全文获取类型
收费全文 | 477篇 |
免费 | 35篇 |
出版年
2024年 | 1篇 |
2023年 | 3篇 |
2022年 | 7篇 |
2021年 | 27篇 |
2020年 | 9篇 |
2019年 | 11篇 |
2018年 | 21篇 |
2017年 | 15篇 |
2016年 | 20篇 |
2015年 | 19篇 |
2014年 | 26篇 |
2013年 | 40篇 |
2012年 | 45篇 |
2011年 | 38篇 |
2010年 | 31篇 |
2009年 | 24篇 |
2008年 | 28篇 |
2007年 | 30篇 |
2006年 | 23篇 |
2005年 | 24篇 |
2004年 | 22篇 |
2003年 | 16篇 |
2002年 | 14篇 |
2001年 | 2篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 3篇 |
排序方式: 共有512条查询结果,搜索用时 15 毫秒
251.
Pompilio A Piccolomini R Picciani C D'Antonio D Savini V Di Bonaventura G 《FEMS microbiology letters》2008,287(1):41-47
We tested 40 clinical Stenotrophomonas maltophilia strains to investigate the possible correlation between adherence to and formation of biofilm on polystyrene, and cell surface properties such as hydrophobicity and motility. Most of the strains were able to adhere and form biofilm, although striking differences were observed. Eleven (27.5%) of the strains were hydrophobic, with hydrophobicity greatly increasing as S. maltophilia attached to the substratum. A positive correlation was observed between hydrophobicity and levels of both adhesion and biofilm formation. Most of the isolates showed swimming and twitching motility. A highly significant negative correlation was observed between swimming motility and level of hydrophobicity. Hydrophobicity is thus a significant determinant of adhesion and biofilm formation on polystyrene surfaces in S. maltophilia. 相似文献
252.
Micco I Nencini A Quinn J Bothmann H Ghiron C Padova A Papini S 《Bioorganic & medicinal chemistry》2008,16(5):2313-2328
Alpha7 agonists were identified via GOLD (CCDC) docking in the putative agonist binding site of an alpha7 homology model and a series of aminoalkyl benzoimidazoles was synthesised to obtain potentially brain penetrant drugs. The array was prepared starting from the reaction of ortho-fluoronitrobenzenes with a selection of diamines, followed by reduction of the nitro group to obtain a series of monoalkylated phenylene diamines. N,N'-Carbonyldiimidazole (CDI) mediated acylation, followed by a parallel automated work-up procedure, afforded the monoacylated phenylenediamines which were cyclised under acidic conditions. Parallel work-up and purification afforded the array products in good yields and purities with a robust parallel methodology which will be useful for other libraries. Screening for alpha7 activity revealed compounds with agonist activity for the receptor. 相似文献
253.
254.
Scarselli M Padula MG Bernini A Spiga O Ciutti A Leoncini R Vannoni D Marinello E Niccolai N 《Biochimica et biophysica acta》2003,1645(1):40-48
The rat liver threonine deaminase is a cytoplasmic enzyme that catalyses the pyridoxal-phosphate-dependent dehydrative deamination of L-threonine and L-serine to ammonia and alpha-ketobutyrate and pyruvate, respectively, in vivo. During deamination, a molecule of the cofactor is converted to pyridoxamine phosphate. Recently, the ability of this enzyme to accomplish an inverse half-reaction, restoring pyridoxal-phosphate and L-alanine or L-aminobutyrate, respectively, from pyruvate or 2-oxobutyrate, was reported. In order to investigate the molecular mechanisms of this transaminating activity, a molecular model of rat liver threonine deaminase was constructed on the basis of sequence homology with the biosynthetic threonine deaminase of Escherichia coli, the crystal structure of which is known. The model has structural features shared by aminotransferases, suggesting that tertiary structural elements may be responsible for the transaminating activity observed for rat liver threonine deaminase. 相似文献
255.
