Digital Commons Network^™

Sedation And Acute Encephalopathy In A Pediatric Patient Following Ingestion Of Delta-8-Tetrahydrocannabinol Gummies, Peter Akpunonu, Regan A. Baum, Andrew Reckers, Blake Davidson, Ross Ellison, Matthew Riley, Jordan Trecki, Roy Gerona

Emergency Medicine Faculty Publications

BACKGROUND Delta-8 tetrahydrocannabinol (delta-8 THC) is an isomer of delta-9-tetrahydrocannabinol (delta-9 THC), the primary psychoactive cannabinoid in the marijuana plant. Typically found at lower concentrations in marijuana, delta-8 THC exhibits psychoactive properties similar to delta-9 THC. Products containing delta-8 THC are readily available across the US and currently there is a lack of available confirmatory testing specific to delta-8 THC as there is cross-reactivity to other naturally occurring cannabinoids in standard immunoassays. Pediatric exposures to this substance are on the rise.

CASE REPORT We present a case with laboratory confirmation of a previously healthy 2-year-old girl ingesting approximately 15 mg/kg …

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 …

Breastfeeding And Risk Of Overweight In Childhood And Beyond: A Systematic Review With Emphasis On Sibling-Pair And Intervention Studies, Kathryn G Dewey, Darcy Güngör, Sharon M Donovan, Emily M Madan, Sudha Venkatramanan, Teresa A Davis, Ronald E Kleinman, Elsie M Taveras, Regan L Bailey, Rachel Novotny, Nancy Terry, Gisela Butera, Julie Obbagy, Janet De Jesus, Eve Stoody

Children’s Nutrition Research Center Staff Publications

BACKGROUND: Breastfeeding is associated with a lower risk of subsequent overweight or obesity, but it is uncertain whether this is a causal relation because most studies have not adequately reduced risk of bias due to confounding.

OBJECTIVES: The aim of this review was to examine whether 1) ever compared with never consuming human milk and 2) different durations of human milk consumption among infants fed human milk are related to later risk of overweight or obesity, with emphasis on sibling-pair and intervention studies.

METHODS: The 2020 Dietary Guidelines Advisory Committee, together with the Nutrition Evidence Systematic Review team, conducted a …

Physical Activity And Fat-Free Mass During Growth And In Later Life, Klaas R Westerterp, Yosuke Yamada, Hiroyuki Sagayama, Philip N Ainslie, Lene F Andersen, Liam J Anderson, Lenore Arab, Issaad Baddou, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Pascal Bovet, Maciej S Buchowski, Nancy F Butte, Stefan G J A Camps, Graeme L Close, Jamie A Cooper, Sai K Das, Richard Cooper, Lara R Dugas, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Annelies H Goris, Michael Gurven, Catherine Hambly, Asmaa El Hamdouchi, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek M Joosen, Peter Katzmarzyk, Kitty P Kempen, Misaka Kimura, William E Kraus, Robert F Kushner, Estelle V Lambert, William R Leonard, Nader Lessan, Corby K Martin, Anine C Medin, Erwin P Meijer, James C Morehen, James P Morton, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto A Rabinovich, Susan B Racette, David A Raichlen, Eric Ravussin, Rebecca M Reynolds, Susan B Roberts, Albertine J Schuit, Anders M Sjödin, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jonathan C K Wells, George Wilson, Brian M Wood, Jack Yanovski, Tsukasa Yoshida, Xueying Zhang, Alexia J Murphy-Alford, Cornelia U Loechl, Amy H Luke, Herman Pontzer, Jennifer Rood, Dale A Schoeller, William W Wong, John R Speakman

Children’s Nutrition Research Center Staff Publications

BACKGROUND: Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass.

OBJECTIVES: A study is presented of the association between FFM and physical activity in relation to age.

METHODS: In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical …

Identification Of An Atp/P2x7/Mast Cell Pathway Mediating Ozone-Induced Bronchial Hyperresponsiveness, Xiaomei Kong, William C Bennett, Corey M Jania, Kelly D Chason, Zachary German, Jennifer Adouli, Samuel D Budney, Brandon T Oby, Catharina Van Heusden, Eduardo R Lazarowski, Ilona Jaspers, Scott H Randell, Barry A Hedgespeth, Glenn Cruse, Xiaoyang Hua, Stephen A Schworer, Gregory J Smith, Samir Np Kelada, Stephen L Tilley

