Biology subjects

McDonald, S. A.

Publications and source records attributed to McDonald, S. A..

4 recordsLinked to original sources

bioRxiv2026

INTERFERON-REGULATORY FACTOR 7: A NEUROIMMUNE ROLE FOR VAPOR-INDUCED ESCALATIONS IN ETHANOL SELF-ADMINISTRATION

Neuroimmune signaling is increased in postmortem brain tissue from individuals with alcohol use disorder (AUD), and growing evidence suggests that it contributes to persistent alcohol-related neuroadaptations. Interferon regulatory factor 7 (IRF7), a transcription factor downstream of endosomal Toll-like receptor signaling, is induced in alcohol-relevant brain regions and may contribute to escalated drinking. Here, we tested whether chronic intermittent ethanol (CIE) vapor exposure engages IRF7 signaling during subsequent alcohol self-administration and whether this is associated with altered molecular E/I balance in the aIC and altered functional E/I balance in aICnucleus accumbens projection neurons. Female Wistar rats (n=30) were trained to self-administer alcohol (15% v/v; FR2 vs inactive lever) during 30-minute sessions. After establishing baseline drinking, rats underwent 1-3 cycles of CIE, which increased alcohol self-administration at the 72 h post vapor test. This increase positively correlated with IRF7 levels in the anterior insular cortex (aIC) and nucleus accumbens, while molecular, and immunofluorescence showed that CIE shifted aIC excitatory/inhibitory (E/I) balance toward reduced excitation. Electrophysiological recordings further showed reduced functional E/I balance in aIC neurons projecting to the nucleus accumbens. Knockdown of IRF7 in the aIC attenuated CIE induced escalation of alcohol self-administration, supporting a role for insular IRF7 signaling in alcohol related neuroadaptations that promote escalated drinking.

neuroscience↗

bioRxiv2025

PKN2 regulates cell-junctions to limit colitis and colon tumour formation

Intestinal barrier failure is a defining feature of inflammatory bowel disease and a key driver of inflammation-associated colorectal cancer. However, the epithelial mechanisms that preserve barrier stability during inflammatory stress remain incompletely defined. Here, we identify the Rho-regulated kinase PKN2 as a non-redundant safeguard of tight junction integrity and a candidate tumour suppressor in colitis-associated colorectal cancer. Conditional PKN2 deletion in mice sensitised the colon to inflammatory injury and significantly increased adenoma formation in an inflammatory cancer model, with tumour burden tightly correlating with colitis severity. Mechanistically, PKN2 localises to tight junctions and is required to stabilise barrier integrity during injury in mouse and organoid models. PKN2 loss induces transcriptional programs conserved in human inflammatory bowel disease, where reduced PKN2 expression associates with increased disease severity and altered therapeutic response. Notably, PKN2 is encoded within genomic loci previously linked to intestinal inflammation susceptibility and tumour suppression in both humans and mice. Our findings identify PKN2 as a functional effector underlying these phenotypes and demonstrate that even heterozygous loss is sufficient to confer heightened sensitivity to inflammatory injury and tumour initiation, positioning PKN2 as a central regulator of tight junction stability that shapes disease severity, treatment response and cancer risk.

cell biology↗

bioRxiv2025

Alterations of the composition and spatial organization of the microenvironment following non-dysplastic Barrett's esophagus through progression to cancer

Barretts esophagus (BE), a metaplastic condition that is the only known precursor for esophageal adenocarcinoma (EAC), is relatively common, but progression to cancer is infrequent. BE is inflamed but the contribution of the immune system to the carcinogenic process is unknown. To this end, we contrasted non-dysplastic metaplasia of BE patients, captured when they did not progress (non-progressors), did subsequently, but had not yet progressed (pre-progressors) or had already progressed to EAC (progressors). Using spatial multiplexed 56-protein analysis, serial laser capture microdissection (LCM) RNAseq and shallow whole genome sequencing, we identified prooncogenic immune neighbourhoods and dysregulated immune cell populations predictive of subsequent progression to EAC. Indeed, spatial analysis revealed that M1 macrophages, regulatory natural killer (NK) cells, neutrophils and altered ratios of intraepithelial CD4+ and CD8+ lymphocytes typify tumor microenvironmental (TME) changes associated with cancer initiation. Spatially derived cell-to-cell interactions revealed progression-specific immune cell interaction signatures predominantly involving M1 macrophages NK cells and plasma cells. Furthermore, LCM RNAseq analysis identified gene expression hot signatures enriched in pre-progression and progression samples. Notably, we also observed a correlation between immune cells and copy number alterations in progressor metaplasia. By exposing coordinated changes in the immune cell landscape in patients at high risk of developing EAC, this multi-omic dataset provides novel diagnostic and therapeutic opportunities

cancer biology↗

bioRxiv2021

Clonal dynamics of normal hepatocyte expansions in homeostatic human livers and their association with the biliary epithelium

The majority of human liver research is disease-focused such that far less is known of cellular dynamics within normal human liver. We have leveraged cytochrome c oxidase deficiency as a marker of clonal hepatocyte populations in such tissues. We demonstrate these populations commonly associate with portal tracts and lineage-trace hepatocytes with cholangiocytes, indicating the presence of a bipotential common ancestor at this niche. We also observe rare periportal SOX9+ hepatocytes progenitor candidates in our human tissues. To understand clonal expansion dynamics, we measured methylation diversity and identified mtDNA variants by next-generation sequencing within spatially-defined clonal hepatocyte patches. We coupled our sequencing with mathematical modelling and Bayesian inference to compare spatial patterns of mtDNA variants under assumptions with or without faster expansion from a portal-associated niche. These datasets support the existence of a periportal progenitor niche and indicate that clonal patches slowly expand, perhaps due to acute environmental stimuli, then quiesce. These findings crucially contribute to our understanding of hepatocyte dynamics in normal human liver and provide a baseline for understanding how such dynamics may be modulated in diseased liver.

cell biology↗