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Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia. 相似文献
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Milne JC Lambert PD Schenk S Carney DP Smith JJ Gagne DJ Jin L Boss O Perni RB Vu CB Bemis JE Xie R Disch JS Ng PY Nunes JJ Lynch AV Yang H Galonek H Israelian K Choy W Iffland A Lavu S Medvedik O Sinclair DA Olefsky JM Jirousek MR Elliott PJ Westphal CH 《Nature》2007,450(7170):712-716
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes. 相似文献
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Regenerating functional heart tissue for myocardial repair 总被引:1,自引:1,他引:0
Alcon A Cagavi Bozkulak E Qyang Y 《Cellular and molecular life sciences : CMLS》2012,69(16):2635-2656
Heart disease is one of the leading causes of death worldwide and the number of patients with the disease is likely to grow with the continual decline in health for most of the developed world. Heart transplantation is one of the only treatment options for heart failure due to an acute myocardial infarction, but limited donor supply and organ rejection limit its widespread use. Cellular cardiomyoplasty, or cellular implantation, combined with various tissue-engineering methods aims to regenerate functional heart tissue. This review highlights the numerous cell sources that have been used to regenerate the heart as well as cover the wide range of tissue-engineering strategies that have been devised to optimize the delivery of these cells. It will probably be a long time before an effective regenerative therapy can make a serious impact at the bedside. 相似文献
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RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing 总被引:10,自引:0,他引:10
Noma K Sugiyama T Cam H Verdel A Zofall M Jia S Moazed D Grewal SI 《Nature genetics》2004,36(11):1174-1180
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Freedman ML Reich D Penney KL McDonald GJ Mignault AA Patterson N Gabriel SB Topol EJ Smoller JW Pato CN Pato MT Petryshen TL Kolonel LN Lander ES Sklar P Henderson B Hirschhorn JN Altshuler D 《Nature genetics》2004,36(4):388-393
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies. 相似文献
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Block BA Teo SL Walli A Boustany A Stokesbury MJ Farwell CJ Weng KC Dewar H Williams TD 《Nature》2005,434(7037):1121-1127
Electronic tags that archive or transmit stored data to satellites have advanced the mapping of habitats used by highly migratory fish in pelagic ecosystems. Here we report on the electronic tagging of 772 Atlantic bluefin tuna in the western Atlantic Ocean in an effort to identify population structure. Reporting electronic tags provided accurate location data that show the extensive migrations of individual fish (n = 330). Geoposition data delineate two populations, one using spawning grounds in the Gulf of Mexico and another from the Mediterranean Sea. Transatlantic movements of western-tagged bluefin tuna reveal site fidelity to known spawning areas in the Mediterranean Sea. Bluefin tuna that occupy western spawning grounds move to central and eastern Atlantic foraging grounds. Our results are consistent with two populations of bluefin tuna with distinct spawning areas that overlap on North Atlantic foraging grounds. Electronic tagging locations, when combined with US pelagic longline observer and logbook catch data, identify hot spots for spawning bluefin tuna in the northern slope waters of the Gulf of Mexico. Restrictions on the time and area where longlining occurs would reduce incidental catch mortalities on western spawning grounds. 相似文献
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Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma 总被引:3,自引:0,他引:3
Schwartzentruber J Korshunov A Liu XY Jones DT Pfaff E Jacob K Sturm D Fontebasso AM Quang DA Tönjes M Hovestadt V Albrecht S Kool M Nantel A Konermann C Lindroth A Jäger N Rausch T Ryzhova M Korbel JO Hielscher T Hauser P Garami M Klekner A Bognar L Ebinger M Schuhmann MU Scheurlen W Pekrun A Frühwald MC Roggendorf W Kramm C Dürken M Atkinson J Lepage P Montpetit A Zakrzewska M Zakrzewski K Liberski PP Dong Z Siegel P Kulozik AE Zapatka M Guha A Malkin D Felsberg J Reifenberger G 《Nature》2012,482(7384):226-231
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis. 相似文献
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Defects in whirlin,a PDZ domain molecule involved in stereocilia elongation,cause deafness in the whirler mouse and families with DFNB31 总被引:22,自引:0,他引:22
Mburu P Mustapha M Varela A Weil D El-Amraoui A Holme RH Rump A Hardisty RE Blanchard S Coimbra RS Perfettini I Parkinson N Mallon AM Glenister P Rogers MJ Paige AJ Moir L Clay J Rosenthal A Liu XZ Blanco G Steel KP Petit C Brown SD 《Nature genetics》2003,34(4):421-428
The whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain-containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia. 相似文献
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Ellinghaus E Ellinghaus D Stuart PE Nair RP Debrus S Raelson JV Belouchi M Fournier H Reinhard C Ding J Li Y Tejasvi T Gudjonsson J Stoll SW Voorhees JJ Lambert S Weidinger S Eberlein B Kunz M Rahman P Gladman DD Gieger C Wichmann HE Karlsen TH Mayr G Albrecht M Kabelitz D Mrowietz U Abecasis GR Elder JT Schreiber S Weichenthal M Franke A 《Nature genetics》2010,42(11):991-995