Digital Commons Network^™

Notch Signaling Regulates The Secretion Of Pro-Metastatic Factors In Extracellular Vesicles In Liposarcoma, Menchus Quan, Yi-Kai Liu, Ying Zhao, Madeline Kay, Kai Sun, Timothy P Gavin, Raphael E Pollock, W Andy Tao, Shihuan Kuang

The Brown Foundation: Institute of Molecular Medicine

Notch signaling is an emerging regulator of liposarcoma (LPS), but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters the proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile the EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice, and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favor tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that …

Myeloid Mmp14 Couples Extracellular Proteolysis To Inflammatory And Metabolic Remodeling During Obesity, Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun

The Brown Foundation: Institute of Molecular Medicine

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring …

The Biological Response Of Human Np Cells To Soluble Collagen Vi, Jonathan Dalton, Srikanth N. Divi, Yasmine Eichbaum, Panya Luksanapruksa, Mitchell K. Ng, Rachel Huang, Alan S. Hilibrand, Alex R. Vaccaro, Dessislava Z. Markova, Christopher K. Kepler

Department of Orthopaedic Surgery Faculty Papers

Extracellular matrix (ECM) dysregulation plays a significant role in the development of intervertebral disc disease (IVDD). The ECM around the chondrocytes in the nucleus pulposus (NP) is unique in that it contains ColVI. While linked to chondrocyte proliferation in cartilage, ColVI's specific role in IVD degeneration is less clear. Our aim was to determine the expression of ColVI in NP cells from degenerative IVDs, along with the effects of soluble ColVI on NP cells. Thus, we compared the expression levels of ColVI in human degenerated IVD samples, along with the effect of soluble ColVI on primary human NP cells. A …

Neural-Immune-Cardiovascular Axis: From Mechanistic Crosstalk To Therapeutic Targets In Cardiovascular Disease, Junkang Cheng, Shuang Gao, Haowei Zhang, Wei Gao, Zeyuan Mei, Xiaoling Liu, Jocelyn Gao, Chenghu Guo, Guipeng An

Student Papers, Posters & Projects

The neural-immune-cardiovascular axis represents an emerging and highly integrated physiological and pathophysiological concept, describing a complex bidirectional communication network between the nervous, immune, and vascular systems. This review systematically examines the pivotal role of this axis in maintaining cardiovascular homeostasis and in the pathogenesis of cardiovascular diseases. We first provide an overview of the fundamental signaling pathways between the components of this axis. Subsequently, we delve into the specific crosstalk mechanisms within the axis in the context of major cardiovascular conditions, including atherosclerosis, hypertension, and heart failure. A central focus is placed on critically evaluating the potential therapeutic targets and …

Cervical Cancer Screening Coverage And Associated Factors Among Women Aged 25-59 In Eswatini: Insights From The 2021 Population-Based Hiv Impact Assessment (Phia), Abenezer Melaku Tafese, Bikiltu Dirbaba, Meseker Fentie, Charnita Zeigler-Johnson

College of Population Health Faculty Papers

BACKGROUND: Cervical cancer is the most common cancer and the leading cause of cancer mortality among women in Eswatini, which reported the highest cervical cancer incidence and mortality rates globally in 2022. However, recent nationally representative published data on cervical cancer screening coverage in Eswatini remain limited. This study aimed to estimate cervical cancer screening coverage and identify factors associated with screening uptake among women aged 25-59 years in Eswatini.

