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81.
Anhydride modified cantharidin analogues: synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity 总被引:3,自引:0,他引:3
McCluskey A Bowyer MC Collins E Sim ATR Sakoff JA Baldwin ML 《Bioorganic & medicinal chemistry letters》2000,10(15):1687-1690
Two series of anhydride modified cantharidin analogues were synthesised and screened for their phosphatase inhibition (PP1 and PP2A) and cytotoxicity in various cancer cell lines (Ovarian A2780, ADDP; Osteosarcoma 143B; and Colon HCT116 and HT29). One series was synthesised by a novel, high yielding one-pot hydrogenation-ring-opening-esterification procedure, the other by acid catalysed acetal formation. Analogues 5-7 and 9 displayed moderate PP2A selectivity (ca. 5- to 20-fold) and inhibition typically in the low microM range (comparable, in some cases to cantharidin). The anticancer activity of these analogues varied with the cell line under study; however, many of them showed selective cytotoxicity for the colon tumour cell lines. 相似文献
82.
Sesma L Galocha B Vázquez M Purcell AW Marcilla M McCluskey J López de Castro JA 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(12):7833-7844
Tapasin (Tpn) is a chaperone of the endoplasmic reticulum involved in peptide loading to MHC class I proteins. The influence of mouse Tpn (mTpn) on the HLA-B*2705-bound peptide repertoire was analyzed to characterize the species specificity of this chaperone. B*2705 was expressed on Tpn-deficient human 721.220 cells cotransfected with human (hTpn) or mTpn. The heterodimer to beta(2)-microglobulin-free H chain ratio on the cell surface was reduced with mTpn, suggesting lower B*2705 stability. The B*2705-bound peptide repertoires loaded with hTpn or mTpn shared 94-97% identity, although significant differences in peptide amount were observed in 16-17% of the shared ligands. About 3-6% of peptides were bound only with either hTpn or mTpn. Nonamers differentially bound with mTpn had less suitable anchor residues and bound B*2705 less efficiently in vitro than those loaded only with hTpn or shared nonamers. Decamers showed a different pattern: those found only with mTpn had similarly suitable residues as shared decamers and bound B*2705 with high efficiency. Peptides differentially presented by B*2705 on human or mouse cells showed an analogous pattern of residue suitability, suggesting that the effect of mTpn on B*2705 loading is comparable in both cell types. Thus, mTpn has quantitative and qualitative effects on the B*2705-bound peptide repertoire, impairing presentation of some suitable ligands and allowing others with suboptimal anchor residues and lower affinity to be presented. Our results favor a size-dependent peptide editing role of Tpn for HLA-B*2705 that is species-dependent and suboptimally performed, at least for nonamers, by mTpn. 相似文献
83.
Webb AI Dunstone MA Williamson NA Price JD de Kauwe A Chen W Oakley A Perlmutter P McCluskey J Aguilar MI Rossjohn J Purcell AW 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(6):3810-3818
A major hurdle in designing successful epitope-based vaccines resides in the delivery, stability, and immunogenicity of the peptide immunogen. The short-lived nature of unmodified peptide-based vaccines in vivo limits their therapeutic application in the immunotherapy of cancers and chronic viral infections as well as their use in generating prophylactic immunity. The incorporation of beta-amino acids into peptides decreases proteolysis, yet its potential application in the rational design of T cell mimotopes is poorly understood. To address this, we have replaced each residue of the SIINFEKL epitope individually with the corresponding beta-amino acid and examined the resultant efficacy of these mimotopes. Some analogs displayed similar MHC binding and superior protease stability compared with the native epitope. Importantly, these analogs were able to generate cross-reactive CTLs in vivo that were capable of lysing tumor cells that expressed the unmodified epitope as a surrogate tumor Ag. Structural analysis of peptides in which anchor residues were substituted with beta-amino acids revealed the basis for enhanced MHC binding and retention of immunogenicity observed for these analogs and paves the way for future vaccine design using beta-amino acids. We conclude that the rational incorporation of beta-amino acids into T cell determinants is a powerful alternative to the traditional homologous substitution of randomly chosen naturally occurring alpha-amino acids, and these mimotopes may prove particularly useful for inclusion in epitope-based vaccines. 相似文献
84.
