Digital Commons Network^™

Mathematical Modeling And Association Analysis Decipher The Impact Of The Gut Microbiome On Cancer Immunotherapy, Andreas G Hadjigeorgiou, Constantinos Harkos, Aditya K Mishra, Golnaz Morad, Sarah B Johnson, Nadim J Ajami, Jennifer A Wargo, Lance L Munn, Triantafyllos Stylianopoulos, Rakesh K Jain

Faculty, Staff and Student Publications

The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, a better understanding of the underlying mechanisms by which the microbiome influences immunotherapy is needed to identify strategies to optimize outcomes. To this end, we developed a mathematical model to obtain insights into the effect of the microbiome on the immune system and immunotherapy response. This model was based on (i) gut microbiome data derived from preclinical studies, (ii) mathematical modeling of the antitumor immune response, (iii) association analysis of microbiome profiles with model-predicted immune profiles, and (iv) statistical models that correlate model parameters with …

Transcriptional Remodeling Shapes Therapeutic Vulnerability To Necroptosis In Acute Lymphoblastic Leukemia, Anna Saorin, Anna Dehler, Bartimée Galvan, Fabio Steffen, Marine Ray, Dong Lu, Xin Yu, James Kim, Aneta Drakul, Samanta Kisele, Jin Wang, Jean-Pierre Bourquin, Beat C Bornhauser

Faculty, Staff and Students Publications

Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated prosurvival and antiapoptotic signaling, leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbors a distinct propensity to undergo cell death by receptor-interacting protein kinase 1 (RIPK1)-dependent necroptosis, activated by small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent …

Male Caregiving Experience Alters Hippocampal Neuroplasticity And Transcription Independent Of Reproduction In A Biparental Species., Maria E Colt, Priyanka Agarwal, Erica R Glasper, Heidi Fisher

Faculty Research 2025

In mammals, measurable changes in brain and behavior accompany the transition to parenthood. In the biparental California mouse, Peromyscus californicus, fathers experience enhanced neuroplasticity, including increased hippocampal dendritic spine density, reduced anxiety, and improved memory. Here, we first investigate whether siring offspring or pup interaction drives structural neuroplasticity in fathers and find that hippocampal spine density is positively associated with caregiving experience, even in the absence of reproduction. Next, we evaluate the transcriptional response to caregiving in the hippocampus of these males and identify 158 differentially expressed genes between fathers and non-fathers, many of which are associated with neurogenesis, neuronal …

Ribosome Deficiency Induces Salmonella Filamentation Within Host Cells, Zhihui Lyu, Cierra Wilson, Kalyn Weiss, Spencer Lewis, Kurt Fredrick, William Margolin, Jiqiang Ling

Faculty, Staff and Student Publications

The ribosome is the central hub for protein synthesis and is heavily targeted by antibiotics. Ribosomal mutations, antibiotic treatment, and nutrient starvation can alter translational efficiency and lead to stressed cells. Ribosome deficiency plays a critical role in stress responses and disease progression; yet, how it affects bacteria-host interactions remains poorly understood. In this study, we show that a ribosome-deficient strain exhibits a surprising morphological change from rod shape to filamentous in Salmonella cells growing inside host macrophages. Such filamentation depends on an acidic condition within macrophages and in a defined medium mimicking macrophage conditions. Further genetic analyses revealed that …

Structural Insights Into Ssna1 Self-Assembly And Its Microtubule Binding For Centriole Maintenance, Lorenzo Agostini, Jason A Pfister, Nirakar Basnet, Jienyu Ding, Rui Zhang, Christian Biertümpfel, Kevin F O'Connell, Naoko Mizuno

2020-Current year OA Pubs

SSNA1 is a fibrillar protein involved in dynamic microtubule remodeling, including nucleation, co-polymerization, and microtubule branching. The underlying molecular mechanism has remained unclear due to a lack of structural information. Here, we determine the cryo-EM structure of C.elegans SSNA-1 at 4.55-Å resolution and evaluate its role in embryonic development. We find that SSNA-1 forms an anti-parallel coiled-coil, with self-assembly facilitated by an overhang of 16 C-terminal residues that form a triple-stranded helical junction. The microtubule-binding region is within the triple-stranded junction, suggesting that self-assembly of SSNA-1 creates hubs for effective microtubule interaction. Genetical analysis elucidates that SSNA-1 deletion significantly reduces …

