Enrichment of G‐to‐U Substitution in SARS‐CoV‐2 Functional Regions and Its Compensation via Concurrent Mutations

We surveyed single nucleotide variant (SNV) patterns from 5 903 647 complete SARS-CoV-2 genomes. Among 10 012 SNVs, APOBEC-mediated C-to-U (C > U) deamination was the most prevalent, followed by G > U and other RNA editing-related substitutions including (A > G, U > C, G > A). However, C > U mutations were less frequent in functional regions, for example, S protein, intrinsic disordered regions, and nonsynonymous mutations, where G > U were over-represented. Notably, G-loss substitutions rarely appeared together. Instead, G-gain mutations tended to more frequently co-occur with others, with a marked preference in the S protein, suggesting a compensatory mechanism for G loss in G > U mutations. The temporal patterns revealed C > U frequency declined until late 2021 then resurged in early 2022. Conversely, G > U steadily decreased, with a pronounced drop in January 2022, coinciding with reduced COVID-19 severity. Vaccinated individuals exhibited a slightly but significantly higher C > U frequency and a notably lower G > U frequency compared to the unvaccinated group. Additionally, cancer patients had higher G > U frequency than general patients during the same period. Interestingly, none of the C > U SNVs were uniquely identified in 2724 environmental samples. These findings suggest novel functional roles of G > U in COVID-19 symptoms, potentially linked to oxidative stress and reactive oxygen species, while C > U remains the dominant substitution, likely driven by host immune-mediated RNA editing

Decreased Natural Killer Cell Function in Pediatric Severe Malaria in Areas of Higher Transmission

IUINatural killer (NK) cells inhibit Plasmodium falciparum parasite growth through antibody-dependent cellular cytotoxicity (ADCC) in vitro. Research conducted in malaria-endemic regions has demonstrated that memory-like NK cells are elevated in individuals exposed to malaria, exhibit enhanced ADCC activity, and correlate with reduced parasitemia and protection against uncomplicated malaria. However, the role of NK cells in pediatric severe malaria (SM) is not known. To evaluate the NK cell phenotype and function in SM, we used flow cytometry to evaluate CD56 bright, CD56 dim, and CD56 neg NK cell subsets in Ugandan children 6 months – 4 years of age with SM (cerebral malaria (CM), n=11), severe malarial anemia (SMA), n=10) and asymptomatic community children as controls (CC, n=19). Children were enrolled from sites of moderate (Jinja) and low (Kampala) malaria transmission. Analysis revealed that children with SM had a lower proportion of total NK cells and CD56 bright NK cells; however, absolute counts of NK cells per ml did not differ. In addition, LILRB1, an inhibitory receptor, was the only phenotypic marker whose proportions were significantly increased in children with SM compared to CC. Functionally, children with SM had a higher proportion of degranulating (CD107a+, IFN-γ-) memory-like NK cells. However, memory-like NK cell subsets from children with SM had a lower proportion of interferon-γ only (CD107a-, IFN-γ+)-production than CC. In addition, when comparing malaria transmission intensities with NK cell function, NK cells of children with SM in moderate transmission area exhibited a lower proportion of degranulation compared to the area of low transmission. Conversely, in low malaria transmission areas, NK cells of children with SM demonstrated a higher proportion of degranulation compared to CC. These findings elucidate distinct functional differences in NK cells among children with SM in areas of low versus moderate malaria transmission

The radiogenomic and spatiogenomic landscapes of glioblastoma and their relationship to oncogenic drivers

Background: Glioblastoma is a highly heterogeneous brain tumor, posing challenges for precision therapies and patient stratification in clinical trials. Understanding how genetic mutations influence tumor imaging may improve patient management and treatment outcomes. This study investigates the relationship between imaging features, spatial patterns of tumor location, and genetic alterations in IDH-wildtype glioblastoma, as well as the likely sequence of mutational events. Methods: We conducted a retrospective analysis of 357 IDH-wildtype glioblastomas with pre-operative multiparametric MRI and targeted genetic sequencing data. Radiogenomic signatures and spatial distribution maps were generated for key mutations in genes such as EGFR, PTEN, TP53, and NF1 and their corresponding pathways. Machine and deep learning models were used to identify imaging biomarkers and stratify tumors based on their genetic profiles and molecular heterogeneity. Results: Here, we show that glioblastoma mutations produce distinctive imaging signatures, which are more pronounced in tumors with less molecular heterogeneity. These signatures provide insights into how mutations affect tumor characteristics such as neovascularization, cell density, invasion, and vascular leakage. We also found that tumor location and spatial distribution correlate with genetic profiles, revealing associations between tumor regions and specific oncogenic drivers. Additionally, imaging features reflect the cross-sectionally inferred evolutionary trajectories of glioblastomas. Conclusions: This study establishes clinically accessible imaging biomarkers that capture the molecular composition and oncogenic drivers of glioblastoma. These findings have potential implications for noninvasive tumor profiling, personalized therapies, and improved patient stratification in clinical trials

CV1-secreting sCAR-T cells potentiate the abscopal effect of microwave ablation in heterogeneous tumors

