Digital Commons Network^™

Cd36 Maintains The Gastric Mucosa And Associates With Gastric Disease, Miriam Jacome-Sosa, Zhi-Feng Miao, Vivek S Peche, Edward F Morris, Ramkumar Narendran, Kathryn M Pietka, Dmitri Samovski, Hei-Yong G Lo, Terri Pietka, Latisha Love-Gregory, Nada A Abumrad, Et Al

Open Access Publications

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36

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 …

U2af1 Is A Haplo-Essential Gene Required For Hematopoietic Cancer Cell Survival In Mice, Brian A Wadugu, Sridhar Nonavinkere Srivatsan, Amanda Heard, Michael O Alberti, Matthew Ndonwi, Jie Liu, Sarah Grieb, Joseph Bradley, Jin Shao, Tanzir Ahmed, Cara L Shirai, Ajay Khanna, Christopher A Miller, Matthew J Walter, Et Al

Open Access Publications

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant-expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of …

Biofilm Formation And Virulence Of Shigella Flexneri Are Modulated By Ph Of Gastrointestinal Tract, I-Ling Chiang, Yi Wang, Satoru Fujii, Brian D Muegge, Qiuhe Lu, Phillip I Tarr, Thaddeus S Stappenbeck

Open Access Publications

No abstract provided.

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, …

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 …

Oncogenic Kras-Induced Feedback Inflammatory Signaling In Pancreatic Cancer: An Overview And New Therapeutic Opportunities, Sapana Bansod, Paarth B Dodhiawala, Kian-Huat Lim

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the

Motor Improvements Enabled By Spinal Cord Stimulation Combined With Physical Training After Spinal Cord Injury: Review Of Experimental Evidence In Animals And Humans, Ismael Seáñez, Marco Capogrosso

Open Access Publications

Electrical spinal cord stimulation (SCS) has been gaining momentum as a potential therapy for motor paralysis in consequence of spinal cord injury (SCI). Specifically, recent studies combining SCS with activity-based training have reported unprecedented improvements in motor function in people with chronic SCI that persist even without stimulation. In this work, we first provide an overview of the critical scientific advancements that have led to the current uses of SCS in neurorehabilitation: e.g. the understanding that SCS activates dormant spinal circuits below the lesion by recruiting large-to-medium diameter sensory afferents within the posterior roots. We discuss how this led to …

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 …

Biotechnological Applications Of Polymeric Nanofiber Platforms Loaded With Diverse Bioactive Materials, M R El-Aassar, Omar M Ibrahim, Ziad H Al-Oanzi

2020-Current year OA Pubs

This review article highlights the critical research and formative works relating to nanofiber composites loaded with bioactive materials for diverse applications, and discusses the recent research on the use of electrospun nanofiber incorporating bioactive compounds such as essential oils, herbal bioactive components, plant extracts, and metallic nanoparticles. Inevitably, with the common advantages of bioactive components and polymer nanofibers, electrospun nanofibers containing bioactive components have attracted intense interests for their applications in biomedicine and cancer treatment. Many studies have only concentrated on the production and performance of electrospun nanofiber loaded with bioactive components; in this regard, the features of different types …

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 …

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

Comparative Genomics Of Mycobacterium Avium Complex Reveals Signatures Of Environment-Specific Adaptation And Community Acquisition, Eric C Keen, Joohee Choi, Meghan A Wallace, Michelle Azar, Carlos R Mejia-Chew, Shail B Mehta, Thomas C Bailey, Lindsay J Caverly, Carey-Ann D Burnham, Gautam Dantas

Open Access Publications

Nontuberculous mycobacteria, including those in the Mycobacterium avium complex (MAC), constitute an increasingly urgent threat to global public health. Ubiquitous in soil and water worldwide, MAC members cause a diverse array of infections in humans and animals that are often multidrug resistant, intractable, and deadly. MAC lung disease is of particular concern and is now more prevalent than tuberculosis in many countries, including the United States. Although the clinical importance of these microorganisms continues to expand, our understanding of their genomic diversity is limited, hampering basic and translational studies alike. Here, we leveraged a unique collection of genomes to characterize …

