全文获取类型
收费全文 | 3571篇 |
免费 | 342篇 |
出版年
2023年 | 12篇 |
2022年 | 30篇 |
2021年 | 59篇 |
2020年 | 33篇 |
2019年 | 50篇 |
2018年 | 53篇 |
2017年 | 51篇 |
2016年 | 71篇 |
2015年 | 135篇 |
2014年 | 140篇 |
2013年 | 205篇 |
2012年 | 259篇 |
2011年 | 251篇 |
2010年 | 141篇 |
2009年 | 117篇 |
2008年 | 227篇 |
2007年 | 233篇 |
2006年 | 207篇 |
2005年 | 220篇 |
2004年 | 192篇 |
2003年 | 176篇 |
2002年 | 152篇 |
2001年 | 58篇 |
2000年 | 39篇 |
1999年 | 57篇 |
1998年 | 61篇 |
1997年 | 52篇 |
1996年 | 35篇 |
1995年 | 41篇 |
1994年 | 29篇 |
1993年 | 30篇 |
1992年 | 29篇 |
1991年 | 38篇 |
1990年 | 28篇 |
1989年 | 27篇 |
1988年 | 15篇 |
1987年 | 26篇 |
1986年 | 21篇 |
1985年 | 25篇 |
1984年 | 18篇 |
1983年 | 14篇 |
1982年 | 18篇 |
1981年 | 20篇 |
1980年 | 17篇 |
1979年 | 13篇 |
1978年 | 14篇 |
1977年 | 14篇 |
1974年 | 18篇 |
1973年 | 15篇 |
1972年 | 13篇 |
排序方式: 共有3913条查询结果,搜索用时 31 毫秒
111.
112.
Linking phospholipase C isoforms with differentiation function in human vascular smooth muscle cells
Louise S. Mackenzie Joanne S. Lymn Alun D. Hughes 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2013,1833(12):3006-3012
The phosphoinositol-phospholipase C (PLC) family of enzymes consists of a number of isoforms, each of which has different cellular functions. PLCγ1 is primarily linked to tyrosine kinase transduction pathways, whereas PLCδ1 has been associated with a number of regulatory proteins, including those controlling the cell cycle. Recent studies have shown a central role of PLC in cell organisation and in regulating a wide array of cellular responses. It is of importance to define the precise role of each isoform, and how this changes the functional outcome of the cell. Here we investigated differences in PLC isoform levels and activity in relation to differentiation of human and rat vascular smooth muscle cells. Using Western blotting and PLC activity assay, we show that PLCδ1 and PLCγ1 are the predominant isoforms in randomly cycling human vascular smooth muscle cells (HVSMCs). Growth arrest of HVSMCs for seven days of serum deprivation was consistently associated with increases in PLCδ1 and SM α-actin, whereas there were no changes in PLCγ1 immuno-reactivity. Organ culture of rat mesenteric arteries in serum free media (SFM), a model of de-differentiation, led to a loss of contractility as well as a loss of contractile proteins (SM α-actin and calponin) and PLCδ1, and no change in PLCγ1 immuno-reactivity. Taken together, these data indicate that PLCδ1 is the predominant PLC isoform in vascular smooth muscle, and confirm that PLCδ1 expression is affected by conditions that affect the cell cycle, differentiation status and contractile function. 相似文献
113.
Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol’s neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases. 相似文献
114.
David R. Bauman Alan Whitehead Lisa C. Contino Jisong Cui Margarita Garcia-Calvo Xin Gu Nancy Kevin Xiuying Ma Lee-yuh Pai Kashmira Shah Xiaolan Shen Sloan Stribling Hratch J. Zokian Joe Metzger Diane E. Shevell Sherman T. Waddell 《Bioorganic & medicinal chemistry letters》2013,23(12):3650-3653
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway. 相似文献
115.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Michael A. Briggs Andrew R. Calver Barry Crook Robert P. Davis Susannah Davis David K. Dean Leanne Harris Tom D. Heightman Terry Panchal Christopher A. Parr Nigel Quashie Jon G.A. Steadman Joanne Schogger Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6897-6901
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. 相似文献
116.
117.
Yong-Jin Wu Huan He Robert Bertekap Ryan Westphal Snjezana Lelas Amy Newton Tanya Wallace Matthew Taber Carl Davis John E. Macor Joanne Bronson 《Bioorganic & medicinal chemistry》2013,21(8):2217-2228
This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders. 相似文献
118.
119.
M. Joanne Lemieux 《Protein science : a publication of the Protein Society》2013,22(4):425-433
The overexpression of milligram quantities of protein remains a key bottleneck in membrane protein structural biology. A challenge of particular difficulty has been the overproduction of eukaryotic membrane proteins. In order to cope with the frequently poor expression levels associated with these challenging proteins, it is often necessary to screen a large number of homologues to find a well expressing clone. To facilitate this process using the heterologous, eukaryotic expression host Pichia pastoris, we have developed a simple fluorescent induction plate‐screening assay that allows for the rapid detection of well expressing clones of eukaryotic membrane proteins that have been fused to GFP. Using a eukaryotic membrane protein known to express well in P. pastoris (human aquaporin 4) and homologues of the ER associated membrane protein phosphatidylethanolamine N‐methyltransferase (PEMT), we demonstrate that when a large number of clones are screened, a small number of highly expressing “jackpot” clones can be isolated. A jackpot PEMT clone resulted in 5 mg/L yield after purification. The method allows for the facile simultaneous screening of hundreds of clones providing an alternate to in‐culture screening and will greatly accelerate the search for overexpressing eukaryotic membrane proteins. 相似文献
120.
Mark Clendenning Joanne P. Young Michael D. Walsh Sonja Woodall Julie Arnold Mark Jenkins Aung Ko Win John L. Hopper Kevin Sweet Steven Gallinger Christophe Rosty Susan Parry Daniel D. Buchanan 《PloS one》2013,8(6)