Digital Commons Network^™

Ccr2 Signaling Restricts Sars-Cov-2 Infection, Abigail Vanderheiden, Jeronay Thomas, Allison L Soung, Meredith E Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A Cowan, Kathryn Pellegrini, Pei-Yong Shi, Arash Grakoui, Robyn S Klein, Steven E Bosinger, Jacob E Kohlmeier, Vineet D Menachery, Mehul S Suthar

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of …

Skin Bacterial Metacommunities Of San Francisco Bay Area Salamanders Are Structured By Host Genus And Habitat Quality., Shannon Buttimer, Obed Hernandez-Gomez, Erica Bree Rosenblum

Natural Sciences and Mathematics | Faculty Scholarship

Host-associated microbial communities can influence physiological processes of macroorganisms, including contributing to infectious disease resistance. For instance, some bacteria that live on amphibian skin produce antifungal compounds that inhibit two lethal fungal pathogens, Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal). Therefore, differences in microbiome composition among host species or populations within a species can contribute to variation in susceptibility to Bd/Bsal. This study applies 16S rRNA sequencing to characterize the skin bacterial microbiomes of three widespread terrestrial salamander genera native to the western United States. Using a metacommunity structure analysis, we identified dispersal barriers for these influential bacteria between salamander …

Il-4i1 Regulation Of Immune Protection During Mycobacterium Tuberculosis Infection., Lerato Hlaka, Mumin Ozturk, Julius E Chia, Shelby-Sara Jones, Shandre Pillay, Sibongiseni K L Poswayo, Thabo Mpotje, Justin K Nono, Simphiwe R N Simelane, Suraj P Parihar, Sugata Roy, Harukazu Suzuki, Frank Brombacher, Reto Guler

Faculty Research 2021

BACKGROUND: Interleukin 4 (IL-4i1)-induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied.

METHODS: We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and proinflammatory responses were measured in vitro and in vivo. Histopathological analysis, lung immune cell recruitment, and macrophage activation were assessed at the early and chronic stages of Mtb infection. …

Stat3 Inhibitor Mitigates Cerebral Amyloid Angiopathy And Parenchymal Amyloid Plaques While Improving Cognitive Functions And Brain Networks, Jogender Mehla, Itender Singh, Deepti Diwan, James W Nelson, Molly Lawrence, Eunjae Lee, Adam Q Bauer, David M Holtzman, Gregory J Zipfel

2020-Current year OA Pubs

Previous reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-β (Aβ) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer's disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aβ peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. …

Transcriptional Reprogramming Differentiates Active From Inactive Esr1 Fusions In Endocrine Therapy-Refractory Metastatic Breast Cancer, Xuxu Gou, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Genomic analysis has recently identified multiple

Inhibition Of Nadph Oxidase Blocks Netosis And Reduces Thrombosis In Heparin-Induced Thrombocytopenia, Halina H L Leung, Jose Perdomo, Zohra Ahmadi, Feng Yan, Steven E. Mckenzie, Beng H Chong

Department of Medicine Faculty Papers

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis …

Defining The Transcriptional Control Of Pediatric Aml Highlights Rara As A Superenhancer-Regulated Druggable Dependency, Monika W Perez, Oscar Sias-Garcia, Alfred Daramola, Helen Wei, Maci Terrell, Raushan Rashid, Woojun D Park, Kevin Duong, Terzah M Horton, Feng Li, Nikitha Cherayil, Jost Vrabic Koren, Vincent U Gant, Jacob J Junco, Choladda V Curry, Alexandra M Stevens, Charles Y Lin, Joanna S Yi

Faculty, Staff and Students Publications

Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML …

Activation Of The Α1Β2Γ2l Gaba Receptor By Physiological Agonists, Spencer R Pierce, Allison L Germann, Gustav Akk

Open Access Publications

The Cl

Intra-Tumoral Nerve-Tracing In A Novel Syngeneic Model Of High-Grade Serous Ovarian Carcinoma, Jeffrey L Barr, Allison Kruse, Anthony C Restaino, Natalia Tulina, Sarah Stuckelberger, Samuel J Vermeer, Caitlin S Williamson, Daniel W Vermeer, Marianna Madeo, Jillian Stamp, Maria Bell, Mark Morgan, Ju-Yoon Yoon, Marilyn A Mitchell, Anna Budina, Dalia K Omran, Lauren E Schwartz, Ronny Drapkin, Paola D Vermeer

