全文获取类型
收费全文 | 828篇 |
免费 | 61篇 |
专业分类
889篇 |
出版年
2023年 | 7篇 |
2022年 | 12篇 |
2021年 | 16篇 |
2020年 | 14篇 |
2019年 | 14篇 |
2018年 | 13篇 |
2017年 | 17篇 |
2016年 | 22篇 |
2015年 | 35篇 |
2014年 | 42篇 |
2013年 | 64篇 |
2012年 | 82篇 |
2011年 | 63篇 |
2010年 | 47篇 |
2009年 | 31篇 |
2008年 | 41篇 |
2007年 | 51篇 |
2006年 | 41篇 |
2005年 | 30篇 |
2004年 | 31篇 |
2003年 | 27篇 |
2002年 | 26篇 |
2001年 | 12篇 |
2000年 | 7篇 |
1999年 | 9篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 10篇 |
1992年 | 8篇 |
1991年 | 9篇 |
1990年 | 7篇 |
1989年 | 2篇 |
1988年 | 6篇 |
1987年 | 10篇 |
1986年 | 12篇 |
1985年 | 7篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1981年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1975年 | 3篇 |
1972年 | 2篇 |
1970年 | 2篇 |
1969年 | 3篇 |
1968年 | 2篇 |
1967年 | 2篇 |
排序方式: 共有889条查询结果,搜索用时 15 毫秒
1.
Nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) is an indispensable component of the HCV replication and assembly machineries. Although its precise mechanism of action is not yet clear, current evidence indicates that its structure and function are regulated by the cellular peptidylprolyl isomerase cyclophilin A (CyPA). CyPA binds to proline residues in the C-terminal half of NS5A, in a distributed fashion, and modulates the structure of the disordered domains II and III. Cyclophilin inhibitors (CPIs), including cyclosporine (CsA) and its nonimmunosuppressive derivatives, inhibit HCV infection of diverse genotypes, both in vitro and in vivo. Here we report a mechanism by which CPIs inhibit HCV infection and demonstrate that CPIs can suppress HCV assembly in addition to their well-documented inhibitory effect on RNA replication. Although the interaction between NS5A and other viral proteins is not affected by CPIs, RNA binding by NS5A in cell culture-based HCV (HCVcc)-infected cells is significantly inhibited by CPI treatment, and sensitivity of RNA binding is correlated with previously characterized CyPA dependence or CsA sensitivity of HCV mutants. Furthermore, the difference in CyPA dependence between a subgenomic and a full-length replicon of JFH-1 was due, at least in part, to an additional role that CyPA plays in HCV assembly, a conclusion that is supported by experiments with the clinical CPI alisporivir. The host-directed nature and the ability to interfere with more than one step in the HCV life cycle may result in a higher genetic barrier to resistance for this class of HCV inhibitors. 相似文献
2.
A 81-fold purification of human seminal plasma acid phosphatase was obtained by a three-step procedure, involving ammonium sulfate precipitation, DEAE-cellulose chromatography and Sephadex G-200 gel filtration. Homogeneity of the preparation during purification steps was tested by polyacrylamide gel electrophoresis and only one major band was obtained after the final step. The pH optimum for the activity of the purified enzyme was 5.6 and thermal stability was obtained even up to 40 degrees C. PNPP was the most specific synthetic substrate. The Km of purified seminal acid phosphatase towards PNPP was 1.5 X 10(-3) M. Among the metal ions tested, Hg+2 showed an I50 value of 4.2 X 10(-7) M. Studies with PCMB, PMSF and EDTA did not show any inhibition, whereas NaF and L(+)tartrate, at 1 mM concentration, inhibited the enzyme by 95% and 85%, respectively. 相似文献
3.
Shyamali Mukherjee Mihir Nag Tultul Nayyar Indrani Maitra Parul Chakrabarti Pramod R. Dasgupta 《Journal of biosciences》1986,10(3):311-317
The effect of estradiol-17β and progesterone given separately as well as in combination on the rate of hydrogen peroxide formation
and lipid peroxidation in the uteri of ovariectomized rats was studied. Estradiol in 3μg dose per day per animal elicited maximum stimulatory response and progesterone (100μg), on the other hand, was without any such effect. However, progesterone given along with estradiol completely prevented the
effect due to the latter. In the same way, vitamin E, a well known antioxidant was found to be extremelv effective in protecting
the uterus from the highly peroxidative action of estradiol-17β. 相似文献
4.
5.
6.
