全文获取类型
收费全文 | 364篇 |
免费 | 13篇 |
出版年
2022年 | 2篇 |
2021年 | 3篇 |
2020年 | 3篇 |
2019年 | 6篇 |
2018年 | 2篇 |
2017年 | 4篇 |
2016年 | 7篇 |
2015年 | 14篇 |
2014年 | 10篇 |
2013年 | 22篇 |
2012年 | 21篇 |
2011年 | 23篇 |
2010年 | 16篇 |
2009年 | 7篇 |
2008年 | 36篇 |
2007年 | 37篇 |
2006年 | 34篇 |
2005年 | 22篇 |
2004年 | 26篇 |
2003年 | 19篇 |
2002年 | 21篇 |
2001年 | 2篇 |
2000年 | 3篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 3篇 |
1973年 | 2篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1965年 | 1篇 |
1964年 | 1篇 |
排序方式: 共有377条查询结果,搜索用时 406 毫秒
91.
Conformational changes of the Na+/K+-ATPase isolated large cytoplasmic segment connecting transmembrane helices M4 and M5 (C45) induced by the interaction with enzyme ligands (i.e. Mg2+ and/or ATP) were investigated by means of the intrinsic tryptophan fluorescence measurement and molecular dynamic simulations. Our data revealed that this model system consisting of only two domains retained the ability to adopt open or closed conformation, i.e. behavior, which is expected from the crystal structures of relative Ca2+-ATPase from sarco(endo)plasmic reticulum for the corresponding part of the entire enzyme. Our data revealed that the C45 is found in the closed conformation in the absence of any ligand, in the presence of Mg2+ only, or in the simultaneous presence of Mg2+ and ATP. Binding of the ATP alone (i.e. in the absence of Mg2+) induced open conformation of the C45. The fact that the transmembrane part of the enzyme was absent in our experiments suggested that the observed conformational changes are consequences only of the interaction with ATP or Mg2+ and may not be related to the transported cations binding/release, as generally believed. Our data are consistent with the model, where ATP binding to the low-affinity site induces conformational change of the cytoplasmic part of the enzyme, traditionally attributed to E2 → E1 transition, and subsequent Mg2+ binding to the enzyme-ATP complex induces in turn conformational change traditionally attributed to E1 → E2 transition. 相似文献
92.
Pathogens of two important bark beetles, Ips typographus and Ips duplicatus, both in outbreaks connected with infestation of spruces by the fungus Armillaria ostoyae, were compared at four localities in the eastern Czech Republic. Low infestations of Chytridiopsis typographi, Nosema typographi, Menzbieria chalcographi, and Gregarina typographi were detected in I. typographus. In I. duplicatus, only C. typographi and G. typographi were found and with low infection levels. The microsporidium, Larssoniella duplicati, was not detected in I. typographus, but was detected in I. duplicatus at all localities in almost 80% of the samples (a sample consisted of 40–50 beetles collected at one locality in one period)
and often with a very high infection level (up to 57% of the beetles infected in a sample). The infection level of L. duplicati did not differ between generations of I. duplicatus. I. duplicatus overwinters mainly in the adult stage, and no decrease in the number of infected overwintering I. duplicatus was observed. The relatively constant infection level of L. duplicati suggests that transmission is unlikely to be horizontal via oral ingestion. 相似文献
93.