Polo-Like Kinase 1 Inactivation Enhances Pi3k Inhibition-Mediated Apoptosis Of Notch1-Mutant Head And Neck Squamous Cell Carcinoma, Pooja A Shah, Tuhina Mazumdar, Soma Ghosh, Lacin Yapindi, Reid T Powell, Yong S Park, Li Shen, Anne M Fernandez, Clifford C Stephan, Jing Wang, Andrew G Sikora, Jawad Kazi, Mitchell J Frederick, Faye M Johnson

Children’s Nutrition Research Center Staff Publications

PI3K inhibition causes apoptosis selectively in NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC), but modest single-agent responses and acquired resistance (AR) limit the clinical efficacy of targeted agents. To address these limitations, we investigated novel combination therapies. We tested the efficacy of 5768 compounds as single agents and 139 in combination with PI3K inhibitors in sensitive and AR NOTCH1-mutant HNSCC cell lines. We generated synergy/efficacy classifications for the combinations using multiple metrics of statistical drug synergy and growth rate indices. The PLK1/PI3K combination's efficacy was validated using orthogonal in vitro methods and in two HNSCC xenograft models. Compound efficacy …

Vaccination With Acinetobacter Baumannii Adhesin Abp2d Provides Protection Against Catheter-Associated Urinary Tract Infection, Morgan R Timm, Kevin O Tamadonfar, Taylor M Nye, Jesús Bazán Villicaña, Jerome S Pinkner, Karen W Dodson, Ali H Ellebedy, Scott J Hultgren

2020-Current year OA Pubs

Catheter-associated urinary tract infections (CAUTIs) contribute greatly to the burden of healthcare-associated infections. Acinetobacter baumannii is a Gram-negative bacterium with high levels of antibiotic resistance that is of increasing concern as a CAUTI pathogen. A. baumannii expresses fibrinogen-binding adhesins (Abp1D and Abp2D) that mediate biofilm formation on catheters, which become coated with fibrinogen upon insertion. Here we develop a protein subunit vaccine against the Abp1D and Abp2D receptor binding domains (RBD) and show that vaccination significantly reduces bacterial titers in a female mouse model of CAUTI. We further demonstrate that immunity to Abp2D

Regional Heterogeneity Of The Blood-Brain Barrier, Marie Blanchette, Kaja Bajc, Benjamin D Gastfriend, Caterina P Profaci, Nadine Ruderisch, Cayce E Dorrier, Guo Zhong, Raquel Cuevas-Diaz Duran, Sean S Harvey, Iris H Garcia-Pak, Lucija Pintarić, Manon Leclerc, Louise Reveret, Vincent Émond, Annette Wang, Deepti Pant, Linus T Tsai, Frédéric Calon, Nina Isoherranen, Sean P Palecek, Eric V Shusta, Jiaqian Wu, Richard Daneman

The Brown Foundation: Institute of Molecular Medicine

The blood-brain barrier (BBB), formed by specialized endothelial cells (ECs), regulates the extracellular composition of the central nervous system (CNS). Little is known about whether there are regional specializations of the BBB that may control the function of specific neural circuits. We use single cell RNA-seq to characterize ECs from nine CNS regions in male mice: cortex, hippocampus, cerebellum, spinal cord, striatum, thalamus, hypothalamus, midbrain, and medulla/pons. Although there is a core BBB transcriptional profile, there are significant regional specializations. Stra6, a retinoid transporter, is highly enriched in the BBB of the nucleus accumbens shell (ShNAc) and ventral cochlear nucleus, …

In Vivo Prime Editing Rescues Alternating Hemiplegia Of Childhood In Mice., Alexander A Sousa, Markus Terrey, Holt A Sakai, Christine Q Simmons, Elena Arystarkhova, Natalia S Morsci, Laura C. Anderson, Jun Xie, Fabian Suri-Payer, Linda C Laux, Emmanuel Roze, Sylvie Forlani, Guangping Gao, Simon Frost, Nina Frost, Kathleen J Sweadner, Alfred L George, Cathleen Lutz, David R Liu

Faculty Research 2025

Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na⁺/K⁺ ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%–90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain …

The Effect Of Coadministration Of D156844 And Ar42 (Rec-2282) On The Survival And Motor Phenotype Of Mice With Spinal Muscular Atrophy, Ashlee W. Harris, Rod C. Scott, Matthew E. R. Butchbach

