全文获取类型
收费全文 | 15818篇 |
免费 | 1227篇 |
国内免费 | 973篇 |
出版年
2024年 | 40篇 |
2023年 | 273篇 |
2022年 | 349篇 |
2021年 | 572篇 |
2020年 | 636篇 |
2019年 | 1054篇 |
2018年 | 670篇 |
2017年 | 418篇 |
2016年 | 418篇 |
2015年 | 573篇 |
2014年 | 926篇 |
2013年 | 1532篇 |
2012年 | 787篇 |
2011年 | 979篇 |
2010年 | 626篇 |
2009年 | 677篇 |
2008年 | 739篇 |
2007年 | 713篇 |
2006年 | 775篇 |
2005年 | 807篇 |
2004年 | 636篇 |
2003年 | 602篇 |
2002年 | 639篇 |
2001年 | 499篇 |
2000年 | 326篇 |
1999年 | 309篇 |
1998年 | 251篇 |
1997年 | 174篇 |
1996年 | 143篇 |
1995年 | 130篇 |
1994年 | 97篇 |
1993年 | 85篇 |
1992年 | 85篇 |
1991年 | 88篇 |
1990年 | 28篇 |
1989年 | 45篇 |
1988年 | 25篇 |
1987年 | 39篇 |
1986年 | 20篇 |
1985年 | 31篇 |
1984年 | 40篇 |
1983年 | 26篇 |
1982年 | 30篇 |
1981年 | 29篇 |
1980年 | 19篇 |
1979年 | 24篇 |
1978年 | 9篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1975年 | 7篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
161.
The effect of ethanol on maxi Ca2+-activated K+ channels (BK channels) in GH3 pituitary tumor cells was investigated using single-channel recordings and focusing on intracellular
signal transduction. In outside-out patches, ethanol caused a transient concentration-dependent increase of BK-channel activity.
30 mm (1.4‰) ethanol significantly increased mean channel open time and channel open probability by 26.3 ± 9% and 78.8 ± 10%, respectively;
single-channel current amplitude was not affected by ethanol. The augmenting effect of ethanol was blocked in the presence
of protein kinase C (PKC) inhibitors staurosporine, bisindolylmaleimide, and PKC (19–31) pseudosubstrate inhibitor as well
as by AMP-PNP (5′-adenylylimidodiphosphate), a nonhydrolyzable ATP-analogue, but not by the phospholipase C blocker U-73122.
Phosphatase inhibitors microcystin-LR and okadaic acid promoted the ethanol effect. The blocking effect was released at higher
concentrations of ethanol (100 mm) suggesting a second site of action or a competition between blockers and ethanol. Our results suggest that the effect of
ethanol on BK-channels is mediated by PKC stimulation and phosphorylation of the channels which increases channel activity
and hence may influence action potentials duration and hormone secretion.
Received: 24 July 1996/Revised: 27 December 1996 相似文献
162.
Protein Phosphorylation and Calcium Uptake into Rat Forebrain Synaptosomes: Modulation by the σ Ligand, 1,3-Ditolylguanidine 总被引:1,自引:0,他引:1
Paul J. Brent Lynn Herd Heather Saunders Alistair T. R. Sim Peter R. Dunkley 《Journal of neurochemistry》1997,68(5):2201-2211
Abstract: The σ ligand 1,3-di- O -tolylguanidine (DTG) increased basal dynamin and decreased depolarization-stimulated phosphorylation of the synaptosomal protein synapsin Ib without having direct effects on protein kinases or protein phosphatases. DTG dose-dependently decreased the basal cytosolic free Ca2+ concentration ([Ca2+ ]i ) and blocked the depolarization-dependent increases in [Ca2+ ]i . These effects were inhibited by the σ antagonists rimcazole and BMY14802. The nitric oxide donors sodium nitroprusside (SNP) and 8-( p -chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate decreased basal [Ca2+ ]i and the KCl-evoked rise in [Ca2+ ]i to an extent similar to DTG. SNP, but not DTG, produced a rise in cyclic GMP levels, suggesting that the effect of DTG on [Ca2+ ]i was not mediated via downstream regulation of cyclic GMP levels. DTG increased 45 Ca2+ uptake and efflux under basal conditions and inhibited the 45 Ca2+ uptake induced by depolarization with KCl. The KCl-evoked rise in [Ca2+ ]i was inhibited by ω-conotoxin (ω-CgTx)-GVIA and -MVIIC but not nifedipine and ω-agatoxin-IVA. The effect of DTG on decreasing the KCl-evoked rise in [Ca2+ ]i was additive with ω-CgTx-MVIIC but not with ω-CgTx-GVIA. These data suggest that DTG was producing some of its effects on synapsin I and dynamin phosphorylation and intrasynaptosomal Ca2+ levels via inhibition of N-type Ca2+ channels. 相似文献
163.
