Biology subjects

Dunn, E.

Publications and source records attributed to Dunn, E..

3 recordsLinked to original sources

bioRxiv2026

Intergenerational epigenetic signatures of prenatal adversity and their role in emerging child psychopathology

BackgroundAdversity during pregnancy is associated with alterations in offspring brain development. DNA methylation (DNAm) is a type of epigenetic modification is a putative mechanism for the intergenerational transfer of prenatal adversity on developmental outcomes. We examined the effects of prenatal social disadvantage (PSD) and prenatal psychosocial stress (PSS) on offspring epigenome-wide DNAm at four time points from infancy to age 4, and tested whether persistent DNAm signals mediated associations between PSD, PSS, and child psychopathology at ages 4-6. MethodsLongitudinal DNAm data (birth, Y1, Y2, Y3) was derived from salivary tissue of 281 infants (43.7% female) in the eLABE study. We examined epigenome-wide associations between DNAm and PSD and PSS. Linear models were adjusted for age, child sex, child race, maternal tobacco smoking, cell type composition, and batch effects. Mediation analyses tested whether birth DNAm mediated associations between prenatal exposures and internalizing and externalizing symptoms at ages 4-6. ResultsPSD was associated with 47 FDR-significant CpGs at birth and 3 at year 1. PSS was associated with 3 FDR-significant CpGs at birth. Thirteen CpGs showed PSD-associated significance across all four timepoints, including two CpGs associated with genes involved with neuronal maturation (BCL11B) and one CpG associated with a gene implicated in brain vascular health (ZNF474). Exploratory mediation analyses revealed an indirect effect of methylation at ZNF474 (cg19980369; p=0.028; pFDR=0.360) on the association between PSD and year 4-6 externalizing symptoms. ConclusionsPSD was associated with epigenetic signatures at birth, with a subset of associations persisting across early childhood and converging on cellular stress response biology. PSS showed minimal epigenetic associations, suggesting differential biological embedding of structural versus psychological dimensions of adversity.

genomics↗

bioRxiv2019

Simulation of closed-loop deep brain stimulation control schemes for suppression of pathological beta oscillations in Parkinson's disease

This study presents a computational model of closed-loop control of deep brain stimulation (DBS) for Parkinsons disease (PD) to investigate clinically-viable control schemes for suppressing pathological beta-band activity. Closed-loop DBS for PD has shown promising results in preliminary clinical studies and offers the potential to achieve better control of patient symptoms and side effects with lower power consumption than conventional open-loop DBS. However, extensive testing of algorithms in patients is difficult. The model presented provides a means to explore a range of control algorithms in silico and optimize control parameters before preclinical testing. The model incorporates (i) the extracellular DBS electric field, (ii) antidromic and orthodromic activation of STN afferent fibers, (iii) the LFP detected at non-stimulating contacts on the DBS electrode and (iv) temporal variation of network beta-band activity within the thalamo-cortico-basal ganglia loop. The performance of on-off and dual-threshold controllers for suppressing beta-band activity by modulating the DBS amplitude were first verified, showing levels of beta suppression and reductions in power consumption comparable with previous clinical studies. Proportional (P) and proportional-integral (PI) closed-loop controllers for amplitude and frequency modulation were then investigated. A simple tuning rule was derived for selecting effective PI controller parameters to target long duration beta bursts while respecting clinical constraints that limit the rate of change of stimulation parameters. Of the controllers tested, PI controllers displayed superior performance for regulating network beta-band activity whilst accounting for clinical considerations. Proportional controllers resulted in undesirable rapid fluctuations of the DBS parameters which may exceed clinically tolerable rate limits. Overall, the PI controller for modulating DBS frequency performed best, reducing the mean error by 83% compared to DBS off and the mean power consumed to 25% of that utilized by open-loop DBS. The network model presented captures sufficient physiological detail to act as a surrogate for preclinical testing of closed-loop DBS algorithms using a clinically accessible biomarker, providing a first step for deriving and testing novel, clinically-suitable closed-loop DBS controllers.

bioengineering↗

bioRxiv2018

FANCM-family branchpoint translocases remove co-transcriptional R-loops

Co-transcriptional R-loops arise from physiological or aberrant stalling of RNA polymerase, leading to formation of stable DNA:RNA hybrids. Unresolved R-loops can promote genome instability. Here, we show that the Fanconi anemia- and breast cancer-associated FANCM protein can directly unwind DNA-RNA hybrids from co-transcriptional R-loops in vitro. FANCM processively unwinds both short and long R-loops, irrespective of sequence, topology or coating by replication protein A. R-loops can also be unwound in the same assay by the yeast and bacterial orthologs of FANCM, Mph1 and RecG, indicating an evolutionary conserved function. Consistent with this biochemical activity of FANCM, we show that FANCM deficient cells are sensitive to drugs that stabilize R-loop formation. Our work reveals a mechanistic basis for R-loop metabolism that is critical for genome stability.

biochemistry↗