Digital Commons Network^™

Gh Alters Lymphatic Vessels In Female Mice And Stat5 Phosphorylation In Human Lymphatic Endothelial Cells, Christopher Walsh, Emily Scott, Elise Wagner, Jerome Walsh, Shashank Reddy, Arshad Ahmad, Reetobrata Basu, Eva Sevick-Muraca, Rich Brody, Uday Sandbhor, Sebastian Neggers, John J Kopchick

The Brown Foundation: Institute of Molecular Medicine

Disruption of lymphatic function underlies a broad spectrum of inflammatory and metabolic disorders, yet the hormonal pathways that regulate lymphatic biology remain poorly defined. GH, which is implicated in similar disease states, has an unclear role in lymphatic homeostasis. To address this gap, we investigated how chronic alterations in GH signaling alter lymphatic structure and function. Using transgenic mouse lines with increased, decreased, or absent GH action, we quantified the effect of GH on lymphatic pumping rate and lymphangiogenic remodeling during wound healing using near-infrared fluorescent imaging. We also measured markers of lymphatic endothelial cells using Western blot and immunohistochemistry …

Sex-Specific Evolutionary Programs Shape Recombination Rate Evolution In House Mice., Lydia K Wooldridge, Micah Pietraho, Peyton Disiena, Sam Littman, Benjamin Clauss, Beth L Dumont

Faculty Research 2026

Recombination rates vary across species, populations, and sexes. House mice (Mus musculus) present a particularly extreme example. Prior studies have established large differences in global recombination rates between M. musculus subspecies and inbred strains, with males exhibiting more extensive variation than females. The observation of sex-limited variation has prompted the hypothesis that male and female recombination rates may evolve by distinct evolutionary mechanisms in M. musculus. Here, we formally evaluate this hypothesis in a phylogenetic framework. We combine cytogenetic estimates of genomic crossover counts with published data to compile a large dataset of sex-specific crossover rate estimates totaling >6,000 single …

Characterization Of Inflammatory Pseudotumors In A Large Animal Model Of Liver Cancer, Erik N K Cressman, Samantha Hicks, Natalie W Fowlkes, Danielle L Stolley, Maria Sophia Stenkamp

Faculty, Staff and Student Publications

Background: The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease. Transgenic approaches hold promise in addressing this complex problem. One such model, the Oncopig, has been reported to develop tumors of up to 4 cm in diameter within 7-14 days at sites of in situ vector inoculation. However, the resulting lesions reportedly contained an extensive inflammatory component that has not been evaluated in detail.

Methods: Herein, we describe our results from multiparametric characterization of the lesions generated using liver biopsy cores incubated in vector solution and replaced …

3d Reconstruction Of Spatial Transcriptomics With Spatial Pattern Enhanced Graph Convolutional Neural Network, Chen Tang, Yuansheng Zhou, Xue Xiao, Lei Dong, Lei Yu, Qiwei Li, Guanghua Xiao, Lin Xu

Faculty, Staff and Student Publications

Spatially resolved transcriptomics (SRT) is a promising new technology that enables simultaneous analysis of gene expression and spatial information for biomedical research. However, the existing statistical and deep learning algorithms used for analyzing SRT data rely solely on two-dimensional (2D) spatial coordinates, which limits their ability to accurately identify spatial domains, spatially variable genes (SVGs), cell-to-cell communications, and developmental trajectories in a three-dimensional (3D) spatial manner. To address these limitations, we introduced Spa3D, which utilized the anti-leakage Fourier transform and graph convolutional neural network model to reconstruct 3D-based spatial structures from multiple 2D SRT slices. We demonstrate that Spa3D is …

Harnessing Microbial Tools: Escherichia Coli As A Vehicle For Neuropeptide Functional Analysis In Caenorhabditis Elegans, Elizabeth M Diloreto, Shruti Shastry, Emily J Leptich, Douglas K Reilly, Rachel N Arey, Jagan Srinivasan

