Digital Commons Network^™

Comparative Genomics Of Borderline Oxacillin-Resistant Staphylococcus Aureus Detected During A Pseudo-Outbreak Of Methicillin-Resistant S. Aureus In A Neonatal Intensive Care Unit, Sanjam S Sawhney, Eric M Ransom, Meghan A Wallace, Patrick J Reich, Gautam Dantas, Carey-Ann D Burnham

Open Access Publications

Active surveillance for methicillin-resistant Staphylococcus aureus (MRSA) is a component of our neonatal intensive care unit (NICU) infection prevention efforts. Recent atypical trends prompted review of 42 suspected MRSA isolates. Species identification was confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and methicillin resistance was reevaluated by PBP2a lateral flow assay, cefoxitin/oxacillin susceptibility testing,

Post-Hpv-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation Of Undiagnosed Pre-Existing Mast Cell Disease?, Lawrence B Afrin, Tania T Dempsey, Leonard B Weinstock

Open Access Publications

For nearly a decade, case reports and series have emerged regarding dysautonomias-particularly postural orthostatic tachycardia syndrome (POTS)-presenting soon after vaccination against human papilloma virus (HPV). We too have observed a number of such cases (all following vaccination with the Gardasil product), and have found several to have detectable mast cell activation syndrome (MCAS) as well as histories suggesting that MCAS was likely present long before vaccination. We detail 11 such cases here, posing a hypothesis that HPV vaccination (at least with the Gardasil product) may have triggered or exacerbated MCAS in teenagers previously not recognized to have it. Only recently …

Murine Roseolovirus Does Not Accelerate Amyloid-Β Pathology And Human Roseoloviruses Are Not Over-Represented In Alzheimer Disease Brains, Tarin M Bigley, Monica Xiong, Muhammad Ali, Yun Chen, Chao Wang, Javier Remolina Serrano, Abdallah Eteleeb, Oscar Harari, Liping Yang, Swapneel J Patel, Carlos Cruchaga, Wayne M Yokoyama, David M Holtzman

2020-Current year OA Pubs

BACKGROUND: The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen …

Nipah Virus V Protein Binding Alters Mda5 Helicase Folding Dynamics, Nicole D Wagner, Hejun Liu, Henry W Rohrs, Gaya K Amarasinghe, Michael L Gross, Daisy W Leung

2020-Current year OA Pubs

Nipah virus (NiV) is an emerging and deadly zoonotic paramyxovirus that is responsible for periodic epidemics of acute respiratory illness and encephalitis in humans. Previous studies have shown that the NiV V protein antagonizes host antiviral immunity, but the molecular mechanism is incompletely understood. To address this gap, we biochemically characterized NiV V binding to the host pattern recognition receptor MDA5. We find that the C-terminal domain of NiV V (V

Dansr: A Tool For The Detection Of Annotated And Novel Small Rnas, Jin Zhang, Abdallah M Eteleeb, Emily B Rozycki, Matthew J Inkman, Amy Ly, Russell E Scharf, Kay Jayachandran, Bradley A Krasnick, Thomas Mazur, Nicole M White, Ryan C Fields, Christopher A Maher

Open Access Publications

Existing small noncoding RNA analysis tools are optimized for processing short sequencing reads (17-35 nucleotides) to monitor microRNA expression. However, these strategies under-represent many biologically relevant classes of small noncoding RNAs in the 36-200 nucleotides length range (tRNAs, snoRNAs, etc.). To address this, we developed DANSR, a tool for the detection of annotated and novel small RNAs using sequencing reads with variable lengths (ranging from 17-200 nt). While DANSR is broadly applicable to any small RNA dataset, we applied it to a cohort of matched normal, primary, and distant metastatic colorectal cancer specimens to demonstrate its ability to quantify annotated …

Metabolic Sensing In Agrp Neurons Integrates Homeostatic State With Dopamine Signalling In The Striatum, Alex Reichenbach, Alexxai V. Kravitz, Et Al