Neutralizing Monoclonal Antibodies That Target The Spike Receptor Binding Domain Confer Fc Receptor-Independent Protection Against Sars-Cov-2 Infection In Syrian Hamsters, Wen Su, Sin Fun Sia, Aaron J Schmitz, Traci L Bricker, Tyler N Starr, Allison J Greaney, Jackson S Turner, Bassem M Mohammed, Zhuoming Liu, Ka Tim Choy, Tamarand L Darling, Astha Joshi, Ka Man Cheng, Alvina Y L Wong, Houda H Harastani, John M Nicholls, Sean P J Whelan, Jesse D Bloom, Hui-Ling Yen, Ali H Ellebedy, Adrianus C M Boon

Open Access Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action

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 …

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, …

Adaptable P Body Physical States Differentially Regulate Bicoid Mrna Storage During Early Drosophila Development, M Sankaranarayanan, Ryan J Emenecker, Elise L Wilby, Marcus Jahnel, Irmela R E A Trussina, Matt Wayland, Simon Alberti, Alex S Holehouse, Timothy T Weil

2020-Current year OA Pubs

Ribonucleoprotein condensates can exhibit diverse physical states in vitro and in vivo. Despite considerable progress, the relevance of condensate physical states for in vivo biological function remains limited. Here, we investigated the physical properties of processing bodies (P bodies) and their impact on mRNA storage in mature Drosophila oocytes. We show that the conserved DEAD-box RNA helicase Me31B forms viscous P body condensates, which adopt an arrested physical state. We demonstrate that structurally distinct proteins and protein-protein interactions, together with RNA, regulate the physical properties of P bodies. Using live imaging and in situ hybridization, we show that the arrested …

Non-Invasive Monitoring Of Arthritis Treatment Response Via Targeting Of Tyrosine-Phosphorylated Annexin A2 In Chondrocytes, Shaw-Wei D Tsen, Luke E Springer, Krishna Sharmah Gautam, Rui Tang, Kexian Liang, Gail Sudlow, Amir Kucharski, Christine T N Pham, Samuel Achilefu

2020-Current year OA Pubs

BACKGROUND: The development and optimization of therapies for rheumatoid arthritis (RA) is currently hindered by a lack of methods for early non-invasive monitoring of treatment response. Annexin A2, an inflammation-associated protein whose presence and phosphorylation levels are upregulated in RA, represents a potential molecular target for tracking RA treatment response.

METHODS: LS301, a near-infrared dye-peptide conjugate that selectively targets tyrosine 23-phosphorylated annexin A2 (pANXA2), was evaluated for its utility in monitoring disease progression, remission, and early response to drug treatment in mouse models of RA by fluorescence imaging. The intraarticular distribution and localization of LS301 relative to pANXA2 was determined …

Comparison Of 2-Year Outcomes With Car T Cells (Zuma-1) Vs Salvage Chemotherapy In Refractory Large B-Cell Lymphoma, Sattva S. Neelapu, Nancy L. Bartlett, Et Al

Open Access Publications

No abstract provided.

Brief Electrical Stimulation Accelerates Axon Regeneration And Promotes Recovery Following Nerve Transection And Repair In Mice, Junichi Sayanagi, Jesús A Acevedo-Cintrón, Deng Pan, Lauren Schellhardt, Daniel A Hunter, Alison K Snyder-Warwick, Susan E Mackinnon, Matthew D Wood

Open Access Publications

BACKGROUND: Clinical outcomes following nerve injury repair can be inadequate. Pulsed-current electrical stimulation (ES) is a therapeutic method that facilitates functional recovery by accelerating axon regeneration. However, current clinical ES protocols involve the application of ES for 60 minutes during surgery, which can increase operative complexity and time. Shorter ES protocols could be a strategy to facilitate broader clinical adoption. The purpose of the present study was to determine if a 10-minute ES protocol could improve outcomes.