Faculty, Staff and Students Publications

Animals respond to changes in their environment and internal states via neuromodulation. Neuropeptides modulate neural circuits with flexibility because 1 gene can produce either multiple copies of the same neuropeptide or different neuropeptides. However, with this architectural complexity, the function of discrete and active neuropeptides is muddled. Here, we design a genetic tool that facilitates functional analysis of individual peptides. We engineered Escherichia coli bacteria to express active peptides, fed loss-of-function Caenorhabditis elegans, and rescued the activity of genes with varying lengths and functions: pdf-1, flp-3, ins-6, and ins-22. Some peptides were functionally redundant, while others exhibit unique and previously …

N-Palmitoyl Glutamine Is A Candidate Mediator Of Cardiorespiratory Fitness, Jeremy M Robbins, Mark Benson, Anthony R P Verkerke, Gaurav Tiwari, Shuliang Deng, Prashant Rao, Usman A Tahir, Julian Avila-Pacheco, Xu Shi, Yuntian Guan, Foje-Geh Tendoh, Jacob L Barber, Patricia E Miller, Andrew S Perry, Michael E Hall, Alexis C Wood, Kent D Taylor, Wendy S Post, Stephen S Rich, Matthew Nayor, James G Wilson, Gregory D Lewis, Ravi V Shah, Jerome I Rotter, Scott A Summers, Laura M Raffield, Shingo Kajimura, Claude Bouchard, Clary B Clish, Mark A Sarzynski, Robert E Gerszten

Children’s Nutrition Research Center Staff Publications

Background: Cardiorespiratory fitness is an integrative measure of cardiometabolic health and predictor of survival, yet little is known about its molecular underpinnings. Small molecule metabolites and lipids are increasingly recognized as exercise-stimulated signaling molecules and candidate molecular transducers of cardiorespiratory fitness.

Methods: We performed nontargeted liquid chromatography mass spectrometry-based plasma metabolomics in 654 participants (mean age, 35 years; 55% women) from the HERITAGE Family Study (Health, Risk Factors, Exercise Training, and Genetics) who had cardiorespiratory fitness (maximal oxygen uptake [VO2max]) measured by cardiopulmonary exercise testing and underwent 20 weeks of supervised endurance training. Metabolite-VO2max relationships were assessed using linear regression …

Bromodomain And Extra-Terminal Protein Inhibitors Modulate Natural Killer Cell Function And Differentiation., Eric S. Geanes, Gage Greening, Maria Aggelakopoulou, Linh Huyen Truong, Santosh Khanal, Cas Lemaster, Marc L. Herman, Rebecca Mclennan, Persephone Borrow, Todd Bradley

Manuscripts, Articles, Book Chapters and Other Papers

Natural killer (NK) cells are integral to the innate immune system, playing a crucial role in immune surveillance and the rapid response to virally infected and tumor cells. Epigenetic gene expression regulation significantly influences NK cell function and differentiation. Using a high-throughput small-molecule drug screening approach, we identified bromodomain and extra-terminal domain (BET) inhibitors (BETi) as potent modulators of NK cell function, reducing proinflammatory cytokine secretion while increasing markers of NK cell maturation and cytotoxicity. During NK lineage specification from hematopoietic stem cells, we demonstrated that BETi reduced NK cell fate and promoted increased myeloid cell differentiation. Moreover, differentiated NK …

Circadian-Shaped Immune Variability Predicts Infection Outcome, Jonathan Lalsiamthara, Mariko Locke, Alejandro Aballay

Faculty, Staff and Student Publications

Disease risk and severity are influenced by genetics, epigenetics, and environmental factors. However, immune responses vary even among genetically similar or related individuals, shaped by inherited and noninherited factors. Using Caenorhabditis elegans, we found that pathogen susceptibility can be predicted by preinfection biomarkers. Individuals with high-basal expression of irg-5, an infection response gene regulated by the p38 mitogen-activated protein kinase-1 (PMK-1) pathway, were more susceptible to Pseudomonas aeruginosa infection. A genome-wide screen identified the myeloid ecotropic viral integration site-1 (MEIS) homeobox protein UNC-62 as a regulator of irg-5 expression, acting through PMK-1 and GATA binding erythroid-like transcription factor …

A Flupirtine Benzyl Carbamate Improves Neurocognitive Deficits And Molecular Pathology In The Cln6nclf Mouse, Victoria Chaoul, Omar Shmoury, Ramy Alam, Sara Saab, Joelle Makoukji, Lynn Al Aridi, Nadine J. Makhoul, Jihane Soueid, Angelica V. Carmona, Princess Simeon, Paul C. Trippier, Rose-Mary Boustany