Department of Pediatrics Faculty Papers

Spinal muscular atrophy (SMA) is characterized by degeneration of spinal motor neurons and is a leading genetic cause of pediatric death worldwide. SMA results from the loss of or pathological variant in the survival motor neuron 1 (SMN1) gene. Disease severity is dependent on the number of copies of the orthologous SMN2 gene, which is nearly identical to SMN1 except for some key nucleotide differences. As disease severity is inversely related to SMN2 copy number, most SMA therapeutics trials have focused on identifying ways to increase SMN2 expression at different levels of gene regulation. Other studies have investigated compounds which …

Tet2-Mutant Myeloid Cells Mitigate Alzheimer’S Disease Progression Via Cns Infiltration And Enhanced Phagocytosis In Mice, Katie A Matatall, Trisha K Wathan, Minh Nguyen, Hu Chen, Alexandra Mcdonald, Guantong Qi, Julia A Belk, Marcus A Florez, Duy T Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M Buttigieg, Chih-Wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E Kennedy, Arushana A Maknojia, Apoorva Thatavarty, Josaura V Fernandez Sanchez, Hind Bouzid, Surabi Veeraragavan, Susan Crocker, Margaret A Goodell, Antony Rodriguez, Siddhartha Jaiswal, Michael J Rauh, Eirini P Papapetrou, Samuele G Marro, Katherine Y King

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than …

Artificial Transneurons Emulate Neuronal Activity In Different Areas Of Brain Cortex, Rivu Midya, Ambarish S Pawar, Debi P Pattnaik, Eric Mooshagian, Pavel Borisov, Thomas D Albright, Lawrence H Snyder, R Stanley Williams, J Joshua Yang, Alexander G Balanov, Sergei Gepshtein, Sergey E Savel'ev

2020-Current year OA Pubs

Rapid development of memristive elements emulating biological neurons creates new opportunities for brain-like computation at low energy consumption. A first step toward mimicking complex neural computations is the analysis of single neurons and their characteristics. Here we measure and model spiking activity in artificial neurons built using diffusive memristors. We compare activity of these artificial neurons with the spiking activity of biological neurons measured in sensory, pre-motor, and motor cortical areas of the monkey (male) brain. We find that artificial neurons can operate in diverse self-sustained and noise-induced spiking regimes that correspond to the activity of different types of cortical …

Analysis Of Lifespan Across Diversity Outbred Mouse Studies Identifies Multiple Longevity-Associated Loci., Martin N Mullis, Kevin M Wright, Anil Raj, Daniel M Gatti, Peter C. Reifsnyder, Kevin Flurkey, Jonathan R Archer, Laura Robinson, Andrea Di Francesco, Karen L. Svenson, Ron Korstanje, David E Harrison, J Graham Ruby, Gary Churchill

Faculty Research 2025

Lifespan is an integrative phenotype whose genetic architecture is likely to highlight multiple processes with high impact on health and aging. Here, we conducted a genetic mega-analysis of longevity in Diversity Outbred (DO) mice that included 2,444 animals from 3 independently conducted lifespan studies. We identified 8 loci that contributed significantly to lifespan independently of diet and drug treatment in at least one study. One of these loci also influenced lifespan in a sex-dependent manner, and we detected an additional locus with a diet-specific effect on lifespan. Collectively, these loci explained over half of the estimated heritable variation in lifespan …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U. Rehman, Carol J. Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W. Scherer, Ingo Helbig, Amita Sehgal

Manuscripts, Articles, Book Chapters and Other Papers

Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in BMAL1, a core component of the molecular clock. Instead of an isolated circadian phenotype seen with disease-causing variants in other molecular clock genes, all individuals carrying BMAL1 variants surprisingly share a clinical syndrome manifest as developmental delay and autism spectrum disorder, with variably penetrant sleep disturbances, seizures, and marfanoid habitus. Variants were functionally tested in cultured cells using a Per2-promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested BMAL1 variants disrupted PER2 mRNA …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U Rehman, Carol Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W Scherer, Ingo Helbig, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Children with neurodevelopmental disorders exhibit highly penetrant sleep and circadian dysfunction, but the underlying mechanisms are unclear. We asked whether a subset of individuals with neurodevelopmental disorders might have genetic variants in genes known to drive circadian rhythms. Through international collaboration, we identified ten individuals with very rare genetic variants in BMAL1, a core component of the molecular clock. These individuals exhibited overlapping signs and symptoms including developmental delay, autism spectrum disorder, and variably penetrant marfanoid features. We functionally tested the identified BMAL1 variants in cell culture and in vivo and found disrupted BMAL1 function. These findings demonstrate that …

