全文获取类型
收费全文 | 1648篇 |
免费 | 93篇 |
国内免费 | 10篇 |
出版年
2023年 | 21篇 |
2022年 | 29篇 |
2021年 | 72篇 |
2020年 | 63篇 |
2019年 | 95篇 |
2018年 | 79篇 |
2017年 | 61篇 |
2016年 | 70篇 |
2015年 | 98篇 |
2014年 | 98篇 |
2013年 | 149篇 |
2012年 | 117篇 |
2011年 | 126篇 |
2010年 | 73篇 |
2009年 | 74篇 |
2008年 | 61篇 |
2007年 | 55篇 |
2006年 | 53篇 |
2005年 | 48篇 |
2004年 | 45篇 |
2003年 | 26篇 |
2002年 | 24篇 |
2001年 | 3篇 |
2000年 | 10篇 |
1999年 | 9篇 |
1998年 | 3篇 |
1997年 | 5篇 |
1996年 | 3篇 |
1995年 | 9篇 |
1994年 | 8篇 |
1993年 | 4篇 |
1992年 | 9篇 |
1991年 | 12篇 |
1990年 | 17篇 |
1989年 | 13篇 |
1988年 | 22篇 |
1987年 | 15篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 15篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1976年 | 2篇 |
1975年 | 4篇 |
1973年 | 2篇 |
1956年 | 2篇 |
排序方式: 共有1751条查询结果,搜索用时 299 毫秒
971.
Muhammad Junaid Cheng-Dong Li Masaud Shah Abbas Khan Haoyue Guo Dong-Qing Wei 《Proteins》2019,87(10):837-849
Half of the world population is infected by the Gram-negative bacterium Helicobacter pylori (H. pylori). It colonizes in the stomach and is associated with severe gastric pathologies including gastric cancer and peptic ulceration. The most virulent factor of H. pylori is the cytotoxin-associated gene A (CagA) that is injected into the host cell. CagA interacts with several host proteins and alters their function, thereby causing several diseases. The most well-known target of CagA is the tumor suppressor protein ASPP2. The subdomain I at the N-terminus of CagA interacts with the proline-rich motif of ASPP2. Here, in this study, we carried out alanine scanning mutagenesis and an extensive molecular dynamics simulation summing up to 3.8 μs to find out hot spot residues and discovered some new protein-protein interaction (PPI)-modulating molecules. Our findings are in line with previous biochemical studies and further suggested new residues that are crucial for binding. The alanine scanning showed that mutation of Y207 and T211 residues to alanine decreased the binding affinity. Likewise, dynamics simulation and molecular mechanics with generalized Born surface area (MMGBSA) analysis also showed the importance of these two residues at the interface. A four-feature pharmacophore model was developed based on these two residues, and top 10 molecules were filtered from ZINC, NCI, and ChEMBL databases. The good binding affinity of the CHEMBL17319 and CHEMBL1183979 molecules shows the reliability of our adopted protocol for binding hot spot residues. We believe that our study provides a new insight for using CagA as the therapeutic target for gastric cancer treatment and provides a platform for a future experimental study. 相似文献
972.
Brijesh S. Yadav Navaneet Chaturvedi Pavan K. Yadav Ninoslav Marina Magdah Ganash George E. Barreto Ghulam Md Ashraf Khurshid Ahmad Mohammad H. Baig 《Journal of cellular physiology》2019,234(8):14285-14295
Interleukin-18 (IL-18) belongs to the superfamily of IL-1 protein and exerts a pleiotropic pro-inflammatory effect on the body. Generally, this protein is significantly involved in immune defense during infection in cells, but sometimes its anomalous activities produce some inflammatory diseases like rheumatoid arthritis and Crohn’s disease. In the present study, the IL-18 gene was isolated from mice and was subsequently cloned and sequenced. Further, the network analysis was carried out to explore the functional role of IL-18 protein in animals. The 3D protein structure of the IL-18 protein was generated and docked with appropriate 3-([3-cholamidopropyl]dimethylammonio)-1-propanesulfonate (CPS) ligand. Later the complex structure of the protein was subjected to molecular dynamics simulation (MDS) for 50 ns to determine the effect of ligand on protein. The network analysis explored the correlation of IL-18 protein with others proteins and their involvement in the different significant pathway to defend the cell from various diseases. As confirmed by MDS, the CPS:IL-18 complex was found to be highly stable. Our results further indicated that CPS ligand has the potential to act as a drug molecule, in future, for counteracting IL-18 activity. To date, no structural details were available for animal IL-18. Hence, the finding of this study will be useful in broadening the horizon towards a better understanding of the functional and structural aspects of IL-18 in animals. 相似文献
973.
