全文获取类型
收费全文 | 3868篇 |
免费 | 242篇 |
国内免费 | 156篇 |
出版年
2023年 | 36篇 |
2022年 | 91篇 |
2021年 | 124篇 |
2020年 | 143篇 |
2019年 | 175篇 |
2018年 | 187篇 |
2017年 | 116篇 |
2016年 | 129篇 |
2015年 | 104篇 |
2014年 | 352篇 |
2013年 | 367篇 |
2012年 | 278篇 |
2011年 | 362篇 |
2010年 | 273篇 |
2009年 | 189篇 |
2008年 | 184篇 |
2007年 | 171篇 |
2006年 | 141篇 |
2005年 | 120篇 |
2004年 | 96篇 |
2003年 | 83篇 |
2002年 | 84篇 |
2001年 | 42篇 |
2000年 | 33篇 |
1999年 | 34篇 |
1998年 | 23篇 |
1997年 | 38篇 |
1996年 | 23篇 |
1995年 | 18篇 |
1994年 | 17篇 |
1993年 | 14篇 |
1992年 | 16篇 |
1991年 | 15篇 |
1990年 | 9篇 |
1989年 | 7篇 |
1988年 | 10篇 |
1987年 | 8篇 |
1986年 | 4篇 |
1985年 | 27篇 |
1984年 | 22篇 |
1983年 | 21篇 |
1982年 | 16篇 |
1981年 | 16篇 |
1980年 | 11篇 |
1979年 | 11篇 |
1978年 | 4篇 |
1977年 | 3篇 |
1976年 | 9篇 |
1974年 | 2篇 |
1973年 | 3篇 |
排序方式: 共有4266条查询结果,搜索用时 609 毫秒
31.
Ann E. Ehrenhofer-Murray Friedrich E. Würgler Christian Sengstag 《Molecular & general genetics : MGG》1994,244(3):287-294
Several pleiotropic drug sensitivities have been described in yeast. Some involve the loss of putative drug efflux pumps analogous to mammalian P-glycoproteins, others are caused by defects in sterol synthesis resulting in higher plasma membrane permeability. We have constructed a Saccharomyces cerevisiae strain that exhibits a strong crystal violet-sensitive phenotype. By selecting cells of the supersensitive strain for normal sensitivity after transformation with a wild-type yeast genomic library, a complementing 10-kb DNA fragment was isolated, a 3.4-kb subfragment of which was sufficient for complementation. DNA sequence analysis revealed that the complementing fragment comprised the recently sequenced SGE1 gene, a partial multicopy suppressor of gal11 mutations. The supersensitive strain was found to be a sge1 null mutant. Overexpression of SGE1 on a high-copy-number plasmid increased the resistance of the supersensitive strain. Disruption of SGE1 in a wild-type strain increased the sensitivity of the strain. These features of the SGE1 phenotype, as well as sequence homologies of SGE1 at the amino acid level, confirm that the Sge1 protein is a member of the drug-resistance protein family within the major facilitator superfamily (MFS). 相似文献
32.
