首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   1380篇
  免费   76篇
  国内免费   1篇
  2024年   1篇
  2023年   15篇
  2022年   24篇
  2021年   60篇
  2020年   82篇
  2019年   128篇
  2018年   98篇
  2017年   72篇
  2016年   74篇
  2015年   74篇
  2014年   94篇
  2013年   131篇
  2012年   93篇
  2011年   104篇
  2010年   59篇
  2009年   65篇
  2008年   63篇
  2007年   54篇
  2006年   55篇
  2005年   30篇
  2004年   29篇
  2003年   15篇
  2002年   17篇
  2001年   1篇
  2000年   1篇
  1999年   1篇
  1997年   3篇
  1996年   2篇
  1995年   2篇
  1994年   2篇
  1991年   1篇
  1989年   1篇
  1988年   1篇
  1986年   1篇
  1980年   3篇
  1968年   1篇
排序方式: 共有1457条查询结果,搜索用时 46 毫秒
991.
Hydrogen peroxide (H2O2), a major non-radical reactive oxygen species (ROS) could elicit intracellular oxidative damage and/or cause extracellular free calcium influx by activating the NMDA receptor or through calcium channels. In the present study, NMDA receptor antagonist MK-801 fully blocked H2O2-induced neuronal cell death, whereas green tea (GT) extract containing-antioxidants only partially suppressed the neurotoxicity of H2O2. These suggest that majority of ROS overproduction is downstream of H2O2-induced calcium influx. A novel neuroprotectant PAN-811 was previously demonstrated to efficiently attenuate ischemic neurotoxicity. PAN-811 hereby fully blocks H2O2-elicited neuronal cell death with a more advanced neuroprotective profile than that of GT extract. PAN-811 was also shown to protect against CaCl2-elicited neurotoxicity. Efficient protection against oxidative stress-induced neurotoxicity by PAN-811 indicates its potential application in treatment of ROS-mediated neurodegenerative diseases. W.P. and C.M.D. had equal contributions to this project  相似文献   
992.
Epithelial–mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-β1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-β1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-β1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and α-smooth muscle actin. Interestingly, TGF-β1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-β1-stimulated cells. Most importantly, treatment of TGF-β1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-β1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-β1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.  相似文献   
993.
Cytotoxic, phytotoxic, antimicrobial and antioxidant effects of quercetin 3-O-glucoside (Q3G) isolated by HPLC from aerial parts of Prangos ferulaceae was studied by MTT assay, lettuce germination assay, disk diffusion and DPPH method. Our results showed that Q3G exhibits high antioxidant effect with RC50 of 22 μg/mL, it has low cytotoxicity and no antibacterial effects. Q3G exhibits high phytotoxic effect with IC50 value of 282.7 μg/ml, as well. It is assumed that Q3G does not play a defense role in plants and it may act as an allelopatic agent. The article is published in the original.  相似文献   
994.
In this study we introduce a computationally‐driven enzyme redesign workflow for altering cofactor specificity from NADPH to NADH. By compiling and comparing data from previous studies involving cofactor switching mutations, we show that their effect cannot be explained as straightforward changes in volume, hydrophobicity, charge, or BLOSUM62 scores of the residues populating the cofactor binding site. Instead, we find that the use of a detailed cofactor binding energy approximation is needed to adequately capture the relative affinity towards different cofactors. The implicit solvation models Generalized Born with molecular volume integration and Generalized Born with simple switching were integrated in the iterative protein redesign and optimization (IPRO) framework to drive the redesign of Candida boidinii xylose reductase (CbXR) to function using the non‐native cofactor NADH. We identified 10 variants, out of the 8,000 possible combinations of mutations, that improve the computationally assessed binding affinity for NADH by introducing mutations in the CbXR binding pocket. Experimental testing revealed that seven out of ten possessed significant xylose reductase activity utilizing NADH, with the best experimental design (CbXR‐GGD) being 27‐fold more active on NADH. The NADPH‐dependent activity for eight out of ten predicted designs was either completely abolished or significantly diminished by at least 90%, yielding a greater than 104‐fold change in specificity to NADH (CbXR‐REG). The remaining two variants (CbXR‐RTT and CBXR‐EQR) had dual cofactor specificity for both nicotinamide cofactors.  相似文献   
995.
