全文获取类型
收费全文 | 1699篇 |
免费 | 87篇 |
国内免费 | 13篇 |
出版年
2022年 | 8篇 |
2021年 | 26篇 |
2020年 | 31篇 |
2019年 | 19篇 |
2018年 | 36篇 |
2017年 | 29篇 |
2016年 | 46篇 |
2015年 | 85篇 |
2014年 | 98篇 |
2013年 | 100篇 |
2012年 | 127篇 |
2011年 | 121篇 |
2010年 | 70篇 |
2009年 | 62篇 |
2008年 | 98篇 |
2007年 | 95篇 |
2006年 | 79篇 |
2005年 | 64篇 |
2004年 | 78篇 |
2003年 | 68篇 |
2002年 | 48篇 |
2001年 | 41篇 |
2000年 | 45篇 |
1999年 | 30篇 |
1998年 | 18篇 |
1997年 | 16篇 |
1996年 | 10篇 |
1995年 | 10篇 |
1994年 | 6篇 |
1992年 | 13篇 |
1991年 | 8篇 |
1990年 | 19篇 |
1989年 | 10篇 |
1988年 | 20篇 |
1987年 | 16篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 10篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1978年 | 9篇 |
1976年 | 5篇 |
1975年 | 9篇 |
1974年 | 7篇 |
1973年 | 7篇 |
1972年 | 10篇 |
1971年 | 9篇 |
1970年 | 9篇 |
1968年 | 6篇 |
1965年 | 4篇 |
排序方式: 共有1799条查询结果,搜索用时 31 毫秒
81.
Kirillov DA Chaĭnikova IN Perunova NB Chelpachenko OE Pan'kov AS Smoliagin AI Valyshev AV 《Zhurnal mikrobiologii, epidemiologii, i immunobiologii》2003,(4):74-78
The effect of the synthetic immunomodulator polyoxydonium (PO) on some biological properties of pathogenic bacteria (Shigella flexneri, Salmonella enteritidis), opportunistic bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacteroides fragilis, Peptostreptococcus anaerobius, Prevotella melaninogenica, Propionibacterium propionicum, Clostridium difficile) and fungi (Candida albicans), isolated during enteric infections, enteric dysbiosis, pyoinflammatory diseases, was evaluated in a number of in vitro experiments. The study revealed that the recommended therapeutic concentration of PO decreased antilysozyme activity (ALA) and the anticomplement activity in Klebsiella, Shigella, Propionibacterium, Clostridium, bacteroids, fungi of the genus Candida, but increased ALA in nonhemolytic Escherichia. Under the action of PO an increased sensitivity of the microorganisms under study to definite antibiotics of the lincosamide, fluoroquinolon, carbapenem and cephalosporin groups was noted. The data obtained in this study reveal one of the possible mechanisms of the corrective action of PO on the microbiocenosis of the intestine in dysbiosis, enteric infections and pyoinflammatory diseases. 相似文献
82.
Previously, we reported that the yeast cytoplasmic thiol peroxidase type II isoform (cTPx II), a member of the TSA/AhpC family, showed a very low peroxidase activity when compared with other cytoplasmic yeast isoforms, and that cTPx II mutant (cTPx II Delta) showed a severe growth retardation compared with that of the wild-type cells. To reveal the physiological function of cTPx II in yeast cell growth, we searched for proteins which react with cTPx II. In this study, we identified a novel interaction between cTPx II and CSR1p using the yeast two-hybrid system. CSR1p (SFH2p) has been known to be one member of Sec14 homologous (SFH2) proteins. SFH2p exhibits phosphatidylinositol transfer protein activity. Interestingly, we found that cTPx II selectively bound to SFH2p among the five types of SFH proteins and Sec14p. The interaction required the dimerization of cTPx II. In addition, SFH2p also specifically bound to cTPx II among the yeast thiol peroxidase isoforms. The selective interaction of the dimer form of cTPx II (the oxidized form) with SFH2p was also confirmed by glutathione S-transferase pull-down and immunoprecipitation assays. The growth retardation, clearly reflected by the length of the lag phase, of cTPx II Delta was rescued by deleting SFH2p in the cTPx II Delta strain. The SFH2 Delta strain did not show any growth retardation. In addition, the double mutant showed a higher susceptibility to oxidative stress. This finding provides the first in vivo demonstration of the specific interaction of cTPx II with SFH2p in an oxidative stress-sensitive manner and a novel physiological function of the complex of cTPx II and SFH2p. 相似文献
83.
Choi J Choi S Choi J Cha MK Kim IH Shin W 《The Journal of biological chemistry》2003,278(49):49478-49486
Thioredoxin-dependent thiol peroxidase (Tpx) from Escherichia coli represents a group of antioxidant enzymes that are widely distributed in pathogenic bacterial species and which belong to the peroxiredoxin (Prx) family. Bacterial Tpxs are unique in that the location of the resolving cysteine (CR) is different from those of other Prxs. E. coli Tpx (EcTpx) shows substrate specificity toward alkyl hydroperoxides over H2O2 and is the most potent reductant of alkyl hydroperoxides surpassing AhpC and BCP, the other E. coli Prx members. Here, we present the crystal structure of EcTpx in the oxidized state determined at 2.2-A resolution. The structure revealed that Tpxs are the second type of atypical 2-Cys Prxs with an intramolecular disulfide bond formed between the peroxidatic (CP, Cys61) and resolving (Cys95) cysteine residues. The extraordinarily long N-terminal chain of EcTpx folds into a beta-hairpin making the overall structure very compact. Modeling suggests that, in atypical 2-Cys Prxs, the CR-loop as well as the CP-loop may alternately assume the fully folded or locally unfolded conformation depending on redox states, as does the CP-loop in typical 2-Cys Prxs. EcTpx exists as a dimer stabilized by hydrogen bonds. Its substrate binding site extends to the dimer interface. A modeled structure of the reduced EcTpx in complex with 15-hydroperoxyeicosatetraenoic acid suggests that the size and shape of the binding site are particularly suited for long fatty acid hydroperoxides consistent with its greater reactivity. 相似文献
84.