Junji Inokoshi Hiroshi Tomoda Hideaki Hashimoto Akemi Watanabe Hideo Takeshima Satoshi ōmura 《Molecular & general genetics : MGG》1994,244(1):90-96
Cerulenin, an antifungal antibiotic produced by Cephalosporium caerulens, is a potent inhibitor of fatty acid synthase in various organisms, including Saccharomyces cerevisiae. The antibiotic inhibits the enzyme by binding covalently to the active center cysteine of the condensing enzyme domain. We isolated 12 cerulenin-resistant mutants of S. cerevisiae following treatment with ethyl methanesulfonate. The mechanism of cerulenin resistance in one of the mutants, KNCR-1, was studied. Growth of the mutant was over 20 times more resistant to cerulenin than that of the wild-type strain. Tetrad analysis suggested that all mutants mapped at the same locus, FAS2, the gene encoding the subunit of the fatty acid synthase. The isolated fatty acid synthase, purified from the mutant KNCR-1, was highly resistant to cerulenin. The cerulenin concentration causing 50% inhibition (IC50) of the enzyme activity was measured to be 400 M, whereas the IC50 value was 15 M for the enzyme isolated from the wild-type strain, indicating a 30-fold increase in resistance to cerulenin. The FAS2 gene was cloned from the mutant. Sequence replacement experiments suggested that an 0.8 kb EcoRV-HindIII fragment closely correlated with cerulenin resistance. Sequence analysis of this region revealed that the GGT codon encoding Gly-1257 of the FAS2 gene was altered to AGT in the mutant, resulting in the codon for Ser. Furthermore, a recombinant FAS2 gene, in which the 0.8 Kb EcoRV-HindIII fragment of the wild-type FAS2 gene was replaced with the same region from the mutant, when introduced into FAS2-defective S. cerevisiae complemented the FAS2 pheno-type and showed cerulenin resistance. These data indicate that one amino acid substitution (Gly Ser) in the subunit of fatty acid synthase is responsible for the cerulenin resistance of the mutant KNCR-1. 相似文献
33.
J. Garforth J. H. McKie R. Jaouhari T. J. Benson A. H. Fairlamb K. T. Douglas 《Amino acids》1994,6(3):295-299
Summary The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the activesites of TR and human GR, subsequently confirmed by the TR crystal structure. Enzyme kinetics confirmed that forT. cruzi TR benzoyl-Leu-Arg-Arg-ß-naphthylamide was an inhibitor (Ki 13.8µM) linearly competitive with the native substrate, trypanothione disulphide, and did not inhibit glutathione reductase. 相似文献
34.
棉铃虫对氰戊菊酯抗性和敏感品系的选育 总被引:40,自引:9,他引:31
用氰戊菊酯对来自阳谷的棉铃虫(YG)Heliothis armigera(Hubncr) 进行抗性晶系的筛选。在15代期间经过9代的室内选育,获得抗性品系(Fcn-R),抗性倍数高达2“3倍,筛选后F15代LD50值(24.1412μg/头)比筛选前F1代lD50值(0.2020μg/头)提高了119.5倍。对来自偃师的棉铃虫(YS)进行了连续两代单对筛选,得到敏感品系(Fen-S),敏感晶系的LD50值为0.0116μg/头,接近1983年东台敏感晶系的LD50值(0.0098μg/头)Fcn-R抗性晶系筛选前后分别测定了七种杀虫剂的剂量-死亡回归线,发现Fen-R抗性品系对溴氰菊酯[LD50(Fen-R)/LD50(YG)=5.2X] 和氯氰菊酯(2.5X)具有一定程度的交互抗性;而对功夫菊酯(0.66X),氯菊酯(0.89x)、灭多威(0.74X)及久效磷(1.5x)没有交互抗性。氰戊菊酯加Pb的增效试验结果表明棉铃虫对氰戊菊酯的抗性主要是由于多功能氧化酶的代谢作用。毒理学资料还暗示抗性为多因子(基因)的。 相似文献
35.
36.
Yannick Azou Monique Laval 《Biology of the cell / under the auspices of the European Cell Biology Organization》1993,77(2):155-164
Summary— We have previously shown the presence, in the amplified DNA of a Drosophila cell line resistant to N-phosphonacetyl-L-aspartate (PALA), of two units of 150 kb and 120 kb respectively duplicated and amplified. The two joints (J1 and J2) linking these units as well as their respective wild-type counterparts have been sequenced. Sequence analysis indicates that a region of the Drosophila genome which corresponds to the proximal boundary of the 150 kb unit is common to both joints. In addition to this common region, the J1 junction possesses a 26-nucleotide sequence belonging to the J2 junction. This indicates that the J2 junction was the first formed, and that J1, therefore, results from recombination between J2 and a region of the wild-type genome 120 kb distal to J2. Sequence analysis also reveals that the joints result from illegitimate recombination between unrelated regions. AT-rich sequences, strand bias composition and putative topoisomerase I and II sites were found in at least one of the two parental sequences involved in the formation of the joints. On the basis of these results we can hypothesize that after two illegitimate recombinations between sister chromatids, leading first to J2 and then to J1, the amplification may have arisen by a series of homologous (unequal crossing-over) or illegitimate recombinations, or by an intrachromosomal rolling circle. 相似文献
37.
