全文获取类型
收费全文 | 1477篇 |
免费 | 156篇 |
出版年
2023年 | 7篇 |
2022年 | 17篇 |
2021年 | 28篇 |
2020年 | 21篇 |
2019年 | 28篇 |
2018年 | 45篇 |
2017年 | 31篇 |
2016年 | 41篇 |
2015年 | 58篇 |
2014年 | 64篇 |
2013年 | 84篇 |
2012年 | 103篇 |
2011年 | 80篇 |
2010年 | 71篇 |
2009年 | 65篇 |
2008年 | 72篇 |
2007年 | 70篇 |
2006年 | 55篇 |
2005年 | 63篇 |
2004年 | 61篇 |
2003年 | 45篇 |
2002年 | 50篇 |
2001年 | 32篇 |
2000年 | 39篇 |
1999年 | 32篇 |
1998年 | 24篇 |
1997年 | 17篇 |
1996年 | 13篇 |
1995年 | 15篇 |
1994年 | 13篇 |
1993年 | 20篇 |
1992年 | 30篇 |
1991年 | 23篇 |
1990年 | 21篇 |
1989年 | 23篇 |
1988年 | 17篇 |
1987年 | 20篇 |
1986年 | 17篇 |
1985年 | 18篇 |
1984年 | 13篇 |
1983年 | 16篇 |
1982年 | 4篇 |
1981年 | 11篇 |
1980年 | 7篇 |
1979年 | 9篇 |
1978年 | 4篇 |
1976年 | 4篇 |
1973年 | 4篇 |
1971年 | 4篇 |
1967年 | 3篇 |
排序方式: 共有1633条查询结果,搜索用时 31 毫秒
91.
Pierrel F Hernandez HL Johnson MK Fontecave M Atta M 《The Journal of biological chemistry》2003,278(32):29515-29524
In Escherichia coli, the MiaB protein catalyzes the methylthiolation of N-6-isopentenyl adenosine in tRNAs, the last reaction step during biosynthesis of 2-methylthio-N-6-isopentenyl adenosine (ms2i6A-37). For the first time the thermophilic bacterium Thermotoga maritima is shown here to contain such a MiaB tRNA-modifying enzyme, named MiaBTm, and to synthesize ms2i6A-37 as demonstrated by an analysis of modified nucleosides from tRNA hydrolysates. The corresponding gene (TM0653) was identified by sequence similarity to the miaB gene cloned and expressed in E. coli. MiaBTm was purified to homogeneity and thoroughly characterized by biochemical and spectroscopic methods. It is a monomer of 443 residues with a molecular mass of 50,710 kilodaltons. Its amino acid sequence shares the CysXXX-CysXXCys sequence with MiaB from E. coli as well as with biotin synthase and lipoate synthase. This sequence was shown to be essential for chelation of an iron-sulfur center and for activity in these enzymes. As isolated, MiaBTm contains both iron and sulfide and an apoprotein form can coordinate up to 4 iron and 4 sulfur atoms per polypeptide chain. UV-visible absorption, resonance Raman, variable temperature magnetic circular dichroism, and EPR spectroscopy of MiaBTm indicate the presence of a [4Fe-4S]+2/+1 cluster under reducing and anaerobic conditions, whereas [3Fe-4S]+1 and [2Fe-2S]+2 forms are generated under aerobic conditions. The redox potential of the [4Fe-4S]+2/+1 transition is -495 +/- 10 mV (versus the normal hydrogen electrode). Finally, the expression of MiaBTm from T. maritima in an E. coli mutant strain lacking functional miaB gene allowed production of ms2i6A-37. These results provide further information on the enzymes involved in methylthiolation of tRNAs. 相似文献
92.
Bryant ML Bridges EG Placidi L Faraj A Loi AG Pierra C Dukhan D Gosselin G Imbach JL Hernandez B Juodawlkis A Tennant B Korba B Cote P Cretton-Scott E Schinazi RF Sommadossi JP 《Nucleosides, nucleotides & nucleic acids》2001,20(4-7):597-607
A unique series of simple unnatural L-nucleosides that specifically inhibit hepatitis B virus (HBV) replication has been discovered. These molecules have in common a hydroxyl group in the 3'-position (3'-OH) of the beta-L-2'-deoxyribose sugar that confers antiviral activity specifically against hepadnaviruses. Replacement of the 3'-OH broadens activity to other viruses. Substitution in the base decreases antiviral potency and selectivity. Human DNA polymerases and mitochondrial function are not effected. Plasma viremia is reduced up to 8 logs in a woodchuck model of chronic HBV infection. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection. 相似文献
93.