Jörg B. Schulz Dirk Bremen John C. Reed Jürgen Lommatzsch Shinichi Takayama Ullrich Wüllner Peter-A. Löschmann Thomas Klockgether Michael Weller 《Journal of neurochemistry》1997,69(5):2075-2086
Abstract: Neuronally differentiated PC12 cells undergo synchronous apoptosis when deprived of nerve growth factor (NGF). Here we show that NGF withdrawal induces actinomycin D- and cycloheximide-sensitive caspase (ICE-like) activity. The peptide inhibitor of caspase activity, N -acetyl-Asp-Glu-Val-Asp-aldehyde, was more potent than acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone in preventing NGF withdrawal-induced apoptosis, suggesting an important role for caspase-3 (CPP32)-like proteases. We observed a peak of reactive oxygen species (ROS) 6 h after NGF withdrawal. ROS appear to be required for apoptosis, because cell death is prevented by the free radical spin trap, N-tert -butyl-α-phenylnitrone, and the antioxidant, N -acetylcysteine. ROS production was blocked by actinomycin D, cycloheximide, and caspase protease inhibitors, suggesting that ROS generation is downstream of new mRNA and protein synthesis and activation of caspases. Forced expression of either BCL-2 or the BCL-2-binding protein BAG-1 blocked NGF withdrawal-induced apoptosis, activation of caspases, and ROS generation, showing that they function upstream of caspases. Coexpression of BCL-2 and BAG-1 was more protective than expression of either protein alone. 相似文献
164.
Shigeki Nagao Yoshihiro Kawabata Takashige Nishikawa Haruhiko Takada 《Microbiology and immunology》1995,39(12):1011-1014
Guinea pigs immunized with Freund's complete adjuvant received challenge injection of the purified protein derivative of Mycobacterium tuberculosis in the flanks and the corneas to prepare delayed-type hypersensitivity (DTH) reactions. The animals were injected subcutaneously with lipopolysaccharide (LPS) or a synthetic lipid A (LA-15-PP). At the skin site primed with DTH reaction, increased swelling and hemorrhagic reaction followed by a definite necrotic reaction occurred. Severe corneal reactions were also observed in the animals. These findings indicate that bacterial endotoxin modulates DTH reactions and induces severe inflammatory reactions. 相似文献
165.
Zbigniew Darzynkiewicz 《Journal of cellular biochemistry》1995,58(2):151-159
There is a strong evidence that administration of antitumor drugs triggers apoptotic death of target cells. A characteristic feature of appotosis is active participation of the affected cell in its demise. Attempts have been made, therefore, to potentiate the cytotoxicity of a variety of agents by modulating the propensity of cells to respond by apoptosis. Several strategies to enhance apoptosis that involve modulation of the cell cycle or differentiation are discussed. Loss of control of the G1 checkpoint in tumor cells allows one to design treatments that arrest normal cells at the checkpoint and attempt to selectively kill tumor cells with S phase specific drugs. The possibility of a restoration of the apoptosis triggering function of the tumor suppressor gene p53 when the G1 checkpoint function is abolished is expected to increase tumor cells' sensitivity to S phase poisons. Because induction of apoptosis by many antitumor drugs is cell cycle phase specific, drug combinations that preferentially trigger apoptosis at different phases of the cycle, or recruitment of cells to the sensitive phase, offer another antitumor strategy. There is also evidence that apoptosis is potentiated when cell differentiation is triggered follwing DNA damage. This observation suggests that strategies which combine DNA damaging and differentiating drugs, under conditions where the latter are administered following DNA damage caused by the former, may be successful. 相似文献
166.
