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281.
Highly efficient endogenous human gene correction using designed zinc-finger nucleases 总被引:4,自引:0,他引:4
Urnov FD Miller JC Lee YL Beausejour CM Rock JM Augustus S Jamieson AC Porteus MH Gregory PD Holmes MC 《Nature》2005,435(7042):646-651
Permanent modification of the human genome in vivo is impractical owing to the low frequency of homologous recombination in human cells, a fact that hampers biomedical research and progress towards safe and effective gene therapy. Here we report a general solution using two fundamental biological processes: DNA recognition by C2H2 zinc-finger proteins and homology-directed repair of DNA double-strand breaks. Zinc-finger proteins engineered to recognize a unique chromosomal site can be fused to a nuclease domain, and a double-strand break induced by the resulting zinc-finger nuclease can create specific sequence alterations by stimulating homologous recombination between the chromosome and an extrachromosomal DNA donor. We show that zinc-finger nucleases designed against an X-linked severe combined immune deficiency (SCID) mutation in the IL2Rgamma gene yielded more than 18% gene-modified human cells without selection. Remarkably, about 7% of the cells acquired the desired genetic modification on both X chromosomes, with cell genotype accurately reflected at the messenger RNA and protein levels. We observe comparably high frequencies in human T cells, raising the possibility of strategies based on zinc-finger nucleases for the treatment of disease. 相似文献
282.
Meyre D Bouatia-Naji N Tounian A Samson C Lecoeur C Vatin V Ghoussaini M Wachter C Hercberg S Charpentier G Patsch W Pattou F Charles MA Tounian P Clément K Jouret B Weill J Maddux BA Goldfine ID Walley A Boutin P Dina C Froguel P 《Nature genetics》2005,37(8):863-867
We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions. 相似文献
283.
Churchill GA Airey DC Allayee H Angel JM Attie AD Beatty J Beavis WD Belknap JK Bennett B Berrettini W Bleich A Bogue M Broman KW Buck KJ Buckler E Burmeister M Chesler EJ Cheverud JM Clapcote S Cook MN Cox RD Crabbe JC Crusio WE Darvasi A Deschepper CF Doerge RW Farber CR Forejt J Gaile D Garlow SJ Geiger H Gershenfeld H Gordon T Gu J Gu W de Haan G Hayes NL Heller C Himmelbauer H Hitzemann R Hunter K Hsu HC Iraqi FA Ivandic B Jacob HJ Jansen RC Jepsen KJ Johnson DK Johnson TE Kempermann G 《Nature genetics》2004,36(11):1133-1137
The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease. 相似文献
284.
285.
Nykjaer A Lee R Teng KK Jansen P Madsen P Nielsen MS Jacobsen C Kliemannel M Schwarz E Willnow TE Hempstead BL Petersen CM 《Nature》2004,427(6977):843-848
Sortilin (approximately 95 kDa) is a member of the recently discovered family of Vps10p-domain receptors, and is expressed in a variety of tissues, notably brain, spinal cord and muscle. It acts as a receptor for neurotensin, but predominates in regions of the nervous system that neither synthesize nor respond to this neuropeptide, suggesting that sortilin has additional roles. Sortilin is expressed during embryogenesis in areas where nerve growth factor (NGF) and its precursor, proNGF, have well-characterized effects. These neurotrophins can be released by neuronal tissues, and they regulate neuronal development through cell survival and cell death signalling. NGF regulates cell survival and cell death via binding to two different receptors, TrkA and p75NTR (ref. 10). In contrast, proNGF selectively induces apoptosis through p75NTR but not TrkA. However, not all p75NTR-expressing cells respond to proNGF, suggesting that additional membrane proteins are required for the induction of cell death. Here we report that proNGF creates a signalling complex by simultaneously binding to p75NTR and sortilin. Thus sortilin acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF. 相似文献
286.
Söllner C Rauch GJ Siemens J Geisler R Schuster SC Müller U Nicolson T;Tübingen Screen Consortium 《Nature》2004,428(6986):955-959
Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (cdh23). Mutations in Cdh23 also cause deafness and vestibular defects in mice and humans, and the protein is present in hair bundles. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputnik(tc317e) larvae. Moreover, tip links are absent in larvae carrying weak alleles of cdh23 that affect mechanotransduction but not hair bundle integrity. We conclude that Cdh23 is an essential tip link component required for hair-cell mechanotransduction. 相似文献
287.
Structure of the signal recognition particle interacting with the elongation-arrested ribosome 总被引:1,自引:0,他引:1
Cotranslational translocation of proteins across or into membranes is a vital process in all kingdoms of life. It requires that the translating ribosome be targeted to the membrane by the signal recognition particle (SRP), an evolutionarily conserved ribonucleoprotein particle. SRP recognizes signal sequences of nascent protein chains emerging from the ribosome. Subsequent binding of SRP leads to a pause in peptide elongation and to the ribosome docking to the membrane-bound SRP receptor. Here we present the structure of a targeting complex consisting of mammalian SRP bound to an active 80S ribosome carrying a signal sequence. This structure, solved to 12 A by cryo-electron microscopy, enables us to generate a molecular model of SRP in its functional conformation. The model shows how the S domain of SRP contacts the large ribosomal subunit at the nascent chain exit site to bind the signal sequence, and that the Alu domain reaches into the elongation-factor-binding site of the ribosome, explaining its elongation arrest activity. 相似文献
288.
通常将科学家描绘为知识渊博之人,这种想法是有一定道理的.为了胜任科学研究,你至少得接受某一门科学的专项训练,数学、物理学、化学或者生物学.事实上,大多数时候,通常还需要学习更多学科的知识、接受多方面的锻炼.此外,你得对自己的专业领域有真切的了解,特别是应当清楚同行正在做什么.当然,成为科学家所应知道的远远不止这些.但是,"无所不知"并非成为科学家的充分条件--正如名画收藏者并不必然是艺术家一样.衡量科学家的真正标准,是看其能否产生新的知识,或者更准确而言,看其是否具有从事科学所需的理解力.因为,科学的使命正在于理解世界. 相似文献
289.
290.
Christian Hennig 《Journal of Classification》2002,19(2):249-276
In this paper an
algorithm is developed, which aims to find all FPCs of a dataset corresponding
to well separated linear regression subpopulations. Its ability to find such
subpopulations under the occurence of outliers is compared to methods based on
ML-estimation of mixture models by means of a simulation study. Furthermore,
FPC analysis is applied to a real dataset. 相似文献