METHOD: Data were drawn from the 2021 Eswatini Population-based HIV Impact Assessment (PHIA), a nationally representative cross-sectional household survey. Survey-weighted bivariable and multivariable logistic regression analyses were conducted to identify …

Rsv Can Infect The Human Nasal Epithelium Via The Basolateral Route And Shows Distinct Subgroup Infectivity And Basal Cell Tropism, Ashley Murray, Divya Nagaraj, Emily M Schultz, Gina Aloisio, Erin Nicholson, Sarah E Blutt, Vasanthi Avadhanula, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) causes millions of lower respiratory tract infections (LRTIs) in young children, older adults, and immunocompromised populations every year. RSV infection initiates in the upper respiratory tract and can progress to the lower airways, resulting in bronchiolitis, pneumonia, and even death. RSV primarily infects epithelial cells apically, but we hypothesized that basolateral exposure of the respiratory epithelium could provide an alternative mechanism of infection that contributes to LRTI development. Using a human nose organoid-air-liquid interface (HNO-ALI) model, we performed apical and basolateral inoculations with contemporaneous RSV strains (RSV/A/Ontario [RSV/A/ON] and RSV/B/Buenos Aires [RSV/B/BA]) representing the two RSV …

Optimising Professional Support For Doctors Who Experience Work Performance Issues: A Realist Evaluation, Nicola Brennan, Ellie Reynolds, Tristan Price, Geoff Wong, Jennifer Cleland, Helen Lloyd, Lyndsey Withers, Thomas Gale

Peninsula Medical School

Background The optimal performance of doctors is critical to delivering high-quality, safe healthcare. However, 6–12% of doctors may experience challenges that impact their work performance. In many countries, including the UK, there is variation in the practice and quality of professional support services between different types of organisations. The aims of our study were (1) to identify why, how, in what contexts and for whom professional support works, (2) to develop a guide for healthcare organisations to use to optimise professional support.Methods We carried out a realist evaluation consistent with Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) II standards. …

Tau Seeds Induce Neurofibrillary Tangle Formation Across Brain Regions Via Individual-Specific Connectivity, Audrey J Weber, Bernard Ng, Kelsey M Greathouse, David A Bennett, Shinya Tasaki, Chris Gaiteri, Jeremy H Herskowitz

Faculty, Staff and Student Publications

The spread of tau pathology across the cerebral cortex is closely tied to cognitive decline in Alzheimer's disease (AD). To investigate mechanisms underlying tau spread, we measured bioactivity of tau seeds from inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) synaptosomes in 128 individuals and demonstrated that tau seed bioactivity associates with tau phosphorylation, neurofibrillary tangles (NFTs), and cognitive impairment. Incorporating genotype data from the same individuals within a Mendelian randomization framework showed that tau seeds in ITG induce NFTs locally as well as drive tau seeds and NFTs in SFG. Integrating antemortem functional magnetic resonance imaging data from …

Expert Opinion: Management Of Intraocular Inflammation And Vasculitis After Intravitreal Pegcetacoplan For Geographic Atrophy, Thomas Albini, Steven Yeh, Carl Regillo, Roy Schwartz, Philip Ferrone, Caroline Baumal, Charles Wykoff

Wills Eye Hospital Papers

BACKGROUND AND OBJECTIVE: This expert opinion review is intended to provide guidelines for diagnosis and management of intraocular inflammation (IOI) and vasculitis following pegcetacoplan.

PATIENTS AND METHODS: A case series of all post-marketing reports classified by experts as definite or suspected vasculitis over an 18-month period was assessed.

RESULTS: A total of 306,000 pegcetacoplan intravit real injections were given in the real world between March 1, 2023, and August 31, 2024. Twenty-four eyes from 22 patients (mean age 76 years, 59% female) with definite or suspected vasculitis were evaluated. Comorbidities included hypertension (55%), hypo thyroidism (27%), and recent COVID-19 infection …

Bridging Pediatric To Adult Care In Cystinosis: A Scoping Review Of Healthcare Transition Of Care Protocols And A Roadmap For Future Practice., Sanat Subhash, Nicholas Pantelakis, Kyle Backston, Ruhaan Bajpai, Amir Safadi, Brandon Petrovich, Bradley A. Warady, Maria Diaz-Gonzalez De Ferris, Rupesh Raina