Faculty, Staff and Student Publications

Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input. The origin, specific nerve type, and the mechanisms promoting innervation and driving nerve-cancer cell communications in ovarian cancer remain largely unknown. The technique of neuro-tracing enhances the study of tumor innervation by offering a means for identification and mapping of nerve sources that may directly and indirectly affect the tumor microenvironment. …

Hypothalamic Steroid Receptor Coactivator-2 Regulates Adaptations To Fasting And Overnutrition, Yongjie Yang, Yanlin He, Hailan Liu, Wenjun Zhou, Chunmei Wang, Pingwen Xu, Xing Cai, Hesong Liu, Kaifan Yu, Zhou Pei, Ilirjana Hyseni, Makoto Fukuda, Qingchun Tong, Jianming Xu, Zheng Sun, Bert W O'Malley, Yong Xu

Faculty, Staff and Students Publications

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety …

Bi-Allelic Variants In Ogdhl Cause A Neurodevelopmental Spectrum Disease Featuring Epilepsy, Hearing Loss, Visual Impairment, And Ataxia, Zheng Yie Yap, Stephanie Efthymiou, Simone Seiffert, Karen Vargas Parra, Sukyeong Lee, Alessia Nasca, Reza Maroofian, Isabelle Schrauwen, Manuela Pendziwiat, Sunhee Jung, Elizabeth Bhoj, Pasquale Striano, Kshitij Mankad, Barbara Vona, Sanmati Cuddapah, Anja Wagner, Javeria Raza Alvi, Elham Davoudi-Dehaghani, Mohammad-Sadegh Fallah, Srinitya Gannavarapu, Costanza Lamperti, Andrea Legati, Bibi Nazia Murtaza, Muhammad Shahid Nadeem, Mujaddad Ur Rehman, Kolsoum Saeidi, Vincenzo Salpietro, Sarah Von Spiczak, Abigail Sandoval, Sirous Zeinali, Massimo Zeviani, Adi Reich, Synaps Study Group, University Of Washington Center For Mendelian Genomics, Cholsoon Jang, Ingo Helbig, Tahsin Stefan Barakat, Daniele Ghezzi, Suzanne M Leal, Yvonne Weber, Henry Houlden, Wan Hee Yoon

Faculty, Staff and Students Publications

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the …

Tavr In Older Adults: Moving Toward A Comprehensive Geriatric Assessment And Away From Chronological Age: Jacc Family Series, Joy M Schmitz, Scott D Lane, Michael F Weaver, Ponnada A Narayana, Khader M Hasan, Delisa D Russell, Robert Suchting, Charles E Green

Faculty, Staff and Student Publications

Cocaine use continues to be a significant public health problem with limited treatment options and no approved pharmacotherapies. Cognitive-behavioral therapy (CBT) remains the mainstay treatment for preventing relapse, however, people with chronic cocaine use display cognitive impairments that are associated with poor response to CBT. Emerging evidence in animal and human studies suggests that the peroxisome proliferator-activated receptor-gamma (PPAR- γ) agonist, pioglitazone, improves white matter integrity that is essential for cognitive function. This project will determine whether adjunctive use of pioglitazone enhances the effect of CBT in preventing relapse during the early phase of recovery from cocaine use disorder. This …

Transient Ascaris Suum Larval Migration Induces Intractable Chronic Pulmonary Disease And Anemia In Mice, Yifan Wu, Evan Li, Morgan Knight, Grace Adeniyi-Ipadeola, Li-Zhen Song, Alan R Burns, Ana Clara Gazzinelli-Guimaraes, Ricardo Fujiwara, Maria Elena Bottazzi, Jill E Weatherhead

Faculty, Staff and Students Publications

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host's lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through the host lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that …

Intermittent Bolus Feeding Does Not Enhance Protein Synthesis, Myonuclear Accretion, Or Lean Growth More Than Continuous Feeding In A Premature Piglet Model, Marko Rudar, Jane K Naberhuis, Agus Suryawan, Hanh V Nguyen, Barbara Stoll, Candace C Style, Mariatu A Verla, Oluyinka O Olutoye, Douglas G Burrin, Marta L Fiorotto, Teresa A Davis

Children’s Nutrition Research Center Staff Publications

Optimizing enteral nutrition for premature infants may help mitigate extrauterine growth restriction and adverse chronic health outcomes. Previously, we showed in neonatal pigs born at term that lean growth is enhanced by intermittent bolus compared with continuous feeding. The objective was to determine if prematurity impacts how body composition, muscle protein synthesis, and myonuclear accretion respond to feeding modality. Following preterm delivery, pigs were fed equivalent amounts of formula delivered either as intermittent boluses (INT; n = 30) or continuously (CONT; n = 14) for 21 days. Body composition was measured by dual-energy X-ray absorptiometry (DXA) and muscle growth was …

