Digital Commons Network^™

Vaccine Effectiveness Against Influenza A(H1n1), A(H3n2), And B-Associated Hospitalizations, United States, 1 September 2023 To 31 May 2024, Nathaniel M Lewis, Jennie H Kwon, Et Al.

2020-Current year OA Pubs

BACKGROUND: The 2023-2024 influenza season included sustained elevated activity from December 2023 to February 2024 and continued activity through May 2024. Influenza A(H1N1), A(H3N2), and B viruses circulated during the season.

METHODS: During 1 September 2023 to 31 May 2024, a multistate sentinel surveillance network of 24 medical centers in 20 US states enrolled adults aged ≥18 years hospitalized with acute respiratory illness. Consistent with a test-negative design, cases tested positive for influenza viruses by molecular or antigen test, and controls tested negative for influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccine effectiveness (VE) against influenza-associated hospitalization …

Characterization And Prediction Of Prolonged Severe Neutropenia In Pediatric Patients Receiving Tisagenlecleucel., Swati Naik, Subodh Selukar, Aimee C. Talleur, Samira Deshpande, Gabriela Llaurador Caraballo, Vanessa A. Fabrizio, Rayne H. Rouce, Xiaopei L. Zeng, Anant Vatsayan, Jenna Rossoff, Holly L. Pacenta, Samuel John, Christine L. Phillips, Julie-An Talano, Amy Moskop, Michael R. Verneris, G Doug Myers, Erin Hall, Nicole Karras, Challice L. Bonifant, Muna Qayed, Emily Bakinowski, Amy K. Keating, Susanne H C Baumeister, Emily Tomilson, Michelle L. Hermiston, Prakash Satwani, Christa Krupski, Vasant Chinnabhandar, Heather E. Stefanski, Emily Egeler, Kevin J. Curran, Theodore W. Laetsch, Crystal L. Mackall, Snehit Prabhu, Khanh P. Nguyen, Christina Baggott, Liora Michal Schultz, Kevin O. Mcnerney

Manuscripts, Articles, Book Chapters and Other Papers

Hematotoxicity is the most frequent severe toxicity after chimeric antigen receptor T-cell (CAR-T) therapy. However, limited data exist on risk factors and outcomes for hematotoxicity for children and young adults (CAYAs) with B-acute lymphoblastic leukemia treated with tisagenlecleucel. We conducted a multi-institutional study involving 326 CAYAs, with 144 evaluable in an initial training cohort and 141 evaluable in a validation cohort, through the Pediatric Real-World CAR Consortium to characterize the incidence and outcomes of prolonged severe neutropenia (PSN) and to develop a predictive risk score for PSN, tailored for use in this population. The incidence of PSN, defined as an …

Optimal Control In Combination Therapy For Heterogeneous Cell Populations With Drug Synergies., Simon F. Martina-Perez, Samuel W S Johnson, Rebecca M. Crossley, Jennifer C. Kasemeier, Paul M. Kulesa, Ruth E. Baker

Manuscripts, Articles, Book Chapters and Other Papers

Cell heterogeneity plays an important role in patient responses to drug treatments. In many cancers, it is associated with poor treatment outcomes. Many modern drug combination therapies aim to exploit cell heterogeneity, but determining how to optimise responses from heterogeneous cell populations while accounting for multi-drug synergies remains a challenge. In this work, we introduce and analyse a general optimal control framework that can be used to model the treatment response of multiple cell populations that are treated with multiple drugs that mutually interact. In this framework, we model the effect of multiple drugs on the cell populations using a …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty For Below-The-Knee Peripheral Artery Disease: 2-Year Results From The Life-Btk Trial., Brian G Derubertis, Ramon L Varcoe, Prakash Krishnan, Marc P Bonaca, David J O'Connor, Richard Pin, David C Metzger, Andrew Holden, Jen-Kuang Lee, Osamu Iida, Ehrin J Armstrong, Steven W C Kum, Raghu Kolluri, Danielle R Bajakian, Lawrence A Garcia, Mehdi H Shishehbor, Shawn Yu, Karine Ruster, Brad J Martinsen, Zsuzsanna Igyarto, Sahil A Parikh