Manuscripts, Articles, Book Chapters and Other Papers

Cystinosis is a rare lysosomal storage disorder that affects approximately 1 in 100,000 to 200,000 live births worldwide. Long-term graft success in cystinosis depends on cysteamine adherence and structured multidisciplinary transition, supported by protocols developed by both pediatric nephrologists and hospital organizations. This review explores institutional and regional care models, structured programs such as the RISE protocol and Got Transition's Six Core Elements, and major barriers including adult nephrology expertise, psychosocial stressors, and insurance coverage gaps. Additionally, we explore the impact of digital health tools for their role in supporting cysteamine adherence and maintaining continuity of care. Emerging technologies such …

Llm-As-A-Judge For Infection Prevention And Control And Antimicrobial Resistance Impact: Comparing Three Main Llms Vs. Human Experts' Assessment, Marcello Di Pumpo, Leonardo Villani, Maria Rosaria Gualano, Danilo Buonsenso, Francesca Raffaelli, Daniele Donà, Patrizia Laurenti, Vittorio Maio, Stefania Boccia, Walter Ricciardi

College of Population Health Faculty Papers

BACKGROUND: Large language models (LLMs) are increasingly used to generate health information, yet their reliability as evaluators remains unclear. This study investigated the feasibility of an LLM-as-a-judge methodology in the context of infection prevention and antimicrobial resistance (AMR), comparing automated ratings with human expert benchmarks.

METHODS: We performed a secondary analysis of an expert-annotated dataset of health messages. Three leading LLMs (ChatGPT, Claude, Gemini) independently evaluated the same messages using an adapted DISCERN tool across five domains: information reliability, quality, AMR impact, persuasiveness, and overall score. We utilized descriptive statistics, intra-rater reliability tests, and mixed-effects ordinal regression to analyze divergence …

Subjective Sleep Disruption, Coping, And Anxiety And Related Symptoms In The Perinatal Period: Findings From A Longitudinal Study, Rebecca C Cox, Caroline P Hoyniak, Jack Samuels, Jonathan S Abramowitz, Gerald Nestadt, Eric A Storch, Rashelle Musci, Paul Nestadt, Lauren M Osborne, Mary Kimmel

Faculty, Staff and Students Publications

Study objectives: Anxiety is common during the perinatal period and is associated with adverse maternal and infant outcomes, highlighting a need to identify predictors of perinatal anxiety. Accumulating research implicates sleep disruption in perinatal anxiety and related symptoms, including obsessive-compulsive symptoms. We examined the associations among insomnia symptoms and sleep duration with perinatal anxiety, obsessive beliefs, and obsessive-compulsive symptoms and the moderating role of coping from pregnancy through postpartum.

Methods: A sample of 231 women (agemean = 32.97 ± 4.36 years; 74% white) completed interview and self-report measures of sleep, coping, perinatal anxiety, obsessive beliefs, and obsessive-compulsive symptoms in early …

Unbiased Avidity-Based Isolation Of Antigen-Specific T Cells, Amanda Montoya, Meredith L Frank, Peixin Jiang, Hui Nie, Minying Zhang, Emily Bontekoe, Jared K Slone, Ludovica L Posta, Sofia Rosy Caterina Sorice, Tina Cascone, Maura Gillison, Don L Gibbons, Jianjun Zhang, Eleonora Dondossola, Lydia Kavraki, Pamela L Wenzel, John V Heymach, Alexandre Reuben

The Brown Foundation: Institute of Molecular Medicine

Background: Cancer immunotherapies have significantly improved treatment efficacy and patient survival by exploiting antigen-specific T cells to eliminate cancer cells. However, current approaches for identifying and isolating antigen-specific T cells typically require prior knowledge of target antigens, limiting discovery, and reducing the ability to consistently detect rare tumor-reactive T cells. We therefore sought to develop an unbiased platform for the identification and enrichment of antigen-specific T cells using naturally processed and presented tumor antigens.