The development of an enantioselective flow-through chemiluminescence immunosensor for amino acids is described. The approach is based on a competitive assay using enantioselective antibodies. Two different instrumental approaches, a flow-injection (FIA) and a sequential-injection system (SIA), are used. Compared to the flow-injection technique, the sequential injection-mode showed better repeatability. Both systems use an immunoreactor consisting of a flow cell packed with immobilized haptens. The haptens (4-amino-L- or D-phenylalanine) are immobilized onto a hydroxysuccinimide-activated polymer (Affi-prep 10) via a tyramine spacer. Stereoselective antibodies, raised against 4-amino-L- or D-phenylalanine, are labeled with an acridinium ester. Stereoselective inhibition of binding of the acridinum-labeled antibodies to the immobilized hapten by amino acids takes place. Chiral recognition was observed not only for the hapten molecule but also for a series of different amino acids. One assay cycle including regeneration takes 6:30 min in the FIA mode and 4:40 min in the SIA mode. Using D-phenylalanine as a sample, the detection limit was found to be 6.13 pmol/ml (1.01 ng/ml) for the flow-injection immunoassay (FIIA) and 1.76 pmol/ml (0.29 ng/ml ) for the sequential-injection immunoassay (SIIA) which can be lowered to 0.22 pmol/ml (0.036 ng/ml) or 0.064 pmol/ml (0.01 ng/ml) by using a stopped flow system. The intra-assay repeatability was found to be about 5% RSD and the inter-assay repeatability below 6% (within 3 days).  相似文献   
996.
BACKGROUND: Autonomous thyroid nodules can be treated by a variety of methods. We assessed the efficacy of percutaneous ethanol injection in treating autonomous thyroid nodules. METHODS: 35 patients diagnosed by technetium-99 scanning with hyperfunctioning nodules and suppressed sensitive TSH (sTSH) were given sterile ethanol injections under ultrasound guidance. 29 patients had clinical and biochemical hyperthyroidism. The other 6 had sub-clinical hyperthyroidism with suppressed sTSH levels (<0.24 &mgr;IU/ml) and normal thyroid hormone levels. Ethanol injections were performed once every 1-4 weeks. Ethanol injections were stopped when serum T3, T4 and sTSH levels had returned to normal, or else injections could no longer be performed because significant side effects. Patients were followed up at 3, 6 and, in 15 patients, 24 months after the last injection. RESULTS: Average pre-treatment nodule volume [18.2 PlusMinus; 12.7 ml] decreased to 5.7 PlusMinus; 4.6 ml at 6 months follow-up [P < 0.001]. All patients had normal thyroid hormone levels at 3 and 6 months follow-up [P < 0.001 relative to baseline]. sTSH levels increased from 0.09 PlusMinus; 0.02 &mgr;IU/ml to 0.65 PlusMinus; 0.8 &mgr;IU/ml at the end of therapy [P < 0.05]. Only 3 patients had persistent sTSH suppression at 6 months post-therapy. T4 and sTSH did not change significantly between 6 months and 2 years [P > 0.05]. Ethanol injections were well tolerated by the patients, with only 2 cases of transient dysphonia. CONCLUSION: Our findings indicate that ethanol injection is an alternative to surgery or radioactive iodine in the treatment of autonomous thyroid nodules.  相似文献   
997.
Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.  相似文献   
998.