Ogr1-Dependent Regulation Of The Allergen-Induced Asthma Phenotype, Ajay P Nayak, Deepak A. Deshpande, Phd, Sushrut D. Shah, Dominic R Villalba, Roslyn Yi, Nadan Wang, Raymond B. Penn

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

The proton-sensing receptor, ovarian cancer G protein-coupled receptor (OGR1), has been shown to be expressed in airway smooth muscle (ASM) cells and is capable of promoting ASM contraction in response to decreased extracellular pH. OGR1 knockout (OGR1KO) mice are reported to be resistant to the asthma features induced by inhaled allergen. We recently described certain benzodiazepines as OGR1 activators capable of mediating both procontractile and prorelaxant signaling in ASM cells. Here we assess the effect of treatment with the benzodiazepines lorazepam or sulazepam on the asthma phenotype in wild-type (WT) and OGR1KO mice subjected to inhaled house dust mite (HDM; …

Single-Cell Rna-Sequencing Analysis Of The Ciliary Epithelium And Contiguous Tissues In The Mouse Eye, J C Youkilis, S Bassnett

2020-Current year OA Pubs

The ciliary epithelium plays a central role in ocular homeostasis but cells of the pigmented and non-pigmented layers are difficult to isolate physically and study. Here we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptional signatures of cells harvested from the ciliary body and contiguous tissues. Microdissected tissue was dissociated by collagenase digestion and the transcriptomes of individual cells were obtained using a droplet-based scRNA-seq approach. In situ hybridization was used to verify the expression patterns of selected differentially-expressed genes. High quality transcriptomes were obtained from 10,024 cells and unsupervised clustering distinguished 22 cell types. Although efforts were made to …

Clustering Of Aromatic Residues In Prion-Like Domains Can Tune The Formation, State, And Organization Of Biomolecular Condensates, Alex S Holehouse, Garrett M Ginell, Daniel Griffith, Elvan Böke

2020-Current year OA Pubs

In immature oocytes, Balbiani bodies are conserved membraneless condensates implicated in oocyte polarization, the organization of mitochondria, and long-term organelle and RNA storage. In

A Reevaluation Of The Tolerability And Effects Of Single-Dose Ivermectin Treatment On Onchocerca Volvulus Microfilariae In The Skin And Eyes In Eastern Ghana, Nicholas O Opoku, Michael E Gyasi, Felix Doe, Daphne Lew, Augustine R Hong, Sithembele Chithenga, Peter U Fischer, Christopher L King, Gary J Weil

Open Access Publications

Mass administration of ivermectin (IVM) has significantly reduced onchocerciasis prevalence, intensity, and morbidity in most endemic areas. Most IVM clinical trials were performed long ago in persons with high-intensity infections that are uncommon in West Africa today. This cohort treatment study recruited participants from a hypoendemic area in eastern Ghana to reevaluate the efficacy and tolerability of IVM with a special focus on the kinetics of microfilaria (Mf) clearance. Mf in the skin and anterior chambers (AC) were assessed by skin snip and slit lamp examinations at baseline and at 3 and 6 months after treatment with IVM 150 μg/kg. …

Large-Scale Dna Demethylation Occurs In Proliferating Ovarian Granulosa Cells During Mouse Follicular Development, Tomoko Kawai, Joanne S Richards, Masayuki Shimada

Faculty, Staff and Students Publications

During ovarian follicular development, granulosa cells proliferate and progressively differentiate to support oocyte maturation and ovulation. To determine the underlying links between proliferation and differentiation in granulosa cells, we determined changes in 1) the expression of genes regulating DNA methylation and 2) DNA methylation patterns, histone acetylation levels and genomic DNA structure. In response to equine chorionic gonadotropin (eCG), granulosa cell proliferation increased, DNA methyltransferase (DNMT1) significantly decreased and Tet methylcytosine dioxygenase 2 (TET2) significantly increased in S-phase granulosa cells. Comprehensive MeDIP-seq analyses documented that eCG treatment decreased methylation of promoter regions in approximately 40% of the genes in granulosa …

