Digital Commons Network^™

Optimizing Human Fcrn Mouse Models To Improve Pharmacokinetic Evaluation Of Antibody Drug Candidates., Gregory J. Christianson, Zachary M Howard, Samantha Kenney, Emily Lowell, Nijaguna Bethur, Derry C. Roopenian, Elena Gonzalo-Gil

Faculty Research 2026

The use of animal models that can reliably predict drug performance in human patients is critical to antibody therapeutic development. Along with assessing toxicity and efficacy, determining the pharmacokinetic (PK) properties of therapeutics in Tg32 and Tg276 mice is essential to preclinical characterization. While Tg32 mice have been well established as indispensable in their ability to model the PK properties of antibody therapeutics, their intact immunity leaves them capable of mounting anti-drug antibody responses that interfere with PK interpretation. Here, we demonstrate the negative impact anti-drug responses can have on PK parameters derived from Tg32 mice, and provide strong evidence …

Optimizing Human Fcrn Mouse Models To Improve Pharmacokinetic Evaluation Of Antibody Drug Candidates., Gregory J. Christianson, Zachary M Howard, Samantha Kenney, Emily Lowell, Nijaguna Bethur, Derry C. Roopenian, Elena Gonzalo-Gil

Faculty Research 2026

The use of animal models that can reliably predict drug performance in human patients is critical to antibody therapeutic development. Along with assessing toxicity and efficacy, determining the pharmacokinetic (PK) properties of therapeutics in Tg32 and Tg276 mice is essential to preclinical characterization. While Tg32 mice have been well established as indispensable in their ability to model the PK properties of antibody therapeutics, their intact immunity leaves them capable of mounting anti-drug antibody responses that interfere with PK interpretation. Here, we demonstrate the negative impact anti-drug responses can have on PK parameters derived from Tg32 mice, and provide strong evidence …

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Nuri Sung, Eunsu Kim, Yosef Gilad, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8

Mtorc2-Nav1.2 Signaling Drives Early Hyperexcitability In Alzheimer’S Disease Mouse Model, Nolan M Dvorak, Jeffrey L Noebels

Faculty, Staff and Students Publications

Hyperexcitability is a biomarker of early-stage Alzheimer’s Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced …

Assessment Of Timp1, Transgelin-2, And Procalcitonin As Protein Biomarkers For Diagnosis And Prognosis Of Bloodstream Infection In A Critically Ill Cohort, Sajal Tiwary, Caroline A O'Neil, Sydney Lawless, Olivia Arter, Meghan Brown, Brittany Roemmich, Carleigh Samuels, Jennie H Kwon, Christopher W Farnsworth

2020-Current year OA Pubs

BACKGROUND: Bloodstream infections (BSI) are a significant contributor to morbidity and mortality among hospitalized patients. Rapid diagnosis of BSI is critical for timely and appropriate clinical management, but current diagnostic strategies have a prolonged turnaround time or only identify select pathogens with minimal prognostic information.

METHODS: We examined serial serologic samples from 77 intensive care unit (ICU) patients at time points before, during, and after diagnosis of presumptive BSI to identify host-derived protein biomarkers associated with specific organisms and with clinical outcomes in BSI. ICU patients with and without BSI were included. Two candidate biomarkers, tissue metalloproteinase 1 (TIMP-1) and …

Androgens Mediate Sexual Dimorphism In Pilarowski-Bjornsson Syndrome., Kimberley Jade Anderson, Eirny Tholl Thorolfsdottir, Ilana M. Nodelman, Sara Tholl Halldorsdottir, Stefania Benonisdottir, Malak A. Alghamdi, Naif A M Almontashiri, Brenda J. Barry, Matthias Begemann, Jacquelyn F. Britton, Sarah Burke, Benjamin Cogne, Ana S A Cohen, Carles De Diego Boguñá, Evan E. Eichler, Elizabeth C. Engle, Jill A. Fahrner, Laurence Faivre, Mélanie Fradin, Nico Fuhrmann, Christine W. Gao, Gunjan Garg, Dagmar Grečmalová, Mina Grippa, Jacqueline R. Harris, Kendra Hoekzema, Tova Hershkovitz, Sydney Hubbard, Katrien Janssens, Julie A. Jurgens, Stanislav Kmoch, Cordula Knopp, Meral Aktas Koptagel, Farah A. Ladha, Pablo Lapunzina, Tobias Lindau, Marije Meuwissen, Andreina Minicucci, Emily Neuhaus, Mathilde Nizon, Lenka Nosková, Kristen Park, Chirag Patel, Rolph Pfundt, Pankaj Prasun, Nils Rahner, Nathaniel H. Robin, Carey Ronspies, Jasmin Roohi, Jill Rosenfeld, Margarita Saenz, Carol J. Saunders, Zornitza Stark, Isabelle Thiffault, Sarah Thull, Danita Velasco, Clara Velmans, Jolijn Verseput, Antonio Vitobello, Tianyun Wang, Karin Weiss, Ingrid M. Wentzensen, Genay Pilarowski, Thor Eysteinsson, Madelyn Gillentine, Kári Stefánsson, Agnar Helgason, Gregory D. Bowman, Hans Tomas Bjornsson