METHODS: C57BL/6J mice were randomized to 3 groups: no ES, 10 minutes of ES, and 60 minutes of ES. In all groups, the …

Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia In Subarachnoid Hemorrhage In Response To Hypoxic Postconditioning, Deepti Diwan, Ananth K Vellimana, Diane J Aum, Julian Clarke, James W Nelson, Molly Lawrence, Byung Hee Han, Jeffrey M Gidday, Gregory J Zipfel

Open Access Publications

Background Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. Methods and Results In this study, we found that hypoxic postconditioning (8% O

Neurotoxins Subvert The Allosteric Activation Mechanism Of Sarm1 To Induce Neuronal Loss, Tong Wu, Jian Zhu, Amy Strickland, Kwang Woo Ko, Yo Sasaki, Caitlin B Dingwall, Yurie Yamada, Matthew D Figley, Xianrong Mao, Alicia Neiner, A Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

Open Access Publications

SARM1 is an inducible TIR-domain NAD

Nrf2 Promotes Urothelial Cell Response To Bacterial Infection By Regulating Reactive Oxygen Species And Rab27b Expression, Chetanchandra S Joshi, Amy Mora, Paul A Felder, Indira U Mysorekar

Open Access Publications

Uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs) by invading urothelial cells. In response, the host mounts an inflammatory response to expel bacteria. Here, we show that the NF-E2-related factor 2 (NRF2) pathway is activated in response to UPEC-triggered reactive oxygen species (ROS) production. We demonstrate the molecular sequence of events wherein NRF2 activation in urothelial cells reduces ROS production, inflammation, and cell death, promotes UPEC expulsion, and reduces the bacterial load. In contrast, loss of NRF2 leads to increased ROS production, bacterial burden, and inflammation, both in vitro and in vivo. NRF2 promotes UPEC expulsion by regulating transcription …

Trem2 Modulates Differential Deposition Of Modified And Non-Modified Aβ Species In Extracellular Plaques And Intraneuronal Deposits, Pranav Joshi, Florian Riffel, Sathish Kumar, Nàdia Villacampa, Sandra Theil, Samira Parhizkar, Christian Haass, Marco Colonna, Michael T Heneka, Thomas Arzberger, Jochen Herms, Jochen Walter

2020-Current year OA Pubs

Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer's disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we …

Alternative Pre-Mrna Splicing Of The Mu Opioid Receptor Gene, Oprm1: Insight Into Complex Mu Opioid Actions, Shan Liu, Wen-Jia Kang, Anna Abrimian, Jin Xu, Luca Cartegni, Susruta Majumdar, Patrick Hesketh, Alex Bekker, Ying-Xian Pan

Open Access Publications

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene,

Aducanumab For Alzheimer Disease: The Amyloid Hypothesis Moves From Bench To Bedside, Erik S. Musiek, Teresa Gomez-Isla, David M Holtzman

Open Access Publications

No abstract provided.

Untargeted Metabolomic Analysis Of Human Milk From Mothers Of Preterm Infants, Lila S Nolan, Angela N Lewis, Qingqing Gong, James J Sollome, Olivia N Dewitt, Robert D Williams, Misty Good

2020-Current year OA Pubs

The application of metabolomics in neonatology offers an approach to investigate the complex relationship between nutrition and infant health. Characterization of the metabolome of human milk enables an investigation into nutrients that affect the neonatal metabolism and identification of dietary interventions for infants at risk of diseases such as necrotizing enterocolitis (NEC). In this study, we aimed to identify differences in the metabolome of breast milk of 48 mothers with preterm infants with NEC and non-NEC healthy controls. A minimum significant difference was observed in the human milk metabolome between the mothers of infants with NEC and mothers of healthy …

Cullin4 E3 Ubiquitin Ligases Regulate Male Gonocyte Migration, Proliferation And Blood-Testis Barrier Homeostasis, Yan Yin, Liming Zhu, Qiufang Li, Pengbo Zhou, Liang Ma

Open Access Publications

Ubiquitination, an essential posttranslational modification, plays fundamental roles during mammalian spermatogenesis. We previously reported the requirement of two Cullin 4 ubiquitin ligase family genes, Cullin 4a (