Rescue Of Male Infertility By Human Prss55 In Transgenic Mice Establishes A Contraceptive Research Model, Courtney M Sutton, Kohei Umezu, Daisuke Mashiko, Masahito Ikawa, Irina V Larina, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility phenotypes of their respective knockout mouse lines. We generated transgenic mouse lines expressing human PRSS55 with either an extracellularly or intracellularly positioned C-terminal 3xFLAG tag (RES GPI or RES TM), and a line expressing human TMPRSS12 with a C-terminal 3xFLAG tag (T12 RES), all on their respective mouse null backgrounds. Fertility was assessed through continuous mating trials, and sperm parameters were evaluated. Both …

An Ethanol-Induced Loss Of The Lipid Droplet-Associated Segregase Vcp/P97 Leads To Hepatic Steatosis, Sandhya Sen, Shaun Weller, Ryan J Schulze, Donglin Ding, Carol A Casey, Conrad Weihl, Mark A Mcniven

2020-Current year OA Pubs

The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17β13) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor …

Stem Cell-Derived Corneal Epithelium: Engineering Barrier Function For Ocular Surface Repair, Emily Elizabeth Fresenko, Jian-Xing Ma, Matthew Giegengack, Atalie Carina Thompson, Anthony Atala, Andrew J W Huang, Yuanyuan Zhang

2020-Current year OA Pubs

The cornea, the transparent anterior window of the eye, critically refracts light and protects intraocular structures. Corneal pathologies, including trauma, infection, chemical injury, metabolic diseases, genetic conditions, and age-related degeneration, can lead to significant visual impairment. While penetrating keratoplasty or full-thickness corneal transplantation remains a standard and effective intervention for severe corneal dysfunction, limitations in donor tissue availability and the risk of immunogenic graft rejection necessitate alternative therapeutic strategies. Furthermore, for cases of isolated epithelial disfunction, a full-thickness cornea graft may not be required or effective. This review examines the potential of corneal epithelial constructs derived from autologous stem cells …

Inhibition Of Epithelial Cell Yap-Tead/Lox Signaling Attenuates Pulmonary Fibrosis In Preclinical Models, Darcy Elizabeth Wagner, Hani N Alsafadi, Nilay Mitash, Aurelien Justet, Qianjiang Hu, Ricardo Pineda, Claudia Staab-Weijnitz, Martina Korfei, Nika Gvazava, Kristin Wannemo, Ugochi Onwuka, Molly Mozurak, Adriana Estrada-Bernal, Juan Cala-Garcia, Katrin Mutze, Rita Costa, Deniz Bölükbas, John Stegmayr, Wioletta Skronska-Wasek, Stephan Klee, Chiharu Ota, Hoeke A Baarsma, Jingtao Wang, John Sembrat, Anne Hilgendorff, Jun Ding, Andreas Günther, Rachel Chambers, Ivan Rosas, Stijn De Langhe, Naftali Kaminski, Mareike Lehmann, Oliver Eickelberg, Melanie Königshoff

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX …

Mitochondrial Complex I Deficiency Induces Alzheimer's Disease-Like Signatures That Are Reversible By Targeted Therapy., Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina

Faculty Research 2025

INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4

METHODS: Cortico-hippocampal tissue from Ndufs4

RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4

DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest …

Sustained Lung Inflammation Post-Sars-Cov-2 Infection In Mice Is Associated With Increased Pulmonary T Cells., Sophie Y Guan, Patricia P Ogger, Ana Farias, Minerva Garcia Martín, Joy Nakawesi, Olivia Bedard, Candice N Baker, Nadia Rosenthal, Cecilia Johansson

Faculty Research 2025

Many SARS-CoV-2 patients experience chronic pulmonary symptoms and long-term inflammation despite viral clearance. While these clinical manifestations have been linked to the dysregulation of the adaptive immune response, the underlying immunopathology remains poorly understood due to a lack of suitable animal models. To investigate long-term pulmonary consequences of SARS-CoV-2 infection, we used a genetic cross of 129 mice and C57BL/6 (B6)-K18-hACE2 transgene mice, a model previously shown to survive infection. 129xB6-K18-hACE2 mice or littermate controls were infected with a low dose (5 × 10² PFU) of ancestral SARS-CoV-2. Complete viral clearance and full recovery from weight loss …