Saffari Y  Sadrzadeh SM 《Life sciences》2004,74(12):1513-1518
Green tea polyphenols like epigallocatechin gallate (EGCG) have been proposed as a cancer chemopreventative. Several studies have shown that EGCG can act as an antioxidant by trapping proxyl radicals and inhibiting lipid peroxidation. The main propose of this study is to investigate the antioxidant capacity of EGCG using erythrocyte membrane-bound ATPases as a model. The effects of EGCG on t-butylhydroperoxide-induced lipid peroxidation and the activity of membrane-bound ATPases in human erythrocyte membranes were studied. The extent of oxidative damage in membranes was assessed by measuring lipid peroxidation, (TBARS, thiobarbituric acid reactive substances formation) and the activity of ATPases (Na(+)/K(+), Ca(2+), and CaM-activated Ca(2+) pump ATPases). EGCG blocked t-BHP induced lipid peroxidation in erythrocyte membranes, significantly (0.45 +/- 0.02 vs 0.20 +/- 0.01; t-BHP vs t-BHP + EGCG respectively, microm/L TBARS) (p < 0.05). EGCG also protected ATPases against t-BHP induced damage; for Na/K ATPase (2.4 +/- 0.2 vs 1.6 +/- 0.1 vs 2.44 +/- 0.2, nmol Pi/min/mg protein, control vs t-BHP vs t-BHP and EGCG respectively), for Ca ATPase (5.8 +/- 0.4 vs 3.9 +/- 0.3 vs 5.6 +/- 0.34, nmol Pi/min/mg protein, control vs t-BHP vs t-BHP and EGCG respectively) and for CaM-Ca ATPase (14.7 +/- 0.7 vs 7.3 +/- 0.4 vs 11.6 +/- 0.55, nmol Pi/min/mg protein, control vs t-BHP vs t-BHP and EGCG respectively) (p < 0.05). In conclusion our results indicate that EGCG is a powerful antioxidant that is capable protecting erythrocyte membrane-bound ATPases against oxidative stress.  相似文献   
999.
Atienza SG  Jafary H  Niks RE 《Planta》2004,220(1):71-79
Nonhost resistance is the most common type of resistance in plants. Understanding the factors that make plants susceptible or resistant may help to achieve durably effective resistance in crop plants. Screening of 109 barley (Hordeum vulgare L.) accessions in the seedling stage indicated that barley is a complete nonhost to most of the heterologous rust fungi studied, while it showed an intermediate status with respect to Puccinia triticina, P. hordei-murini, P. hordei-secalini, P. graminis f. sp. lolii and P. coronata ff. spp. avenae and holci. Accessions that were susceptible to a heterologous rust in the seedling stage were much more or completely resistant at adult plant stage. Differential interaction between barley accessions and heterologous rust fungi was found, suggesting the existence of rust-species-specific resistance. In particular, many landrace accessions from Ethiopia and Asia, and naked-seeded accessions, tended to be susceptible to several heterologous rusts, suggesting that some resistance genes in barley are effective against more than one heterologous rust fungal species. Some barley accessions had race-specific resistance against P. hordei-murini. We accumulated genes for susceptibility to P. triticina and P. hordei-murini in two genotypes called SusPtrit and SusPmur, respectively. In the seedling stage, these accessions were as susceptible as the host species to the target rusts. They also showed unusual susceptibility to other heterologous rusts. These two lines are a valuable asset to further experimental work on the genetics of resistance to heterologous rust fungi.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00425-004-1319-1Abbreviations ff. spp Formae speciales - RIL Recombinant inbred line - DC Double cross - DC-S Progeny produced by selfing of double-cross plants  相似文献   
1000.
AIMS: To evaluate the prevalence of congenital hypothyroidism (CH) in a screening program performed for the first time in Isfahan, Iran. METHODS: From May 2002 to December 2002, T4 and TSH serum concentrations of 20,000 3- to 7-day-old newborns, born in all 17 hospitals of the city, were measured by radioimmunoassay and immunoradiometric assay, respectively. The newborns with abnormal screening results (TSH >20 mIU/l, T4 <6.5 microg/dl and based on the weight) were re-examined. RESULTS: Of 531 recalled subjects (recall rate 2.6%), 54 were confirmed to be hypothyroid, showing a prevalence of 1:370 for CH. CONCLUSION: Considering the high frequency of CH, the necessity of implementing a routine screening program in the healthcare system of Isfahan Province is emphasized.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号