Digital Commons Network^™

Mitophagy Deficiency Increases Nlrp3 To Induce Brown Fat Dysfunction In Mice, Myoung Seok Ko, Ji Young Yun, In-Jeoung Baek, Jung Eun Jang, Jung Jin Hwang, Seung Eun Lee, Seung-Ho Heo, David A Bader, Chul-Ho Lee, Jaeseok Han, Jong-Seok Moon, Jae Man Lee, Eun-Gyoung Hong, In-Kyu Lee, Seong Who Kim, Joong Yeol Park, Sean M Hartig, Un Jung Kang, David D Moore, Eun Hee Koh, Ki-Up Lee

Faculty, Staff and Students Publications

Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 …

Pathological Mechanisms Of Vacuolar Aggregate Myopathy Arising From A Casq1 Mutation, Amy D Hanna, Chang Seok Lee, Lyle Babcock, Hui Wang, Joseph Recio, Susan L Hamilton

Faculty, Staff and Students Publications

Mice with a mutation (D244G, DG) in calsequestrin 1 (CASQ1), analogous to a human mutation in CASQ1 associated with a delayed onset human myopathy (vacuolar aggregate myopathy), display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age. The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER). Decreased junctional CASQ1 reduces SR Ca

Restructuring The Gut Microbiota By Intermittent Fasting Lowers Blood Pressure, Huanan Shi, Bojun Zhang, Taylor Abo-Hamzy, James W Nelson, Chandra Shekar R Ambati, Joseph F Petrosino, Robert M Bryan, David J Durgan

Faculty, Staff and Students Publications

Rationale:

In recent years, it has been demonstrated that a pathological change in the gut microbiota, termed gut dysbiosis, can be an underlying factor for the development of hypertension. Prevention of this dysbiosis can attenuate or abolish hypertension. Translational mechanisms to prevent gut dysbiosis as well as understanding of the mechanisms linking gut dysbiosis to hypertension are lacking.

Objective:

We first examined the efficacy of intermittent fasting (IF) in altering the gut microbiota and lowering blood pressure (BP). Next, we utilized a multi-omics approach to examine microbial influenced metabolites that may serve as the link between the gut microbiota and …

Proteomic Investigation Of Glyceraldehyde-Derived Intracellular Ages And Their Potential Influence On Pancreatic Ductal Cells, Lakmini Senavirathna, Cheng Ma, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, …

Tocilizumab In Hospitalized Patients With Severe Covid-19 Pneumonia, Ivan O Rosas, Norbert Bräu, Michael Waters, Ronaldo C Go, Bradley D Hunter, Sanjay Bhagani, Daniel Skiest, Mariam S Aziz, Nichola Cooper, Ivor S Douglas, Sinisa Savic, Taryn Youngstein, Lorenzo Del Sorbo, Antonio Cubillo Gracian, David J De La Zerda, Andrew Ustianowski, Min Bao, Sophie Dimonaco, Emily Graham, Balpreet Matharu, Helen Spotswood, Larry Tsai, Atul Malhotra

Faculty, Staff and Students Publications

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.

METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants …

Dexmedetomidine Or Propofol For Sedation In Mechanically Ventilated Adults With Sepsis, Christopher G Hughes, Patrick T Mailloux, John W Devlin, Joshua T Swan, Robert D Sanders, Antonio Anzueto, James C Jackson, Aimee S Hoskins, Brenda T Pun, Onur M Orun, Rameela Raman, Joanna L Stollings, Amy L Kiehl, Matthew S Duprey, Lan N Bui, Hollis R O'Neal, Allison Snyder, Michael A Gropper, Kalpalatha K Guntupalli, Gregg J Stashenko, Mayur B Patel, Nathan E Brummel, Timothy D Girard, Robert S Dittus, Gordon R Bernard, E Wesley Ely, Pratik P Pandharipande, Mends2 Study Investigators

Faculty, Staff and Students Publications

BACKGROUND: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.

