全文获取类型
收费全文 | 1451篇 |
免费 | 84篇 |
专业分类
1535篇 |
出版年
2023年 | 7篇 |
2022年 | 10篇 |
2021年 | 19篇 |
2020年 | 13篇 |
2019年 | 20篇 |
2018年 | 23篇 |
2017年 | 14篇 |
2016年 | 38篇 |
2015年 | 53篇 |
2014年 | 66篇 |
2013年 | 94篇 |
2012年 | 92篇 |
2011年 | 97篇 |
2010年 | 58篇 |
2009年 | 62篇 |
2008年 | 82篇 |
2007年 | 103篇 |
2006年 | 95篇 |
2005年 | 79篇 |
2004年 | 111篇 |
2003年 | 93篇 |
2002年 | 90篇 |
2001年 | 19篇 |
2000年 | 8篇 |
1999年 | 11篇 |
1998年 | 17篇 |
1997年 | 15篇 |
1996年 | 16篇 |
1995年 | 8篇 |
1994年 | 23篇 |
1993年 | 9篇 |
1992年 | 12篇 |
1991年 | 15篇 |
1990年 | 7篇 |
1988年 | 6篇 |
1987年 | 2篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 5篇 |
1976年 | 5篇 |
1975年 | 3篇 |
1968年 | 2篇 |
1959年 | 2篇 |
1958年 | 2篇 |
1956年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有1535条查询结果,搜索用时 0 毫秒
11.
Block of CDK1‐dependent polyadenosine elongation of Cyclin B mRNA in metaphase‐i‐arrested starfish oocytes is released by intracellular pH elevation upon spawning 下载免费PDF全文
12.
13.
Nakagami H Nishikawa T Tamura N Maeda A Hibino H Mochizuki M Shimosato T Moriya T Morishita R Tamai K Tomono K Kaneda Y 《Journal of cellular and molecular medicine》2012,16(7):1629-1639
We previously identified a novel angiogenic peptide, AG30, with antibacterial effects that could serve as a foundation molecule for the design of wound-healing drugs. Toward clinical application, in this study we have developed a modified version of the AG30 peptide characterized by improved antibacterial and angiogenic action, thus establishing a lead compound for a feasibility study. Because AG30 has an α-helix structure with a number of hydrophobic and cationic amino acids, we designed a modified AG30 peptide by replacing several of the amino acids. The replacement of cationic amino acids (yielding a new molecule, AG30/5C), but not hydrophobic amino acids, increased both the angiogenic and the antimicrobial properties of the peptide. AG30/5C was also effective against methicillin-resistant Staphylococcus aureus (MRSA) and antibiotic-resistant Pseudomonas aeruginosa. In a diabetic mouse wound-healing model, the topical application of AG30/5C accelerated wound healing with increased angiogenesis and attenuated MRSA infection. To facilitate the eventual clinical investigation/application of these compounds, we developed a large-scale procedure for the synthesis of AG30/5C that employed the conventional solution method and met Good Manufacturing Practice guidelines. In the evaluation of stability of this peptide in saline solution, RP-HPLC analysis revealed that AG30/5C was fairly stable under 5°C for 12 months. Therefore, we propose the use of AG30/5C as a wound-healing drug with antibacterial and angiogenic actions. 相似文献
14.
Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates 总被引:1,自引:0,他引:1
Preston DL Pierce DA Shimizu Y Cullings HM Fujita S Funamoto S Kodama K 《Radiation research》2004,162(4):377-389
The Radiation Effects Research Foundation has recently implemented a new dosimetry system, DS02, to replace the previous system, DS86. This paper assesses the effect of the change on risk estimates for radiation-related solid cancer and leukemia mortality. The changes in dose estimates were smaller than many had anticipated, with the primary systematic change being an increase of about 10% in gamma-ray estimates for both cities. In particular, an anticipated large increase of the neutron component in Hiroshima for low-dose survivors did not materialize. However, DS02 improves on DS86 in many details, including the specifics of the radiation released by the bombs and the effects of shielding by structures and terrain. The data used here extend the last reported follow-up for solid cancers by 3 years, with a total of 10,085 deaths, and extends the follow-up for leukemia by 10 years, with a total of 296 deaths. For both solid cancer and leukemia, estimated age-time patterns and sex difference are virtually unchanged by the dosimetry revision. The estimates of solid-cancer radiation risk per sievert and the curvilinear dose response for leukemia are both decreased by about 8% by the dosimetry revision, due to the increase in the gamma-ray dose estimates. The apparent shape of the dose response is virtually unchanged by the dosimetry revision, but for solid cancers, the additional 3 years of follow-up has some effect. In particular, there is for the first time a statistically significant upward curvature for solid cancer on the restricted dose range 0-2 Sv. However, the low-dose slope of a linear-quadratic fit to that dose range should probably not be relied on for risk estimation, since that is substantially smaller than the linear slopes on ranges 0-1 Sv, 0-0.5 Sv, and 0- 0.25 Sv. Although it was anticipated that the new dosimetry system might reduce some apparent dose overestimates for Nagasaki factory workers, this did not materialize, and factory workers have significantly lower risk estimates. Whether or not one makes allowance for this, there is no statistically significant city difference in the estimated cancer risk. 相似文献
15.
