Medicine and Health Sciences Commons^™

Tempo And Mode Of Gene Expression Evolution In The Brain Across Primates, Katherine Rickelton, Trisha M Zintel, Jason Pizzollo, Emily Miller, John J Ely, Mary Ann Raghanti, William D Hopkins, Patrick R Hof, Chet C Sherwood, Amy L Bauernfeind, Courtney C Babbitt

2020-Current year OA Pubs

Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien and Higham, 2019; Powell et al., 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-seq data from four brain regions in an unprecedented eighteen species. Here, we …

An Orally Available Compound Suppresses Glucagon Hypersecretion And Normalizes Hyperglycemia In Type 1 Diabetes, Farzad Asadi, Subhadra C. Gunawardana, Roland E. Dolle, David W. Piston

2020-Current year OA Pubs

Suppression of glucagon hypersecretion can normalize hyperglycemia during type 1 diabetes (T1D). Activating erythropoietin-producing human hepatocellular receptor type-A4 (EphA4) on α cells reduced glucagon hypersecretion from dispersed α cells and T1D islets from both human donor and mouse models. We synthesized a high-affinity small molecule agonist for the EphA4 receptor, WCDD301, which showed robust plasma and liver microsome metabolic stability in both mouse and human preparations. In islets and dispersed islet cells from nondiabetic and T1D human donors, WCDD301 reduced glucagon secretion comparable to the natural EphA4 ligand, Ephrin-A5. In diabetic NOD and streptozotocin-treated mice, once-daily oral administration of WCDD301 …

Neuronal Deletion Of The Circadian Clock Gene Bmal1 Induces Cell-Autonomous Dopaminergic Neurodegeneration, Michael K. Kanan, Patrick W. Sheehan, Jessica N. Haines, Pedro G. Gomez, Adya Dhuler, Collin J. Nadarajah, Zachary M. Wargel, Brittany M. Freeberg, Hemanth R. Nelvagal, Mariko Izumo, Joseph S. Takahashi, Jonathan D. Cooper, Albert A. Davis, Erik S. Musiek

2020-Current year OA Pubs

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia …

Cpsa Mediates Infection Of Recruited Lung Myeloid Cells By Mycobacterium Tuberculosis, Steven J Grigsby, G V R Krishna Prasad, Joshua B Wallach, Ekansh Mittal, Fong-Fu Hsu, Dirk Schnappinger, Jennifer A Philips

2020-Current year OA Pubs

Mycobacterium tuberculosis (Mtb) possesses an arsenal of virulence factors to evade host immunity. Previously, we showed that the Mtb protein CpsA, which protects Mtb against the host NADPH oxidase, is required in mice during the first 3 weeks of infection but is thereafter dispensable for full virulence. Using flow cytometry, we find that ΔcpsA Mtb is retained in alveolar macrophages, impaired in recruiting and disseminating into monocyte-derived cells, and more likely to be localized in airway cells than wild-type Mtb. The lungs of ΔcpsA-infected mice also have markedly fewer antigen-specific T cells, indicating a delay in adaptive immunity. Thus, we …

A New Perspective On Intervertebral Disc Calcification-From Bench To Bedside, Emanuel Novais, Rajkishen Narayanan, Jose Canseco, Koen Van De Wetering, Christopher Kepler, Alan Hilibrand, Alex Vaccaro, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Disc degeneration primarily contributes to chronic low back and neck pain. Consequently, there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis, ectopic calcification, herniation, or mixed phenotypes. Amongst these phenotypes, disc calcification is the least studied. Ectopic calcification, by definition, is the pathological mineralization of soft tissues, widely studied in the context of conditions that afflict vasculature, skin, and cartilage. Clinically, disc calcification is associated with poor surgical outcomes and back pain refractory to conservative treatment. It is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular …

Microglia-Derived Exosomes Modulate Myelin Regeneration Via Mir-615-5p/Myrf Axis, Xiao-Yu Ji, Yu-Xin Guo, Li-Bin Wang, Wen-Cheng Wu, Jia-Qi Wang, Jin He, Rui Gao, Javad Rasouli, Meng-Yuan Gao, Zhen-Hai Wang, Dan Xiao, Wei-Feng Zhang, Bogoljub Ciric, Yuan Zhang, Xing Li

