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11.
Leung JY Bennett WR Herbert RP West AK Lee PR Wake H Fields RD Chuah MI Chung RS 《Cellular and molecular life sciences : CMLS》2012,69(5):809-817
Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of
a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating
regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal
root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT. The application
of MT led to a significant increase in regenerative sprouting of neurons 16 h after injury. We show that the pro-regenerative
effect of MT involves an interaction with the low-density lipoprotein receptor megalin, which could be blocked using the competitive
antagonist RAP. Pre-treatment with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 also completely abrogated
the effect of exogenous MT in promoting axonal outgrowth. Interestingly, we only observed megalin expression in neuronal soma
and not axons in the DRG explants. To investigate this matter, an in vitro injury model was established using Campenot chambers,
which allowed the application of MT selectively into either the axonal or cell body compartments after scratch injury was
performed to axons. At 16 h after injury, regenerating axons were significantly longer only when exogenous MT was applied
solely to the soma compartment, in accordance with the localized expression of megalin in neuronal cell bodies. This study
provides a clear indication that MT promotes axonal regeneration of DRG neurons, via a megalin- and MAPK-dependent mechanism. 相似文献
12.
Common variants in WFS1 confer risk of type 2 diabetes 总被引:10,自引:0,他引:10
Sandhu MS Weedon MN Fawcett KA Wasson J Debenham SL Daly A Lango H Frayling TM Neumann RJ Sherva R Blech I Pharoah PD Palmer CN Kimber C Tavendale R Morris AD McCarthy MI Walker M Hitman G Glaser B Permutt MA Hattersley AT Wareham NJ Barroso I 《Nature genetics》2007,39(8):951-953
We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes. 相似文献
13.
Eeles RA Kote-Jarai Z Giles GG Olama AA Guy M Jugurnauth SK Mulholland S Leongamornlert DA Edwards SM Morrison J Field HI Southey MC Severi G Donovan JL Hamdy FC Dearnaley DP Muir KR Smith C Bagnato M Ardern-Jones AT Hall AL O'Brien LT Gehr-Swain BN Wilkinson RA Cox A Lewis S Brown PM Jhavar SG Tymrakiewicz M Lophatananon A Bryant SL;UK Genetic Prostate Cancer Study Collaborators;British Association of Urological Surgeons' Section of Oncology;UK ProtecT Study Collaborators Horwich A Huddart RA 《Nature genetics》2008,40(3):316-321
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at =60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3. 相似文献
14.
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
15.
Recent spending cuts in the area of adult social care raise policy concerns about the proportion of older people whose need for social care is not being met. Such concerns are emphasised in the context of population ageing and other demographic changes. For example, the increasing proportion of the population aged 75 and over places greater pressure on formal and informal systems of care and support provision, while changes in the living arrangements of older people may affect the supply of informal care within the household. This article explores the concept of 'unmet need' for support in relation to specific Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs), using data on the receipt of support (informal, formal state or formal paid) from the General Household Survey, the English Longitudinal Study of Ageing and the British Household Panel Survey. The results show that different kinds of need tend to be supported by particular sources of care, and that there is a significant level of 'unmet need' for certain activities. 相似文献