Hunter Eby

Osteoarthritis (OA) affects women more often than men, and estrogen has been implicated in joint homeostasis, yet its effects on meniscal fibrochondrocytes (MFCs) remain poorly defined. We reanalyzed a public RNA sequencing dataset (Gene Expression Omnibus, GSE199087) of MFCs from two age-matched donors, one female and one male (both 47 years old). Cells from each donor were treated in triplicate with pulsed 17β-estradiol (E2, 240 µM for 1 h every 24 h over 72 h) or vehicle control. Differential expression was assessed with limma-voom, and pathways were identified with Gene Set Enrichment Analysis (GSEA), Enrichr, and iLINCS, retaining only Gene Ontology terms supported by all three. In the female donor’s cells, E2 upregulated DNA replication and cell-cycle pathways and lowered MMP1, MMP2, IL12A, and MYD88. In the male donor’s cells, E2 upregulated chromatin remodeling and developmental signaling pathways, with NOTCH1 among the leading-edge genes, and downregulated antigen presentation pathways and mitochondrial genes. At the gene level, some changes were shared by both donors, including lower TIMP1. Because each sex was represented by one donor, these differences cannot be attributed to sex with confidence. The findings are hypothesis-generating and identify candidate pathways for validation in larger, sex-balanced cohorts.

Pediatric anxiety, depression, and suicide rates are on the rise across the U.S. and Ohio. This mental health crisis has placed significant burden on both the emergency department and primary care providers. The emergency department does not have the resources for the long-term care of pediatric patients struggling with mental health. Furthermore, primary care providers do not feel their training has equipped them to manage the psychiatric conditions plaguing today’s youth. To help address this crisis and decreased the number of patients resorting to emergency care, primary care and pediatric residency programs can implement seminars, simulations, and trauma-informed care trainings. Additionally, robust screening protocols, discussions about pediatric mental health in office, and increasing connections between physicians and mental health services will ensure patients are appropriately screened, diagnosed, and treated for psychiatric conditions.

Schizophrenia is a complex neuropsychiatric disorder with significant sex differences in onset, symptoms, and outcomes, suggesting that biological sex may influence disease mechanisms. However, molecular differences between males and females with schizophrenia remain poorly defined. This study examined sex-specific transcriptional alterations in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia using publicly available RNA-sequencing data (GSE144136). Differential gene expression (DGE) analyses were performed separately for male and female cohorts, followed by gene set enrichment analysis (GSEA), leading-edge (LE) gene analysis, and perturbagen signature matching using the Library of Integrated Network-Based Cellular Signatures (iLINCS). No genes reached significance after correction, but unadjusted analyses revealed marked sex differences. Using the uncorrected analysis, Males exhibited over 2,000 differentially expressed genes distributed evenly between up- and downregulation, whereas females showed a smaller set of differentially expressed genes that were skewed towards upregulation. Pathway-level analyses showed that males displayed upregulation of metabolic pathways and downregulation of synaptic transport processes, while females exhibited upregulation of immune pathways alongside downregulation of vesicle organization and phosphoinositide metabolism. LE gene analysis supported the pathway changes. iLINCS analysis further highlighted sex-specific drug candidates whose expression profiles were discordant schizophrenia-associated signatures. FDA approved medications with high discordance included JAK2/mTOR pathway inhibitors and metabolic regulators in males, and immune or hormonal modulators in females. Taken together, these results reveal divergent molecular signatures that may underlie sex differences in schizophrenia pathophysiology. The identification of candidate drugs with discordant transcriptomic effects suggests potential therapeutic avenues and emphasizes the importance of sex stratified approaches in schizophrenia research.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Protein kinases are central to healthy brain function, regulating critical cellular processes through complex signaling networks. However, understanding differences in kinase signaling of brain cells remains a preeminent challenge of neuroscience. This study aimed to characterize kinase pathways enriched in astrocytes and microglia isolated from male and female murine prefrontal cortex. Using the PamGene PamStation®12 platform, we discovered cell-type-specific kinomic profiles and computationally reconstructed each cell type’s unique active signaling protein-protein interaction network. Notably, our analysis revealed minimal overlap between kinase activity and respective cell-subtype specific kinase transcriptional profiles identified in the Allen Mouse Whole Brain Transcriptomic Cell Type Atlas, highlighting an important limitation of relying solely on gene mRNA expression levels for functional inference in kinase focused studies. These findings also suggest that cell- and sex-specific protein kinase signaling may influence susceptibility to deleterious brain conditions and consequently underscore the importance of considering activity as a biological variable in systems research, offering a new framework for developing targeted therapeutic interventions in precision medicine.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of canonical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.

Omics studies use large-scale high-throughput data to explain changes underlying different traits or conditions. However, omics analysis often results in long lists of pathways that are difficult to interpret. Therefore, it is of interest to describe a tool named PAVER (Pathway Analysis Visualization with Embedding Representations) for large scale genomic analysis. PAVER curates similar pathways into groups, identifies the pathway most representative of each group, and provides publication-ready intuitive visualizations. PAVER clusters pathways defined by their vector embedding representations and then identifies the term most cosine similar to its respective cluster’s average embedding. PAVER can integrate multiple pathway analyses, highlight relevant biological insights, and work with any pathway database.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.