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排序方式: 共有301条查询结果,搜索用时 15 毫秒
61.
Christophe Bodenreider David Beer Thomas H. Keller Sebastian Sonntag Daying Wen LiJian Yap Yin Hoe Yau Susana Geifman Shochat Danzhi Huang Ting Zhou Amedeo Caflisch Xun-Cheng Su Kiyoshi Ozawa Gottfried Otting Subhash G. Vasudevan Julien Lescar Siew Pheng Lim 《Analytical biochemistry》2009,395(2):195-204
In drug discovery, the occurrence of false positives is a major hurdle in the search for lead compounds that can be developed into drugs. A small-molecular-weight compound that inhibits dengue virus protease at low micromolar levels was identified in a screening campaign. Binding to the enzyme was confirmed by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). However, a structure–activity relationship study that ensued did not yield more potent leads. To further characterize the parental compound and its analogues, we developed a high-speed, low-cost, quantitative fluorescence quenching assay. We observed that specific analogues quenched dengue protease fluorescence and showed variation in IC50 values. In contrast, nonspecifically binding compounds did not quench its fluorescence and showed similar IC50 values with steep dose–response curves. We validated the assay using single Trp-to-Ala protease mutants and the competitive protease inhibitor aprotinin. Specific compounds detected in the binding assay were further analyzed by competitive ITC, NMR, and surface plasmon resonance, and the assay’s utility in comparison with these biophysical methods is discussed. The sensitivity of this assay makes it highly useful for hit finding and validation in drug discovery. Furthermore, the technique can be readily adapted for studying other protein–ligand interactions. 相似文献
62.
Fibrillar protein aggregates (amyloids) are involved in several common pathologies, e.g., Alzheimer's disease and type II diabetes. Accumulating evidence suggests that toxicity in amyloid-related diseases originates from the deposition of protein aggregates on the cell membrane, which results in bilayer disruption and cell leakage. The molecular mechanism of damage to the membrane, however, is still obscure. To shed light on it we have performed coarse-grained molecular dynamics simulations of fibril-forming amphipathic peptides in the presence of lipid vesicles. The simulation results show that highly amyloidogenic peptides fibrillate on the surface of the vesicle, damaging the bilayer and promoting leakage. In contrast, the ordered aggregation of peptides with low amyloidogenicity is hindered by the vesicles. Remarkably, leakage from the vesicle is caused by growing aggregates, but not mature fibrils. The simulation results provide a basis for understanding the range of aggregation behavior that is observed in experiments with fibril-forming (poly)peptides. 相似文献
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64.
Aimee L. Crombie Thomas M. Antrilli Brandon A. Campbell David L. Crandall Amedeo A. Failli Yanan He Jeffrey C. Kern William J. Moore Lisa M. Nogle Eugene J. Trybulski 《Bioorganic & medicinal chemistry letters》2010,20(12):3742-3745
A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V1a- and good V2-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program’s mixed V1a/V2-receptor antagonist standard. 相似文献
65.
Antonio Carrieri Alessandro Piergentili Fabio Del Bello Mario Giannella Maria Pigini Amedeo Leonardi Francesca Fanelli Wilma Quaglia 《Bioorganic & medicinal chemistry》2010,18(19):7065-7077
A series of novel openphendioxan analogues were synthesized and tested at α1-adrenoreceptor (AR) subtypes by binding and functional assays. The α1d-AR binding profile was also examined by means of 2D, 3D-QSAR together with docking studies. Multiple regression analysis suggested the relevance of adequate number of heteroatoms in the whole molecule and of passive membrane diffusion to enhance α1d-AR affinity. Docking simulations against a computational structural model of the biological target further proved this evidence and furnished support for chemiometric analysis, where polar, electrostatic, hydrophobic and shape effects of the ortho substituents in the phenoxy terminal, most likely governing ligand binding, helped the depiction of pharmacophore hypothesis for the examined ligands data set. 相似文献
66.