Innate immunity is an evolutionarily conserved self-defense mechanism against microbial infections. In Drosophila, induction of antimicrobial peptides is a major immune response that is regulated by two distinct signaling pathways called the IMD pathway and the Toll pathway, similar to the tumor necrosis factor-alpha signaling and Toll-like receptor/interleukin-1 signaling pathways, respectively, in mammals. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Previously, based on the striking conservation between the mechanisms that regulate Drosophila immunity and human innate immunity, we established an ex vivo culture in which compounds acting on innate immunity can be evaluated using a reporter gene that reflects activation of the IMD pathway [Yajima et al. [Yajima, M., Takada, M., Takahashi, N., Kikuchi, H., Natori, S., Oshima, Y., Kurata, S., 2003. A newly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A2-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity. The Biochemical Journal 371(Pt 1), 205-210] Biochem J 371, 205-210]. Here, we combined the ex vivo culture with a reporter gene that reflects the heat shock response and demonstrated that the resulting systems are useful for screening compounds that act specifically on innate immunity, including mammalian innate immune responses. Identification of target molecules is essential for the development of more potent medicines with fewer side effects. In this study, we also established ex vivo systems capable of identifying target molecules of the identified compounds using targeted activation of the IMD pathway. 相似文献
16.
OsWRKY28, a PAMP-responsive transrepressor, negatively regulates innate immune responses in rice against rice blast fungus 总被引:1,自引:0,他引:1
17.
Aixinjueluo W Furukawa K Zhang Q Hamamura K Tokuda N Yoshida S Ueda R Furukawa K 《The Journal of biological chemistry》2005,280(33):29828-29836
Anti-GD2 ganglioside antibodies could be a promising, novel therapeutic approach to the eradication of human small cell lung cancers, as anti-GD2 monoclonal antibodies (mAbs) induced apoptosis of small cell lung cancer cells in culture. In this study, we analyzed the mechanisms for the apoptosis of these cells by anti-GD2 mAbs and elucidated the mechanisms by which apoptosis signals were transduced via reduction in the phosphorylation levels of focal adhesion kinase (FAK) and the activation of a MAPK family member, p38, upon the antibody binding. Knock down of FAK resulted in apoptosis and p38 activation. The inhibition of p38 activity blocked antibody-induced apoptosis, indicating that p38 is involved in this process. Immunoprecipitation-immunoblotting analysis of immune precipitates with anti-FAK or anti-integrin antibodies using an anti-GD2 mAb revealed that GD2 could be precipitated with integrin and/or FAK. These results suggested that GD2, integrin, and FAK form a huge molecular complex across the plasma membrane. Taken together with the fact that GD2+ cells showed marked detachment from the plate during apoptosis, GD2+ small cell lung cancer cells seemed to undergo anoikis through the conformational changes of integrin molecules and subsequent FAK dephosphorylation. 相似文献
18.
Yamanaka K Saito Y Yamamori T Urano Y Noguchi N 《The Journal of biological chemistry》2011,286(28):24666-24673
24(S)-Hydroxycholesterol (24S-OHC) produced by cholesterol 24-hydroxylase expressed mainly in neurons plays an important physiological role in the brain. Conversely, it has been reported that 24S-OHC possesses potent cytotoxicity. The molecular mechanisms of 24S-OHC-induced cell death have not yet been fully elucidated. In this study, using human neuroblastoma SH-SY5Y cells and primary cortical neuronal cells derived from rat embryo, we characterized the form of cell death induced by 24S-OHC. SH-SY5Y cells treated with 24S-OHC exhibited neither fragmentation of the nucleus nor caspase activation, which are the typical characteristics of apoptosis. 24S-OHC-treated cells showed necrosis-like morphological changes but did not induce ATP depletion, one of the features of necrosis. When cells were treated with necrostatin-1, an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1) required for necroptosis, 24S-OHC-induced cell death was significantly suppressed. The knockdown of RIPK1 by transfection of small interfering RNA of RIPK1 effectively attenuated 24S-OHC-induced cell death. It was found that neither SH-SY5Y cells nor primary cortical neuronal cells expressed caspase-8, which was regulated for RIPK1-dependent apoptosis. Collectively, these results suggest that 24S-OHC induces neuronal cell death by necroptosis, a form of programmed necrosis. 相似文献
19.
20.
Masaya Sakamoto Rimei Nishimura Taiga Irako Daisuke Tsujino Kiyotaka Ando Kazunori Utsunomiya 《Cardiovascular diabetology》2012,11(1):1-7