Heart and Vascular Articles

BACKGROUND: Limited treatment options exist for infrapopliteal disease in patients with chronic limb-threatening ischemia (CLTI), a condition associated with a high risk of limb loss. Interventional management of diseased infrapopliteal vessels with percutaneous transluminal angioplasty (PTA) is associated with high rates of restenosis and reintervention. In the LIFE-BTK randomized controlled trial (Pivotal Investigation of Safety and Efficacy of BRS Treatment-Below the Knee), the drug-eluting resorbable scaffold (DRS) demonstrated superior 12-month efficacy compared with PTA in a selected CLTI population with predominantly noncomplex, mildly to moderately calcified lesions. This report presents the 2-year safety and efficacy outcomes of the Esprit BTK …

Organism-Specific Sequence Motifs Link Ribosomal Rnas To Brain Disorders, Isidore Rigoutsos, Stepan Nersisyan, Eric Londin, Iliza Nazeraj, Bonnie Dong, Anastasios Vourekas, Phillipe Loher

Computational Medicine Center Faculty Papers

We report that in humans, mice, fruit flies, and worms, the ribosomal RNAs and the transcribed spacers of 45S are densely packed with organism-specific sequence motifs that are primarily shared with nervous system genes. The human ribosomal RNAs and 45S spacers contain 1,723 such motifs. Specific combinations of these motifs are predominantly found in 3,430 human nervous system genes, of which 1,046 are genes associated with brain disorders, including autism spectrum disorder and schizophrenia. The sequences of the 1,723 motifs and their locations in the introns and exons of nervous system genes are unique to primates. Experimental evidence indicates that …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Functional Roles Of The Complement Immune System In Cardiac Inflammation And Hypertrophy, Kathryn D Hok, Haydn E Rich, Anthony Shadid, Lavanya Gunamalai, Tingting Weng-Mills, Rajarajan A Thandavarayan, Nirmal K Banda, Marie-Francoise Doursout, Marcos I Restrepo, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation-classical, lectin, and alternative-are implicated in developing cardiac damage, inflammation, and hypertrophy due to …

Targeting The Bcl2 Family: Advances And Challenges In Bh3 Mimetic-Based Therapies, Nabanita Mukherjee, James Sheetz, Yiqun Shellman

Student Papers, Posters & Projects

The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt …

Glucagon-Like Peptide 1 Receptor Agonists And The Clinical Outcomes Of Inflammatory Bowel Disease: A Systematic Review And Meta-Analysis, Ahmed B. Bayoumy, Lindsay M. Clarke, Parakkal Deepak, Aakash Desai, Priya Sehgal, Uri Gorelik, Haggai Bar-Yoseph, Marie Villumsen, Chris J. J. Mulder, Dirk J. Stenvers, Maarten E. Tushuizen, Nanne K. H. De Boer

Division of Gastroenterology and Hepatology Faculty Papers

BACKGROUND: Prior studies showed worse outcomes in obese inflammatory bowel disease (IBD) patients, especially those related to hospitalizations, surgery, and steroid-free remission. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) have demonstrated significant metabolic benefits for patients with type 2 diabetes mellitus (T2DM) and obesity. Hence, GLP1-RAs may improve clinical outcomes in patients with IBD, especially those with obesity. The objective was to systematically evaluate the impact of GLP1-RAs on clinical outcomes in patients with IBD.

METHODS: A comprehensive literature search was performed using the databases PubMed, Embase, Web of Science, and Cochrane Library from inception to March 15, 2025. Studies reporting outcomes …

Ligand-Receptor Interactions Induce And Mediate Regulatory Functions Of Batf3+ B Cells, Hui Yan, Rui Wang, Suryavathi Viswanadhapalli, Christian Cervantes, Funan He, Shuai Wu, Azad Khosh, Weiwei Luo, Jingwei Wang, Maria J Fernandez, Uday P Pratap, Mustafa Khan, Karli Hinton, Sai Eashan Vankamamidi, Dariela Perez, Carlos E Rivera, Harshita B Gupta, Fushun Zhang, Zhenqing Ye, Yidong Chen, Xiao-Dong Li, Gangadhara R Sareddy, Hong Zan, Yue Li, Exing Wang, Evelien M Bunnik, Guangming Zhong, Christopher A Hunter, Ross M Kedl, Zhinan Yin, Booki Min, Diako Ebrahimi, Siyuan Zheng, Tyler J Curiel, Yan Xiang, Ratna K Vadlamudi, Paolo Casali, Zhenming Xu

Faculty, Staff and Student Publications

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27–IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 …