Spiga O Bernini A Scarselli M Ciutti A Bracci L Lozzi L Lelli B Di Maro D Calamandrei D Niccolai N 《FEBS letters》2002,511(1-3):33-35
The structural features of the complexes that alpha-bungarotoxin forms with three different synthetic peptides, mimotopes of the nicotinic acetylcholine receptor binding site, have been compared to the corresponding nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR) data. For the considered peptides, the observed different affinities towards the toxin could not be accounted simply by static structural considerations. A combined analysis of the SPR- and NMR-derived dynamic parameters shows new correlations between complex formation and dissociation and the overall pattern of intramolecular and intermolecular nuclear Overhauser effects. These features could be crucial for a rational design of protein ligands. 相似文献
256.
Ferrochelatase (EC 4.99.1.1), the terminal enzyme of the heme biosynthetic pathway, catalyzes the insertion of ferrous iron into the protoporphyrin IX ring. Ferrochelatases can be arbitrarily divided into two broad categories: those with and those without a [2Fe-2S] center. In this work we have used X-ray absorption spectroscopy to investigate the metal ion binding sites of murine and Saccharomyces cerevisiae (yeast) ferrochelatases, which are representatives of the former and latter categories, respectively. Co(2+) and Zn(2+) complexes of both enzymes were studied, but the Fe(2+) complex was only studied for yeast ferrochelatase because the [2Fe-2S] center of the murine enzyme interferes with the analysis. Co(2+) and Zn(2+) binding to site-directed mutants of the murine enzyme were also studied, in which the highly conserved and potentially metal-coordinating residues H207 and Y220 were substituted by residues that should not coordinate metal (i.e., H207N, H207A, and Y220F). Our experiments indicate four-coordinate zinc with Zn(N/O)(3)(S/Cl)(1) coordination for the yeast and Zn(N/O)(2)(S/Cl)(2) coordination for the wild-type murine enzyme. In contrast to zinc, a six-coordinate site for Co(2+) coordinated with oxygen or nitrogen was present in both the yeast and murine (wild-type and mutated) enzymes, with evidence of two histidine ligands in both. Like Co(2+), Fe(2+) bound to yeast ferrochelatase was coordinated by approximately six oxygen or nitrogen ligands, again with evidence of two histidine ligands. For the murine enzyme, mutation of both H207 and Y220 significantly changed the spectra, indicating a likely role for these residues in metal ion substrate binding. This is in marked disagreement with the conclusions from X-ray crystallographic studies of the human enzyme, and possible reasons for this are discussed. 相似文献
257.
Lu Y Sousa A Franco R Mangravita A Ferreira GC Moura I Shelnutt JA 《Biochemistry》2002,41(26):8253-8262
Resonance Raman (RR) spectroscopy is used to examine porphyrin substrate, product, and inhibitor interactions with the active site of murine ferrochelatase (EC 4.99.1.1), the terminal enzyme in the biosynthesis of heme. The enzyme catalyzes in vivo Fe(2+) chelation into protoporphyrin IX to give heme. The RR spectra of native ferrochelatase show that the protein, as isolated, contains varying amounts of endogenously bound high- or low-spin ferric heme, always at much less than 1 equiv. RR data on the binding of free-base protoporphyrin IX and its metalated complexes (Fe(III), Fe(II), and Ni(II)) to active wild-type protein were obtained at varying ratios of porphyrin to protein. The binding of ferric heme, a known inhibitor of the enzyme, leads to the formation of a low-spin six-coordinate adduct. Ferrous heme, the enzyme's natural product, binds in the ferrous high-spin five-coordinate state. Ni(II) protoporphyrin, a metalloporphyrin that has a low tendency toward axial ligation, becomes distorted when bound to ferrochelatase. Similarly for free-base protoporphyrin, the natural substrate of ferrochelatase, the RR spectra of porphyrin-protein complexes reveal a saddling distortion of the porphyrin. These results corroborate and extend our previous findings that porphyrin distortion, a crucial step of the catalytic mechanism, occurs even in the absence of bound metal substrate. Moreover, RR data reveal the presence of an amino acid residue in the active site of ferrochelatase which is capable of specific axial ligation to metals. 相似文献
258.
