全文获取类型
收费全文 | 1998篇 |
免费 | 170篇 |
国内免费 | 2篇 |
出版年
2022年 | 17篇 |
2021年 | 27篇 |
2020年 | 18篇 |
2019年 | 21篇 |
2018年 | 21篇 |
2017年 | 28篇 |
2016年 | 57篇 |
2015年 | 98篇 |
2014年 | 102篇 |
2013年 | 146篇 |
2012年 | 164篇 |
2011年 | 145篇 |
2010年 | 100篇 |
2009年 | 80篇 |
2008年 | 112篇 |
2007年 | 88篇 |
2006年 | 82篇 |
2005年 | 76篇 |
2004年 | 78篇 |
2003年 | 66篇 |
2002年 | 56篇 |
2001年 | 55篇 |
2000年 | 49篇 |
1999年 | 37篇 |
1998年 | 21篇 |
1997年 | 21篇 |
1996年 | 26篇 |
1995年 | 11篇 |
1994年 | 24篇 |
1993年 | 12篇 |
1992年 | 24篇 |
1991年 | 28篇 |
1990年 | 19篇 |
1989年 | 12篇 |
1988年 | 18篇 |
1987年 | 17篇 |
1986年 | 17篇 |
1985年 | 15篇 |
1984年 | 9篇 |
1983年 | 16篇 |
1982年 | 13篇 |
1981年 | 11篇 |
1980年 | 11篇 |
1979年 | 20篇 |
1978年 | 10篇 |
1976年 | 19篇 |
1975年 | 12篇 |
1974年 | 6篇 |
1973年 | 8篇 |
1970年 | 8篇 |
排序方式: 共有2170条查询结果,搜索用时 187 毫秒
151.
Zho S Chiang D Chin R Kestell P Paxton JW 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2002,767(1):19-26
By screening potential inhibitors of drug metabolism using the in vitro models, potential drug-drug interactions in vivo may be predicted with the use of appropriate pharmacokinetic principles. This study aimed to develop a rapid screening system using human liver microsomes to efficiently identify the potential inhibitors of DMXAA metabolism. Initial IC50 was estimated by using a two-point method, and then Ki values were determined if required and compared with those initial IC50 values. More than 100 compounds including known substrates and inhibitors of human uridine diphosphate glucuronosyltransferases (UGTs) and cytochrome P450 (CYP), anti-cancer drugs and xanthenone analogues were screened for their inhibitory effect on DMXAA glucuronidation and 6-methylhydroxylation in human liver microsomes. Both metabolites of DMXAA, DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA), formed in human liver microsomes were quantitated by validated HPLC methods. The results indicated that there was a significant relationship (r2 = 0.966, P < 0.001) between the two-point IC50 values and the apparent Ki values for 20 compounds showing significant inhibitory effects on DMXAA metabolism, suggesting the usefulness of the two-point determination for the initial screening of compounds. This study has been completed using a strategy for rapid HPLC analysis and thus provided early access to detailed information for potential inhibitors of DMXAA metabolism and allows for further DMXAA-drug interaction studies. 相似文献
152.