Manuscripts, Articles, Book Chapters and Other Papers

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1^R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1^R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants …

The American Society Of Extracorporeal Technology Standards And Guidelines For Pediatric And Congenital Perfusion Practice: 2025 Update☆., Molly Elisabeth Oldeen, Carrie Whittaker Striker, Ronald Angona, Dafne Andrea Chianella, Chelsea Capone, Ashley B Walczak, Thomas Klein

Heart and Vascular Articles

Background: In 2019, the American Society of ExtraCorporeal Technology (AmSECT) approved the inaugural Standards and Guidelines for Pediatric and Congenital Perfusion Practice. These standards and guidelines were created with the intent of periodic revision to ensure continued alignment with evolving best practices. In 2023, an AmSECT subcommittee initiated this review in consideration of current literature and contemporary clinical practices.

Methods: The subcommittee, consisting of pediatric and congenital perfusionists, conducted a systematic literature review assessing each standard and guideline to determine if current evidence supports elevation of guidelines to standards, incorporation of new guidelines or standards, or whether existing standards and …

Spinal Cord Imaging For Multiple Sclerosis: Advances, Priorities, And Opportunities, Cornelia Laule, Matthew R Brier, Et Al.

2020-Current year OA Pubs

The spinal cord plays a central role in the pathophysiology and clinical manifestations of multiple sclerosis (MS), yet remains under-studied compared with the brain. This review summarizes key insights from the 2025 North American Imaging in MS Spinal Cord Imaging Workshop, highlighting recent advances, ongoing challenges, and future opportunities in MS spinal cord imaging. We review pathological studies and outline the clinical relevance of spinal cord lesions and atrophy for diagnosis, prognosis, and disease monitoring, highlighting emerging biomarkers of progression independent of relapse activity. Correlations between magnetic resonance imaging, histopathology, and clinical outcomes support the validation and translational potential of …

Unlocking Cis-Regulatory Landscapes Across 500 Million Years Of Evolution And Disease Mechanisms, Tássia Mangetti Gonçalves, Casey L Stewart, Samantha D Baxley, Jason Xu, Kevin Boyer, Bijesh George, Daofeng Li, Chengran Yang, Harrison W Gabel, Xianhua Piao, Carlos Cruchaga, Yang E Li, Ting Wang, Oshri Avraham, Guoyan Zhao

2020-Current year OA Pubs

Genomic DNA encodes regulatory information that determines where, when, and to what extent genes are expressed. Theoretically, we should be able to identify these transcriptional "instructions" by examining genomic DNA sequence alone, yet this has remained challenging. Here we present the Vertebrate Regulatory MOdule Detector (VRMOD), a method that accurately predicts gene regulatory sequences using only the query genomic sequences. We applied VRMOD to 309 Ensembl genomes, generating a compendium of high-resolution, genome-position-fixed

Single Immunoglobulin Interleukin1-Related Receptor-Twist1 Axis Regulates Barrier Function In Neonatal Intestine., Aparna Venkatraman, Wei Yu, Heather Menden, Sherry M. Mabry, Joshua Wheatley, Shahid Umar, Susana Chavez-Bueno, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND & AIMS: The genetic basis of impaired intestinal barrier function in preterm infants is poorly understood. Variants in single immunoglobulin interleukin1-related receptor, a negative regulator of Toll-like receptor signaling, have been identified in preterm infants with necrotizing enterocolitis. We hypothesized that single immunoglobulin interleukin1-related receptor variants associated with necrotizing enterocolitis impair gut barrier function to pathobionts. The aim of this study was to determine how single immunoglobulin interleukin1-related receptor genetic variants disrupt neonatal intestinal barrier integrity and promote susceptibility to Gram-negative bacteria implicated in sepsis and necrotizing enterocolitis pathogenesis.