Methods: We developed ATTACH (Assessment of T cells Tethered to Antigen Class I Histocompatibility), a microfluidic platform that applies controlled shear stress and leverages tumor cells …

Longitudinal Genomic Surveillance Of Sars-Cov-2 In A University Microcosm Reflects Global Evolutionary Trends, Sankar Prasad Chaki, Melissa M Kahl-Mcdonagh, Benjamin W Neuman, Loni A Taylor, Rebecca S B Fischer, Blake M Hanson, Marlisa S Hardy, Jo Ann Culpepper, Eric Boerwinkle, Kurt A Zuelke

Faculty, Staff and Student Publications

SARS-CoV-2 transmission has declined, yet ongoing viral evolution continues to pose public health challenges. This study conducted long-term (2020-2024) genomic surveillance within a large and globally diverse university community. Viral genomes obtained from clinical (n = 1,786) and surveillance (n = 888) testing samples were classified under clade, lineage, and variant systems, and compared with global genomic data sets. Local patterns broadly paralleled global evolutionary trends, including the phased emergence of major variants, episodic introductions of new lineages, and shifts in dominant clades. Lineage diversity peaked during fall semesters and was highest among undergraduate-aged individuals, with similar distributions …

Erk-Mediated Phosphorylation Of Yap Defines A Noncanonical Fgf Signaling Mechanism In Stem Cells, Xiaolei Zhao, Shannon Erhardt, Li Tang, Xiaotong Chen, Stephen M Farmer, Zixiu Cheng, Wen Chen, Ella Ziyuan Lu, Kihan Sung, Chang-Ru Tsai, Mingjie Zheng, Sheng Zhang, Yang Liu, Jianxin Wang, Min Li, James F Martin, Jun Wang

Faculty, Staff and Student Publications

While Fgf and Hippo-Yap signaling are fundamental for proper development, homeostasis, and disease, their crosstalk remains largely unknown. Here, we identified that Yap and Taz, canonical Hippo effectors, function as noncanonical effectors of Fgf signaling to maintain the proper function of neural crest (NC) lineages. NC cells are a multipotent stem cell population during vertebrate embryogenesis that contribute to numerous structures and diverse cell lineages, including craniofacial and cardiac tissues, neurons, and suture mesenchymal cells (SMCs), a specified cell population required for cranial bone growth and repair. We observed that activation of Fgf signaling in NC cells and NC-derived SMCs …

A Phase-Ii Randomized Controlled Pilot Study Of Nicotinamide Riboside Supplementation In Older Adults With Amnestic Mild Cognitive Impairment, Christopher Martens, Kevin Decker, Theodore Deconne, Faria Sanjana, Fiona Horvat, Nicholas Rizzi, Catherine Awad, Elizabeth Habash, Joshua Hobson, Mary Kramer, Michael Armstrong, Nichole Reisdorph, Ryan Pohlig, Alyssa Lanzi, Curtis Johnson, Matthew Cohen, James Ellison

Department of Psychiatry and Human Behavior Faculty Papers

INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD+) may elevate risk of Alzheimer's disease.

METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD+ precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).

RESULTS: 42 participants completed the study (NR = 22, placebo = 20). Adherence was similar between groups with no serious adverse effects. Blood NAD+ increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). …

Board Exam Preparation Resource Trends In Academic Health Sciences Libraries Serving Colleges Of Osteopathic Medicine Programs., Joanne Muellenbach, Kyle Robinson, Hsin-Liang (Oliver) Chen, Harold S Bright, Lori Fitterling

PCOM Scholarly Works

BACKGROUND: The study seeks to identify the board exam preparation (prep) resources made available to medical students by academic health sciences libraries and other departments within U.S. colleges of osteopathic medicine (COM) programs, and the extent to which these resources are utilized by medical students and educators.

METHODS: The study was conducted in two phases. In phase one, forty-two COM library directors were invited to complete a survey regarding their usage, funding, and access models for available board prep resources. In phase two, semi-structured interviews were conducted via Zoom to explore the library's role in providing access to these resources. …

Blinded, Bias-Controlled Multi-Rater Evaluation Of Human-Versus-Ai Brain Metastasis Segmentation Using A Hybrid Foundation-Model Framework, Yiding Han, Enze Zhu, Mhd Hasan Ai Mekdash, Omar Awad, Piyush Pathak, Shixiao Liang, Daniel Allan Hamstra, Xizhe Zhang, Zaid Ali Siddiqui, Baozhou Sun

Faculty, Staff and Students Publications

Background: Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance.

