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101.
Natalia F. Zakirova Alexander V. Shipitsyn Maxim V. Jasko Maria M. Prokofjeva Valeria L. Andronova Georgiy A. Galegov Vladimir S. Prassolov Sergey N. Kochetkov 《Bioorganic & medicinal chemistry》2012,20(19):5802-5809
The antiviral activity against HIV and HSV and the chemical stability of ACV phosphoramidate derivatives were studied. The phosphoramidates of ACV demonstrated moderate activity. The best compound appeared to be 9-(2-hydroxymethyl)guanine phosphoromonomorpholidate (7), which inhibited virus replication in pseudo-HIV-1 particles by 50% at 50 μM. It also inhibited replication of wild-type HSV-1 (9.7 μM) as well as an acyclovir-resistant strain (25 μM). None of the synthesised compounds showed any cytotoxicity. 相似文献
102.
Seferovic MD Krughkov V Pinto D Han VK Gupta MB 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2008,865(1-2):147-152
Proteomic analysis of plasma is challenging because of its large dynamic range, which prevents the detection of low abundance proteins. Immunodepletion of high abundance proteins, such as albumin and IgG, has emerged as a favored technology to overcome this problem; however its suitability in quantitative expression proteomics has not yet been adequately addressed. In this study, albumin and IgG immunodepletion was evaluated by ELISAs and the reproducibility of depletion was tested with 2-DGE. Depletion of plasma resulted in removal of 62+/-1.2% of the total protein, 93+/-1.4% of the albumin (0.43 microg/microL, residual), and 94+/-1.5% of the IgG (0.21 microg/microL, residual). These results were confirmed by immunoblotting. Computerized image analysis of 2-D gels using Progenesis SameSpots software revealed an enhancement in the number of visible spots (675-1325), with 10+/-6% inter-gel variability in spot density. LC-ESI-MS/MS identification of newly resolved protein spots further validated the procedure. An innovative application of the software employed led to identification of 11 proteins lost non-specifically during depletion. This study demonstrates the effectiveness of immunodepletion of albumin and IgG in quantitative 2-DGE-based differential analysis of plasma proteins. 相似文献
103.
Paul R. Carlier Troy D. Anderson Dawn M. Wong Danny C. Hsu Joshua Hartsel Ming Ma Eric A. Wong Ranginee Choudhury Polo C.-H. Lam Maxim M. Totrov Jeffrey R. Bloomquist 《Chemico-biological interactions》2008,175(1-3):368
Anopheles gambiae is the major mosquito vector of malaria in sub-Saharan Africa. At present, insecticide-treated nets (ITNs) impregnated with pyrethroid insecticides are widely used in malaria-endemic regions to reduce infection; however the emergence of pyrethroid-resistant mosquitoes has significantly reduced the effectiveness of the pyrethroid ITNs. An acetylcholinesterase (AChE) inhibitor that is potent for An. gambiae but weakly potent for the human enzyme could potentially be safely deployed on a new class of ITNs. In this paper we provide a preliminary pharmacological characterization of An. gambiae AChE, discuss structural features of An. gambiae and human AChE that could lead to selective inhibition, and describe compounds with 130-fold selectivity for inhibition of An. gambiae AChE relative to human AChE. 相似文献
104.
Simple stochastic models for phylogenetic trees on species have been well studied. But much paleontology data concerns time
series or trees on higher-order taxa, and any broad picture of relationships between extant groups requires use of higher-order
taxa. A coherent model for trees on (say) genera should involve both a species-level model and a model for the classification
scheme by which species are assigned to genera. We present a general framework for such models, and describe three alternate
classification schemes. Combining with the species-level model of Aldous and Popovic (Adv Appl Probab 37:1094–1115, 2005),
one gets models for higher-order trees, and we initiate analytic study of such models. In particular we derive formulas for
the lifetime of genera, for the distribution of number of species per genus, and for the offspring structure of the tree on
genera.