Joseph Gabriele Giuseppe F. Pontoriero Nancy Thomas Christy A. Thomson Kevin Skoblenick Zdenek B. Pristupa Ram K. Mishra 《Cell stress & chaperones》2009,14(6):555-567
Catecholamine-regulated proteins (CRPs) have been shown to bind dopamine and other structurally related catecholamines; in
particular, the 40-kDa CRP (CRP40) protein has been previously cloned and functionally characterized. To determine putative
human homologs, BLAST analysis using the bovine CRP40 sequence identified a human established sequence tag (EST) with significant
homology (accession #BQ224193). Using this EST, we cloned a recombinant human brain CRP40-like protein, which possessed chaperone
activity. Radiolabeled dopamine binding studies with recombinant human CRP40 protein demonstrated the ability of this protein
to bind dopamine with low affinity and high capacity. The full-length human CRP40 nucleotide sequence was elucidated (accession
#DQ480334) with RNA ligase-mediated rapid amplification of complementary DNA ends polymerase chain reaction, while Northern
blot hybridization suggested that human CRP40 is an alternative splice variant of the 70-kDa mitochondrial heat shock protein,
mortalin. Human SH-SY5Y neuroblastoma cells treated with the antipsychotic drug, haloperidol, exhibited a significant increase
in CRP40 messenger RNA expression compared to untreated control cells, while other dopamine agonists/antagonists also altered
CRP40 expression and immunolocalization. In conclusion, these results show that we have cloned a splice variant of mortalin
with a novel catecholamine binding function and that this chaperone-like protein may be neuroprotective in dopamine-related
central nervous system disorders. 相似文献
94.
The Pt(II) and Pd(II) complexes of the types cis-[Pt(L(1))(2)Cl(2)].H(2)O (1), cis-[Pt(L(2))(2)Cl(2)].3H(2)O (2), trans-[Pd(L(1))(2)Cl(2)].H(2)O (3), trans-[Pd(L(2))(2)Cl(2)].H(2)O (4), trans-[Pd(L(3))(2)Cl(2)].2DMF (5) and trans-[Pd(L(4))(2)Cl(2)].2DMF (6) (L(1)-L(4)=cyclin-dependent kinase inhibitors derived from 6-benzylamino-9-isopropylpurine) have been prepared and characterized. The complexes have been studied by elemental analyses, conductivity measurements, ES+ MS, FT-IR, (1)H, (13)C and (195)Pt NMR spectra, differential scanning calorimetry and thermogravimetric analysis. The molecular structures of L(1), trans-[Pd(L(3))(2)Cl(2)].2DMF (5) and trans-[Pd(L(4))(2)Cl(2)].2DMF (6) have been determined by single crystal X-ray analysis. The complexes have been tested in vitro due to their presumable anticancer activity against the following human cancer cell lines: K-562, MCF7, G-361 and HOS. Satisfying results were obtained for the complex 1 with IC(50) values of 6 microM acquired against G-361 as well as against HOS cell lines. The lowest values of IC(50) were achieved for the complexes 3 and 4 against MCF 7 cell line with IC(50) 3 microM(for 3) and also 3 microM (for 4). 相似文献
95.
96.
97.
Bacterial intoxication evokes cellular senescence with persistent DNA damage and cytokine signalling
Hana Blazkova Katerina Krejcikova Pavel Moudry Teresa Frisan Zdenek Hodny Jiri Bartek 《Journal of cellular and molecular medicine》2010,14(1-2):357-367
Cytolethal distending toxins (CDTs) are proteins produced and secreted by facultative pathogenic strains of Gram-negative bacteria with potentially genotoxic effects. Mammalian cells exposed to CDTs undergo cell type-dependent cell-cycle arrest or apoptosis; however, the cell fate responses to such intoxication are mechanistically incompletely understood. Here we show that both normal and cancer cells (BJ, IMR-90 and WI-38 fibroblasts, HeLa and U2-OS cell lines) that survive the acute phase of intoxication by Haemophilus ducreyi CDT possess the hallmarks of cellular senescence. This characteristic phenotype included persistently activated DNA damage signalling (detected as 53BP1/γH2AX+ foci), enhanced senescence-associated β-galactosidase activity, expansion of promyelocytic leukaemia nuclear compartments and induced expression of several cytokines (especially interleukins IL-6, IL-8 and IL-24), overall features shared by cells undergoing replicative or premature cellular senescence. We conclude that analogous to oncogenic, oxidative and replicative stresses, bacterial intoxication represents another pathophysiological stimulus that induces premature senescence, an intrinsic cellular response that may mechanistically underlie the 'distended' morphology evoked by CDTs. Finally, the activation of the two anticancer barriers, apoptosis and cellular senescence, together with evidence of chromosomal aberrations (micronucleation) reported here, support the emerging genotoxic and potentially oncogenic effects of this group of bacterial toxins, and warrant further investigation of their role(s) in human disease. 相似文献
98.
