全文获取类型
收费全文 | 135篇 |
免费 | 1篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 1篇 |
理论与方法论 | 2篇 |
现状及发展 | 40篇 |
研究方法 | 22篇 |
综合类 | 68篇 |
自然研究 | 4篇 |
出版年
2024年 | 1篇 |
2021年 | 1篇 |
2020年 | 1篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 4篇 |
2016年 | 5篇 |
2015年 | 1篇 |
2014年 | 4篇 |
2013年 | 5篇 |
2012年 | 14篇 |
2011年 | 20篇 |
2010年 | 5篇 |
2009年 | 4篇 |
2008年 | 9篇 |
2007年 | 13篇 |
2006年 | 8篇 |
2005年 | 10篇 |
2004年 | 9篇 |
2003年 | 7篇 |
2002年 | 5篇 |
1981年 | 2篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有137条查询结果,搜索用时 0 毫秒
61.
Crasta K Ganem NJ Dagher R Lantermann AB Ivanova EV Pan Y Nezi L Protopopov A Chowdhury D Pellman D 《Nature》2012,482(7383):53-58
The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement. 相似文献
62.
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups 总被引:1,自引:0,他引:1
Curtis C Shah SP Chin SF Turashvili G Rueda OM Dunning MJ Speed D Lynch AG Samarajiwa S Yuan Y Gräf S Ha G Haffari G Bashashati A Russell R McKinney S;METABRIC Group Langerød A Green A Provenzano E Wishart G Pinder S Watson P Markowetz F Murphy L Ellis I Purushotham A Børresen-Dale AL Brenton JD Tavaré S Caldas C Aparicio S 《Nature》2012,486(7403):346-352
63.
Berger MF Hodis E Heffernan TP Deribe YL Lawrence MS Protopopov A Ivanova E Watson IR Nickerson E Ghosh P Zhang H Zeid R Ren X Cibulskis K Sivachenko AY Wagle N Sucker A Sougnez C Onofrio R Ambrogio L Auclair D Fennell T Carter SL Drier Y Stojanov P Singer MA Voet D Jing R Saksena G Barretina J Ramos AH Pugh TJ Stransky N Parkin M Winckler W Mahan S Ardlie K Baldwin J Wargo J Schadendorf D Meyerson M Gabriel SB Golub TR Wagner SN Lander ES Getz G Chin L Garraway LA 《Nature》2012,485(7399):502-506
Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma. 相似文献
64.
Summary Amantadine, like amphetamine, exerts a depletory effect upon noradrenaline containing vesicles of the adrenal medulla. The microtubular system seems to play a role in the releasing process.The authors want to thank Dr. Diaz-Flores Feo for his help and advice in the accomplishment of this study. 相似文献
65.
The human APOBEC3G (apolipoprotein B messenger-RNA-editing enzyme, catalytic polypeptide-like 3G) protein is a single-strand DNA deaminase that inhibits the replication of human immunodeficiency virus-1 (HIV-1), other retroviruses and retrotransposons. APOBEC3G anti-viral activity is circumvented by most retroelements, such as through degradation by HIV-1 Vif. APOBEC3G is a member of a family of polynucleotide cytosine deaminases, several of which also target distinct physiological substrates. For instance, APOBEC1 edits APOB mRNA and AID deaminates antibody gene DNA. Although structures of other family members exist, none of these proteins has elicited polynucleotide cytosine deaminase or anti-viral activity. Here we report a solution structure of the human APOBEC3G catalytic domain. Five alpha-helices, including two that form the zinc-coordinating active site, are arranged over a hydrophobic platform consisting of five beta-strands. NMR DNA titration experiments, computational modelling, phylogenetic conservation and Escherichia coli-based activity assays combine to suggest a DNA-binding model in which a brim of positively charged residues positions the target cytosine for catalysis. The structure of the APOBEC3G catalytic domain will help us to understand functions of other family members and interactions that occur with pathogenic proteins such as HIV-1 Vif. 相似文献
66.
67.
Elena Rapizzi Maria Letizia Taddei Tania Fiaschi Chiara Donati Paola Bruni Paola Chiarugi 《Cellular and molecular life sciences : CMLS》2009,66(19):3207-3218
Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts through a family of G-protein-coupled receptors. Herein, we report
evidence of a novel redox-based cross-talk between S1P and insulin signaling pathways. In skeletal muscle cells S1P, through
engagement of its S1P2 receptor, is found to produce a transient burst of reactive oxygen species through a calcium-dependent activation of the
small GTPase Rac1. S1P-induced redox-signaling is sensed by protein tyrosine phosphatase-1B, the main negative regulator of
insulin receptor phosphorylation, which undergoes oxidation and enzymatic inhibition. This redox-based inhibition of the phosphatase
provokes a ligand-independent trans-phosphorylation of insulin receptor and a strong increase in glucose uptake. Our results propose a new role of S1P, recognizing
the lipid as an insulin-mimetic cue and pointing at reactive oxygen species as critical regulators of the cross-talk between
S1P and insulin pathways. Any possible implication of S1P-directed insulin signaling in diabetes and insulin resistance remains
to be established. 相似文献
68.
69.
McDermott-Roe C Ye J Ahmed R Sun XM Serafín A Ware J Bottolo L Muckett P Cañas X Zhang J Rowe GC Buchan R Lu H Braithwaite A Mancini M Hauton D Martí R García-Arumí E Hubner N Jacob H Serikawa T Zidek V Papousek F Kolar F Cardona M Ruiz-Meana M García-Dorado D Comella JX Felkin LE Barton PJ Arany Z Pravenec M Petretto E Sanchis D Cook SA 《Nature》2011,478(7367):114-118
Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy. 相似文献
70.
Yusa K Rashid ST Strick-Marchand H Varela I Liu PQ Paschon DE Miranda E Ordóñez A Hannan NR Rouhani FJ Darche S Alexander G Marciniak SJ Fusaki N Hasegawa M Holmes MC Di Santo JP Lomas DA Bradley A Vallier L 《Nature》2011,478(7369):391-394
Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies. 相似文献