Purpose: To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment.

Methods: TUM-SAM integrates nnU-Net-based lesion detection with a …

Mental Health Stigma In Latin American Youth With Obsessive-Compulsive Disorder, Ryan J Mccarty, Matias Jensen, Elissa Paz Jensen Santa Cruz, Melisa N Sagarnaga, Pamela Claisse Quiroz, Tomás Miño, Paola Giusti-Rodriguez, Mayra C Martinez Mallen, Maria B Moyano, Dayan Berrones, Jacey L Anderberg, Renee M Frederick, Hannah C Moore, Josselyn S Muñoz, Vanessa Zavala Cruz, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Working Group (Gttoc), Ogechi C Onyeka, Andrew D Wiese, James J Crowley, Eric A Storch

Faculty, Staff and Students Publications

Obsessive-compulsive disorder (OCD) is an impairing mental health condition that affects individuals across the lifespan. Some literature has evaluated mental health stigma in adults with OCD but limited attention has been given to youth, as well as those of Latino ancestry. The present study reported the extent of stigma experiences among Latin American youth with OCD, as well as examined sociodemographic, clinical and psychological correlates. 235 youth with clinician confirmed diagnoses of OCD from 10 North and South American countries completed questionnaires assessing stigma experiences, symptomatology, and functioning. Sociodemographic and clinical variables were also collected. The average OCD stigma response …

Perceptions Of Research Participation Among Underrepresented Groups: Insights Using Freelisting Methodology, Tamar Klaiman, Jasmine Silvestri, Emma Britez Ferrante, Dorothy Sheu, Adina Lieberman, Erich Dress, Modele Ogunniyi, Neal Dickert, Meghan Lane-Fall, Rosemary Frasso, Rachel Kohn

College of Population Health Faculty Papers

BACKGROUND: Low enrollment and retention in clinical research disproportionately impact Black, Hispanic or Latinx, women, and rural populations, undermining generalizability and perpetuating health disparities. However, few studies have compared mechanisms driving underrepresentation across populations. Freelisting is a qualitative methodology that elicits lists of terms, explores perspectives about domains, and identifies common themes within groups with shared characteristics; however, it has not been systematically applied to understand research participation across underrepresented populations.

OBJECTIVE: To explore perspectives on clinical research participation across underrepresented populations using freelisting methodology to ultimately inform culturally-responsive recruitment strategies.

METHODS: We conducted a web-based freelisting survey among adults …

Obesity And Keratoconus: A Mediation Study Based On The Chinese Keratoconus Cohort, Kaili Yang, Anqi Chang, Runqi Tu, Liyan Xu, Yuwei Gu, Qi Fan, Shanshan Yin, Yi Yuan, Yifan Wang, Chenchen Yin, Yonghao Zang, Changxiu Li, Chenjiu Pang, Daniela Oehring, Yibin Hao, Shengwei Ren

School of Health Professions

Purpose: Growing evidence indicates a strong association between obesity and keratoconus (KC), although the potential mediating factors remain largely unknown. This study aimed to explore the potential pathways through which corneal biomechanical and topographic parameters might link obesity and KC using structural equation modeling (SEM). Methods: This case-control study included 759 participants (363 patients with KC and 396 controls) from the Chinese Keratoconus (CKC) Cohort Study. Associations among body mass index (BMI), corneal biomechanical parameters, topographic parameters, and KC were analyzed using generalized linear regression models. SEM was used to construct latent variables for corneal biomechanical and topographic parameters. Three …

Pruritus Associated With Systemic Sclerosis: A Systematic Review Of Treatment-Based Clinical Trials, Kiana Mortezaei, Rishika Pasula, Meryem Nursoy, Amit Syal, Ioannis Panayiotou, Geeta Kumari, Andreas Chatzitoffis, Pavle Milutinovic, Olajumoke O. Fadugba, Chris T. Derk