Tumor promoters, proinflammatory cytokines, endotoxins, and protein synthesis inhibitors can modulate cell cycle kinetics of various cell types, stimulate production of reactive oxygen species, and induce keratinocytes to produce interleukin-8 (IL-8), a potent chemotactant for polymorphonuclear neutrophils and T lymphocytes. The aim of this study was to determine whether perturbations of cytogenetic responses correlated with the induction of IL-8 expression. Cultures of primary human keratinocytes were grown in serum-free medium with 5 mol/L bromodeoxyuridine to label DNA and exposed either to phorbol-13-myristate-12-acetate (PMA) (0.0001–100 ng/ml), cycloheximice (CHX) (0.01–50 g), lipopolysaccharide (0.1–100 g/ml), tumor necrosis factor- (TNF) (3.13–50 ng/ml), or interleukin-1 (IL-1) (1–182 pg/ml). Metaphase chromosome preparations were stained by a fluorescence-plus-Giemsa technique to differentiate sister chromatids. For IL-8 production, keratinocytes were grown to 70% confluency and then exposed to chemicals for 24 h. Immunoreactive IL-8 was quantitated from the supernatants by ELISA. With the exception of benzo(a)pyrene used as a positive control, none of the agents induced sister chromatid exchanges. However, PMA and TNF induced IL-8 production that coincided with significant cell cycle inhibition. IL-1 had no effect on cytogenetic endpoints, yet stimulated a 6.3-fold increase in IL-8. CHX inhibited cell cycle progression and mitotic activity at concentrations that were 200 times lower than required for IL-8 induction; however, puromycin (0.31–10 g/ml), another protein synthesis inhibitor, did not induce IL-8. At all concentrations tested, TNF reduced the mitotic index by 45%, slowed cell cycle progression by 3.5 h, and induced a flat, albeit large, IL-8 response at concentrations 12.5 ng/ml. These agent-specific response patterns suggest that induction of IL-8 production is not always the inevitable result of cell cycle perturbations or genetic damage.Abbreviations B(a)P
benzo(a)pyrene
- BrdU
5-bromo-2-deoxyuridine
- CHX
cycloheximide
- ICAM
intercellular adhesion molecules
- IL-1
interleukin-1
- IL-8
interleukin-8
- KGM
keratinocyte growth medium
- LPS
lipopolysaccharide
- PKC
protein kinase C
- PMA
phorbol-13-myristate-12-acetate
- PMN
polymorphonuclear neutrophil
- ROS
reactive oxygen species
- SCE
sister chromatid exchange
- TNF
tumor necrosis factor 相似文献
167.
Witold Lasek Anna Wańkowicz Katarzyna Kuc Wojciech Feleszko Jakub Golab Adam Giermasz Wiesŀaw Wiktor-J/cedrzejczak Marek Jakóbisiak 《Cancer immunology, immunotherapy : CII》1995,40(5):315-321
The efficacy of systemic infusion of recombinant human macrophage-colony-stimulating factor (M-CSF) in combination with local treatment with human recombinant tumor necrosis factor (TNF) and mouse recombinant interferon (IFN) was studied in vivo on a subclone of B16 melanoma (MmB16) in mice. Short-term intravenous administration of M-CSF at a dose of 106 units daily had no antitumor effect in vivo. Similarly, local treatment of tumor with TNF (5 g daily) did not produce any therapeutic effect. However, simultaneous administration of the same dose of TNF with IFN (1000 units daily) resulted in a synergistic effects manifested by the retardation of tumor growth. Addition of systemic infusion of M-CSF to the local therapy with TNF and IFN induced further augmentation of antitumor efficacy and delayed progression of MmB16 melanoma. The strengthened antitumor effect of combination therapy including M-CSF, TNF and IFN was most probably due to the increased release of monocytes from the bone marrow, their recruitment into the site of tumor growth and subsequent local stimulation of their antitumor activity. 相似文献
168.
David W. Deerfield Douglas J. Fox Martin Head-Gordon Richard G. Hiskey Lee G. Pedersen 《Proteins》1995,21(3):244-255
The first coordination shell of an Mg(II) ion in a model protein environment is studied. Complexes containing a model carboxylate, an Mg(II) ion, various ligands (NH3, H2S, imidazole, and formaldehyde) and water of hydration about the divalent metal ion were geometry optimized. We find that for complexes with the same coordination number, the unidentate carboxylate–Mg(II) ion is greater than 10 kcal mol?1 more stable than the bidentate orientation. Imidazole was found to be the most stable ligand, followed in order by NH3 formaldehyde, H2O, and H2S. © 1995 Wiley-Liss, Inc. 相似文献
169.
170.
Mouse hybridoma cells cultured on the verge of starvation-induced apoptosis, i.e. in a medium diluted with saline, proved to serve as a sensitive screening system for apoptosis-suppressing activity of nutrient medium components. Conventional amino acid mixtures were found to suppress the starvation-induced apoptosis, whereas a vitamin mixture was ineffective. (Frank F (1995) Biotechnol. Bioeng. 45: 86–90). Recent experiments showed that suppression of apoptosis, and concurrent resumption of growth, could be achieved by addition of single substances at millimolar concentrations. The set of active substances included certain coded L-amino acids (glycine, alanine, serine, threonine, proline, asparagine, glutamine, histidine), non-coded amino acids (-alanine, taurine, 4-aminobutyric acid), and a non-metabolizable analogue (2-aminoisobutyric acid). This finding shows that some amino acids do not act solely as nutrients, but also as specific signal molecules. The specificity of the effect points to the involvement of adaptively regulated amino acid transport systems A and N in maintaining the balance between triggering and suppression of starvation-induced apoptosis. 相似文献