Intracellular pH regulatory mechanism in human atrial myocardium: functional evidence for Na(+)/H(+) exchanger and Na(+)/HCO(3)(-) symporter 总被引:1,自引:0,他引:1
Loh SH Chen WH Chiang CH Tsai CS Lee GC Jin JS Cheng TH Chen JJ 《Journal of biomedical science》2002,9(3):198-205
Intracellular pH (pH(i)) exerts considerable influence on cardiac contractility and rhythm. Over the last few years, extensive progress has been made in understanding the system that controls pH(i) in animal cardiomyocytes. In addition to the housekeeping Na(+)-H(+) exchanger (NHE), the Na(+)-HCO(3)(-) symporter (NHS) has been demonstrated in animal cardiomyocytes as another acid extruder. However, whether the NHE and NHS functions exist in human atrial cardiomyocytes remains unclear. We therefore investigated the mechanism of pH(i) recovery from intracellular acidosis (induced by NH(4)Cl prepulse) using intracellular 2',7'-bis(2-carboxethyl)-5(6)-carboxy-fluorescein fluorescence in human atrial myocardium. In HEPES (nominally HCO(3)(-)-free) Tyrode solution, pH(i) recovery from induced intracellular acidosis could be blocked completely by 30 microM 3-methylsulfonyl-4-piperidinobenzoyl, guanidine hydrochloride (HOE 694), a specific NHE inhibitor, or by removing extracellular Na(+). In 3% CO(2)-HCO(3)(-) Tyrode solution, HOE 694 only slowed the pH(i) recovery, while addition of HOE 694 together with 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (an NHS inhibitor) or removal of extracellular Na(+) inhibited the acid extrusion entirely. Therefore, in the present study, we provided evidence that two acid extruders involved in acid extrusion in human atrial myocytes, one which is HCO(3)(-) independent and one which is HCO(3)(-) dependent, are mostly likely NHE and NHS, respectively. When we checked the percentage of contribution of these two carriers to pH(i) recovery following induced acidosis, we found that the activity of NHE increased steeply in the acid direction, while that of NHS did not change. Our present data indicate for the first time that two acid extruders, NHE and NHS, exist functionally and pH(i) dependently in human atrial cardiomyocytes. 相似文献
153.
Genistein inhibits the inward rectifying potassium current in guinea pig ventricular myocytes 总被引:3,自引:0,他引:3
Genistein is an isoflavone with potent inhibitory activity on protein tyrosine kinase. Previous studies have shown that genistein has additional effects, among which the direct blocking effects on various ionic channels have recently been disclosed. Using whole-cell voltage clamp and current clamp techniques, we demonstrate that micromolar concentrations of genistein dose-dependently and reversibly inhibit the inward rectifying K(+) current, and depolarize the resting membrane potential, resulting in abnormal automaticity in guinea pig ventricular myocytes. Interestingly, another potent tyrosine kinase inhibitor, tyrphostin 51, did not produce the same inhibitory effect, while the inactive analogue of genistein, daidzein, had a similar blocking effect. We suggest that genistein directly blocks the inward rectifying K(+) current in ventricular myocytes, and one should be cautious of its pro-arrhythmic effect in clinical use. 相似文献
154.
155.
MeKE: discovering the functions of gene products from biomedical literature via sentence alignment 总被引:3,自引:0,他引:3
MOTIVATION: Research on roles of gene products in cells is accumulating and changing rapidly, but most of the results are still reported in text form and are not directly accessible by computers. To expedite the progress of functional bioinformatics, it is, therefore, important to efficiently process large amounts of biomedical literature and transform the knowledge extracted into a structured format usable by biologists and medical researchers. Our aim was to develop an intelligent text-mining system that will extract from biomedical documents knowledge about the functions of gene products and thus facilitate computing with function. RESULTS: We have developed an ontology-based text-mining system to efficiently extract from biomedical literature knowledge about the functions of gene products. We also propose methods of sentence alignment and sentence classification to discover the functions of gene products discussed in digital texts. AVAILABILITY: http://ismp.csie.ncku.edu.tw/~yuhc/meke/ 相似文献
156.
Single-cell transcript analysis of pancreas development 总被引:9,自引:0,他引:9
157.
