Digital Commons Network^™

Application Of Freezetb, A Targeted Nanopore Sequencing Assay, For Identification Of Drug Resistance And Lineages Among Pulmonary Tuberculosis Cases In Alaska, Bryce Inman, Jeremy Butler, Soren George-Nichol, Ganna Kovalenko, Theresa Savidge, Yvette Vergnetti, Catherine Pongratz, Elizabeth Bee, Andrew R Dinardo, Alexander Kay, Anna Mandalakas, Eric Bortz, Tara E Ness

Faculty, Staff and Students Publications

Alaska has the highest incidence of tuberculosis (TB) in the United States, with 8% mortality while undergoing TB treatment. With a quarter of TB cases lacking sputum culture to enable drug resistance testing, FreezeTB aimed to develop tools tailored to meet the challenges in Alaska while being translatable to other settings. We designed a rapid and cost-effective laboratory workflow and software to identify drug-resistant mutations in Mycobacterium tuberculosis using targeted next-generation sequencing (tNGS). FreezeTB, a Fast, Reliable, Economical Evaluation tool to Zap Endemic Tuberculosis, amplifies 22 gene loci associated with resistance to 16 anti-tuberculosis drugs. M. tuberculosis isolates from Alaska …

Tlr2 Agonism Suppresses Myeloid Leukemogenesis By Reprogramming Leukemia Stem Cells, Michael E. Lawler, Jennifer S. Romer-Seibert, Michael S. Bowman, Ramkrishna Mitra, Christine M. Eischen, Robert L. Bowman, Sara E. Meyer

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The consequences of activated innate immune signaling in acute myeloid leukemia (AML) is not well understood. Using ligands directed at the toll-like family receptors (TLR) in models of high-risk AML, we uncover that TLR2 ligands exert unique antileukemic effects that are distinct from other TLRs. Although TLR2 signaling broadly induces inflammatory gene expression in AML cells, at the single-cell level, cell-type-dependent, divergent transcriptional responses coordinate cellular outputs of proliferation, differentiation, cell death, and activation of immune cell function. TLR2 ligands were the only TLR agonists capable of extending survival of AML-bearing mice through leukemia stem cell (LSC) reprogramming that elevated …

Family Caregivers' Perspectives On Challenges And Support Needs In Hospital-Based Palliative Care For Persons Living With Dementia, Jung Kwak, Anita Chary, Sarah Stayer, Kwaku Duah Oppong, Sumin Yoon, Snehal Patel, Elizabeth A Kvale

Faculty, Staff and Students Publications

Palliative care needs of hospitalized persons living with dementia (PLWD) and their family caregivers remain poorly understood. This mixed-methods study explored caregivers' perspectives on challenges and support needs when hospitalized PLWD received specialist palliative care consultations. Thirty-two caregivers were recruited from two hospitals; 18 completed interviews and surveys, and 14 completed surveys only. Participants were racially and ethnically diverse (19% Black or African American, 34% Latino or Hispanic). Most identified as women (65%) and adult children (56%). Commonly reported challenges included managing health issues (59%), emotional distress (56%), and decision-making (47%). Thematic analysis of interviews revealed three themes: the value …

Autostent: A Semi-Automated Approach To Designing Customized 3d-Printed Oral Radiation Stents For Patients With Head And Neck Cancer, Anshuman Agrawal, Rance B Tino, Mohamed Zaid, Millicent Roach, Lianchun Xiao, Mark S Chambers, Anna Lee, Eugene J Koay

Faculty, Staff and Student Publications

Background: Oral stents may reduce toxicities during radiation therapy for head and neck cancer (HNC). Customized 3D-printed oral stents offer faster production and achieve comparable patient-reported outcomes to conventionally fabricated stents. However, their design process remains time-consuming, lacks standardization, and relies heavily on skilled technicians. We hypothesized that semi-automating the design process for 3D-printed, mouth-opening, tongue-depressing (MOTD) stents could standardize the design workflow and decrease design time.