Department of Neurology Faculty Papers

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to …

Hormonal Basis Of Sex Differences In Anesthetic Sensitivity, Andrzej Z Wasilczuk, Cole Rinehart, Adeeti Aggarwal, Martha E Stone, George A Mashour, Michael S Avidan, Max B Kelz, Alex Proekt, Reccognition Study Group

2020-Current year OA Pubs

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, …

Susceptibility Of Toxoplasma Gondii To Autophagy In Human Cells Relies On Multiple Interacting Parasite Loci, Nicholas Rinkenberger, Alex Rosenberg, Joshua B Radke, Jaya Bhushan, Tadakimi Tomita, Louis M Weiss, L David Sibley

2020-Current year OA Pubs

Autophagy is a process used by cells to recycle organelles and macromolecules and to eliminate intracellular pathogens. Previous studies have shown that some stains of

Catalytic Isoforms Of Amp-Activated Protein Kinase Differentially Regulate Impdh Activity And Photoreceptor Neuron Function, Tae Jun Lee, Yo Sasaki, Philip A. Ruzycki, Norimitsu Ban, Joseph B. Lin, Hung-Ting Wu, Andrea Santeford, Rajendra S. Apte

2020-Current year OA Pubs

AMP-activated protein kinase (AMPK) plays a crucial role in maintaining ATP homeostasis in photoreceptor neurons. AMPK is a heterotrimeric protein consisting of α, β, and γ subunits. The independent functions of the 2 isoforms of the catalytic α subunit, PRKAA1 and PRKAA2, are uncharacterized in specialized neurons, such as photoreceptors. Here, we demonstrate in mice that rod photoreceptors lacking PRKAA2, but not PRKAA1, showed altered levels of cGMP, GTP, and ATP, suggesting isoform-specific regulation of photoreceptor metabolism. Furthermore, PRKAA2-deficient mice displayed visual functional deficits on electroretinography and photoreceptor outer segment structural abnormalities on transmission electron microscopy consistent with neuronal dysfunction, …

Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through C-C Chemokine Receptor Type 2 Downregulation And Enhanced Extracellular Matrix Balance, Sergio Sastriques-Dunlop, Santiago Elizondo-Benedetto, Batool Arif, Rodrigo Meade, Mohamed S Zaghloul, Hannah Luehmann, Gyu S Heo, Sean J English, Yongjian Liu, Mohamed A Zayed

2020-Current year OA Pubs

Abdominal aortic aneurysms (AAAs) are prevalent with aging, and AAA rupture is associated with increased mortality. There is currently no effective medical therapy to prevent AAA rupture. The monocyte chemoattractant protein (MCP-1)/C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. We therefore hypothesized that a diet intervention that can modulate CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we evaluated whether systemic ketosis in vivo could reduce CCR2 and AAA progression. Male Sprague-Dawley rats underwent surgical AAA …

Ephrinb2 Knockdown In Cervical Spinal Cord Preserves Diaphragm Innervation In A Mutant Sod1 Mouse Model Of Als, Mark W. Urban, Brittany A. Charsar, Nicolette M. Heinsinger, Shashirekha S. Markandaiah, Lindsay Sprimont, Wei Zhou, Eric V. Brown, Nathan T. Henderson, Samantha J. Thomas, Biswarup Ghosh, Rachel E. Cain, Davide Trotti, Piera Pasinelli, Megan C. Wright, Matthew B. Dalva, Angelo C. Lepore

Farber Institute for Neuroscience Staff Papers and Presentations

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via …

Fecal Pharmacokinetics And Gut Microbiome Effects Of Oral Omadacycline Versus Vancomycin In Healthy Volunteers, Jinhee Jo, Chenlin Hu, Khurshida Begum, Weiqun Wang, Thanh M Le, Samantha Agyapong, Blake M Hanson, Hossaena Ayele, Chris Lancaster, M Jahangir Alam, Anne J Gonzales-Luna, Kevin W Garey

Journal Articles

BACKGROUND: Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults.