Faculty, Staff and Student Publications

Ozone is a highly reactive environmental pollutant with well-recognized adverse effects on lung health. Bronchial hyperresponsiveness (BHR) is one consequence of ozone exposure, particularly for individuals with underlying lung disease. Our data demonstrated that ozone induced substantial ATP release from human airway epithelia in vitro and into the airways of mice in vivo and that ATP served as a potent inducer of mast cell degranulation and BHR, acting through P2X7 receptors on mast cells. Both mast cell-deficient and P2X7 receptor-deficient (P2X7-/-) mice demonstrated markedly attenuated BHR to ozone. Reconstitution of mast cell-deficient mice with WT mast cells and P2X7-/- mast …

Competitive Binding Of E3 Ligases Trim26 And Wwp2 Controls Sox2 In Glioblastoma, Tatenda Mahlokozera, Bhuvic Patel, Hao Chen, Patrick Desouza, Xuan Qu, Diane D Mao, Daniel Hafez, Wei Yang, Rukayat Taiwo, Mounica Paturu, Afshin Salehi, Amit D Gujar, Gavin P Dunn, Nima Mosammaparast, Allegra A Petti, Hiroko Yano, Albert H Kim

2020-Current year OA Pubs

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, …

A Class Ii Mhc-Targeted Vaccine Elicits Immunity Against Sars-Cov-2 And Its Variants, Novalia Pishesha, Paul W Rothlauf, Mariel J Liebeskind, Maria A Vakaki, Louis-Marie Bloyet, Marjorie Cornejo Pontelli, Ma Xenia G Ilagan, William J Buchser, Sean P J Whelan, Et Al

Open Access Publications

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (Spike

Reward Deficiency Syndrome (Rds): A Cytoarchitectural Common Neurobiological Trait Of All Addictions, Kenneth Blum, Abdalla Bowirrat, Eric R Braverman, David Baron, Jean Lud Cadet, Shan Kazmi, Igor Elman, Panyotis K Thanos, Rajendra D Badgaiyan, William B Downs, Debasis Bagchi, Luis Llanos-Gomez, Mark S Gold

2020-Current year OA Pubs

Alcohol and other substance use disorders share comorbidity with other RDS disorders, i.e., a reduction in dopamine signaling within the reward pathway. RDS is a term that connects addictive, obsessive, compulsive, and impulsive behavioral disorders. An estimated 2 million individuals in the United States have opioid use disorder related to prescription opioids. It is estimated that the overall cost of the illegal and legally prescribed opioid crisis exceeds one trillion dollars. Opioid Replacement Therapy is the most common treatment for addictions and other RDS disorders. Even after repeated relapses, patients are repeatedly prescribed the same opioid replacement treatments. A recent …

Cytokine Exposure Mediates Transcriptional Activation Of The Orphan Nuclear Receptor Nur77 In Hematopoietic Cells, Orsola Di Martino, Haixia Niu, Gayla Hadwiger, Margaret A Ferris, John S Welch

Open Access Publications

The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side groups. Naturally occurring, cell-endogenous ligands have not been identified, and Nur77 transcriptional activity is thought to be regulated through posttranslational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in …

Interleukin-10 Suppression Enhances T-Cell Antitumor Immunity And Responses To Checkpoint Blockade In Chronic Lymphocytic Leukemia., J R Rivas, Y Liu, S S Alhakeem, J M Eckenrode, F Marti, J P Collard, Y Zhang, K A Shaaban, N Muthusamy, G C Hildebrandt, L Chen, J S Thorson, M Leggas, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTM

Surgical Treatment Of Valvular Heart Disease In Nigeria: A 6-Year Experience, Ikechukwu A Nwafor, John C Eze, Maureen N Nwafor

The Texas Heart Institute Journal

Surgical treatment of valvular heart disease in Nigeria, the most populous country in sub-Saharan Africa, is adversely affected by socioeconomic factors such as poverty and ignorance. To evaluate our experience in this context, we identified all patients who underwent surgery for acquired or congenital valvular heart disease at our Nigerian center from February 2013 through January 2019. We collected data from their medical records, including patient age and sex, pathophysiologic causes and types of valvular disease, surgical treatment, and outcomes. Ninety-three patients (43 males [46.2%]; mean age, 38.9 ± 10.0 yr [range, 11–80 yr]) underwent surgical treatment of a total …

Citalopram For Treatment Of Cocaine Use Disorder: A Bayesian Drop-The-Loser Randomized Clinical Trial, Robert Suchting, Charles E Green, Constanza De Dios, Jessica Vincent, F Gerard Moeller, Scott D Lane, Joy M Schmitz

Faculty, Staff and Student Publications

BACKGROUND: Medication development research for cocaine use disorder (CUD) has been a longstanding goal in addiction research, but has not resulted in an FDA-approved treatment. Rising cocaine use rates underscore the need for efficient adaptive designs. This study compared differences between two doses of the selective serotonin reuptake inhibitor (SSRI) citalopram (versus placebo) on duration of cocaine abstinence and applied adaptive decision rules to select the 'best efficacy' dose.