Methods: Using oral stent design principles established over decades by oral oncologists, we created a customized computer program (Autostent) using MATLAB to semi-automate the design process of MOTD stents. We subsequently compared Autostent …

Disinhibited Behavior Associated With Rapid Clinical Response To Deep Brain Stimulation For Obsessive-Compulsive Disorder: Illustrative Cases, Sarah S Soubra, Tommy B Liu, Zain U Naqvi, Thomas Hamre, Danika L Paulo, Kalman A Katlowitz, Nisha Giridharan, Katie Van Arsdel, Jonathan H Bentley, Kasra A Mansourian, Davin Devara, Eric A Storch, Sarah R Heilbronner, Sameer A Sheth, Wayne Goodman, Nicole R Provenza

Faculty, Staff and Students Publications

Background: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) can alleviate symptoms of obsessive-compulsive disorder (OCD) refractory to conventional therapies. Overstimulation, however, can elicit pathological behaviors marked by disinhibition and recklessness.

Observations: Two patients with OCD underwent DBS of the VC/VS region and met responder status within 1 month of stimulation onset, as evidenced by a ≥ 35% reduction in their Yale-Brown Obsessive Compulsive Scale score. Notably, both patients exhibited signs of disinhibited behavior soon after DBS activation, including gambling, sleep disruption, and interpersonal relationship volatility. Through careful management, responder status persisted stably beyond the transient period of …

Comparing Diagnostic Tools For Heart Failure With Preserved Ejection Fraction Across Community And Clinical Cohorts, Luca Monzo, Olivier Huttin, Biykem Bozkurt, Kévin Duarte, Cecilia Linde, Lars H Lund, Camilla Hage, Erwan Donal, Martin Magnusson, Peter Nilsson, Margret Leosdottir, Erwan Bozec, Guillaume Baudry, Faiez Zannad, Nicolas Girerd

Faculty, Staff and Students Publications

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging, particularly in older adults. While the Heart Failure Association (HFA)-PEFF and H2FPEF Scores offer structured diagnostic approaches, their clinical utility is still debated. This study aims to compare the diagnostic accuracy of HFpEF Scores versus inclusion criteria used in sodium-glucose cotransporter-2 inhibitors (SGLT2i) trials, age-adjusted N-terminal pro B-type natriuretic peptide (NT-proBNP) thresholds and the universal definition of heart failure (HF).

Methods: Diagnostic tools were assessed using sex-weighted and age-weighted propensity score adjustment in individuals aged 60-80 years from two established HFpEF cohorts (MEtabolic Road to DIAstolic Heart Failure (MEDIA), …

Describing The Determinants Of Fluid Prescribing And Fluid Balance Optimization In The Pediatric Intensive Care Unit: A Qualitative Study At A Community Hospital, Salvador Roland Maffei, Graciela Sanabria, Matthew Pesek, Ayse Akcan-Arikan, Satid Thammasitboon, Patrick G Lyons

Faculty, Staff and Students Publications

Background: Critically ill children tend to receive fluid volumes exceeding physiologic requirements despite evidence demonstrating harm with increasing net positive fluid balance. However, interventions aimed at optimizing fluid balance have yet to demonstrate significant clinical benefit, likely because there are multiple drivers of this complex problem. In this study, we used qualitative inquiry to describe the current practice at a community pediatric intensive care unit and discover potential barriers and facilitators to clinical practice change.

Methods: We designed a semi-structured interview guide informed by the consolidated framework in implementation research (CFIR) and conducted interviews with attending physicians, dietitians, nurses, nurse …

Oculocardiac Reflex Causing Bradycardia In A Trauma Patient Following Firearm Injury, Jennifer E. Geller, Saba Daneshpooy, Sophia Block, Meera Kohli, Megan Lundy

Department of Surgery Faculty Papers

The oculocardiac reflex is a vagal response to pressure on the globe or periorbital structures resulting in a reduction in heart rate greater than 20 %. Here, we describe the case of a patient who sustained extensive craniofacial and orbital trauma from a firearm injury whose otherwise unexplained bradycardia resolved following surgical decompression.

