全文获取类型
收费全文 | 3704篇 |
免费 | 273篇 |
国内免费 | 275篇 |
出版年
2024年 | 7篇 |
2023年 | 44篇 |
2022年 | 119篇 |
2021年 | 199篇 |
2020年 | 124篇 |
2019年 | 149篇 |
2018年 | 153篇 |
2017年 | 102篇 |
2016年 | 151篇 |
2015年 | 242篇 |
2014年 | 242篇 |
2013年 | 300篇 |
2012年 | 345篇 |
2011年 | 280篇 |
2010年 | 156篇 |
2009年 | 187篇 |
2008年 | 225篇 |
2007年 | 190篇 |
2006年 | 152篇 |
2005年 | 126篇 |
2004年 | 119篇 |
2003年 | 104篇 |
2002年 | 86篇 |
2001年 | 68篇 |
2000年 | 60篇 |
1999年 | 60篇 |
1998年 | 31篇 |
1997年 | 39篇 |
1996年 | 19篇 |
1995年 | 25篇 |
1994年 | 17篇 |
1993年 | 18篇 |
1992年 | 19篇 |
1991年 | 10篇 |
1990年 | 18篇 |
1989年 | 11篇 |
1988年 | 16篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1974年 | 1篇 |
1969年 | 1篇 |
1949年 | 1篇 |
1948年 | 1篇 |
排序方式: 共有4252条查询结果,搜索用时 46 毫秒
101.
Molecular docking and pharmacophore model approaches were used to characterise the binding features of four different series of Rho kinase (ROCK) inhibitors. Docking simulation of 20 inhibitors with ROCK was performed. The binding conformations and binding affinities of these inhibitors were obtained using AutoDock 4.0 software. The predicted binding affinities correlate well with the activities of these inhibitors (R 2 = 0.904). 3D pharmacophore models were generated for ROCK based on highly active inhibitors implemented in Catalyst 4.11 program. The best pharmacophore model consists of one hydrogen bond acceptor feature and two hydrophobic features, and they all seemed to be essential for inhibitors in terms of their binding activities. It is anticipated that the findings reported in this paper may provide very useful information for designing new ROCK inhibitors. 相似文献
102.
Xiang Liu Chun-Miao Feng Robert Franks Rongda Qu De-Yu Xie Qiu-Yun Jenny Xiang 《Plant cell reports》2013,32(1):77-87
Key message
Efficient Agrobacterium -mediated genetic transformation for investigation of genetic and molecular mechanisms involved in inflorescence architectures in Cornus species.Abstract
Cornus canadensis is a subshrub species in Cornus, Cornaceae. It has recently become a favored non-model plant species to study genes involved in development and evolution of inflorescence architectures in Cornaceae. Here, we report an effective protocol of plant regeneration and genetic transformation of C. canadensis. We use young inflorescence buds as explants to efficiently induce calli and multiple adventitious shoots on an optimized induction medium consisting of basal MS medium supplemented with 1 mg/l of 6-benzylaminopurine and 0.1 mg/l of 1-naphthaleneacetic acid. On the same medium, primary adventitious shoots can produce a large number of secondary adventitious shoots. Using leaves of 8-week-old secondary shoots as explants, GFP as a reporter gene controlled by 35S promoter and hygromycin B as the selection antibiotic, a standard procedure including pre-culture of explants, infection, co-cultivation, resting and selection has been developed to transform C. canadensis via Agrobacterium strain EHA105-mediated transformation. Under a strict selection condition using 14 mg/l hygromycin B, approximately 5 % explants infected by Agrobacterium produce resistant calli, from which clusters of adventitious shoots are induced. On an optimized rooting medium consisting of basal MS medium supplemented with 0.1 mg/l of indole-3-butyric acid and 7 mg/l hygromycin B, most of the resistant shoots develop adventitious roots to form complete transgenic plantlets, which can grow normally in soil. RT-PCR analysis demonstrates the expression of GFP transgene. Green fluorescence emitted by GFP is observed in transgenic calli, roots and cells of transgenic leaves under both stereo fluorescence microscope and confocal microscope. The success of genetic transformation provides an appropriate platform to investigate the molecular mechanisms by which the various inflorescence forms are developed in Cornus plants. 相似文献103.
104.
Yun Xia Wei Qu Li-Na Zhao Hao Han Xue-Feng Yang Xiu-Fa Sun Li-Ping Hao Jian Xu 《Biological trace element research》2013,154(1):103-110
Iodine excess is emerging as a new focus. A better understanding of its hazardous effects on the liver will be of great benefit to health. The aim of this study is to illustrate the effects of iodine excess on hepatic lipid homeostasis and explore its possible mechanisms. One hundred twenty BaLB/c mice were given iodine at different levels (0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/L) in drinking water for 1 or 3 months. Lipid parameters and serum thyroid hormones were measured. Hepatic type 1 deiodinase activity and oxidative stress parameters were evaluated. The mRNA expression of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) was detected by real-time polymerase chain reaction. Dose-dependent increase of hepatic triglyceride content was detected (r?=?0.680, P?<?0.01) in iodine-loaded groups. Evident hepatic steatosis was observed in 2.4 and 4.8 mg I/L iodine-loaded groups. The activities of antioxidant enzymes (glutathione peroxidase and superoxide dismutase) were decreased, and the malondialdehyde level was increased by excessive iodine in both serum and liver in a dose-dependent manner, accompanying the decrease of hepatic D1 activity. That resulted in the increase of serum total thyroxine and the decrease of serum total triiodothyronine in iodine-loaded groups. The mRNA expression of SREBP-1c and FAS was increased in iodine-loaded groups in response to the change of serum triiodothyronine. Present findings demonstrated that iodine excess could dose dependently induce hepatic steatosis. Furthermore, our data suggested that the disturbance of thyroid hormone metabolism involving oxidative stress may play a critical role in iodine excess-induced hepatic steatosis. 相似文献
105.
