Uncovering the compounding effects of COVID-19 and racism on mental health disparities among biomedical PhD and MD students

The increasing visibility of mental health challenges for academic and graduate trainee populations has led to discussion of the role higher education institutions should play to address trainee mental health, particularly during the COVID-19 pandemic and ongoing racial injustice. To address the growing concern about training impacts on medical and biomedical doctoral trainee mental health, a cross-sectional study (n=957) was conducted using institutional annual survey data analyzed by type of training program, race/ethnicity, and survey year on measures of depression, anxiety, hazardous alcohol use, problems related to substance use, and suicidal ideation. Results indicated significant differences for rates of depression, anxiety, and suicidal ideation, with biomedical doctoral trainees showing greater incidence than medical doctoral trainees, and underrepresented minority trainees showing greater incidence than well-represented trainees. The concerningly high rates of depression, anxiety, and suicidal ideation among these trainee populations suggest that medical and biomedical doctoral training environments must be transformed in addition to expanding mental health support resources.

Novel gene-specific translation mechanism of dysregulated, chronic inflammation reveals promising, multifaceted COVID-19 therapeutics

Hyperinflammation and lymphopenia provoked by SARS-CoV-2-activated macrophages contribute to the high mortality of Coronavirus Disease 2019 (COVID-19) patients. Thus, defining host pathways aberrantly activated in patient macrophages is critical for developing effective therapeutics. We discovered that G9a, a histone methyltransferase that is overexpressed in COVID-19 patients with high viral load, activates translation of specific genes that induce hyperinflammation and impairment of T cell function or lymphopenia. This noncanonical, pro-translation activity of G9a contrasts with its canonical epigenetic function. In endotoxin-tolerant (ET) macrophages that mimic conditions which render patients with pre-existing chronic inflammatory diseases vulnerable to severe symptoms, our chemoproteomic approach with a biotinylated inhibitor of G9a identified multiple G9a-associated translation regulatory pathways that were upregulated by SARS-CoV-2 infection. Further, quantitative translatome analysis of ET macrophages treated progressively with the G9a inhibitor profiled G9a-translated proteins that unite the networks associated with viral replication and the SARS-CoV-2-induced host response in severe patients. Accordingly, inhibition of G9a-associated pathways produced multifaceted, systematic effects, namely, restoration of T cell function, mitigation of hyperinflammation, and suppression of viral replication. Importantly, as a host-directed mechanism, this G9a-targeted, combined therapeutics is refractory to emerging antiviral-resistant mutants of SARS-CoV-2, or any virus, that hijacks host responses.