human plasminogen, has in vivo biological activity in this assay indistinguishable from that of the full-length Angiostatin K1-4 protein and that the fourth kringle of plasminogen, when linked in sequence to K1-3, plays no direct role in the antitumor activity of Angiostatin. 相似文献
184.
Influence of a natural and a synthetic inhibitor of factor XIIIa on fibrin clot rheology 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《Biophysical journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
We investigated the origins of greater clot rigidity associated with FXIIIa-dependent cross-linking. Fibrin clots were examined in which cross-linking was controlled through the use of two inhibitors: a highly specific active-center-directed synthetic inhibitor of FXIIIa, 1,3-dimethyl-4,5-diphenyl-2[2(oxopropyl)thio]imidazolium trifluoromethylsulfonate, and a patient-derived immunoglobulin directed mainly against the thrombin-activated catalytic A subunits of thrombin-activated FXIII. Cross-linked fibrin chains were identified and quantified by one- and two-dimensional gel electrophoresis and immunostaining with antibodies specific for the alpha- and gamma-chains of fibrin. Gamma-dimers, gamma-multimers, alpha(n)-polymers, and alpha(p)gamma(q)-hybrids were detected. The synthetic inhibitor was highly effective in preventing the production of all cross-linked species. In contrast, the autoimmune antibody of the patient caused primarily an inhibition of alpha-chain cross-linking. Clot rigidities (storage moduli, G') were measured with a cone and plate rheometer and correlated with the distributions of the various cross-linked species found in the clots. Our findings indicate that the FXIIIa-induced dimeric cross-linking of gamma-chains by itself is not sufficient to stiffen the fibrin networks. Instead, the augmentation of clot rigidity was more strongly correlated with the formation of gamma-multimers, alpha(n)-polymers, and alpha(p)gamma(q)-hybrid cross-links. A mechanism is proposed to explain how these cross-linked species may enhance clot rigidity. 相似文献
185.
186.
Carvalho SE Freitas D Murad AM Franco OL Simões-Barbosa A 《Experimental parasitology》2005,111(4):260-263
This work describes the identification of a triacylglycerol lipase named TVLip directly onto blood-LB-agar plates by hemolytic screening of a Trichomonas vaginalis cDNA expression library. Sharing significant similarity in the primary sequence with other lipases, the theoretical 3D structure of the TVLip was resolved. The structure reveals the predictive conserved characteristics of other lipases from EC3.1.1.3 group, although presenting one amino acid change in the catalytic triad Ser-His-Asp. Finally, analysis of Northern blot indicates that the expression of the TVLip gene is up-regulated by iron. 相似文献
187.
Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production 总被引:7,自引:0,他引:7
Kukar T Murphy MP Eriksen JL Sagi SA Weggen S Smith TE Ladd T Khan MA Kache R Beard J Dodson M Merit S Ozols VV Anastasiadis PZ Das P Fauq A Koo EH Golde TE 《Nature medicine》2005,11(5):545-550
Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising compounds increase Abeta42 levels in the brains of mice. The elevations in Abeta42 by these compounds are comparable to the increases in Abeta42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Abeta42 production in humans. 相似文献
188.
Marsupials and monotremes sort genome treasures from junk 总被引:1,自引:0,他引:1
A recent landmark paper demonstrates the unique contribution of marsupials and monotremes to comparative genome analysis, filling an evolutionary gap between the eutherian mammals (including humans) and more distant vertebrate species. 相似文献
189.
190.
This study describes the relative contribution of the 10 cysteine residues in lysyl hydroxylase 1 (LH1) to enzyme activity. We have identified a novel mutation of a 15-bp deletion in exon 11 in one LH1 allele, that codes for amino acids 367-371 (DLCRQ), in two unrelated compound heterozygous patients with Ehlers-Danlos type VI. The mutations in their other alleles were a C1119T change (exon 10) and a predicted Q49X (exon 2). We confirmed that the loss of cysteine 369 in the deleted sequence contributed to the diminished enzyme activity by structure/function analysis of mutant LH1 constructs, in which C369 and the nine other cysteines were individually mutated to serine by site-directed mutagenesis of a normal pAcGP67/LH1cDNA construct. Following their expression in an Sf9 insect cell/baculovirus system, SDS-PAGE and Western analysis showed that equivalent levels of correctly-sized (85-kDa) products were secreted. The mutation of residues C369 and also C375, C552 and C687 virtually eliminated LH activity, whereas mutations of C267, C270, and C680 had an intermediate effect. In contrast, the C204S, C484S and C566S constructs had normal activity. Although disulfide bond formation may affect the relative contribution of each cysteine to LH activity, catalytic activity does not appear to be directly related to dimerization of the enzyme. 相似文献