Biology subjects

Watts, T.

Publications and source records attributed to Watts, T..

5 recordsLinked to original sources

bioRxiv2026

Preclinical Evaluation of Chemoradiation Resistance Using 18F-FDG PET/CT in Head and Neck Squamous Cell Carcinoma

PurposeThere is an urgent need for improved prognostic tools and biological understanding of chemoradiation resistance in head and neck squamous cell carcinoma (HNSCC). This study established a preclinical imaging dataset aimed at identifying prognostic imaging features from 18F-FDG micro-PET/CT scans in HNSCC mouse models. MethodsThree orthotopic murine models were utilized: two human papillomavirus (HPV)-negative (MOC1, MOC2) and one HPV-positive (MLM1). When tumor volume exceeded 50 mm3, chemoradiation was initiated using cisplatin (5 mg/kg) and image-guided radiation therapy (8 Gy) on days 0 and 7. 18F-FDG micro-PET/CT imaging was performed on day 14. Tumors were manually segmented on PET/CT, and quantitative image features including tumor volume, SUVmean, and SUVmax were extracted. Treatment response was evaluated by relative tumor size on day 11 compared to day 0. Tumor growth and survival were compared across models using multiple-effects model and log-rank. Imaging feature associations were evaluated by Mann-Whitney U tests. Associations between survival, SUVmax, and tumor volume were assessed using Cox proportional hazards modeling and Kaplan-Meier analysis with log-rank testing. ResultsA total of 121 mice were treated and imaged. Significant differences in tumor growth and survival were observed among the three models (p < 0.01 for pairwise growth comparisons; p < 0.0001 for survival). Day 11 treatment response groups demonstrated significantly different growth trajectories following chemoradiation (p < 0.0001). SUVmax was significantly associated with survival (p = 0.0009), whereas SUVmean was not significant (p = 0.13). PET tumor volume demonstrated the strongest association with survival (p < 0.0001). A multivariate Cox proportional hazards model incorporating SUVmax and tumor volume significantly stratified survival risk (p < 0.0001). ConclusionOverall, these findings demonstrate that 18F-FDG PET/CT-derived metrics, particularly SUVmax and tumor volume, are robust predictors of chemoradiation response in orthotopic murine models of HNSCC.

cancer biology↗

bioRxiv2025

Atmospheric hydrogen consumption is regulated by catabolite repression in mycobacteria

Consumption of atmospheric hydrogen (H2) enables diverse aerobic microorganisms to grow and persist in resource-deprived environments. In the aerobic saprophyte Mycobacterium smegmatis, hydrogen oxidation is catalyzed by two differentially expressed, high-affinity, oxygen-insensitive uptake hydrogenases, Huc and Hhy. Huc enables mixotrophic growth and facilitates the transition from growth to dormancy. Although the huc operon is known to be upregulated in response to organic carbon deprivation, the specific signals and regulators modulating its expression remain unresolved. Here, we show that GylR, a glycerol-3-phosphate-sensing regulator of glycerol metabolism, plays a role in repression of huc expression in response to the availability of glycerol but not other carbon sources. Based on proteomic analyses and activity assays, mutation or knockdown of gylR leads to enhanced Huc production and activity. GylR and other key catabolite repressor proteins (Crp1, Crp2) do not directly bind the huc operon, indicating repression is mediated by unidentified transcription factors, with GylR acting as an upstream sensor. Here, we present data that suggests atmospheric H2 oxidation is regulated in response to organic carbon source availability through the process of catabolite repression. By identifying a key signal that prompts atmospheric H2 oxidation, these findings advance understanding of how aerobic bacteria adapt to changing environmental conditions and suggest that organic carbon levels are a key factor regulating the main sink of atmospheric H2 in soils globally. ImportanceSoil microorganisms collectively consume 70 million tonnes of atmospheric H2 a year, regulating atmospheric composition and climate change. In turn, consuming this dependable trace gas enables these microorganisms to survive even when their preferred organic energy sources are exhausted. Despite the importance of H2 consumption for soil biodiversity and atmospheric regulation, the signals and sensors that regulate this process remain to be understood. Here, we demonstrate that a model soil bacterium turns on the machinery required for atmospheric H2 consumption in direct response to being limited by organic carbon availability, through the process of catabolite repression. Specifically, in the absence of a sensor of the organic carbon source glycerol, a H2-consuming hydrogenase is highly expressed and active. These findings suggest that organic carbon levels have a major role in regulating trace gas oxidation, with implications for predicting how trace gas consumption and soil biodiversity respond to environmental change.

microbiology↗

bioRxiv2025

Declining intracellular proteostasis capacity drives misfolded protein secretion in senescent human cells.