Comparing The Effects Of Ect And Intravenous Ketamine In Psychiatric Patients With Major Depressive Episodes, Julia Myerson, Katrina A Rufino, Sanjay J Mathew, Marie Fletcher, Neil Puri, Hyuntaek Oh

Faculty, Staff and Students Publications

Background: Electroconvulsive therapy (ECT) and intravenous (IV) ketamine are treatments used for severe depression and/or treatment-resistant depression (TRD). ECT is considered one of the most effective treatments for severe depression, although there is debate within the field regarding the effectiveness between ECT and IV ketamine in comparable TRD patient groups.

Methods: This retrospective chart review of open-label, nonrandomized treatment from a psychiatric hospital compared the effects of up to three weeks of ECT and IV ketamine in patients with major depressive episodes (MDEs). Our cohort included 146 inpatients and outpatients aged 18 to 74 years old. 94 patients received subanesthetic …

Advancements In Understanding Spasticity: A Neuromusculoskeletal Modeling Perspective, Mohammad S Shourijeh, Argyrios Stampas, Shuo-Hsiu Chang, Radha Korupolu, Gerard E Francisco

Faculty, Staff and Student Publications

Spasticity, a complex consequence of upper motor neuron lesions, poses challenges for clinical assessment due to its neural and mechanical origins. Traditional scales like the Modified Ashworth and Tardieu Scales provide subjective, context-limited insights, often missing spasticity's dynamic nature. Neuromusculoskeletal (NMS) modeling offers objective, quantitative insights by integrating patient-specific muscle-tendon properties, reflex dynamics, and multi-joint biomechanics. This scoping review examines advancements in spasticity modeling, comparing mechanical, neurological, and integrated approaches, and their applications in conditions like cerebral palsy and stroke. We highlight barriers to clinical translation, including computational demands and regulatory challenges, and propose future directions, such as real-time simulation …

Imaging Features Of High-Grade Astrocytoma With Piloid Features: A Single Center Case Series, Heba Al Qudah, Jackson D Hamilton, Maria A Gubbiotti, Ahmed Msherghi, Hamza A Salim, Sahar Alizada, Ho-Ling Liu, Vinodh A Kumar, Max Wintermark, Rami W Eldaya

Faculty, Staff and Student Publications

High-grade astrocytoma with piloid features (HGAP) is a recently described IDH-wildtype tumor with limited literature describing its imaging features. We present our institution's experience and the largest imaging-focused cohort of HGAP reported to date, offering a comprehensive analysis of MRI features of seventeen intracranial and one spinal HGAP, while introducing novel imaging features that have not been previously described. These include focal areas of diffusion restriction, surrounding spiculated, finger-like enhancement and increased perfusion metrics. Additionally, we highlight imaging features of HGAP arising in patients with Neurofibromatosis Type 1, such as intraventricular tumor spread, unusual temporal lobe location and multifocal presentation.

Late Morbidity And Mortality In Survivors Of Childhood Ependymoma: A Report From The Childhood Cancer Survivor Study (Ccss), Katharine R Lange, Peter De Blank, Mengqi Xing, Sedigheh Mirzaei, Deo Kumar Srivastava, Kevin Oeffinger, Joseph Neglia, Kevin Krull, Paul C Nathan, Rebecca Howell, Kirsten K Ness, Lucie M Turcotte, Wendy Leisenring, Gregory T Armstrong, Tara Brinkman, Daniel C Bowers, Mehmet Fatih Okcu

Faculty, Staff and Student Publications

Background/objectives: Treatment of childhood ependymoma evolved from 1970 to 1999 by reducing radiation volumes and incorporating chemotherapy. The impact of these changes on long-term health outcomes remains unknown. In this report, we evaluated temporal changes in all-cause and cause-specific late mortality, chronic health conditions (CHCs), and subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort of adult survivors of pediatric ependymoma, diagnosed between 1970 and 1999.

