Eisner, M. | Search bioRxiv

bioRxiv2024

Peer victimization in adolescence alters gene expression and cytokine profiles

Social adversity downregulates antiviral genes and upregulates inflammatory genes, altering cytokine levels. This study investigated the effects of peer victimization (PV) during adolescence on gene expression, cellular dynamics, and cytokine profiles in young adulthood. Data from the Zurich Brain and Immune Gene Study (z-GIG, n = 200; 47% female) captured PV between ages 11 and 20, with mRNA and plasma cytokines analyzed in 144 participants at age 22. A counterfactual design with genetically informed inverse probability weighting adjusted for baseline confounders in individual and environmental characteristics. In silico deconvolution revealed altered leukocyte composition in victims, including an M2-like monocyte-skewed profile. Differentially expressed genes in victims were enriched in preselected Reactome pathways, including Interferon signaling, Metabolism and Signal transduction. Exploratory Reactome-wide queries confirmed pathways in the Immune System and Metabolism, highlighted their downregulation, and identified additional pathways, such as those involved in Chromatin organization and Metabolism of proteins. Transcription factors STAT2, IRF2, and NF-{kappa}B emerged as key regulators in victims, with target genes prominently mapped to Interferon signaling and Chromatin organization pathways. Victims exhibited altered cytokine levels, including pro-inflammatory CCL4, TNF, CXCL9, and CXCL10. These findings suggest that adolescent PV can lead to changes in gene regulation and cytokine levels, potentially altering the immune profile into young adulthood. The results underscore the importance of health policies aimed at prevention, building resilience, and mitigating the long-term effects of PV.

genomics↗

bioRxiv2021

Disordered yet functional atrial t-tubules on recovery from heart failure

Transverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete loss of atrial t-tubules in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and if restored t-tubules are functional. Sheep were tachypaced to induce HF and recovered when pacing was stopped. Serial block face Scanning Electron Microscopy and confocal imaging were used to understand t-tubule ultrastructure and function. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and causality determined using expression studies. Sheep atrial t-tubules reappeared following recovery from HF. Despite being disordered (branched, longer and longitudinally arranged) recovered t-tubules triggered Ca2+ release and were associated with restoration of systolic Ca2+. Telethonin and myotubularin abundance correlated with t-tubule density and altered the density and structure of BIN1-driven tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. Recovery from HF restores atrial t-tubules and systolic Ca2+ and myotubularin facilitates this process. Atrial t-tubule restoration could present a new and viable therapeutic strategy. Brief SummaryThe loss of atrial transverse (t)-tubules and the associated dysfunction in heart failure is reversible and the protein myotubularin plays an important role.

physiology↗