METHODS: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale …

Proteogenomic And Metabolomic Characterization Of Human Glioblastoma, Liang-Bo Wang, Alla Karpova, Marina A Gritsenko, Jennifer E Kyle, Song Cao, Yize Li, Dmitry Rykunov, Antonio Colaprico, Joseph H Rothstein, Runyu Hong, Vasileios Stathias, Macintosh Cornwell, Francesca Petralia, Yige Wu, Boris Reva, Karsten Krug, Pietro Pugliese, Emily Kawaler, Lindsey K Olsen, Wen-Wei Liang, Xiaoyu Song, Yongchao Dou, Michael C Wendl, Wagma Caravan, Wenke Liu, Daniel Cui Zhou, Jiayi Ji, Chia-Feng Tsai, Vladislav A Petyuk, Jamie Moon, Weiping Ma, Rosalie K Chu, Karl K Weitz, Ronald J Moore, Matthew E Monroe, Rui Zhao, Xiaolu Yang, Seungyeul Yoo, Azra Krek, Alexis Demopoulos, Houxiang Zhu, Matthew A Wyczalkowski, Joshua F Mcmichael, Brittany L Henderson, Caleb M Lindgren, Hannah Boekweg, Shuangjia Lu, Jessika Baral, Lijun Yao, Kelly G Stratton, Lisa M Bramer, Erika Zink, Sneha P Couvillion, Kent J Bloodsworth, Shankha Satpathy, Weiva Sieh, Simina M Boca, Stephan Schürer, Feng Chen, Maciej Wiznerowicz, Karen A Ketchum, Emily S Boja, Christopher R Kinsinger, Ana I Robles, Tara Hiltke, Mathangi Thiagarajan, Alexey I Nesvizhskii, Bing Zhang, D R Mani, Michele Ceccarelli, Xi S Chen, Sandra L Cottingham, Qing Kay Li, Albert H Kim, David Fenyö, Kelly V Ruggles, Henry Rodriguez, Mehdi Mesri, Samuel H Payne, Adam C Resnick, Pei Wang, Richard D Smith, Antonio Iavarone, Milan G Chheda, Jill S Barnholtz-Sloan, Karin D Rodland, Tao Liu, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM …

Functional Interpretation Of Atad3a Variants In Neuro-Mitochondrial Phenotypes, Zheng Yie Yap, Yo Han Park, Saskia B Wortmann, Adam C Gunning, Shlomit Ezer, Sukyeong Lee, Lita Duraine, Ekkehard Wilichowski, Kate Wilson, Johannes A Mayr, Matias Wagner, Hong Li, Usha Kini, Emily Davis Black, Kristin G Monaghan, James R Lupski, Sian Ellard, Dominik S Westphal, Tamar Harel, Wan Hee Yoon

Faculty, Staff and Students Publications

BACKGROUND: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.

METHODS: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 …

Obstructive Sleep Apnea And Dementia-Common Gene Associations Through Network-Based Identification Of Common Driver Genes, Hyun-Hwan Jeong, Arvind Chandrakantan, Adam C Adler

Faculty, Staff and Students Publications

BACKGROUND: Obstructive Sleep Apnea (OSA) occurs in 7% of the adult population. The relationship between neurodegenerative diseases such as dementia and sleep disorders have long attracted clinical attention; however, no comprehensive data exists elucidating common gene expression between the two diseases. The objective of this study was to (1) demonstrate the practicability and feasibility of utilizing a systems biology approach called network-based identification of common driver genes (NICD) to identify common genomic features between two associated diseases and (2) utilize this approach to identify genes associated with both OSA and dementia.

METHODS: This study utilized 2 public databases (PCNet, DisGeNET) …

Zno Nucleation Into Trititanate Nanotubes By Ald Equipment Techniques, A New Way To Functionalize Layered Metal Oxides, Mabel Moreno, Miryam Arredondo, Quentin M Ramasse, Matthew Mclaren, Philine Stötzner, Stefan Förster, Eglantina Benavente, Caterina Salgado, Sindy Devis, Paula Solar, Luis Velasquez, Guillermo González

Faculty, Staff and Students Publications

In this contribution, we explore the potential of atomic layer deposition (ALD) techniques for developing new semiconductor metal oxide composites. Specifically, we investigate the functionalization of multi-wall trititanate nanotubes, H2Ti3O7 NTs (sample T1) with zinc oxide employing two different ALD approaches: vapor phase metalation (VPM) using diethylzinc (Zn(C2H5)2, DEZ) as a unique ALD precursor, and multiple pulsed vapor phase infiltration (MPI) using DEZ and water as precursors. We obtained two different types of tubular H2Ti3O7 species containing ZnO in their structures. Multi-wall trititanate nanotubes with ZnO intercalated inside the tube wall sheets were the main products from the VPM infiltration …