974.
Calcitonin gene-related peptide (CGRP) is a well-validated target for migraine therapy and a known potent systemic vasodilator. LBR-101 is a monoclonal antibody against CGRP in clinical development for the preventive treatment of episodic and chronic migraine. Understanding the hemodynamic and cardiovascular consequences of chronic CGRP inhibition is therefore warranted. Given the conservation in CGRP sequence between monkeys and humans, addressing this question in monkeys is ideal as it allows dosing at super-therapeutic levels. To this end, two independent studies were conducted in monkeys: a single dedicated cardiovascular safety study and a repeat-dose, chronic study, both with electrocardiogram and hemodynamic assessments. LBR-101 was very well tolerated in both studies, with no clinically significant changes noted in any hemodynamic parameter, nor any relevant changes noted in any ECG parameter. In cynomolgus monkeys, cardiovascular and hemodynamic parameters do not appear to be affected by long-term inhibition of CGRP with LBR-101. 相似文献
975.
Li Jie Yu Daoqian Qanmber Ghulam Lu Lili Wang Lingling Zheng Lei Liu Zhao Wu Huanhuan Liu Xiaodong Chen Quanjia Li Fuguang Yang Zuoren 《中国科学:生命科学英文版》2019,62(1):63-75
Drought stress results in significant losses in agricultural production, and especially that of cotton. The molecular mechanisms that coordinate drought tolerance remain elusive in cotton. Here, we isolated a drought-response gene GhKLCR1, which is a close homolog of AtKLCR1, which encodes a kinesin light chain-related protein enriched with a tetratrico peptide-repeat region.A subcellular localization assay showed that GhKLCR1 is associated with the cell membrane. A tissue-specific expression profile analysis demonstrated that GhKLCR1 is a cotton root-specific gene. Further abiotic and hormonal stress treatments showed that GhKLCR1 was upregulated during abiotic stresses, especially after polyethylene glycol treatments. In addition, the glucuronidase(GUS) staining activity increased as the increment of mannitol concentration in transgenic Arabidopsis plants harboring the fusion construct PGhKLCR1::GUS. The root lengths of 35 S::GhKLCR1 lines were significantly reduced compared with that of wild type. Additionally, seed germination was strongly inhibited in 35 S::GhKLCR1 lines after 300-mmol L~(-1) mannitol treatments as compared with Columbia-0, indicating the sensitivity of GhKLCR1 to drought. These findings provide a better understanding of the structural, physiological and functional mechanisms of kinesin light chain-related proteins. 相似文献
976.
977.
The generalized nonlinear Klien-Gordon equation plays an important role in quantum mechanics. In this paper, a new three-time level implicit approach based on cubic trigonometric B-spline is presented for the approximate solution of this equation with Dirichlet boundary conditions. The usual finite difference approach is used to discretize the time derivative while cubic trigonometric B-spline is applied as an interpolating function in the space dimension. Several examples are discussed to exhibit the feasibility and capability of the approach. The absolute errors and error norms are also computed at different times to assess the performance of the proposed approach and the results were found to be in good agreement with known solutions and with existing schemes in literature. 相似文献
978.
A K Abbas 《Journal of immunology (Baltimore, Md. : 1950)》1979,123(5):2011-2018
Alloreactive cells generated by in vitro stimulation of C57BL/6 (H-2b) spleen lymphocytes with irradiated MOPC 315 or MOPC 104E(H-2d) cells were shown to lyse 51Cr-labeled myeloma targets at high effector:target ratios under conditions of inefficient cell contact, the alloreactive cells cause variable and frequently minimal lysis of myeloma targets but markedly suppress antibody secretion even by viable myeloma cells. The suppressor cells are radioresistant T cells lacking I-J subregion-encoded surface determinants; their precursors are insensitive to cyclophosphamide; suppression is H-2 specific and not mediated by secreted factors; and the suppression is blocked by Cytochalasin B, a known inhibitor of T cell-mediated cytolysis. These properties are typical of cytolytic T lymphocytes (CTL) and not of defined suppressor T cells, suggesting that inhibition of myeloma function probably represents a pre-lytic effect of the alloreactive CTL, although a CTL-like suppressor cell effect cannot be definitively excluded. These results are discussed with reference to the possible relationships between suppressor and cytolytic T lymphocytes. 相似文献
979.
980.
Saeid Shahrabi Mostafa Paridar Marzieh Zeinvand-Lorestani Arsalan Jalili Kazem Zibara Mohammad Abdollahi Abbas Khosravi 《Journal of cellular physiology》2019,234(12):21746-21757
Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation. 相似文献