Dna Methylation And Machine Learning: Challenges And Perspective Toward Enhanced Clinical Diagnostics, Erfan Aref-Eshghi, Arash B Abadi, Mohammad-Erfan Farhadieh, Amirreza Hooshmand, Fatemeh Ghasemi, Leila Youssefian, Hassan Vahidnezhad, Taylor Martin Kerrins, Xiaonan Zhao, Mahdi Akbarzadeh, Hakon Hakonarson, Amir Hossein Saeidian

Faculty, Staff and Students Publications

DNA methylation is an epigenetic modification that regulates gene expression by adding methyl groups to DNA, affecting cellular function and disease development. Machine learning, a subset of artificial intelligence, analyzes large datasets to identify patterns and make predictions. Over the past two decades, advances in bioinformatics technologies for arrays and sequencing have generated vast amounts of data, leading to the widespread adoption of machine learning methods for analyzing complex biological information for medical problems. This review explores recent advancements in DNA methylation studies that leverage emerging machine learning techniques for more precise, comprehensive, and rapid patient diagnostics based on DNA …

Vaccine And Treatment Evaluation Units: A Historical Perspective, Robert B Belshe, David I Bernstein, Kathryn M Edwards, Sharon E Frey, Wendy A Keitel, Myron M Levine, John J Treanor, Peter F Wright

Faculty, Staff and Students Publications

On 27 February 1962, Surgeon General Luther Terry announced a new vaccine development program within the National Institute of Allergy and Infectious Diseases (NIAID). Initially, the plan had three components: (1) special laboratories and facilities for development of prototype vaccines; (2) pilot lot production facilities and preliminary vaccine trial sites; and (3) larger lot production capacity and expanded human testing. Respiratory viruses were targeted as the top priority for vaccine development. Over 5 decades, this program has evolved and expanded to include multiple academic vaccine evaluation sites within the network, now labeled as the Vaccine and Treatment Evaluation Units (VTEUs). …

Just-In-Time Adaptive Intervention To Improve Hiv Prevention And Substance Use In Youth Experiencing Homelessness (My-Ride): Protocol For A Randomized Controlled Trial, Diane Santa Maria, Nikhil Padhye, Michael Businelle, Natasha Slesnick, Stefani Ricondo, Marguerita Lightfoot

Faculty, Staff and Students Publications

Background: Youth who are experiencing homelessness face a higher risk of HIV infection compared to their housed peers, and suicide and overdose remain the leading causes of death among homeless youth. Just-in-Time Adaptive Interventions (JITAIs) are gaining momentum for HIV prevention and substance use research. Yet, most interventions for homeless youth have not addressed modifiable real-time factors.

Objective: This paper describes the development and implementation of a randomized attention-controlled trial to assess the efficacy of motivating youth to reduce infections, disconnections, and emotional dysregulation (MY-RIDE), a JITAI to improve HIV prevention and substance use in homeless youth.

Methods: This study …

The Effect Of Type 2 Diabetes Genetic Predisposition On Non-Cardiovascular Comorbidities, Ana Luiza Arruda, Ozvan Bocher, Henry J Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C Wood, Ken Suzuki, Josep M Mercader, Cassandra N Spracklen, James B Meigs, Marijana Vujkovic, George Davey Smith, Jerome I Rotter, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini

Faculty, Staff and Students Publications

Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts …

Evaluating The Potential And Limitations Of Nanopore Adaptive Sampling For Targeted Transcriptome Sequencing, Nicole Debruyne, Feng Wang, Yang Xu, Lan Lin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Long-read RNA sequencing is a powerful technology for transcriptomics, but low throughput and high cost pose challenges. Adaptive sampling, a feature of Oxford Nanopore Technologies, offers real-time enrichment by selectively ejecting non-target molecules. We evaluate adaptive sampling for human transcriptome analysis. Adaptive sampling modestly enriches target transcripts (1.3 × for cDNA sequencing, 1.9 × for direct RNA sequencing) while preserving gene expression and splicing profiles, but is significantly less effective than cDNA hybridization capture. Short read lengths and low sequencing quality limit performance. Adaptive sampling on direct RNA sequencing can boost target yield (~ 20%) within fixed run times, potentially …

Germline Determinants Of Toxicity And Efficacy In Patients With Large B-Cell Lymphoma Treated With Car T-Cell Therapy, Paolo Strati, Amanda Brandt, Anath C Lionel, Jared Henderson, Jason R Westin, Sherry Adkins, Elizabeth J Shpall, Partow Kebriaei, Jeremy Ramdial, Neeraj Saini, Sairah Ahmed, Christopher Flowers, Sattva S Neelapu, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.

