全文获取类型
收费全文 | 30409篇 |
免费 | 2948篇 |
国内免费 | 5533篇 |
出版年
2024年 | 81篇 |
2023年 | 511篇 |
2022年 | 837篇 |
2021年 | 1726篇 |
2020年 | 1255篇 |
2019年 | 1582篇 |
2018年 | 1388篇 |
2017年 | 1106篇 |
2016年 | 1355篇 |
2015年 | 2014篇 |
2014年 | 2503篇 |
2013年 | 2545篇 |
2012年 | 3154篇 |
2011年 | 2800篇 |
2010年 | 1858篇 |
2009年 | 1761篇 |
2008年 | 1932篇 |
2007年 | 1741篇 |
2006年 | 1489篇 |
2005年 | 1341篇 |
2004年 | 1046篇 |
2003年 | 925篇 |
2002年 | 791篇 |
2001年 | 552篇 |
2000年 | 458篇 |
1999年 | 413篇 |
1998年 | 282篇 |
1997年 | 223篇 |
1996年 | 212篇 |
1995年 | 160篇 |
1994年 | 144篇 |
1993年 | 100篇 |
1992年 | 103篇 |
1991年 | 92篇 |
1990年 | 76篇 |
1989年 | 69篇 |
1988年 | 60篇 |
1987年 | 41篇 |
1986年 | 37篇 |
1985年 | 47篇 |
1984年 | 16篇 |
1983年 | 19篇 |
1982年 | 16篇 |
1981年 | 12篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1977年 | 2篇 |
1969年 | 2篇 |
1965年 | 1篇 |
1950年 | 3篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
992.
Xiaoyan Cheng Yan Wu Jianping Guo Bo Du Rongzhi Chen Lili Zhu Guangcun He 《The Plant journal : for cell and molecular biology》2013,76(4):687-698
Seed germination and innate immunity both have significant effects on plant life spans because they control the plant's entry into the ecosystem and provide defenses against various external stresses, respectively. Much ecological evidence has shown that seeds with high vigor are generally more tolerant of various environmental stimuli in the field than those with low vigor. However, there is little genetic evidence linking germination and immunity in plants. Here, we show that the rice lectin receptor‐like kinase OslecRK contributes to both seed germination and plant innate immunity. We demonstrate that knocking down the OslecRK gene depresses the expression of α–amylase genes, reducing seed viability and thereby decreasing the rate of seed germination. Moreover, it also inhibits the expression of defense genes, and so reduces the resistance of rice plants to fungal and bacterial pathogens as well as herbivorous insects. Yeast two‐hybrid and co‐immunoprecipitation experiments revealed that OslecRK interacts with an actin‐depolymerizing factor (ADF) in vivo via its kinase domain. Moreover, the rice adf mutant exhibited a reduced seed germination rate due to the suppression of α–amylase gene expression. This mutant also exhibited depressed immune responses and reduced resistance to biotic stresses. Our results thus provide direct genetic evidence for a common physiological pathway connecting germination and immunity in plants. They also partially explain the common observation that high‐vigor seeds often perform well in the field. The dual effects of OslecRK may be indicative of progressive adaptive evolution in rice. 相似文献
993.
994.
Yan Cheng Ling Cao Sheng Wang Yongpeng Li Xianzong Shi Han Liu Lixia Li Zhengli Zhang Larry C. Fowke Hong Wang Yongming Zhou 《The Plant journal : for cell and molecular biology》2013,75(4):642-655
The ICK/KRP cyclin‐dependent kinase (CDK) inhibitors are important plant cell cycle factors sharing only limited similarity with the metazoan CIP/KIP family of CDK inhibitors. Little is known about the specific functions of different ICK/KRP genes in planta. In this study, we created double and multiple mutants from five single Arabidopsis ICK/KRP T‐DNA mutants, and used a set of 20 lines for the functional investigation of the important gene family. There were gradual increases in CDK activity from single to multiple mutants, indicating that ICK/KRPs act as CDK inhibitors under normal physiological conditions in plants. Whereas lower‐order mutants showed no morphological phenotypes, the ick1 ick2 ick6 ick7 and ick1 ick2 ick5 ick6 ick7 mutants had a slightly altered leaf shape. The quintuple mutant had larger cotyledons, leaves, petals and seeds than the wild‐type control. At the cellular level, the ICK/KRP mutants had more but smaller cells in all the organs examined. These phenotypic effects became more apparent as more ICK/KRPs were downregulated, suggesting that to a large extent ICK/KRPs function in plants redundantly in a dosage‐dependent manner. Analyses also revealed increased expression of E2F‐dependent genes, and elevated RBR1 as well as an increased level of phospho‐RBB1 protein in the quintuple mutant. Thus, downregulation of multiple ICK/KRP genes increases CDK activity, upregulates the E2F pathway and stimulates cell proliferation, resulting in increased cell numbers, and larger organs and seeds. 相似文献
995.
