全文获取类型
收费全文 | 2130篇 |
免费 | 332篇 |
专业分类
2462篇 |
出版年
2021年 | 29篇 |
2017年 | 22篇 |
2016年 | 33篇 |
2015年 | 48篇 |
2014年 | 53篇 |
2013年 | 82篇 |
2012年 | 94篇 |
2011年 | 84篇 |
2010年 | 59篇 |
2009年 | 44篇 |
2008年 | 74篇 |
2007年 | 76篇 |
2006年 | 61篇 |
2005年 | 80篇 |
2004年 | 65篇 |
2003年 | 61篇 |
2002年 | 62篇 |
2001年 | 67篇 |
2000年 | 61篇 |
1999年 | 54篇 |
1998年 | 20篇 |
1997年 | 21篇 |
1996年 | 23篇 |
1995年 | 24篇 |
1993年 | 24篇 |
1992年 | 48篇 |
1991年 | 40篇 |
1990年 | 51篇 |
1989年 | 47篇 |
1988年 | 36篇 |
1987年 | 41篇 |
1986年 | 36篇 |
1985年 | 40篇 |
1984年 | 38篇 |
1983年 | 48篇 |
1982年 | 40篇 |
1980年 | 33篇 |
1979年 | 28篇 |
1978年 | 35篇 |
1977年 | 21篇 |
1976年 | 23篇 |
1975年 | 23篇 |
1974年 | 27篇 |
1973年 | 32篇 |
1972年 | 28篇 |
1971年 | 23篇 |
1970年 | 23篇 |
1969年 | 29篇 |
1968年 | 30篇 |
1966年 | 26篇 |
排序方式: 共有2462条查询结果,搜索用时 15 毫秒
1.
2.
Shreaya Chakroborty Clark Briggs Megan B. Miller Ivan Goussakov Corinne Schneider Joyce Kim Jaime Wicks Jill C. Richardson Vincent Conklin Benjamin G. Cameransi Grace E. Stutzmann 《PloS one》2012,7(12)
Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients. 相似文献
3.
A new method for the analysis of NMR data in terms of the solution structure of proteins has been developed. The method consists of two steps: first a systematic search of the conformational space to define the region allowed by the initial set of experimental constraints, and second, the narrowing of this region by the introduction of additional constraints and optional refinement procedures. The search of the conformational space is guided by heuristics to make it computationally feasible. The method is therefore called the heuristic refinement method and is coded in an expert system called PROTEAN. The paper describes the validation of the first step of the method using an artificial NMR data set generated from the known crystal structure of sperm whale carbon monoxymyoglobin. It is shown that the initial search procedure yields a low-resolution structure of the myoglobin molecule, accurately reproducing its main topological features, and that the precision of the structure depends on the quality of the initial data set. 相似文献
4.
5.
6.
7.
8.
9.
Ion-Exchange Chromatography Separates Activities Synthesizing and Degrading Fructose 2,6-Bisphosphate from C3 and C4 Leaves but Not from Rat Liver 总被引:1,自引:1,他引:0 下载免费PDF全文
Fructose-6-phosphate,2-kinase and fructose-2,6-bisphosphatase were separated on the basis of charge from leaves of C3 (spinach, lettuce, and pea) and C4 (sorghum and amaranthus) plants but not from rat liver—a tissue known to contain a bifunctional enzyme with both activities. [2-32P]Fructose 2,6-bisphosphate binding experiments also suggest that the major forms of these activities reside on different proteins in leaves. 相似文献
10.
Protein translocation into Escherichia coli membrane vesicles is inhibited by functional synthetic signal peptides 总被引:7,自引:0,他引:7
A synthetic peptide corresponding to the signal sequence of wild type Escherichia coli lambda-receptor protein (LamB) inhibits in vitro translocation of precursors of both alkaline phosphatase and outer membrane protein A into E. coli membrane vesicles (half-maximal inhibition at 1-2 microM). By contrast, the inhibitory effect was nearly absent in a synthetic peptide corresponding to the signal sequence from a mutant strain that harbors a deletion mutation in the LamB signal region and displays an export-defective phenotype for this protein in vivo. Two peptides derived from pseudorevertant strains that arose from the deletion mutant and exported LamB in vivo were found to inhibit in vitro translocation with effectiveness that correlated with their in vivo export ability. Controls indicated that these synthetic signal peptides did not disrupt the E. coli membrane vesicles. These results can be interpreted to indicate that the presequences of exported proteins interact specifically with a receptor either in the E. coli inner membrane or in the cytoplasmic fraction. However, biophysical data for the family of signal peptides studied here reveal that they will spontaneously insert into a lipid membrane at concentrations comparable to those that cause inhibition. Hence, an indirect effect mediated by the lipid bilayer of the membrane must be considered. 相似文献