Bestrophin 3 (Best3), a member of the bestrophin Cl? channel family, is a candidate of cGMP-sensitive, Ca2+-activated Cl? channel in vascular smooth muscle cells. The Best3 channel was recently found to play an important role in vasomotion. However, the mechanism for its activation has not been clarified. In previous studies, we found that a Best3 C-terminal sequence (amino acids 353–404) was associated with the cellular membrane. The sequence includes an autoinhibitory domain (356IPSFLGS362) and a downstream basic residue domain (amino acids 384–397). In this study, we found that the sequence (368–383) between the two domains is actually a determinant for Best3 C-terminal membrane associability. Deletion of the sequence almost abolished the membrane association but did not activate the Best3 channel. Treatment of Best3-expressing HEK293 cells with the PI3Kα inhibitor IV (a Best3 activator) could not abolish but weakened the Best3 membrane association. The result supports the assumption that the positively charged basic residues in the Best3 C terminus are likely associated with the membranous negatively charged phospholipids, which plays a role in the regulation of Best3 activation. But the relationship between membrane associability and Best3 activation seems more complicated than expected. 相似文献
106.
107.
Junhong Guan Han Li Tao Lv Duo Chen Ye Yuan Shengtao Qu 《Biochemical and biophysical research communications》2013
A mild cerebral ischemic insult, also known as ischemic preconditioning (IPC), confers transient tolerance to a subsequent ischemic challenge in the brain. This study was conducted to investigate whether bone morphogenetic protein-7 (BMP-7) is involved in neuroprotection elicited by IPC in a rat model of ischemia. Ischemic tolerance was induced in rats by IPC (15 min middle cerebral artery occlusion, MCAO) at 48 h before lethal ischemia (2 h MCAO). The present data showed that IPC increased BMP-7 mRNA and protein expression after 24 h reperfusion following ischemia in the brain. In rats of ischemia, IPC-induced reduction of cerebral infarct volume and improvement of neuronal morphology were attenuated when BMP-7 was inhibited either by antagonist noggin or short interfering RNA (siRNA) pre-treatment. Besides, cerebral IPC-induced up-regulation of B-cell lymphoma 2 (Bcl-2) and down-regulation of cleaved caspase-3 at 24 h after ischemia/reperfusion (I/R) injury were reversed via inhibition of BMP-7. These findings indicate that BMP-7 mediates IPC-induced tolerance to cerebral I/R, probably through inhibition of apoptosis. 相似文献
108.
Ling Xu Xuejun Hu Xiujuan Qu Kezuo Hou Huachuan Zheng Yunpeng Liu 《Biochemical and biophysical research communications》2013
TRAIL is a member of the tumor necrosis factor family that selectively induces cancer cell apoptosis. However, gastric cancer cells are insensitive to TRAIL. Our and others studies showed that the inhibition of EGFR pathway activation could increase the sensitivity of TRAIL in cancer cells. But the detailed mechanism is not fully understood. In the present study, compared with TRAIL or cetuximab (an anti-EGFR monoclonal antibody) alone, treatment with the TRAIL/cetuximab combination significantly promoted death receptor 4 (DR4) clustering as well as the translocation of both DR4 and Fas-associated death domain-containing protein (FADD) into lipid rafts. This in turn resulted in caspase-8 cleavage and the formation of the death-inducing signaling complex (DISC) in these lipid rafts. Cholesterol-depletion with methyl-β-cyclodextrin partially prevented DR4 clustering and DISC formation, and thus partially reversed apoptosis induced by the TRAIL/cetuximab dual treatment. These results indicate that cetuximab increases TRAIL-induced gastric cancer cell apoptosis at least partially through the promotion of DISC formation in lipid rafts. 相似文献
109.
110.
Ling Xu Xiujuan Qu Xuejun Hu Zhitu Zhu Ce Li Enze Li Yanju Ma Na Song Yunpeng Liu 《FEBS letters》2013
Gastric cancer cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and the resistance mechanism is not fully understood. In human gastric cancer MGC803 and BGC823 cells, TRAIL induces insulin-like growth factor-1 receptor (IGF-1R) pathway activation. Treatment with IGF-1R inhibitor OSI-906 or small interfering RNAs against IGF-1R, prevents IGF-1R pathway activation and increases TRAIL-induced apoptosis. The TRAIL-induced IGF-1R pathway activation is promoted by IGF-1R translocation into lipid rafts. Moreover, the translocation of IGF-1R into lipid rafts is regulated by Casitas B-lineage lymphoma b (Cbl-b). Taken together, TRAIL-induced IGF-1R activation antagonizes TRAIL-induced apoptosis by Cbl-b-regulated distribution of IGF-1R in lipid rafts. 相似文献