全文获取类型
收费全文 | 1076篇 |
免费 | 59篇 |
出版年
2022年 | 1篇 |
2021年 | 19篇 |
2020年 | 11篇 |
2019年 | 20篇 |
2018年 | 17篇 |
2017年 | 20篇 |
2016年 | 26篇 |
2015年 | 42篇 |
2014年 | 38篇 |
2013年 | 84篇 |
2012年 | 108篇 |
2011年 | 99篇 |
2010年 | 65篇 |
2009年 | 42篇 |
2008年 | 78篇 |
2007年 | 90篇 |
2006年 | 78篇 |
2005年 | 64篇 |
2004年 | 40篇 |
2003年 | 50篇 |
2002年 | 53篇 |
2001年 | 9篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 7篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 1篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1963年 | 1篇 |
1962年 | 1篇 |
1956年 | 1篇 |
1954年 | 1篇 |
排序方式: 共有1135条查询结果,搜索用时 15 毫秒
81.
82.
Pospichalova V Tureckova J Fafilek B Vojtechova M Krausova M Lukas J Sloncova E Takacova S Divoky V Leprince D Plachy J Korinek V 《Genesis (New York, N.Y. : 2000)》2011,49(3):142-151
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene located on chromosome 17p13.3, a region frequently hypermethylated or deleted in human neoplasias. In mouse, Hic1 is essential for embryonic development and exerts an antitumor role in adult animals. Since Hic1-deficient mice die perinatally, we generated a conditional Hic1 null allele by flanking the Hic1-coding region by loxP sites. When crossed to animals expressing Cre recombinase in a cell-specific manner, the Hic1 conditional mice will provide new insights into the function of Hic1 in developing and mature tissues. Additionally, we used gene targeting to replace sequence-encoding amino acids 186-893 of Hic1 by citrine fluorescent protein cDNA. We demonstrate that the distribution of Hic1-citrine fusion polypeptide corresponds to the expression pattern of wild-type Hic1. Consequently, Hic1-citrine "reporter" mice can be used to monitor the activity of the Hic1 locus using citrine fluorescence. 相似文献
83.
Vermachova M Purkrtova Z Santrucek J Jolivet P Chardot T Kodicek M 《Proteomics》2011,11(16):3430-3434
Plant seed oil bodies, subcellular lipoprotein inclusions providing storage reserves, are composed of a neutral lipid core surrounded by a phospholipid monolayer with several integrated proteins that play a significant role in stabilization of the particles and probably also in lipid mobilization. Oil bodies' proteins are generally very hydrophobic, due to the long uncharged sequences anchoring them into the lipid core, which makes them extremely difficult to handle and to digest successfully. Although oil bodies have been intensively studied during last decades, not all their proteins have been identified yet. To overcome the problems connected with their identification, a method based on SDS-PAGE, in-gel digestion and LC-MS/MS analysis was used. Digestion was carried out with trypsin and chymotrypsin, single or in combination, which increased significantly the number of identified peptides, namely the hydrophobic ones. Thanks to this methodology it was possible to achieve an extensive coverage of proteins studied, to analyze their N-terminal modifications and moreover, to detect four new oil bodies' protein isoforms, which demonstrates the complexity of oil bodies' protein composition. 相似文献
84.
85.
Singh P Sachdeva S Raj R Kumar V Mahajan MP Nasser S Vivas L Gut J Rosenthal PJ Feng TS Chibale K 《Bioorganic & medicinal chemistry letters》2011,21(15):4561-4563
3-Azido-, 3-amino- and 3-(1,2,3-triazol-1-yl)-β-lactams were synthesized and evaluated for their antiplasmodial activity against four strains of Plasmodium falciparum and KB cells for their cytotoxicity profiles. The presence of a cyclohexyl substituent at N-1 and a phenyl group on the triazole ring markedly improved the activity profiles of triazole-tethered β-lactam exhibiting IC50 values of 1.13, 1.21 and 1.00 μM against 3D7, K1 and W2 strains respectively. 相似文献
86.
Zhang YK Plattner JJ Freund YR Easom EE Zhou Y Gut J Rosenthal PJ Waterson D Gamo FJ Angulo-Barturen I Ge M Li Z Li L Jian Y Cui H Wang H Yang J 《Bioorganic & medicinal chemistry letters》2011,21(2):644-651
A series of boron-containing benzoxaborole compounds was designed and synthesized for a structure-activity relationship investigation surrounding 7-(HOOCCH2CH2)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1) with the goal of discovering a new antimalarial treatment. Compound 1 demonstrates the best potency (IC50 = 26 nM) against Plasmodium falciparum and has good drug-like properties, with low molecular weight (206.00), low ClogP (0.86) and high water solubility (750 μg/mL at pH 7). 相似文献
87.
Zitko J Dolezal M Svobodova M Vejsova M Kunes J Kucera R Jilek P 《Bioorganic & medicinal chemistry》2011,19(4):1471-1476
A series of fifteen new compounds related to pyrazinamide (PZA) were synthesized, characterized with analytical data and screened for antimycobacterial, antifungal and antibacterial activity. The series consists of 6-chloro-5-cyanopyrazine-2-carboxamide and N-substituted 6-amino-5-cyanopyrazine-2-carboxamides, derived from the previous by nucleophilic substitution with various non-aromatic amines (alkylamines, cycloalkylamines, heterocyclic amines). Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis equal to pyrazinamide (12.5-25 μg/mL). More importantly, 6-chloro-5-cyanopyrazine-2-carboxamide and 5-cyano-6-(heptylamino)pyrazine-2-carboxamide were active against Mycobacterium kansasii and Mycobacterium avium, which are unsusceptible to PZA. Basic structure-activity relationships are presented. Only weak antifungal and no antibacterial activity was detected. 相似文献
88.
Goris MG Wagenaar JF Hartskeerl RA van Gorp EC Schuller S Monahan AM Nally JE van der Poll T van 't Veer C 《PloS one》2011,6(3):e18279
Background
Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. The bacteria enter the human body via abraded skin or mucous membranes and may disseminate throughout. In general the clinical picture is mild but some patients develop rapidly progressive, severe disease with a high case fatality rate. Not much is known about the innate immune response to leptospires during haematogenous dissemination. Previous work showed that a human THP-1 cell line recognized heat-killed leptospires and leptospiral LPS through TLR2 instead of TLR4. The LPS of virulent leptospires displayed a lower potency to trigger TNF production by THP-1 cells compared to LPS of non-virulent leptospires.Methodology/Principal Findings
We investigated the host response and killing of virulent and non-virulent Leptospira of different serovars by human THP-1 cells, human PBMC''s and human whole blood. Virulence of each leptospiral strain was tested in a well accepted standard guinea pig model. Virulent leptospires displayed complement resistance in human serum and whole blood while in-vitro attenuated non-virulent leptospires were rapidly killed in a complement dependent manner. In vitro stimulation of THP-1 and PBMC''s with heat-killed and living leptospires showed differential serovar and cell type dependence of cytokine induction. However, at low, physiological, leptospiral dose, living virulent complement resistant strains were consistently more potent in whole blood stimulations than the corresponding non-virulent complement sensitive strains. At higher dose living virulent and non-virulent leptospires were equipotent in whole blood. Inhibition of different TLRs indicated that both TLR2 and TLR4 as well as TLR5 play a role in the whole blood cytokine response to living leptospires.Conclusions/Significance
Thus, in a minimally altered system as human whole blood, highly virulent Leptospira are potent inducers of the cytokine response. 相似文献89.
90.