Journal Articles: Pharmaceutical Sciences

Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6^nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in …

Differential Sensitivity Of Leukocyte Populations To Staphylococcus Aureus Biofilm, Nichole D. Brandquist, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of prosthetic joint infection (PJI) typified by biofilm formation. Anti-inflammatory granulocytic myeloid-derived suppressor cells (G-MDSCs) represent the main leukocyte population in a mouse model of S. aureus PJI, followed by neutrophils (PMNs), and macrophages (Mφs), which is also seen during human PJI. Defining how each leukocyte population responds to S. aureus biofilm vs planktonic bacteria could have important implications for how S. aureus evades immune detection to facilitate biofilm persistence. This study compared the kinetics of leukocyte death and relationship to mitochondrial ROS (mtROS) production following exposure to planktonic S. aureus or biofilm. Mφs …

Mitochondrial Transfer To Granulocytic Myeloid-Derived Suppressor Cells Augments Immunosuppressive Activity, Prabhakar Arumugam, Cortney E. Heim, Rachel W. Fallet, Dhananjay Shinde, Vinai Chittezham Thomas, Rafael J. Argüello, Tammy Kielian

Journal Articles: Pathology and Microbiology

The anti-inflammatory properties of granulocytic myeloid-derived suppressor cells (G-MDSCs) promote Staphylococcus aureus (S. aureus) biofilm persistence. Evidence suggests that G-MDSC activity is shaped not only by S. aureus products but also by intrinsic metabolic programs. This study explores whether G-MDSC activity can be modulated by increasing mitochondrial abundance using a co-culture paradigm with macrophages as a mitochondrial donor. Macrophages transfer mitochondria directly to G-MDSCs via tunneling nanotubes, enhancing G-MDSC respiration, as reflected by increased basal, maximal, and spare respiratory capacity. Augmenting mitochondrial abundance in G-MDSCs enhances T cell-suppressive activity and reduces tumor necrosis factor (TNF) and interleukin 6 (IL-6) production. …

Overcoming Egfr-Mediated Dendritic Cell Dysfunction To Enhance Anti-Tumor Immunity In Egfr-Mutant Nsclc By Precisely Targeting Cd73 With Ph-Responsive Nanocarriers., Xiaoling Shang, Xudong Geng, Zixu Wang, Shumin Yuan, Shanshan Ding, Ni Liu, Xinchun Ma, Xuan Sun, Huimin Wang, Ying Sun, Xun Qu, Guangwen Ren, Yong Qiang Li, Xiuwen Wang, Yanguo Liu

Faculty Research 2026

EGFR mutations remain a major challenge in immunotherapy for non-small cell lung cancer (NSCLC), with poor responses to immune checkpoint inhibitors driven by mechanisms associated with EGFR mutation-mediated tumor microenvironment (TME) modulation. This study reveals that EGFR mutations prominently impaired dendritic cell (DC) maturation, disrupting their capacity to effectively prime CD8+ T cells and thereby compromising anti-tumor immune responses. By application of clinical specimen analyses, multi-omics approaches, and in vivo mouse models, this work demonstrates that EGFR mutations elicited adenosine production through the ERK/c-Jun signaling axis in tumor cells, establishing an immunosuppressive TME that impeded maturation and antigen presentation of …

Cxcr6+ Natural Killer Cell Immunotherapy Preserves Cd4+ T Helper Cells In Humanized Mice, Naushad Khan, Kayla Frank, Silke Paust

Faculty Research 2026

Human immunodeficiency virus (HIV) persists despite antiretroviral therapy because long-lived viral reservoirs are not eliminated, and ongoing or rebound infection contributes to progressive loss of CD4⁺ T helper cells. Natural killer (NK) cells can acquire adaptive, antigen-experienced functions, including recall responses to HIV envelope protein, suggesting that defined NK-cell subsets may be therapeutically useful against HIV. Because HIV-responsive adaptive NK-cell activity is enriched among CXC chemokine receptor 6-positive (CXCR6⁺) NK cells, we tested whether CXCR6⁺ NK cells provide enhanced antiviral activity and CD4⁺ T-cell protection compared with CXCR6⁻ NK cells. In co-cultures with HIV-infected …