Methods: A total of 404 five-year survivors of ependymoma (47.5% female, 80.7% non-Hispanic White, median 6 (range 0-20) years at diagnosis, 22 (5-49) years from diagnosis) diagnosed between 1970 and 1999 and …

Multisite Assembly Of Gateway Induced Clones (Magic): A Flexible Cloning Toolbox For Use In Vertebrate Model Systems, William B Gillespie, Yuwen Zhang, Oscar E Ruiz, Juan Cerda, Joshua Ortiz-Guzman, Michelle Sherman, Williamson D Turner, Gabrielle Largoza, Lili E Mosser, Esther Fujimoto, Chi-Bin Chien, Kristen M Kwan, Benjamin R Arenkiel, W Patrick Devine, Joshua D Wythe

Duncan NRI Faculty and Staff Publications

Here, we present MultiSite Assembly of Gateway Induced Clones (MAGIC), which leverages Gateway-based recombinatorial cloning technology for rapid, modular assembly of plasmids to facilitate transgenesis in cells and vertebrate animal models. The MAGIC collection of plasmids spans a range of in vitro and in vivo uses, from tools for optically and chemically tunable gene expression, to simultaneous expression of microRNAs and fluorescent reporters, to a suite of distinct subcellular compartmental fluorescent reporters, to Cre and Dre recombinase-dependent gene expression. MAGIC system components are compatible with existing MultiSite Gateway Tol2 systems currently used in zebrafish and mammalian lentiviral and adenoviral Destination …

Image-Based Meta- And Mega-Analysis (Ibmma): A Unified Framework For Large-Scale, Multi-Site, Neuroimaging Data Analysis, Nick Steele, Ashley A Huggins, Rajendra A Morey, Ahmed Hussain, Courtney Russell, Benjamin Suarez-Jimenez, Elena Pozzi, Hadis Jameei, Lianne Schmaal, Ilya M Veer, Lea Waller, Neda Jahanshad, Sophia I Thomopoulos, Lauren E Salminen, Miranda Olff, Jessie L Frijling, Dick J Veltman, Saskia B J Koch, Laura Nawijn, Mirjam Van Zuiden, Li Wang, Ye Zhu, Gen Li, Dan J Stein, Jonathan Ipser, Yuval Neria, Xi Zhu, Orren Ravid, Sigal Zilcha-Mano, Amit Lazarov, Jennifer S Stevens, Kerry Ressler, Tanja Jovanovic, Sanne J H Van Rooij, Negar Fani, Sven C Mueller, Anna R Hudson, Judith K Daniels, Anika Sierk, Antje Manthey, Henrik Walter, Nic J A Van Der Wee, Steven J A Van Der Werff, Robert R J M Vermeiren, Christian Schmahl, Julia I Herzog, Ivan Rektor, Pavel Říha, Milissa L Kaufman, Lauren A M Lebois, Justin T Baker, Isabelle M Rosso, Elizabeth A Olson, Anthony King, Israel Liberzon, Michael Angstadt, Nicholas D Davenport, Seth G Disner, Scott R Sponheim, Thomas Straube, David Hofmann, Guangming Lu, Rongfeng Qi, Xin Wang, Austin Kunch, Hong Xie, Yann Quidé, Wissam El-Hage, Shmuel Lissek, Hannah Berg, Steven E Bruce, Josh Cisler, Marisa Ross, Ryan J Herringa, Daniel W Grupe, Jack B Nitschke, Richard J Davidson, Christine Larson, Terri A Deroon-Cassini, Carissa W Tomas, Jacklynn M Fitzgerald, Jeremy Elman, Matthew Panizzon, Carol E Franz, Michael J Lyons, William S Kremen, Brandee Feola, Jennifer U Blackford, Bunmi O Olatunji, Geoffrey May, Steven M Nelson, Evan M Gordon, Chadi G Abdallah, Ruth Lanius, Maria Densmore, Jean Théberge, Richard W J Neufeld, Paul M Thompson, Delin Sun

Faculty, Staff and Students Publications

The increasing scale and complexity of neuroimaging datasets aggregated from multiple study sites present substantial analytic challenges, as existing statistical analysis tools struggle to handle missing voxel-data, suffer from limited computational speed and inefficient memory allocation, and are restricted in the types of statistical designs they are able to model. We introduce Image-Based Meta- & Mega-Analysis (IBMMA), a novel software package implemented in R and Python that provides a unified framework for analyzing diverse neuroimaging features, efficiently handles large-scale datasets through parallel processing, offers flexible statistical modeling options, and properly manages missing voxel-data commonly encountered in multi-site studies. IBMMA successfully …

