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Constitutive Activation Of Canonical Wnt Signaling Disrupts Choroid Plexus Epithelial Fate, Arpan Parichha, Varun Suresh, Mallika Chatterjee, Aditya Kshirsagar, Lihi Ben-Reuven, Tsviya Olender, M Mark Taketo, Velena Radosevic, Mihaela Bobic-Rasonja, Sara Trnski, Michael J Holtzman, Nataša Jovanov-Milosevic, Orly Reiner, Shubha Tole

Open Access Publications

The choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear β-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human β-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a …

Identification Of Novel Mitochondrial Pyruvate Carrier Inhibitors By Homology Modeling And Pharmacophore-Based Virtual Screening, Lamees Hegazy, Lauren Gill, Kelly Pyles, Christopher Kaiho, Sophia Kchouk, Brian Finck, Kyle Mccommis, Bahaa Elgendy

Open Access Publications

No abstract provided.

Rxra Dt448/9pp Generates A Dominant Active Variant Capable Of Inducing Maturation In Acute Myeloid Leukemia Cells, Orsola Di Martino, Margaret A. Ferris, Gayla Hadwiger, Soyi Sarkar, Anh Vu, María P. Menéndez-Gutiérrez, Mercedes Ricote, John S Welch

Open Access Publications

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of …

Safety And Efficacy Of Mass Drug Administration With A Single-Dose Triple-Drug Regimen Of Albendazole + Diethylcarbamazine + Ivermectin For Lymphatic Filariasis In Papua New Guinea: An Open-Label, Cluster-Randomised Trial, Livingstone Tavul, Kobie O'Brian, Gary J. Weil, Charles W. Goss, Et Al

Open Access Publications

BACKGROUND: Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG.

METHODOLOGY: All consenting, eligible residents of 24 villages in Bogia district, …

Coronavirus Disease 2019 (Covid-19) Research Agenda For Healthcare Epidemiology, Lona Mody, Hilary M Babcock, Jennie H Kwon, Et Al

Open Access Publications

This SHEA white paper identifies knowledge gaps and challenges in healthcare epidemiology research related to coronavirus disease 2019 (COVID-19) with a focus on core principles of healthcare epidemiology. These gaps, revealed during the worst phases of the COVID-19 pandemic, are described in 10 sections: epidemiology, outbreak investigation, surveillance, isolation precaution practices, personal protective equipment (PPE), environmental contamination and disinfection, drug and supply shortages, antimicrobial stewardship, healthcare personnel (HCP) occupational safety, and return to work policies. Each section highlights three critical healthcare epidemiology research questions with detailed description provided in supplementary materials. This research agenda calls for translational studies from laboratory-based …

Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation In A Mycobacterium Tuberculosis/Siv Coinfection Model, Riti Sharan, Allison N Bucsan, Shabaana A Khader, Et Al

Open Access Publications

Studies using the nonhuman primate model of Mycobacterium tuberculosis/simian immunodeficiency virus coinfection have revealed protective CD4+ T cell-independent immune responses that suppress latent tuberculosis infection (LTBI) reactivation. In particular, chronic immune activation rather than the mere depletion of CD4+ T cells correlates with reactivation due to SIV coinfection. Here, we administered combinatorial antiretroviral therapy (cART) 2 weeks after SIV coinfection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented reactivation of LTBI compared to cART initiated 4 weeks after SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication, …

Panobinostat Enhances Olaparib Efficacy By Modifying Expression Of Homologous Recombination Repair And Immune Transcripts In Ovarian Cancer, Andrew J Wilson, Vijayalaxmi G Gupta, Qi Liu, Fiona Yull, Marta A Crispens, Dineo Khabele