METHODS: Transgenic mice and preterm infant-derived enteroids expressing SIGIRR variants …

The Rise And Fall Of Lateral Electrical Surface Stimulation (Less) Through The Lens Of Srs Archives., Ali Rezazadeh Shirazi, Jay I. Kumar, Katie Dold, George H. Thompson, Andrew G. King, Richard M. Schwend, John P. Lubicky, Jay Shapiro, Behrooz A. Akbarnia, History Committee Of The Scoliosis Research Society

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Lateral electrical surface stimulation (LESS), commercially known as the ScoliTron™, emerged in the late 1970s as a noninvasive alternative to bracing for adolescent idiopathic scoliosis. Early clinical reports generated considerable enthusiasm and adoption, but the technique was ultimately abandoned. This study examined the rise and fall of LESS through a combined analysis of the Scoliosis Research Society (SRS) archives and published literature, with the goal of understanding factors that influence the adoption, evaluation, and abandonment of innovation in scoliosis care.

METHODS: A structured historical review was conducted using archival materials from the Scoliosis Research Society (SRS), including meeting abstracts, …

Gamclust: Identification Of Regulated Metabolic Modules In Bulk, Single Cell And Spatial Gene Expression Data, Anastasiia Gainullina, Evgeniia Chikina, Maxim N Artyomov, Alexey Sergushichev

2020-Current year OA Pubs

MOTIVATION: Metabolism operates as a highly interconnected biochemical network, and its regulation emerges from coordinated changes across many reactions and metabolites. The integration of gene expression profiling data with organism-scale metabolic networks has proven to be a valuable tool for understanding cellular metabolic regulation. However, the increasing complexity of profiling technologies and experimental designs requires the development of specialized tools.

RESULTS: Here, we present GAMclust, an R package implementing and extending the previously published GAM-clustering pipeline for identifying transcriptionally regulated metabolic modules in complex gene expression datasets. GAMclust supports bulk, single-cell, and spatial gene expression profiling. It includes built-in KEGG …

Crosstalk Between Upr And Mitochondria: The Triad Of Er-Mitochondria Contacts, Ca²⁺, And Ros, Ester Zito, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease …

Responding To Medetomidine In Philadelphia: Narrative Summary Of The Public Health Response To A New Psychoactive Substance, Tareva Warrick-Stone, Serge-Emile Simpson, Phil Durney, Dennis Goodstein, Catherine Abrams, Raymond Bobb, Kory London, Daniel Teixeira Da Silva

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Despite the emergence of medetomidine as the dominant adulterant in Philadelphia's illicit opioid supply, coordinated public health responses are limited or non-existent in the literature. Thus, we summarize a recent Summit in Philadelphia of outpatient and inpatient service providers who specialize in the care of persons who use drugs to discuss medetomidine response readiness and building ongoing community readiness for potential destabilizing drug supply changes.

PURPOSE: Describe a public health intervention that distributed information about practices across health care settings and mobilized key informants to identify and address barriers to treatment.

METHODS: Descriptive summary of the in-person Summit organized …

Heritable Transgenic Schistosomes As A Living Platform For Sars-Cov-2 Neutralizing Antibody Secretion, Wannaporn Ittiprasert, Bruce A Rosa, Sergej Djuranovic, Makedonka Mitreva, Et Al.

