全文获取类型
收费全文 | 102299篇 |
免费 | 9397篇 |
国内免费 | 67篇 |
出版年
2021年 | 1167篇 |
2020年 | 840篇 |
2019年 | 1037篇 |
2018年 | 1391篇 |
2017年 | 1230篇 |
2016年 | 2224篇 |
2015年 | 3727篇 |
2014年 | 4146篇 |
2013年 | 5434篇 |
2012年 | 6830篇 |
2011年 | 6878篇 |
2010年 | 4474篇 |
2009年 | 3992篇 |
2008年 | 5853篇 |
2007年 | 6034篇 |
2006年 | 5676篇 |
2005年 | 5503篇 |
2004年 | 5477篇 |
2003年 | 5265篇 |
2002年 | 4994篇 |
2001年 | 1118篇 |
2000年 | 818篇 |
1999年 | 1149篇 |
1998年 | 1356篇 |
1997年 | 973篇 |
1996年 | 877篇 |
1995年 | 948篇 |
1994年 | 875篇 |
1993年 | 917篇 |
1992年 | 909篇 |
1991年 | 771篇 |
1990年 | 702篇 |
1989年 | 694篇 |
1988年 | 700篇 |
1987年 | 674篇 |
1986年 | 662篇 |
1985年 | 785篇 |
1984年 | 916篇 |
1983年 | 803篇 |
1982年 | 1007篇 |
1981年 | 976篇 |
1980年 | 915篇 |
1979年 | 590篇 |
1978年 | 673篇 |
1977年 | 648篇 |
1976年 | 559篇 |
1975年 | 488篇 |
1974年 | 579篇 |
1973年 | 535篇 |
1972年 | 362篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
1.
2.
Aruna S. Jaiswal Harekrushna Panda Brian K. Law Jay Sharma Jitesh Jani Robert Hromas Satya Narayan 《PloS one》2015,10(5)
Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC50 of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients. 相似文献
3.
4.
5.
6.
Katherine E. Price Giulia Orazi Kathryn L. Ruoff Wesley P. Hebert George A. O’Toole Paul Mastoridis 《PloS one》2015,10(10)
Cystic Fibrosis (CF) is a human genetic disease that results in the accumulation of thick, sticky mucus in the airways, which results in chronic, life-long bacterial biofilm infections that are difficult to clear with antibiotics. Pseudomonas aeruginosa lung infection is correlated with worsening lung disease and P. aeruginosa transitions to an antibiotic tolerant state during chronic infections. Tobramycin is an aminoglycoside currently used to combat lung infections in individuals with CF. While tobramycin is effective at eradicating P. aeruginosa in the airways of young patients, it is unable to completely clear the chronic P. aeruginosa infections in older patients. A recent report showed that co-addition of tobramycin and mannitol enhanced killing of P. aeruginosa grown in vitro as a biofilm on an abiotic surface. Here we employed a model system of bacterial biofilms formed on the surface of CF-derived airway cells to determine if mannitol would enhance the antibacterial activity of tobramycin against P. aeruginosa grown on a more clinically relevant surface. Using this model system, which allows the growth of robust biofilms with high-level antibiotic tolerance analogous to in vivo biofilms, we were unable to find evidence for enhanced antibacterial activity of tobramycin with the addition of mannitol, supporting the observation that this type of co-treatment failed to reduce the P. aeruginosa bacterial load in a clinical setting. 相似文献
7.
China has recently made available hourly air pollution data from over 1500 sites, including airborne particulate matter (PM), SO2, NO2, and O3. We apply Kriging interpolation to four months of data to derive pollution maps for eastern China. Consistent with prior findings, the greatest pollution occurs in the east, but significant levels are widespread across northern and central China and are not limited to major cities or geologic basins. Sources of pollution are widespread, but are particularly intense in a northeast corridor that extends from near Shanghai to north of Beijing. During our analysis period, 92% of the population of China experienced >120 hours of unhealthy air (US EPA standard), and 38% experienced average concentrations that were unhealthy. China’s population-weighted average exposure to PM2.5 was 52 μg/m3. The observed air pollution is calculated to contribute to 1.6 million deaths/year in China [0.7–2.2 million deaths/year at 95% confidence], roughly 17% of all deaths in China. 相似文献
8.
Paul Linhardt 《Biodegradation》1997,8(3):201-210
Case histories and proposed mechanisms formicrobiologically influenced corrosion of metals andalloys by metal depositing microorganisms arereviewed. Mechanisms with indirect participation ofthese microorganisms, usually iron- and manganeseoxidizing species, are distinguished from anothermechanism which accounts specifically for theelectrochemical properties of deposits containingoxides and hydroxides of Mn in higher oxidationstates. The possible influence of such deposits whichwere formed microbiologically is evaluated. Theevaluation is based on the principles ofelectrochemical corrosion of metals and on theelectrochemical properties of Mn3+/4+- compounds.After briefly reviewing the microbiologicalMn-oxidation, experimental evidence for the predictedcorrosion by such deposits is provided and a model formicrobiologically influenced corrosion by manganeseoxidizing microorganisms is proposed for stainlesssteel. Possible consequences of the model andpractical aspects of such a corrosion are discussed. 相似文献
9.
Continental‐scale macrofungal assemblage patterns correlate with climate,soil carbon and nitrogen deposition 下载免费PDF全文
10.