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Recent Submissions

Embargo
Constitutive Deletion of the Obscurin Ig58/59 Domains Elicits Chamber-Specific and Sex-Specific Cardiac Remodeling
(2025) Brong, Annie; Kontrogianni-Konstantopoulos, Aikaterini
Obscurin is a giant cytoskeletal protein that supports muscle development, tethers intracellular compartments to the sarcolemma, and regulates contraction. In the Obscn-ΔIg58/59 mouse model, expressing obscurin lacking Immunoglobulin (Ig) domains 58 and 59, males exhibit atrial fibrillation accompanied by atrial and ventricular dilation. Following extensive characterization of Obscn-ΔIg58/59 ventricles, we hypothesized that Ig58/59 deletion elicits unique structural, electrical, and functional consequences in the atria. Indeed, electron micrographs of Obscn-ΔIg58/59 atria, but not ventricles, reveal altered ultrastructure with misaligned Z-disks. Spontaneous and stimulated Ca2+ cycling behavior are differentially disrupted in atrial cardiomyocytes from 6- and 12-month Obscn-ΔIg58/59 males. Furthermore, ΔIg58/59 atrial cells show an age-dependent deterioration of the transverse-axial tubule network. These alterations in sarcomeric structure and Ca2+-cycling are associated with changes in the expression and phosphorylation of telethonin (T-cap), theorized to tether t-tubules to the sarcomeric cytoskeleton, and JPH2, which links t-tubules to the sarcoplasmic reticulum. Our work in males indicates that the atria are principally and particularly affected by Ig58/59 elimination and that the Obscn-ΔIg58/59 model mirrors essential aspects of atrial cardiomyopathy. In stark contrast to the males in this line, Obscn-ΔIg58/59 females are phenotypically normal. We sequentially postulated that a) ovarian estrogens and b) dietary phytoestrogens insulate ΔIg58/59 females against cardiac pathologies. To this end, we a) surgically excised the ovaries (OVX) of young Obscn-ΔIg58/59 females or performed sham bilateral surgery, and b) switched them to a soy-free (phytoestrogen-free) chow. Depletion of endogenous and exogenous estrogens induces age-specific remodeling of the left ventricle in ΔIg58/59 females, while either age or stress unmasks arrythmias. Still, the soy-free OVX Obscn-ΔIg58/59 female phenotype is more muted than that of soy-fed Obscn-ΔIg58/59 males. Finally, we examined the effect of soy-diet on male cardiac physiology and found that a soy-free diet ameliorates cardiac dysfunction downstream of ΔIg58/59 deletion in males. Collectively, our work in both sexes emphasizes the profound capacity of phytoestrogens to alter cardiomyopathic phenotypes. Further, it suggests that while ovarian sex hormones (and dietary phytoestrogens) fortify female cardioprotection in this model, additional hormonal and perhaps chromosomal factors shield females facing Ig58/59 ablation.
Embargo
Epigenetic Changes and Gene Expression Dysregulation in Tongue Squamous Cell Carcinoma
(2025) Terry, Diane; Gaykalova, Daria
HPV-negative tongue squamous cell carcinoma (TSCC) is an aggressive subtype of oral squamous cell carcinoma (OSCC) with limited targeted therapies and poor prognosis, particularly in advanced stages. TSCC is frequently diagnosed at a late stage, when lymph node metastasis and local invasion are already present, contributing to poor clinical outcomes and limited therapeutic options. Despite advances in treatment, the 5-year survival rate for advanced TSCC remains around 40%, with minimal improvement over recent decades. To address the urgent need for more effective, biologically informed interventions, this thesis investigates the epigenomic and transcriptomic landscape of TSCC using both patient tissues and patient-derived xenograft (PDX) models. We generated the first enhancer and super-enhancer (ESE) data in primary TSCC by performing H3K27ac ChIP-seq and RNA-seq on matched tumor and adjacent normal tissues from 15 HPV-negative patients. This matched design enabled sensitive detection of tumor-specific regulatory alterations, identifying over 159,000 ESEs, including 6,473 disease-specific regions. Integration with transcriptomic data revealed that tumor-specific ESEs drive oncogene upregulation (e.g., KIF17, MET, PLEK2, SH2D5), while normal-specific ESEs are linked to downregulated tumor suppressors (e.g., SMIM5, SOSTDC1). To evaluate the fidelity of PDX models in recapitulating TSCC biology, we conducted a pilot study integrating spatial ATAC-seq and bulk RNA-seq across two matched tumor–PDX pairs. Twelve distinct clusters were identified, revealing differential expression of epithelial, mesenchymal, and partial epithelial-to-mesenchymal transition (pEMT) markers. Tumor samples exhibited elevated mesenchymal and pEMT signatures, one at invasive fronts, while PDXs retained higher epithelial marker expression. Cell type deconvolution uncovered diverse populations—including malignant cells, CAFs, TAMs, T cells, B cells, and endothelial cells—with spatial co-localization in perivascular niches suggesting functional crosstalk in immune infiltration and tumor expansion. Comparison to a larger TSCC cohort confirmed transcriptional similarity between tumors and PDXs, with regulatory RNA profiles showing stronger conservation across matched pairs. Together, these findings provide a spatially resolved, epigenetically informed framework for understanding TSCC heterogeneity and progression. They underscore the role of enhancer reprogramming, pEMT, and mesenchymal-like stromal cells in shaping tumor behavior and therapeutic resistance, and highlight the utility of PDX models and regulatory RNAs in guiding precision oncology for HPV-negative tongue cancer.