METHODS: This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18-40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations …

A Flexible, Quantitative Plasmonic-Fluor Lateral Flow Assay For The Rapid Detection Of Orthoebolavirus Zairense And Orthoebolavirus Sudanense, Abraham J Qavi, Qisheng Jiang, M Javad Aman, Hong Vu, Larry Zetlin, John M Dye, Jeffrey W Froude, Daisy W Leung, Frederick Holtsberg, Scott L Crick, Gaya K Amarasinghe

2020-Current year OA Pubs

Filoviruses comprise a family of single-stranded, negative-sense RNA viruses with a significant impact on human health. Given the risk for disease outbreaks, as highlighted by the recent outbreaks across Africa, there is an unmet need for flexible diagnostic technologies that can be deployed in resource-limited settings. Herein, we highlight the use of plasmonic-fluor lateral flow assays (PF-LFA) for the rapid, quantitative detection of an Ebolavirus-secreted glycoprotein, a marker for infection. Plasmonic fluors are a class of ultrabright reporter molecules that combine engineered nanorods with conventional fluorophores, resulting in improved analytical sensitivity. We have developed a PF-LFA for

Investigating Clot-Flow Interactions By Integrating Intravital Imaging With In Silico Modeling For Analysis Of Flow, Transport, And Hemodynamic Forces, Chayut Teeraratkul, Maurizio Tomaiuolo, Timothy Stalker, Debanjan Mukherjee

Cardeza Foundation for Hematologic Research

As a blood clot forms, grows, deforms, and embolizes following a vascular injury, local clot-flow interactions lead to a highly dynamic flow environment. The local flow influences transport of biochemical species relevant for clotting, and determines the forces on the clot that in turn lead to clot deformation and embolization. Despite this central role, quantitative characterization of this dynamic clot-flow interaction and flow environment in the clot neighborhood remains a major challenge. Here, we propose an approach that integrates dynamic intravital imaging with computer geometric modeling and computational flow and transport modeling to develop a unified in silico framework to …

Inhibiting Metabotropic Glutamate Receptor 5 After Stroke Restores Brain Function And Connectivity, Jakob Hakon, Miriana J Quattromani, Carin Sjölund, Daniela Talhada, Byungchan Kim, Slavianka Moyanova, Federica Mastroiacovo, Luisa Di Menna, Roger Olsson, Elisabet Englund, Ferdinando Nicoletti, Karsten Ruscher, Adam Q Bauer, Tadeusz Wieloch

2020-Current year OA Pubs

Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative …

Sensory Neurons Promote Immune Homeostasis In The Lung, Masato Tamari, Aaron M Ver Heul, Masato Hoshi, Anna M Trier, Ting-Lin Yang, Sanjay Jain, Steven Van Dyken, Et Al.

2020-Current year OA Pubs

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1

Sarm1 Knockout Prevents Type 1 Diabetic Bone Disease In Females Independent Of Neuropathy, Jennifer M. Brazill, Ivana R. Shen, Clarissa S. Craft, Kristann L. Magee, Jay S. Park, Madelyn Lorenz, Amy Strickland, Natalie K. Wee, Xiao Zhang, Alec T. Beeve, Gretchen A. Meyer, Jeffrey Milbrandt, Aaron Diantonio, Erica L. Scheller

2020-Current year OA Pubs

Patients with diabetes have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild-type mice also developed diabetic bone disease but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone …

The Low-Density Lipoprotein Receptor Promotes Infection Of Multiple Encephalitic Alphaviruses, Hongming Ma, Lucas J Adams, Saravanan Raju, Alan Sariol, Natasha M Kafai, Hana Janova, William B Klimstra, Daved H Fremont, Michael S Diamond

2020-Current year OA Pubs

Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection …

Fatty Acid Synthesis Suppresses Dietary Polyunsaturated Fatty Acid Use, Anna Worthmann, Sangeeta Adak, Clay F Semenkovich, Et Al.

