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81.
The first-order effect of selection on the probability of fixation of an allele, with respect to an intensity of selection s>0 in a diploid population of fixed finite size N, undergoing discrete, non-overlapping generations, is shown to be given by the sum of the average effects of that allele on the coefficient of selection in the current generation and all future generations, given the population state in the current generation. This projected average allelic effect is a weighted sum of average allelic effects in allozygous and autozygous offspring in the initial generation, with weights given in terms of expected coalescence times, under neutrality, for the lineages of two or three gametes chosen at random in the same generation. This is shown in the framework of multiple alleles at one locus, with genotypic values determining either viability or fertility differences, and with either multinomial or exchangeable reproduction schemes. In the limit of weak selection in a large population such that Ns tends to zero, the initial average allelic effects in allozygous offspring and autozygous offspring have the same weight on the fixation probability only in the domain of application of the Kingman coalescent. With frequency-dependent selection in a linear-game-theoretic context with two phenotypes determined by additive gene action, the first-order effect on the fixation probability is a combination of two effects of frequency-independent selection, one in a haploid population, the other in a diploid population. In the domain of application of the Kingman coalescent as the population size goes to infinity and Ns to zero, the first effect is three times more important than the second effect. This explains the one-third law of evolutionary dynamics in this domain, and shows how this law can be extended beyond this domain. 相似文献
82.
Simon Rajendran Slawomir Salwa Xuefeng Gao Sabin Tabirca Deirdre O'Hanlon Gerald C. O'Sullivan Mark Tangney 《Journal of visualized experiments : JoVE》2010,(46)
This video describes the use of patient tissue as an ex vivo model for the study of gene delivery. Fresh patient tissue obtained at the time of surgery is sliced and maintained in culture. The ex vivo model system allows for the physical delivery of genes into intact patient tissue and gene expression is analysed by bioluminescence imaging using the IVIS detection system. The bioluminescent detection system demonstrates rapid and accurate quantification of gene expression within individual slices without the need for tissue sacrifice. This slice tissue culture system may be used in a variety of tissue types including normal and malignant tissue and allows us to study the effects of the heterogeneous nature of intact tissue and the high degree of variability between individual patients. This model system could be used in certain situations as an alternative to animal models and as a complementary preclinical mode prior to entering clinical trial.Download video file.(23M, mov) 相似文献
83.
Jennifer M. Kavran Matthew D. Ward Oyindamola O. Oladosu Sabin Mulepati Daniel J. Leahy 《The Journal of biological chemistry》2010,285(32):24584-24590
Hedgehog (Hh) signaling proteins stimulate cell proliferation, differentiation, and tissue patterning at multiple points in animal development. A single Hh homolog is present in Drosophila, but three Hh homologs, Sonic Hh, Indian Hh, and Desert Hh, are present in mammals. Distribution, movement, and reception of Hh signals are tightly regulated, and abnormal Hh signaling is associated with developmental defects and cancer. In addition to the integral membrane proteins Patched and Smoothened, members of the Drosophila Ihog family of adhesion-like molecules have recently been shown to bind Hh proteins with micromolar affinity and positively regulate Hh signaling. Cell adhesion molecule-related, down-regulated by oncogenes (CDO) and Brother of CDO (BOC) are the closest mammalian relatives of Drosophila Ihog, and CDO binds Sonic Hh with micromolar affinity and positively regulates Hh signaling. Despite these similarities, structural and biochemical studies have shown that Ihog and CDO utilize nonorthologous domains and completely different binding modes to interact with cognate Hh proteins. We report here biochemical and x-ray structural studies of Sonic, Indian, and Desert Hh proteins both alone and complexed with active domains of CDO and BOC. These results show that all mammalian Hh proteins bind CDO and BOC in the same manner. We also show that interactions between Hh proteins and CDO are weakened at low pH. Formation of Hh-mediated Hh oligomers is thought to be an important feature of normal Hh signaling, but no conserved self-interaction between Hh proteins is apparent from inspection of 14 independent Hh-containing crystal lattices. 相似文献
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Buckley GM Cooper N Dyke HJ Galleway FP Gowers L Haughan AF Kendall HJ Lowe C Maxey R Montana JG Naylor R Oxford J Peake JC Picken CL Runcie KA Sabin V Sharpe A Warneck JB 《Bioorganic & medicinal chemistry letters》2002,12(12):1613-1615
A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4). 相似文献
87.
Joseph Guiles Xicheng Sun Ian A. Critchley Urs Ochsner Ming Tregay Kim Stone Jennifer Bertino Louis Green Rob Sabin Frank Dean H. Garry Dallmann Charles S. McHenry Nebojsa Janjic 《Bioorganic & medicinal chemistry letters》2009,19(3):800-802
High throughput screening led to the discovery of a novel series of quinazolin-2-ylamino-quinazolin-4-ols as a new class of DNA polymerase III inhibitors. The inhibition of chromosomal DNA replication results in bacterial cell death. The synthesis, structure–activity relationships and functional activity are described. 相似文献
88.
Buckley GM Ceska TA Fraser JL Gowers L Groom CR Higueruelo AP Jenkins K Mack SR Morgan T Parry DM Pitt WR Rausch O Richard MD Sabin V 《Bioorganic & medicinal chemistry letters》2008,18(11):3291-3295
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR. 相似文献
89.
Ellen J. Coombs Rob Deaville Richard C. Sabin Louise Allan Mick O'Connell Simon Berrow Brian Smith Andrew Brownlow Mariel Ten Doeschate Rod Penrose Ruth Williams Matthew W. Perkins Paul D. Jepson Natalie Cooper 《Marine Mammal Science》2019,35(4):1527-1555
There are many factors that may explain why cetaceans (whales, dolphins, and porpoises) strand. Around the UK and Ireland, over 20,000 stranding records have been collected since 1913, resulting in one of the longest, continuous, systematic stranding data sets in the world. We use this data set to investigate temporal and spatial trends in cetacean strandings and use generalized additive models (GAMs) to investigate correlates of strandings. We find a dramatic increase in strandings since the 1980s, most likely due to increases in recording effort, and the formation of formal strandings networks. We found no correlation between the numbers of cetaceans stranding each year and several potential environmental and anthropogenic predictors: storms, geomagnetic activity, North Atlantic Oscillations, sea‐surface temperature, and fishing catch. We suggest that this is because the scale of change in the variables is too coarse to detect any potential correlations. It may also highlight the idiosyncratic nature of species’ responses to external pressures, and further the need to investigate other potential correlates of strandings, such as bycatch and military sonar. Long‐term cetacean stranding data provide vital information on past and present diversity for common, rare, and inconspicuous species. This study underlines the importance of continued support for stranding networks. 相似文献