全文获取类型
收费全文 | 1250篇 |
免费 | 42篇 |
国内免费 | 47篇 |
出版年
2024年 | 1篇 |
2023年 | 8篇 |
2022年 | 6篇 |
2021年 | 14篇 |
2020年 | 9篇 |
2019年 | 16篇 |
2018年 | 15篇 |
2017年 | 16篇 |
2016年 | 23篇 |
2015年 | 34篇 |
2014年 | 43篇 |
2013年 | 72篇 |
2012年 | 31篇 |
2011年 | 93篇 |
2010年 | 39篇 |
2009年 | 73篇 |
2008年 | 70篇 |
2007年 | 79篇 |
2006年 | 50篇 |
2005年 | 36篇 |
2004年 | 51篇 |
2003年 | 50篇 |
2002年 | 58篇 |
2001年 | 40篇 |
2000年 | 23篇 |
1999年 | 27篇 |
1998年 | 21篇 |
1997年 | 28篇 |
1996年 | 19篇 |
1995年 | 28篇 |
1994年 | 28篇 |
1993年 | 19篇 |
1992年 | 25篇 |
1991年 | 26篇 |
1990年 | 21篇 |
1989年 | 16篇 |
1988年 | 18篇 |
1987年 | 13篇 |
1986年 | 9篇 |
1985年 | 21篇 |
1984年 | 22篇 |
1983年 | 10篇 |
1982年 | 6篇 |
1981年 | 9篇 |
1980年 | 11篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有1339条查询结果,搜索用时 381 毫秒
71.
Pharmacological and genetic studies have implicated the mu opioid receptor (MOR) in the regulation of ethanol intake in animal models and humans. Non-specific antagonists of opioid receptors have been shown to affect ethanol consumption when infused directly into the ventral tegmental area (VTA) of rats. However, administration of MOR-selective antagonists into the VTA has yielded mixed results. We used RNA interference (RNAi) to specifically decrease levels of MOR messenger RNA in the VTA of mice and examined the effect on ethanol consumption in a two-bottle choice paradigm. Mice were injected in the VTA with lentivirus expressing either a small hairpin RNA (shRNA) targeting MOR or a control shRNA. One week after virus injection, mice were examined for ethanol consumption in a two-bottle choice experiment with increasing concentrations of ethanol over the course of 1 month. Expression of an shRNA targeting MOR in the VTA led to a significant reduction in ethanol consumption. These results strengthen the hypothesis that MOR in the VTA is one of the key brain substrates mediating alcohol consumption. The RNAi combined with lentiviral delivery can be used successfully in brain to effect a sustained reduction in expression of specific genes for behavioral analysis. 相似文献
72.
Xianjun Sun Yubao Lv Junjun Wang HuiQin Cheng Jianhua Huang Yijie Du Jingcheng Dong 《Journal of cellular biochemistry》2019,120(10):18128-18141
Clinical application of oxaliplatin, a platinum-based chemotherapeutic agent, in cancer, especially colorectal cancer, is widely used. However, oxaliplatin-induced peripheral neurotoxicity (OIPN) has a high incidence, and to date, there have been few detailed studies on pathogenesis and treatment mechanisms. The present study was performed by using a proteomic approach to explore protein expression profiling of rats treated with oxaliplatin by multiplex isobaric tags for relative and absolute quantification labeling and two-dimensional liquid chromatography-tandem mass spectrometry. There were 74 proteins that showed different expression in sciatic nerve between control rats and OIPN model rats, with 53 upregulated proteins and 21 downregulated proteins detected in OIPN groups compared with control groups. On the basis of Gene Ontology clustering, these proteins were associated with biological processes (eg, muscle contraction, muscle system process, and skeletal muscle contraction), cellular component (eg, myofibril, contractile fiber, and contractile fiber part) and molecular function (structural constituent of muscle, hydro-lyase activity, and calcium ion binding). On the basis of Kyoto Encyclopedia of Genes and Genomes pathway database, these proteins were associated with African trypanosomiasis, malaria, nitrogen metabolism, etc. Real-time polymerase chain reaction, Western blot as well as immunohistochemistry analysis was performed to examine the expression of partially differential protein. In conclusion, our study establishes a protein expression profile of oxaliplatin-induced rats and mechanisms leading to OIPN development, and will be useful for developing novel diagnostic biomarkers and aiding in the prevention and control of OIPN. 相似文献
73.