Characterizing The Metabolites Of The Tyrosine-Kinase Inhibitor Pexidartinib In Mouse Feces, Urine, Plasma, And Liver, Xuan Qin, Si Chen, John M Hakenjos, Jian Wang, Lei Guo, Ashish Dogra, Zhaoyong Hu, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Pexidartinib (PEX, TURALIO®), a tyrosine kinase inhibitor, is approved for treating tenosynovial giant cell tumor in adults. However, its potential to cause fatal liver injury has prompted the U.S. FDA to issue a black box warning, and the mechanisms underlying its hepatotoxicity remain largely unknown. As biotransformation may contribute to PEX-induced hepatotoxicity, understanding its metabolism is essential. Our previous research indicated that PEX forms reactive metabolites in human and mouse liver microsomes and in human hepatocytes. We investigated PEX metabolism and liver distribution in mice with a focus on metabolite characterization. Our data shows that PEX is mainly excreted into …

Vitamin D Is Glucoprotective In Aging Males But Not Females, Olivia Z B Ginnard, Maria Morales, Ji Youn Youn, Yong Xu, Stephanie R Sisley

Faculty, Staff and Students Publications

Vitamin D supplementation is linked to many beneficial health outcomes in the geriatric population, such as decreased mortality, epigenetic aging, and fracture risk. Conversely, type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in …

A Role For Gut Mycobiome And Altered Fungal-Bacterial Interactions In Women With Endometriosis†, Chandni Talwar, Ashirbad Guria, Kristi Hoffman, Scott Biest, Patricia Jimenez, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Endometriosis is a gynecological pathology prevalent in reproductive age women in which the inner uterine wall (endometrium) grows outside as ectopic lesions. The inflammation resulting from these growing implants closely associates with disease severity, causing chronic pain and infertility. Emerging studies have found altered bacterial communities in endometriosis and a causal role for gut bacteria in endometriosis. However, the role of the gut mycobiome, i.e., the fungal component of the microbiome in endometriosis is a current knowledge gap that needs to be addressed. In this study, utilizing the stool samples from women with endometriosis, we found that the gut fungal …

“For Haitian Culture, Being Older [Is] A Blessing”: Perceptions Of Aging, Elderhood, And Dementia In A Haitian Born Sample, Melissa K. Eustache

USF Tampa Graduate Theses and Dissertations

This thesis investigates how first-generation Haitian immigrants in the United States understand and interpret dementia within the intersecting contexts of culture, migration, and biomedicine. While dementia is constructed as a pathological “loss of self” and a public health epidemic, in American biomedical and popular discourse, this study examines how Haitian-born individuals—socialized within a non-Western cultural and spiritual framework—make sense of cognitive decline and impairment in ways that diverge from Western biomedical narratives. Guided by theoretical orientations from medical anthropology, including Mark Nichter’s idioms of distress, Margaret Lock’s local biologies, and neuroanthropology, this research explores how cultural models of illness, aging, …

Oligomeric Cystatin C Supports The Immunosuppressive Activity Of Myeloid Cells Through Interaction With Inhibitory Receptors, Chengcheng Zhang, Yubo He, Xiaoye Liu, Jingjing Xie, Meng Fang, Xing Yang, Ryan Huang, Qi Lou, Bufan Li, Ankit Gupta, Cheryl Lewis, Marc I Diamond, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes …

A Practical Primer On How To Detect And Treat Depression In Ckd, L Parker Gregg, Lynnel Goodman, Ella Q Carroll, S Susan Hedayati

Faculty, Staff and Students Publications

Detection and management of depression have special considerations in people with kidney disease. Screening should be done every 6-12 months using a self-reported questionnaire. Clinicians should rule out symptoms from medical conditions such as dialysis inadequacy or hypothyroidism and confirm the presence of sadness or anhedonia. Sertraline has shown limited efficacy and an increased risk for adverse effects such as gastrointestinal symptoms, so cautious, gradual dose titration is warranted. Cognitive behavioral therapy has potential benefit for depressive symptoms in people with kidney disease. Current trials are evaluating behavioral activation therapy. Physical activity has many benefits and likely improves depression.