Hematopoiesis Under Telomere Attrition At The Single-Cell Resolution, Natthakan Thongon, Feiyang Ma, Andrea Santoni, Matteo Marchesini, Elena Fiorini, Ashley Rose, Vera Adema, Irene Ganan-Gomez, Emma M Groarke, Fernanda Gutierrez-Rodrigues, Shuaitong Chen, Pamela Lockyer, Sarah Schneider, Carlos Bueso-Ramos, Guillermo Montalban-Bravo, Caleb A Class, Kelly A Soltysiak, Matteo Pellegrini, Ergun Sahin, Alison A Bertuch, Courtney D Dinardo, Guillermo Garcia-Manero, Neal S Young, Karen Dwyer, Simona Colla

Faculty, Staff and Students Publications

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. …

Differentiation Of Fetal Hematopoietic Stem Cells Requires Arid4b To Restrict Autocrine Kitlg/Kit-Src Signaling., In-Chi Young, Bogang Wu, Jaclyn Andricovich, Sung-Ting Chuang, Rong Li, Alexandros Tzatsos, Ray-Chang Wu, Mei-Yi Wu

Anatomy and Regenerative Biology Faculty Publications

No abstract provided.

High-Fructose, High-Fat Diet Alters Muscle Composition And Fuel Utilization In A Juvenile Iberian Pig Model Of Non-Alcoholic Fatty Liver Disease, Heather C Spooner, Stefani A Derrick, Magdalena Maj, Rodrigo Manjarín, Gabriella V Hernandez, Deepali S Tailor, Parisa S Bastani, Rob K Fanter, Marta L Fiorotto, Douglas G Burrin, Michael R La Frano, Angelos K Sikalidis, Jason M Blank

Children’s Nutrition Research Center Staff Publications

Non-alcoholic fatty liver disease (NAFLD) is a serious metabolic condition affecting millions of people worldwide. A “Western-style diet” has been shown to induce pediatric NAFLD with the potential disruption of skeletal muscle composition and metabolism. To determine the in vivo effect of a “Western-style diet” on pediatric skeletal muscle fiber type and fuel utilization, 28 juvenile Iberian pigs were fed either a control diet (CON) or a high-fructose, high-fat diet (HFF), with or without probiotic supplementation, for 10 weeks. The HFF diets increased the total triacylglycerol content of muscle tissue but decreased intramyocellular lipid (IMCL) content and the number of …

Low-Dose Dobutamine Cardiovascular Magnetic Resonance Segmental Strain Study Of Early Phase Of Intramyocardial Hemorrhage Rats, Rui Xia, Bo He, Tong Zhu, Yu Zhang, Yushu Chen, Lei Wang, Yang Zhou, Jichun Liao, Jie Zheng, Yongmei Li, Fajin Lv, Fabao Gao

2020-Current year OA Pubs

BACKGROUND: This study investigates the segmental myocardial strain of the early phase of intramyocardial hemorrhage (IMH) caused by reperfused myocardial infarction (MI) in rats by low-dose dobutamine (LDD) cardiovascular magnetic resonance (CMR) feature-tracking.

METHODS: Nine sham rats and nine rats with 60-min myocardial ischemia followed by 48-h reperfusion were investigated using CMR, including T2*-mapping sequence and fast imaging with steady-state precession (FISP)-cine sequence. Another FISP-cine sequence was acquired after 2 min of dobutamine injection; the MI, IMH, and Non-MI (NMI) areas were identified. The values of peak radial strains (PRS) and peak circumferential strains (PCS) of the MI, IMH and …

Bioengineered Models To Study Microenvironmental Regulation Of Glioblastoma Metabolism, Joseph Chen, Hyunchul Lee, Philipp Schmitt, Caleb J. Choy, Donald M. Miller, Brian J. Williams, Elaine L. Bearer, Hermann B. Frieboes

Pathology Research and Scholarship

Despite extensive research and aggressive therapies, glioblastoma (GBM) remains a central nervous system malignancy with poor prognosis. The varied histopathology of GBM suggests a landscape of differing microenvironments and clonal expansions, which may influence metabolism, driving tumor progression. Indeed, GBM metabolic plasticity in response to differing nutrient supply within these microenvironments has emerged as a key driver of aggressiveness. Additionally, emergent biophysical and biochemical interactions in the tumor microenvironment (TME) are offering new perspectives on GBM metabolism. Perivascular and hypoxic niches exert crucial roles in tumor maintenance and progression, facilitating metabolic relationships between stromal and tumor cells. Alterations in extracellular …

