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排序方式: 共有377条查询结果,搜索用时 15 毫秒
81.
82.
Adam Doern Xianjun Cao Arlene Sereno Christopher L. Reyes Angelina Altshuler Flora Huang Cathy Hession Albert Flavier Michael Favis Hon Tran Eric Ailor Melissa Levesque Tracey Murphy Lisa Berquist Susan Tamraz Tracey Snipas Ellen Garber William S. Shestowsky Rachel Rennard Christilyn P. Graff Xiufeng Wu William Snyder Lindsay Cole David Gregson Michael Shields Steffan N. Ho Mitchell E. Reff Scott M. Glaser Jianying Dong Stephen J. Demarest Kandasamy Hariharan 《The Journal of biological chemistry》2009,284(15):10254-10267
83.
To examine the role of the glycosphingolipid (GSL), globotriaosylceramide(Gb3, CD77, pk blood group antigen) in HIV-1 infection, we havepharmacologically modulated Gb3 metabolism in an X4 HIV-1 infectablemonocytic cell line (THP-1) that naturally expresses Gb3 andin a Gb3-expressing glioblastoma cell line (U87) transfectedto express both CD4 and CCR5 to permit R5 HIV-1 infection. THP-1and U87 cells were treated with either a competitive inhibitorof -galactosidase A, 1-deoxygalactonojirimycin (DGJ) to induceGb3 accumulation, or a glucosylceramide synthase inhibitor,phenyl-2-palmitylamino-3-pyrrolidino-1-propanol (P4) to depletecells of Gb3. HIV susceptibility was determined via measurementof p24gag antigen production by ELISA. In addition, total cellularGb3 content was determined using thin layer chromatography followedby Verotoxin1 overlay binding. The cell surface expression ofGb3 was verified by FACS analysis. We found that DGJ significantlydecreased THP-1 and U87 cell susceptibility to HIV-1IIIB andHIV-1BaL infection, respectively, at a concentration of approximately100 µM. In contrast, P4 (2 µM) substantiallyincreased cellular susceptibility to HIV-1 infection. Totalcellular GSL analysis verified increased Gb3 expression in cellstreated with DGJ and considerable reduction of Gb3 in P4-treatedcells as compared to controls. These results show a reciprocalrelationship between Gb3 expression and infection with eitherX4 HIV-1IIIB or R5 HIV-1Ba-L. These results support previousstudies that Gb3 provides resistance to HIV infection. VariableGb3 expression may provide a natural HIV resistance factor inthe general population, and pharmacological manipulation ofGb3 levels may provide an approach to induction of HIV resistance. 相似文献
84.
Marna Pippel Kristen Boyce Hariharan Venkatesan Victor K. Phuong Wen Yan Terrance D. Barrett Guy Lagaud Lina Li Magda F. Morton Clodagh Prendergast Xiaodong Wu Nigel P. Shankley Michael H. Rabinowitz 《Bioorganic & medicinal chemistry letters》2009,19(22):6376-6378
In the previous article we demonstrated how certain CCK2R-selective anthranilic amides could be structurally modified to afford high-affinity, selective CCK1R activity. We now describe our efforts at modulating and optimizing the CCK1R and CCK2R affinities aimed at producing compounds with good pharmacokinetics properties and in vivo efficacy in rat models of gastric acid and pancreatic amylase secretion. 相似文献
85.
86.
Jevon Plunkett Scott Doniger Thomas Morgan Ritva Haataja Mikko Hallman Hilkka Puttonen Ramkumar Menon Edward Kuczynski Errol Norwitz Victoria Snegovskikh Aarno Palotie Leena Peltonen Vineta Fellman Emily A DeFranco Bimal P Chaudhari John Oates Olivier Boutaud Tracy L McGregor Jude J McElroy Kari Teramo Ingrid Borecki Justin C Fay Louis J Muglia 《BMC medical genomics》2010,3(1):1-9
Background
The use of biological annotation such as genes and pathways in the analysis of gene expression data has aided the identification of genes for follow-up studies and suggested functional information to uncharacterized genes. Several studies have applied similar methods to genome wide association studies and identified a number of disease related pathways. However, many questions remain on how to best approach this problem, such as whether there is a need to obtain a score to summarize association evidence at the gene level, and whether a pathway, dominated by just a few highly significant genes, is of interest.Methods
We evaluated the performance of two pathway-based methods (Random Set, and Binomial approximation to the hypergeometric test) based on their applications to three data sets of Crohn's disease. We consider both the disease status as a phenotype as well as the residuals after conditioning on IL23R, a known Crohn's related gene, as a phenotype.Results
Our results show that Random Set method has the most power to identify disease related pathways. We confirm previously reported disease related pathways and provide evidence for IL-2 Receptor Beta Chain in T cell Activation and IL-9 signaling as Crohn's disease associated pathways.Conclusions
Our results highlight the need to apply powerful gene score methods prior to pathway enrichment tests, and that controlling for genes that attain genome wide significance enable further biological insight. 相似文献87.