Student Papers, Posters & Projects

This paper aims to examine the latest research on treatments for itch (pruritus) in people with systemic sclerosis (SSc), identify areas where information is lacking, and propose suggestions for future studies.A comprehensive literature search was performed in PubMed and Scopus in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies evaluating therapeutic interventions for pruritus in SSc. Eligible studies included randomized controlled trials, cohort studies, and case series comprising a minimum of three patients. Data extraction encompassed study design, patient demographics, pruritus assessment instruments including validated and non-validated measures, and clinical outcomes. Studies …

Rna G-Quadruplexes Function As A Tunable Switch Of Fus Phase Separation, Jenny L. Carey, Miyuki Hayashi, Emily A. Welebob, Laura R. Ganser, Huan Wang, Kerry Buckhaults, Jacquelyn A. Depierro, Zheng Shi, James Shorter, Sua Myong, Aaron R. Haeusler, Lin Guo

Department of Biochemistry and Molecular Biology Faculty Papers

Fused in sarcoma (FUS) undergoes liquid-liquid phase separation (LLPS) to support essential cellular functions, but aberrant phase transitions promote toxic aggregation in neurodegenerative disease. Short RNA oligonucleotides can reverse this behavior, yet the structural determinants that govern RNA activity remain poorly defined. Here, we identify RNA G-quadruplexes (rG4s) as tunable structural motifs that potently modulate FUS LLPS. rG4 activity depends on its concentration and is modulated by rG4 length and stability: increasing repeat number switches rG4s from inhibitor to nucleator of FUS assembly, whereas chemical modifications that stabilize rG4 enhance inhibitory function and render these activities resilient to ionic perturbation. …

Neddylation Maintains Oocyte Quality By Stabilizing Mitochondrial Transcription, Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J Mckenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas

Faculty, Staff and Students Publications

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle–stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated …

Macropinocytosis Inhibition Attenuates Profibrotic Responses In Lung Fibroblasts And Pulmonary Fibrosis Models, Ivan O Rosas, Aaron K Mcdowell-Sanchez, Santiago Sanchez, Juan D Cala-Garcia, Alan R Waich Cohen, Elisa Ruiz-Echartea, Scott A Ochsner, Daniel C Kraushaar, Lindsay J Celada, Dandan Sun, Francesca Polverino, Cristian Coarfa, Neil J Mckenna, Konstantin Tsoyi

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular environment under stress conditions. Here, we studied the role of macropinocytosis in experimental pulmonary fibrosis models. We found that macropinocytosis is increased in human lung fibroblasts (HLFs) derived from patients with IPF. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-β1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin-injured (Bleo-injured) mice. EIPA exerted its antifibrotic effects by regulating amino acid uptake, mammalian target of rapamycin complex 1 …

Autophagic Flux Blockade Under Hypocapnia Reveals Co2-Sensitive Regulation Of Autophagy-Lysosome Homeostasis, Naghmana Ashraf, Zhen Sun, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

Hypocapnia, a reduction in partial pressure of carbon dioxide (CO2), commonly occurs in clinical contexts such as mechanical ventilation, panic disorder, and brain injury, yet its impact on cellular homeostasis remains poorly understood. Given the central role of autophagy in stress adaptation, we investigated how low CO2 influences autophagic flux and lysosomal function. We found that hypocapnia induces autophagosome accumulation while impairing cargo degradation, indicating a blockade in autophagic flux. This response was accompanied by increased lysosome biogenesis but, paradoxically, reduced autophagosome-lysosome fusion and lysosomal proteolytic activity. Mechanistically, hypocapnia promoted TFE3 dephosphorylation and nuclear translocation, driving transcriptional activation of lysosomal …

