全文获取类型
收费全文 | 2345篇 |
免费 | 189篇 |
国内免费 | 1篇 |
出版年
2023年 | 10篇 |
2022年 | 30篇 |
2021年 | 33篇 |
2020年 | 19篇 |
2019年 | 29篇 |
2018年 | 28篇 |
2017年 | 22篇 |
2016年 | 53篇 |
2015年 | 129篇 |
2014年 | 158篇 |
2013年 | 179篇 |
2012年 | 195篇 |
2011年 | 194篇 |
2010年 | 110篇 |
2009年 | 109篇 |
2008年 | 130篇 |
2007年 | 121篇 |
2006年 | 109篇 |
2005年 | 108篇 |
2004年 | 102篇 |
2003年 | 72篇 |
2002年 | 70篇 |
2001年 | 66篇 |
2000年 | 56篇 |
1999年 | 46篇 |
1998年 | 28篇 |
1997年 | 16篇 |
1996年 | 13篇 |
1995年 | 11篇 |
1994年 | 12篇 |
1993年 | 7篇 |
1992年 | 26篇 |
1991年 | 40篇 |
1990年 | 24篇 |
1989年 | 17篇 |
1988年 | 19篇 |
1987年 | 14篇 |
1986年 | 13篇 |
1985年 | 13篇 |
1983年 | 6篇 |
1981年 | 5篇 |
1980年 | 6篇 |
1979年 | 8篇 |
1978年 | 11篇 |
1977年 | 11篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1974年 | 8篇 |
1971年 | 4篇 |
1969年 | 5篇 |
排序方式: 共有2535条查询结果,搜索用时 15 毫秒
151.
Miller LN Nakane M Hsieh GC Chang R Kolasa T Moreland RB Brioni JD 《Life sciences》2003,72(9):1015-1025
Nitric oxide (NO) is a key mediator in many physiological processes and one of the major receptors through which NO exerts its effects is soluble guanylyl cyclase. Guanylyl cyclase converts GTP to cyclic GMP as part of the cascade that results in physiological processes such as smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation and immune response. The properties of A-350619, a novel soluble guanylyl cyclase activator, were examined to determine the modulatory effect on the catalytic properties of soluble guanylyl cyclase. A-350619 increased V(max) from 0.1 to 14.5 micromol/min/mg (145 fold increase), and lowered K(m) from 300 to 50 microM (6 fold decrease). When YC-1 (another sGC activator) and A-350619 were combined, a 156 fold increase in V(max) and a 5 fold decrease in Km were observed, indicating that the modulation of the enzyme brought about by YC-1 and A-350619 are not additive, suggesting a common binding site. Activation of soluble guanylyl cyclase by A-350619 was partially inhibited by ODQ, a specific inhibitor of soluble guanylyl cyclase by oxidation of the enzyme heme. YC-1 and A-350619 after pre-treatment with N-omega-nitro-L-arginine, an NO-synthase inhibitor, relaxed cavernosum tissue strips in a dose-dependent manner with EC(50) of 50 microM and 80 microM, respectively. Addition of SNP potentiated the relaxation effect of YC-1 and A-350619, shifting the dose-response curve to the left to 3 microM and 10 microM, respectively. Consistent with its biochemical activity, A-350619 (1 micromol/kg) alone induced penile erection in a conscious rat model. Activation of soluble guanylyl cyclase in cavernosum tissue as an alternate method of enhancing the effect of NO may provide a novel treatment of sexual dysfunction. 相似文献
152.
