全文获取类型
收费全文 | 8598篇 |
免费 | 297篇 |
国内免费 | 238篇 |
出版年
2023年 | 116篇 |
2022年 | 85篇 |
2021年 | 151篇 |
2020年 | 170篇 |
2019年 | 201篇 |
2018年 | 219篇 |
2017年 | 143篇 |
2016年 | 166篇 |
2015年 | 173篇 |
2014年 | 238篇 |
2013年 | 589篇 |
2012年 | 167篇 |
2011年 | 269篇 |
2010年 | 243篇 |
2009年 | 296篇 |
2008年 | 301篇 |
2007年 | 342篇 |
2006年 | 314篇 |
2005年 | 251篇 |
2004年 | 257篇 |
2003年 | 247篇 |
2002年 | 223篇 |
2001年 | 190篇 |
2000年 | 171篇 |
1999年 | 164篇 |
1998年 | 157篇 |
1997年 | 165篇 |
1996年 | 166篇 |
1995年 | 173篇 |
1994年 | 185篇 |
1993年 | 144篇 |
1992年 | 148篇 |
1991年 | 148篇 |
1990年 | 138篇 |
1989年 | 104篇 |
1988年 | 126篇 |
1987年 | 115篇 |
1986年 | 90篇 |
1985年 | 194篇 |
1984年 | 225篇 |
1983年 | 170篇 |
1982年 | 252篇 |
1981年 | 160篇 |
1980年 | 157篇 |
1979年 | 130篇 |
1978年 | 74篇 |
1977年 | 55篇 |
1976年 | 59篇 |
1974年 | 29篇 |
1973年 | 31篇 |
排序方式: 共有9133条查询结果,搜索用时 31 毫秒
931.
932.
María B Mazzucco Laura B Talarico Sezen Vatansever Ana C Carro Mirta L Fascio Norma B D’Accorso Cybele C García Elsa B Damonte 《Journal of biomedical science》2015,22(1)
Background
Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized.Results
The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 μM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 μM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2.Conclusions
The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis. 相似文献933.
Synthetic peptides mimicking the binding site of human acetylcholinesterase for its inhibitor fasciculin 2
下载免费PDF全文
![点击此处可从《Journal of peptide science》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Uwe Kafurke Ariel Erijman Yonatan Aizner Julia M. Shifman Jutta Eichler 《Journal of peptide science》2015,21(9):723-730
Molecules capable of mimicking protein binding and/or functional sites present useful tools for a range of biomedical applications, including the inhibition of protein–ligand interactions. Such mimics of protein binding sites can currently be generated through structure‐based design and chemical synthesis. Computational protein design could be further used to optimize protein binding site mimetics through rationally designed mutations that improve intermolecular interactions or peptide stability. Here, as a model for the study, we chose an interaction between human acetylcholinesterase (hAChE) and its inhibitor fasciculin‐2 (Fas) because the structure and function of this complex is well understood. Structure‐based design of mimics of the hAChE binding site for Fas yielded a peptide that binds to Fas at micromolar concentrations. Replacement of hAChE residues known to be essential for its interaction with Fas with alanine, in this peptide, resulted in almost complete loss of binding to Fas. Computational optimization of the hAChE mimetic peptide yielded a variant with slightly improved affinity to Fas, indicating that more rounds of computational optimization will be required to obtain peptide variants with greatly improved affinity for Fas. CD spectra in the absence and presence of Fas point to conformational changes in the peptide upon binding to Fas. Furthermore, binding of the optimized hAChE mimetic peptide to Fas could be inhibited by hAChE, providing evidence for a hAChE‐specific peptide–Fas interaction. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
934.
