Increasing Maternal or Post-Weaning Folic Acid Alters Gene Expression and Moderately Changes Behavior in the Offspring

Background Studies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice. Methods Dams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring. Results Results from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns’ cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

High maternal FA alters the expression of Slc17a7p and Vgll2p in the cerebral hemispheres of female newborn pups.

<p>Total cell lysates from the cerebral hemispheres of female (F) newborn pups were prepared from both 0.4 mg/kg and 4 mg/kg FA diet groups and proteins were resolved on 10% Tris/HEPES/SDS-polyacrylamide gels. The blot was probed with Slc17a7p antibody (<b>A</b>, <b>B</b>) or with Vgll2p antibody (<b>C</b>, <b>D</b>). To confirm equal protein loading, the membranes were re-probed with GAPDH/β-tubulin antibodies. The left panel represents one representative blot and the right panel shows densitometric evaluation of two independent experiments. Densitometric evaluation of the bands were calculated by using the Image J software and normalized to the densities of GAPDH//β-tubulin. The values corresponding to 0.4 mg/kg FA diet were arbitrarily set to 100%, and the 4 mg/kg values are presented relative to this. The densitometric values represent the mean, and the error bar represents the inter-variability among independent experiments.</p

The schematic diagram of the experimental design for this study.

<p>The schematic diagram of the experimental design for this study.</p

A: Quantitative RT-PCR confirmation of microarray data.

<p>Relative expression of the <i>Cpn2</i>, <i>Zfp353</i>, <i>Htr4</i>, <i>Nkx6-3</i> and <i>Xist</i> transcripts in the cerebral hemispheres of male newborn pups, from mothers supplemented with FA at 4 mg/kg of diet. The results were normalized to <i>Hprt</i> transcript expression, and expressed as relative values in comparison to corresponding transcripts from newborn pups with FA at 0.4 mg/kg diet. Results represent means ± S.D; asterisks denote statistically significant change (***<i>P</i><0.001, **<i>P</i><0.01 and *<i>P</i><0.05). <b>B</b>): <b>Quantitative RT PCR confirmation of microarray data</b>. Relative expression of the <i>Vgll2</i>, <i>Leprel1</i>, <i>Nfix</i> and <i>Slc17a7</i> transcripts from the cerebral hemispheres of female newborn pups, from mothers supplemented with FA at 4 mg/kg of diet. The results were normalized to <i>Gapdh</i> transcript expression, and were expressed as relative values in comparison to corresponding transcripts from newborn pups with FA at 0.4 mg/kg diet. Results represent means ± S.D; asterisks denote statistically significant change (***<i>P</i><0.001, **<i>P</i><0.01 and *<i>P</i><0.05).</p

Neural genes altered ≥2 fold in the cerebral hemisphere of female pups from mothers having FA supplementation during gestation at 4 mg/kg in comparison to mothers at 0.4 mg/kg diet.

<p>Neural genes altered ≥2 fold in the cerebral hemisphere of female pups from mothers having FA supplementation during gestation at 4 mg/kg in comparison to mothers at 0.4 mg/kg diet.</p

Marine invasion genomics: Revealing ecological and evolutionary consequences of biological invasions

Genomic approaches are increasingly being used to study biological invasions. Here, we first analyse how high-throughput sequencing has aided our understanding of the mechanisms associated with biological invasions. These include the transport of propagules to pre-invaded areas, an exploration of the consequences of hybridisation during range expansions, and the pre- and post- invasion adaptation of colonising populations. We then explore how contemporary genomic methods have been used to probe and monitor the spread of non-indigenous species. More specifically, we focus on the detection of species richness from environmental samples, measures of quantitative traits that may promote invasive- ness, analysis of rapid adaptation, and the study of phenotypic plasticity. Finally, we look to the future, exploring how genomic approaches will assist future biodiversity conservationists in their efforts to mitigate the spread and effects of biological invasions. Ultimately, although the use of genomic tools to study non-indigenous species has so far been rather limited, studies to date indicate that genomic tools offer unparalleled research opportunities to continually improve our understanding of marine biological invasion