Hageman, E. | Search bioRxiv

bioRxiv2026

A two-step organoid screen identifies transient p53 activation as a senolytic strategy for radiation-induced salivary gland dysfunction

Radiotherapy significantly improves the survival of head and neck cancer patients. However, it frequently damages the salivary glands, causing persistent hyposalivation and xerostomia. Radiation-induced cellular senescence within the salivary gland stem/progenitor cell niche contributes to hyposalivation, suggesting that selective elimination of senescent cells could promote tissue recovery. However, the effectiveness of senolytic compounds is strongly context dependent, varying with tissue of origin and potentially impairing regenerative cells required for functional restoration. Here, we developed a two-step organoid-based screening methodology that integrates the preferential induction of apoptosis in irradiated, senescence enriched, salivary gland organoids with the preservation of stem/progenitor cell regenerative capacity. As a first step, the senolytic activity of candidate drugs was tested to identify drugs that induced apoptosis in senescent cells of irradiated organoids but were not or less toxic to unirradiated organoids. As a second step, the confirmed senolytic compounds were tested for effects on stem cell self-renewal potential. Using this approach, we identified Nutlin3a, an MDM2 inhibitor and p53 activator, as the compound with the most favorable toxicity profile in salivary glands. Last, we confirmed the anti-senescence and pro-regenerative potential of Nutlin3a in an in vivo mouse model of radiation-induced hyposalivation, where localized Nutlin3a delivery resulted in a robust increase in saliva production, as early as two weeks after administration. These findings establish an organoid-based strategy for identifying tissue-adapted senolytic interventions and propose transient local p53 activation with Nutlin3a as a potential approach to mitigate radiation-induced salivary gland dysfunction.

cell biology↗

bioRxiv2025

Sub-daily Bermuda Atlantic Time Series virus sampling reveals taxonomy, host, and functional differences at the population, but not community level

Ocean microbes contribute to biogeochemical cycles and ecosystem function, but they do so under top-down pressure imposed by viruses. While viruses are increasingly understood spatially and beginning to be incorporated into predictive modeling, high-frequency ocean virus dynamics remain understudied due to methodological challenges. Here we sampled stratified Bermuda Atlantic Time Series (BATS) waters for 112 hours at sub-daily 4-(surface) or 12-(deep chlorophyll maximum) hour intervals, purified viral particles from these samples, sequenced their metagenomes, and used the resulting data to characterize high-frequency virus community dynamics. Aggregated community diversity metrics changed with depth, but were not statistically significant temporally at a fixed location. However, finer-scale population-level analyses revealed both depth and temporal change, including physicochemical depth-driven differences and, in surface waters, thousands of viral populations that exhibited statistically significant diel rhythms. Statistical analyses revealed three main archetypes of temporal dynamics that themselves differed in abundance patterns, host predictions, viral taxonomy, and gene functions. Among these, highlights include viruses resembling an archetype with a night peaking pattern in activity that include an over-representation of viruses that putatively infect Prochlorococcus, a phototrophic cyanobacteria. Together, these efforts provide baseline community-and population-scale short-time-frame observations relevant to future climate state modeling.

microbiology↗