全文获取类型
收费全文 | 3042篇 |
免费 | 266篇 |
国内免费 | 1篇 |
专业分类
3309篇 |
出版年
2022年 | 28篇 |
2021年 | 56篇 |
2020年 | 30篇 |
2019年 | 34篇 |
2018年 | 50篇 |
2017年 | 36篇 |
2016年 | 67篇 |
2015年 | 163篇 |
2014年 | 134篇 |
2013年 | 235篇 |
2012年 | 241篇 |
2011年 | 241篇 |
2010年 | 136篇 |
2009年 | 133篇 |
2008年 | 168篇 |
2007年 | 218篇 |
2006年 | 175篇 |
2005年 | 164篇 |
2004年 | 135篇 |
2003年 | 138篇 |
2002年 | 123篇 |
2001年 | 39篇 |
2000年 | 32篇 |
1999年 | 46篇 |
1998年 | 40篇 |
1997年 | 40篇 |
1996年 | 30篇 |
1995年 | 31篇 |
1994年 | 28篇 |
1993年 | 23篇 |
1992年 | 13篇 |
1991年 | 15篇 |
1990年 | 20篇 |
1989年 | 8篇 |
1988年 | 8篇 |
1987年 | 13篇 |
1986年 | 13篇 |
1985年 | 8篇 |
1984年 | 12篇 |
1982年 | 8篇 |
1981年 | 7篇 |
1980年 | 8篇 |
1979年 | 15篇 |
1978年 | 8篇 |
1976年 | 11篇 |
1975年 | 9篇 |
1974年 | 6篇 |
1973年 | 9篇 |
1971年 | 7篇 |
1969年 | 6篇 |
排序方式: 共有3309条查询结果,搜索用时 15 毫秒
91.
92.
We reported previously (Cayabyab, F. S., and Schlichter, L. C. (2002) J. Biol. Chem. 277, 13673-13681) a functional interaction between the ERG-1 K(+) channel and Src tyrosine kinase, which increased the current. We now show that the tyrosine phosphatase, SHP-1, which is present in microglia, is increased after brain damage, and is activated by colony-stimulating factor-1, associates with ERG-1 and regulates the current. Patch clamp recordings from the MLS-9 microglia cells were made with pipette solutions containing a recombinant SHP-1 protein: wild type (SHP-1 wild type (wt)), catalytically active (SHP-1 S6), or the substrate-trapping mutant (SHP-1 Cys --> Ser). SHP-1 wt and SHP-1 S6 proteins decreased the current, an effect that was reversed by the phosphatase inhibitor, pervanadate, whereas SHP-1 Cys --> Ser increased the current. Moreover, transient transfection with cDNA for SHP-1 wt or SHP-1 S6 decreased the ERG current without decreasing the protein level. Tyrosine phosphorylation of ERG-1 was decreased by transfection with SHP-1 wt and increased by SHP-1 Cys --> Ser. The decrease in current by active SHP-1 was partly attributed to changes in the voltage dependence of activation and steady-state conductance, whereas inactivation kinetics and voltage dependence were not affected. Our results show that ERG-1 is a SHP-1 substrate constituting the first report that an ion current is regulated by SHP-1. 相似文献
93.
HLA-DP4, the most frequent HLA II molecule,defines a new supertype of peptide-binding specificity 总被引:8,自引:0,他引:8
Castelli FA Buhot C Sanson A Zarour H Pouvelle-Moratille S Nonn C Gahery-Ségard H Guillet JG Ménez A Georges B Maillère B 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(12):6928-6934
Among HLA-DP specificities, HLA-DP4 specificity involves at least two molecules, HLA-DPA1*0103/DPB1*0401 (DP401) and HLA-DPA1*0103/DPB1*0402 (DP402), which differ from each other by only three residues. Together, they are present worldwide at an allelic frequency of 20-60% and are the most abundant human HLA II alleles. Strikingly, the peptide-binding specificities of these molecules have never been investigated. Hence, in this study, we report the peptide-binding motifs of both molecules. We first set up a binding assay specific for the immunopurified HLA-DP4 molecules. Using multiple sets of synthetic peptides, we successfully defined the amino acid preferences of the anchor residues. With these assays, we were also able to identify new peptide ligands from allergens and viral and tumor Ags. DP401 and DP402 exhibit very similar patterns of recognition in agreement with molecular modeling of the complexes. Pockets P1 and P6 accommodate the main anchor residues and interestingly contain only two polymorphic residues, beta86 and beta11, respectively. Both positions are almost dimorphic and thus produce a limited number of pocket combinations. Taken together, our results support the existence of three main binding supertypes among HLA-DP molecules and should significantly contribute to the identification of universal epitopes to be used in peptide-based vaccines for cancer, as well as for allergic or infectious diseases. 相似文献
94.
95.
96.
97.