2020-Current year OA Pubs

We report the generation and propagation of not only the first heritable transgenic schistosome line but also a line that secretes a functional therapeutic protein in vivo. Using multiplexed CRISPR/Cas-mediated homology-directed knock-in targeted to a predicted genomic safe-harbor, we inserted a VHH-IgG1 Fc (termed C5-Fc) transgene into Schistosoma mansoni eggs. Single-miracidium infections of Biomphalaria glabrata yielded parental P0 lines; serial passage through snail and mouse hosts produced an F2 cohort in which all parasites carried the C5-Fc transgene and secreted C5-Fc into the murine venous circulation. Molecular assays confirmed chromosomal insertion, germline transmission and systemic secretion. Sera from mice harboring …

Redo-Transcatheter Aortic Valve Replacement With Self-Expanding Valves: A U.S. Registry Analysis., Toby Rogers, Vinayak N Bapat, Stanley J Chetcuti, Harold L Dauerman, John K Forrest, Sachin S Goel, Kendra J Grubb, Wah Wah Htun, Rishi Puri, Michael J Reardon, Gilbert H L Tang, Amit N Vora, Steven J Yakubov, Ruth Eisenberg, Guilherme F Attizzani

Heart and Vascular Articles

BACKGROUND: Redo-transcatheter aortic valve replacement (TAVR) for failed transcatheter heart valves is expected to increase, but data on outcomes with self-expanding valves remain limited.

OBJECTIVES: The aims of this study were to evaluate procedural, clinical, and quality-of-life outcomes following redo-TAVR using self-expanding Evolut valves and to compare these outcomes with those among a contemporary native TAVR cohort.

METHODS: Outcomes after redo-TAVR with Evolut R, Evolut PRO, and Evolut PRO+ valves in the Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry were analyzed and compared with outcomes after native-valve TAVR using the same valve platform during the …

Cells And Networks In Flux: Rethinking Ontogenesis And Pathogenesis, Mark L. Tykocinski

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Organ and tissue functions emerge from the coordinated activity of cell networks. Therapeutics that act on pathogenic cell networks, modulating their cellular interplay, follow naturally. Over several decades, our laboratory has developed a series of approaches for rewiring cell networks, culminating in a class of cell surface-directed signal converter proteins (SCPs) that do so by modulating juxtacrine and autocrine signaling in and among their nodal cells. A first such SCP has now produced encouraging clinical data for cancer immunotherapy. Yet, these early network-directed fusion proteins rest on a deliberately simplified picture: discrete end-cell types plugged into graphically tractable networks. That …

7th International Workshop On Sox Transcription Factors., Aya Uchida

Faculty Research 2026

Marking the 20th anniversary of a well-established meeting series focused on the biological and clinical importance of SOX genes as regulators of cell fate, the 7th International Workshop on SOX Transcription Factors held from 8-11 September 2025 at the Prince Resort MICE Karuizawa in Nagano, Japan, brought together 83 participants from 17 countries. The meeting showcased the foundations of SOX gene research and recent technological and conceptual breakthroughs across diverse model systems and human research, illustrating the field's evolution and emerging directions for future research. Reflecting the breadth of SOX biology - from early embryonic development and sex determination to …

Th17 Effector Cytokines Induce Shared And Distinct Microglial And Endothelial Cell Responses In A Mouse Model For Post-Streptococcal Encephalitis, Charlotte Wayne, Uğur Akcan, Travis Faust, Violeta Durán-Laforet, Danny Jamoul, Luca Bremner, Nicole Ampatey, Büşra Akcan, Sarah Ho, Bogoljub Ciric, Shannon Delaney, Wendy Vargas, Susan Swedo, Vilas Menon, Dorothy Schafer, Tyler Cutforth, Dritan Agalliu

Department of Neurology Faculty Papers

Group A Streptococcus (GAS) infections cause neuropsychiatric complications in children, but the mechanisms linking peripheral infection to brain dysfunction remain unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory transcriptional programs in microglia and brain endothelial cells (BECs), accompanied by loss of blood-brain barrier (BBB) gene expression in female mice. Spatial transcriptomic analyses reveal that GAS-responsive microglia localize near infiltrating CD4+ T cells. Several microglial chemokines induced in mice are elevated in sera from affected patients. Deletion of GM-CSF in CD4⁺ T cells partially reduces microglial chemokine gene expression, without restoring BBB …

Malt1 Protease Inhibition Restrains Glioblastoma Progression By Reversing Tumor-Associated Macrophage-Dependent Immunosuppression In Mice, Juliana Hofstätter Azambuja, Saigopalakrishna Yerneni, Lisa Maurer, Hannah Crentsil, Gabriela Debom, Linda Klei, Mei Smyers, Chaim Sneiderman, Kristina Schwab, Rajesh Acharya, Aivi Nguyen, Josie Emery, John Little, Jeffrey Meridew, Yijen Lin Wu, Prasanna Ekambaram, Dong Hu, Pete Gough, John Bertin, Ari Melnick, Gary Kohanbash, Riyue Bao, Peter Lucas, Linda Mcallister-Lucas