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …

Primary Intramedullary Spinal Melanocytomas: Case Report And Review Of Clinical Features, Diagnosis, And Management, Gil Kimchi, Samantha Varela, Juan Pablo Zuluaga-Garcia, Francisco Call-Orellana, Esteban Ramirez Ferrer, Romulo Augusto Andrade De Almeida, Maria A Gubbiotti, Isabella C Glitza, Andrew J Bishop, Jonathan D Grant, Robert Y North, Christopher A Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Objective: Intramedullary melanocytomas are extremely rare spinal cord tumors with distinct histopathological and imaging characteristics. This report reviews the literature on this pathology and presents a representative case study, highlighting aspects of diagnosis and management.

Methods: A scoping review of PubMed, Web of Science, and Embase databases was conducted to identify reports on intramedullary melanocytomas, focusing on clinical presentation, imaging features, histopathology, treatment, and outcomes. Case reports and case series were included due to the rarity of these tumors.

Results: Twelve manuscripts met the inclusion criteria, including 15 patients. In the majority of patients, intramedullary melanocytomas present with progressive myelopathy …

The Unfolded Protein Response-Novel Mechanisms, Challenges, And Key Considerations For Therapeutic Intervention, P M Quan Mai, Tam-Anh Truong, Sai Kumar Samala, Bhoomika Muruvekere Lakshmisha, Prapannajeet Biswal, Khadijeh Koushki, Prudhvi Chand Mallepaddi, Geraldine Vijay, Sunil Krishnan

Faculty, Staff and Student Publications

Background: The unfolded protein response (UPR) is an evolutionarily conserved, synchronized, and orchestrated process triggered by eukaryotic cells in response to endoplasmic reticulum (ER) stress. UPR restores the ER's capacity to handle large protein loads within it, and still fold and process these proteins accurately. Many recent studies have documented the non-canonical roles of the UPR, outside of protein quality control, in the context of lipid metabolism and the immune system in cancer. Cancer cells have been known to hijack the UPR to promote survival and evade immune surveillance. However, the underlying mechanisms remain poorly understood.

Objectives: Here, we critically …

Developing A General Ai Model For Integrating Diverse Genomic Modalities And Comprehensive Genomic Knowledge, Zhenhao Zhang, Xinyu Bao, Linghua Jiang, Xin Luo, Zheyu Zhang, Jing Yin, Meiqi Zhao, Yichun Wang, Annelise Comai, Joerg Waldhaus, Anders S Hansen, Wenbo Li, Jie Liu

Faculty, Staff and Student Publications

Advances in next-generation sequencing technologies have vastly expanded the availability of diverse genomic, epigenomic, and transcriptomic data, presenting the opportunity to develop a general AI model that integrates comprehensive genomic knowledge into a unified model. Unlike previous predictive models, which are typically specialized to certain tasks, our general AI model unifies a wide range of genomic modalities, such as nascent RNA and ultra-high-resolution chromatin organization, within a multi-task architecture. Using ATAC-seq and DNA sequences as inputs, we incorporated diverse genomic modalities as output, and the model exhibits strong generalizability across different cell types and tissues in all tasks we trained. …

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …

Genetic And Embryonic Transcriptome Analyses Reveal The Molecular And Developmental Basis Of Mayer-Rokitansky-Küster-Hauser Syndrome, Na Chen, Xi Cheng, Sen Zhao, Hengqiang Zhao, Chenglu Qin, Yaru Zhang, Xijuan Lin, Qing Li, Yuan Wang, Jia Kang, Jing Yu, Jianbin Guo, Qianqian Gao, Jiali Duan, Yuchen Niu, Jianzhong Su, Zhihong Wu, Terry Jianguo Zhang, Wanlu Liu, Pengfei Liu, Shan Deng, Nan Wu, Lan Zhu

Faculty, Staff and Students Publications

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterised by aplasia of the uterus, cervix and upper part of the vagina. The genetic aetiology remains incompletely understood.

Methods: We performed gene-level and gene set-level burden analyses based on exome sequencing/genome sequencing data from 727 probands with MRKHS and 2504 female control individuals. Single-cell RNA sequencing (scRNA-seq) was performed on human and mouse embryonic metanephros at different developmental stages. Genetic and transcriptomic data were integrated to prioritise suboptimal genetic signals, identify relevant cell types and determine key developmental stages. Potential digenic inheritance was assessed and prioritised using coexpression patterns from scRNA-seq data.