Open Access Publications

Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (

Myocardial Afterload Is A Key Biomechanical Regulator Of Atrioventricular Myocyte Differentiation In Zebrafish, Neha Ahuja, Paige Ostwald, Alex Gendernalik, Elena Guzzolino, Letizia Pitto, David Bark, Deborah M Garrity

Open Access Publications

Heart valve development is governed by both genetic and biomechanical inputs. Prior work has demonstrated that oscillating shear stress associated with blood flow is required for normal atrioventricular (AV) valve development. Cardiac afterload is defined as the pressure the ventricle must overcome in order to pump blood throughout the circulatory system. In human patients, conditions of high afterload can cause valve pathology. Whether high afterload adversely affects embryonic valve development remains poorly understood. Here we describe a zebrafish model exhibiting increased myocardial afterload, caused by vasopressin, a vasoconstrictive drug. We show that the application of vasopressin reliably produces an increase …

Serpinb3 (Scca1) Inhibits Cathepsin L And Lysoptosis, Protecting Cervical Cancer Cells From Chemoradiation, Songyan Wang, Cliff J Luke, Stephen C Pak, Victoria Shi, Liyun Chen, Jonathan Moore, Arlise P Andress, Kay Jayachandran, Jin Zhang, Yi Huang, Marina Platik, Anthony A Apicelli, Julie K Schwarz, Perry W Grigsby, Gary A Silverman, Stephanie Markovina

Open Access Publications

The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhanced sensitivity to IR-induced cell death. Knock out of SERPINB3 sensitizes cells to a greater extent than cisplatin, the current standard of care. IR in SERPINB3 deficient cervical carcinoma cells induces predominantly necrotic cell death, …

Lysoptosis Is An Evolutionarily Conserved Cell Death Pathway Moderated By Intracellular Serpins, Cliff J Luke, Stephanie Markovina, Misty Good, Ira E Wight, Brian J Thomas, John M Linneman, Wyatt E Lanik, Olga Koroleva, Maggie R Coffman, Mark T Miedel, Qingqing Gong, Arlise Andress, Marlene Campos Guerrero, Songyan Wang, Liyun Chen, Wandy L Beatty, Kelsey N Hausmann, Frances V White, James A J Fitzpatrick, Anthony Orvedahl, Stephen C Pak, Gary A Silverman

Open Access Publications

Lysosomal membrane permeabilization (LMP) and cathepsin release typifies lysosome-dependent cell death (LDCD). However, LMP occurs in most regulated cell death programs suggesting LDCD is not an independent cell death pathway, but is conscripted to facilitate the final cellular demise by other cell death routines. Previously, we demonstrated that Caenorhabditis elegans (C. elegans) null for a cysteine protease inhibitor, srp-6, undergo a specific LDCD pathway characterized by LMP and cathepsin-dependent cytoplasmic proteolysis. We designated this cell death routine, lysoptosis, to distinguish it from other pathways employing LMP. In this study, mouse and human epithelial cells lacking srp-6 homologues, mSerpinb3a and SERPINB3, …

Targeting The Fusion Process Of Sars-Cov-2 Infection By Small Molecule Inhibitors, Seung Bum Park, Parker Irvin, Zongyi Hu, Mohsin Khan, Xin Hu, Qiru Zeng, Catherine Chen, Miao Xu, Madeleine Leek, Ruochen Zang, James Brett Case, Wei Zheng, Siyuan Ding, T. Jake Liang

Open Access Publications

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a serious threat to global public health, underscoring the urgency of developing effective therapies. Therapeutics and, more specifically, direct-acting antiviral development are still very much in their infancy. Here, we report that two hepatitis C virus (HCV) fusion inhibitors identified in our previous study, dichlorcyclizine and fluoxazolevir, broadly block human coronavirus entry into various cell types. Both compounds were effective against various human-pathogenic CoVs in multiple assays based on vesicular stomatitis virus (VSV) pseudotyped with the spike protein and spike-mediated syncytium formation. The antiviral effects …

Astrocytic 4r Tau Expression Drives Astrocyte Reactivity And Dysfunction, Lubov A. Ezerskiy, Kathleen M. Schoch, Chihiro Sato, Mariana Beltcheva, Kanta Horie, Frank Rigo, Ryan Martynowicz, Celeste M. Karch, Randall J. Bateman, Timothy M. Miller

Open Access Publications

The protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the role of specific tau isoforms in disease. Preferential expression of 4R tau in human tau-expressing (hTau-expressing) mice was previously shown to increase seizure severity and phosphorylated tau deposition without neuronal or synaptic loss. In this study, we observed strong colocalization of 4R tau within reactive astrocytes …

Fasn-Dependent De Novo Lipogenesis Is Required For Brain Development, Daniel Gonzalez-Bohorquez, Isabel M Gallego López, Baptiste N Jaeger, Sibylle Pfammatter, Megan Bowers, Clay F Semenkovich, Sebastian Jessberger

Open Access Publications

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of

P300 Or Cbp Is Required For Insulin-Stimulated Glucose Uptake In Skeletal Muscle And Adipocytes, Vitor F. Martins, Gretchen A. Meyer, Et Al.

2020-Current year OA Pubs

While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this …

Microbial Enzymes Induce Colitis By Reactivating Triclosan In The Mouse Gastrointestinal Tract, Jianan Zhang, Morgan E. Walker, Katherine Z. Sanidad, Hongna Zhang, Michael B. Major, Dennis Goldfarb, Et Al

Open Access Publications

No abstract provided.

Total Energy Expenditure Is Repeatable In Adults But Not Associated With Short-Term Changes In Body Composition, Rebecca Rimbach, Susan B. Racette, John R. Speakman, Herman Pontzer, Et Al

Open Access Publications

No abstract provided.

Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related To Alzheimer's Disease, Evan E Hubbard, Randall J Bateman, Richard J Perrin, Et Al.

2020-Current year OA Pubs

One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant …

Transcriptomes Of Peripheral Blood Mononuclear Cells From Juvenile Dermatomyositis Patients Show Elevated Inflammation Even When Clinically Inactive, Elisha D O Roberson, Rosana A Mesa, Gabrielle A Morgan, Li Cao, Wilfredo Marin, Lauren M Pachman

Open Access Publications

In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage. We hoped to understand the molecular underpinnings of JDM, particularly when untreated, which would facilitate the identification of novel mechanisms and clinical targets that might disrupt disease progression. We studied the RNA-Seq data from untreated JDM peripheral blood mononuclear cells (PBMCs; n = 11), PBMCs from a subset of the same patients when clinically inactive (n = 8/11), and separate samples of untreated JDM skin and muscle (n = 4 each). All JDM …

Place Is Power: Investing In Communities As A Systemic Leverage Point To Reduce Breast Cancer Disparities By Race, Matthew Jay Lyons, Senaida Fernandez Poole, Ross C Brownson, Rodney Lyn

2020-Current year OA Pubs

Racial disparities in breast cancer present a vexing and complex challenge for public health. A diverse array of factors contributes to disparities in breast cancer incidence and outcomes, and, thus far, efforts to improve racial equity have yielded mixed results. Systems theory offers a model that is well-suited to addressing complex issues. In particular, the concept of a systemic leverage point offers a clue that may assist researchers, policymakers, and interventionists in formulating innovative and comprehensive approaches to eliminating racial disparities in breast cancer. Naming systemic racism as a fundamental cause of disparities, we use systems theory to identify residential …

Constitutively Active Sarm1 Variants That Induce Neuropathy Are Enriched In Als Patients, A Joseph Bloom, Xianrong Mao, Amy Strickland, Yo Sasaki, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

BACKGROUND: In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD

METHODS: To investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo.