Structure, Function And Inhibition Of Critical Protein-Protein Interactions Involving Mixed Lineage Leukemia 1 And Its Fusion Oncoproteins, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5-10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains …

Single-Cell Transcriptomics Identifies Limbal Stem Cell Population And Cell Types Mapping Its Differentiation Trajectory In Limbal Basal Epithelium Of Human Cornea, De-Quan Li, Sangbae Kim, Jin-Miao Li, Qianmiao Gao, Jongsu Choi, Fang Bian, Jiaoyue Hu, Yun Zhang, Jin Li, Rong Lu, Yumei Li, Stephen C Pflugfelder, Hongyu Miao, Rui Chen

Faculty, Staff and Students Publications

PURPOSE: This study aimed to uncover novel cell types in heterogenous basal limbus of human cornea for identifying LSC at single cell resolution.

METHODS: Single cells of human limbal basal epithelium were isolated from young donor corneas. Single-cell RNA-Sequencing was performed using 10x Genomics platform, followed by clustering cell types through the graph-based visualization method UMAP and unbiased computational informatic analysis. Tissue RNA in situ hybridization with RNAscope, immunofluorescent staining and multiple functional assays were performed using human corneas and limbal epithelial culture models.

RESULTS: Single-cell transcriptomics of 16,360 limbal basal cells revealed 12 cell clusters belonging to three lineages. …

Mitochondrial Transfer From Mesenchymal Stem Cells Improves Neuronal Metabolism After Oxidant Injury In Vitro: The Role Of Miro1, Nancy Tseng, Scott C Lambie, Christopher Q Huynh, Bridget Sanford, Manisha Patel, Paco S Herson, D Ryan Ormond

Faculty, Staff and Students Publications

Stroke-induced cerebral ischemia is a major cause of death and disability. The disruption of blood flow results in neuronal and glial cell death leading to brain injury. Reperfusion restores oxygen to the affected tissue, but can also cause damage through an enhanced oxidative stress and inflammatory response. This study examines mitochondrial transfer from MSC to neurons and the role it plays in neuronal preservation after oxidant injury. We observed the transfer of mitochondria from MSC to mouse neurons in vitro following hydrogen peroxide exposure. The observed transfer was dependent on cell-to-cell contact and led to increased neuronal survival and improved …

A Millifluidic Perfusion Cassette For Studying The Pathogenesis Of Enteric Infections Using Ex-Vivo Organoids, Reid L Wilson, Sarah A Hewes, Anubama Rajan, Shih-Ching Lin, Carolyn Bomidi, Takanori Iida, Mary K Estes, Anthony W Maresso, K Jane Grande-Allen

Faculty, Staff and Students Publications

To generate physiologically-relevant experimental models, the study of enteric diarrheal diseases is turning increasingly to advanced in vitro models that combine ex vivo, stem cell-derived "organoid" cell lines with bioengineered culture environments that expose them to mechanical stimuli, such as fluid flow. However, such approaches require considerable technical expertise with both microfabrication and organoid culture, and are, therefore, inaccessible to many researchers. For this reason, we have developed a perfusion system that is simple to fabricate, operate, and maintain. Its dimensions approximate the volume and cell culture area of traditional 96-well plates and allow the incorporation of fastidious primary, stem …

The Impact Of Covid-19 On Kidney Transplantation And The Kidney Transplant Recipient – One Year Into The Pandemic, Pascale Khairallah, Nidhi Aggarwal, Ahmed A Awan, Chandan Vangala, Medha Airy, Jenny S Pan, Bhamidipati V R Murthy, Wolfgang C Winkelmayer, Venkat Ramanathan

Faculty, Staff and Students Publications

The COVID‐19 pandemic has significantly changed the landscape of kidney transplantation in the United States and worldwide. In addition to adversely impacting allograft and patient survival in postkidney transplant recipients, the current pandemic has affected all aspects of transplant care, including transplant referrals and listing, organ donation rates, organ procurement and shipping, and waitlist mortality. Critical decisions were made during this period by transplant centers and individual transplant physicians taking into consideration patient safety and resource utilization. As countries have begun administering the COVID vaccines, new and important considerations pertinent to our transplant population have arisen. This comprehensive review focuses …