The macrolide antibiotic, tylosin (Ty), is produced by Streptomyces fradiae. Two resistance determinants (tlrA, synonym ermSF, and tlrD) conferring resistance to macrolide, lincosamide and streptogramin B type (MLS) antibiotics were previously isolated from this strain, and their products shown to methylate 23S ribosomal RNA (rRNA) at a common site, thereby rendering the ribosomes MLS resistant. However, the T1rA and T1rD proteins differ in their action; the former dimethylates, and the latter monomethylates, the target nucleotide. Here, 2.2 kb of DNA from the tylLM region of the tylosin biosynthetic gene cluster of S. fradiae has been sequenced and shown to encompass tlrD. Comparison of the sequences of tlrA and tlrD (and of their deduced products) with those of related (‘erm-type’) genes from other actinomycetes suggests that the combined presence of tlrA and tlrD in S. fradiae is not the result of recent gene duplication. 相似文献
7.
Psychoactive drugs like chlorpromazine (CPZ), imipramine, lithium and amphetamine in one way or another affect behaviour. The drug responses are presumably mediated by inducing a change in the activity of membrane bound enzymes. CPZ is very potent in inhibiting the alkaline phosphatase activity in rat brain. The combined effect of CPZ with other drugs shows that CPZ and imipramine together inhibit the enzyme activity significantly greater than the individual inhibition either by CPZ or by imipramine alone. Effective inhibition of the alkaline phosphatase activity with a single drug or combined drugs may lead to a change in neuronal permeability through glucocorticoids thereby affecting mood. 相似文献
8.
9.
B Nag S S Akella P A Cann D S Tewari D G Glitz R R Traut 《The Journal of biological chemistry》1991,266(33):22129-22135
Monoclonal antibodies against Escherichia coli ribosomal proteins L9 and L10 were obtained and their specificity confirmed by Western blot analysis of total ribosomal protein. This was particularly important for the L9 antibody, since the immunizing antigen mixture contained predominantly L11. Each antibody recognized both 70 S ribosomes and 50 S subunits. Affinity-purified antibodies were tested for their effect on in vitro assays of ribosome function. Anti-L10 and anti-L9 inhibited poly(U)-directed polyphenylalanine synthesis almost completely. The antibodies had no effect on subunit association or dissociation and neither antibody inhibited peptidyltransferase activity. Both antibodies inhibited the binding of the ternary complex that consisted of aminoacyl-tRNA, guanylyl beta, gamma-methylenediphosphonate, and elongation factor Tu, and the binding of elongation factor G to the ribosome. The intact antibodies were more potent inhibitors than the Fab fragments. In contrast to the previously established location of L10 at the base of the L7/L12 stalk near the factor-binding site, the site of anti-L9 binding to 50 S subunits was shown by immune electron microscopy to be on the L1 lateral protuberance opposite the L7/L12 stalk as viewed in the quasisymmetric projection. The inhibition of factor binding by both antibodies, although consistent with established properties of L10 in the ribosome, suggests a long range effect on subunit structure that is triggered by the binding of anti-L9. 相似文献
10.
B Nag D Passmore T Kendrick H Bhayani S D Sharma 《The Journal of biological chemistry》1992,267(31):22624-22629
To evaluate the functional role of the N-linked oligosaccharides of major histocompatibility complex (MHC) class II molecules, affinity-purified murine IAs class II molecules were deglycosylated in the presence of asparagine amidase enzyme. The deglycosylated IAs molecules were characterized by 12% SDS-polyacrylamide gel analysis under reduced and native conditions and the complete enzymatic removal of all three N-linked sugar components from the alpha/beta heterodimer was confirmed by lectin-link Western blot analysis. Like the native IAs molecules, the deglycosylated IAs molecules were fully capable of binding an antigenic peptide from myelin basic protein MBP(89-101). The kinetics of dissociation of preformed complexes of IAs.MBP(89-101) and deglycosylated IAs.MBP(89-101) were compared at 4 and at 37 degrees C. Both complexes were equally stable at 4 degrees C; however, at 37 degrees C the deglycosylated IAs.MBP(89-101) complexes showed an increased rate of dissociation as compared with the native IAs.MBP(89-101) complexes. When tested for their ability to recognize the T cell receptor on T cells, both complexes bound to cloned HS-1 T cells that recognize and respond to IAs.MBP(89-101). Finally, the complexes of deglycosylated IAs.MBP(89-101) were tested for the induction of in vitro nonresponsiveness and compared with native IAs.MBP(89-101) complexes. Both complexes were capable of inducing 95-100% nonresponsiveness in a proliferation assay. These results suggest that the N-linked oligosaccharide of MHC class II molecules may not be essential for either antigenic peptide binding or T cell recognition. In addition results obtained here provide evidence that the carbohydrate moities of MHC class II molecules may not be involved in induction of T cell clonal anergy. 相似文献