METHODS: A double-blind, placebo-controlled, randomized Bayesian drop-the-loser (DTL) trial with three arms compared placebo to citalopram 20 mg and 40 mg. Adults (N = 107) with CUD attended thrice-weekly clinic visits …

Revisiting The Controversy: The Role Of Fungi In Chronic Rhinosinusitis, Matthew A Tyler, Kent Lam, Michael J Marino, William C Yao, Isaac Schmale, Martin J Citardi, Amber U Luong

Faculty, Staff and Student Publications

In the last two decades, the development of culture-independent genomic techniques has facilitated an increased appreciation of the microbiota-immunity interactions and their role in a multitude of chronic inflammatory diseases such as chronic rhinosinusitis (CRS), asthma, inflammatory bowel disease and dermatitis. While the pathologic role of bacteria in chronic inflammatory diseases is generally accepted, the understanding of the role of fungi remains controversial.

Chronic rhinosinusitis, specifically the phenotype linked to nasal polyps, represents a spectrum of chronic inflammatory diseases typically characterized by a Type 2 immune response. Studies on the microbiota within sinus cavities from healthy and diseased patients have …

Positron Emission Tomography In The Covid-19 Pandemic Era, Chentao Jin, Xiaoyun Luo, Shufang Qian, Kai Zhang, Yuanxue Gao, Rui Zhou, Peili Cen, Zhoujiao Xu, Hong Zhang, Mei Tian

Faculty, Staff and Student Publications

Coronavirus disease 2019 (COVID-19) has become a major public health problem worldwide since its outbreak in 2019. Currently, the spread of COVID-19 is far from over, and various complications have roused increasing awareness of the public, calling for novel techniques to aid at diagnosis and treatment. Based on the principle of molecular imaging, positron emission tomography (PET) is expected to offer pathophysiological alternations of COVID-19 in the molecular/cellular perspectives and facilitate the clinical management of patients. A number of PET-related cases and research have been reported on COVID-19 over the past one year. This article reviews the current studies of …

Approaches To Treat Sensorineural Hearing Loss By Hair-Cell Regeneration: The Current State Of Therapeutic Developments And Their Potential Impact On Audiological Clinical Practice, Ashley S. Hinton, Aizhen Yang-Hood, Angela D. Schrader, Christopher Loose, Kevin K. Ohlemiller, Will J. Mclean

2020-Current year OA Pubs

Sensorineural hearing loss (SNHL) is typically a permanent and often progressive condition that is commonly attributed to sensory cell loss. All vertebrates except mammals can regenerate lost sensory cells. Thus, SNHL is currently only treated with hearing aids or cochlear implants. There has been extensive research to understand how regeneration occurs in nonmammals, how hair cells form during development, and what limits regeneration in maturing mammals. These studies motivated efforts to identify therapeutic interventions to regenerate hair cells as a treatment for hearing loss, with a focus on targeting supporting cells to form new sensory hair cells. The approaches include …

Comparison Of Culture With Antibiogram To Next-Generation Sequencing Using Bacterial Isolates And Formalin-Fixed, Paraffin-Embedded Gastric Biopsies, Kristina G Hulten, Robert M Genta, Ira N Kalfus, Yi Zhou, Hongjun Zhang, David Y Graham

Faculty, Staff and Students Publications

BACKGROUND & AIMS: The decline in Helicobacter pylori cure rates emphasizes the need for readily available methods to determine antimicrobial susceptibility. Our aim was to compare targeted next-generation sequencing (NGS) and culture-based H pylori susceptibility testing using clinical isolates and paired formalin-fixed, paraffin-embedded (FFPE) gastric biopsies.

METHODS: H pylori isolates and FFPE tissues were tested for susceptibility to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifabutin using agar dilution and NGS targeted to 23S rRNA, gyrA, 16S rRNA, pbp1, rpoB and rdxA. Agreement was quantified using κ statistics.

