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Heterogeneity in the incidence of postoperative atrial fibrillation (POAF) following heart surgery implies that underlying genetic and/or physiological factors impart a higher risk of this complication to certain patients. Glutathione peroxidase-4 (GPx4) is a vital selenoenzyme responsible for neutralizing lipid peroxides, mediators of oxidative stress known to contribute to postoperative arrhythmogenesis. Here, we sought to determine whether GPX4 single nucleotide variants are associated with POAF, and whether any of these variants are linked with altered GPX4 enzyme content or activity in myocardial tissue. Sequencing analysis was performed across the GPX4 coding region within chromosome 19 from a cohort of patients (N = 189) undergoing elective coronary artery bypass graft (−/+ valve) surgery. GPx4 enzyme content and activity were also analyzed in matching samples of atrial myocardium from these patients. Incidence of POAF was 25% in this cohort. Five GPX4 variants were associated with POAF risk (permutated p ≤ 0.05), and eight variants associated with altered myocardial GPx4 content and activity (p < 0.05). One of these variants (rs713041) is a well-known modifier of cardiovascular disease risk. Collectively, these findings suggest GPX4 variants are potential risk modifiers and/or predictors of POAF. Moreover, they illustrate a genotype–phenotype link with this selenoenzyme, which will inform future mechanistic studies. [ABSTRACT FROM AUTHOR]

Sleep deprivation disrupts the lives of millions of people every day and has a profound impact on the molecular biology of the brain. These effects begin as changes within a neuron, at the DNA and RNA level, and result in alterations in neuronal plasticity and dysregulation of many cognitive functions including learning and memory. The epigenome plays a critical role in regulating gene expression in the context of memory storage. In this review article, we begin by describing the effects of epigenetic alterations on the regulation of gene expression, focusing on the most common epigenetic mechanisms: (i) DNA methylation; (ii) histone modifications; and (iii) non-coding RNAs. We then discuss evidence suggesting that sleep loss impacts the epigenome and that these epigenetic alterations might mediate the changes in cognition seen following disruption of sleep. The link between sleep and the epigenome is only beginning to be elucidated, but clear evidence exists that epigenetic alterations occur following sleep deprivation. In the future, these changes to the epigenome could be utilized as biomarkers of sleep loss or as therapeutic targets for sleep-related disorders. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD., Methods: We analyzed peripheral blood mononuclear cells (bipolar disorder N=39, control N=30), serum cytokines (bipolar disorder N=86, control N=58), whole blood RNA (bipolar disorder N=25, control N=25), and whole blood DNA (bipolar disorder N=104, control N=66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls., Results: Flow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk., Discussion: Our findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.

Protein Kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer to two catalytic (C) subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined postmortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry, and behavioral assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioral and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the C-subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The t(12;21) (p13;q22) chromosomal translocation resulting in the ETV6/RUNX1 fusion gene is the most frequent structural cytogenetic abnormality in children with acute lymphoblastic leukemia (ALL). The erythropoietin receptor (EPOR), usually associated with erythroid progenitor cells, is highly expressed in ETV6/RUNX1 positive cases compared to other B-lineage ALL subtypes. Gene expression analysis of a microarray database and direct quantitative analysis of patient samples revealed strong correlation between EPOR and GATA2 expression in ALL, and higher expression of GATA2 in t(12;21) patients. The mechanism of EPOR regulation was mainly investigated using two B-ALL cell lines: REH, which harbor and express the ETV6/RUNX1 fusion gene; and NALM-6, which do not. Expression of EPOR was increased in REH cells compared to NALM-6 cells. Moreover, of the six GATA family members only GATA2 was differentially expressed with substantially higher levels present in REH cells. GATA2 was shown to bind to the EPOR 5'-UTR in REH, but did not bind in NALM-6 cells. Overexpression of GATA2 led to an increase in EPOR expression in REH cells only, indicating that GATA2 regulates EPOR but is dependent on the cellular context. Both EPOR and GATA2 are hypomethylated and associated with increased mRNA expression in REH compared to NALM-6 cells. Decitabine treatment effectively reduced methylation of CpG sites in the GATA2 promoter leading to increased GATA2 expression in both cell lines. Although Decitabine also reduced an already low level of methylation of the EPOR in NALM-6 cells there was no increase in EPOR expression. Furthermore, EPOR and GATA2 are regulated post-transcriptionally by miR-362 and miR-650, respectively. Overall our data show that EPOR expression in t(12;21) B-ALL cells, is regulated by GATA2 and is mediated through epigenetic, transcriptional and post-transcriptional mechanisms, contingent upon the genetic subtype of the disease.