College of Life Sciences Faculty Papers

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive ('M2-like') phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor 'M1-like' phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages …

Translational Reading Frame Predicts The Pathogenicity Of C-Terminal Frameshift Deletions In Mecp2, Jacky Guy, Elena Hein, Beatrice Alexander-Howden, Timur Von Bock Und Polach, Tricia Mathieson, Benjamin P Kleinstiver, Huda Y Zoghbi, Adrian Bird

Duncan NRI Faculty and Staff Publications

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline …

Cigarette Smoke Induces Fasn-Dependent Fatty Acid Metabolic Rewiring To Drive Bladder Cancer Progression, Chandra Sekhar Amara, Danthasinghe Waduge Badrajee Piyarathna, Abu Hena Mostafa Kamal, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, Minjae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri

Faculty, Staff and Students Publications

Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via …

Non-Enzymatic Hepatic Abhd6 Interacts With Akt-Foxo1 Axis To Regulate Metabolic Health, Guannan Li, Laurence T Maeyens, Jiyuan Yin, Jan-Bernd Funcke, Chanmin Joung, Ruizhen Li, Ziying Xu, Ting Wu, Xin Li, Nisi Jiang, Mbolle Ekane, Maria Paula Lopez, Pengju Cao, Sijia He, Adam B Salmon, S R Murthy Madiraju, Marc Prentki, Juli Bai, James F Nelson, Xianlin Han, Yi Zhu, Shangang Zhao

Children’s Nutrition Research Center Staff Publications

The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin …

Mir155, Triplicated In Down Syndrome, Regulates The Development Of Neural Stem Cells And Gabaergic Interneurons In Alzheimer's Disease Mouse And Human Ipsc Models., Xiaodong Zhu, Jean-Vianney Haure-Mirande, Mesude Bicak, Pengfei Dong, Ilya Kruglikov, Aiqun Li, Aisha Al-Subaie, Valentina Fossati, Scott Noggle, Sam Gandy, Michelle E Ehrlich

Faculty Research 2026

INTRODUCTION: Dysfunctional microRNAs and GABAergic interneurons are features of Alzheimer's disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown.

METHODS: We utilized in silico analyses of published databases, MIR155-deleted and -overexpressing human induced pluripotent stem cell (hiPSC)-derived cells, cortical organoids, and amyloid beta precursor protein (APP)/PS1-miR155 knockout mouse.

RESULTS: MIR155HG (miR155 host gene) colocalizes with APP in a neuron-specific, topologically associated domain (TAD) in chromosome 21. In human neural stem cells (NSCs), neurons, and cortical organoids, MIR155 deletion enhanced NSC proliferation and GABAergic interneuron generation. MIR155 overexpression inhibited NSC marker expression …

The Past, The Present, And The Future Of Preclinical Mouse Models For Alzheimer's Disease And Related Dementias., Adrian L Oblak, Michael Sasner, Gregory W. Carter, Gareth R Howell, Stacey J Sukoff Rizzo, Karina Leal, Paul R Territo, Bruce T Lamb

Faculty Research 2026

Over the past decade, the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium has transformed preclinical Alzheimer's disease (AD) research by addressing critical limitations in traditional mouse models that failed to translate to human disease. By leveraging human genetic discoveries, MODEL-AD has developed > 70 genetically informed mouse models, standardized phenotyping pipelines, and an open-access data infrastructure aligned with late-onset AD biology. These models incorporate human risk variants, environmental factors, and aging to better capture disease complexity, including emerging recognition of mixed pathologies such as vascular contributions, Lewy body disease, and TDP-43 proteinopathy. Despite substantial progress, key challenges …

Stromal Cell Senescence Augments Haematopoietic Cell Fitness In Clonal Haematopoiesis., Jayna J Mistry, Kira Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J. Trowbridge

