全文获取类型
收费全文 | 289篇 |
免费 | 45篇 |
出版年
2019年 | 2篇 |
2018年 | 4篇 |
2017年 | 3篇 |
2016年 | 3篇 |
2015年 | 6篇 |
2014年 | 7篇 |
2013年 | 5篇 |
2012年 | 12篇 |
2011年 | 10篇 |
2010年 | 8篇 |
2009年 | 3篇 |
2008年 | 6篇 |
2007年 | 15篇 |
2006年 | 13篇 |
2005年 | 17篇 |
2004年 | 16篇 |
2003年 | 12篇 |
2002年 | 9篇 |
2001年 | 12篇 |
2000年 | 12篇 |
1999年 | 10篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 10篇 |
1989年 | 11篇 |
1988年 | 8篇 |
1987年 | 12篇 |
1986年 | 6篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 5篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1974年 | 5篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1970年 | 3篇 |
1967年 | 3篇 |
1966年 | 2篇 |
1954年 | 1篇 |
排序方式: 共有334条查询结果,搜索用时 15 毫秒
91.
Effective antivirals are few and far between, and as such, the appearance of resistance toward such treatments is an obvious medical concern. In this article, we analyze the mechanism by which influenza attains resistance toward amantadine, a blocker of the viral M2 H(+) channel. Binding analyses of amantadine to M2 peptides from different viral strains showed that the virus has developed two alternate routes to avoid blockage of its channel: (1) a conventional route, in which the channel no longer binds the blocker and, hence, the blocker cannot exert its inhibitory function; and (2) a novel mechanism, in which binding of the blocker is retained, yet the function of the protein is unaffected. Pore diameter profiles revealed the molecular mechanism by which the virus may attain this novel type of resistance: an increase in the size of the channel. Thus, despite the drug binding the channel, it may not be able to block the pore, since the channel diameter has increased. Our findings may have broad ramifications in the design of new antivirals, and of novel blockers against malfunctioning human channels implicated in disease. 相似文献
92.
Modulation of cardiac sodium channel gating by protein kinase A can be altered by disease-linked mutation 总被引:3,自引:0,他引:3
Tateyama M Rivolta I Clancy CE Kass RS 《The Journal of biological chemistry》2003,278(47):46718-46726
Mutations associated with sodium channel-linked inherited Long-QT syndrome often result in a gain of channel function by disrupting channel inactivation. A small fraction of channels fail to inactivate (burst) at depolarized potentials where normal (wild type) channels fully inactivate. These noninactivating channels give rise to a sustained macroscopic current. We studied the effects of protein kinase A stimulation on sustained current in wild type and three disease-linked C-terminal mutant channels (D1790G, Y1795C, and Y1795H). We show that protein kinase A stimulation differentially affects gating in the mutant channels. Wild type, Y1795C, and Y1795H channels are insensitive to protein kinase A stimulation, whereas "bursting" in the D1790G mutant is markedly enhanced by protein kinase A-dependent phosphorylation. Our results suggest that the charge at position 1790 of the C terminus of the channel modulates the response of the cardiac sodium channel to protein kinase A stimulation and that phosphorylation of residue 36 in the N terminus and residue 525 in the cytoplasmic linker joining domains I and II of the channel alpha subunit facilitate destabilization of inactivation and thereby increase sustained current. 相似文献
93.
Bivalacqua TJ Hyman AL Kadowitz PJ Paolocci N Kass DA Champion HC 《Regulatory peptides》2002,108(2-3):129-133
Calcitonin gene-related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and may be involved in modulating the pulmonary vascular response to chronic hypoxia. In the present study, an adenoviral vector encoding CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP to the lung on increases in PVR, right ventricular mass, and pulmonary vascular remodeling that occurs in chronic hypoxia in the mouse. Following intratracheal administration of AdRSVCGRP or reporter gene mice were exposed to 16 days of chronic hypoxia (FIO(2) 0.10). The increase in pulmonary arterial pressure (PAP), PVR, right ventricular mass, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing CGRP, whereas systemic arterial pressure was not altered. Following exposure to hypoxia, a subgroup of mice were treated with capsaicin, which did not significantly alter CGRP expression in the mouse lung. These data show that in vivo transfer of the CGRP gene to the lung attenuates the increase in PVR, right ventricular mass, and pulmonary vascular remodeling in chronically hypoxic mice with little effect on the systemic circulation. Moreover, these data suggest that adenoviral gene transfer of CGRP to the lung results in expression of the gene product in non-neural tissue. 相似文献
94.