Three Decades Of Classifying Threatened Species: Lessons Learned From And About The Iucn Red List Criteria For Quantifying Extinction Risk, H. Resit Akçakaya, E. J. Milner-Gulland, Mike Hoffmann, Helen M. Regan, Ilona Naujokaitis-Lewis, Andre E. Punt, Kevin J. Gaston, David A. Keith, Stuart H. M. Butchart, Simon N. Stuart, Nigel J. Collar, Moreno Di Marco, Monika Bohm, Alex J. Berryman, David P. Mallon, Axel Hochkirch, Nicholas K. Dulvy, Malin Rivers, Thomas M. Brooks, James R. S. Westrip, Jonathan Paul Rodriguez, Craig Hilton-Taylor, Janet Scott, Simon Tarr, Sophie H. Ledger, Christi Linardich

Biological Sciences Faculty Publications

The IUCN Red List of Threatened Species, the most widely used global system for assessing species' extinction risk, has become a foundational source of information for conservation management, policy and research. Since the adoption of quantitative extinction risk criteria more than three decades ago, the Red List has expanded substantially in scope and influence, informing decisions ranging from species conservation and protected area designation to international agreements, corporate risk assessments and global biodiversity indicators. Given its central role, maintaining scientific rigour, transparency and trust in the Red List system is essential. Feedback from users, emerging from evolving applications and scientific …

Larval Genomics As A Viable, Fisheries-Independent Tool For Investigating Population Structure In Tropical Pacific Tunas, Jacob E. Jaskiel, Hannah E. Aichelman, Giulia Anderson, Louw Claassens, James E. Fifer, Christina M. Hernandez, Alexa K. Huzar, Joel K. Llopiz, Jan W. Witting, Sean P. Mullen, Randi D. Rotjan

Biological Sciences Faculty Publications

Understanding how dispersal, life history, and environmental variability shape genetic connectivity in the open ocean remains a central challenge in evolutionary biology. Highly migratory marine predators like tunas have traditionally been considered genetically homogeneous across ocean basins, yet emerging genomic evidence suggests that cryptic population structure can persist even in species with high gene flow and large effective population sizes. We used 2bRAD sequencing of 348 larval and subadult skipjack (Katsuwonus pelamis), yellowfin (Thunnus albacares), and bigeye tuna (T. obesus) collected from the central Pacific across 7 years of sampling to examine species boundaries, …

Markov Chain Wave Generative Adversarial Network For Bee Bioacoustic Signal Synthesis, Kumudu Samarappuli, Iman Ardekani, Mahsa Mohaghegh, Abdolhossein Sarrafzadeh

Electrical & Computer Engineering Faculty Publications

This paper presents a framework for synthesizing bee bioacoustic signals associated with hive events. While existing approaches like WaveGAN have shown promise in audio generation, they often fail to preserve the subtle temporal and spectral features of bioacoustic signals critical for event-specific classification. The proposed method, MCWaveGAN, extends WaveGAN with a Markov Chain refinement stage, producing synthetic signals that more closely match the distribution of real bioacoustic data. Experimental results show that this method captures signal characteristics more effectively than WaveGAN alone. Furthermore, when integrated into a classifier, synthesized signals improved hive status prediction accuracy. These results highlight the potential …

An Anti-Adhesive Compound Modulating The Production Of Staphylococcus Aureus Cell Wall-Anchored Proteins, Allison C. Leonard, Ruina Bao, Cindy Menjivar, Megan J. Myers, Telmo O. Paiva, Zhiyong Zheng, Kirsten A. Berry, Kenneth W. Bayles, Ronald S. Flannagan, Yves F. Dufrêne, Jeffrey L. Bose, David E. Heinrichs, Georgina Cox

Journal Articles: Pathology and Microbiology

As one of the leading global causes of death associated with antimicrobial resistance, Staphylococcus aureus frequently colonizes the human nasal cavity and adheres to keratinized skin, establishing reservoirs that drive subsequent infections and emphasize the need for new decolonization strategies. Using a high-throughput, whole-cell screening platform, here we identify geranylgeranoic acid (GGA), a naturally occurring polyunsaturated, branched-chain fatty acid, as having dual activity against methicillin-resistant S. aureus (MRSA). At elevated concentrations, GGA exhibits microbicidal effects, whereas at sub‑microbicidal doses, it effectively inhibits MRSA adhesion to keratin, fibronectin, fibrinogen, and immunoglobulins. GGA possesses anti-adhesive activity against a panel of multidrug-resistant S. …

Bulletin 4936: Guidelines To Importing And Keeping Regulated Animals In Western Australia, Win Kirkpatrick

Bulletins 4000 -

Updated:

• January 2026 after a review of permit keeping conditions.
• December 2025 for transfer of restricted keeping bird permit business to DPIRD.