Miles JJ Elhassen D Borg NA Silins SL Tynan FE Burrows JM Purcell AW Kjer-Nielsen L Rossjohn J Burrows SR McCluskey J 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(6):3826-3834
MHC class I molecules generally present peptides of 8-10 aa long, forming an extended coil in the HLA cleft. Although longer peptides can also bind to class I molecules, they tend to bulge from the cleft and it is not known whether the TCR repertoire has sufficient plasticity to recognize these determinants during the antiviral CTL response. In this study, we show that unrelated individuals infected with EBV generate a significant CTL response directed toward an HLA-B*3501-restricted, 11-mer epitope from the BZLF1 Ag. The 11-mer determinant adopts a highly bulged conformation with seven of the peptide side chains being solvent-exposed and available for TCR interaction. Such a complex potentially creates a structural challenge for TCR corecognition of both HLA-B*3501 and the peptide Ag. Surprisingly, unrelated B*3501 donors recognizing the 11-mer use identical or closely related alphabeta TCR sequences that share particular CDR3 motifs. Within the small number of dominant CTL clonotypes observed, each has discrete fine specificity for the exposed side chain residues of the peptide. The data show that bulged viral peptides are indeed immunogenic but suggest that the highly constrained TCR repertoire reflects a limit to TCR diversity when responding to some unusual MHC peptide ligands. 相似文献
85.
We study a model of the chemostat with two species competing for two perfectly substitutable resources in the case of linear
functional response. Lyapunov methods are used to provide sufficient conditions for the global asymptotic stability of the
coexistence equilibrium. Then, using compound matrix techniques, we provide a global analysis in a subset of parameter space.
In particular, we show that each solution converges to an equilibrium, even in the case that the coexistence equilibrium is
a saddle. Finally, we provide a bifurcation analysis based on the dilution rate. In this context, we are able to provide a
geometric interpretation that gives insight into the role of the other parameters in the bifurcation sequence.
Funding was provided by the National Science Foundation-funded ADVANCE Institutional Transformation Program at New Mexico
State University, fund # NSF0123690.
Research partially supported by the Natural Science and Engineering Research Council of Canada. 相似文献
86.
A convenient assay to score repeat-induced point mutation (RIP) inNeurospora employs theerg-3 locus as a mutagenesis target. Using this assay we screened 132 wild-isolatedNeurospora crassa strains for ability to dominantly suppress RIP. RIP was exceptionally inefficient in crosses with the wild isolates Sugartown
(P0854) and Adiopodoume-7 (P4305), thereby suggesting the presence of dominant RIP suppressors in these strains. In other
experiments, we found no evidence for dominant RIP suppression by theSpore killer haplotypesSk-2 andSk-3. 相似文献
87.
88.
Conn McCluskey 《BMJ (Clinical research ed.)》1946,2(4481):791-792
89.
90.
Kubicek CP Herrera-Estrella A Seidl-Seiboth V Martinez DA Druzhinina IS Thon M Zeilinger S Casas-Flores S Horwitz BA Mukherjee PK Mukherjee M Kredics L Alcaraz LD Aerts A Antal Z Atanasova L Cervantes-Badillo MG Challacombe J Chertkov O McCluskey K Coulpier F Deshpande N von Döhren H Ebbole DJ Esquivel-Naranjo EU Fekete E Flipphi M Glaser F Gómez-Rodríguez EY Gruber S Han C Henrissat B Hermosa R Hernández-Oñate M Karaffa L Kosti I Le Crom S Lindquist E Lucas S Lübeck M Lübeck PS Margeot A 《Genome biology》2011,12(4):R40