RESULTS: Paired comparisons included 170 isolates and FFPE tissue for amoxicillin, clarithromycin, metronidazole, …

Ckb Inhibits Epithelial-Mesenchymal Transition And Prostate Cancer Progression By Sequestering And Inhibiting Akt Activation, Zheng Wang, Mohit Hulsurkar, Lijuan Zhuo, Jinbang Xu, Han Yang, Samira Naderinezhad, Lin Wang, Guoliang Zhang, Nanping Ai, Linna Li, Jeffrey T Chang, Songlin Zhang, Ladan Fazli, Chad J Creighton, Fang Bai, Michael M Ittmann, Martin E Gleave, Wenliang Li

Faculty, Staff and Students Publications

Epithelial-mesenchymal transition (EMT) contributes to tumor invasion, metastasis and drug resistance. AKT activation is key in a number of cellular processes. While many positive regulators for either EMT or AKT activation have been reported, few negative regulators are established. Through kinase cDNA screen, we identified brain-type creatine kinase (CKB or BCK) as a potent suppressor for both. As a ubiquitously expressed kinase in normal tissues, CKB is significantly downregulated in several solid cancer types. Lower CKB expression is significantly associated with worse prognosis. Phenotypically, CKB overexpression suppresses, while its silencing promotes, EMT and cell migration, xenograft tumor growth and metastasis …

Phase I Study Of Single Agent Niz985, A Recombinant Heterodimeric Il-15 Agonist, In Adult Patients With Metastatic Or Unresectable Solid Tumors, Kevin Conlon, Andrea Wang-Gillam, Et Al

2020-Current year OA Pubs

BACKGROUND: NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.

METHODS: Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, …

The Impact Of Outpatient Laboratory Alerting Mechanisms In Patients With Aki, Nicole V Tolan, Salman Ahmed, Tolumofe Terebo, Zain M Virk, Athena K Petrides, Jaime R Ransohoff, Christiana A Demetriou, Yvelynne P Kelly, Stacy E F Melanson, Mallika L Mendu

Faculty, Staff and Students Publications

BACKGROUND: AKI is an abrupt decrease in kidney function associated with significant morbidity and mortality. Electronic notifications of AKI have been utilized in patients who are hospitalized, but their efficacy in the outpatient setting is unclear.

METHODS: We evaluated the effect of two outpatient interventions: an automated comment on increasing creatinine results (intervention I; 6 months;

RESULTS: Providers were more likely to document AKI in interventions I (

CONCLUSIONS: An automated comment was associated with improved documented recognition of AKI and the additive intervention of an email alert was associated with increased discontinuation of nephrotoxins, but neither improved clinical outcomes. …

Coffee, Tea, And Mammographic Breast Density In Premenopausal Women, Adashi Margaret Odama, Valerie Otti, Shuai Xu, Olamide Adebayo, Adetunji T Toriola

2020-Current year OA Pubs

Studies have investigated the associations of coffee and tea with mammographic breast density (MBD) in premenopausal women with inconsistent results. We analyzed data from 375 premenopausal women who attended a screening mammogram at Washington University School of Medicine, St. Louis, MO in 2016, and stratified the analyses by race (non-Hispanic White (NHW) vs. Black/African American). Participants self-reported the number of servings of coffee, caffeinated tea, and decaffeinated tea they consumed. Volpara software was used to determine volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV). We used generalized linear regression models to quantify the associations of coffee and …

High Seropositivity Rate Of Neutralizing Antibodies To Astrovirus Va1 In Human Populations, Andrew B Janowski, Macee C Owen, Holly Dudley, Tomás López, Rafaela Espinosa, Memory Elvin-Lewis, Alejandro Colichon, Carlos F Arias, Peter D Burbelo, David Wang

Open Access Publications

Astroviruses are common pathogens of the human gastrointestinal tract, but they have been recently identified from cases of fatal meningoencephalitis. Astrovirus VA1 is the most frequently detected astrovirus genotype from cases of human encephalitis, but the prevalence of neutralizing antibodies to VA1 in human sera is unknown. We developed a focus reduction neutralization assay (FRNT) for VA1 and measured the seroprevalence of neutralizing antibodies from two cohorts of adult and pediatric serum samples: (i) an age-stratified cohort from St. Louis, MO, collected from 2007 to 2008 and (ii) a cohort from the Peruvian Amazonian River Basin collected in the late …