T. Amanda Strom Serdar Durdagi Suha Salih Ersoz Ramin Ekhteiari Salmas Claudiu T. Supuran Andrew R. Barron 《Journal of peptide science》2015,21(12):862-870
A series of Fmoc‐Phe(4‐aza‐C60)‐OH of fullerene amino acid derived peptides have been prepared by solid phase peptide synthesis, in which the terminal amino acid, Phe(4‐aza‐C60)‐OH, is derived from the dipolar addition to C60 of the Fmoc‐Nα‐protected azido amino acids derived from phenylalanine: Fmoc‐Phe(4‐aza‐C60)‐Lys3‐OH ( 1 ), Fmoc‐Phe(4‐aza‐C60)‐Pro‐Hyp‐Lys‐OH ( 2 ), and Fmoc‐Phe(4‐aza‐C60)‐Hyp‐Hyp‐Lys‐OH ( 3 ). The inhibition constant of our fullerene aspartic protease PRIs utilized FRET‐based assay to evaluate the enzyme kinetics of HIV‐1 PR at various concentrations of inhibitors. Simulation of the docking of the peptide Fmoc‐Phe‐Pro‐Hyp‐Lys‐OH overestimated the inhibition, while the amino acid PRIs were well estimated. The experimental results show that C60‐based amino acids are a good base structure in the design of protease inhibitors and that their inhibition can be improved upon by the addition of designer peptide sequences. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
935.
The amino acid taurine is essential for the function of skeletal muscle and administration is proposed as a treatment for Duchenne Muscular Dystrophy (DMD). Taurine homeostasis is dependent on multiple processes including absorption of taurine from food, endogenous synthesis from cysteine and reabsorption in the kidney. This study investigates the cause of reported taurine deficiency in the dystrophic mdx mouse model of DMD. Levels of metabolites (taurine, cysteine, cysteine sulfinate and hypotaurine) and proteins (taurine transporter [TauT], cysteine deoxygenase and cysteine sulfinate dehydrogenase) were quantified in juvenile control C57 and dystrophic mdx mice aged 18 days, 4 and 6 weeks. In C57 mice, taurine content was much higher in both liver and plasma at 18 days, and both cysteine and cysteine deoxygenase were increased. As taurine levels decreased in maturing C57 mice, there was increased transport (reabsorption) of taurine in the kidney and muscle. In mdx mice, taurine and cysteine levels were much lower in liver and plasma at 18 days, and in muscle cysteine was low at 18 days, whereas taurine was lower at 4: these changes were associated with perturbations in taurine transport in liver, kidney and muscle and altered metabolism in liver and kidney. These data suggest that the maintenance of adequate body taurine relies on sufficient dietary intake of taurine and cysteine availability and metabolism, as well as retention of taurine by the kidney. This research indicates dystrophin deficiency not only perturbs taurine metabolism in the muscle but also affects taurine metabolism in the liver and kidney, and supports targeting cysteine and taurine deficiency as a potential therapy for DMD. 相似文献
936.
937.
938.
α-Amylase from Aspergillus oryzae was covalently immobilized onto polystyrene pellets with pentaethylenehexamine (PS-PEHA-Ald) and pentaethylene glycol (PS-PG-Ald) carrying a terminal aldehyde group. Optimum immobilization occured at pH 8.0 and 25 °C, and at pH 7.0 and 35 °C for PS-PEHA-Ald and PS-PG-Ald, respectively. PS-PEHA-Ald immobilized enzyme retained approximately 75% of the initial activity over 45 days of storage, 70% of the initial activity after nine runs of recycling and displayed the better resistance to detrimental metal ions. PS-PG-Ald immobilized enzyme retained approximately 50% of the initial activity in 8h at 70 °C. The catalytic efficiencies of PS-PEHA-Ald immobilized and PS-PG-Ald immobilized amylase were 1.42 and 1.29 times higher than that of native enzyme. The activation energy of the reaction mediated by the amylase was reduced by 58.1% and 57.3% when PS-PEHA-Ald and PS-PG-Ald used as support respectively. 相似文献
939.
Mori K 《Chirality》2011,23(6):449-462
Mori's synthetic works on bioactive natural products in general and pheromones in particular started about 40 years ago to establish their absolute configurations and also to clarify their stereochemistry-bioactivity relationships. Results indicate that bioactive natural products are not always enantiomerically pure, and the stereochemistry-bioactivity relationships are not simple but complicated. For example, neither (R)- nor (S)-sulcatol, the aggregation pheromone of an ambrosia beetle, is behaviorally bioactive, whereas their mixture is active. In the case of olean, the sex pheromone of the olive fruit fly, its (R)-isomer is active against the males and the (S)-isomer is active against the females. Recent synthesis of two new insect pheromones is discussed to illustrate the modern methods in enantioselective synthesis. 相似文献
940.