全文获取类型
收费全文 | 634篇 |
免费 | 0篇 |
国内免费 | 8篇 |
专业分类
系统科学 | 6篇 |
教育与普及 | 1篇 |
理论与方法论 | 4篇 |
现状及发展 | 62篇 |
研究方法 | 137篇 |
综合类 | 401篇 |
自然研究 | 31篇 |
出版年
2021年 | 3篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 4篇 |
2017年 | 10篇 |
2016年 | 6篇 |
2015年 | 7篇 |
2014年 | 8篇 |
2013年 | 9篇 |
2012年 | 58篇 |
2011年 | 103篇 |
2010年 | 23篇 |
2009年 | 7篇 |
2008年 | 58篇 |
2007年 | 67篇 |
2006年 | 46篇 |
2005年 | 61篇 |
2004年 | 50篇 |
2003年 | 41篇 |
2002年 | 42篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1998年 | 1篇 |
1997年 | 3篇 |
1995年 | 2篇 |
1992年 | 4篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1980年 | 1篇 |
1978年 | 5篇 |
1975年 | 1篇 |
1970年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有642条查询结果,搜索用时 0 毫秒
521.
522.
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo 总被引:73,自引:0,他引:73
Walsh DM Klyubin I Fadeeva JV Cullen WK Anwyl R Wolfe MS Rowan MJ Selkoe DJ 《Nature》2002,416(6880):535-539
Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically. 相似文献
523.
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation 总被引:104,自引:0,他引:104
The ATM protein kinase, mutations of which are associated with the human disease ataxia-telangiectasia, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described 'FAT' domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation, and our data indicate that ATM activation is not dependent on direct binding to DNA strand breaks, but may result from changes in the structure of chromatin. 相似文献
524.
Adrianto I Wen F Templeton A Wiley G King JB Lessard CJ Bates JS Hu Y Kelly JA Kaufman KM Guthridge JM Alarcón-Riquelme ME;BIOLUPUS GENLES Networks Anaya JM Bae SC Bang SY Boackle SA Brown EE Petri MA Gallant C Ramsey-Goldman R Reveille JD Vila LM Criswell LA Edberg JC Freedman BI Gregersen PK Gilkeson GS Jacob CO James JA Kamen DL Kimberly RP Martin J Merrill JT Niewold TB Park SY Pons-Estel BA Scofield RH Stevens AM Tsao BP Vyse TJ Langefeld CD Harley JB Moser KL Webb CF Humphrey MB 《Nature genetics》2011,43(3):253-258
Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE. 相似文献
525.
Lindström S Vachon CM Li J Varghese J Thompson D Warren R Brown J Leyland J Audley T Wareham NJ Loos RJ Paterson AD Rommens J Waggott D Martin LJ Scott CG Pankratz VS Hankinson SE Hazra A Hunter DJ Hopper JL Southey MC Chanock SJ Silva Idos S Liu J Eriksson L Couch FJ Stone J Apicella C Czene K Kraft P Hall P Easton DF Boyd NF Tamimi RM 《Nature genetics》2011,43(3):185-187
High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 × 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer. 相似文献
526.
The genome of the mesopolyploid crop species Brassica rapa 总被引:21,自引:0,他引:21
Wang X Wang H Wang J Sun R Wu J Liu S Bai Y Mun JH Bancroft I Cheng F Huang S Li X Hua W Wang J Wang X Freeling M Pires JC Paterson AH Chalhoub B Wang B Hayward A Sharpe AG Park BS Weisshaar B Liu B Li B Liu B Tong C Song C Duran C Peng C Geng C Koh C Lin C Edwards D Mu D Shen D Soumpourou E Li F Fraser F Conant G Lassalle G King GJ Bonnema G Tang H Wang H Belcram H Zhou H Hirakawa H Abe H Guo H Wang H Jin H Parkin IA Batley J Kim JS Just J Li J Xu J Deng J Kim JA Li J Yu J Meng J Wang J Min J 《Nature genetics》2011,43(10):1035-1039
We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops. 相似文献
527.
Putoux A Thomas S Coene KL Davis EE Alanay Y Ogur G Uz E Buzas D Gomes C Patrier S Bennett CL Elkhartoufi N Frison MH Rigonnot L Joyé N Pruvost S Utine GE Boduroglu K Nitschke P Fertitta L Thauvin-Robinet C Munnich A Cormier-Daire V Hennekam R Colin E Akarsu NA Bole-Feysot C Cagnard N Schmitt A Goudin N Lyonnet S Encha-Razavi F Siffroi JP Winey M Katsanis N Gonzales M Vekemans M Beales PL Attié-Bitach T 《Nature genetics》2011,43(6):601-606
528.
Soler Artigas M Loth DW Wain LV Gharib SA Obeidat M Tang W Zhai G Zhao JH Smith AV Huffman JE Albrecht E Jackson CM Evans DM Cadby G Fornage M Manichaikul A Lopez LM Johnson T Aldrich MC Aspelund T Barroso I Campbell H Cassano PA Couper DJ Eiriksdottir G Franceschini N Garcia M Gieger C Gislason GK Grkovic I Hammond CJ Hancock DB Harris TB Ramasamy A Heckbert SR Heliövaara M Homuth G Hysi PG James AL Jankovic S Joubert BR Karrasch S Klopp N Koch B Kritchevsky SB Launer LJ Liu Y Loehr LR 《Nature genetics》2011,43(11):1082-1090
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. 相似文献
529.
Helgadottir A Thorleifsson G Magnusson KP Grétarsdottir S Steinthorsdottir V Manolescu A Jones GT Rinkel GJ Blankensteijn JD Ronkainen A Jääskeläinen JE Kyo Y Lenk GM Sakalihasan N Kostulas K Gottsäter A Flex A Stefansson H Hansen T Andersen G Weinsheimer S Borch-Johnsen K Jorgensen T Shah SH Quyyumi AA Granger CB Reilly MP Austin H Levey AI Vaccarino V Palsdottir E Walters GB Jonsdottir T Snorradottir S Magnusdottir D Gudmundsson G Ferrell RE Sveinbjornsdottir S Hernesniemi J Niemelä M Limet R 《Nature genetics》2008,40(2):217-224
Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases. 相似文献
530.
Haiman CA Garcia RR Kolonel LN Henderson BE Wu AH Le Marchand L 《Nature genetics》2008,40(3):259-60; author reply 260-1