Search

Peer victimisation has been associated with depressive symptoms during adolescence, however not all peer victimised adolescents will exhibit such symptoms. This study tested whether having a genetic predisposition to developing depression increased the risk of experiencing depressive symptoms in peer victimised youth. To date, no study has explored such gene-environment interaction using a polygenic risk score for depression (PRS-depression) in the context of peer victimisation and depressive symptoms in adolescence.The sample included 748 participants born in 1997/98 from the Quebec Longitudinal Study of Child Development with genotype data and prospectively collected information on peer victimisation (12-13 years) obtained from both self- and teacher-reports, as well as self-reported depressive symptoms (15-17 years). The PRS-depression was based on the genome-wide association meta-analysis of broad depression by Howard et al. (2019).Self- and teacher-reported peer victimisation in early adolescence were both associated with depressive symptoms in adolescence (β = 0.34, p .001; β = 0.14, p = .001 respectively), and this association remained significant when accounting for PRS-depression (β = 0.33, p .001; β = 0.13, p = .002 respectively). PRS-depression was independently associated with depressive symptoms, but there was no significant PRS-depression by peer victimisation interaction (self-reported and teacher-reported). PRS-depression was correlated with self-reported, but not teacher-reported, peer victimisation.Our findings suggested that a partial measure of an individual's genetic predisposition to depression, as measured by PRS-depression, and being exposed to peer victimisation (self- and teacher-reported) were independently associated with depressive symptoms in adolescence. Furthermore, PRS-depression did not exacerbate the risk of depressive symptoms among adolescents who had been peer victimised. Lastly, we found evidence of a gene-environment correlation between PRS-depression and self-reported peer victimisation. Future studies are needed to replicate this finding and to further understand the role of genetic predispositions in experiencing depressive symptoms following peer victimisation.

BackgroundAdverse childhood experiences (ACEs) are correlated with accelerated epigenetic aging, but it is not clear whether altered epigenetic aging from childhood adversities persists into adulthood and can be transmitted to the next generation. Thus, we tested whether mothers’ childhood adversity is associated with accelerated epigenetic aging during pregnancy and in their newborn offspring.MethodsData were from the Avon Longitudinal Study of Parents and Children (ALSPAC) sub-study, Accessible Resource for Integrated Epigenomic Studies (ARIES). Women provided retrospective self-reports during pregnancy of ACE exposure. DNA methylation was measured in mothers during pregnancy and cord blood at birth. Estimates of epigenetic age acceleration were calculated using Principal Components of Horvath, Hannum skin & blood, GrimAge, PhenoAge, and DunedinPACE epigenetic clocks for mothers; and the Knight and Bohlin cord blood clocks for newborns. Associations between a cumulative maternal ACE score and epigenetic age acceleration were estimated using linear regression models, adjusting for maternal age at pregnancy, smoking during pregnancy, education, and pre-pregnancy BMI. Models for offspring were stratified by sex and additionally adjusted for gestation age.ResultsMothers’ total ACE score was positively associated with accelerated maternal PhenoAge and GrimAge. In newborn offspring, mothers’ total ACE score was positively associated with accelerated epigenetic aging in males using the Bohlin clock, but not in females using either epigenetic clock. We found male offsprings’ epigenetic age was accelerated in those born to mothers exposed to neglect using the Knight clock; and parental substance abuse using the Bohlin clock.ConclusionOur results show that mothers’ ACE exposure is associated with DNAm age acceleration in male offspring, supporting the notion that DNAm age could be a marker of intergenerational biological embedding of mothers’ childhood adversity. This is consistent with findings on vulnerability of male fetuses to environmental insults.

Alzheimer’s disease (AD) is a heterogeneous disorder with abnormalities in multiple biological domains. In an advanced machine learning analysis of postmortem brain and in vivo blood multi-omics molecular data ( N = 1863), we integrated epigenomic, transcriptomic, proteomic, and metabolomic profiles into a multilevel biological AD taxonomy. We obtained a personalized multilevel molecular index of AD dementia progression that predicts severity of neuropathologies, and identified three robust molecular-based subtypes that explain much of the pathologic and clinical heterogeneity of AD. These subtypes present distinct patterns of alteration in DNA methylation, RNA, proteins, and metabolites, identifiable in the brain and subsequently in blood. In addition, the genetic variations that predispose to the various AD subtypes in brain predict distinct spatial patterns of alteration in cell types, suggesting a unique influence of each putative AD variant on neuropathological mechanisms. These observations support that an individually tailored multi-omics molecular taxonomy of AD may represent distinct targets for preventive or treatment interventions.