Open Access
Why AI Could Finally Crack the Global Mental Health Crisis
(2026-02-05) Wallace, Scott
1 billion people have a mental disorder right now. That’s one in seven humans walking around with diagnosable conditions that are destroying their quality of life. Depression is the leading cause of disability globally, not heart disease or cancer. In any other area of health, numbers like this would be treated as a five-alarm emergency, not an unfortunate background condition of modern life. Every 40 seconds, someone decides their mental suffering has become so unbearable that death is the better option. And here’s the part that should make you upset: fewer than 7% of people with mental disorders globally receive effective treatment. In low-income countries, that number drops to fewer than 10% receiving any care at all. Meanwhile, the crisis is accelerating. Anxiety disorders among adolescents have spiked in recent years. A large share of Gen Z report needing mental health help. Tens of millions of people live in areas with mental health provider shortages.
Open Access
Cultivating Resilience Through Inclusive Leadership
(Society for Human Resources Management's (SHRM), 2026-01-26) Teitelbaum, Aaron
Constant volatility and unrelenting change mark today’s business environment, in which only the most resilient teams thrive. In fact, 90% of C-suite leaders said the pace of change has accelerated since January 2025, with 84% expecting this pace to increase further, according to the Accenture Pulse of Change survey. Resilience enables teams to weather internal adjustments and external pressures and is linked to key markers of success such as innovation, engagement, and performance. Recent research from the McKinsey Health Institute showed that employees who scored high in resilience and adaptability were three times more likely to report high engagement and four times more likely to report innovative behaviors than their peers.
Embargo
Sleep Behaviors and Weight Status Among Children and Adolescents During the Coronavirus Disease 2019 Pandemic
(2025) Kim, Edward K.; Albrecht, Jennifer S.; Hager, Erin
Background: In the U.S., poor sleep is linked to childhood obesity. During the Coronavirus Disease 2019 (COVID-19) pandemic, home confinement and school closures intensified obesogenic sleep behaviors, potentially contributing to increased childhood obesity and overweight prevalence, particularly among marginalized children. Objective: To examine the association between sleep behaviors and weight in children (preschool) and young adolescents (school-aged) during the COVID-19 pandemic, exploring socioeconomic status and race/ethnicity as potential mediators of this association. Methods: We examined data from a longitudinal cohort study of U.S. children aged 4 to 15 years. Participating families were drawn from a COVID-19 family study, including data collected early and mid-pandemic, and included pre-pandemic data for those re-enrolled from two cluster randomized-controlled trials. Nighttime sleep behaviors were assessed using actigraphy for sleep onset trajectories and surveys for sleep disturbance and bedtime resistance. Regression models examined the association between these sleep behaviors and mid-pandemic BMI-for-age z-scores. Results: The investigation of objectively measured sleep onset in both preschool and school-aged cohorts revealed trajectory-defined shifts in sleep onset yet did not detect a statistically significant association with mid-pandemic BMIz after accounting for confounders. For school-aged children, sleep disturbance was a modest predictor of mid-pandemic BMIz after adjusting for sleep duration and other covariates, where a one-unit standard deviation change in sleep disturbance score was positively associated with mid-pandemic BMIz; however, this association attenuated after adjusting for baseline weight. Evidence also suggested that socioeconomic status was an effect modifier. For preschoolers, a statistically significant independent association between bedtime resistance and mid-pandemic BMIz was not observed, nor was there evidence that race/ethnicity moderated this relationship in this sample. Conclusions: Obesity prevention efforts should address multiple behaviors, including sufficient and high-quality sleep, to promote healthy weight rather than targeting single aspects of poor sleep. Sleep hygiene interventions are needed for vulnerable children affected most by public health emergencies. Future research should examine pediatric cohorts using comprehensive, long-term assessments of sleep exposures.