Evaluation Of Bone Formation On Orthopedic Implant Surfaces Using An Ex-Vivo Bone Bioreactor System, Rupak Dua, Hugh Jones, Philip C Noble

Faculty, Staff and Student Publications

Recent advances in materials and manufacturing processes have allowed the fabrication of intricate implant surfaces to facilitate bony attachment. However, refinement and evaluation of these new design strategies are hindered by the cost and complications of animal studies, particularly during early iterations in the development process. To address this problem, we have previously constructed and validated an ex-vivo bone bioreactor culture system that can maintain the viability of bone samples for an extended period ex-vivo. In this study, we investigated the mineralization of a titanium wire mesh scaffold under both static and dynamic culturing using our ex vivo bioreactor system. …

Optimization Of Non-Coding Regions For A Non-Modified Mrna Covid-19 Vaccine, Makda S Gebre, Susanne Rauch, Adrianus C M Boon, Et Al

Open Access Publications

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans

Nrf1 Association With Auts2-Polycomb Mediates Specific Gene Activation In The Brain, Sanxiong Liu, Kimberly A Aldinger, Chi Vicky Cheng, Takae Kiyama, Mitali Dave, Hanna K Mcnamara, Wukui Zhao, James M Stafford, Nicolas Descostes, Pedro Lee, Stefano G Caraffi, Ivan Ivanovski, Edoardo Errichiello, Christiane Zweier, Orsetta Zuffardi, Michael Schneider, Antigone S Papavasiliou, M Scott Perry, Jennifer Humberson, Megan T Cho, Astrid Weber, Andrew Swale, Tudor C Badea, Chai-An Mao, Livia Garavelli, William B Dobyns, Danny Reinberg

Faculty, Staff and Student Publications

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its …

Gαi/O-Coupled Htr2c In The Paraventricular Nucleus Of The Hypothalamus Antagonizes The Anorectic Effect Of Serotonin Agents, Eun-Seon Yoo, Li Li, Lin Jia, Caleb C Lord, Charlotte E Lee, Shari G Birnbaum, Claudia R Vianna, Eric D Berglund, Kathryn A Cunningham, Yong Xu, Jong-Woo Sohn, Chen Liu

Children’s Nutrition Research Center Staff Publications

The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In …

Gasdermin D Deficiency Attenuates Arthritis Induced By Traumatic Injury But Not Autoantibody-Assembled Immune Complexes, Tong Yang, Kai Sun, Chun Wang, Gaurav Swarnkar, Songtao Quan, Dustin Kress, Jianqiu Xiao, Yael Alippe, Hongjun Zheng, Robert H Brophy, Dingjun Hao, Audrey Mcalinden, Yousef Abu-Amer, Jie Shen, Gabriel Mbalaviele

2020-Current year OA Pubs

BACKGROUND: Gasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intracellular protein complexes called inflammasomes. Caspase-1 also converts pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively. GSDMD amino-terminal fragments form plasma membrane pores, which mediate the secretion of IL-1β and IL-18 and cause the inflammatory form of cell death pyroptosis. Here, we tested the hypothesis that GSDMD contributes to joint degeneration in the K/BxN serum transfer-induced arthritis (STIA) model in which autoantibodies against glucose-6-phosphate isomerase promote the formation of pathogenic immune complexes on the surface of myeloid cells, which highly express the inflammasomes. …

Tracing Transmission Of Sin Nombre Virus And Discovery Of Infection In Multiple Rodent Species, Samuel M Goodfellow, Robert A. Nofchissey, Kurt C. Schwalm, Joseph A. Cook, Jonathan L. Dunnum, Yan Guo, Chunyan Ye, Gregory J. Mertz, Kartik Chandran, Michelle Harkins, Daryl B. Domman, Darrell L. Dinwiddie, Steven B. Bradfute

Pediatrics Research and Scholarship

Sin Nombre orthohantavirus (SNV), a negative-sense, single-stranded RNA virus that is carried and transmitted by the North American deer mouse Peromyscus maniculatus, can cause infection in humans through inhalation of aerosolized excreta from infected rodents. This infection can lead to hantavirus cardiopulmonary syndrome (HCPS), which has an ∼36% case-fatality rate. We used reverse transcriptase quantitative PCR (RT-qPCR) to confirm SNV infection in a patient and identified SNV in lung tissues in wild-caught rodents from potential sites of exposure. Using viral whole-genome sequencing (WGS), we identified the likely site of transmission and discovered SNV in multiple rodent species not previously known …