Introduced, exotic or alien animals are species that have been brought to a country or location where they do not occur naturally. (Hereafter referred to as introduced species). Mammals, birds, reptiles, and amphibians that are introduced or relocated to new areas often cause problems to agriculture, the environment and the community. Problems occur when introduced species:

• damage agricultural crops
• displace and compete with native animals and plants
• carry disease or parasites
• damage property
• cause land degradation
• have a …

Overcoming Radiation Resistance: Ferroptosis Induction To Sensitize Solid Tumors To Radiation Therapy, Joseph Carmicheal, Caden M. Fritson, Alexandra Seas, Heidi M. Vieira, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Radiation therapy (RT) is a mainstay of treatment for a myriad of cancers, often utilized for tumors that are unable to be resected, as well as an adjunct to surgery and chemotherapy. Unfortunately, many cancers are resistant to RT-induced damage and subsequent cell death. This has spurred the pursuit of novel radiation sensitizers that could potentiate the effects of this widely used and important treatment modality. Since its discovery as a regulated cell death mechanism in 2012, ferroptosis has been studied for its connection to cancer and other known oxidative pathways. With this, the interplay between RT and ferroptosis in …

Estrogen Deprivation During Primate (Papio Anubis) Pregnancy: Impact On Systemic Microvascular Flow And Cardiovascular Development And Function After Birth In Offspring, Sifa Turan, Jeffery S. Babischkin, Graham W. Aberdeen, Gerald J. Pepe, Eugene D. Albrecht

Department of Biomedical and Translational Sciences Faculty Publications

Background

Suppressing estradiol (E₂) during baboon pregnancy lowers offspring skeletal muscle capillary density, vital for insulin-mediated glucose uptake, and induces insulin resistance. We examined whether E₂ deprivation also impairs microvascular flow and cardiac function.

Methods

Offspring of untreated baboons, letrozole-treated baboons, or letrozole plus E₂ (maternal s.c. injections during the second half of gestation) underwent contrast-enhanced microbubble ultrasonography to quantify microvessel flow and echocardiography to assess cardiac performance.

Results

Letrozole reduced maternal serum E₂ by 95% (p <  0.01). In letrozole offspring, microbubble flux rate (β) fell 55% (p <  0.02), replenishment was 5 s slower (p <  0.03), and microvessel flow declined 40% (p = 0.05); all were restored by added E₂. Indices of systolic (isovolumic contraction), diastolic (isovolumic relaxation), global performance (Tei index), and cardiac output were unchanged.

Conclusion

Prolonged gestational E₂ deprivation programs a reduction in microvascular flow without altering cardiac function; maternal E₂ prevents this, supporting E₂'s role in …

The Structure Of The Native Cardiac Crossbridge In The Rigor State, Cristina M. Risi, Tyler Nguyen, Betty Belknap, Howard D. White, Jose R. Pinto, Prescott B. Chase, Vitold E. Galkin

Department of Biomedical and Translational Sciences Faculty Publications

Cardiac contraction is driven by double-headed myosin cycling on cardiac thin filaments, where troponin-tropomyosin regulates myosin access to actin. Prior high-resolution structural studies used a single-headed myosin bound to bare actin, thereby limiting insight into coordination between myosin heads and the influence of troponin-tropomyosin on actomyosin interactions. Here, we report a high-resolution structure of the native cardiac rigor cross-bridge formed by heavy meromyosin bound to the thin filament. We show that direct communication between the two bound heads, uneven interactions between the heads and tropomyosin, and spatial constraints imposed by troponin govern myosin placement along the thin filament. Additionally, the …