2020-Current year OA Pubs

Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition …

Hat: De Novo Variant Calling For Highly Accurate Short-Read And Long-Read Sequencing Data, Jeffrey K Ng, Tychele N Turner

2020-Current year OA Pubs

MOTIVATION: de novo variants (DNVs) are variants that are present in offspring but not in their parents. DNVs are both important for examining mutation rates as well as in the identification of disease-related variation. While efforts have been made to call DNVs, calling of DNVs is still challenging from parent-child sequenced trio data. We developed Hare And Tortoise (HAT) as an automated DNV detection workflow for highly accurate short-read and long-read sequencing data. Reliable detection of DNVs is important for human genomics and HAT addresses this need.

RESULTS: HAT is a computational workflow that begins with aligned read data (i.e. …

Investigation Into Cardiac Myhc-Α 334-352-Specific Tcr Transgenic Mice Reveals A Role For Cytotoxic Cd4 T Cells In The Development Of Cardiac Autoimmunity, Meghna Sur, Mahima T. Rasquinha, Kiruthiga Mone, Chandirasegaran Massilamany, Ninaad Lasrado, Channabasavaiah B. Gurumurthy, Raymond A Sobel, Jay Reddy

Journal Articles: Genetics, Cell Biology & Anatomy

Myocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4⁺ and CD8⁺ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL/6J mice specific to cardiac myosin heavy chain (Myhc)-α 334-352 and found that Myhc-α-specific TCRs were expressed in both CD4⁺ and CD8⁺ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A/J mice. At …

Targeting Transitioning Lung Monocytes/Macrophages As Treatment Strategies In Lung Disease Related To Environmental Exposures, Aaron Schwab, Todd A. Wyatt, Grace Moravec, Geoffrey M. Thiele, Amy J. Nelson, Angela Gleason, Oliver Schanze, Michael J. Duryee, Debra J. Romberger, Ted R. Mikuls, Jill A. Poole

Journal Articles: Pulmonary & Critical Care Med

Background: Environmental/occupational exposures cause significant lung diseases. Agricultural organic dust extracts (ODE) and bacterial component lipopolysaccharide (LPS) induce recruited,transitioning murine lung monocytes/macrophages, yet their cellular role remains unclear.

Methods: CCR2 RFP⁺ mice were intratracheally instilled with high concentration ODE (25%), LPS (10 μg), or gram-positive peptidoglycan (PGN, 100 μg) for monocyte/macrophage cell-trafficking studies. CCR2 knockout (KO) mice and administration of intravenous clodronate liposomes strategies were employed to reduce circulating monocytes available for lung recruitment following LPS exposure.Lung tissues and bronchoalveolar lavage fluid (BALF) were collected. Pro-inflammatory and/or pro-fibrotic cytokines, chemokines, and lung extracellular matrix mediators were quantitated by ELISA. …

Sirtuin3 Ensures The Metabolic Plasticity Of Neurotransmission During Glucose Deprivation, Anupama Tiwari, Arsalan Hashemiaghdam, Marissa A Laramie, Dario Maschi, Tristaan Haddad, Marion I Stunault, Carmen Bergom, Ali Javaheri, Vitaly Klyachko, Ghazaleh Ashrafi

2020-Current year OA Pubs

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose …

Lung-Delivered Il-10 Therapy Elicits Beneficial Effects Via Immune Modulation In Organic Dust Exposure-Induced Lung Inflammation, Aaron D. Schwab, Todd A. Wyatt, Amy J. Nelson, Angela Gleason, Rohit Gaurav, Debra J. Romberger, Jill A. Poole

Journal Articles: Pulmonary & Critical Care Med

Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 μg) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 …

Fused In Sarcoma Regulates Glutamate Signaling And Oxidative Stress Response, Chiong-Hee Wong, Abu Rahat, Howard C Chang

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Mutations in fused in sarcoma (fust-1) are linked to ALS. However, how these ALS causative mutations alter physiological processes and lead to the onset of ALS remains largely unknown. By obtaining humanized fust-1 ALS mutations via CRISPR-CAS9, we generated a C. elegans ALS model. Homozygous fust-1 ALS mutant and fust-1 deletion animals are viable in C. elegans. This allows us to better characterize the molecular mechanisms of fust-1-dependent responses. We found FUST-1 plays a role in regulating superoxide dismutase, glutamate signaling, and oxidative stress. FUST-1 suppresses SOD-1 and VGLUT/EAT-4 in the nervous system. FUST-1 also regulates synaptic AMPA-type glutamate receptor …