99.
Trávnícek Z Malon M Zatloukal M Dolezal K Strnad M Marek J 《Journal of inorganic biochemistry》2003,94(4):307-316
The new square-planar Pt(II) and Pd(II) complexes with cytokinin-derived compounds Bohemine and Olomoucine, having the formulae [Pt(BohH(+))Cl(3)].H(2)O (1), [Pt(Boh)(2)Cl(2)].3H(2)O (2), [Pt(Boh-H)Cl(H(2)O)(2)].H(2)O (3), [Pt(OloH(+))Cl(3)].H(2)O (4), [Pd(BohH(+))Cl(3)].H(2)O (5), [Pd(Boh)Cl(2)(H(2)O)] (6), [Pd(Boh-H)Cl(H(2)O)].EtOH (7) and [Pd(OloH(+))Cl(3)].H(2)O (8), where Boh=6-(benzylamino)-2-[(3-(hydroxypropyl)amino]-9-isopropylpurine and Olo=6-(benzylamino)-2-[(2-(hydroxyethyl)amino]-9-methylpurine, have been synthesized. The complexes have been characterized by elemental analyses, IR, FAB+ mass, 1H, 13C and 195Pt NMR spectra, and conductivity data. The molecular structure of the complex [Pt(BohH(+)-N7)Cl(3)].9/5H(2)O has been determined by an X-ray diffraction study. Results from physical studies show that both Bohemine and Olomoucine are coordinated to transition metals through the N(7) atom of purine ring in all the complexes. The prepared compounds have been tested in vitro for their possible cytotoxic activity against G-361 (human malignant melanoma), HOS (human osteogenic sarcoma), K-562 (human chronic myelogenous leukemia) and MCF-7 (human breast adenocarcinoma) cell lines and IC(50) values have been also determined for all the complexes. IC(50) values estimated for the Pt(II)-Bohemine complexes (2.1-16 microM) allow us to conclude that they could find utilization in antineoplastic therapy. Thus, from a pharmacological point of view, Pt(II) complexes of Bohemine may represent compounds for a new class of antitumor drugs. 相似文献
100.
The interactions between the protein and the solvent were analyzed, and protein regions with a high density of water molecules, as well as structural water molecules, were determined by using molecular dynamics (MD) simulations. A number of water molecules that were in contact with the protein for the whole trajectory were determined. Their interaction energies and hydrogen bonds with protein residues were analyzed. Altogether, 39, 27, 49, and 32 water molecules bound to the protein were found for trajectories of the free CDK2, CDK2/ATP, CDK2/roscovitine, and CDK2/isopentenyladenine complexes, respectively. Positions of observed water molecules were compared with X-ray crystallography data. Special attention was paid to water molecules in the active site of the enzyme, and especially to the deep pocket, where the N9 roscovitine side-chain is buried. Exchange of active-site water molecules with bulk water through the tunnel from the pocket was observed. In the CDK2/isopentenyladenine complex simulation, two water molecules that arrange interaction between the inhibitor and the enzyme via an H-bond were observed. Two stable water molecules in the trajectory of the free CDK2 were found that occupy the same position as the nitrogens N3 and N9 of the isopentenyladenine or N1 and N6 nitrogens of the adenosine triphosphate (ATP). The positions of structural water molecules were compared with the positions of substrate polar groups and crystallographic water molecules found in the Brookhaven Protein Data Bank for various CDK2 complexes. It was concluded that tracing tightly bound water molecules may substantially help in designing new inhibitors. 相似文献