Prolonged Qt Interval In Hiv-1 Infected Humanized Mice Treated Chronically With Dolutegravir/Tenofovir Disoproxil Fumarate/Emtricitabine, Ali Namvaran, Julian V. Garcia, Mahendran Ramasamy, Kayla Nguyen, Farzaneh Tavakkoli Ghazani, Bryan T. Hackfort, Prasanta Dash, Reagan E. Fisher, Benson J. Edagwa, Santhi Gorantla, Keshoer R. Bidasee

Journal Articles: Cellular & Integrative Physiology

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. …

“Shaking The Ladder” Reveals How Analytic Choices Can Influence Associations In Nutrition Epidemiology: Beef Intake And Coronary Heart Disease As A Case Study, Colby J Vorland, Lauren E O'Connor, Beate Henschel, Cuiqiong Huo, James M Shikany, Carlos A Serrano, Robert Henschel, Stephanie L Dickinson, Keisuke Ejima, Aurelian Bidulescu, David B Allison, Andrew W Brown

Children’s Nutrition Research Center Staff Publications

Nutrition epidemiological models involve many analytic decisions, such as defining exposures, selecting which covariates to include, or configuring variables in different ways. We explored the impact of analytical decisions on conclusions in nutrition epidemiology using self-reported beef intake and incident coronary heart disease as a case study. We used REasons for Geographic and Racial Differences in Stroke (REGARDS) data, and selected covariates and their configurations from published literature to recapitulate common models used to assess associations between meat intake and health outcomes. Three model sets were designed: sets one and two used continuous and quintile-defined beef intakes, respectively, each with …

Investigation Of A Global Mouse Methylome Atlas Reveals Subtype-Specific Copy Number Alterations In Pediatric Cancer Models., Melanie Schoof, Tuyu Zheng, Martin Sill, Roland Imle, Alessia Cais, Lea Altendorf, Alicia Fürst, Nina Hofmann, Kati Ernst, Dominik Vonficht, Kenneth Chun-Ho Chan, Tim Holland-Letz, Andreas Postlmayr, Ryo Shiraishi, Wanchen Wang, Alaide Morcavallo, Michael Spohn, Carolin Göbel, Judith Niesen, Levke-Sophie Peter, Franck Bourdeaut, Zhi-Yan Han, Yanxin Pei, Najiba Murad, Fredrik J. Swartling, Jessica Taylor, Monika Yadav, Garrett R. Gibson, Richard J. Gilbertson, Matthias Dottermusch, Rajanya Roy, Kornelius Kerl, Rainer Glass, Jiying Cheng, Martin A. Horstmann, Gerrit Wolters-Eisfeld, Haotian Zhao, Dominik Sturm, Viveka Nand Yadav, Louis Chesler, Simon Haas, William A. Weiss, Paul A. Northcott, Lena M. Kutscher, Ana Guerreiro Stucklin, Olivier Ayrault, Julia E. Neumann, Daisuke Kawauchi, David T W Jones, Kristian Pajtler, Ana Banito, Stefan M. Pfister, Ulrich Schüller, Marc Zuckermann

Manuscripts, Articles, Book Chapters and Other Papers

Copy number alterations (CNAs) are hallmarks of cancer, yet investigation of their oncogenic role has been hindered by technical limitations and missing model systems. Here we generated a genome-wide DNA methylation and CNA atlas of 106 genetic mouse models across 31 pediatric tumor types, including 18 new models for pediatric glioma. We demonstrated their epigenetic resemblance to human disease counterparts and identified entity-specific patterns of immune infiltration. We discovered that mouse tumors harbor highly recurrent CNA signatures that occur distinctly based on the tumor subgroup and driving oncogene and showed that these CNAs share syntenic regions with the matching human …

T Cells Modulate The Development And Maintenance Of Painful Paclitaxel-Induced Peripheral Neuropathy In Rnu Rats, Ahmed Olalekan Bakare, Gerard Limerick, Vasudha Goel, Ratan K Banik, Lei Zheng, Andrew J Shepherd, Kristine Glunde, Qin Zheng, Eellan Sivanesan