Rev-Erb In Gabaergic Neurons Controls Diurnal Hepatic Insulin Sensitivity, Guolian Ding, Xin Li, Xinguo Hou, Wenjun Zhou, Yingyun Gong, Fuqiang Liu, Yanlin He, Jia Song, Jing Wang, Paul Basil, Wenbo Li, Sichong Qian, Pradip Saha, Jinbang Wang, Chen Cui, Tingting Yang, Kexin Zou, Younghun Han, Christopher I Amos, Yong Xu, Li Chen, Zheng Sun

Faculty, Staff and Students Publications

Systemic insulin sensitivity shows diurnal rhythm with a peak at wakening1,2. The molecular mechanism underlying such a temporal pattern is unclear. Here we demonstrate that nuclear receptors Rev-erbα/β in the GABAergic neurons in the suprachiasmatic nucleus (SCNGABA) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviors under the regular light-dark cycles. Rev-erb regulates the rhythmic expression of genes involved in neurotransmission in the SCN and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at wakening causes glucose intolerance, while restoration …

Serial Block-Face Scanning Electron Microscopy (Sbf-Sem) Of Biological Tissue Samples, Justin A Courson, Paul T Landry, Thao Do, Eric Spehlmann, Pascal J Lafontant, Nimesh Patel, Rolando E Rumbaut, Alan R Burns

Faculty, Staff and Students Publications

Serial block-face scanning electron microscopy (SBF-SEM) allows for the collection of hundreds to thousands of serially-registered ultrastructural images, offering an unprecedented three-dimensional view of tissue microanatomy. While SBF-SEM has seen an exponential increase in use in recent years, technical aspects such as proper tissue preparation and imaging parameters are paramount for the success of this imaging modality. This imaging system benefits from the automated nature of the device, allowing one to leave the microscope unattended during the imaging process, with the automated collection of hundreds of images possible in a single day. However, without appropriate tissue preparation cellular ultrastructure can …

Loss Of Bone Morphogenetic Protein-Binding Endothelial Regulator Causes Insulin Resistance, Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K Saha, Huaizhu Wu, Christie M Ballantyne, Sean M Hartig, Liang Xie, Xinchun Pi

Faculty, Staff and Students Publications

Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)–binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that …

A Principal Components Analysis Of Factors Associated With Successful Implementation Of An Lvad Decision Support Tool, Kristin M Kostick, Meredith Trejo, Arvind Bhimaraj, Andrew Civitello, Jonathan Grinstein, Douglas Horstmanshof, Ulrich P Jorde, Matthias Loebe, Mandeep R Mehra, Nasir Z Sulemanjee, Vinay Thohan, Barry H Trachtenberg, Nir Uriel, Robert J Volk, Jerry D Estep, J S Blumenthal-Barby

Faculty, Staff and Students Publications

BACKGROUND: A central goal among researchers and policy makers seeking to implement clinical interventions is to identify key facilitators and barriers that contribute to implementation success. Despite calls from a number of scholars, empirical insights into the complex structural and cultural predictors of why decision aids (DAs) become routinely embedded in health care settings remains limited and highly variable across implementation contexts.

METHODS: We examined associations between "reach", a widely used indicator (from the RE-AIM model) of implementation success, and multi-level site characteristics of nine LVAD clinics engaged over 18 months in implementation and dissemination of a decision aid for …

Single-Cell Rna-Seq Analysis Reveals Compartment-Specific Heterogeneity And Plasticity Of Microglia, Junying Zheng, Wenjuan Ru, Jay R Adolacion, Michael S Spurgat, Xin Liu, Subo Yuan, Rommel X Liang, Jianli Dong, Andrew S Potter, S Steven Potter, Ken Chen, Rui Chen, Navin Varadarajan, Shao-Jun Tang

Faculty, Staff and Students Publications

Microglia are ubiquitous central nervous system (CNS)-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single-cell RNA-seq to compare microglial subtypes in the cortex and the spinal cord. A multi-way comparative analysis was carried out on samples from C57/BL and HIV gp120 transgenic mice at two, four, and eight months of age. The results revealed overlapping but distinct microglial populations in the cortex and the spinal cord. The differential heterogeneity of microglia in these CNS regions was further suggested by their disparity of plasticity in …