Schaphorst KL Chiang E Jacobs KN Zaiman A Natarajan V Wigley F Garcia JG 《American journal of physiology. Lung cellular and molecular physiology》2003,285(1):L258-L267
In vitro and in vivo evidence indicates that circulating platelets affect both vascular integrity and hemostasis. How platelets enhance the permeability barrier of the vascular endothelium is not well understood. We measured the effect of isolated human platelets on human pulmonary artery endothelial cell (EC) barrier integrity by monitoring transmonolayer electrical resistance. EC barrier function was significantly increased by the addition of platelets ( approximately 40% maximum, 2.5 x 106 platelets/ml). Platelet supernatants, derived from 2.5 x 106 platelets/ml, reproduced the barrier enhancement and reversed the barrier dysfunction produced by the edemagenic agonist thrombin, which implicates a soluble barrier-promoting factor. The barrier-enhancing effect of platelet supernatants was heat stable but was attenuated by either charcoal delipidation (suggesting a vasoactive lipid mediator) or pertussis toxin, implying involvement of a Gialpha-coupled receptor signal transduction pathway. Sphingosine-1-phosphate (S1P), a sphingolipid that is released from activated platelets, is known to ligate G protein-coupled EC differentiation gene (EDG) receptors, increase EC electrical resistance, and reorganize the actin cytoskeleton (Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, and English D. J Clin Invest 108: 689-701, 2001). Infection of EC with an adenoviral vector expressing an antisense oligonucleotide directed against EDG-1 but not infection with control vector attenuated the barrier-enhancing effect of both platelet supernatants and S1P. These results indicate that a major physiologically relevant vascular barrier-protective mediator produced by human platelets is S1P. 相似文献
158.
The incidence of obesity has reached epidemic proportions within industrial societies; however, research on human obesity has been hampered by our inability to control genetic and environmental factors. The control of energy homeostasis appears to be conserved among species. Recent creative research in Caenorhabditis elegans, including the application of a genome-wide RNA interference analysis, has provided insight into the genes involved in energy balance. In this article, we discuss the results of these studies and their potential importance to humans. 相似文献
159.
TCGAP,a multidomain Rho GTPase-activating protein involved in insulin-stimulated glucose transport 总被引:5,自引:0,他引:5
Insulin stimulates glucose uptake in fat and muscle cells via the translocation of the GLUT4 glucose transporter from intracellular storage vesicles to the cell surface. The signaling pathways linking the insulin receptor to GLUT4 translocation in adipocytes involve activation of the Rho family GTPases TC10alpha and beta. We report here the identification of TCGAP, a potential effector for Rho family GTPases. TCGAP consists of N-terminal PX and SH3 domains, a central Rho GAP domain and multiple proline-rich regions in the C-terminus. TCGAP specifically interacts with cdc42 and TC10beta through its GAP domain. Although it has GAP activity in vitro, TCGAP is not active as a GAP in intact cells. TCGAP translocates to the plasma membrane in response to insulin in adipocytes. The N-terminal PX domain interacts specifically with phos phatidylinositol-(4,5)-bisphosphate. Overexpression of the full-length and C-terminal fragments of TCGAP inhibits insulin-stimulated glucose uptake and GLUT4 translocation. Thus, TCGAP may act as a downstream effector of TC10 in the regulation of insulin-stimulated glucose transport. 相似文献
160.
The exocytotic trafficking of TC10 occurs through both classical and nonclassical secretory transport pathways in 3T3L1 adipocytes 下载免费PDF全文
Watson RT Furukawa M Chiang SH Boeglin D Kanzaki M Saltiel AR Pessin JE 《Molecular and cellular biology》2003,23(3):961-974
To examine the structural determinants necessary for TC10 trafficking, localization, and function in adipocytes, we generated a series of point mutations in the carboxyl-terminal targeting domain of TC10. Wild-type TC10 (TC10/WT) localized to secretory membrane compartments and caveolin-positive lipid raft microdomains at the plasma membrane. Expression of a TC10/C206S point mutant resulted in a trafficking and localization pattern that was indistinguishable from that of TC10/WT. In contrast, although TC10/C209S or the double TC10/C206,209S mutant was plasma membrane localized, it was excluded from both the secretory membrane system and the lipid raft compartments. Surprisingly, inhibition of Golgi membrane transport with brefeldin A did not prevent plasma membrane localization of TC10 or H-Ras. Moreover, inhibition of trans-Golgi network exit with a 19 degrees C temperature block did not prevent the trafficking of TC10 or H-Ras to the plasma membrane. These data demonstrate that TC10 and H-Ras can both traffic to the plasma membrane by at least two distinct transport mechanisms in adipocytes, one dependent upon intracellular membrane transport and another independent of the classical secretory membrane system. Moreover, the transport through the secretory pathway is necessary for the localization of TC10 to lipid raft microdomains at the plasma membrane. 相似文献