Biology subjects

Dickson, S.

Publications and source records attributed to Dickson, S..

4 recordsLinked to original sources

bioRxiv2026

Therapeutic signature mapping of paired direct and indirect LPS injury in an ex vivo human lung perfusion platform reveals injury-specific druggable programs

Acute Respiratory Distress Syndrome (ARDS) remains highly morbid and lacks approved disease-modifying pharmacotherapies. Direct (pulmonary) and indirect (extrapulmonary) insults may initiate biologically distinct early injury programs, but human tissue-level evidence from the first hours is scarce. Here we establish a paired, acellular ex vivo lung perfusion (EVLP) platform using human donor lungs unsuitable for transplantation to model direct (endobronchial) and indirect (perfusate) lipopolysaccharide (LPS) injury within the same donor. We profiled lung tissue proteomes at 4 h post-insult and performed therapeutic nomination by querying proteomics-derived injury signatures against the CLUE L1000 perturbational compendium with independent cross-platform validation. Both models developed histological injury and robust cytokine release. Direct injury preferentially enriched neutrophil degranulation, extracellular matrix remodelling and metabolic reprogramming modules, whereas indirect injury showed prominent complement/coagulation perturbation with greater endothelial activation markers in perfusate. Cross-platform prioritisation converged on tractable signalling and epigenetic axes, including JAK/STAT, PI3K/AKT/mTOR, SYK, CDK and HDAC inhibitor classes - yielding a tiered shortlist for EVLP intervention testing. This intact human lung perturbation platform enables injury-stratified mechanistic inference and therapeutic prioritisation in early lung injury relevant to ARDS.

immunology↗

bioRxiv2025

Far-Ultraviolet Light Causes Direct DNA Damage in Human Lung Cells and Tissues

Far-ultraviolet C (Far-UVC) radiation, with a wavelength range from 200 to 235 nm, is germicidal and holds potential for clinical applications. However, its use against deep-seated and internal infections, such as those affecting the lungs, remains less well established. The safety profile of Far-UVC irradiation requires further investigation across different human tissues. In this study, we utilised a krypton-chloride (KrCl) excimer lamp and a pulsed laser system to examine the effects of Far-UVC irradiation on human lung cells in vitro and primary human tracheal tissue. Primary human tracheal tissue and cells exposed to continuous wave (222 nm) and pulsed 206 nm and 222 nm light at doses of 5, 25, and 50 mJ/cm2 exhibited Deoxyribonucleic acid (DNA) damage, including phosphorylation of {gamma}H2AX (Ser139). The continuous wave and pulsed 222 nm irradiation caused the formation of pyrimidine-pyrimidone (6-4) photoproducts. Irradiated human lung cells demonstrated reduced viability in vitro, and increased lactate dehydrogenase release into the culture medium 48 hours post-irradiation. Our findings reveal that even low doses of Far-UVC (206 nm, 222 nm) light can penetrate monolayers of human lung epithelial cells, causing direct DNA damage in the form of (6-4) photoproducts and DNA double-strand breaks, ultimately leading to cell death.

cell biology↗

bioRxiv2025

Colonic inflammation modulates the intestinal circadian landscape

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that carries significant morbidity. The circadian (24h) clock regulates many aspects of immunity and circadian disruption is implicated in inflammatory disease. We examined the impact of acute dextran sulphate sodium-induced colitis on the intestinal circadian landscape and investigated consequences of intestinal epithelial cell (IEC) clock disruption on immune function in health and under inflammatory stress. Within the inflamed colon, we observed attenuated IEC clock function. Furthermore, de novo oscillations in numbers of colonic regulatory T cells emerged, associated with diurnal variation in proliferation and activation markers. IEC-specific deletion of core clock gene Bmal1 drove alterations in the rhythmic colonic transcriptome (impacting key immune pathways) and marked damping of microbiota rhythmicity. IEC-specific Bmal1 deletion did not impact colitis severity. These results highlight the impact of colonic inflammation on circadian processes and suggest that circadian logic could be applied in IBD treatment.

immunology↗

bioRxiv2021

Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism

Mutualistic interactions with the commensal microbiota are enforced through a range of immune responses that confer metabolic benefits for the host and ensure tissue health and homeostasis. Immunoglobulin (Ig)A responses directly determine the composition of commensal species that colonize the intestinal tract but require significant metabolic resources to fuel antibody production by tissue-resident plasma cells. Here we demonstrate IgA responses are subject to diurnal regulation by dietary-derived metabolic cues and a cell-intrinsic circadian clock. Rhythmicity in IgA secretion conferred oscillatory patterns on the commensal microbial community and its associated metabolic activity, resulting in changes to metabolite availability over the course of the circadian day. Our findings suggest circadian networks comprising intestinal IgA, the diet and the microbiota align to ensure metabolic health. One-Sentence SummaryWe demonstrate diurnal rhythms in intestinal IgA act to cross-regulate oscillations in the abundance of commensal microbes to foster mutualism.

immunology↗