Prior Sleep Problems And Adverse Post-Traumatic Neuropsychiatric Sequelae Of Motor Vehicle Collision In The Aurora Study, Thomas C Neylan, Ronald C Kessler, Kerry J Ressler, Gari Clifford, Francesca L Beaudoin, Xinming An, Jennifer S Stevens, Donglin Zeng, Sarah D Linnstaedt, Laura T Germine, Sophia Sheikh, Alan B Storrow, Brittany E Punches, Kamran Mohiuddin, Nina T Gentile, Meghan E Mcgrath, Sanne J H Van Rooij, John P Haran, David A Peak, Robert M Domeier, Claire Pearson, Leon D Sanchez, Niels K Rathlev, William F Peacock, Steven E Bruce, Jutta Joormann, Deanna M Barch, Diego A Pizzagalli, John F Sheridan, Steven E Harte, James M Elliott, Irving Hwang, Maria V Petukhova, Nancy A Sampson, Karestan C Koenen, Samuel A Mclean

Faculty, Staff and Students Publications

STUDY OBJECTIVES: Many patients in Emergency Departments (EDs) after motor vehicle collisions (MVCs) develop post-traumatic stress disorder (PTSD) or major depressive episode (MDE). This report from the AURORA study focuses on associations of pre-MVC sleep problems with these outcomes 8 weeks after MVC mediated through peritraumatic distress and dissociation and 2-week outcomes.

METHODS: A total of 666 AURORA patients completed self-report assessments in the ED and at 2 and 8 weeks after MVC. Peritraumatic distress, peritraumatic dissociation, and pre-MVC sleep characteristics (insomnia, nightmares, daytime sleepiness, and sleep duration in the 30 days before the MVC, trait sleep stress reactivity) were …

Synthesis, Structure-Activity Relationships, And Antiviral Activity Of Allosteric Inhibitors Of Flavivirus Ns2b-Ns3 Protease, Shenyou Nie, Yuan Yao, Fangrui Wu, Xiaowei Wu, Jidong Zhao, Yuanda Hua, Jingyu Wu, Tong Huo, Yi-Lun Lin, Alexander R Kneubehl, Megan B Vogt, Josephine Ferreon, Rebecca Rico-Hesse, Yongcheng Song

Faculty, Staff and Students Publications

Flaviviruses, including Zika, dengue and West Nile virus, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screen followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile virus and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus …

Association Of Blood Pressure Variability And Diuretics With Cardiovascular Events In Patients With Chronic Kidney Disease Stages 1-5, L Parker Gregg, S Susan Hedayati, Hui Yang, Peter N Van Buren, Subhash Banerjee, Sankar D Navaneethan, Salim S Virani, Wolfgang C Winkelmayer, Carlos A Alvarez

Faculty, Staff and Students Publications

Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events in the general population. Data are scarce in chronic kidney disease (CKD). We hypothesized that BPV would be associated with cardiovascular outcomes, death, and end-stage kidney disease (ESKD) and that diuretics would modify these associations in patients with CKD.

We studied U.S. Veterans with non-dialysis CKD stages 1-5 and hypertension on non-diuretic antihypertensive monotherapy. At the time of second antihypertensive agent prescription, we propensity-matched for exposure to a loop or thiazide diuretic vs. any other antihypertensive. BPV was defined as the coefficient of variation of systolic blood pressure over …

Glucagon Blockade Restores Functional Β-Cell Mass In Type 1 Diabetic Mice And Enhances Function Of Human Islets, May-Yun Wang, E Danielle Dean, Ezekiel Quittner-Strom, Yi Zhu, Kamrul H Chowdhury, Zhuzhen Zhang, Shangang Zhao, Na Li, Reshing Ye, Young Lee, Yiyi Zhang, Shiuhwei Chen, Xinxin Yu, Derek C Leonard, Greg Poffenberger, Alison Von Deylen, S Kay Mccorkle, Amnon Schlegel, Kyle W Sloop, Alexander M Efanov, Ruth E Gimeno, Philipp E Scherer, Alvin C Powers, Roger H Unger, William L Holland

Faculty, Staff and Students Publications

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8–induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially …

Discovery And Characterization Of Bromodomain 2-Specific Inhibitors Of Brdt, Zhifeng Yu, Angela F Ku, Justin L Anglin, Rajesh Sharma, Melek Nihan Ucisik, John C Faver, Feng Li, Pranavanand Nyshadham, Nicholas Simmons, Kiran L Sharma, Sureshbabu Nagarajan, Kevin Riehle, Gundeep Kaur, Banumathi Sankaran, Marta Storl-Desmond, Stephen S Palmer, Damian W Young, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined …

Tbx5-Encoded T-Box Transcription Factor 5 Variant T223m Is Associated With Long Qt Syndrome And Pediatric Sudden Cardiac Death, Alexandra M Markunas, Perathu K R Manivannan, Jordan E Ezekian, Agnim Agarwal, William Eisner, Katherina Alsina, Hugh D Allen, Gregory A Wray, Jeffrey J Kim, Xander H T Wehrens, Andrew P Landstrom

Faculty, Staff and Students Publications

Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype-negative. Whole-exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype-negative LQTS and sudden death. The TBX5-T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen-2, Provean, …

Racial And Geographic Disparities In Influenza Vaccination In The Us Among Individuals With Atherosclerotic Cardiovascular Disease: Renewed Importance In The Setting Of Covid-19, Mahmoud Al Rifai, Umair Khalid, Arunima Misra, Jing Liu, Khurram Nasir, Miguel Cainzos-Achirica, Dhruv Mahtta, Christie M Ballantyne, Laura A Petersen, Salim S Virani

Faculty, Staff and Students Publications

INTRODUCTION: The importance of receiving an annual influenza vaccine among patients with atherosclerotic cardiovascular disease (ASCVD) is well established. With the rapid community spread and the possibility of another wave of COVID-19 infections in the fall, receiving an influenza vaccine is of particular importance to mitigate the risk associated with overlapping influenza and COVID-19 infections.

METHODS: We utilized cross-sectional data from the 2016 to 2019 Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative U.S. telephone-based survey of adults 18 years or older. Race/ethnicity was our exposure of interest. We assessed the relative difference in influenza vaccination by race/ethnicity for …

Testosterone Therapy And Bone Quality In Men With Diabetes And Hypogonadism: Study Design And Protocol, Vittoria Russo, Georgia Colleluori, Rui Chen, Sanjay Mediwala, Clifford Qualls, Michael Liebschner, Dennis T Villareal, Reina Armamento-Villareal

Faculty, Staff and Students Publications

CONTEXT: Type 2 diabetes mellitus (T2D) is often accompanied by male hypogonadism and both conditions are associated with increased risk for fractures. Testosterone (T) has been shown to improve the bone health of hypogonadal men but has not been tested in patients who also have T2D in addition to low T. To date, there is no treatment that is specifically recommended for bone disease among patients with T2D. This study will evaluate the effect of T therapy on the bone health of male veterans with low T who also have T2D.

METHODS: This is a randomized double-blind placebo-controlled trial of …

Mental Health Disorders Among Patients With Acute Myocardial Infarction In The United States, Jayakumar Sreenivasan, Muhammad Shahzeb Khan, Safi U Khan, Urvashi Hooda, Wilbert S Aronow, Julio A Panza, Glenn N Levine, Yvonne Commodore-Mensah, Roger S Blumenthal, Erin D Michos

Faculty, Staff and Students Publications

OBJECTIVE: To assess the prevalence, temporal trends and sex- and racial/ethnic differences in the burden of mental health disorders (MHD) and outcomes among patients with myocardial infarction (MI) in the United States.

METHODS: Using the National Inpatient Sample Database, we evaluated a contemporary cohort of patients hospitalized for acute MI in the United States over 10 years period from 2008 to 2017. We used multivariable logistic regression analysis for in-hospital outcomes, yearly trends and estimated annual percent change (APC) in odds of MHD among MI patients.

RESULTS: We included a total sample of 6,117,804 hospitalizations for MI (ST elevation MI …

Ceramide Synthase Tlcd3b Is A Novel Gene Associated With Human Recessive Retinal Dystrophy, Renae Elaine Bertrand, Jun Wang, Kaitlyn H Xiong, Chinthana Thangavel, Xinye Qian, Rola Ba-Abbad, Qingnan Liang, Renata T Simões, Shirley A M Sampaio, Keren J Carss, F Lucy Raymond, Anthony G Robson, Andrew R Webster, Gavin Arno, Fernanda Belga Ottoni Porto, Rui Chen

Faculty, Staff and Students Publications

PURPOSE: Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration.

METHODS: Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses.

RESULTS: Here we have identified four patients with …