Patterns Of Brain-Wide Associations Reflect Socioeconomics, Scott Marek, Meghan Rose Donohue, Nicole R Karcher, Caroline P Hoyniak, Roselyne J Chauvin, Ashley C Meyer, John Miller, Andrew N Van, Anxu Wang, Noah J Baden, Vahdeta Suljic, Kristen M Scheidter, Julia Monk, Forrest I Whiting, Nadeshka J Ramirez-Perez, Samuel R Krimmel, Athanasia Metoki, Rebecca F Schwarzlose, Steven E Petersen, Joan Luby, Benjamin P Kay, Evan M Gordon, Timothy O Laumann, Deanna M Barch, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Previous brain-wide association studies (BWAS) have linked specific environmental and behavioral variables to brain variability. In this work, we mapped 649 variables to children's brains and compared the resultant BWAS maps with each other and with neurobiological reference patterns. Socioeconomic status (SES) showed the strongest brain-wide associations. The SES associations were strongest in motor and sensory but not cognitive regions, a pattern shared across many BWAS maps, including intelligence quotient (IQ). A single, common BWAS brain pattern existed across variables that was most reflective of a child's socioeconomics. Adjusting for SES weakened brain-IQ associations, eliminating the BWAS motor and sensory …

The Effect Of Hunger On The Likelihood Of Glucose Excursions In Adults With Overweight Or Obesity: Continuous Glucose Monitoring And Ecological Momentary Assessment Observational Study, Byunggul Lim, Phrashiah Githinji, Yue Liao, Jacob Szeszulski, Alexandra L Macmillan Uribe, Rebecca A Seguin-Fowler, Jane Anderson, Chad D Rethorst

Faculty, Staff and Students Publications

Background: Maintaining stable glucose levels is important for metabolic health. Glucose excursions (GEs), which are marked increases in glucose following food intake, have been associated with a higher risk for cardiovascular disease and metabolic dysfunction. Individuals with overweight or obesity who do not have diabetes may still show impaired glucose regulation, as reflected in increased glucose variability. Hunger, as a real-time physiological cue, may be associated with subsequent glucose changes and represents a potential target for just-in-time adaptive interventions.

Objective: This study aimed to investigate the temporal relationship between self-reported hunger and subsequent glucose dynamics, including the likelihood of GE …

Cure Sickle Cell Initiative Recommendations On Common Data Elements For Sickle Cell Disease Gene Therapy Trials, Sophie Lanzkron, Victoria H. Coleman-Cowger, Alexis A. Thompson, C. Patrick Carroll, Traci Clemons, Michael Debaun, Julie Kanter, Punam Malik, Deepa Manwani, Francis John Pierciey, Mark C. Walters, Sherita Alai

Cardeza Foundation for Hematologic Research

The Cure Sickle Cell Initiative (CureSCi), created by the National Heart, Lung, and Blood Institute, has developed data standards to increase interoperability and meta-analysis of studies specifically investigating gene therapy for sickle cell disease (SCD). The aims of the CureSCi Common Data Elements (CDE) initiative are to facilitate the development of safe, effective, and accessible gene therapies. Five working groups (WGs) comprising people living with SCD, stakeholders, clinicians, and researchers reviewed current definitions used for SCD clinical studies, including those from the American Society of Hematology, US Food and Drug Administration, PhenX catalog of consensus measures for phenotypes and exposures, …

In Vivo Orf Overexpression Screening Identifies Ccn4 As A Regulator Of Glioblastoma Growth Validated Across Multiple Models, Pushan Dasgupta

Faculty, Staff and Students Publications

Despite current multimodal therapies for glioblastoma (GBM), its prognosis remains grim. Thus, a tremendous need exists to identify new genetic drivers that may serve as potential therapeutic targets in glioblastoma (GBM). We describe an in vivo overexpression screening strategy to identify drivers of glioblastoma where we have leveraged TCGA datasets to conduct a functional genomics screen of prioritized open reading frames (ORFs) that are overexpressed and/or amplified in GBM. To interrogate these potential drivers within a more relevant physiological context, the screening was accomplished in vivo in an orthotopic patient-derived glioma stem-like cell (GSC) model. Among 5 positive "hits" from …