Junyoung Park Sun-Hyung Ha Fukushi Abekura Hakseong Lim Young-Chae Chang Moon-Jo Lee Miri Lee Young-Choon Lee Cheorl-Ho Kim 《Journal of cellular biochemistry》2019,120(2):1742-1753
In our previous studies, structurally similar compounds of ascochlorin and ascofuranone exhibited anti-inflammatory activity. Neural inflammation plays a significant role in the commence and advancement of neurodegenerative diseases. It is not known whether 4-O-carboxymethylascochlorin (AS-6) regulates the initial stage of inflammatory responses at the cellular level in BV2 microglia cells. We here investigated the anti-inflammatory effects of AS-6 treatment in microglia cells with the microglial protection in neurons. We found that the lipopolysaccharide (LPS)-stimulated production of nitric oxide, a main regulator of inflammation, is suppressed by AS-6 in BV2 microglial cells. In addition, AS-6 dose-dependently suppressed the increase in COX-2 protein and messenger RNA levels in LPS-stimulated BV2 cells. Moreover, AS-6 inhibited the expression and secretion of proinflammatory cytokines in BV2 microglial cells. At the intracellular level, AS-6 inhibited LPS-activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in BV2 microglial cells. AS-6 negatively affected mitogen-activated protein kinases (MAPK) and Akt phosphorylation: Phosphorylated forms of ERK, JNK, p38, and Akt decreased. To check whether AS-6 protects against inflammatory inducer-mediated neurotoxicity, neuronal SH-SY5Y cells were coincubated with BV2 cells in conditioned medium. AS-6 exerted a neuroprotective effect by suppressing microglial activation by LPS or amyloid-β peptide. AS-6 is a promising suppressor of inflammatory responses in LPS-induced BV2 cells by attenuating NF-κB and MAPKs signaling. AS-6 protected against microglial-mediated neurotoxicity in SH-SY5Y and BV2 cocultured cells from LPS–induced neuroinflammation and death via inhibiting MAPK, NF-κB, and Akt pathways. 相似文献
74.
Carlos A. Jerez 《FEMS microbiology letters》1988,56(3):289-293
Abstract The heat shock response was studied in a chemolithotrophic thermoacidophilic archaebacterium Sulfolobus acidocaldarius (shifted from 70° to 85°C) and a mesoacidop0ilic microorganism Thiobacillus ferrooxidans (from 30° to 41°C). When transferred from their normal growth temperature to the stress temperature, cells showed a decrease in the incorporation of Na2 14 CO3 into proteins, and at the same time, the synthesis of a specific subset of heat shock proteins was observed. Ethanol (4%) at 30°C, also caused a response similar to the heat shock upon T. ferrooxidans cells, whereas Sulfolobus cells at 70°C did not incorporate radioactive CO2 in the presence of ethanol, apparently being damaged by the organic solvent. 相似文献
75.
The developing central nervous system is a primary target of ethanol toxicity. The teratogenic effect of ethanol may result from its action on prostaglandins. Prostaglandins are generated through the release of arachidonic acid (AA) by the action of cytosolic phospholipase A(2) (cPLA(2)) on membrane-bound phospholipids and the catalytic conversion of AA to prostaglandin E(2) (PGE(2)) by cyclo-oxygenase (COX). COX is expressed in two isoforms, constitutive COX1 and inducible COX2. Cultured astrocytes and neurons from immature cerebral cortex were used as in vitro models to investigate the effect of ethanol on PGE(2) synthesis. In both cell types, neither the activity nor the expression of cPLA(2) was affected by ethanol. PGE(2) was synthesized by astrocytes and neurons. Ethanol (200-400 mg/dL for 24 h) significantly increased PGE(2) production in both cell types and the ethanol-induced increase in PGE(2) accumulation in astrocytes was significantly greater than in neurons. These increases resulted from the effects of ethanol on COX. Overall COX activity was up-regulated by ethanol in astrocytes and neurons, and indomethacin, a nonselective blocker for COX, eliminated the ethanol-induced increases of COX activity in both cell types. Increased COX activity in astrocytes resulted from an increase in COX2 expression. NS-398, a selective COX2 blocker, completely inhibited ethanol-induced alterations in COX activity. In neurons, however, ethanol had a direct effect on COX activity in the absence of a change in COX expression. NS-398 only partially blocked ethanol-induced increases in neuronal COX activity. Thus, astrocytes are a primary target of ethanol and ethanol-induced increases in glial PGE(2) synthesis are mediated by COX, principally COX2. Ethanol toxicity may be mediated through PGE(2) in immature cortical cells. 相似文献
76.
