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101.
102.
Garnett MJ Edelman EJ Heidorn SJ Greenman CD Dastur A Lau KW Greninger P Thompson IR Luo X Soares J Liu Q Iorio F Surdez D Chen L Milano RJ Bignell GR Tam AT Davies H Stevenson JA Barthorpe S Lutz SR Kogera F Lawrence K McLaren-Douglas A Mitropoulos X Mironenko T Thi H Richardson L Zhou W Jewitt F Zhang T O'Brien P Boisvert JL Price S Hur W Yang W Deng X Butler A Choi HG Chang JW Baselga J Stamenkovic I Engelman JA Sharma SV Delattre O Saez-Rodriguez J Gray NS Settleman J Futreal PA Haber DA 《Nature》2012,483(7391):570-575
Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies. 相似文献
103.
BA Peters BG Kermani AB Sparks O Alferov P Hong A Alexeev Y Jiang F Dahl YT Tang J Haas K Robasky AW Zaranek JH Lee MP Ball JE Peterson H Perazich G Yeung J Liu L Chen MI Kennemer K Pothuraju K Konvicka M Tsoupko-Sitnikov KP Pant JC Ebert GB Nilsen J Baccash AL Halpern GM Church R Drmanac 《Nature》2012,487(7406):190-195
Recent advances in whole-genome sequencing have brought the vision of personal genomics and genomic medicine closer to reality. However, current methods lack clinical accuracy and the ability to describe the context (haplotypes) in which genome variants co-occur in a cost-effective manner. Here we describe a low-cost DNA sequencing and haplotyping process, long fragment read (LFR) technology, which is similar to sequencing long single DNA molecules without cloning or separation of metaphase chromosomes. In this study, ten LFR libraries were made using only ~100?picograms of human DNA per sample. Up to 97% of the heterozygous single nucleotide variants were assembled into long haplotype contigs. Removal of false positive single nucleotide variants not phased by multiple LFR haplotypes resulted in a final genome error rate of 1 in 10?megabases. Cost-effective and accurate genome sequencing and haplotyping from 10-20 human cells, as demonstrated here, will enable comprehensive genetic studies and diverse clinical applications. 相似文献
104.
The delayed rise of present-day mammals 总被引:1,自引:0,他引:1
Bininda-Emonds OR Cardillo M Jones KE MacPhee RD Beck RM Grenyer R Price SA Vos RA Gittleman JL Purvis A 《Nature》2007,446(7135):507-512
Did the end-Cretaceous mass extinction event, by eliminating non-avian dinosaurs and most of the existing fauna, trigger the evolutionary radiation of present-day mammals? Here we construct, date and analyse a species-level phylogeny of nearly all extant Mammalia to bring a new perspective to this question. Our analyses of how extant lineages accumulated through time show that net per-lineage diversification rates barely changed across the Cretaceous/Tertiary boundary. Instead, these rates spiked significantly with the origins of the currently recognized placental superorders and orders approximately 93 million years ago, before falling and remaining low until accelerating again throughout the Eocene and Oligocene epochs. Our results show that the phylogenetic 'fuses' leading to the explosion of extant placental orders are not only very much longer than suspected previously, but also challenge the hypothesis that the end-Cretaceous mass extinction event had a major, direct influence on the diversification of today's mammals. 相似文献
105.
A general integrative model for scaling plant growth, carbon flux, and functional trait spectra 总被引:1,自引:0,他引:1
Linking functional traits to plant growth is critical for scaling attributes of organisms to the dynamics of ecosystems and for understanding how selection shapes integrated botanical phenotypes. However, a general mechanistic theory showing how traits specifically influence carbon and biomass flux within and across plants is needed. Building on foundational work on relative growth rate, recent work on functional trait spectra, and metabolic scaling theory, here we derive a generalized trait-based model of plant growth. In agreement with a wide variety of empirical data, our model uniquely predicts how key functional traits interact to regulate variation in relative growth rate, the allometric growth normalizations for both angiosperms and gymnosperms, and the quantitative form of several functional trait spectra relationships. The model also provides a general quantitative framework to incorporate additional leaf-level trait scaling relationships and hence to unite functional trait spectra with theories of relative growth rate, and metabolic scaling. We apply the model to calculate carbon use efficiency. This often ignored trait, which may influence variation in relative growth rate, appears to vary directionally across geographic gradients. Together, our results show how both quantitative plant traits and the geometry of vascular transport networks can be merged into a common scaling theory. Our model provides a framework for predicting not only how traits covary within an integrated allometric phenotype but also how trait variation mechanistically influences plant growth and carbon flux within and across diverse ecosystems. 相似文献
106.