85.
Bae SW Kim HS Cha YN Park YS Jo SA Jo I 《Biochemical and biophysical research communications》2003,306(4):981-987
Bradykinin (BK) acutely increases endothelial nitric oxide (NO) production by activating endothelial NO synthase (eNOS), and this increase is in part correlated with enhanced phosphorylation/dephosphorylation of eNOS by several protein kinases and phosphatases. However, the signaling mechanisms producing this increase are still controversial. In an attempt to delineate the acute effect of BK on endothelial NO production, confluent bovine aortic endothelial cells were incubated with BK, and NO production was measured by NO-specific chemiluminescence. Significant increase in NO levels was detected as early as 1 min after BK treatment, with concomitant increase in the phosphorylation of Ser(1179) (bovine sequence) site of eNOS (eNOS-Ser(1179)). This acute effect of BK on both increases was blocked only by treatment of protein kinase A inhibitor H-89, but not by the inhibitors of calmodulin-dependent kinase II and protein kinase B, suggesting that the rapid increase in NO production by BK is mediated by the PKA-dependent phosphorylation of eNOS-Ser(1179). 相似文献
86.
87.
Kim BS Yoon KH Oh HM Choi EY Kim SW Han WC Kim EA Choi SC Kim TH Yun KJ Kim EC Lyou JH Nah YH Chung HT Cha YN Jun CD 《Cellular immunology》2002,220(2):96-106
Iron is an essential element for the neoplastic cell growth, and iron chelators have been tested for their potential anti-proliferative and cytotoxic effects. To determine the mechanism of cell death induced by iron chelators, we explored the pathways of the three structurally related mitogen-activated protein (MAP) kinase subfamilies during apoptosis induced by iron chelators. We report that the chelator deferoxamine (DFO) strongly activates both p38 MAP kinase and extracellular signal-regulated kinase (ERK) at an early stage of incubation, but slightly activates c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) at a late stage of incubation. Among three MAP kinase blockers used, however, the selective p38 MAP kinase inhibitor SB203580 could only protect HL-60 cells from chelator-induced cell death, indicating that p38 MAP kinase serves as a major mediator of apoptosis induced by iron chelator. DFO also caused release of cytochrome c from mitochondria and induced activation of caspase 3 and caspase 8. Interestingly, treatment of HL-60 cells with SB203580 greatly abolished cytochrome c release, and activation of caspase 3 and caspase 8. Collectively, the current study reveals that p38 MAP kinase plays an important role in iron chelator-mediated cell death of HL-60 cells by activating downstream apoptotic cascade that executes cell death pathway. 相似文献
88.
High-density poly(ethylene glycol) (PEG) molecules are grafted onto Si surfaces in a brush-like configuration. We demonstrate that this surface is an excellent substrate for oligonucleotide immobilization. p-Maleimidophenyl isocyanate is used as a heterobifunctional cross-linker to tether thiol-modified oligonucleotides to terminal OH groups on the PEG brush. This approach gives excellent immobilization specificity and low background. The immobilized oligonucleotides show high sensitivity for the detection of complementary targets. 相似文献
89.
Cha H Kopetzki E Huber R Lanzendörfer M Brandstetter H 《Journal of molecular biology》2002,320(5):1065-1079
Matrix metalloproteinase (MMPs) are critical for the degradation of extracellular matrix components and, therefore, need to be regulated tightly. Almost all MMPs share a homologous C-terminal haemopexin-like domain (PEX). Besides its role in macromolecular substrate processing, the PEX domains appear to play a major role in regulating MMP activation, localisation and inhibition. One intriguing property of MMP9 is its competence to bind different proteins, involved in these regulatory processes, with high affinity at an overlapping recognition site on its PEX domain. With the crystal structure of the PEX9 dimer, we present the first example of how PEX domains accomplish these diverse roles. Blade IV of PEX9 mediates the non-covalent and predominantly hydrophobic dimerisation contact. Large shifts of blade III and, in particular, blade IV, accompany the dimerisation, resulting in a remarkably asymmetric homodimeric structure. The asymmetry provides a novel mechanism of adaptive protein recognition, where different proteins (PEX9, PEX1, and TIMP1) can bind with high affinity to PEX9 at an overlapping site. Finally, the structure illustrates how the dimerisation generates new properties on both a physico-chemical and functional level. 相似文献
90.
The dynamics of pathological changes in the intestine of Aedes aegypti larvae under the influence of toxins Cry11A and Cry4B produced by Bacillus thuringiensis israelensis was studied by means of electron microscope. Most significant ultrastructure changes in the intestine of the second instar larvae were observed in the midgut. The cytoplasm of cells disintegrated, and elongated lacunae appeared. The number of microvilli decreased, or they disappeared in the result of destruction. The peritrophic membrane displaced to the lumen of midgut. Any changes in epithelial cells and cuticle in time of foregut and hindgut were not observed in a comparison to control. The toxin Cry4B caused the most effective destruction of the midgut epithelium. 相似文献