Scarselli M Spiga O Ciutti A Bernini A Bracci L Lelli B Lozzi L Calamandrei D Di Maro D Klein S Niccolai N 《Biochemistry》2002,41(5):1457-1463
A combinatorial library approach was used to produce synthetic peptides mimicking the snake neurotoxin binding site of nicotinic receptors. Among the sequences, which inhibited binding of alpha-bungarotoxin to muscle and neuronal nicotinic receptors, HRYYESSLPWYPD, a 14-amino acid peptide with considerably higher toxin-binding affinity than the other synthesized peptides, was selected, and the structure of its complex with the toxin was analyzed by NMR. Comparison of the solution structure of the free toxin and its complex with this peptide indicated that complex formation induced extensive conformational rearrangements mainly at finger II and the carboxy terminus of the protein. The peptidyl residues P10 and Y4 seemed to be critical for peptide folding and complex stability, respectively. The latter residue of the peptide strongly interacted with the protein by entering a small pocket delimited by D30, C33, S34, R36, and V39 toxin side chains. 相似文献
259.
Kim AL Gautier J Bickers DR Athar M 《Biochemical and biophysical research communications》2002,298(3):377-382
Ubiquitination of cyclin D1 signals for its proteosomal degradation. To assess the possibility that reduced cyclin D1 proteolysis is a putative mechanism for its accumulation during UVB-induced skin tumorigenesis, ubiquitination activity of cyclin D1 was assessed in UVB-induced murine SCCs. Cyclin D1 was rapidly ubiquitinated by control skin extract, whereas ubiquitination of cyclin D1 was significantly reduced in SCCs. Mutant cyclin D1, in which residues important for GSK3beta-mediated degradation of cyclin D1 are altered to non-phosphorylatable alanine, was not ubiquitinated. We also observed phosphorylation-dependent inactivation of GSK3beta in SCCs. Our results indicate reduced ubiquitination of cyclin D1 in UVB-induced murine SCCs and suggest that inactivation of GSK3beta-dependent cyclin D1 degradation pathway contributes to the accumulation of cyclin D1 in UVB-induced murine SCCs. 相似文献
260.
The meso-angioblast: a multipotent,self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues 总被引:16,自引:0,他引:16
Minasi MG Riminucci M De Angelis L Borello U Berarducci B Innocenzi A Caprioli A Sirabella D Baiocchi M De Maria R Boratto R Jaffredo T Broccoli V Bianco P Cossu G 《Development (Cambridge, England)》2002,129(11):2773-2783
We have previously reported the origin of a class of skeletal myogenic cells from explants of dorsal aorta. This finding disagrees with the known origin of all skeletal muscle from somites and has therefore led us to investigate the in vivo origin of these cells and, moreover, whether their fate is restricted to skeletal muscle, as observed in vitro under the experimental conditions used. To address these issues, we grafted quail or mouse embryonic aorta into host chick embryos. Donor cells, initially incorporated into the host vessels, were later integrated into mesodermal tissues, including blood, cartilage, bone, smooth, skeletal and cardiac muscle. When expanded on a feeder layer of embryonic fibroblasts, the clonal progeny of a single cell from the mouse dorsal aorta acquired unlimited lifespan, expressed hemo-angioblastic markers (CD34, Flk1 and Kit) at both early and late passages, and maintained multipotency in culture or when transplanted into a chick embryo. We conclude that these newly identified vessel-associated stem cells, the meso-angioblasts, participate in postembryonic development of the mesoderm, and we speculate that postnatal mesodermal stem cells may be derived from a vascular developmental origin. 相似文献