Open Access Publications

Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate mechanisms of anti-tumor effects of combined HDACi/PARPi treatment we performed transcriptome analysis in HR- proficient human ovarian cancer cells and tested drug effects in established immunocompetent mouse ovarian cancer models. Human SKOV-3 cells were treated with vehicle (Con), olaparib (Ola), panobinostat (Pano) or Pano+Ola and RNA-seq analysis performed. DESeq2 identified differentially expressed HR repair and immune transcripts. Luciferised syngeneic mouse ovarian cancer cells (ID8-luc) were treated with the HDACi panobinostat alone or combined with olaparib and effects on cell viability, apoptosis, DNA …

Liposomal Phytohemagglutinin: In Vivo T-Cell Activator As A Novel Pan-Cancer Immunotherapy, Kinan Alhallak, Jennifer Sun, Barbara Muz, Amanda Jeske, Julie O'Neal, Julie K Ritchey, Samuel Achilefu, John F Dipersio, Abdel Kareem Azab

Open Access Publications

Immunotherapy is an attractive approach for treating cancer. T-cell engagers (TCEs) are a type of immunotherapy that are highly efficacious; however, they are challenged by weak T-cell activation and short persistence. Therefore, alternative solutions to induce greater activation and persistence of T cells during TCE immunotherapy is needed. Methods to activate T cells include the use of lectins, such as phytohemagglutinin (PHA). PHA has not been used to activate T cells in vivo, for immunotherapy, due to its biological instability and toxicity. An approach to overcome the limitations of PHA while also preserving its function is needed. In this study, …

Hierarchical And Nonhierarchical Features Of The Mouse Visual Cortical Network, Rinaldo D D'Souza, Quanxin Wang, Weiqing Ji, Andrew M Meier, Henry Kennedy, Kenneth Knoblauch, Andreas Burkhalter

Open Access Publications

Neocortical computations underlying vision are performed by a distributed network of functionally specialized areas. Mouse visual cortex, a dense interareal network that exhibits hierarchical properties, comprises subnetworks interconnecting distinct processing streams. To determine the layout of the mouse visual hierarchy, we have evaluated the laminar patterns formed by interareal axonal projections originating in each of ten areas. Reciprocally connected pairs of areas exhibit feedforward/feedback relationships consistent with a hierarchical organization. Beta regression analyses, which estimate a continuous hierarchical distance measure, indicate that the network comprises multiple nonhierarchical circuits embedded in a hierarchical organization of overlapping levels. Single-unit recordings in anaesthetized …

Pevonedistat Targets Malignant Cells In Myeloproliferative Neoplasms In Vitro And In Vivo Via Nfκb Pathway Inhibition, Tim Kong, Angelo B A Laranjeira, Taylor B Collins, Elisa S De Togni, Abigail J Wong, Mary C Fulbright, Marianna Ruzinova, Hamza Celik, Grant A Challen, Daniel A C Fisher, Stephen T Oh

Open Access Publications

Targeted inhibitors of JAK2 (eg ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists and remains susceptible to disease transformation. These observations suggest that targeting alternative dysregulated signaling pathways may provide therapeutic benefit. Previous studies identified NFκB pathway hyperactivation in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) that was insensitive to JAK2 inhibition. Here, we provide evidence that NFκB pathway inhibition via pevonedistat targets malignant cells in MPN patient samples as well as in MPN and patient-derived xenograft mouse models that are nonredundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF …

Bicyclic Azetidines Target Acute And Chronic Stages Of Toxoplasma Gondii By Inhibiting Parasite Phenylalanyl T-Rna Synthetase, Joshua B Radke, Bruno Melillo, Payal Mittal, Manmohan Sharma, Amit Sharma, Yong Fu, Taher Uddin, Arthur Gonse, Eamon Comer, Stuart L Schreiber, Anil K Gupta, Arnab K Chatterjee, L David Sibley

Open Access Publications

Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world's human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a …

Enrichment Of The Exocytosis Protein Stx4 In Skeletal Muscle Remediates Peripheral Insulin Resistance And Alters Mitochondrial Dynamics Via Drp1, Karla E Merz, Jinhee Hwang, Chunxue Zhou, Rajakrishnan Veluthakal, Erika M Mccown, Angelica Hamilton, Eunjin Oh, Wenting Dai, Patrick T Fueger, Lei Jiang, Janice M Huss, Debbie C Thurmond

