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排序方式: 共有611条查询结果,搜索用时 15 毫秒
471.
GoDARTS UKPDS Diabetes Pharmacogenetics Study Group;Wellcome Trust Case Control Consortium Zhou K Bellenguez C Spencer CC Bennett AJ Coleman RL Tavendale R Hawley SA Donnelly LA Schofield C Groves CJ Burch L Carr F Strange A Freeman C Blackwell JM Bramon E Brown MA Casas JP Corvin A Craddock N Deloukas P Dronov S Duncanson A Edkins S Gray E Hunt S Jankowski J Langford C Markus HS Mathew CG Plomin R Rautanen A Sawcer SJ Samani NJ Trembath R Viswanathan AC Wood NW;MAGIC investigators 《Nature genetics》2011,43(2):117-120
Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. 相似文献
472.
Hollingworth P Harold D Sims R Gerrish A Lambert JC Carrasquillo MM Abraham R Hamshere ML Pahwa JS Moskvina V Dowzell K Jones N Stretton A Thomas C Richards A Ivanov D Widdowson C Chapman J Lovestone S Powell J Proitsi P Lupton MK Brayne C Rubinsztein DC Gill M Lawlor B Lynch A Brown KS Passmore PA Craig D McGuinness B Todd S Holmes C Mann D Smith AD Beaumont H Warden D Wilcock G Love S Kehoe PG Hooper NM Vardy ER Hardy J Mead S Fox NC Rossor M Collinge J Maier W Jessen F Rüther E Schürmann B 《Nature genetics》2011,43(5):429-435
We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)). 相似文献
473.
Stein JL Medland SE Vasquez AA Hibar DP Senstad RE Winkler AM Toro R Appel K Bartecek R Bergmann Ø Bernard M Brown AA Cannon DM Chakravarty MM Christoforou A Domin M Grimm O Hollinshead M Holmes AJ Homuth G Hottenga JJ Langan C Lopez LM Hansell NK Hwang KS Kim S Laje G Lee PH Liu X Loth E Lourdusamy A Mattingsdal M Mohnke S Maniega SM Nho K Nugent AC O'Brien C Papmeyer M Pütz B Ramasamy A Rasmussen J Rijpkema M Risacher SL Roddey JC Rose EJ Ryten M Shen L Sprooten E Strengman E Teumer A 《Nature genetics》2012,44(5):552-561
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)). 相似文献
474.
KE Holt S Baker FX Weill EC Holmes A Kitchen J Yu V Sangal DJ Brown JE Coia DW Kim SY Choi SH Kim WD da Silveira DJ Pickard JJ Farrar J Parkhill G Dougan NR Thomson 《Nature genetics》2012,44(9):1056-1059
Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery, spreading efficiently via low-dose fecal-oral transmission. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries but is now emerging as a problem in the developing world, seeming to replace the more diverse Shigella flexneri in areas undergoing economic development and improvements in water quality. Classical approaches have shown that S. sonnei is genetically conserved and clonal. We report here whole-genome sequencing of 132 globally distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and that diversified into several distinct lineages with unique characteristics. Our analysis suggests that the majority of this diversification occurred in Europe and was followed by more recent establishment of local pathogen populations on other continents, predominantly due to the pandemic spread of a single, rapidly evolving, multidrug-resistant lineage. 相似文献
475.
476.
477.
Cheema U Brown RA Alp B MacRobert AJ 《Cellular and molecular life sciences : CMLS》2008,65(1):177-186
Tissue hypoxia results in rapid angiogenesis in vivo, triggered by angiogenic proteins, including vascular endothelial growth factor (VEGF). Current views of tissue viability
are founded on whether ‘deeper-lying’ cells receive sufficient nutrients and oxygen for normal activity and ultimately survival.
For intact tissues, levels of such essential nutrients are governed by micro-vascular perfusion. However, there have been
few effective quantitatively defined 3D models, which enable testing of the interplay or interdependence of matrix and cell
density, and path diffusion on oxygen consumption in vitro. As a result, concepts on cell vulnerability to low oxygen levels, together with the nature of cellular responses are ill
defined. The present study has adapted a novel, optical fibre-based system for in situ, real-time oxygen monitoring within three-dimensionally-spiralled cellular collagen constructs, which were then unfurled
to enable quantitative, spatial measurements of VEGF production in different parts of the same construct exposed to different
oxygen levels. A VEGF response was elicited by cells exposed to low oxygen levels (20 mmHg), primarily within the construct
core.
Received 3 August 2007; received after revision 24 October 2007; accepted 29 October 2007
An erratum to this article is available at . 相似文献
478.
A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva 总被引:5,自引:0,他引:5
Shore EM Xu M Feldman GJ Fenstermacher DA Cho TJ Choi IH Connor JM Delai P Glaser DL LeMerrer M Morhart R Rogers JG Smith R Triffitt JT Urtizberea JA Zasloff M Brown MA Kaplan FS 《Nature genetics》2006,38(5):525-527
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP. 相似文献
479.
High mutation rates have driven extensive structural polymorphism among human Y chromosomes 总被引:15,自引:0,他引:15
Repping S van Daalen SK Brown LG Korver CM Lange J Marszalek JD Pyntikova T van der Veen F Skaletsky H Page DC Rozen S 《Nature genetics》2006,38(4):463-467
Although much structural polymorphism in the human genome has been catalogued, the kinetics of underlying change remain largely unexplored. Because human Y chromosomes are clonally inherited, it has been possible to capture their detailed relationships in a robust, worldwide genealogical tree. Examination of structural variation across this tree opens avenues for investigating rates of underlying mutations. We selected one Y chromosome from each of 47 branches of this tree and searched for large-scale variation. Four chromosomal regions showed extensive variation resulting from numerous large-scale mutations. Within the tree encompassed by the studied chromosomes, the distal-Yq heterochromatin changed length > or = 12 times, the TSPY gene array changed length > or = 23 times, the 3.6-Mb IR3/IR3 region changed orientation > or = 12 times and the AZFc region was rearranged > or = 20 times. After determining the total time spanned by all branches of this tree (approximately 1.3 million years or 52,000 generations), we converted these mutation counts to lower bounds on rates: > or = 2.3 x 10(-4), > or = 4.4 x 10(-4), > or = 2.3 x 10(-4) and > or = 3.8 x 10(-4) large-scale mutations per father-to-son Y transmission, respectively. Thus, high mutation rates have driven extensive structural polymorphism among human Y chromosomes. At the same time, we found limited variation in the copy number of Y-linked genes, which raises the possibility of selective constraints. 相似文献
480.
Harvey R. Brown Jos Uffink 《Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics》2001,32(4):525-538
This paper investigates what the source of time asymmetry is in thermodynamics, and comments on the question whether a time-symmetric formulation of the Second Law is possible. 相似文献