Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target

Genome-wide DNA methylation patterns associated with sleep and mental health in children: a population-based study

Background: DNA methylation (DNAm) has been implicated in the biology of sleep. Yet, how DNAm patterns across the genome relate to different sleep outcomes, and whether these associations overlap with mental health is currently unknown. Here, we investigated associations of DNAm with sleep and mental health in a pediatric population. Methods: This cross-sectional study included 465 10-year-old children (51.3% female) from the Generation R Study. Genome-wide DNAm levels were measured using the Illumina 450K array (peripheral blood). Sleep problems were assessed from self-report and mental health outcomes from maternal questionnaires. Wrist actigraphy was used in 188 11-year-old children to calculate sleep duration and midpoint sleep. Weighted gene co-expression network analysis was used to identify highly comethylated DNAm ‘modules’, which were tested for associations with sleep and mental health outcomes. Results: We identified 64 DNAm modules, one of which associated with sleep duration after covariate and multiple testing adjustment. This module included CpG sites spanning 9 genes on chromosome 17, including MAPT – a key regulator of Tau proteins in the brain involved in neuronal function – as well as genes previously implicated in sleep duration. Follow-up analyses suggested that DNAm variation in this region is under considerable genetic control and shows strong blood–brain concordance. DNAm modules associated with sleep did not overlap with those associated with mental health. Conclusions: We identified one DNAm region associated with sleep duration, including genes previously reported by recent GWAS studies. Further research is warranted to examine the functional role of this region and its longitudinal association with sleep

Epigenomics of being bullied: changes in DNA methylation following bullying exposure

Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = −2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation

Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation

Background Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Methods Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3-and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Results Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10-07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. Conclusions These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses

Frequent bullying involvement and brain morphology in children

Background: Over the past few decades, bullying has been recognized as a considerable public health concern. Involvement in bullying is associated with poor long-term social and psychiatric outcomes for both perpetrators and targets of bullying. Despite this concerning prognosis, few studies have investigated possible neurobiological correlates of bullying involvement that may explain the long-term impact of bullying. Cortical thickness is ideally suited for examining deviations in typical brain development, as it has been shown to detect subtle differences in children with psychopathology. We tested associations between bullying involvement and cortical thickness using a large, population-based cohort. Methods: The study sample consisted of 2,602 participants from the Generation R Study. When children were 8 years old, parents and teachers reported on common forms of child bullying involvement (physical, verbal, and relational). Questions ascertained whether a child was involved as a perpetrator (n = 82), a target of bullying (n = 92), as a combined perpetrator and target of bullying (n = 47), or uninvolved in frequent bullying (n = 2,38

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD(+) depletion in experimental atrial fibrillation

Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD+), induces further DNA damage and contractile dysfunction. Accordingly, NAD+ replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF

TOI-222: A single-transit TESS candidate revealed to be a 34-d eclipsing binary with CORALIE, EulerCam, and NGTS

We report the period, eccentricity, and mass determination for the Transiting Exoplanet Survey Satellite (TESS) single-transit event candidate TOI-222, which displayed a single 3000 ppm transit in the TESS 2-min cadence data from Sector 2. We determine the orbital period via radial velocity measurements (P = 33.9 d), which allowed for ground-based photometric detection of two subsequent transits. Our data show that the companion to TOI-222 is a low-mass star, with a radius of 0.18+−003910 R☉ and a mass of 0.23 ± 0.01 M☉. This discovery showcases the ability to efficiently discover long-period systems from TESS single-transit events using a combination of radial velocity monitoring coupled with high-precision ground-based photometry

Three short-period Jupiters from TESS: HIP 65Ab, TOI-157b, and TOI-169b

We report the confirmation and mass determination of three hot Jupiters discovered by the Transiting Exoplanet Survey Satellite (TESS) mission: HIP 65Ab (TOI-129, TIC-201248411) is an ultra-short-period Jupiter orbiting a bright (V = 11.1 mag) K4-dwarf every 0.98 days. It is a massive 3.213 ± 0.078 MJ planet in a grazing transit configuration with an impact parameter of b = 1.17-0.08+0.10. As a result the radius is poorly constrained, 2.03-0.49+0.61RJ. The planet's distance to its host star is less than twice the separation at which it would be destroyed by Roche lobe overflow. It is expected to spiral into HIP 65A on a timescale ranging from 80 Myr to a few gigayears, assuming a reduced tidal dissipation quality factor of Qs′ = 107 - 109. We performed a full phase-curve analysis of the TESS data and detected both illumination- and ellipsoidal variations as well as Doppler boosting. HIP 65A is part of a binary stellar system, with HIP 65B separated by 269 AU (3.95 arcsec on sky). TOI-157b (TIC 140691463) is a typical hot Jupiter with a mass of 1.18 ± 0.13 MJ and a radius of 1.29 ± 0.02 RJ. It has a period of 2.08 days, which corresponds to a separation of just 0.03 AU. This makes TOI-157 an interesting system, as the host star is an evolved G9 sub-giant star (V = 12.7). TOI-169b (TIC 183120439) is a bloated Jupiter orbiting a V = 12.4 G-type star. It has a mass of 0.79 ±0.06 MJ and a radius of 1.09-0.05+0.08RJ. Despite having the longest orbital period (P = 2.26 days) of the three planets, TOI-169b receives the most irradiation and is situated on the edge of the Neptune desert. All three host stars are metal rich with [Fe / H] ranging from 0.18 to0.24