Mixed-model reanalysis of primate data suggests tissue and species biases in oligonucleotide-based gene expression profiles 总被引:13,自引:0,他引:13
An emerging issue in evolutionary genetics is whether it is possible to use gene expression profiling to identify genes that are associated with morphological, physiological, or behavioral divergence between species and whether these genes have undergone positive selection. Some of these questions were addressed in a recent study (Enard et al. 2002) of the difference in gene expression among human, chimp, and orangutan, which suggested an accelerated rate of divergence in gene expression in the human brain relative to liver. Reanalysis of the Affymetrix data set using analysis of variance methods to quantify the contributions of individuals and species to variation in expression of 12,600 genes indicates that as much as one-quarter of the genome shows divergent expression between primate species at the 5% level. The magnitude of fold change ranges from 1.2-fold up to 8-fold. Similar conclusions apply to reanalysis of Enard et al. 2002 parallel murine data set. However, biases inherent to short oligonucleotide microarray technology may account for some of the tissue and species effects. At high significance levels, more differences were observed in the liver than in the brain in each of the pairwise species comparisons, so it is not clear that expression divergence is accelerated in the human brain. Further, there is an apparent bias toward upregulation of gene expression in the brain in both primates and mice, whereas genes are equally likely to be up- or downregulated in the liver when these species diverge. A small subset of genes that are candidates for adaptive divergence may be identified on the basis of a high ratio of interspecific to intraspecific divergence. 相似文献
153.
154.
155.
Alani E Lee JY Schofield MJ Kijas AW Hsieh P Yang W 《The Journal of biological chemistry》2003,278(18):16088-16094
During mismatch repair ATP binding and hydrolysis activities by the MutS family proteins are important for both mismatch recognition and for transducing mismatch recognition signals to downstream repair factors. Despite intensive efforts, a MutS.ATP.DNA complex has eluded crystallographic analysis. Searching for ATP analogs that strongly bound to Thermus aquaticus (Taq) MutS, we found that ADP.beryllium fluoride (ABF), acted as a strong inhibitor of several MutS family ATPases. Furthermore, ABF promoted the formation of a ternary complex containing the Saccharomyces cerevisiae MSH2.MSH6 and MLH1.PMS1 proteins bound to mismatch DNA but did not promote dissociation of MSH2.MSH6 from mismatch DNA. Crystallographic analysis of the Taq MutS.DNA.ABF complex indicated that although this complex was very similar to that of MutS.DNA.ADP, both ADP.Mg(2+) moieties in the MutS. DNA.ADP structure were replaced by ABF. Furthermore, a disordered region near the ATP-binding pocket in the MutS B subunit became traceable, whereas the equivalent region in the A subunit that interacts with the mismatched nucleotide remained disordered. Finally, the DNA binding domains of MutS together with the mismatched DNA were shifted upon binding of ABF. We hypothesize that the presence of ABF is communicated between the two MutS subunits through the contact between the ordered loop and Domain III in addition to the intra-subunit helical lever arm that links the ATPase and DNA binding domains. 相似文献
156.
Thrombopoietin receptor (TPOR) is a member of the cytokine receptor superfamily expressed primarily on hematopoietic cells. TPOR plays an important role in regulating platelet production. Due to its low expression level in human tissue, studies on the biochemical and biophysical properties of TPOR have been limited. In the present study, an extracellular domain of recombinant human TPOR (rh TPOR-EN) was expressed in Escherichia coli as inclusion bodies. Purification was achieved by metal chelated chromatography under denaturing condition and was refolded by gel filtration chromatography. Far UV circular dichroism spectroscopy and surface plasmon resonance experiments were performed to demonstrate that the protein was in a refolded state and could bind with its ligand. Thus, a production and purification scheme was developed by which sufficient quantities of rh TPOR-EN can be made available for biochemical and biophysical characterizations. 相似文献
157.
