Chromosomal mosaicism (CM) is a biological phenomenon defined as an individual who has arisen from a single zygote and has two or more populations of cells with distinct genotypes. 1 The main underlying mechanisms leading to mosaicism formation involve mitotic or meiotic non-disjunction errors, anaphase lagging and trisomy rescue, endoreplication events, and uniparental disomy (UPD) associated with trisomy rescue. 2 Theoretically, the pattern of the mosaic distribution in the foetus and placenta is largely determined by the

Selective intrauterine growth restriction (sIUGR) is a severe complication in monochorionic (MC) twin pregnancies, and it carries increased risks of poor prognosis. Current data suggest that vascular anastomoses and unequal placental sharing may be the key contributor to discordant foetal growth. While MC twins derive from a single zygote and have almost identical genetic information, the precise mechanisms remain unknown. DNA hydroxymethylation is a newly discovered epigenetic feature associated with gene regulation and modification. Here, we investigate discordant hydroxymethylation patterns between two placental shares of sIUGR and analyse the potential role of aberrant hydroxymethylation of angiopoietin-like 4 (ANGPTL4) in placental dysplasia. Hydroxymethylation DNA immunoprecipitation (hMeDIP)-chip and mRNA sequencing were performed to identify hydroxymethylation-associated genes. Real-time qPCR, western blotting, and immunohistochemistry were used to confirm ANGPTL4 expression. The mechanisms regulating ANGPTL4 were investigated by cell migration assay, invasion assay, viability assay, and apoptotic ratio assays, western blotting and hMeDIP-qPCR. Decreased ANGPTL4 was detected in the smaller placental shares of sIUGR. ANGPTL4 knockdown suppressed trophoblast invasiveness and migration, which possibly occurred through hypoxia inducible factor 1α (HIF-1α) and HIF-1 signalling pathway. Hypoxia leads to aberrant expression of ANGPTL4 and HIF-1α, positively correlated with their aberrant hydroxymethylation levels in promoter regions. Aberrant hydroxymethylation of ANGPTL4 may contribute to placental impairment by the HIF-1 signalling pathway in smaller placental shares of sIUGR.

Dysregulated inflammation is closely associated with increased mortality in sepsis. Platelets have emerged as key inflammatory cells implicated in the pathology of sepsis, including the development of thrombosis, thrombocytopenia, and neutrophil extracellular traps (NETs). Platelet’s contributions to rapid clinical deterioration and dysregulated inflammation in sepsis have not been defined. In our cohort, the incidence of thrombocytopenia, thrombocytopathy and excessive inflammatory cytokines released in patients with severe sepsis were significantly increased. Platelet proteomic analysis revealed significant up-regulation of Gasdermin D (GSDMD). Using platelet-specific Gsdmd deficient mice, we demonstrated a requirement for GSDMD in triggering platelet pyroptosis in cecal ligation and puncture (CLP)-induced sepsis. We further demonstrated that GSDMD-dependent platelet pyroptosis was induced by high levels of S100A8/A9 targeting platelet toll-like receptor 4 (TLR4). Pyroptotic platelet-derived oxidized mitochondrial DNA (ox-mtDNA) potentially promoted NET formation, which in turn contributed to platelet pyroptosis via the release of S100A8/A9, forming a positive feedback loop that led to excessive inflammatory cytokines release. Both pharmacological inhibition using Paquinimod and genetic ablation of the S100A8/A9-TLR4 signaling axis suppressed GSDMD-dependent platelet pyroptosis, thereby alleviating NET-mediated inflammation and improving survival in CLP-induced sepsis mice. Taken together, these findings provide new insights into the proinflammatory role of platelet pyroptosis in severe sepsis.