Open Access Publications

Mitochondrial dysfunction is implicated in skeletal muscle insulin resistance. Syntaxin 4 (STX4) levels are reduced in human diabetic skeletal muscle, and global transgenic enrichment of STX4 expression improves insulin sensitivity in mice. Here, we show that transgenic skeletal muscle-specific STX4 enrichment (skmSTX4tg) in mice reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress. Specifically, skmSTX4tg reversed insulin resistance caused by high-fat diet (HFD) without altering body weight or food consumption. Electron microscopy of wild-type mouse muscle revealed STX4 localisation at or proximal to the mitochondrial membrane. STX4 enrichment prevented HFD-induced mitochondrial fragmentation and dysfunction through …

The Immunoregulatory Landscape Of Human Tuberculosis Granulomas, Erin F. Mccaffrey, Shabaana A. Khader, Et Al

Open Access Publications

No abstract provided.

The Gut Microbiota Of Chickens In A Commercial Farm Treated With A Salmonella Phage Cocktail, Viviana Clavijo, Tatiana Morales, Martha Josefina Vives-Flores, Alejandro Reyes Muñoz

Open Access Publications

The microbiota in broiler chicken intestines affects the animals' health, metabolism, and immunity both positively and negatively. Accordingly, it has a significant impact on animal productivity. Phages, host-specific parasites of bacterial cells, are a promising antimicrobial alternative that selectively target pathogens without disturbing the microbiota. The purpose of this study is to further characterize the commensal microbial community at production scale in broiler chickens treated with a Salmonella phage treatment. We evaluated the cecal microbiota of broilers reared in a commercial farming system where a phage cocktail against Salmonella, SalmoFree was supplied to animals. To do so, two field trials …

Pegylated Arginine Deiminase Drives Arginine Turnover And Systemic Autophagy To Dictate Energy Metabolism, Yiming Zhang, Cassandra B Higgins, Brian A Van Tine, John S Bomalaski, Brian J Debosch

Open Access Publications

Obesity is a multi-systemic disorder of energy balance. Despite intense investigation, the determinants of energy homeostasis remain incompletely understood, and efficacious treatments against obesity and its complications are lacking. Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase,

Jib-04 Has Broad-Spectrum Antiviral Activity And Inhibits Sars-Cov-2 Replication And Coronavirus Pathogenesis, Juhee Son, Shimeng Huang, Qiru Zeng, Traci L Bricker, James Brett Case, Ruochen Zang, Zhuoming Liu, Tamarand L Darling, Jian Xu, Houda H Harastani, Maria Florencia Gomez Castro, Hinissan P Kohio, Gaopeng Hou, Paul W Rothlauf, Adam L Bailey, Steven L Brody, Sean P J Whelan, Michael S Diamond, Adrianus C M Boon, Siyuan Ding, Et Al

Open Access Publications

Pathogenic coronaviruses are a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified small-molecule inhibitors that potently block the replication of severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with a 50% effective concentration of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed

Spotlight On Nociceptin/Orphanin Fq Receptor In The Treatment Of Pain, Amal El Daibani, Tao Che

Open Access Publications

No abstract provided.

Reevaluation Of The Role Of Lip-1 As An Erk/Mpk-1 Dual Specificity Phosphatase In The C. Elegans Germline, Debabrata Das, Jacob Seemann, David Greenstein, Tim Schedl, Swathi Arur

Open Access Publications

The fidelity of a signaling pathway depends on its tight regulation in space and time. Extracellular signal-regulated kinase (ERK) controls wide-ranging cellular processes to promote organismal development and tissue homeostasis. ERK activation depends on a reversible dual phosphorylation on the TEY motif in its active site by ERK kinase (MEK) and dephosphorylation by DUSPs (dual specificity phosphatases). LIP-1, a DUSP6/7 homolog, was proposed to function as an ERK (MPK-1) DUSP in the

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 …

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, …

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

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.

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 …

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