全文获取类型
收费全文 | 3606篇 |
免费 | 413篇 |
出版年
2023年 | 17篇 |
2022年 | 37篇 |
2021年 | 81篇 |
2020年 | 48篇 |
2019年 | 48篇 |
2018年 | 59篇 |
2017年 | 54篇 |
2016年 | 97篇 |
2015年 | 150篇 |
2014年 | 152篇 |
2013年 | 238篇 |
2012年 | 286篇 |
2011年 | 268篇 |
2010年 | 174篇 |
2009年 | 139篇 |
2008年 | 207篇 |
2007年 | 214篇 |
2006年 | 220篇 |
2005年 | 186篇 |
2004年 | 155篇 |
2003年 | 152篇 |
2002年 | 141篇 |
2001年 | 71篇 |
2000年 | 62篇 |
1999年 | 58篇 |
1998年 | 38篇 |
1997年 | 29篇 |
1996年 | 29篇 |
1995年 | 22篇 |
1994年 | 27篇 |
1993年 | 27篇 |
1992年 | 37篇 |
1991年 | 35篇 |
1990年 | 27篇 |
1989年 | 26篇 |
1988年 | 32篇 |
1987年 | 28篇 |
1986年 | 18篇 |
1985年 | 21篇 |
1984年 | 29篇 |
1982年 | 27篇 |
1980年 | 16篇 |
1979年 | 17篇 |
1978年 | 15篇 |
1977年 | 19篇 |
1975年 | 15篇 |
1974年 | 17篇 |
1973年 | 18篇 |
1972年 | 15篇 |
1970年 | 14篇 |
排序方式: 共有4019条查询结果,搜索用时 15 毫秒
151.
Michael Mueller Paula Barros Abigail?S. Witherden Amy?L. Roberts Zhou Zhang Helmut Schaschl Chack-Yung Yu Matthew?E. Hurles Catherine Schaffner R.?Andres Floto Laurence Game Karyn?Meltz Steinberg Richard?K. Wilson Tina?A. Graves Evan?E. Eichler H.?Terence Cook Timothy?J. Vyse Timothy?J. Aitman 《American journal of human genetics》2013,92(1):28-40
Reduced FCGR3B copy number is associated with increased risk of systemic lupus erythematosus (SLE). The five FCGR2/FCGR3 genes are arranged across two highly paralogous genomic segments on chromosome 1q23. Previous studies have suggested mechanisms for structural rearrangements at the FCGR2/FCGR3 locus and have proposed mechanisms whereby altered FCGR3B copy number predisposes to autoimmunity, but the high degree of sequence similarity between paralogous segments has prevented precise definition of the molecular events and their functional consequences. To pursue the genomic pathology associated with FCGR3B copy-number variation, we integrated sequencing data from fosmid and bacterial artificial chromosome clones and sequence-captured DNA from FCGR3B-deleted genomes to establish a detailed map of allelic and paralogous sequence variation across the FCGR2/FCGR3 locus. This analysis identified two highly paralogous 24.5 kb blocks within the FCGR2C/FCGR3B/FCGR2B locus that are devoid of nonpolymorphic paralogous sequence variations and that define the limits of the genomic regions in which nonallelic homologous recombination leads to FCGR2C/FCGR3B copy-number variation. Further, the data showed evidence of swapping of haplotype blocks between these highly paralogous blocks that most likely arose from sequential ancestral recombination events across the region. Functionally, we found by flow cytometry, immunoblotting and cDNA sequencing that individuals with FCGR3B-deleted alleles show ectopic presence of FcγRIIb on natural killer (NK) cells. We conclude that FCGR3B deletion juxtaposes the 5′-regulatory sequences of FCGR2C with the coding sequence of FCGR2B, creating a chimeric gene that results in an ectopic accumulation of FcγRIIb on NK cells and provides an explanation for SLE risk associated with reduced FCGR3B gene copy number. 相似文献
152.