Microwave ablation (MWA) triggers a weak systemic immune response that leads to the abscopal regression of distant metastases while killing local tumors, known as the abscopal effect. Combining MWA with chimeric antigen receptor (CAR)-T cells demonstrates promise in enhancing the abscopal effect in antigen-homogeneous tumors. However, the loss of the antigen recognized by CAR or intrinsic antigenic heterogeneity in solid tumors poses a major obstacle. SIRPα variant (CV1)-secreting CAR-T (sCAR-T) cells elicit an abscopal effect on distant tumors with antigen heterogeneity in mice receiving local MWA. Mechanistically, sCAR-T cells can locally eliminate antigen-positive tumors and secrete CV1, whereas the secreted CV1 can activate macrophages that migrate to non-ablated tumor sites in response to post-MWA chemokines, eliciting a macrophage-dependent abscopal effect that enables phagocytosis of antigen-heterogeneous cancer cells. This macrophage-dependent abscopal effect instigated by MWA and sCAR-T cells offers a clinically translatable strategy in metastatic solid tumors with antigen heterogeneity

Retinal dysfunction in APOE4 knock‐in mouse model of Alzheimer's disease

Introduction: Late-onset Alzheimer's Disease (LOAD) is the predominant form of Alzheimer's disease (AD), and apolipoprotein E (APOE) ε4 is a strong genetic risk factor for LOAD. As an integral part of the central nervous system, the retina displays a variety of abnormalities in LOAD. Our study is focused on age-dependent retinal impairments in humanized APOE4-knock-in (KI) and APOE3-KI mice developed by the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium. Methods: All the experiments were performed on 52- to 57-week-old mice. The retina was assessed by optical coherence tomography, fundoscopy, fluorescein angiography, electroretinography, optomotor response, gliosis, and neuroinflammation. mRNA sequencing was performed to find molecular pathways. Results: APOE4-KI mice showed impaired retinal structure, vasculature, function, vision, increased gliosis and neuroinflammation, and downregulation of synaptogenesis. Discussion: The APOE ε4 allele is associated with increased susceptibility to retinal degeneration compared to the APOE ε3 allele. Highlights: Apolipoprotein E (APOE)4 mice exhibit structural and functional deficits of the retina. The retinal defects in APOE4 mice are attributed to increased neuroinflammation. APOE4 mice show a unique retinal transcriptome, yet with key brain similarities. The retina offers a non-invasive biomarker for the detection and monitoring of Alzheimer's disease

Bridging the Gap: Student Access to IU Mental Health Resources: Chancellor's Student Mental Health Council Research Project 2025

The Chancellor's Student Mental Health Council at Indiana University Indianapolis conducted a study to understand student access to campus mental health resources. This presentation, led by Yamana Uno, Sofia Breuer, and Casandra Carrillo, explores the barriers students face in accessing mental health support, such as time constraints, overwhelming processes, long wait times, and limited service hours. Through focus groups, the research identifies key issues. The findings highlight the need for improved communication strategies, targeted outreach, and enhanced resource accessibility. Recommendations for immediate, short-term, and long-term actions are proposed to address these challenges, including the development of webinars, active involvement of mental health professionals, and the implementation of a Canvas course to centralize resources. The study aims to foster a more supportive and accessible mental health environment for all students at IU Indianapolis

A Case of Hybrid Cellular Neurothekeoma and Perineurioma With a Folliculin Gene Mutation

Hybrid peripheral nerve sheath tumors (PNSTs) are benign tumors that show features of more than one type of PNST. Benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma (BCPHTPCN) is a rare, recently described entity that shows various combinations of histomorphologic and immunophenotypic features of the PNSTs perineurioma and cellular neurothekeoma. Our case describes a middle-aged man initially presenting with an acute papulopustular rosacea flare. Rosacea treatment unmasked a prominent erythematous papule on the forehead. A biopsy was taken, and histopathological examination showed a proliferation of epithelioid, ovoid, and spindled cells arranged in a compact nested and intersecting fascicular growth. Immunohistochemical stains were positive for NKI/C3, CD10, PGP9.5, MITF, and GLUT-1. There was weak reactivity with EMA and minimal reactivity with Claudin-1. Tumor cells were negative for SOX10, CD163, CD68, CD34, ALK, and Pan-TRK. The patient was diagnosed with BCPHTPCN. DNA and RNA sequencing showed a folliculin (FLCN) gene mutation, which is most commonly associated with Birt-Hogg-Dubé syndrome. The patient underwent excision and has remained without recurrence or complications several months post-diagnosis. We hope to expand the clinical and histopathologic characteristics of this peculiar neoplasm, as well as provide additional insight that might improve our understanding of BCPHTPCN tumorigenesis

Traumatic Brain Injury Discharge Planning from Inpatient Rehabilitation: A Doctoral Capstone Report

IUIA traumatic brain injury (TBI) may have lifelong impacts on physical and psychosocial well-being, affecting patients and their support systems. Due to the complexity and variability of TBIs, determining post-discharge needs is often challenging. An interdisciplinary approach, combined with robust education and training, can aid in smoother transitions of care. However, barriers such as low health literacy and disorganized information delivery often hinder the discharge process. A multiphase needs assessment at the capstone site revealed similar gaps and barriers. The capstone student utilized the Person-Environment-Occupation-Performance model, Occupational Justice frame of reference, and Adult Learning theory to address the needs identified by the capstone site. The student provided the brain injury unit team at the inpatient rehabilitation hospital with information delivery checklists, an evidence-based resource binder, and access to a shared resource drive. Additionally, the capstone student conducted a brief educational session and collected pre- and post- survey data. Survey results confirmed the project was successful and positively impacted both the capstone student and the site.Occupational Therap

After 201 transplants, this surgeon feels most at home in the OR

Dr. Mark Turrentine: “There’s nothing else I can imagine ever having wanted to do more than this and feel like maybe I did something to impact somebody’s life for the better.