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Sequencing technologies are becoming cheap enough to apply to large numbers of study participants and promise to provide new insights into human phenotypes by bringing to light rare and previously unknown genetic variants. We develop a new framework for the analysis of sequence data that incorporates all of the major features of previously proposed approaches, including those focused on allele counts and allele burden, but is both more general and more powerful. We harness population genetic theory to provide prior information on effect sizes and to create a pooling strategy for information from rare variants. Our method, EMMPAT (Evolutionary Mixed Model for Pooled Association Testing), generates a single test per gene (substantially reducing multiple testing concerns), facilitates graphical summaries, and improves the interpretation of results by allowing calculation of attributable variance. Simulations show that, relative to previously used approaches, our method increases the power to detect genes that affect phenotype when natural selection has kept alleles with large effect sizes rare. We demonstrate our approach on a population-based re-sequencing study of association between serum triglycerides and variation in ANGPTL4. 相似文献
995.
Testing for genetic effects on mean values of a quantitative trait has been a very successful strategy. However, most studies to date have not explored genetic effects on the variance of quantitative traits as a relevant consequence of genetic variation. In this report, we demonstrate that, under plausible scenarios of genetic interaction, the variance of a quantitative trait is expected to differ among the three possible genotypes of a biallelic SNP. Leveraging this observation with Levene''s test of equality of variance, we propose a novel method to prioritize SNPs for subsequent gene–gene and gene–environment testing. This method has the advantageous characteristic that the interacting covariate need not be known or measured for a SNP to be prioritized. Using simulations, we show that this method has increased power over exhaustive search under certain conditions. We further investigate the utility of variance per genotype by examining data from the Women''s Genome Health Study. Using this dataset, we identify new interactions between the LEPR SNP rs12753193 and body mass index in the prediction of C-reactive protein levels, between the ICAM1 SNP rs1799969 and smoking in the prediction of soluble ICAM-1 levels, and between the PNPLA3 SNP rs738409 and body mass index in the prediction of soluble ICAM-1 levels. These results demonstrate the utility of our approach and provide novel genetic insight into the relationship among obesity, smoking, and inflammation. 相似文献
996.
Kimberly Pelak Kevin V. Shianna Dongliang Ge Jessica M. Maia Mingfu Zhu Jason P. Smith Elizabeth T. Cirulli Jacques Fellay Samuel P. Dickson Curtis E. Gumbs Erin L. Heinzen Anna C. Need Elizabeth K. Ruzzo Abanish Singh C. Ryan Campbell Linda K. Hong Katharina A. Lornsen Alexander M. McKenzie Nara L. M. Sobreira Julie E. Hoover-Fong Joshua D. Milner Ruth Ottman Barton F. Haynes James J. Goedert David B. Goldstein 《PLoS genetics》2010,6(9)
We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten “case” genomes from individuals with severe hemophilia A and ten “control” genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways. 相似文献
997.
Franck E. Dayan Pankaj R. Daga Stephen O. Duke Ryan M. Lee Patrick J. Tranel Robert J. Doerksen 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(7):1548-1556
A rare Gly210 deletion in protoporphyrinogen oxidase (PPO) was recently discovered in herbicide-resistant Amaranthus tuberculatus. According to the published X-ray structure of Nicotiana tabacum PPO, Gly210 is adjacent to, not in, the PPO active site, so it is a matter of interest to determine why its deletion imparts resistance to herbicides. In our kinetic experiments, this deletion did not affect the affinity of protoporphyrinogen IX nor the FAD content, but decreased the catalytic efficiency of the enzyme. The suboptimal Kcat was compensated by a significant increase in the Kis for inhibitors and a switch in their interactions from competitive to mixed-type inhibition. In our protein modeling studies on herbicide-susceptible PPO and resistant PPO, we show that Gly210 plays a key role in the αL helix-capping motif at the C-terminus of the α-8 helix which helps to stabilize the helix. In molecular dynamics simulations, the deletion had significant architecture consequences, destabilizing the α-8 helix-capping region and unraveling the last turn of the helix, leading to enlargement of the active site cavity by ∼ 50%. This seemingly innocuous deletion of Gly210 of the mitochondrial PPO imparts herbicide resistance to this dual-targeted protein without severely affecting its normal physiological function, which may explain why this unusual mutation was the favored evolutionary path for achieving resistance to PPO inhibitors. 相似文献
998.
Jiang Wu Peter Warren Quazi Shakey Eric Sousa Andrew Hill Terence E. Ryan Tao He 《Proteomics》2010,10(11):2224-2234
Recent advances in MS instrumentation and progresses in phosphopeptide enrichment, in conjunction with more powerful data analysis tools, have facilitated unbiased characterization of thousands of site‐specific phosphorylation events. Combined with stable isotope labeling by amino acids in cell culture metabolic labeling, these techniques have made it possible to quantitatively evaluate phosphorylation changes in various physiological states in stable cell lines. However, quantitative phosphoproteomics in primary cells and tissues remains a major technical challenge due to the lack of adequate techniques for accurate quantification. Here, we describe an integrated strategy allowing for large scale quantitative profiling of phosphopeptides in complex biological mixtures. In this technique, the mixture of proteolytic peptides was subjected to phosphopeptide enrichment using a titania affinity column, and the purified phosphopeptides were subsequently labeled with iTRAQ reagents. After further fractionation by strong‐cation exchange, the peptides were analyzed by LC‐MS/MS on an Orbitrap mass spectrometer, which collects CID and high‐energy collisional dissociation (HCD) spectra sequentially for peptide identification and quantitation. We demonstrate that direct phosphopeptide enrichment of protein digests by titania affinity chromatography substantially improves the efficiency and reproducibility of phosphopeptide proteomic analysis and is compatible with downstream iTRAQ labeling. Conditions were optimized for HCD normalized collision energy to balance the overall peptide identification and quantitation using the relative abundances of iTRAQ reporter ions. Using this approach, we were able to identify 3557 distinct phosphopeptides from HeLa cell lysates, of which 2709 were also quantified from HCD scans. 相似文献
999.
P.J. Nico de Bruyn Elissa Z. Cameron Cheryl A. Tosh W. Chris Oosthuizen Ryan R. Reisinger N. Thomas Mufanadzo Mashudu V. Phalanndwa Martin Postma Mia Wege Derek S. van der Merwe Marthán N. Bester 《Mammalian Biology》2010,75(6):555-560
Non-offspring maternal care should be rare due to the high costs of raising offspring, particularly lactation, but nonetheless occurs in a variety of taxa. Misguided parental care, associated with recognition errors and/or inattentiveness by lactating females, has been hypothesized as an explanation for allolactation in mammals. In an extension of this hypothesis, we suggest that milk-stealing is parasitism instigated by non-filial offspring, and that maternal behaviour is of secondary interest in an evolutionary context if she is unaware of the interaction. We provide evidence for frequent milk-stealing attempts by Subantarctic fur seal (Arctocephalus tropicalis) pups, including an example of sustained non-maternal care (> three months) for one pup during the confirmed absence of his mother, leading to a weaning mass equal to the population mean. We also present only the second account of fostering/twins in the species at this locality. We suggest that rather than the hitherto suggested rare and anomalous behaviour, milk-stealing behaviour (while not always successful) is common. 相似文献
1000.
The discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) raised the exciting possibility of modeling diseases with patient-specific cells. Marchetto et?al. (2010) now use iPSC technology to generate, characterize, and treat an in?vitro model for the autism spectrum disorder Rett syndrome. 相似文献