Hsp70 Is A Critical Regulator Of Hsp90 Inhibitor's Effectiveness In Preventing Hcl-Induced Chronic Lung Injury And Pulmonary Fibrosis, Ruben M. L. Colunga Biancatelli, Pavel A. Solopov, Tierney Day, Betsy Gregory, Michael Osei-Nkansah, Christiana Dimitropoulou, John D. Catravas

Bioelectrics Publications

Exposure to hydrochloric acid (HCl) can provoke acute and chronic lung injury. Because of its extensive production for industrial use, frequent accidental exposures occur, making HCl one of the top five chemicals causing inhalation injuries. There are no Food and Drug Administration (FDA)-approved treatments for HCl exposure. Heat shock protein 90 (HSP90) inhibitors modulate transforming growth factor-β (TGF-β) signaling and the development of chemical-induced pulmonary fibrosis. However, little is known on the role of Heat Shock Protein 70 (HSP70) during injury and treatment with HSP90 inhibitors. We hypothesized that administration of geranylgeranyl-acetone (GGA), an HSP70 inducer, or gefitinib (GFT), an …

Listeria Adhesion Protein Orchestrates Caveolae-Mediated Apical Junctional Remodeling Of Epithelial Barrier For Listeria Monocytogenes Translocation, Rishi Drolia, Donald B. Bryant, Shivendra Tenguria, Zuri A. Jules-Culver, Jessie Thind, Breanna Amelunke, Donqi Liu, Nicholas L. F. Gallina, Krishna K. Mishra, Manalee Samaddar, Manoj R. Sawale, Dharmendra K. Mishra, Abigail D. Cox, Arun K. Bhunia

Biological Sciences Faculty Publications

The cellular junctional architecture remodeling by Listeria adhesion protein-heat shock protein 60 (LAP-Hsp60) interaction for Listeria monocytogenes (Lm) passage through the epithelial barrier is incompletely understood. Here, using the gerbil model, permissive to internalin (Inl) A/B-mediated pathways like in humans, we demonstrate that Lm crosses the intestinal villi at 48 h post-infection. In contrast, the single isogenic (lap− or ΔinlA) or double (lap−ΔinlA) mutant strains show significant defects. LAP promotes Lm translocation via endocytosis of cell-cell junctional complex in enterocytes that do not display luminal E-cadherin. In comparison, InlA facilitates …

The Forkhead Transcription Factor Foxj1 Controls Vertebrate Olfactory Cilia Biogenesis And Sensory Neuron Differentiation, Dheeraj Rayamajhi, Steven L. Brody, Et Al.

2020-Current year OA Pubs

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the …

Hyperbaric Oxygen Augments Susceptibility To C. Difficile Infection By Impairing Gut Microbiota Ability To Stimulate The Hif-1Α-Il-22 Axis In Ilc3, José L Fachi, Laís P Pral, Helder C Assis, Sarah Oliveira, Vinícius R Rodovalho, Jefferson A C Dos Santos, Mariane F Fernandes, Valquíria A Matheus, Renata Sesti-Costa, Paulo J Basso, Marina Flóro E Silva, Niels O S Câmara, Selma Giorgio, Marco Colonna, Marco A R Vinolo

2020-Current year OA Pubs

Hyperbaric oxygen (HBO) therapy is a well-established method for improving tissue oxygenation and is typically used for the treatment of various inflammatory conditions, including infectious diseases. However, its effect on the intestinal mucosa, a microenvironment known to be physiologically hypoxic, remains unclear. Here, we demonstrated that daily treatment with hyperbaric oxygen affects gut microbiome composition, worsening antibiotic-induced dysbiosis. Accordingly, HBO-treated mice were more susceptible to

The Type Ii Raf Inhibitor Tovorafenib In Relapsed/Refractory Pediatric Low-Grade Glioma: The Phase 2 Firefly-1 Trial, Lindsay B Kilburn, Mohamed S Abdelbaki, Et Al.

2020-Current year OA Pubs

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m