A venture into the epigenetics of aging and Alzheimer’s Disease

This dissertation examines the epigenetic factors involved in normal aging and the development of Alzheimer’s disease. Unlike genetic factors, epigenetic factors can be affected by various environmental influences and behavioural patterns such as physical and mental activity, diet, social interaction and stress. Therefore, these factors are thought to play an important role in the development of diseases that are not entirely genetic, such as the common sporadic form of Alzheimer’s disease. The results show that the development of Alzheimer’s disease is associated with other global and gene-specific epigenetic changes than those in normal aging, some of which are detectable in the brain and blood. The discovery of epigenetic indicators in blood prior to the development of dementia due to Alzheimer’s disease in particular may provide new opportunities for early diagnosis and treatment of this diseas

Seasonal changes in a sandy beach fish assemblage at Canto Grande, Santa Catarina, South Brazil

Copyright © 2004 Coastal Education and Research Foundation (CERF).Neste trabalho realizaramse amostragens, com uma rede de praia, de modo a estudar a comunidade de peixes de substrato arenoso na enseada de Canto Grande, Santa Catarina, Brasil. As amostragens realizaramse em intervalos de 3 horas durante períodos de 24 h, numa base bimensal, entre Abril de 1996 e Fevereiro de 1997. Verificouse existir uma variação sazonal no número de espécies, densidade de peixes e biomassa, tendo os valores mais elevados ocorrido em Fevereiro (38 espécies, 257.6 peixes 1000 mˉ², 2286.4 g 1000 mˉ²). Recolheuse um total de 67 espécies, pertencentes a 56 géneros e a 33 famílias, sendo a comunidade dominada por sete espécies pertencentes a três famílias: Atherinella brasiliensis (Atherinidae); Brevoortia pectinata, Harengula clupeola e Sardinella brasiliensis (Clupeidae); Anchoviella lepidontostole, Cetengraulis edentulus e Lycengraulis grossidens (Engraulidae). Tanto a diversidade de espécies (H′) como a equitabilidade (J′) foram médias a elevadas ao longo do ano devido à baixa dominância. A maior mudança na estrutura da comunidade ocorreu entre os meses de Inverno (Julho e Agosto) e as outras estações. Nenhuma das espécies dominantes pode ser classificada como residente. Os principais predadores foram Pomatomus saltator (Inverno) e Trichiurus lepturus (Verão). A maior parte das espécies observadas foram ou peixes juvenis ou espécies pelágicas de pequeno tamanho e fortemente gregárias.ABSTRACT: A shallow-water fish assemblage, over a soft, sandy bottom, at Canto Grande, Santa Catarina, Brazil, was sampled with a beach seine. Sampling was undertaken at 3 h intervals over 24 h on a bimonthly basis between April 1996 and February 1997. There was a seasonal variation in the number of species, density of fishes and biomass with the highest values in February (38 species, 257.6 fish 1000 mˉ², 2286.4 g 1000 mˉ²). A total of 67 species, belonging to 56 genera and 33 families were collected and the assemblage was dominated by seven species belonging to three families: Atherinella brasiliensis (Atherinidae); Brevoortia pectinata, Harengula clupeola and Sardinella brasiliensis (Clupeidae); Anchoviella lepidontostole, Cetengraulis edentulus and Lycengraulis grossidens (Engraulidae). Species diversity (H′) and equitability (J′) were medium to high throughout the year due to the low dominance. The largest change in the assemblage structure occurred between winter months (July and August) and the other seasons. None of the dominant species can be classified as a resident. Main predators were Pomatomus saltator (winter) and Trichiurus lepturus (summer). Most of the species observed were either juvenile fish or small pelagic and strongly gregarious species

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation

Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer:A Randomized Clinical Trial

PURPOSE:Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking.METHODS:Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior &lt;.0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality.RESULTS:Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior =.0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior =.0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P =.4940).CONCLUSION:On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.</p

Integrated DNA methylation analysis reveals a potential role for ANKRD30B in Williams syndrome

エピゲノム異常がウィリアムズ症候群に関わることを発⾒ --多彩な症状の原因を説明する⼿がかりに--. 京都大学プレスリリース. 2020-04-24.Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS

Age-related disturbances in DNA (hydroxy)methylation in APP/PS1 mice

Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer’s disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice

Age-related disturbances in DNA (hydroxy)methylation in APP/PS1 mice

Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer's disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice

Age-related Disturbances in DNA (hydroxy)methylation in APP/PS1 Mice.

Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer's disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice