Digital Commons Network^™

Microglia Control Small Vessel Calcification Via Trem2, Yvette Zarb, Sucheta Sridhar, Sina Nassiri, Sebastian Guido Utz, Johanna Schaffenrath, Upasana Maheshwari, Elisabeth J Rushing, K Peter R Nilsson, Mauro Delorenzi, Marco Colonna, Melanie Greter, Annika Keller

Open Access Publications

Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification,

The Dark Side Of The Gut: Virome-Host Interactions In Intestinal Homeostasis And Disease, Yuhao Li, Scott A. Handley, Megan T. Baldridge

Open Access Publications

The diverse enteric viral communities that infect microbes and the animal host collectively constitute the gut virome. Although recent advances in sequencing and analysis of metaviromes have revealed the complexity of the virome and facilitated discovery of new viruses, our understanding of the enteric virome is still incomplete. Recent studies have uncovered how virome-host interactions can contribute to beneficial or detrimental outcomes for the host. Understanding the complex interactions between enteric viruses and the intestinal immune system is a prerequisite for elucidating their role in intestinal diseases. In this review, we provide an overview of the enteric virome composition and …

Atoh7-Independent Specification Of Retinal Ganglion Cell Identity, Justin Brodie-Kommit, Brian S Clark, Fion Shiau, Philip A Ruzycki, Et Al

Open Access Publications

Retinal ganglion cells (RGCs) relay visual information from the eye to the brain. RGCs are the first cell type generated during retinal neurogenesis. Loss of function of the transcription factor

Loss Of Quaking Rna Binding Protein Disrupts The Expression Of Genes Associated With Astrocyte Maturation In Mouse Brain, Kristina Sakers, Yating Liu, Lorida Llaci, Scott M. Lee, Michael J. Vasek, Michael A. Rieger, Sean Brophy, Eric Tycksen, Renate Lewis, Susan E. Maloney, Joseph D. Dougherty

Open Access Publications

No abstract provided.

Microbiota Signals Suppress B Lymphopoiesis With Aging In Mice, Joseph R Krambs, Darlene A Monlish, Feng Gao, Laura G Schuettpelz, Daniel C Link

Open Access Publications

Aging is associated with significant changes in hematopoiesis that include a shift from lymphopoiesis to myelopoiesis and an expansion of phenotypic hematopoietic stem cells (HSCs) with impaired self-renewal capacity and myeloid-skewed lineage differentiation. Signals from commensal flora support basal myelopoiesis in young mice; however, their contribution to hematopoietic aging is largely unknown. Here, we characterize hematopoiesis in young and middle-aged mice housed under specific pathogen free (SPF) and germ-free (GF) conditions. The marked shift from lymphopoiesis to myelopoiesis that develops during aging of SPF mice is mostly abrogated in GF mice. Compared with aged SPF mice, there is a marked …

Noninvasive Immuno-Pet Imaging Of Cd8 + T Cell Behavior In Influenza A Virus-Infected Mice, Paul W Rothlauf, Zeyang Li, Novalia Pishesha, Yushu Joy Xie, Andrew W Woodham, Djenet Bousbaine, Stephen C Kolifrath, Vincent L Verschoor, Hidde L Ploegh

Open Access Publications

Immuno-positron emission tomography (immuno-PET) is a noninvasive imaging method that enables tracking of immune cells in living animals. We used a nanobody that recognizes mouse CD8α and labeled it with

Evaluation Of Kratom Opioid Derivatives As Potential Treatment Option For Alcohol Use Disorder, Anna M Gutridge, Soumen Chakraborty, Balazs R Varga, Elizabeth S Rhoda, Alexander R French, Arryn T Blaine, Quinten H Royer, Haoyue Cui, Jinling Yuan, Robert J Cassell, Márk Szabó, Susruta Majumdar, Richard M Van Rijn

Open Access Publications

No abstract provided.

Endocannabinoid System Unlocks The Puzzle Of Autism Treatment, Tangfeng Su, Yu Yan, Qiang Li, Jiacai Ye, Lei Pei

Open Access Publications

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of …

High Affinity Associations With Α-Snap Enable Calcium Entry Via Orai1 Channels, Ramanagouda Ramanagoudr-Bhojappa, Yong Miao, Monika Vig

Open Access Publications

Molecular steps that activate store-operated calcium entry (SOCE) via Orai channel supramolecular complex remain incompletely defined. We have earlier shown that α-SNAP regulates the on-site functional assembly and calcium selectivity of Orai1 channels. Here we investigate the molecular basis of its association with Orai, Stim and find that the affinity of α-SNAP for Orai and Stim is substantially higher than previously reported affinities between Stim and Orai sub-domains. α-SNAP binds the coiled-coil 3 (CC3) sub-domain of Stim1. Mutations of Tryptophan 430 in Stim1-CC3 disrupted α-SNAP association and SOCE, demonstrating a novel α-SNAP dependent function for this crucial subdomain. Further, α-SNAP …

Pharmacological And Biophysical Characteristics Of Picrotoxin-Resistant, Δsubunit-Containing Gabaa Receptors, Hong-Jin Shu, Xinguo Lu, John Bracamontes, Joe Henry Steinbach, Charles F Zorumski, Steven Mennerick

Open Access Publications

GABA

Successful Treatment Of Noise-Induced Hearing Loss By Mesenchymal Stromal Cells: An Rnaseq Analysis Of Protective/Repair Pathways, Athanasia Warnecke, Jennifer Harre, Matthew Shew, Adam J Mellott, Igor Majewski, Martin Durisin, Hinrich Staecker

Open Access Publications

Mesenchymal stromal cells (MSCs) are an adult derived stem cell-like population that has been shown to mediate repair in a wide range of degenerative disorders. The protective effects of MSCs are mainly mediated by the release of growth factors and cytokines thereby modulating the diseased environment and the immune system. Within the inner ear, MSCs have been shown protective against tissue damage induced by sound and a variety of ototoxins. To better understand the mechanism of action of MSCs in the inner ear, mice were exposed to narrow band noise. After exposure, MSCs derived from human umbilical cord Wharton's jelly …

Viral Evasion Of Innate Immune Defense: The Case Of Resistance Of Pandemic H1n1 Influenza A Virus To Human Mannose-Binding Proteins, Mitchell R White, Nikolaos M Nikolaidis, Francis Mccormack, Erika C Crouch, Kevan L Hartshorn

Open Access Publications

Mannose-binding lectins effectively inhibit most seasonal strains of influenza A virus and contribute to the innate host defense vs. these viruses. In contrast, pandemic IAV strains are largely resistant to these lectins, likely contributing to increased spread and worse outcomes. In this paper, we evaluated the inhibition of IAV by mannose-binding lectins of human, bacterial, and fungal origin to understand and possibly increase activity vs. the pandemic IAV. A modified version of the human surfactant protein D (SP-D) neck and carbohydrate recognition domain (NCRD) with combinatorial substitutions at the 325 and 343 positions, previously shown to inhibit pandemic H3N2 IAV

Zo-1 Intracellular Localization Organizes Immune Response In Non-Small Cell Lung Cancer, Déborah Neyrinck-Leglantier, Julien Lesage, Silvia Blacher, Arnaud Bonnomet, Walter Hunziker, Agnès Noël, Valérian Dormoy, Béatrice Nawrocki-Raby, Christine Gilles, Myriam Polette

Open Access Publications

Delocalization of zonula occludens-1 (ZO-1) from tight junctions plays a substantial role in epithelial cell plasticity observed during tumor progression.

Bladder Exposure To Gardnerella Activates Host Pathways Necessary For Escherichia Coli Recurrent Uti, Valerie P O'Brien, Amanda L Lewis, Nicole M Gilbert

Open Access Publications

Recurrent urinary tract infections (rUTI) are a costly clinical problem affecting millions of women worldwide each year. The majority of rUTI cases are caused by uropathogenic

Helminth-Virus Interactions: Determinants Of Coinfection Outcomes, Pritesh Desai, Michael S Diamond, Larissa B Thackray

Open Access Publications

Viral infections are often studied in model mammalian organisms under specific pathogen-free conditions. However, in nature, coinfections are common, and infection with one organism can alter host susceptibility to infection with another. Helminth parasites share a long coevolutionary history with mammalian hosts and have shaped host physiology, metabolism, immunity, and the composition of the microbiome. Published studies suggest that helminth infection can either be beneficial or detrimental during viral infection. Here, we discuss coinfection studies in mouse models and use them to define key determinants that impact outcomes, including the type of antiviral immunity, the tissue tropism of both the …

Antibiotic-Driven Intestinal Dysbiosis In Pediatric Short Bowel Syndrome Is Associated With Persistently Altered Microbiome Functions And Gut-Derived Bloodstream Infections, Robert Thänert, Anna Thänert, Jocelyn Ou, Adam Bajinting, Carey-Ann D Burnham, Holly J Engelstad, Maria E Tecos, I Malick Ndao, Carla Hall-Moore, Colleen Rouggly-Nickless, Mike A Carl, Deborah C Rubin, Nicholas O Davidson, Phillip I Tarr, Barbara B Warner, Gautam Dantas, Brad W Warner

Open Access Publications

Surgical removal of the intestine, lifesaving in catastrophic gastrointestinal disorders of infancy, can result in a form of intestinal failure known as short bowel syndrome (SBS). Bloodstream infections (BSIs) are a major challenge in pediatric SBS management. BSIs require frequent antibiotic therapy, with ill-defined consequences for the gut microbiome and childhood health. Here, we combine serial stool collection, shotgun metagenomic sequencing, multivariate statistics and genome-resolved strain-tracking in a cohort of 19 patients with surgically-induced SBS to show that antibiotic-driven intestinal dysbiosis in SBS enriches for persistent intestinal colonization with BSI causative pathogens in SBS. Comparing the gut microbiome composition of …

Paeonol Ameliorates Chronic Itch And Spinal Astrocytic Activation Via Cxcr3 In An Experimental Dry Skin Model In Mice, Wen Wang, Qiaoyun Li, Zhongqiu Zhao, Yutong Liu, Yi Wang, Hui Xiong, Zhinan Mei

Open Access Publications

Paeonol is a bioactive phenol presents mainly in

Perceptions Of Clinical Dental Students Toward Online Education During The Covid-19 Crisis: An Egyptian Multicenter Cross-Sectional Survey, Reham Hassan, Ayman R Khalifa, Tarek Elsewify, Mohamed G Hassan

Open Access Publications

No abstract provided.

Superior Verbal Memory Outcome After Stereotactic Laser Amygdalohippocampotomy, Daniel L Drane, Jon T Willie, Et Al

Open Access Publications

No abstract provided.

Care Gaps And Recommendations In Vestibular Migraine: An Expert Panel Summit, Monica P Mallampalli, Joel A Goebel, Et Al

Open Access Publications

Vestibular migraine (VM) is an increasingly recognized pathology yet remains as an underdiagnosed cause of vestibular disorders. While current diagnostic criteria are codified in the 2012 Barany Society document and included in the third edition of the international classification of headache disorders, the pathophysiology of this disorder is still elusive. The Association for Migraine Disorders hosted a multidisciplinary, international expert workshop in October 2020 and identified seven current care gaps that the scientific community needs to resolve, including a better understanding of the range of symptoms and phenotypes of VM, the lack of a diagnostic marker, a better understanding of …

Encephalitic Arboviruses Of Africa: Emergence, Clinical Presentation And Neuropathogenesis, Robyn S Klein

Open Access Publications

Many mosquito-borne viruses (arboviruses) are endemic in Africa, contributing to systemic and neurological infections in various geographical locations on the continent. While most arboviral infections do not lead to neuroinvasive diseases of the central nervous system, neurologic diseases caused by arboviruses include flaccid paralysis, meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and post-infectious autoimmune or memory disorders. Here we review endemic members of the

Hyperexcitability Of Sensory Neurons In Fragile X Mouse Model, Pan-Yue Deng, Oshri Avraham, Valeria Cavalli, Vitaly A Klyachko

Open Access Publications

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in

Rubella Virus Infected Macrophages And Neutrophils Define Patterns Of Granulomatous Inflammation In Inborn And Acquired Errors Of Immunity, Ludmila Perelygina, Amy Musiek, Et Al

Open Access Publications

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, …

A Real-World Observation Of Antipsychotic Effects On Brain Volumes And Intrinsic Brain Activity In Schizophrenia, Yifan Chen, Fay Y Womer, Ruiqi Feng, Xizhe Zhang, Yanbo Zhang, Jia Duan, Miao Chang, Zhiyang Yin, Xiaowei Jiang, Shengnan Wei, Yange Wei, Yanqing Tang, Fei Wang

Open Access Publications

Background: The confounding effects of antipsychotics that led to the inconsistencies of neuroimaging findings have long been the barriers to understanding the pathophysiology of schizophrenia (SZ). Although it is widely accepted that antipsychotics can alleviate psychotic symptoms during the early most acute phase, the longer-term effects of antipsychotics on the brain have been unclear. This study aims to look at the susceptibility of different imaging measures to longer-term medicated status through real-world observation.