Metals are known to influence the oxidative status of marine organisms, and antioxidant enzymes have been often proposed as biomarkers of effect. The clam Ruditapes decussatus is a well-known metal bioindicator. In this species cadmium (Cd) induces metallothionein (MT) synthesis only after 7 days of exposure. Before MT synthesis is induced, the other mechanisms capable of handling the excess of Cd are unknown. In order to identify some of these mechanisms, variations in antioxidant systems (superoxide dismutase, catalase, selenium-dependent glutathione peroxidase and non-selenium-dependent glutathione peroxidase), malondialdehyde (MDA) and MT were studied in the gills of R. decussatus exposed to different Cd concentrations (4, 40 and 100 gl-1) for 28 days. These parameters, together with total proteins and Cd concentrations, were measured in the gills of the clams over different periods of exposure. Results indicate that Cd accumulation increased linearly in the gills of R. decussatus with the increase in Cd concentration. This increase induces an imbalance in the oxygen metabolism during the first days of Cd exposure. An increase in cytosolic superoxide dismutase (SOD) activity and a decrease in mitochondrial SOD activity was observed at the same time as or after a decrease in cytosolic and mitochondrial catalase activity and of selenium-dependent and non-selenium-dependent glutathione peroxidase activity. After 14 days of exposure, Cd no longer affect these enzymes but there was elevation of other cellular activities, such as MDA and MT production. MT bound excess Cd present in the cell. These variations in these parameters suggest their potential use as biomarkers of effects such as oxidative stress resulting from Cd contamination in molluscs. 相似文献
98.
Briand L Eloit C Nespoulous C Bézirard V Huet JC Henry C Blon F Trotier D Pernollet JC 《Biochemistry》2002,41(23):7241-7252
Odorant-binding proteins (OBPs) are small abundant extracellular proteins belonging to the lipocalin superfamily. They are thought to participate in perireceptor events of odor detection by carrying, deactivating, and/or selecting odorant molecules. Putative human OBP genes (hOBP) have recently been described [Lacazette et al. (2000) Hum. Mol. Genet. 9, 289-301], but the presence of the corresponding proteins remained to be established in the human olfactory mucus. This paper reports the first evidence of such expression in the mucus covering the olfactory cleft, where the sensory olfactory epithelium is located. On the contrary, hOBPs were not observed in the nasal mucus covering the septum and the lower turbinate. To demonstrate the odorant binding activity of these proteins, a corresponding recombinant protein variant, hOBP(IIa)(alpha), was secreted by the yeast Pichia pastoris and thoroughly characterized. It appears as a monomer with one disulfide bond located between C59 and C151, a conservative feature of all other vertebrate OBPs. By measuring the displacement of several fluorescent probes, we show that hOBP(IIa)(alpha) is able to bind numerous odorants of diverse chemical structures, with a higher affinity for aldehydes and large fatty acids. A computed 3D model of hOBP(IIa)(alpha) is proposed and reveals that two lysyl residues of the binding pocket may account for the increased affinity for aldehydes. The relatively limited specificity of hOBP(IIa)(alpha) suggests that other human OBPs are expected to take into account the large diversity of odorant molecules. 相似文献
99.
Florence Bettens Flemming Kristensen Guy D. Bonnard Alain L. de Weck 《Cellular immunology》1984,86(2):337-346
The question of whether lymphocytes which have once been activated and have completed one or several cell cycle(s) can return to the G0 phase and stay ready for a new activation (G0-G1 transition), rather than simply die, was investigated. To do so interleukin 2 (IL-2) was removed from cultures of continuously proliferating human T lymphocytes and the formation of resting (G0) cells was measured. Kinetic analyses in freshly prepared peripheral blood lymphocytes (PBL) revealed that the onset of detectable RNA synthesis and the appearance of structures binding the anti-Tac antibody occurred simultaneously. This allowed the expansion of the definition of G0 T lymphocytes as cells having a low RNA (and DNA) content, and no Tac antigen. When cultured human T cells proliferating continuously by means of IL-2 were characterized in terms of their distribution in the cell cycle, 7 days after the initial PHA stimulation, it could be demonstrated that very few cells were in the G0 phase, supporting the concept of direct S/G2/M-G1 transition. However, when IL-2 was removed from the cultures, the [3H]thymidine incorporation per 104 cells and correspondingly the number of cells in the S/G2/M and G1 phases were reduced drastically and during the following 72-hr period, the number of G0 cells increased markedly. Restimulation of such in vitro formed G0 cells, under conditions permitting observation of their shift from the G0 to G0 phase, demonstrated that most cells could respond normally. Based on these observations, it was concluded that IL-2 not only ensures T-lymphocyte survival and proliferation, but IL-2 starvation induces many continuously proliferating T lymphocytes to stop cycling and to return to the G0 phase of the cell cycle where they remain functional. 相似文献
100.
The mechanism(s) by which zinc is transported into cells has not been identified. Since zinc uptake is inhibited by reducing
the temperature, zinc uptake may depend on the movement of plasma membrane micoenvironments, such as endocytosis or potocytosis.
We investigated the potential role of potocytosis in cellular zinc uptake by incubating normal and acrodermatitis enteropathica
fibroblasts with nystatin, a sterol-binding drug previously shown to inhibit potocytosis. Zinc uptake was determined during
initial rates of uptake (10 min) following incubation of the fibroblasts in 50 μg nystatin/mL or 0.1% dimethyl-sulfoxide for
10 min at 37°C. The cells were then incubated with 1 to 30 μM
65zinc. Michaelis-Menten kinetics were observed for zinc uptake. Nystatin inhibited zinc uptake in both the normal and AE fibroblasts.
Reduced cellular uptake of zinc was associated with its internalization, not its external binding. In normal fibroblasts,
nystatin significantly reduced theK
m 56% and theV
max 69%. In the AE fibroblasts, nystatin treatment significantly reduced theV
max 59%, but did not significantly affect theK
m. The AE mutation alone affected theV
max for cellular zinc uptake. The control AE fibroblasts exhibited a 40% reduction inV
max compared to control normal fibroblasts. We conclude that nystatin exerts its effect on zinc uptake by reducing the velocity
at which zinc traverses the cell membrane, possibly through potocytosis. Furthermore, the AE mutation also effects zinc transport
by reducing zinc transport. 相似文献