Faculty Research 2026

Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic …

A Collaborative Framework For Uncovering Molecular And Cellular Drivers Of Vcid: Foundations For Future Interventions In Dementia., M Luisa Iruela-Arispe, Jason D Hinman, Andrew C Yang, Fabrice Dabertrand, Jin-Moo Lee, Gareth R Howell, The Vcid Centers Without Walls Network

Faculty Research 2026

Vascular-related factors are now considered major contributors to most forms of dementia, including Alzheimer's disease. However, the degree to which vascular deficits contribute to risk, onset, and progression of cognitive impairment and dementia has only recently been appreciated. Our understanding of the mechanisms by which vascular deficits drive cognitive decline in dementia is still limited. Further, the testing of therapeutic approaches to prevent vascular deficits to treat dementia are few. These factors motivated the establishment of the Vascular Contributions to Cognitive Impairment and Dementia (VCID) Center Without Walls (CWOW) network, comprising institutes across the United States. We describe the current …

Inhibition Of Moesin And Cd44 In Stem Cell-Derived Neurons Affects The Pathological Genetic Signature Associated With Alzheimer's Disease., Eiden H Brewer, Charles A Williams, Gregory Cary, Ranjita Betarbet, Inez K A Pranoto, Elizabeth L Zoeller, Haian Fu, Allan I Levey, Jesse C Wiley, Gregory W. Carter, Jessica E Young, Treat-Ad Consortium

Faculty Research 2026

INTRODUCTION: Post mortem proteomic analysis of Alzheimer's disease (AD) brain tissue has identified novel target genes and proteins for potential therapeutic development. Moesin (MSN) and CD44 were identified as candidate targets. Using human induced pluripotent stem cells (hiPSCs)-derived neurons, we assayed how reducing gene expression of MSN and CD44 affected amyloid beta secretion, tau phosphorylation, and transcriptional state.

METHODS: Knockdown of MSN and CD44 in hiPSC-derived neurons was performed using short hairpin RNA (shRNA). Amyloid precursor protein processing and intracellular tau phosphorylation was measured using chemiluminescent ELISA assays. Global gene expression was analyzed by bulk RNA sequencing (RNA-seq).

RESULTS: Knockdown …

Effects Of Concurrent Neuropathologies With Alzheimer Disease Neuropathologic Change On Cognitive Decline: Minimal Impact Of Vascular Brain Injury Compared With Other Combinations, Sarah M Yasuda, Charles Mock, Kathryn Gauthreaux, Kwun C G Chan, C Dirk Keene, Jessica E Culhane, Yen-Chi Chen, Walter Kukull

2020-Current year OA Pubs

We examined cognitive changes associated with several neuropathologic entities, alone and in combination. We studied 808 participants from the National Alzheimer's Coordinating Center to assess associations between neuropathologic diagnoses (from autopsy) and neuropsychologic test scores (trajectories over time for 5 domains: overall cognition, episodic memory, attention, language, executive function). Neuropathologies included: Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), vascular brain injury (VBI), and limbic-predominant age-related TDP43 encephalopathy neuropathologic change (LATE-NC). Using linear mixed-effects models, we examined trajectories of cognitive decline for ADNC alone compared to ADNC plus LBD, VBI, or LATE-NC. We also examined differences between observed trajectories …

Hyperadhesive Von Willebrand Factor Contributes To Pathogenesis Of Preeclampsia, Yajuan Wang, Chenyu Wang, Katie L Houck, Xiaoli Gao, Yuanyuan Chen, Xin Xu, Xue Zhao, Miguel A Cruz, Shu Zhang, Chester Q Li, Fengxia Xue, Min Li, Swati Shree, Jing-Fei Dong, Cha Han

Children’s Nutrition Research Center Staff Publications

Background: Preeclampsia is the most common complication of pregnancy, significantly affecting maternal and fetal health, and is characterized by placental and systemic endotheliopathy. Patients with preeclampsia have elevated levels of VWF (von Willebrand Factor), which is associated with poor clinical outcomes. However, whether VWF serves as a marker for endotheliopathy or contributes to the pathogenesis of preeclampsia remains poorly understood.

Methods: We investigated the role of hyperadhesive VWF in the development of preeclampsia by studying patients, evaluating mouse models, and performing in vitro experiments.

Results: We show that patients develop VWF- and fibrin-rich thrombosis in the placenta and have significantly …