Eisen JA Coyne RS Wu M Wu D Thiagarajan M Wortman JR Badger JH Ren Q Amedeo P Jones KM Tallon LJ Delcher AL Salzberg SL Silva JC Haas BJ Majoros WH Farzad M Carlton JM Smith RK Garg J Pearlman RE Karrer KM Sun L Manning G Elde NC Turkewitz AP Asai DJ Wilkes DE Wang Y Cai H Collins K Stewart BA Lee SR Wilamowska K Weinberg Z Ruzzo WL Wloga D Gaertig J Frankel J Tsao CC Gorovsky MA Keeling PJ Waller RF Patron NJ Cherry JM Stover NA Krieger CJ del Toro C Ryder HF Williamson SC Barbeau RA 《PLoS biology》2006,4(9):e286
The ciliate Tetrahymena thermophila is a model organism for molecular and cellular biology. Like other ciliates, this species has separate germline and soma functions that are embodied by distinct nuclei within a single cell. The germline-like micronucleus (MIC) has its genome held in reserve for sexual reproduction. The soma-like macronucleus (MAC), which possesses a genome processed from that of the MIC, is the center of gene expression and does not directly contribute DNA to sexual progeny. We report here the shotgun sequencing, assembly, and analysis of the MAC genome of T. thermophila, which is approximately 104 Mb in length and composed of approximately 225 chromosomes. Overall, the gene set is robust, with more than 27,000 predicted protein-coding genes, 15,000 of which have strong matches to genes in other organisms. The functional diversity encoded by these genes is substantial and reflects the complexity of processes required for a free-living, predatory, single-celled organism. This is highlighted by the abundance of lineage-specific duplications of genes with predicted roles in sensing and responding to environmental conditions (e.g., kinases), using diverse resources (e.g., proteases and transporters), and generating structural complexity (e.g., kinesins and dyneins). In contrast to the other lineages of alveolates (apicomplexans and dinoflagellates), no compelling evidence could be found for plastid-derived genes in the genome. UGA, the only T. thermophila stop codon, is used in some genes to encode selenocysteine, thus making this organism the first known with the potential to translate all 64 codons in nuclear genes into amino acids. We present genomic evidence supporting the hypothesis that the excision of DNA from the MIC to generate the MAC specifically targets foreign DNA as a form of genome self-defense. The combination of the genome sequence, the functional diversity encoded therein, and the presence of some pathways missing from other model organisms makes T. thermophila an ideal model for functional genomic studies to address biological, biomedical, and biotechnological questions of fundamental importance. 相似文献
67.
68.
Fortunato D Giuffrida MG Cavaletto M Garoffo LP Dellavalle G Napolitano L Giunta C Fabris C Bertino E Coscia A Conti A 《Proteomics》2003,3(6):897-905
Milk fat globule membrane (MFGM) contains proteins derived from the apical membrane of secreting epithelial cells of the mammary gland. Between 2-4% of total human milk protein content is associated with the fat globule fraction, as MFGM proteins. While MFGM proteins have very low classical nutritional value, they play important roles in various cell processes and defence mechanisms for the newborn. To date, fewer than 30 human MFGM proteins have been identified and characterized, either by immunological methods or by Edman sequencing and mass spectrometry. This study aimed to update the structural proteome of human colostral MFGM proteins and to create an annotated two-dimensional electrophoresis (2-DE) MFGM protein database available on-line. More than one hundred 2-DE spots derived from human colostral MFGM proteins were investigated by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and proteins were identified by three different software packages available on the web (PeptIdent, MS-Fit and ProFound); uncertain identifications were solved by nanoelectrospray ionization-ion trap mass spectrometry using SEQUEST software. 相似文献
69.
Host T-cell response to Helicobacter pylori is important for the clinical outcome of the infection. A Th1-polarized response, preferentially against CagA, is associated with peptic ulcer, whereas mixed Th1 and Th0 responses are present in non-ulcer gastritis. A deregulated H. pylori-driven Th0 cell-dependent B-cell activation is found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. 相似文献
70.