Associative Coding Of Conditioned Fear In The Thalamic Nucleus Reuniens In Rodents And Humans, Tuğçe Tuna, Michael S Totty, Muhammad Badarnee, Flávio Afonso Gonçalves Mourão, Shaun Peters, Mohammad R Milad, Stephen Maren

Faculty, Staff and Student Publications

The nucleus reuniens (RE) is a midline thalamic structure interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Recent work in both rodents and humans implicates the RE in the adaptive regulation of emotional memories, including the suppression of learned fear. However, the neural correlates of aversive learning in the RE of rodents and humans remain unclear. To address this, we recorded RE activity in humans (BOLD fMRI) and rats (fiber photometry) during Pavlovian fear conditioning and extinction. In both rats and humans, we found that conditioned stimulus (CS)-evoked activity in RE reflects the associative value of the CS. …

Sugar Functionalized Collagen Material For Local Modulation Of Innate Immunity, Francesca Taraballi, Claudia Corbo, Julia Enterria-Rosales, John Otto Martinez, Silvia Minardi, Laura Pandolfi, Xing Wang, Ennio Tasciotti, Kavindra V Singh, Cesar A Arias, Bruna Corradetti

Faculty, Staff and Students Publications

Small alterations during the early stages of the innate immune response to an implant can drive large changes in adaptive immunity. Biomaterials for regenerative purposes can be engineered to modulate this immune response in beneficial ways. This study presents an innovative patch designed and functionalized to target the innate immunity at the implant site. Mannose moieties are incorporated into collagen patches, resulting in a technology called Local Immunotuning Patch (LIP), designed to directly interact with antigen presenting cells through their mannose receptor. In vitro, LIP shows anti-inflammatory effects on bone marrow-derived macrophages and inhibitory properties even on methicillin-resistant bacterial strains. …

Low-Dose Metformin Requires Brain Rap1 For Its Antidiabetic Action, Hsiao-Yun Lin, Weisheng Lu, Yanlin He, Yukiko Fu, Kentaro Kaneko, Peimeng Huang, Ana B De La Puente-Gomez, Chunmei Wang, Yongjie Yang, Feng Li, Yong Xu, Makoto Fukuda

Faculty, Staff and Students Publications

Metformin is the most commonly prescribed antidiabetes drug, yet its precise mechanism of action remains controversial. Previous studies have suggested that metformin acts peripherally by reducing hepatic glucose output and altering gut functions. Here, we report a neural mechanism via the small guanosine triphosphatase Ras-related protein 1 (Rap1). Mice with forebrain-specific Rap1 knockout exhibited resistance to the antidiabetic effects of low-dose metformin while remaining sensitive to other antidiabetic agents. Centrally administered metformin inhibited brain Rap1 and reduced hyperglycemia. Conversely, forced activation of brain Rap1 increased glycemia and abolished the glycemic effect of metformin. Metformin activated a specific subset of neurons …

The Importance Of Imperfect Pre-Clinical Models In Adolescent Idiopathic Scoliosis, Diane S Sepich, Ryan S Gray, Nadav Ahituv, Christina A Gurnett, Jonathan J Rios, Lila Solnica-Krezel, Carol A Wise

2020-Current year OA Pubs

Adolescent idiopathic scoliosis (AIS) is a twisting spinal deformity that occurs in otherwise healthy children at the time of rapid pre-pubescent growth. AIS affects ∼3% of children worldwide and is the most common musculoskeletal diagnosis in pediatric populations, posing a significant physiological, psychosocial and financial burden to patients. Genetic predisposition is a clear and major contributor to AIS, and insights from genomic discoveries are inspiring translational studies ultimately aimed at developing novel diagnostics and therapies. Pre-clinical animal models of AIS are now essential to validate human genetic findings, understand gene-by-environment interactions, and speed etiologic and therapeutic discovery. In this Perspective, …

Autophagy Regulates Müller Glial Cell Inflammatory Activation, Teresa A Doggett, Zhenqing Zhou, Sohini Rebba, Jacqueline Unsinger, Philip A Ruzycki, Thomas A Ferguson

2020-Current year OA Pubs

PURPOSE: We tested whether Müller cells utilize autophagy to support immune privilege in the eye.