Ten plant communities containing bitter nightshade ( Solanum dulcamara ) were studied and the ecology and naturalizing relationships of bitter nightshade in central Utah area were investigated. Biotic and abiotic factors from each area were statistically analyzed. The data indicated that bitter nightshade was negatively correlated (P 相似文献
107.
Huw Price 《Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics》2012,43(2):75-83
It has often been suggested that retrocausality offers a solution to some of the puzzles of quantum mechanics: e.g., that it allows a Lorentz-invariant explanation of Bell correlations, and other manifestations of quantum nonlocality, without action-at-a-distance. Some writers have argued that time-symmetry counts in favour of such a view, in the sense that retrocausality would be a natural consequence of a truly time-symmetric theory of the quantum world. Critics object that there is complete time-symmetry in classical physics, and yet no apparent retrocausality. Why should the quantum world be any different?This note throws some new light on these matters. I call attention to a respect in which quantum mechanics is different, under some assumptions about quantum ontology. Under these assumptions, the combination of time-symmetry without retrocausality is unavailable in quantum mechanics, for reasons intimately connected with the differences between classical and quantum physics (especially the role of discreteness in the latter). Not all interpretations of quantum mechanics share these assumptions, however, and in those that do not, time-symmetry does not entail retrocausality. 相似文献
108.
Kimberly A. Dodds Karen M. Clancy Kathryn J. Leyva David Greenberg Peter W. Price 《西北部美国博物学家》2011,56(2)
The western spruce budworm ( Choristoneura occidentalis Freeman) prefers to feed on flushing buds and current-year needles of Douglas-fir ( Pseudotsuga menziesii [Mirb.] Franco). Budworm larvae will not typically consume older age classes of needles unless all current-year foliage is depleted. We tested the following null hypotheses: (1) budworm larvae can feed on foliage with a wide range of qualities (i.e., current 1-, 2-, or 3-year-old needles) without measurable effects on fitness; and (2) budworm adults do not show any oviposition preference linked to the age of the foliage they fed on as larvae. We used both laboratory and field experiments. There was strong evidence to support rejection of hypothesis 1. Budworm larvae had greater survival from the 4th instar to pupal stage when they fed on current-year foliage (43%-52% survival) versus older age classes of foliage (0-25% survival). Pupae from current-year foliage were also heavier than pupae from ≥ 1-year-old foliage. There was weak evidence to support rejecting hypothesis 2; budworm adults that fed had fed on current-year or 3-year-old foliage as larvae preferred to oviposit on current-year foliage. Similar conclusions were drawn from the laboratory and field experiments. 相似文献
109.
Houlston RS Cheadle J Dobbins SE Tenesa A Jones AM Howarth K Spain SL Broderick P Domingo E Farrington S Prendergast JG Pittman AM Theodoratou E Smith CG Olver B Walther A Barnetson RA Churchman M Jaeger EE Penegar S Barclay E Martin L Gorman M Mager R Johnstone E Midgley R Niittymäki I Tuupanen S Colley J Idziaszczyk S;COGENT Consortium Thomas HJ Lucassen AM Evans DG Maher ER;CORGI Consortium;COIN Collaborative Group;COINB Collaborative Group Maughan T Dimas A Dermitzakis E Cazier JB 《Nature genetics》2010,42(11):973-977
Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10?1? and rs6687758, OR = 1.09, P = 2.27 × 10??, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10??), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10?1? and rs7136702, OR = 1.06, P = 4.02 × 10??) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10?1?). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered. 相似文献
110.
Principal components analysis corrects for stratification in genome-wide association studies 总被引:8,自引:0,他引:8
Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers. 相似文献