Methods: Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was …

Polychlorinated Biphenyls Alter Estrogen Receptor Β-Mediated Epigenetic Regulation, Promoting Endometriosis, Yuri Park, Nuri Sung, Eunsu Kim, Jaeyeong Jeong, Juhee Sim, Mi Jin Park, John P Lydon, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A …

Dual Targeting Of Orphan Nuclear Receptors Nr4a1 And Nr4a2 For Nonhormonal Endometriosis Therapy, Wai Ning Tiffany Tsui, Yuri Park, Srijana Upadhyay, Da Mi Kim, Lei Zhang, Gus Wright, Amanuel Hailemariam, Arafat Rahman Oany, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Previous studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3'-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell …

Structural Variation, Selection, And Diversification Of The Npip Gene Family From The Human Pangenome., Philip C. Dishuck, Katherine M. Munson, Alexandra P. Lewis, Max L. Dougherty, Jason G. Underwood, William T. Harvey, Pinghsun Hsieh, Tomi Pastinen, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

The NPIP gene family is among the most positively selected gene families in humans/apes and drives independent duplication in primate lineages. These duplications promote genetic instability, leading to recurrent disease-associated microduplication and microdeletion syndromes. Despite its importance, little is known about its function or variation in humans, as short-read sequencing cannot distinguish high-identity duplications. Using long-read assemblies of 169 human haplotypes, we find extreme variation in the content and organization of NPIP loci. We identify fixed and polymorphic paralogs and observe ongoing positive selection. With long-read RNA sequencing (RNA-seq), we create paralog-specific gene models, the majority of which were not …

One-Sided Matching Portal (Osmp): A Tool To Facilitate Rare Disease Patient Matchmaking., Matthew Osmond, E Magda Price, Orion J. Buske, Mackenzie Frew, Madeline Couse, Taila Hartley, Conor Klamann, Hannah G B H Le, Jenny Xu, Delvin So, Anjali Jain, Kevin Lu, Kevin Mo, Hannah Wyllie, Erika Wall, Hannah G. Driver, Warren A. Cheung, Ana S A Cohen, Emily G. Farrow, Isabelle Thiffault, Care Rare Canada Consortium, Andrei L. Turinsky, Tomi Pastinen, Michael Brudno, Kym M. Boycott

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Genomic matchmaking-the process of identifying individuals with overlapping phenotypes and rare variants in the same gene-is an important tool facilitating gene discoveries for unsolved rare genetic disease (RGD) patients. Current approaches are two-sided, meaning both patients being matched must have the same candidate gene flagged. This limits the number of RGD patients eligible for matchmaking. One-sided matchmaking, in which a gene of interest is queried in the genome-wide sequencing data of RGD patients, would make matchmaking possible for previously undiscoverable individuals. However, platforms and workflows for this approach have not been well established.

RESULT: We released a beta version …

Synaptic Transmission Promotes Brain Metastatic Outgrowth In Breast Cancer, Jayanta Mondal, Patrick Nylund, Prit Benny Malgulwar, William E Johnson, Jason T Huse

Faculty, Staff and Student Publications

This work demonstrates that normal neuron-to-neuron signaling machinery is hijacked by metastasizing cancer cells during their outgrowth in the central nervous system.

Quiescent Oxphos-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend On Bcl-Xl For Survival, Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea

Faculty, Staff and Student Publications

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, …

Mechanistic Study Of Pexidartinib-Induced Toxicity In Human Hepatic Cells, Si Chen, Yuxi Li, Xilin Li, Nan Mei, Xiaobo He, Matthew S Bryant, Xuan Qin, Feng Li, Lei Guo

Faculty, Staff and Students Publications

Pexidartinib, a tyrosine kinase inhibitor, was approved by the U.S. Food and Drug Administration in 2019 for treating adult patients with symptomatic tenosynovial giant cell tumors. Because of its hepatotoxicity risks, pexidartinib received a boxed warning; however, mechanistic studies on this hepatotoxicity remain limited. In this study, we demonstrate that pexidartinib decreases cell viability in primary human hepatocytes and hepatic HepG2 cells. A 24-h treatment with pexidartinib led to apoptosis in HepG2 cells, as evidenced by increased caspase 3/7 activity and the induction of cleaved PARP and γ-H2A.X. Pexidartinib-induced endoplasmic reticulum (ER) stress was observed at early time points of …