Microglial secreted cathepsin B induces neuronal apoptosis 总被引:6,自引:0,他引:6
Activated microglia release a number of substances that can influence neuronal signalling and survival. Here we report that microglia stimulated with the peptide chromogranin A (CGA), secreted the cysteine protease, cathepsin B. Conditioned medium from CGA exposed microglia was neurotoxic to the HT22 hippocampal cell line and to primary cultures of cerebellar granule neurones. In both neuronal cell types, the neurotoxicity could be significantly attenuated with z-FA-fmk or by depletion of microglial conditioned medium with cathepsin B antibody. Conditioned medium from activated microglia or cathepsin B alone induced neuronal apoptosis and caspase 3 activation. Our data indicate that CGA-activated microglia can trigger neuronal apoptosis and that this may be mediated through the secretion of cathepsin B. Since cathepsins may also play a role in the amyloidogenic processing of amyloid precursor protein, these results may have significance for tissue damage and neuronal loss in the neuropathology of Alzheimer's disease. 相似文献
77.
Nitric oxide (NO) has been implicated in both the pathogenesis of and protection from NMDA receptor-mediated neuronal injury. This apparent paradox has been attributed to alternate redox states of nitrogen monoxide, whereby, depending on the redox milieu, nitrogen monoxide can be neuroprotective via nitrosation chemistry or react with superoxide to form secondary toxic species. In our murine mixed cortical cell culture system, the NONOate-type NO donors diethylamine/NO complex sodium (Dea/NO), (Z)-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium++ +-1,2-diolate (Papa/NO), and spermine/NO complex sodium (Sper/NO), as well as the S-nitrosothiols S-nitroso-L-glutathione (GSNO) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) (NO+ equivalents), decreased NMDA-induced neuronal injury in a concentration-dependent manner. 8-Bromo-cyclic GMP did not mimic the inhibitory effects of the donors, suggesting that the neuroprotection was not the result of NO-stimulated neuronal cyclic GMP production. Furthermore, neuronal injury induced by exposure of cultures to H2O2 was not altered by the presence of Dea/NO, indicating the absence of a direct antioxidant effect. NONOates did, however, reduce NMDA-stimulated uptake of 45Ca2+, whereas high potassium-induced 45Ca2+ accumulation, a measurement of entry via voltage-gated calcium channels, was unaffected. The parallel reduction of 45Ca2+ accumulation and NMDA neurotoxicity by NONOates mimicked that seen with an NMDA receptor antagonist. Electrochemical measurements of NO via an NO-sensitive electrode demonstrated that neuroprotective concentrations of all donors produced appreciable amounts of NO over the 5-min time frame. Determination of the formation of NO+ equivalents, as assessed by N-nitrosation of 2,3-diaminonaphthylene, revealed little or no observable N-nitrosation by Sper/NO, GSNO, and SNAP with significant N-nitrosation observed by Papa/NO and Dea/NO. However, addition of ascorbate (400 microM) effectively prevented the nitrosation of 2,3-diaminonaphthylene produced by Dea/NO and Papa/NO without altering their neuroprotective properties or their effects on 45Ca2+ accumulation. Present results indicate that the intrinsic NO/NO+ characteristics of NO donor compounds may not be a good predictor of their ability to inhibit NMDA receptor-mediated neurotoxicity at the cellular level. 相似文献
78.
Ding H Goldberg MM Raymer JH Holmes J Stanko J Chaney SG 《Biological trace element research》1999,67(1):1-11
This study evaluated the performance of inductively coupled plasma mass spectrometry for the determination of platinum (Pt)
in rat dorsal root ganglion. The method detection limit was found to be 0.008 ng/mL of Pt, which corresponds to 4 pg of Pt
per milligram of ganglia. The standard deviations in the tissue matrix were 5.7% or better and minimum matrix effect was observed.
Compared to indium, the use of iridium or a combination of iridium and bismuth as internal standard(s) provided more accurate
measurement. The Pt in the tissue digestate was stable for a minimum of 46 d at levels above 0.05 ng/mL. Flow injection analysis
using undiluted digestates resulted in approximately 20% signal enhancement. Internal standard correction was necessary to
obtain accurate results. The method was used in initial studies in which rats were dosed with cisplatin and has shown that
Pt accumulates and persists in dorsal rat ganglion following treatment.
Paper presented at the Pittsburgh Conference, Atlanta, GA, March 1997 相似文献
79.
Summary. Research has suggested that catalase plays a role in mediating ethanols psychopharmacological effects. Catalase is an enzyme that oxidizes ethanol to acetaldehyde. It has been reported that when catalase activity is reduced by 3-amino-1,2,4-triazole (AT), rats reduce their intake and preference for ethanol. The present study assessed the effects of AT on the brain amino acids levels following ethanol administration in Wistar rats. The study consisted of three parts. In the first part, we found no effects of acute and chronic intraperitoneally administered acetaldehyde on amino acids dialysate levels in nucleus accumbens. In the second part, AT was administered five hours prior to ethanol or its vehicle. Ethanol significantly affected the levels of taurine in rat pre-treated with AT. In the final part, ethanol was administered following the pre-treatment with AT but the dependent variable was the concentration of ethanol in the brain. 相似文献
80.