95.
Summary Kittens fed diets containing 2.0 and 3.0 times (X) the NRC (1986) essential amino acid (EAA) requirement (EAArq) and 210 to 560g crude protein (CP)/kg diet had growth rates and plasma amino acid patterns that were not significantly different than kittens fed a control diet (CD) containing 1.5 X EAArq and 350 g CP/kg diet. Growth rates of kittens fed diets containing only EAA (with nontoxic levels of arginine and methionine) and 280 to 460 g CP/kg diet were equivalent to those of kittens fed CD. Kittens fed only EAA and 140 and 210 g CP/kg diet had growth rates that were significantly lower than kittens fed CD. Since the growth rate of kittens fed 1.5X EAArq and 210 g CP/kg diet in a previous experiment was equivalent to kittens fed CD (Taylor et al., 1997), it is suggested that the requirement for CP is higher (up to 280 g CP/kg diet) when only EAA are fed. The higher crude protein requirement appears to be primarily a consequence of the high obligatory nitrogen loss as urea (especially from arginine) incurred in the conversion of nitrogen from EAA to dispensable amino acids in the liver and secondarily because of a slow rate of catabolism of the EAA. A 3-dimensional plot of weight gains vs. CP levels and EAA to total nitrogen (E: T) ratios of kittens shows a broad range of CP levels and E: T ratios that support optimal growth in the kitten. It is suggested that similar patterns would occur in the chick, rat and other species if adverse effects caused by excesses of specific amino acids are avoided.Presented in part at the Biology '96 Meeting in Washington, DC [Taylor TP, Deberry J, Morris JG, Rogers QR (1996) Effects of dietary nitrogen level and essential amino acid: total nitrogen (E: T) ratio on kitten weight gain. FASEB J 10: A737 (abs. 4259)] and in part at the Proceedings of the Waltham International Symposium, Pet Nutrition and Health in the 21st Century, Orlando, Florida, USA [Rogers QR, Taylor TP, Morris JG (1997) Optimizing dietary amino acid patterns at various levels of crude protein for the cat. J Nutr (abs.) (in press). 相似文献
96.
M. J. Mehlman J. R. Botkin A. Scarrow A. Woodhall J. Kass E. Siebenschuh 《American journal of human genetics》1994,55(5):1054-1060
This article examines the extent to which the technologies expected to emerge from genetic research are likely to be covered under Government-mandated health insurance programs such as those being proposed by advocates of national health reform. Genetic technologies are divided into three broad categories; genetic information services, including screening, testing, and counseling; experimental technologies; and gene therapy. This article concludes that coverage of these technologies under national health reform is uncertain. The basic benefits packages provided for in the major health reform plans are likely to provide partial coverage of experimental technologies; relatively broad coverage of information services; and varying coverage of gene therapies, on the basis of an evaluation of their costs, benefits, and the degree to which they raise objections on political and religious grounds. Genetic services that are not included in the basic benefits package will be available only to those who can purchase supplemental insurance or to those who can purchase the services with personal funds. The resulting multitiered system of access to genetic services raises serious questions of fairness. 相似文献
97.
Rabbit antisera capable of detecting chicken fetal antigen (CFA) was prepared against 1-day chick red blood cells (RBCs) and made specific by exhaustive adsorption with adult chicken peripheral RBCs (PRBCs) from the same strain. Microcytotoxicity was used to study the incidence of CFA on lymphocytes obtained from several organs at different developmental stages in the chicken. Lymphocyte-associated CFA (LA-CFA) determinants and erythrocyte-specific CFA (ES-CFA) determinants were distinguished through the use of adsorption analysis. The high incidence of CFA-positive lymphocytes found in the fetal bursa and thymus was not equaled in the peripheral organs of the spleen, cecal tonsils, and gland of Harder. CFA expression on adult lymphocytes was restricted to the thymus and peripheral blood. It is suggested that these cells may represent a subpopulation of T lymphocytes. Adult spleen, cecal tonsils, and gland of Harder were virtually devoid of CFA-bearing lymphocytes. At fetal developmental stages when greater than 94% of the bursal B cells were CFA-positive, few, if any, of the highly differentiated Harderian B cells possessed CFA. It is suggested that LA-CFA expression is dependent upon B cell differentiation and/or the bursa (central) vs gland of Harder (peripheral) microenvironment. The pattern of CFA expression on bursacytes is discussed in light of the properties of age resistance and bursal-dependent target cells associated with virally induced lymphoid leukosis. 相似文献
98.