A six-year prospective study of Chlamydia trachomatis infection and ocular disease in Tanzanian village children was conducted to identify the determinants of trachoma endemicity using sequencing of ompA. Overall, 749 conjunctival samples were obtained, with 176 children sampled in both 1989 and 1995. 31.1% (233/749) were positive by PCR-enzyme immunoassay, and 76% (176/233) of the positives were sequenced in variable domains (VD) 1 to 4 (22 children in both 1989 and 1995). Twenty-six ompA genotypes of serovar A, and 19 of B/Ba were identified, and only 20% of genotypes identified in 1995 matched those found in 1989. In particular, B/Ba genotypes exhibited a 15-base region in VD 2 with increased nucleotide substitution, and these types were associated with age and water availability. Homotypic infection and infection with multiple genotypes and high chlamydial load did predict subsequent severe trachoma (odds ratio (OR) = 10.14, 95% confidence interval (CI): 1.71, 60.23; OR = 6.40, 95% CI: 0.75, 54.41; OR = 6.74, 95% CI: 0.82, 55.38, respectively). And, multitypic infection was clustered with residence of village and associated with familial cattle ownership. In conclusion, high ompA polymorphism and the inability of some hosts to clear infection with the same ompA genotype suggest two distinct but converging mechanisms of endemic severe trachoma. 相似文献
158.
Mechanism of fenretinide (4-HPR)-induced cell death 总被引:7,自引:0,他引:7
Wu JM DiPietrantonio AM Hsieh TC 《Apoptosis : an international journal on programmed cell death》2001,6(5):377-388
4-HPR (fenretinide) is a synthetic analog of retinoic acid (RA) whose potential as a chemopreventative agent has gained support from in vitro and animal experiments and in limited clinical trials. Comparative analyses of cellular, biochemical, and molecular properties of fenretinide with RA using various tissue culture cells reveal that a key distinction between these two retinoids lies in the ability of fenretinide to induce programmed cell death, also known as apoptosis. Here we review the composite evidence for induction of apoptosis in fenretinide-treated cells. Assays used to validate apoptosis in various cell types are also summarized. Apoptosis in response to fenretinide primarily occurs by a receptor-independent mechanism, which is accompanied by increases in signaling molecules, e.g., ceramide, and cysteine-dependent aspartate-directed proteases, termed caspases, including execution caspase-3. Both caspase-3 inhibitor DEVD-CHO and ceramide synthase inhibitor fumonisin B1 (FB1) block fenretinide-induced apoptosis. Increase in caspase-3 appears to result from fenretinide-elicited stabilization of procaspase-3 zymogen. We also review apoptotic regulatory proteins such as inhibitor of apoptosis (IAPs) and second mitochondria-derived activator of caspase (SMACs) that participate in the coordinate control of caspase activities. The existence of a large number of proteins capable of modulating apoptosis via activation or inhibition of caspases, coupled with the fact that both the initiation and execution phases of apoptosis utilize pre-existing zymogens, which, once set in motion, culminates in an irreversible apoptotic cascade, raise the possibility that the on/off switch of apoptosis is linked to an intricate intracellular regulatory network, capable of responding to external stimuli such as fenretinide. This network functions to provide checks/balances of the need for apoptosis as well as to minimize and prevent untimely errors in apoptosis. We suggest that dynamic and coordinated regulation of apoptosis by such a hypothetical network in vivo may involve co-localization of pro- and anti-apoptotic proteins and their respective activators/inhibitors in a macromolecular modular unit which we propose to be named caspasomes. Fenretinide also induces apoptosis by elevating reactive oxygen species (ROS), unrelated to changes in ceramide-caspases. Thus multiple, distinct pathways contribute to the induction of apoptosis by fenretinide. 相似文献
159.
In the present study, we utilize the well-characterized Escherichia coli lac repressor/operator system to demonstrate that protein binding can lead to demethylation at the binding sites in the chromosome. Similar to the findings using the episome, we found that the presence of LacI in the cells can lead to demethylation of methylated lacO in the chromosome and the LacI inhibitor, isopropyl-beta-D-thiogalactopyranoside (IPTG), can prevent demethylation of the methylated lacO. The lacO sites become progressively more demethylated over time with the presence of LacI, supporting the role of protein occupancy in demethylation targeting. These results validate our earlier conclusions using a stable episomal system, and establish for the first time that protein binding can specify sites of demethylation in the chromosome. 相似文献
160.