David Aldous’s research was supported by NSF Grant DMS-0704159. 相似文献
105.
106.
State of the art docking algorithms predict an incorrect binding pose for about 50-70% of all ligands when only a single fixed receptor conformation is considered. In many more cases, lack of receptor flexibility results in meaningless ligand binding scores, even when the correct pose is obtained. Incorporating conformational rearrangements of the receptor binding pocket into predictions of both ligand binding pose and binding score is crucial for improving structure-based drug design and virtual ligand screening methodologies. However, direct modeling of protein binding site flexibility remains challenging because of the large conformational space that must be sampled, and difficulties remain in constructing a suitably accurate energy function. Here we show that using multiple fixed receptor conformations, either experimentally determined by crystallography or NMR, or computationally generated, is a practical shortcut that may improve docking calculations. In several cases, such an approach has led to experimentally validated predictions. 相似文献
107.
Sergey N Arkhipov Maxim Berezovski Julia Jitkova Sergey N Krylov 《Cytometry. Part A》2005,63(1):41-47
BACKGROUND: Chemical cytometry is an emerging technology that analyzes chemical contents of single cells by means of capillary electrophoresis or capillary chromatography. It has a potential to become an indispensable tool in analyses of heterogeneous cell populations such as those in tumors. Ras oncogenes are found in 30% of human cancers. To become fully functional products, oncogenic Ras proteins require at least three posttranslational modifications: farnesylation, endoproteolysis, and carboxyl-methylation. Therefore, enzymes that catalyze the three reactions, farnesyltransferase (FTase), endoprotease (EPase), and methyltransferase (MTase), are considered highly attractive therapeutic targets. In this work, we used chemical cytometry to study the metabolism of a pentapeptide substrate that can mimic Ras proteins with respect to their posttranslational modifications in solution. METHODS: Mouse mammary gland tumor cells (4T1) and mouse embryo fibroblasts (NIH3T3) were incubated with a fluorescently labeled pentapeptide substrate, 2',7'-difluorofluorescein-5-carboxyl-Gly-Cys-Val-Ilu-Ala. Cells were washed from the substrate and resuspended in phosphate buffered saline. Uptake of the substrate by the cells was monitored by laser scanning confocal microscopy. Single cells were injected into the capillary, lysed, and subjected to capillary electrophoresis. Fluorescent metabolic products were detected by laser-induced fluorescence and compared with products obtained by the conversion of the substrate by FTase, EPase, and MTase in solution. Co-sampling of single cells with the in-vitro products was used for such comparison. RESULTS: Confocal microscopy data showed that the substrate permeated the plasma membrane and clustered in the cytoplasm. Further capillary electrophoresis and chemical cytometry analyses showed that the substrate was converted into three fluorescently labeled products, two of which were secreted in the culture medium and one remained in the cells. The intracellular product was present at approximately 100,000 molecules per cell. The three metabolic products of the substrate were found to be different from the products of its processing by FTase, EPase, and MTase in solution. CONCLUSIONS: This is the first report of chemical cytometry in the context of Ras-signaling studies. The chemical cytometry method used in this work will find applications in the development of suitable peptide substrates for monitoring enzyme activities in single cells. 相似文献
108.