Results: We …

Design, Optimization, And Development Of Ripk1 Degraders With Improved Pharmacokinetic And Pharmacodynamic Properties, Dong Lu, Xin Yu, Hanfeng Lin, Ran Cheng, Bin Yang, Min Zhang, Jingjing Chen, Feng Li, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Pharmacological degradation of receptor-interacting protein kinase 1 (RIPK1) offers a compelling therapeutic strategy to overcome its scaffolding role in tumor resistance and to enhance the efficacy of immune checkpoint blockade (ICB) therapies. In this study, we report the discovery of a novel RIPK1 degrader, LD5097(24b), developed through systematic optimization of its precursor compound, LD4172—specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. LD5097(24b) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated apoptosis in Jurkat cells. Compared to LD4172, LD5097(24b) demonstrates markedly improved metabolic stability and pharmacokinetic properties. In …

Implementing Pst In Older Adults Facing Major Surgery: A Randomised Controlled Pilot Study, Victoria Tang, Lejla Pepic, Erika Higuchi, Christina Keny, Elizabeth Macias Lopez, Ezenwa C Onyema, Harleen Sandhu, Veronica Yank, Patrick J Raue

Faculty, Staff and Student Publications

Introduction: Depressive symptoms are common in the growing geriatric surgical population and are associated with important patient-centred surgical outcomes, including postoperative delirium, discharge to postacute care facility and decline in functional status. Few interventions have been developed to address depressive symptoms in the perioperative setting.

Methods and analysis: We designed a feasibility and acceptability study of a nine-session problem-solving therapy (PST) telehealth perioperative intervention aimed at reducing postoperative functional decline and depressive symptoms among at-risk older adults undergoing major surgical procedures. Acceptability will be evaluated using a patient-centred five-question survey, assessing participant satisfaction and perceived usefulness of the perioperative intervention. …

Discovery Of A Novel Small Molecule Degrader Of Wild Type And Mutant Estrogen Receptors Using Dna Encoded Libraries, Anil Kumar Devakrishnan, Chandrashekhar Madasu, Yong Wang, Ramkumar Modukuri, Kurt M Bohren, Kevin R Mackenzie, Damian W Young, Suzanne A W Fuqua, Martin M Matzuk, Murugesan Palaniappan

Faculty, Staff and Students Publications

Estrogen receptor α (ERα) variants with mutations in the ligand binding domain (LBD) are less sensitive than wild type to standard-of-care drugs that bind ERα directly. To identify novel small-molecule drugs that target ERα mutants, we screened our multibillion-compound DNA-encoded libraries against ERα LBD variants. CDD-1274, which was highly enriched with all three variants, blocked spontaneous coactivator peptide recruitment to mutant ERα LBDs and inhibited estradiol-driven proliferative markers in several ER-positive breast cancer cell lines, but not in ER-negative breast cancer cells. We demonstrated that CDD-1274 induced proteasomal degradation of ERα variants in breast cancer cell lines and caused Y537S …

Genome-Wide Discovery Of Multiple Sclerosis Genetic Risk Variant Allelic Regulatory Activity, Marissa Granitto, Lois Parks, Molly S Shook, Carmy Forney, Xiaoting Chen, Lee E Edsall, Omer A Donmez, Sreeja Parameswaran, Kristen S Fisher, Aram Zabeti, Lucinda P Lawson, Matthew T Weirauch, Leah C Kottyan

Faculty, Staff and Students Publications

Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system with a complex etiology involving environmental and genetic factors. Numerous genetic risk loci for multiple sclerosis have been nominated through genome-wide association studies, with most associated variants residing in noncoding regions. However, further work is needed to understand how genetic variation contributes to disease-related alterations to gene expression. Here, we use Massively Parallel Reporter Assays to identify genetic risk variants with genotype-dependent enhancing or silencing activity within a set of 14,275 variants distributed among multiple sclerosis risk loci that have reached genome-wide or suggestive significance. We applied our …