Faculty, Staff and Student Publications

The role of T cells in chemotherapy-induced peripheral neuropathy (CIPN) is complex and shaped by biological and experimental factors, including sex, hormonal status, genetic background, and cancer model. This complexity has contributed to inconsistent findings among studies, limiting therapeutic progress. In this study, we investigate how T cells contribute to painful paclitaxel (PTX)-induced peripheral neuropathy (PIPN). Adult male T cell-competent (RNU+/−) and T cell-deficient (RNU−/−) rats were subcutaneously inoculated with tumor cells and subsequently treated with intraperitoneal PTX (8 mg/kg total dose). Reflexive (mechanical, heat, cold) and non-reflexive (burrowing, gait) pain behaviors were assessed from baseline through week 6. Immunohistochemistry …

The Lysine Demethylase Kdm4c Is An Oncogenic Driver And Regulates Erk Activity In Kras-Mutant Pancreatic Ductal Adenocarcinoma, Menna-T-Allah Shaheen, Sarah Dhebat, Kimal I Rajapakshe, Bidyut Ghosh, Benson Chellakkan Selvanesan, Shariq S Ansari, Cara L Haymaker, Dorsay Sadeghian, Huamin Wang, Ching-Fei Li, Haoqiang Ying, Anirban Maitra

Faculty, Staff and Student Publications

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin-modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell–like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared with nonneoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomic analyses revealed that loss of KDM4C in both human and …

Preclinical Ischemic Stroke Multicenter Trials (Prism) Collective Statement: Opportunities, Challenges, And Recommendations For A New Era, Cenk Ayata, Philip M Bath, Anna M Planas, Stuart M Allan, Johannes Boltze, Ryan P Cabeen, Claire L Gibson, Marilyn J Cipolla, Marcio A Diniz, Stefano Fumagalli, Fahmeed Hyder, Raymond C Koehler, Arthur Liesz, Sarah K Mccann, Tim Magnus, Louise D Mccullough, Emily S Sena, Simone Beretta, Jaroslaw Aronowski, Francesca Bosetti, Clinton B Wright, Patrick D Lyden, Lauren H Sansing

Faculty, Staff and Student Publications

Preclinical stroke research faces a critical translational gap, with animal studies failing to reliably predict clinical efficacy. To address this, the field is moving toward rigorous, multicenter preclinical randomized controlled trials (mpRCTs) that mimic phase 3 clinical trials in several key components. This collective statement, derived from experts involved in mpRCTs, outlines considerations for designing and executing such trials. mpRCTs offer advantages such as increased sample sizes, robust statistical design, incorporation of heterogeneity, and standardized protocols, but they face challenges in finding the right balance between standardization and heterogeneity, appropriate stroke model selection, and outcome measures, as well as the …

Blood Flow Regulates Metabolism In Hematopoietic Development, Pamela L Wenzel

Faculty, Staff and Student Publications

Blood flow modifies oxygen availability and biomechanical forces within the vasculature of the embryo as the hematopoietic system develops. The aorta-gonad-mesonephros (AGM) envelops the largest artery in the body and is a critical site for the emergence of hematopoietic stem cells (HSCs). Herein, I discuss the role of hypoxia-inducible factors (HIFs) and force as determinants of metabolism and fate determination. To address the effects of blood flow on hematopoietic development, I employ mouse embryo models and biomimetic culture. Real-time cell metabolic analyses show that oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) are altered by flow in cultures of …

Senolytic-Resistant Senescent Cells Have A Distinct Sasp Profile And Functional Impact: The Path To Developing Senosensitizers, Utkarsh Tripathi, Masayoshi Suda, Vagisha Kulshreshtha, Bryan T Piatkowski, Allyson K Palmer, Nino Giorgadze, Christina Inman, Nathan Gasek, Ming Xu, Kurt O Johnson, Tamar Pirtskhalava, Selim Chaib, Larissa P G Langhi Prata, Yi Zhu, Renuka Kandhaya-Pillai, Stefan G Tullius, Saranya P Wyles, Rambabu Majji, Hari Krishna Yalamanchili, David B Allison, Tamar Tchkonia, James L Kirkland

Faculty, Staff and Students Publications

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%-70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30%-70% of human senescent preadipocytes or human umbilical …

Astrocytic Sox9 Overexpression In Alzheimer’S Disease Mouse Models Promotes Aβ Plaque Phagocytosis And Preserves Cognitive Function, Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes …