65 research outputs found
Detection of icaAD gene and biofilm formation in Staphylococcus aureus isolates from wound infections
Get PDFWound infections are a common cause of staphylococcal infections. An ability of S.aureus is to adhere and form biofilm on host surfaces. Biofilm is an exopolysaccharide, a slime matrix around multiple layers of cells and is mediated by expression of the icaADBC operon. The present study evaluated the biofilm forming capacity and the presence of icaAD gene among S.aureus isolated from wound infections. Slime production assay was performed by cultivation on Congo Red Agar plate. In addition, Quantitative biofilm formation determined by microtiter plate assay PCR method used for detection of icaAD gene. Fifty strains were identified, 54 of the isolates produced black colonies on CRA plate, 52 were positive biofilm forming, and all strains carried the icaAD gene. Regarding the ability of Saureus to form biofifms helps the bacterium to survive hostile environments within the host, suggests that biofilm production is a risk factor for infection. It is important in rapid diagnosis and treatment biofilm forming strains, because biofilm formation may lead to increased antimicrobial resistance and create a significant impediment to wound healing
Peripheral DNA methylation, cognitive decline and brain ageing: Pilot findings from the Whitehall II Imaging Study
Get PDFBackground DNA methylation (DNAm) has been linked with the pathophysiology of brain aging, cognitive impairment and dementia. Methods The present study investigated the association between blood genome-wide DNAm profiles, cognitive dysfunction and brain magnetic resonance imaging (MRI) measures in 48 participants of the Whitehall II imaging sub-study. Results We identified eight differentially methylated regions (DMRs) associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to beta-amyloid processing and glutamatergic signalling Conclusion Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging
Applying Digital Spatial Profiling of the Transcriptome to Elucidate Disease Mechanisms of Psychosis in Alzheimer’s disease
Get PDFBackground:
Psychosis occurs in 30-40% of individuals with AD. New insights into disease mechanisms may lead to novel pharmacological targets and treatments. Previous studies have focused on bulk tissue analysis with limited results. Digital spatial profiling (DSP) is a new technique for spatial analysis of RNA or proteins in fixed tissue. It allows quantitative profiling with spatial complexity to be collected from samples in a non-destructive manner. In this pilot study we used DSP to compare whole transcriptome data in amyloid beta and non-amyloid beta regions in participants with and without psychosis (AD+P; AD-P).
Method:
Six post-mortem brain samples from prefrontal cortex were provided by the Kings College London Brains for Dementia Research (BDR) brain bank. Frozen and formalin fixed, paraffin embedded (FFPE) sections were supplied in order to test the platform on each type. Psychosis positive and negative groups were selected based on Neuropsychiatric Inventory (NPI) assessments. Samples were hematoxylin and eosin (H&E) stained as well as stained with fluorescent antibodies for AT8, NeuN, SYTO13 and Aβ. Regions of interest (ROIs) are selected based on morphology markers and tissue morphology (see Figure 1 for Amyloid ROI selection).
Result:
H&E staining revealed the frozen samples to be too badly degraded so the analysis was conducted on FFPE sections. AT8 staining showed widespread tau pathology to the extent that it was not possible to confidently select non-tau ROIs. Analysis of Aβ plaque containing and Aβ plaque free regions, comparing AD+P and AD-P groups, found 314 differentially expressed genes in plaque free regions, and 172 differentially expressed genes in plaque containing regions (Figure 2). Of these 172 genes, 28 were not differentially expressed in plaque free regions, forming a plaque-specific signature of genes differentially expressed in AD+P.
Conclusion:
This pilot study demonstrates the potential of the NanoString GeoMx™ DSP platform as an innovative spatial transcriptomics methodology for investigating AD+P with the potential to uncover differentially expressed genes that may be missed by bulk RNA sequencing studies. FFPE sections appear to be optimal. Analysing earlier stage disease and more sections per subject may help with better differentiation of tau and non-tau ROIs
Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder
Get PDFIn order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD
Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons
Get PDFInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases
Epigenetic insights into neuropsychiatric and cognitive symptoms in Parkinson’s disease: A DNA co-methylation network analysis
Get PDFData availability:
DNA methylation data used in this study was provided for the study by the authors of a previous publication45. It is available via figshare https://doi.org/10.17035/cardiff.27195645.v1. Data used in the preparation of this article were obtained on 1st June 2020 from the Parkinson’s Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. This analysis used data openly available from PPMI. For up-to-date information on the study, visit http://www.ppmi-info.org.Code availability:
All codes are available at https://github.com/JoshHarveyGit/PD_TraitNetworkAnalysis.Supplementary information is available online at: https://www.nature.com/articles/s41531-025-00877-5#Sec18 .Parkinson’s disease is a highly heterogeneous disorder, encompassing a complex spectrum of clinical presentation including motor, sleep, cognitive and neuropsychiatric symptoms. We aimed to investigate genome-wide DNA methylation networks in post-mortem Parkinson’s disease brain samples and test for region-specific association with common neuropsychiatric and cognitive symptoms. Of traits tested, we identify a co-methylation module in the substantia nigra with significant correlation to depressive symptoms. Notably, expression of the genes annotated to the methylation loci present within this module are found to be significantly enriched in neuronal subtypes within the substantia nigra. These findings highlight the potential involvement of neuronal-specific changes within the substantia nigra with regards to depressive symptoms in Parkinson’s disease.This work was funded by research grants from the Medical Research Council (MRC (MR/S011625/1), the National Institute of Aging (NIA) of the National Institutes of Health (NIH) (R01AG067015), BRACE and the Charles Wolfson Charitable Trust to KL and from Parkinson’s UK (Project Grants G-1309 and G-1502) to NW. This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre
An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene
Get PDFThis is the final version. Available from the publisher via the DOI in this record.A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.Alzheimer's Society, United KingdomMedical Research Council (MRC)NIH, United States, R01 grantAlzheimer's Research U
Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder
Get PDFIn order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD
Co-methylation network analysis of Psychosis in Alzheimer’s disease
Get PDFBackground: Psychosis (broadly delusions and hallucinations) has a cumulative disease prevalence of around 40% in Alzheimer’s disease (AD). The epigenomic, genomic, and neuropathological data provide powerful evidence that AD+P has a distinct neurobiological profile. Here, we used the weighted gene co-expression network analysis (WGCNA) method to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 153 post-mortem brain samples. Method: Our primary analysis focused on applying WGCNA to the PITT-ADRC cohort, followed by subsequent replication of its findings in the BDR cohort. The genotype data from PITT-ADRC and the WGCNA results were further utilized to identify the most significant methylation Quantitative Trait Loci (mQTLs) associated with psychosis. Subsequently, we explored RNA sequencing data from PITT-ADRC to identify genes affected by the replicated findings uncovered in our primary analysis. Result: We identified five AD+P-related modules in the PITT-ADRC cohort, with one of them being replicated in the BDR cohort. This replicated AD+P-related module exhibits a high enrichment in the T cell receptor signalling pathway. According to the colocalization analysis results, this module shares significant SNPs in some regions that are also significantly associated with Schizophrenia and Educational Attainment. Conclusion: Understanding molecular differences between AD and Psychosis at the genetic and epigenetic levels could guide us in discovering appropriate treatments for AD+P cases. To this end, we initiated a comprehensive, large sample-sized network analysis study based on genetic and epigenetic data
From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions
Get PDFThis is the final version. Available on open access from Springer via the DOI in this record. Data availability: The Illumina EPIC and RNA sequencing data that support the findings of this study are openly available in the GEO Gene Expression Omnibus (GEO) database under the accession number GSE224457In the progressive phase of multiple sclerosis (MS), the hampered differentiation capacity of oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation of Id2/Id4 is highly involved in OPC differentiation and remyelination. In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity. We compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n = 9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using pyrosequencing. The CRISPR–dCas9-DNMT3a/TET1 system was used to epigenetically edit human-iPSC-derived oligodendrocytes to assess the effect on cellular differentiation. Our data show hypermethylation of CpGs within genes that cluster in gene ontologies related to myelination and axon ensheathment. Cell type-specific validation indicates a region-dependent hypermethylation of MBP, encoding for myelin basic protein, in OPCs obtained from white matter lesions compared to NAWM-derived OPCs. By altering the DNA methylation state of specific CpGs within the promotor region of MBP, using epigenetic editing, we show that cellular differentiation and myelination can be bidirectionally manipulated using the CRISPR–dCas9-DNMT3a/TET1 system in vitro. Our data indicate that OPCs within chronically demyelinated MS lesions acquire an inhibitory phenotype, which translates into hypermethylation of crucial myelination-related genes. Altering the epigenetic status of MBP can restore the differentiation capacity of OPCs and possibly boost (re)myelination.Research Foundation of Flanders (FWO Vlaanderen)Charcot Foundation of Belgiu
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