全文获取类型
收费全文 | 1208篇 |
免费 | 93篇 |
国内免费 | 1篇 |
专业分类
1302篇 |
出版年
2022年 | 7篇 |
2021年 | 14篇 |
2020年 | 13篇 |
2019年 | 11篇 |
2018年 | 15篇 |
2017年 | 16篇 |
2016年 | 16篇 |
2015年 | 33篇 |
2014年 | 46篇 |
2013年 | 75篇 |
2012年 | 59篇 |
2011年 | 59篇 |
2010年 | 36篇 |
2009年 | 38篇 |
2008年 | 63篇 |
2007年 | 62篇 |
2006年 | 64篇 |
2005年 | 59篇 |
2004年 | 63篇 |
2003年 | 54篇 |
2002年 | 61篇 |
2001年 | 9篇 |
2000年 | 13篇 |
1999年 | 17篇 |
1998年 | 20篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 12篇 |
1994年 | 12篇 |
1993年 | 12篇 |
1992年 | 15篇 |
1991年 | 14篇 |
1990年 | 13篇 |
1989年 | 16篇 |
1988年 | 10篇 |
1987年 | 15篇 |
1986年 | 6篇 |
1985年 | 16篇 |
1984年 | 25篇 |
1983年 | 18篇 |
1982年 | 26篇 |
1981年 | 11篇 |
1980年 | 6篇 |
1978年 | 6篇 |
1977年 | 8篇 |
1976年 | 9篇 |
1975年 | 9篇 |
1974年 | 9篇 |
1973年 | 8篇 |
1968年 | 6篇 |
排序方式: 共有1302条查询结果,搜索用时 9 毫秒
71.
P-fimbriae, S-fimbriae and AFA-adhesins are virulence factors responsible for adherence ofEscherichia coli strains to extraintestinal host-cell surface. Detection ofpap-,sfa- andafa-specific sequences performed by PCR revealed 74%pap
+, 65%sfa
+, and 8.3%afa
+ strains in a group of 84 extraintestialE. coli isolates. Detection in a group of fecal strains showed 29%pap
+, 21%sfa
+ and 4%afa
+ strains.pap together withsfa were found as the most frequent combination (56%) among extraintestinal isolates probably due to localization ofpap-andsfa-operons on a common pathogenicity island. The occurrence ofafa-specific sequence among 56 urine strains was 11%, although noafa
+ strain was detected among 28 gynecological isolates. No strains with detected adhesin operons were found among twenty (24%)
extraintestinalE. coli strains. 相似文献
72.
73.
Saleem A Engström M Wurster S Savola JM Pihlaja K 《Zeitschrift für Naturforschung. C, Journal of biosciences》2002,57(3-4):332-338
Forty-two extracts of folk medicinal plant organs from Pakistan were tested in competition binding assays for their interaction with the specific ligand recognition sites on the human alpha2-adrenoceptor subtypes alpha2A, alpha2B and alpha2C Strong binding of the extracts (40 mg/ml) from Acacia nilotica (L.) Delile leaves (88-98% displacement of radiolabel) and Peganum harmala seeds (89-96% displacement) on three subtypes prompted us to extract these plant materials with 40% and 80% methanol, ethanol, and acetone. The extraction results indicated an absence of alpha2-adrenoceptor binding activity in the stalk of A. nilotica and A. tortils, whereas the leaves of both plants contained activity. The extracts of A. nilotica leaves showed a slight, but consistent, preference for the alpha2C-adrenoceptor, whereas the leaves of A. tortils were slightly more active on the alpha2B subtype. The extract of P. harmala stalks was less active than that of its seeds. The binding activities of A. nilotica leaves and P. harmala seeds were mainly concentrated in the water and 30% methanol fractions and further sub-fractions. In a functional activity assay, the active fractions inhibited epinephrine-stimulated 35S-GTPyS binding, thus indicating a predominantly antagonistic nature of the compounds with alpha2-adrenoceptor affinity in these fractions. Among the known major alkaloids of P. harmala (demissidine, harmaline, harmine, 6-methoxyharmalan, and norharmane), only 6-methoxyharmalan showed moderate affinity (dissociation constant (Ki) of 530 +/- 40 nm for alpha2A subtype). This study is a first systematic attempt towards the discovery of potential drug candidates from these plant materials for treating alpha2-adrenoceptor related diseases. 相似文献
74.
Semiempirical (AM1) molecular orbital theory with configuration interaction has been used to investigate the harpooning mechanism proposed from experimental studies on semiflexibly bridged electron donor-acceptor systems. Our calculations on the charge-transfer state of N-phenyl-4-(4-cyano-naphth-1-ylmethyl)-piperidine, 1, confirm the proposed harpooning mechanism including an intermediate loosely folded charge-transfer state and reproduce the thermodynamics obtained from our spectroscopic studies closely. The structural details of the extended (ECT), intermediate (ICT) and compact (CCT) charge-transfer states are discussed, as are the transition states connecting them. Solvent effects have been modeled using self-consistent reaction field (SCRF) calculations within the polarized continuum model. The effect of solvent polarity on the stabilities of the three charge-transfer states is discussed. 相似文献
75.
Boll W Rapoport I Brunner C Modis Y Prehn S Kirchhausen T 《Traffic (Copenhagen, Denmark)》2002,3(8):590-600
The endocytic sorting signal on the low-density lipoprotein receptor for clathrin-mediated internalization is the sequence FDNPVY in the receptor's cytosolic tail. We have used a combination of surface plasmon resonance and crosslinking with a photoactivated peptide probe to demonstrate the interaction between FDNPVY-containing peptides and the μ2 chain of purified AP-2 clathrin adaptors (the complexes responsible for plasma membrane sorting). We show that recognition of the FDNPVY signal is mediated by a binding site in the μ2-subunit that is distinct from the site for the more general YppØ sorting signal, another tyrosine-based sequence also recognized by μ2-adaptin. These results suggest the possibility that low-density lipoprotein receptor uptake may be modulated specifically and independently of other proteins in the clathrin pathway. 相似文献
76.
77.
Firla B Arndt M Frank K Thiel U Ansorge S Täger M Lendeckel U 《Free radical biology & medicine》2002,32(7):584-595
Alanyl aminopeptidase (APN) is a surface-bound metallopeptidase that processes the N-terminals of biologically active peptides such as enkephalins, angiotensins, neurokinins, and cytokines. It exerts profound activity on vital processes such as immune response, cellular growth, and blood pressure control. Inhibition of either APN gene expression or its enzymatic activity severely affects leukocyte growth and function. We show here that oxidoreductase-mediated modulations of the cell surface thiol status affect the enzymatic activity of APN. Additional evidence for the pivotal role of extracellular cysteines in the APN molecule was obtained when substitution of any of these six cysteines caused complete loss of surface expression and enzymatic activity. In contrast, the transmembrane Cys24 appears to have no similar function. Enzymatically inactive cysteine mutants were retained in the endoplasmic reticulum as shown by high-resolution imaging and Endoglycosidase H digestion. In the absence of any crystal-structure data, the demonstration that individual extracellular cysteines contribute to APN expression and function appears to be of particular importance. The data are the first to show thiol-dependent modulation of the activity of a typical surface-bound peptidase at the cell surface, probably reflecting a general regulating mechanism. This may relate to various disease processes such as inflammation or malignant transformation. 相似文献
78.