METHODS: The essential autophagy gene Atg5 was deleted in retinal Müller cells. Inflammation was induced by intravitreal injection of lipopolysaccharide (LPS) that was monitored by hematoxylin and eosin (H&E) staining, immunofluorescent confocal microscopy, and flow cytometry. Single-cell RNA sequencing was performed on retinal Müller cells isolated from control and Atg5-deficient mice. Markers of Müller cell gliosis were assessed, and cytokine production in the eye was measured. Small interfering RNA knockdown techniques were used to examine LPS-induced inflammatory pathways in culture.

RESULTS: We observed increased and …

Formation Control Between Leader And Migratory Follower Tissues Allows Coordinated Growth, Toru Kawanishi, Takamichi Sushida, Tony Y-C Tsai, Hiroyuki Takeda, Sean G Megason

2020-Current year OA Pubs

Coordinated growth of multiple tissues is fundamental to shaping our body, but the underlying mechanisms remain underexplored. In zebrafish embryos, midline tissues composed of the notochord, floorplate, and hypochord elongate synchronously with their lengths aligned. We show that floorplate and hypochord cells collectively migrate posteriorly along the nascent notochord extracellular matrix as it extends posteriorly, maintaining the tripartite configuration. Fibroblast growth factor-mediated migration in a spatially graded manner causes cell stretching, which triggers Yap-dependent proliferation and controls floorplate and hypochord growth. Supported by mathematical modeling, we further suggest that their growth is fine-tuned by mechanical tethering to the notochord via …

Exploring Tricine As A Novel Red Cell Cryopreservative: Lessons And Future Directions, Thomas Bailey-Schmidt, Christine V Saunders, Chloë E George, Thomas G Scorer, Lynn M R Mccallum, Tracey E Madgett

School of Biomedical Sciences

BACKGROUND AND OBJECTIVES: Cryopreservation allows for storage of red blood cells (RBCs) beyond the standard 35-day period. Current glycerol-based methods are labour-intensive and scale-limited in application. Tricine has been identified as a potential alternative cryoprotectant (CPA), demonstrating efficacy in sheep RBC. This study aims to evaluate the biocompatibility and efficacy of tricine in human RBC cryopreservation.

MATERIALS AND METHODS: Human and sheep RBCs were exposed to varying concentrations of tricine (2.0-20.0% w/v) or glycerol (20.0-40.0% w/v). Biocompatibility was assessed via 24-h incubation at 4°C, while cryoprotective efficacy was evaluated following freezing in liquid nitrogen, storage at -80°C and thawing at …

Single-Nuclei Multiomics Analysis Identifies Abnormal Cardiomyocytes In A Murine Model Of Cardiac Development., Riley Leonard, Yi Zhao, Steven Eliason, Kathy Zimmerman, Ariana Batz, Cathy J. Hatcher, Robert M Weiss, Mason Sweat, Xiao Li, Brad A Amendt

PCOM Scholarly Works

Transcription factors such as Tbx5, Gata4, Mef2c and Pitx2 are required during cardiac development, and in adult cardiac homeostasis. We demonstrate that the gene dosage and modulation of these factors are mediated in vivo by the miR-200 family. Inhibition of a single miR-200 family member within the cluster results in defects of the left ventricle and cardiomyocyte maturation during development. Inhibition of the entire miR-200 family results in a ventricular septal defect and embryonic lethality by embryonic day (E)16.5. Inhibition of each miR-200 family has distinct heart phenotypes in cell specific differentiation and maturation. snRNA-sequencing reveals an immature cardiomyocyte cell …

Cd206+Il-4rα+ Macrophages Are Drivers Of Adverse Cardiac Remodeling In Ischemic Cardiomyopathy, Qiongxin Wang, Mohamed Ameen Ismahil, Yujie Zhu, Gregg Rokosh, Tariq Hamid, Guihua Zhou, Steven M. Pogwizd, Sumanth D. Prabhu

2020-Current year OA Pubs

BACKGROUND: The role of cardiac CD (cluster of differentiation) 206

METHODS: Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4Rα deletion and intramyocardial macrophage adoptive transfer defined the functional effects of macrophages polarized by IL-4 (M[IL-4]). Antisense oligonucleotides were used for in vivo IL-4Rα gene silencing in mice.

RESULTS: CD206

CONCLUSIONS: Cardiac CD206