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Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P

Biological aging is the gradual and progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the rate of biological aging are needed to serve as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging to extend healthspan. We report a blood DNA-methylation measure that is sensitive to variation in the pace of biological aging among individuals born in the same year. We first modeled longitudinal change in a panel of 18 biomarkers tracking organ-system integrity across 12 years of follow-up in the Dunedin birth cohort. Rates of change across these biomarkers were composited to form a measure of aging-related decline in system integrity, termed Pace of Aging. We then used elastic-net regression to develop a DNA-methylation predictor of Pace of Aging, called mPoA for (m)ethylation (P)ace (o)f (A)ging. Validation analyses showed mPoA was associated with functional decline in the Dunedin Study, complemented information from other methylation clocks in the Understanding Society Study, was accelerated by early-life adversity in the E-risk Study, and was disrupted by caloric restriction in the CALERIE trial. Findings provide proof-of-principle for mPoA as a single-time-point measure of a person’s pace of biological aging.

We show that Erdős space E is Polishable and prove that E with its Polish topology is homeomorphic to complete Erdős space.

Op 22 mei 2019 overleed in Almelo op 85-jarige leeftijd Pieter Cornelis Baayen, emeritus hoogleraar wiskunde aan de Vrije Universiteit en voormalig wetenschappelijk directeur van het Centrum Wiskunde & Informatica. Hij was in de jaren zeventig en tachtig een van de koersbepalende Nederlandse wiskundigen. Cor Baayen was erelid van het Koninklijk Wiskundig Genootschap. Zijn oud-collega’s / promovendi Gerard Alberts, Teun Koetsier, Jan van Mill en Lex Schrijver herdenken hem.

Op 14 juni 2018 overleed Jan Aarts, emeritus hoogleraar aan de TU Delft en erevoorzitter van studievereniging ‘Christiaan Huygens’. Hij is bestuurslid geweest van het Thomas Stieltjes Instituut en directeur van Mastermath. Kort voor zijn overlijden is er in Delft nog een symposium georganiseerd ter ere van zijn tachtigste verjaardag. In dit artikel herdenken enkele sprekers van dat symposium en enkele oud-collega’s hem.

Bisphenol A (BPA) is a commercially important high production chemical widely used in epoxy resins and polycarbonate plastics, and is ubiquitous in the environment. Previous studies demonstrated that BPA activates estrogenic signaling pathways associated with adverse effects on reproduction in vertebrates and that exposure can induce epigenetic changes. We aimed to investigate the reproductive effects of BPA in a fish model and to document its mechanisms of toxicity. We exposed breeding groups of zebrafish (Danio rerio) to 0.01, 0.1, and 1 mg/L BPA for 15 d. We observed a significant increase in egg production, together with a reduced rate of fertilization in fish exposed to 1 mg/L BPA, associated with significant alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver and gonad tissue at concentrations representing hotspots of environmental contamination (0.1 mg/L) and above. Of note, we observed reduced expression of DNA methyltransferase 1 (dnmt1) at environmentally relevant concentrations of BPA, along with a significant reduction in global DNA methylation, in testes and ovaries following exposure to 1 mg/L BPA. Our findings demonstrate that BPA disrupts reproductive processes in zebrafish, likely via estrogenic mechanisms, and that environmentally relevant concentrations of BPA are associated with altered transcription of key enzymes involved in DNA methylation maintenance. These findings provide evidence of the mechanisms of action of BPA in a model vertebrate and advocate for its reduction in the environment.

Background 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.

Aim: To develop age-, sex-, and ethnic-Appropriate normative reference ranges for standard echocardiographic measurements of the left heart by combining echocardiographic measurements obtained from adult volunteers without clinical cardiovascular disease or significant cardiovascular risk factors, from multiple studies around the world.Methods and results: The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL) collaboration was established and population-based data sets of echocardiographic measurements combined to perform an individual person data meta-Analysis. Data from 43 studies were received, representing 51 222 subjects, of which 22 404 adults aged 18-80 years were without clinical cardiovascular or renal disease, hypertension or diabetes. Quantile regression or an appropriate parametric regression method will be used to derive reference values at the 5th and 95th centile of each measurement against age. Conclusion: This unique data set represents a large, multi-ethnic cohort of subjects resident in a wide range of countries. The resultant reference ranges will have wide applicability for normative data based on age, sex, and ethnicity. © The Author 2013.

We call a function $f: X\to Y$ $P$-preserving if, for every subspace $A \subset X$ with property $P$, its image $f(A)$ also has property $P$. Of course, all continuous maps are both compactness- and connectedness-preserving and the natural question about when the converse of this holds, i.e. under what conditions is such a map continuous, has a long history. Our main result is that any non-trivial product function, i.e. one having at least two non-constant factors, that has connected domain, $T_1$ range, and is connectedness-preserving must actually be continuous. The analogous statement badly fails if we replace in it the occurrences of "connected" by "compact". We also present, however, several interesting results and examples concerning maps that are compactness-preserving and/or continuum-preserving., 8 pages

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP , PSEN1 , PSEN2 , MAPT ), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.

Andrew W O'Keefe,1,2 Sarah De Schryver,1 Jennifer Mill,3 Christopher Mill,3 Alizee Dery,1 Moshe Ben-Shoshan1 1Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada; 2Department of Pediatrics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada; 3Division of Clinical Epidemiology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada Abstract: It is reported that 6% of children and 3% of adults have food allergies, with studies suggesting increased prevalence worldwide over the last few decades. Despite this, our diagnostic capabilities and techniques for managing patients with food allergies remain limited. We have conducted a systematic review of literature published within the last 5 years on the diagnosis and management of food allergies. While the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge, this assessment is resource intensive and impractical in most clinical situations. In an effort to reduce the need for the double-blind, placebo-controlled food challenge, several risk-stratifying tests are employed, namely skin prick testing, measurement of serum-specific immunoglobulin E levels, component testing, and open food challenges. Management of food allergies typically involves allergen avoidance and carrying an epinephrine autoinjector. Clinical research trials of oral immunotherapy for some foods, including peanut, milk, egg, and peach, are under way. While oral immunotherapy is promising, its readiness for clinical application is controversial. In this review, we assess the latest studies published on the above diagnostic and management modalities, as well as novel strategies in the diagnosis and management of food allergy. Keywords: skin prick testing, oral challenge, specific IgE, component testing, oral immunotherapy, epinephrine autoinjector