McElhinny AS Kakinuma K Sorimachi H Labeit S Gregorio CC 《The Journal of cell biology》2002,157(1):125-136
Signaling from receptor tyrosine kinases (RTKs)* requires the sequential activation of the small GTPases Ras and Rac. Son of sevenless (Sos-1), a bifunctional guanine nucleotide exchange factor (GEF), activates Ras in vivo and displays Rac-GEF activity in vitro, when engaged in a tricomplex with Eps8 and E3b1-Abi-1, a RTK substrate and an adaptor protein, respectively. A mechanistic understanding of how Sos-1 coordinates Ras and Rac activity is, however, still missing. Here, we demonstrate that (a) Sos-1, E3b1, and Eps8 assemble into a tricomplex in vivo under physiological conditions; (b) Grb2 and E3b1 bind through their SH3 domains to the same binding site on Sos-1, thus determining the formation of either a Sos-1-Grb2 (S/G) or a Sos-1-E3b1-Eps8 (S/E/E8) complex, endowed with Ras- and Rac-specific GEF activities, respectively; (c) the Sos-1-Grb2 complex is disrupted upon RTKs activation, whereas the S/E/E8 complex is not; and (d) in keeping with the previous result, the activation of Ras by growth factors is short-lived, whereas the activation of Rac is sustained. Thus, the involvement of Sos-1 at two distinct and differentially regulated steps of the signaling cascade allows for coordinated activation of Ras and Rac and different duration of their signaling within the cell. 相似文献
79.
Several activators of bovine leukemia virus (BLV) expression, including lipopolysaccharides, phorbol esters and calcium ionophores, are known to generate reactive oxygen species (ROS). Therefore the influence of H2O2 on BLV expression in two BLV producing cell lines was investigated. The effect of H2O2 on BLV expression is apparently dose-dependent. Incubation of FLK/BLV cells with low concentrations of H2O2 (2.5 to 10 microM) induced a marked enhancement of BLV p24 synthesis and an activation of the long terminal repeat (LTR). Higher concentrations resulted in a decrease of proliferation, induction of apoptosis and in a decrease of BLV synthesis. Furthermore, in both cell lines H2O2 treatment led to the activation of NF-kappaB. Pretreatment of cells with antioxidants abrogated the H2O2-induced BLV expression. Taken together, our findings suggest that oxidative stress stimulates BLV expression via activation of NF-kappaB, raising the possibility that biological sources of H2O2, such as stimulated phagocytes, may influence BLV expression. 相似文献
80.
De Haes P Garmyn M Degreef H Vantieghem K Bouillon R Segaert S 《Journal of cellular biochemistry》2003,89(4):663-673
We investigated the capacity of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to protect human keratinocytes against the hazardous effects of ultraviolet B (UVB)-irradiation, recognized as the most important etiological factor in the development of skin cancer. Cytoprotective effects of 1,25(OH)(2)D(3) on UVB-irradiated keratinocytes were seen morphologically and quantified using a colorimetric survival assay. Moreover, 1,25(OH)(2)D(3) suppressed UVB-induced apoptotic cell death. An ELISA, detecting DNA-fragmentation, demonstrated that pretreatment of keratinocytes with 1,25(OH)(2)D(3) 1 microM for 24 h reduced UVB-stimulated apoptosis by 55-70%. This suppression required pharmacological concentrations 1,25(OH)(2)D(3) and a preincubation period of several hours. In addition, 1,25(OH)(2)D(3) also inhibited mitochondrial cytochrome c release (90%), a hallmark event of UVB-induced apoptosis. Furthermore, we demonstrated that 1,25(OH)(2)D(3) reduced two important mediators of the UV-response, namely, c-Jun-NH(2)-terminal kinase (JNK) activation and interleukin-6 (IL-6) production. As shown by Western blotting, pretreatment of keratinocytes with 1,25(OH)(2)D(3) 1 microM diminished UVB-stimulated JNK activation with more than 30%. 1,25(OH)(2)D(3) treatment (1 microM) reduced UVB-induced IL-6 mRNA expression and secretion with 75-90%. Taken together, these findings suggest the existence of a photoprotective effect of active vitamin D(3) and create new perspectives for the pharmacological use of active vitamin D compounds in the prevention of UVB-induced skin damage and carcinogenesis. 相似文献