本文应用系统分析方法,建立了一种一级吸收药物的生物利用度的简便估计的两点法。这种方法,只需测量血管内和血管外给药后的两个相同时点的血药浓度值。不论该药的处置系统是多少室,均能得到较好的结果。这种方法不仅比目前常用的点一点法和点一面法简单,而且结果更精确。 相似文献
38.
《Saudi Journal of Biological Sciences》2023,30(8):103730
Mycobacterium tuberculosis (MTB) is becoming more and more resistant to drugs and it is a common problem, making current antimicrobials ineffective and highlighting the need for new TB drugs. One of the promising targets for treating MTB is MurB enzymes. This study aimed to identify potential inhibitors of MurB enzymes in M. tuberculosis, as drug resistance among MTB is a significant problem. Attempts are being made to conduct a virtual screening of 30,417 compounds, and thirty-two compounds were chosen for further analysis based on their binding conformations. The selected compounds were assessed for their drug-likeness, pharmacokinetics, and physiochemical characteristics, and seven compounds with binding energy lower than flavin (FAD) were identified. Further, molecular dynamics simulation analysis of these seven compounds found that four of them, namely DB12983, DB15688, ZINC084726167, and ZINC254071113 formed stable complexes with the MurB binding site, exhibiting promising inhibitory activity. These compounds have not been mentioned in any other study, indicating their novelty. The study suggests that these four compounds could be promising candidates for treating MTB, but their effectiveness needs to be validated through in vitro and in vivo experiments. Overall, the findings of this study provide new insight into potential drug targets and candidates for combating drug-resistant MTB. 相似文献
39.
Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm for this class of compounds, it is now clear that they can also be tuned to target proteins in cells, depending on the metal and ligand scaffold. Since metallodrug discovery is dominated by phenotypic screenings, tailored proteomics strategies were crucial to identify and validate protein targets of several investigative and clinically advanced metal-based drugs. Here, such experimental approaches are discussed, which showed that metallodrugs based on ruthenium, gold, rhenium and even platinum, can selectively and specifically target proteins with clear-cut down-stream effects. Target identification strategies are expected to support significantly the mechanism-driven clinical translation of metal-based drugs. 相似文献
40.
Initiatedlselected (ISH) and normal (NH) rat hepatocytes were used to study cytoskeleton modifications induced by three liver acting chemicals: 2-AAF, a liver complete carcinogen; PB, a liver tumor promoter; and 4-AAF, a noncarcinogen analogue of 2-AAF. Cytoskeleton alterations were visualized by disappearance of F-actin fibers and tubulin depolymerization. The three drugs induced actin fragmentation in normal hepatocytes; a net loss of actin protein was observed with PB. They also induced varied tubulin depolymerization. The principal difference between chemicals is that 2-AAF led to non-reversible effects, in comparison with PB and 4-AAF which induced reversible damages on cytoskeleton. By contrast to normal hepatocytes, the cytoskeleton of ISH obtained from rats subjected to the resistant hepatocyte protocol was much less susceptible to the effect of the three chemicals. Moreover, we observed a lack of LDH release in the culture medium and a very rapid inducibility of GST activity after exposure of ISH to drugs. The moderate effect of the three chemicals on actin and tubdin in ISH could thus be explained by the resistant metabolic profile of these cells.Abbreviations TPA
12-O-tetradecanoyl-phorbol-13-acetate
- PB
phenobarbital
- 2-AAF
2-acetylaminofluorene
- 4-AAF
4-acetylaminofluorene
- GSH
reduced glutathione
- GST
glutathione-S-transferase
- LDH
lactatedehydrogenase
- NH
normal hepatocytes
- ISH
initiated/selected hepatocytes
- BSA
bovine serum albumin 相似文献