Biliverdin Reductase A Is A Major Determinant Of Protective Nrf2 Signaling, Chirag Vasavda, Ruchita Kothari, Navneet Ammal Kaidery, Suwarna Chakraborty, Sunil Jamuna Tripathi, Ryan S Dhindsa, Cristina Ricco, Shruthi Shanmukha, Samaneh Saberi, Julia E Lefler, Priyanka Kothari, Kalyani Chaubey, Adele M Snowman, Michael C Ostrowski, Eugenio Barone, Lakshminarayan M Iyer, L Aravind, Sudarshana M Sharma, Andrew A Pieper, Bobby Thomas, Solomon H Snyder, Bindu D Paul

Duncan NRI Faculty and Staff Publications

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major transcriptional regulator of cellular redox signaling. ChIP-seq and RNA-seq analyses reveal that BVRA and NRF2 coordinate the expression of antioxidant genes, many of which are typically dysregulated in neurodegenerative conditions such as Alzheimer's disease. Thus, this noncanonical …

Enhanced Piezo1 Function Contributes To The Pathogenesis Of Sickle Cell Disease, Luis O Romero, Manisha Bade, Laila Elsherif, Jada D Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I Ataga, Shang Ma, Julio F Cordero-Morales, Valeria Vásquez

Faculty, Staff and Student Publications

Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte …

Functional Diversity In Gii.4 Norovirus Entry: Hbga Binding And Capsid Clustering Dynamics, B Vijayalakshmi Ayyar, Carmen V Apostol, Janam Jitendra Dave, Soni Kaundal, Joseph A Kendra, Frederick H Neill, Khalil Ettayebi, Sarah Maher, Ramakrishnan Anish, Gabriel I Parra, Göran Larson, Robert L Atmar, Sue E Crawford, B V Venkataram Prasad, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs), especially GII.4 strains, are the leading cause of acute viral gastroenteritis worldwide, yet no approved vaccines or antivirals exist. The pandemic GII.4 Sydney 2012 strain enters cells via membrane wounding and clathrin-independent carrier-mediated endocytosis, but it is unclear whether this entry mechanism is conserved across GII.4 variants. We compared early binding and entry of multiple GII.4 variants using wild-type and mutant GII.4 virus-like particles (VLPs) and modified human intestinal enteroid cultures. Only a subset of GII.4 variants, including GII.4 Sydney, form distinct, histo-blood group antigen (HBGA)-dependent capsid clusters on the cell surface. Clustering strains display significantly enhanced …

Fiber Recruitment Drives A Phase Transition Of Cell Polarization At A Critical Cell Spacing In Matrix-Mediated Tissue Remodeling, Xiangjun Peng, Yuxuan Huang, Wenyu Kong, Yanan Du, Elliot L Elson, Xi-Qiao Feng, Guy M Genin

2020-Current year OA Pubs

Biological tissues exhibit sharp phase transitions where cells collectively transition from disordered to ordered states at critical densities. We demonstrate through bio-chemo-mechanical modeling that this emergent behavior arises from a nonmonotonic dependence on nonlinear extracellular matrix (ECM) mechanics: mechanical communication between cells is optimized at intermediate stiffness values where cells can both generate sufficient forces and create strain-stiffened tension bands in the ECM. This balance establishes a critical cell spacing threshold for cell-cell communication ([Formula: see text]100 to 200 [Formula: see text]m) that is conserved across experimental observations for a broad range of cell types and collagen densities. Our model …

Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics And Liver Lipid Metabolism, Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan

Faculty, Staff and Student Publications

The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to …

Atg Conjugation-Dependent/Independent Mechanisms Underlie Lysosomal Stress-Induced Tfeb Regulation, Shiori Akayama, Takayuki Shima, Tatsuya Kaminishi, Mengying Cui, Jlenia Monfregola, Kohei Nishino, Andrea Ballabio, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura

Duncan NRI Faculty and Staff Publications

TFEB, a master regulator of autophagy and lysosomal biogenesis, is activated by several cellular stresses including lysosomal damage, but its underlying mechanism is unclear. TFEB activation during lysosomal damage depends on the ATG conjugation system, which mediates lipidation of ATG8 proteins. Here, we newly identify ATG conjugation-independent TFEB regulation that precedes ATG conjugation-dependent regulation, designated Modes I and II, respectively. We reveal unique regulators of TFEB in each mode: APEX1 in Mode I and CCT7 and/or TRIP6 in Mode II. APEX1 interacts with TFEB independently of the ATG conjugation system, and is required for TFEB stability, while both CCT7 and …