RESULTS: Twelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive …

Polyunsaturated Fatty Acids Inhibit A Pentameric Ligand-Gated Ion Channel Through One Of Two Binding Sites, Noah M. Dietzen, Mark J. Arcario, Lawrence J. Chen, John T. Petroff, K. Trent Moreland, Kathiresan Krishnan, Grace Brannigan, Douglas F. Covey, Wayland W.I. Cheng

Open Access Publications

Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABA

Sars-Cov-2 Spreads Through Cell-To-Cell Transmission, Cong Zeng, John P Evans, Tiffany King, Yi-Min Zheng, Eugene M Oltz, Sean P J Whelan, Linda J Saif, Mark E Peeples, Shan-Lu Liu

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting …

The Yersinia High-Pathogenicity Island Encodes A Siderophore-Dependent Copper Response System In Uropathogenic Escherichia Coli, George L Katumba, Hung Tran, Jeffrey P Henderson

Open Access Publications

Siderophores are iron chelators used by microbes to bind and acquire iron, which, once in the cell, inhibits siderophore production through feedback repression mediated by the ferric uptake repressor (Fur). Yersiniabactin (Ybt), a siderophore associated with enhanced pathogenic potential among

Pacs Viewbook 2022-2023, Program In Audiology And Communication Sciences

PACS News

No abstract provided.

Identification Of Gut Bacteria Such As Lactobacillus Johnsonii That Disseminate To Systemic Tissues Of Wild Type And Myd88-/- Mice, Sreeram Udayan, Panagiota Stamou, Fiona Crispie, Ana Hickey, Alexandria N Floyd, Chyi-Song Hsieh, Paul D Cotter, Orla O'Sullivan, Silvia Melgar, Paul W O'Toole, Rodney D Newberry, Valerio Rossini, Ken Nally

Open Access Publications

In healthy hosts the gut microbiota is restricted to gut tissues by several barriers some of which require MyD88-dependent innate immune sensor pathways. Nevertheless, some gut taxa have been reported to disseminate to systemic tissues. However, the extent to which this normally occurs during homeostasis in healthy organisms is still unknown. In this study, we recovered viable gut bacteria from systemic tissues of healthy wild type (WT) and MyD88

Serologic And Cytokine Signatures In Children With Multisystem Inflammatory Syndrome And Coronavirus Disease 2019, Stacey A. Lapp, Carol M. Kao, David A. Hunstad, Et Al

Open Access Publications

Background: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood.

Methods: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and …

Swi/Snf Senses Carbon Starvation With A Ph-Sensitive Low-Complexity Sequence, J. Ignacio Gutierrez, Gregory P. Brittingham, Yonca Karadeniz, Kathleen D. Tran, Arnob Dutta, Alex S. Holehouse, Craig L. Peterson, Liam J. Holt

Open Access Publications

It is increasingly appreciated that intracellular pH changes are important biological signals. This motivates the elucidation of molecular mechanisms of pH sensing. We determined that a nucleocytoplasmic pH oscillation was required for the transcriptional response to carbon starvation in

Washington University Magazine, August 2022

Washington University Magazine

No abstract provided.

Washington University Magazine, December 2022

Washington University Magazine

No abstract provided.

Ethical Discussion Of The Need For Irb Approval, Sarah Fowler-Dixon

Human Research Protection Program (HRPP) Education

No abstract provided.

An Immuno-Enrichment Free, Validated Quantification Of Tau Protein In Human Csf By Lc-Ms/Ms, Wade Self, Khader Awwad, John Paul Savaryn, Michael Schulz

Open Access Publications

Tau protein is a key target of interest in developing therapeutics for neurodegenerative diseases. Here, we sought to develop a method that quantifies extracellular tau protein concentrations in human cerebrospinal fluid (CSF) without antibody-based enrichment strategies. We demonstrate that the fit-for-purpose validated method in Alzheimer's Disease CSF is limited to quasi quantitative measures of tau surrogate peptides. We also provide evidence that CSF total Tau measures by LC-MS are feasible in the presence of monoclonal therapeutic antibodies in human CSF. Our Tau LC-MS/MS method is a translational bioanalytical tool for assaying target engagement and pharmacodynamics for anti-tau antibody drug development …