Methods: We compared gray matter volume (GMV) with amplitude of low-frequency fluctuations (ALFFs) in 89 medicated-schizophrenia (med-SZ), 81 unmedicated-schizophrenia (unmed-SZ), and 235 healthy controls (HC), and the …

Development And Testing Of A Spray-Dried Tuberculosis Vaccine Candidate In A Mouse Model, Mellissa Gomez, Mushtaq Ahmed, Shibali Das, Leah Mellett, Rosemary Swanson, Ananya Gupta, Shabaana A Khader, Et Al

Open Access Publications

Converting a vaccine into a thermostable dry powder is advantageous as it reduces the resource burden linked with the cold chain and provides flexibility in dosage and administration through different routes. Such a dry powder presentation may be especially useful in the development of a vaccine towards the respiratory infectious disease tuberculosis (TB). This study assesses the immunogenicity and protective efficacy of spray-dried ID93+GLA-SE, a promising TB vaccine candidate, against

The T-Type Calcium Channel Isoform Ca V 3.1 Is A Target For The Hypnotic Effect Of The Anaesthetic Neurosteroid (3Β,5Β,17Β)-3-Hydroxyandrostane-17-Carbonitrile, Tamara Timic Stamenic, Simon Feseha, Francesca M Manzella, Damon Wallace, Davis Wilkey, Timothy Corrigan, Hanna Fiedler, Patricia Doerr, Kathiresan Krishnan, Yogendra H Raol, Douglas F Covey, Vesna Jevtovic-Todorovic, Slobodan M Todorovic

Open Access Publications

BACKGROUND: The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown.

METHODS: We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Ca

RESULTS: Patch-clamp recordings showed that 3β-OH inhibited isolated T-currents but had no effect on phasic or tonic γ-aminobutyric acid A currents. Also in acute brain slices, 3β-OH inhibited the spike firing mode more profoundly in WT than in Ca

CONCLUSIONS: The Ca

Kentucky And The Thoroughbred Industries: Prospects And Challenges As Gambling Stagnates, Thomas E. Lambert

Faculty and Staff Scholarship

Over the last 15 to 20 years or so horse racing has seen declines in wagering and fan attendance throughout the US. Because of this, the number of races, horses per race, the number of thoroughbred farms, and new thoroughbreds bred and born each year for about the last 10 to 12 years have also declined. The decline in wagering has occurred despite simulcasting of races, online betting, and gambling machines which employ films of past races (historical horse racing machines). Those racetracks doing well are usually part of larger casino and entertainment complexes (racinos). Kentucky, which has one of …

The Benefits Of Being A Suicidal Curmudgeon: Emil Cioran On Killing Yourself, Glenn M. Trujillo Jr

Faculty and Staff Scholarship

Emil Cioran offers novel arguments against suicide. He assumes a meaningless world. But in such a world, he argues, suicide and death would be equally as meaningless as life or anything else. Suicide and death are as cumbersome and useless as meaning and life. Yet Cioran also argues that we should contemplate suicide to live better lives. By contemplating suicide, we confront the deep suffering inherent in existence. This humbles us enough to allow us to change even the deepest aspects of ourselves. Yet it also reminds us that our peculiar human ability—being able to contemplate suicide—sets us above anything …

Malondialdehyde Acetaldehyde Adducts (Maa-Adducts) Direct Distinctive Pro-Inflammatory Responses In Endothelial And Macrophage Cell Lines, Patrick J. Opperman, Michael J. Duryee, Ted R. Mikuls, Geoffrey M. Thiele, Dahn L. Clemens, Daniel R. Anderson

EMET Projects

Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. At present, the mechanism(s) by which inflammation contributes to this disease isnot entirely understood. Inflammation is known to induce oxidative stress, of which one consequence is lipid peroxidation. This process leads to the production of malondialdehyde (MDA), which can subsequently break down to form acetaldehyde (AA). These two aldehyde by-products can covalently interact with the ε-amino group of lysineswithin proteins and lipoproteins leading to the formation of highly immunogenic malondialdehyde-acetaldehyde adducts (MAA-adducts). The aim of this study was to determine the in-vitro cytokine response of endothelial cells and macrophages …

The Induction Of Autoimmune Arthritis And Sex Differences In Mice Impact The Lung Inflammatory Response To Repetitive Inhalant Organic Dust Extract Exposures, Kathryn Rentfro, Geoffrey M. Thiele, Katherine Janike, Amy J. Nelson, Michael J. Duryee, Bryant R. England, Debra J. Romberger, Joseph Carrington, Dong Wang, Benjamin J. Swanson, Lynell W. Klassen, Ted R. Mikuls, Jill A. Poole

EMET Projects

Asthma, chronic bronchitis and COPD are common adverse respiratory health effects among persons exposed to agriculture organic dust work environments.

• Occupational inhalant exposures have been increasingly associated with the risk of rheumatoid arthritis (RA) disease development, particularly among males. Agriculture workers have increased risk of RA and generalized bone disease.
• Chronic lung disease is associated with production of characteristic autoantibodies associated with RA (e.g.anti-citrullinated antibodies), even in absence of RA disease.
• The mechanistic link between pulmonary inflammation and arthritis (and vice versa) remains poorly understood. Animal models are lacking.