Replication Stress Response Defects Are Associated With Response To Immune Checkpoint Blockade In Nonhypermutated Cancers, Daniel J Mcgrail, Patrick G Pilié, Hui Dai, Truong Nguyen Anh Lam, Yulong Liang, Leonie Voorwerk, Marleen Kok, Xiang H-F Zhang, Jeffrey M Rosen, Amy B Heimberger, Christine B Peterson, Eric Jonasch, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Treatment with immune checkpoint blockade (ICB) has resulted in durable responses for a subset of patients with cancer, with predictive biomarkers for ICB response originally identified largely in the context of hypermutated cancers. Although recent clinical data have demonstrated clinical responses to ICB in certain patients with nonhypermutated cancers, previously established ICB response biomarkers have failed to accurately identify which of these patients may benefit from ICB. Here, we demonstrated that a replication stress response (RSR) defect gene expression signature, but not other proposed biomarkers, is associated with ICB response in 12 independent cohorts of patients with nonhypermutated cancer across …

Structural Mechanism Of Sars-Cov-2 Neutralization By Two Murine Antibodies Targeting The Rbd, John M Errico, Haiyan Zhao, Rita E Chen, Zhuoming Liu, James Brett Case, Meisheng Ma, Aaron J Schmitz, Michael J Rau, James A J Fitzpatrick, Pei-Yong Shi, Michael S Diamond, Sean P J Whelan, Ali H Ellebedy, Daved H Fremont

Open Access Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has necessitated the rapid development of antibody-based therapies and vaccines as countermeasures. Here, we use cryoelectron microscopy (cryo-EM) to characterize two protective anti-SARS-CoV-2 murine monoclonal antibodies (mAbs) in complex with the spike protein, revealing similarities between epitopes targeted by human and murine B cells. The more neutralizing mAb, 2B04, binds the receptor-binding motif (RBM) of the receptor-binding domain (RBD) and competes with angiotensin-converting enzyme 2 (ACE2). By contrast, 2H04 binds adjacent to the RBM and does not compete for ACE2 binding. Naturally occurring sequence variants of SARS-CoV-2 and corresponding neutralization escape …

A Novel Class Of Tmprss2 Inhibitors Potently Block Sars-Cov-2 And Mers-Cov Viral Entry And Protect Human Epithelial Lung Cells, Matthew Mahoney, Vishnu C Damalanka, Michael A Tartell, Anne E Mayer Bridwell, Jorine Voss, Partha Karmakar, Paul W Rothlauf, Cassandra E Thompson, Christina L Stallings, Sean P J Whelan, James W Janetka, Et Al

Open Access Publications

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC

Human Monoclonal Antibodies Against Ns1 Protein Protect Against Lethal West Nile Virus Infection, Alex W Wessel, Michael P Doyle, Taylor B Engdahl, Jessica Rodriguez, James E Crowe, Michael S Diamond

Open Access Publications

Envelope protein-targeted vaccines for flaviviruses are limited by concerns of antibody-dependent enhancement (ADE) of infections. Nonstructural protein 1 (NS1) provides an alternative vaccine target that avoids this risk since this protein is absent from the virion. Beyond its intracellular role in virus replication, extracellular forms of NS1 function in immune modulation and are recognized by host-derived antibodies. The rational design of NS1-based vaccines requires an extensive understanding of the antigenic sites on NS1, especially those targeted by protective antibodies. Here, we isolated human monoclonal antibodies (MAbs) from individuals previously naturally infected with WNV, mapped their epitopes using structure-guided mutagenesis, and …

Energy Compensation And Adiposity In Humans, Vincent Careau, Lewis G Halsey, Herman Pontzer, Philip N Ainslie, Lene F Andersen, Liam J Anderson, Lenore Arab, Issad Baddou, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Maciej S Buchowski, Nancy F Butte, Stefan G J A Camps, Graeme L Close, Jamie A Cooper, Sai Krupa Das, Richard Cooper, Lara R Dugas, Simon D Eaton, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Annelies H Goris, Michael Gurven, Catherine Hambly, Asmaa El Hamdouchi, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek M Joosen, Peter Katzmarzyk, Kitty P Kempen, Misaka Kimura, William E Kraus, Robert F Kushner, Estelle V Lambert, William R Leonard, Nader Lessan, Corby K Martin, Anine C Medin, Erwin P Meijer, James C Morehen, James P Morton, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto A Rabinovich, Susan B Racette, David A Raichlen, Eric Ravussin, John J Reilly, Rebecca M Reynolds, Susan B Roberts, Albertine J Schuit, Anders M Sjödin, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jonathan C K Wells, George Wilson, Brian M Wood, Jack Yanovski, Tsukasa Yoshida, Xueying Zhang, Alexia J Murphy-Alford, Cornelia U Loechl, Amy H Luke, Jennifer Rood, Hiroyuki Sagayama, Dale A Schoeller, William W Wong, Yosuke Yamada, John R Speakman, Iaea Dlw Database Group

Children’s Nutrition Research Center Staff Publications

Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures.