Catheter associated infections are a common complication that occurs in dialysis patients. Current strategies to prevent infection include catheter coatings containing heparin, pyrogallol or silver nanoparticles, which all have an increased risk of causing resistance in bacteria. Therefore, a novel approach for manufacture, such as the use of additive manufacturing (AM), also known as 3D-printing, is required. Filaments were produced by extrusion using thermoplastic polyurethane (TPU) and Tetracycline Hydrochloride (TC) in various concentrations (e.g. 0%, 0.25%, 0.5% and 1%). The extruded filaments were used in a fused deposition modelling (FDM) 3D printer to print catheter constructs at varying concentrations. Release studies in phosphate buffered saline (PBS), microbiology studies, thermal analysis, contact angle, ATR‐FTIR, scanning electron microscopy (SEM) and X-ray Micro Computer Tomography (μCT) analysis were conducted on the printed catheters. The results suggested that TC was uniformly distributed within the TPU matrix. The microbiology testing of the catheters showed that devices containing TC had an inhibitory effect on the growth of Staphylococcus aureus NCTC 10788 bacteria. Catheters containing 1% TC maintained inhibitory effect after 10‐day release studies. After an initial burst release in the first 24 h, there was a steady release of TC in all concentrations of catheters. 3D-printed antibiotic catheters were successfully printed with inhibitory effect on S. aureus bacteria. Finally, TC containing catheters showed resistance to S. aureus adherence to their surfaces when compared with catheters containing no TC. Catheters containing 1% of TC showed a bacterial adherence reduction of up to 99.97%. Accordingly, the incorporation of TC to TPU materials can be effectively used to prepare anti-infective catheters using FDM. This study highlights the potential for drug impregnated medical devices to be created through AM.

Due to their inherent ability to swell in the presence of aqueous solutions, hydrogels offer a means for the delivery of therapeutic agents in a range of applications. In the context of designing functional tissue-engineering scaffolds, their role in providing for the diffusion of nutrients to cells is of specific interest. In particular, the facility to provide such nutrients over a prolonged period within the core of a 3D scaffold is a critical consideration for the prevention of cell death and associated tissue-scaffold failure. The work reported here seeks to address this issue via fabrication of hybrid 3D scaffolds with a component fabricated from mixed-molecular-weight hydrogel formulations capable of storing and releasing nutrient solutions over a predetermined time period. To this end, poly(ethylene) glycol diacrylate hydrogel blends comprising mixtures of PEGDA-575 Mw and PEGDA-2000 Mw were prepared via UV polymerization. The effects of addition of the higher-molecular-weight component and the associated photoinitiator concentration on mesh size and corresponding fluid permeability have been investigated by diffusion and release measurements using a Theophylline as an aqueous nutrient model solution. Fluid permeability across the hydrogel films has also been determined using a Rhodamine B solution and associated fluorescence measurements. The results indicate that addition of PEGDA-2000 Mw to PEGDA-575 Mw coupled with the use of a specific photoinitiator concentration provides a means to change mesh size in a hydrogel network while still retaining an overall microporous material structure. The range of mesh sizes created and their distribution in a 3D construct provides for the conditions required for a more prolonged nutrient release profile for tissue-engineering applications.

Women experience as many symptoms of anxiety, depression, and stress during pregnancy as in the postnatal period. This can affect not only the woman herself but also the development of her fetus, and have long-term effects on several different outcomes including the cognitive ability and behaviour of her child, although most children are not affected. The particular outcomes affected may depend on the timing of the exposure, specific genetic vulnerabilities, and the quality of postnatal care provided. Recent research has shown that increased maternal anxiety is associated with altered placental function, and a greater association between maternal and fetal cortisol. This interrelationship of hormonal associations during the fetal stage could potentially impact on fetal/infant outcomes, and supports the need for continuing research in the field. Chapter 3 covers studies on maternal mood in pregnancy and explores the underlying mechanisms and types of stress.

Rapid photobleaching of fluorescent proteins can limit their use in imaging applications. The underlying kinetics is multi-exponential and strongly depends on the local chromophore environment. The first, reversible, step may be attributed to a rotation around one of the two exocyclic C-C bonds bridging phenol and imidazolinone groups in the chromophore. However it is not clear how the protein environment controls this motion - either by steric hindrances or by modulating the electronic structure of the chromophore through electrostatic interactions. Here we study the first step of the photobleaching kinetics in 13 red fluorescent proteins (RFPs) with different chromophore environment and show that the associated rate strongly correlates with the bond length alternation (BLA) of the two bridge bonds. The sign of the BLA appears to determine which rotation is activated. Our results present experimental evidence for the dominance of electronic effects in the conformational dynamics of the RFP chromophore.