Block of outward current in cardiac purkinje fibers by injection of quaternary ammonium ions 总被引:6,自引:5,他引:1 下载免费PDF全文
We have studied the effects of iontophoretic injection of the quaternary ammonium compounds tetraethylammonium (TEA) and tetrabutylammonium (TBA) in cardiac purkinje fibers. We find that TBA(+) is a more effective blocker than TEA(+), but injection of either compound reduces the time-dependent outward plateau currents, transient outward current (I(to)), and the delayed rectifier (I(x)). Our findings provide evidence that these outward cardiac currents are carried by channels that in some respects are pharmacologically similar to squid axon potassium channels. We demonstrate that this procedure is a new tool that can be useful in the analysis of membrane currents in the heart. 相似文献
99.
Motoike HK Liu H Glaaser IW Yang AS Tateyama M Kass RS 《The Journal of general physiology》2004,123(2):155-165
Electrical activity in nerve, skeletal muscle, and heart requires finely tuned activity of voltage-gated Na+ channels that open and then enter a nonconducting inactivated state upon depolarization. Inactivation occurs when the gate, the cytoplasmic loop linking domains III and IV of the alpha subunit, occludes the open pore. Subtle destabilization of inactivation by mutation is causally associated with diverse human disease. Here we show for the first time that the inactivation gate is a molecular complex consisting of the III-IV loop and the COOH terminus (C-T), which is necessary to stabilize the closed gate and minimize channel reopening. When this interaction is disrupted by mutation, inactivation is destabilized allowing a small, but important, fraction of channels to reopen, conduct inward current, and delay cellular repolarization. Thus, our results demonstrate for the first time that physiologically crucial stabilization of inactivation of the Na+ channel requires complex interactions of intracellular structures and indicate a novel structural role of the C-T domain in this process. 相似文献
100.
Paolocci N Ekelund UE Isoda T Ozaki M Vandegaer K Georgakopoulos D Harrison RW Kass DA Hare JM 《American journal of physiology. Heart and circulatory physiology》2000,279(4):H1982-H1988
Nitric oxide (NO) has concentration-dependent biphasic myocardial contractile effects. We tested the hypothesis, in isolated rat hearts, that NO cardiostimulation is primarily non-cGMP dependent. Infusion of 3-morpholinosydnonimine (SIN-1, 10(-5) M), which may participate in S-nitrosylation (S-NO) via peroxynitrite formation, increased the rate of left ventricular pressure rise (+dP/dt; 19 +/- 4%, P < 0.001, n = 11) without increasing effluent cGMP or cAMP. Superoxide dismutase (SOD; 150 U/ml) blocked SIN-1 cardiostimulation and led to cGMP elaboration. Sodium nitroprusside (10(-10)-10(-7) M), an iron nitrosyl compound, did not augment +dP/dt but increased cGMP approximately eightfold (P < 0.001), whereas diethylamine/NO (DEA/NO; 10(-7) M), a spontaneous NO. donor, increased +dP/dt (5 +/- 2%, P < 0.05, n = 6) without augmenting cGMP. SIN-1 and DEA/NO +dP/dt increase persisted despite guanylyl cyclase inhibition with 1H-(1,2,4)oxadiazolo-(4,3,-a)quinoxalin-1-one (10(-5) M, P < 0.05 for both donors), suggesting a cGMP-independent mechanism. Glutathione (5 x 10(-4) M, n = 15) prevented SIN-1 cardiostimulation, suggesting S-NO formation. SIN-1 also produced SOD-inhibitable cardiostimulation in vivo in mice. Thus peroxynitrite and NO donors can stimulate myocardial contractility independently of guanylyl cyclase activation, suggesting a role for S-NO reactions in NO/peroxynitrite-positive inotropic effects in intact hearts. 相似文献