Vijay Naraynsingh Seetharaman Hariharan Dilip Dan Savrina Bhola Satyadevi Bhola Kerry Nagee 《Cancer epidemiology》2010,34(1):20-23
Background: Breast cancer is the most frequently diagnosed cancer among women worldwide. This study examines the breast cancer mortality patterns and trends in the Caribbean island state, Trinidad and Tobago for the 35-year period, 1970–2004. Methods: A retrospective analysis of the trends in breast cancer mortality from 1970 to 2004 was conducted. Crude mortality per 100,000 women, age-standardized mortality using World Standard population and age-stratified mortality were calculated and comparison was made between age groups above and below 50 years. Results: A general pattern of increase was observed in both crude and age-standardized mortality. The overall average crude mortality was 15.6 per 100,000 women (95% confidence interval (CI) 13.9–17.1) and the average age-standardized mortality was 18.0 per 100,000 women (95% CI 16.7–19.2). There was a pattern of increase in mortality with increasing age. The mortality rate was considerably higher for the age groups above 50 years than those less than 50 years of age both showing an upward trend over the 35-year period. Conclusions: Breast cancer mortality continued to increase over the 35-year period in Trinidad and Tobago. This study did not identify the exact reasons for this increasing trend. However, it is known that Trinidad and Tobago is becoming much more industrialized. It may be speculated that decrease in fertility rates, increase in the incidence of obesity and hormone utilization could have influenced this trend. 相似文献
88.
Effects of subminimum inhibitory concentrations of antibiotics on the Pasteurella multocida proteome
Nanduri B Lawrence ML Boyle CR Ramkumar M Burgess SC 《Journal of proteome research》2006,5(3):572-580
Subminimum inhibitory concentrations (sub-MICs) of antibiotics can be therapeutically effective, but the underlying molecular mechanisms are not well-characterized. We analyzed the Pasteurella multocida proteome response to sub-MICs of amoxicillin, chlortetracycline, and enrofloxacin using isotope-coded affinity tags (ICAT). There were parallel effects on inhibition of growth kinetics and suppression of protein expression by clusters of orthologous groups (COG) categories. Potential compensatory mechanisms enabling antibiotic adaptation were identified, including increased RecA expression caused by enrofloxacin. 相似文献
89.
Molecular docking and virtual screening based on molecular docking have become an integral part of many modern structure-based drug discovery efforts. Hence, it becomes a useful endeavor to evaluate existing docking programs, which can assist in the choice of the most suitable docking algorithm for any particular study. The objective of the current study was to evaluate the ability of ArgusLab 4.0, a relatively new molecular modeling package in which molecular docking is implemented, to reproduce crystallographic binding orientations and to compare its accuracy with that of a well established commercial package, GOLD. The study also aimed to evaluate the effect of the nature of the binding site and ligand properties on docking accuracy. The three dimensional structures of a carefully chosen set of 75 pharmaceutically relevant protein-ligand complexes were used for the comparative study. The study revealed that the commercial package outperforms the freely available docking engine in almost all the parameters tested. However, the study also revealed that although lagging behind in accuracy, results from ArgusLab are biologically meaningful. This taken together with the fact that ArgusLab has an easy to use graphical user interface, means that it can be employed as an effective teaching tool to demonstrate molecular docking to beginners in this area. 相似文献
90.
Carpio RV González-Nilo FD Jayaram H Spencer E Prasad BV Patton JT Taraporewala ZF 《The Journal of biological chemistry》2004,279(11):10624-10633
Octamers formed by the nonstructural protein NSP2 of rotavirus are proposed to function as molecular motors in the packaging of the segmented double-stranded RNA genome. The octamers have RNA binding, helix unwinding, and Mg(2+)-dependent NTPase activities and play a crucial role in assembly of viral replication factories (viroplasms). Comparison of x-ray structures has revealed significant structural homology between NSP2 and the histidine triad (HIT) family of nucleotidyl hydrolases, which in turn has suggested the location of the active site for NTP hydrolysis in NSP2. Consistent with the structural predictions, we show here using site-specific mutagenesis and ATP docking simulations that the active site for NTP hydrolysis is localized to residues within a 25-A-deep cleft between the C- and N-terminal domains of the NSP2 monomer. Although lacking the precise signature HIT motif (H?H?H?? where ? is a hydrophobic residue), our analyses demonstrate that histidines (His(221) and His(225)) represent critical residues of the active site. Similar to events occurring during nucleotide hydrolysis by HIT proteins, NTP hydrolysis by NSP2 was found to produce a short lived phosphorylated intermediate. Evaluation of the biological importance of the NTPase activity of NSP2 by transient expression in mammalian cells showed that such activity has no impact on the ability of NSP2 to induce the hyperphosphorylation of NSP5 or to interact with NSP5 to form viroplasm-like structures. Hence the NTPase activity of NSP2 probably has a role subsequent to the formation of viroplasms, consistent with its suspected involvement in RNA packaging and/or replication. 相似文献