Functionality Of The Putative Surface Glycoproteins Of The Wuhan Spiny Eel Influenza Virus, Guha Asthagiri Arunkumar, Disha Bhavsar, Tiehai Li, Shirin Strohmeier, Veronika Chromikova, Fatima Amanat, Mehman Bunyatov, Patrick C Wilson, Ali H Ellebedy, Geert-Jan Boons, Viviana Simon, Robert P De Vries, Florian Krammer

Open Access Publications

A panel of influenza virus-like sequences were recently documented in fish and amphibians. Of these, the Wuhan spiny eel influenza virus (WSEIV) was found to phylogenetically cluster with influenza B viruses as a sister clade. Influenza B viruses have been documented to circulate only in humans, with certain virus isolates found in harbor seals. It is therefore interesting that a similar virus was potentially found in fish. Here we characterize the putative hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of the WSEIV. Functionally, we show that the WSEIV NA-like protein has sialidase activity comparable to B/Malaysia/2506/2004 influenza B virus NA, …

Super-Resolution Microscopy Reveals Photoreceptor-Specific Subciliary Location And Function Of Ciliopathy-Associated Protein Cep290, Valencia L Potter, Abigail R Moye, Michael A Robichaux, Theodore G Wensel

Faculty, Staff and Students Publications

Mutations in the cilium-associated protein CEP290 cause retinal degeneration as part of multiorgan ciliopathies or as retina-specific diseases. The precise location and the functional roles of CEP290 within cilia and, specifically, the connecting cilia (CC) of photoreceptors, remain unclear. We used super-resolution fluorescence microscopy and electron microscopy to localize CEP290 in the CC and in the primary cilia of cultured cells with subdiffraction resolution and to determine effects of CEP290 deficiency in 3 mutant models. Radially, CEP290 localizes in close proximity to the microtubule doublets in the region between the doublets and the ciliary membrane. Longitudinally, it is distributed throughout …

Effects Of The Tailored Activity Program (Tap) On Dementia-Related Symptoms, Health Events And Caregiver Wellbeing: A Randomized Controlled Trial, Laura N Gitlin, Katherine Marx, Catherine V. Piersol, Nancy A Hodgson, Jin Huang, David L Roth, Constantine Lyketsos

Department of Occupational Therapy Faculty Papers

BACKGROUND: People living with dementia (PLWD) and caregivers are adversely impacted by lack of meaningful activity leading to worse symptoms and impaired quality-of-life. There is a critical need to develop effective and well-tolerated treatments that mitigate clinical symptoms, engage PLWD and support caregiver wellbeing. We tested whether, compared to attention control, the Tailored Activity Program (TAP) reduced clinical symptoms and health-related events, and improved caregiver wellbeing, and if TAP activities were well-tolerated.

METHODS: We conducted a single-blind randomized controlled trial among 250 dyads recruited from Baltimore-Washington DC (2012-2016) with a dementia diagnosis and clinically significant agitation/aggression. Dyads were randomized to …

Equine Ovarian Tissue Xenografting: Impacts Of Cooling, Vitrification, And Vegf., Samara Silva Souza, Francisco Leo Nascimento Aguiar, Benner Geraldo Alves, Kele Amaral Alves, Fabiana Aparecida Santilli Brandão, Danielle Cristina Calado Brito, Ramon Da Silva Raposo, Melba Oliveira Gastal, Ana Paula Ribeiro Rodrigues, José Ricardo Figueiredo, Dárcio Ítalo Alves Teixeira, Eduardo Leite Gastal

Peer-reviewed Articles

Ovarian tissue transplantation methods using cooled and cryopreserved samples have been attractive options for fertility preservation in animal models and humans. The aim of this study was to evaluate the impact of previous exposure to cooling, cryopreservation, and VEGF on the overall efficiency of equine ovarian tissue after heterotopic xenotransplantation in mice. The end points evaluated were follicular morphology and development, follicular and stromal cell densities, angiogenesis (i.e. the density of new and mature blood vessels), collagen types I and III fiber densities, and total fibrosis. Ovaries of adult mares were harvested after ovariectomy, and ovarian fragments were xenografted in …