Biology subjects

Brennan, T.

Publications and source records attributed to Brennan, T..

4 recordsLinked to original sources

bioRxiv2026

Chemotherapy-Induced Oral Mucosal Injury Is Defined by p53 Activation, Cell Cycle Arrest and Diverse Epithelial Progenitor Dynamics

Chemotherapy-induced oral mucositis is a common and debilitating complication, yet the mechanisms underlying oral mucosa injury and repair remain poorly defined. Using a mouse model of 5-fluorouracil (5-FU)-induced mucositis, we define gene networks and oral mucosal cellular landscape dynamics in response to chemotoxic stress. We show that 5-FU-induced epithelial atrophy is driven primarily by cell cycle arrest rather than apoptosis, despite concurrent activation of p53-dependent transcriptional programs linked to both cell fates within individual cells. Relative to intestine, the recovering oral mucosa exhibits a more effective cell cycle checkpoint response and uniquely undergoes metabolic reprogramming toward lipid oxidation. Single-cell RNA sequencing revealed putative epithelial progenitor populations with distinct responses to chemotherapy, including chemoresistant cells with a p53- and AP-1 complex gene signature, reminiscent of lung transitional cell states. These findings define diverse progenitor dynamics and p53-driven responses as key determinants of oral mucosal injury and repair following chemotherapy.

cell biology↗

bioRxiv2026

Neuron-Specific WWOX Gene Therapy Produces Dose-Dependent, Durable Rescue in a Model of WWOX-Related Epileptic Encephalopathy

Biallelic loss-of-function mutations in WWOX cause a spectrum of neurodevelopmental disorders, including the severe, early-onset WOREE syndrome, frequently associated with intractable epilepsy and premature mortality, and the milder SCAR12, characterized by subtler neurological manifestations. While neuronal replacement of WWOX has emerged as a potential therapeutic strategy, the parameters required for safe, durable, and clinically translatable gene delivery remain undefined. Here, we systematically delineate the determinants of effective WWOX gene therapy by evaluating promoter selection, cellular targeting, vector configuration, dose, and developmental timing in a severe Wwox-null mouse model. Neuron-restricted expression driven by the human Synapsin I promoter uniquely enabled sustained phenotypic correction, whereas ubiquitous or oligodendrocyte-restricted expression failed to confer durable benefit. To better regulate transgene expression, we generated a vector lacking the WPRE element, enabling dose calibration within a clinically relevant range. Comparative dose-response analyses identified an optimal therapeutic dose of AAV9-hSynI-WWOX that produced robust, dose-dependent rescue of survival and growth. Moreover, the rescued mice displayed glucose, behavioral function and fertility indistinguishable from WT mice, accompanied by long-term restoration of WWOX DNA, transcript, and protein across central and peripheral neural tissues without detectable hepatic expression. Neuronal WWOX reconstitution promoted widespread myelination and attenuated neuroinflammatory responses, including astrogliosis and microglial activation to levels indistinguishable from WT. Continuous electrocorticographic monitoring uncovered early postnatal neuronal hyperexcitability in Wwox-null mice, which was effectively suppressed by therapeutic WWOX delivery. Finally, our data define an early postnatal therapeutic window in Wwox-null mice, showing that treatment initiated between postnatal days 1 and 5 supports durable rescue. Together, these findings define a rigorously optimized, neuron-targeted AAV9-WWOX gene therapy framework and establish critical design and timing principles for translational treatment of WWOX-associated developmental and epileptic encephalopathies.

neuroscience↗

bioRxiv2025

Distinct neural temporal architectures encode rapid social expressions and sustained internal mood states

Affective processing operates across multiple temporal scales, from rapid social signaling through facial expressions to sustained internal mood states, yet the neural computational principles governing these different timescales remain unclear. Understanding how the brain implements distinct temporal architectures for momentary versus persistent affective phenomena is important to comprehending emotional processing and developing objective biomarkers for psychiatric conditions. Here, we introduced a multimodal approach combining automated facial expression monitoring and continuous intracranial electroencephalography in 2,037 electrode contacts across 16 epilepsy patients, over multiple days. Of these, 15 and 12 patients met criteria for facial expression and for mood analysis, respectively. Among patients meeting criteria, we captured 1,396 naturalistic smiles, and 3,746 neutral expressions - separated by at least 10 seconds, alongside 336 periodic mood assessments. This paradigm revealed distinct behavioral and neural computational architectures. Aperiodic neural activity in the lateral temporal cortex (79.5% accuracy) encoded facial expressions with high cross-participant generalizability. Mood states, however, showed different encoding patterns. Facial expressions provided no consistent mood indicators across participants. Critically, low-gamma power dynamics in limbic regions encoded mood states in only a subset of individuals (5 of 12 participants) with expression-mood behavioral correlations, suggesting a distinct encoding phenotype. Cross-domain analysis confirmed computational independence: neural features optimized for facial expression decoding failed to predict sustained mood states, and vice versa. These findings suggest that multiple neural mechanisms may influence underlying affective processing, with variations in their contributions between individuals. The results provide a framework for understanding individual differences in neural mood representation and establish methodological approaches for objective measurement of naturalistic affective behaviors.

neuroscience↗

bioRxiv2024

Spatio-temporal dynamics of the fibrotic niche in cardiac repair

The heart is one of the least regenerative organs in humans, and ischemic heart disease is the leading cause of death worldwide. Understanding the cellular and molecular processes that occur during cardiac wound healing is an essential prerequisite to reducing health burden and improve cardiac function after myocardial tissue damage. By integrating single-cell RNA-sequencing with imaging-based spatial transcriptomics, we reconstructed the spatio-temporal dynamics of the fibrotic niche after ventricular injury in adult mice. Our analysis reveals dynamic regulation of local cell communication niches over time. We identified interactions that regulate cardiac repair, including fibroblast proliferation silencing by Trem2high macrophages that prevents excessive fibrosis. Moreover, we discovered a rare population of dedifferentiating cardiomyocytes during early post-lesion stages, which was sustained by signals from myeloid and lymphoid cells. Culturing non-regenerative mouse cardiomyocytes or human heart tissue with these niche factors reactivated progenitor gene expression and cell cycle activity. In summary, this spatio-temporal cell type atlas provides valuable insights into the heterocellular interactions that control cardiac repair. HighlightsO_LIscRNA-seq and in situ sequencing reveal spatio-temporal dynamics of heart repair C_LIO_LILocal heterocellular communication niches coordinate overall wound response C_LIO_LIFibroblast cell cycle silencing by Trem2high macrophages suppresses excessive fibrosis C_LIO_LICardiomyocyte plasticity is promoted by myeloid and lymphoid cells C_LI

systems biology↗