Meredith?L. Carpenter Jason?D. Buenrostro Cristina Valdiosera Hannes Schroeder Morten?E. Allentoft Martin Sikora Morten Rasmussen Simon Gravel Sonia Guillén Georgi Nekhrizov Krasimir Leshtakov Diana Dimitrova Nikola Theodossiev Davide Pettener Donata Luiselli Karla Sandoval Andrés Moreno-Estrada Yingrui Li Jun Wang M.?Thomas?P. Gilbert Eske Willerslev William?J. Greenleaf Carlos?D. Bustamante 《American journal of human genetics》2013,93(5):852-864
Most ancient specimens contain very low levels of endogenous DNA, precluding the shotgun sequencing of many interesting samples because of cost. Ancient DNA (aDNA) libraries often contain <1% endogenous DNA, with the majority of sequencing capacity taken up by environmental DNA. Here we present a capture-based method for enriching the endogenous component of aDNA sequencing libraries. By using biotinylated RNA baits transcribed from genomic DNA libraries, we are able to capture DNA fragments from across the human genome. We demonstrate this method on libraries created from four Iron Age and Bronze Age human teeth from Bulgaria, as well as bone samples from seven Peruvian mummies and a Bronze Age hair sample from Denmark. Prior to capture, shotgun sequencing of these libraries yielded an average of 1.2% of reads mapping to the human genome (including duplicates). After capture, this fraction increased substantially, with up to 59% of reads mapped to human and enrichment ranging from 6- to 159-fold. Furthermore, we maintained coverage of the majority of regions sequenced in the precapture library. Intersection with the 1000 Genomes Project reference panel yielded an average of 50,723 SNPs (range 3,062–147,243) for the postcapture libraries sequenced with 1 million reads, compared with 13,280 SNPs (range 217–73,266) for the precapture libraries, increasing resolution in population genetic analyses. Our whole-genome capture approach makes it less costly to sequence aDNA from specimens containing very low levels of endogenous DNA, enabling the analysis of larger numbers of samples. 相似文献
153.
154.
155.
Yanming Du Hong Ye Tina Gill Lijuan Wang Fang Guo Andrea Cuconati Ju-Tao Guo Timothy M. Block Jinhong Chang Xiaodong Xu 《Bioorganic & medicinal chemistry letters》2013,23(7):2172-2176
Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed. A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV. Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity. 相似文献
156.
157.
158.
Drug repositioning applies established drugs to new disease indications with increasing success. A pre-requisite for drug repurposing is drug promiscuity (polypharmacology) – a drug’s ability to bind to several targets. There is a long standing debate on the reasons for drug promiscuity. Based on large compound screens, hydrophobicity and molecular weight have been suggested as key reasons. However, the results are sometimes contradictory and leave space for further analysis. Protein structures offer a structural dimension to explain promiscuity: Can a drug bind multiple targets because the drug is flexible or because the targets are structurally similar or even share similar binding sites? We present a systematic study of drug promiscuity based on structural data of PDB target proteins with a set of 164 promiscuous drugs. We show that there is no correlation between the degree of promiscuity and ligand properties such as hydrophobicity or molecular weight but a weak correlation to conformational flexibility. However, we do find a correlation between promiscuity and structural similarity as well as binding site similarity of protein targets. In particular, 71% of the drugs have at least two targets with similar binding sites. In order to overcome issues in detection of remotely similar binding sites, we employed a score for binding site similarity: LigandRMSD measures the similarity of the aligned ligands and uncovers remote local similarities in proteins. It can be applied to arbitrary structural binding site alignments. Three representative examples, namely the anti-cancer drug methotrexate, the natural product quercetin and the anti-diabetic drug acarbose are discussed in detail. Our findings suggest that global structural and binding site similarity play a more important role to explain the observed drug promiscuity in the PDB than physicochemical drug properties like hydrophobicity or molecular weight. Additionally, we find ligand flexibility to have a minor influence. 相似文献
159.
Magdalena Banas Katarzyna Zabieglo Gopinath Kasetty Monika Kapinska-Mrowiecka Julia Borowczyk Justyna Drukala Krzysztof Murzyn Brian A. Zabel Eugene C. Butcher Jens M. Schroeder Artur Schmidtchen Joanna Cichy 《PloS one》2013,8(3)
Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share similar tertiary structure with antibacterial cathelicidins. Recombinant chemerin has antimicrobial activity. Here we show that endogenous chemerin is abundant in human epidermis, and that inhibition of bacteria growth by exudates from organ cultures of primary human skin keratinocytes is largely chemerin-dependent. Using a panel of overlapping chemerin-derived synthetic peptides, we demonstrate that the antibacterial activity of chemerin is primarily mediated by Val66-Pro85, which causes direct bacterial lysis. Therefore, chemerin is an antimicrobial agent in human skin. 相似文献
160.
J. He S. Bhasin E.F. Binder K.E. Yarasheski C. Castaneda‐Sceppa E.T. Schroeder R. Roubenoff C.‐P. Chou S.P. Azen F.R. Sattler 《Obesity (Silver Spring, Md.)》2013,21(5):968-975