Healthy protein homeostasis ( proteostasis) relies on tightly-regulated protein quality-control (PQC) circuits that co-ordinate sequestration and clearance of potentially toxic aggregation-prone proteins, arising from various internal or external stress throughout an organisms lifespan. At the protein level, proteotoxic stress responses typically involve extensive poly-ubiquitylation and sequestration of aggregation-prone proteins and PQC factors into various protective cytoplasmic and nuclear granules. However, much of our current understanding regarding this aspect of stress responses in humans stems from research in proliferating cells--despite growing evidence that stress responses vary considerably at the transcriptional level across cell proliferation states. Here, we show that the senescent cellular state--considered a major contributor to ageing-associated degeneration due to a chronic inflammatory phenotype--re-wires PQC and expels the misfolded protein load to mitigate proteotoxic stresses. Starting with a multi-dimensional transcriptomics and proteomics approach for measuring levels of total, poly-ubiquitylated, and granule-forming proteins, we have discovered a clear point of divergence between senescent and proliferating or quiescent human cell states in their responses to proteotoxic stress. Although the proteins that were poly-ubiquitylated and degraded during stress were largely conserved across states, the stress-induced sedimentation of a large number of disease-associated RNA-binding proteins (including TDP-43) was impaired only in the senescent state. Strikingly, TDP-43, as well as several other misfolded proteins, were actively secreted through the endo-lysosomal system by a diverse range of senescent cells during acute or chronic stress, through a process that requires the vesicle-associated HSP70 co-chaperone DNAJC5--an established risk factor for several neurodegenerative diseases. Misfolded protein secretion could be rescued by increasing intracellular HSP levels in shallow but not deep senescence, suggesting that secretion is a proteostatic adaptation that becomes less reversible over time. Our findings reveal an unappreciated aspect of the senescent-cell secretory phenotype, which may have important consequences for the non-cell-autonomous impact of senescence at the level of tissue resilience and frailty.

cell biology↗

bioRxiv2024

Concerted modulation of spontaneous behavior and time-integrated whole-brain neuronal activity by serotonin receptors

Serotonin neurons from the raphe nuclei project across the entire brain and modulate diverse physiology and behavior by acting on over a dozen receptors. Here, we took a step towards dissecting this complex process by examining the effects of agonists and antagonists of four widely expressed serotonin receptors (2A, 2C, 1A, and 1B) on spontaneous mouse behavior, which we related to time-integrated whole-brain neuronal activity as assessed by the expression of Fos, a canonical immediate-early gene product. Low-dimensional representations of behavioral and Fos map data revealed the dominant factors of variation in each domain, captured predictable differences across drug groups, and enabled predictions of behavioral changes following perturbations in Fos maps and vice versa. Our study provides a rich resource describing the effects of manipulating serotonin receptors on animal behavior and whole-brain integrated neuronal activity. It also establishes an experimental and analysis paradigm for interrogating the relationship between behavior and neuronal activity across different time scales.

neuroscience↗

bioRxiv2020

Intact nucleosomal context enables chromodomain reader MRG15 to distinguish H3K36me3 from -me2

A wealth of in vivo evidence demonstrates the physiological importance of histone H3 trimethylation at lysine 36 (H3K36me3), to which chromodomain-containing proteins, such as MRG15, bind preferentially compared to their dimethyl (H3K36me2) counterparts. However, in vitro studies using isolated H3 peptides have failed to recapitulate a causal interaction. Here, we show that MRG15 can clearly discriminate between synthetic, fully intact model nucleosomes containing H3K36me2 and H3K36me3. MRG15 docking studies, along with experimental observations and nucleosome structure analysis suggest a model where the H3K36 side chain is sequestered in intact nucleosomes via a hydrogen bonding interaction with the DNA backbone, which is abrogated when the third methyl group is added to form H3K36me3. Hence, this mechanism provides a methyl-switch for contextdependent reader selectivity. These results highlight the importance of such intra-chromatin interactions in understanding epigenetic regulation, a feature which is absent in commonly-used peptide or histone-only models.

biochemistry↗