Yan Zhang Orgil Elbegdorj Yunyun Yuan Irina O. Beletskaya Dana E. Selley 《Bioorganic & medicinal chemistry letters》2013,23(13):3719-3722
Isosterism is commonly used in drug discovery and development to address stability, selectivity, toxicity, pharmacokinetics, and efficacy issues. A series of 14-O-substituted naltrexone derivatives were identified as potent mu opioid receptor (MOR) antagonists with improved selectivity over the kappa opioid receptor (KOR) and the delta opioid receptor (DOR), compared to naltrexone. Since esters are not metabolically very stable under typical physiological conditions, their corresponding amide analogs were thus synthesized and biologically evaluated. Unlike their isosteres, most of these novel ligands seem to be dually selective for the MOR and the KOR over the DOR. The restricted flexibility of the amide bond linkage might be responsible for their altered selectivity profile. However, the majority of the 14-N-substituted naltrexone derivatives produced marginal or no MOR stimulation in the 35S-GTP[γS] assay, which resembled their ester analogs. The current study thus indicated that the 14-substituted naltrexone isosteres are not bioisosteres since they have distinctive pharmacological profile with the regard to their opioid receptor binding affinity and selectivity. 相似文献
996.
Feng Jun-Tao Wang De-Long Wu Yong-Ling Yan He Zhang Xing 《Bioorganic & medicinal chemistry letters》2013,23(15):4393-4397
Thirty new and thirty-four known analogues were designed and synthesized to improve the potential use of the α-methylene-γ-butyrolactone ring, a natural pharmacophore. All structures were confirmed by 1H and 13C NMR, MS, and single-crystal X-ray diffraction analyses. The results of antifungal and cytotoxic activity indicated that the synthesized analogues showed significant inhibitory activity and limited selectivity. Compound 45 exhibited the highest antifungal activity with IC50 = 22.8 μM but moderate cytotoxic activity with IC50 = 28.5 μM (against BGC823 cell line) and 7.7 μM (against HeLa cell line). Analysis of structure–activity relationships revealed that the incorporation of an aromatic ring into the β, γ positions of the lactone ring improved antifungal activity, and that the introduction of electron-withdrawing groups into the aromatic rings increased the activity compared with electron-donating groups. The above results identified 4-phenyl-3-phenyl-2-methylenebutyrolactone (33) as a lead scaffold for discovering and developing novel and improved crop-protection agents. 相似文献
997.
Yong Guo Yuanyuan Yan Xiaoyan Zhi Chun Yang Hui Xu 《Bioorganic & medicinal chemistry letters》2013,23(11):3382-3384
Based on highly selective and irreversible Hg2+-promoted desulfurization reaction, a new and simple phenanthroimidazole-type sensor was prepared and exhibited high selectivity towards Hg2+ ion over other metal ions, accompanied by transformation of a weakly fluorescent thioamide moiety (colorless) to a highly fluorescent amide one (blue), with a 136-fold increase in fluorescent intensity in aqueous solution with a pH span 2.57–9.12. 相似文献
998.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
999.
Peter W. Glunz Xiaojun Zhang Yan Zou Indawati Delucca Alexandra H. Nirschl Xuhong Cheng Carolyn A. Weigelt Daniel L. Cheney Anzhi Wei Rushith Anumula Joseph M. Luettgen Alan R. Rendina Mark Harpel Gang Luo Robert Knabb Pancras C. Wong Ruth R. Wexler E. Scott Priestley 《Bioorganic & medicinal chemistry letters》2013,23(18):5244-5248
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype. 相似文献
1000.
Benjamin D. Stevens John Litchfield Jeffrey A. Pfefferkorn Karen Atkinson Christian Perreault Paul Amor Kevin Bahnck Martin A. Berliner Jessica Calloway Anthony Carlo David R. Derksen Kevin J. Filipski Mike Gumkowski Charanjeet Jassal Margit MacDougall Brendan Murphy Paul Nkansah John Pettersen Yan Zhang 《Bioorganic & medicinal chemistry letters》2013,23(24):6588-6592
Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties. 相似文献