Plo I Hernandez H Kohlhagen G Lautier D Pommier Y Laurent G 《The Journal of biological chemistry》2002,277(35):31407-31415
In this study, we evaluated the influence of protein kinase C zeta (PKC zeta) on topoisomerase II inhibitor-induced cytotoxicity in monocytic U937 cells. In U937-zeta J and U937-zeta B cells, enforced PKC zeta expression, conferred by stable transfection of PKC zeta cDNA, resulted in total inhibition of VP-16- and mitoxantrone-induced apoptosis and decreased drug-induced cytotoxicity, compared with U937-neo control cells. In PKC zeta-overexpressing cells, drug resistance correlated with decreased VP-16-induced DNA strand breaks and DNA protein cross-links measured by alkaline elution. Kinetoplast decatenation assay revealed that PKC zeta overexpression resulted in reduced global topoisomerase II activity. Moreover, in PKC zeta-overexpressing cells, we found that PKC zeta interacted with both alpha and beta isoforms of topoisomerase II, and these two enzymes were constitutively phosphorylated. However, when human recombinant PKC zeta (rH-PKC zeta) was incubated with purified topoisomerase II isoforms, rH-PKC zeta interacted with topoisomerase II beta but not with topoisomerase II alpha. PKC zeta/topoisomerase II beta interaction resulted in phosphorylation of this enzyme and in decrease of its catalytic activity. Finally, this report shows for the first time that topoisomerase II beta is a substrate for PKC zeta, and that PKC zeta may significantly influence topoisomerase II inhibitor-induced cytotoxicity by altering topoisomerase II beta activity through its kinase function. 相似文献
94.
Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice 总被引:7,自引:0,他引:7
Duez H Chao YS Hernandez M Torpier G Poulain P Mundt S Mallat Z Teissier E Burton CA Tedgui A Fruchart JC Fiévet C Wright SD Staels B 《The Journal of biological chemistry》2002,277(50):48051-48057
Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARalpha agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg x apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARalpha agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis. 相似文献
95.
Franzetti B Schoehn G Hernandez JF Jaquinod M Ruigrok RW Zaccai G 《The EMBO journal》2002,21(9):2132-2138
A dodecameric protease complex with a tetrahedral shape (TET) was isolated from Haloarcula marismortui, a salt-loving archaeon. The 42 kDa monomers in the complex are homologous to metal-binding, bacterial aminopeptidases. TET has a broad aminopeptidase activity and can process peptides of up to 30-35 amino acids in length. TET has a central cavity that is accessible through four narrow channels (<17 A wide) and through four wider channels (21 A wide). This architecture is different from that of all the proteolytic complexes described to date that are made up by rings or barrels with a single central channel and only two openings. 相似文献
96.
Ah,sweet mystery of death! Galectins and control of cell fate 总被引:9,自引:0,他引:9
Control of cell death is critical in eukaryotic development, immune system homeostasis, and control of tumorigenesis. The galectin family of lectins is implicated in all of these processes. Other families of molecules function as death receptors or death effectors, but galectins are uniquely capable of acting both extracellularly and intracellularly to control cell death. Extracellularly, galectins cross-link glycan ligands to transduce signals that lead directly to death or that influence other signals regulating cell fate. Intracellular expression of galectins can modulate other signals controlling cell viability. Individual galectins can act on multiple cell types, and multiple galectins can act on the same cell. Understanding how galectins regulate cell viability and function will broaden our knowledge of the roles of galectins in basic biological processes and facilitate development of therapeutic applications for galectins in autoimmunity, transplant-related disease, and cancer. 相似文献
97.
98.
Zhong R Hernandez A Alton KB Kishnani NS Patrick JE 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2002,772(1):191-195
A rapid HPLC method was developed for quantification of unbound evernimicin in human plasma. Protein-free samples prepared by ultrafiltration were injected directly onto a polymeric reversed-phase column and the eluent monitored at 302 nm. Evernimicin that eluted within 3.5 min was well resolved from endogenous components. Linearity was established between peak height and evernimicin concentration from 25 to 2500 ng/ml. Assay precision (C.V.) was within 5% while bias was no greater than 3%. This method has been used for the ex vivo assessment of evernimicin protein binding in human plasma from safety and tolerance as well as liver dysfunction and renal insufficiency studies. 相似文献
99.
Inhibition of cysteine proteases is emerging as an important strategy for the treatment of a variety of human diseases. Intense efforts involving structure-based inhibitor design have been directed toward several cysteine proteases, including cathepsin K, calpain, human rhinovirus 3C protease and several parasitic cysteine protease targets. Other successful recent efforts have involved combinatorial synthesis and screening for identification of new inhibitor templates. 相似文献
100.
The tetrazolium salt 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) has been widely applied to assess microbiological activity in environmental samples. CTC reduction has previously been quantified in a variety of anaerobic systems (i.e., fermentative, nitrate reducing, sulfate reducing) using direct microscopy, solvent extraction, and flow cytometry. In this work, extracellular CTC reduction was observed and distinguished from its intercellular counterparts by the amorphous character and near uniform fluorescence of the resulting formazan precipitates (CTF). Fluorescence yielded by non-cellular-associated formazan precipitates bleached much more rapidly than CTF formed within cells under identical UV exposure (<2 min). Dehydrogenase activity assays and fluorescent in situ hybridization (FISH) were simultaneously carried out in microcosms containing active anaerobic digester biomass, propylene glycol, and settled sewage centrate for direct comparison. In substrate limited microcosms, quantitative FISH measurements remained well above their detection limit indicating sustained intercellular ribosomal RNA concentrations over a 5-day period, while dehydrogenase assays (CTC) decreased to background levels within 14 h of substrate limitation. Results from this work suggest that CTC reduction in cell-free samples may impede accurate enzyme activity measurements, particularly when quantification involves solvent extraction, flow cytometry, or software-aided counting. In addition, activity assessment in anaerobic digesters using FISH and CTC reduction assays may be comparable until substrate becomes limited. 相似文献