Thisstudy investigated the variation along basipetal gradients of the relationshipsbetween the foliage/wood allocation ratios of biomass and of water content, inMediterranean trees and shrubs, at two different locations along a climaticgradient. Understanding of the biomass allocation and water relations inMediterranean trees and shrubs provides useful information on growth patternsofthese species, and on resource dynamics of these plant communities. Twoexperimental sites were selected along a climatological transect that runs fromthe foothills of the Judean Hills to the northern Negev desert in Israel. Ateach site, 16 quadrats of 10 × 10 m (eight on south-facingslopes and eight on north-facing slopes) were marked. The aboveground biomassofdominant tree and shrub species were estimated. Main branches of trees andshrubs were cut, their foliage and wood biomass were separately weighed, andtheir respective water contents were determined. The species studied includedthe evergreen sclerophylls, Quercus calliprinos, Phillyrealatifolia and Pistacia lentiscus, and thesemi-deciduous species, Cistus creticus, Coridothymuscapitatus and Sarcopoterium spinosum. Theresults indicated that the foliage/wood ratio decreased from the periphery ofthe crown to the interior of the trees and shrubs: foliage biomass and waterwere mainly limited to the top 30 cm of the crown in all studiedspecies. Leaves had higher relative water contents than woody tissues in theupper part of the crown. However; when the whole tree or shrub was considered,the relative water content was found to be mostly allocated to the woodystructures. The results are discussed in terms of biomass allocation in variouslife forms of the eastern-Mediterranean plant communities and how they areaffected by slope aspect and climatic conditions. 相似文献
109.
The extent and nature of cyclic electron delocalization in free and coordinated cyclopropenylidene carbenes has been analyzed by combined experimental and theoretical charge-density studies. The significant asymmetry of the C-C bond lengths in substituted cyclopropenylidene carbenes was identified as cooperative effect which depends on contributions of both σ- and π-bonding. We show that analyses of (i) the topology of the Laplacian of the electron density distribution and (ii) the out-of-plane atomic quadrupole moments - the charge-density analogues of pπ occupation - allow to distinguish between the influence of σ- and π-electrons on cyclic electron delocalization. These studies hint for pronounced electron localization in the carbene lone pair region which dominates the electronic structure of free cyclopropenylidene carbenes and hinders the establishment of true aromaticity. We further investigated the electron donating/withdrawing ability of cyclopropenylidene ligands relative to N-heterocyclic carbenes. The experimental benchmark systems LCr(CO)5 (L = 2,3-diphenylcyclopropenylidene and 1,2-dimethylimidazol-2-ylidene) show that the cyclopropenylidene ligand clearly displays the higher π-acceptor capability relative to N-heterocyclic carbenes. 相似文献
110.
Peter V Dubovskii Dmitry M Lesovoy Maxim A Dubinnyi Yuri N Utkin Alexander S Arseniev 《European journal of biochemistry》2003,270(9):2038-2046
The cardiotoxin (cytotoxin II, or CTII) isolated from cobra snake (Naja oxiana) venom is a 60-residue basic membrane-active protein featuring three-finger beta sheet fold. To assess possible modes of CTII/membrane interaction 31P- and 1H-NMR spectroscopy was used to study binding of the toxin and its effect onto multilamellar vesicles (MLV) composed of either zwitterionic or anionic phospholipid, dipalmitoylglycerophosphocholine (Pam2Gro-PCho) or dipalmitoylglycerophosphoglycerol (Pam2Gro-PGro), respectively. The analysis of 1H-NMR linewidths of the toxin and 31P-NMR spectral lineshapes of the phospholipid as a function of temperature, lipid-to-protein ratios, and pH values showed that at least three distinct modes of CTII interaction with membranes exist: (a) nonpenetrating mode; in the gel state of the negatively charged MLV the toxin is bound to the surface electrostatically; the binding to Pam2Gro-PCho membranes was not observed; (b) penetrating mode; hydrophobic interactions develop due to penetration of the toxin into Pam2Gro-PGro membranes in the liquid-crystalline state; it is presumed that in this mode CTII is located at the membrane/water interface deepening the side-chains of hydrophobic residues at the tips of the loops 1-3 down to the boundary between the glycerol and acyl regions of the bilayer; (c) the penetrating mode gives way to isotropic phase, stoichiometrically well-defined CTII/phospholipid complexes at CTII/lipid ratio exceeding a threshold value which was found to depend at physiological pH values upon ionization of the imidazole ring of His31. Biological implications of the observed modes of the toxin-membrane interactions are discussed. 相似文献