Digital Commons Network^™

Amino Acid Metabolism And Autophagy In Skeletal Development And Homeostasis, Akiko Suzuki, Junichi Iwata

Faculty, Staff and Student Publications

Bone is an active organ that is continuously remodeled throughout life via formation and resorption; therefore, a fine-tuned bone (re)modeling is crucial for bone homeostasis and is closely connected with energy metabolism. Amino acids are essential for various cellular functions as well as an energy source, and their synthesis and catabolism (e.g., metabolism of carbohydrates and fatty acids) are regulated through numerous enzymatic cascades. In addition, the intracellular levels of amino acids are maintained by autophagy, a cellular recycling system for proteins and organelles; under nutrient deprivation conditions, autophagy is strongly induced to compensate for cellular demands and to restore …

Acetyl-Coa And Metabolite Fluxes Regulate White Adipose Tissue Expansion, Jessica B Felix, Aaron R Cox, Sean M Hartig

Faculty, Staff and Students Publications

White adipose tissue (WAT) depends on coordinated regulation of transcriptional and metabolic pathways to respond to whole-body energy demands. We highlight metabolites that contribute to biosynthetic reactions for WAT expansion. Recent studies have precisely defined how byproducts of carbohydrate and lipid metabolism affect physiological and endocrine functions in adipocytes. We emphasize the critical emerging roles of short-chain fatty acids (SCFAs) and tricarboxylic acid (TCA) cycle metabolites that connect lipogenesis to WAT energy balance and endocrine functions. These insights address how adipocytes use small molecules generated from central carbon metabolism to measure responses to nutritional stress.

Soluble Angiotensin-Converting Enzyme 2, Cardiac Biomarkers, Structure, And Function, And Cardiovascular Events (From The Atherosclerosis Risk In Communities Study), Aliza Hussain, Olive Tang, Caroline Sun, Xiaoming Jia, Elizabeth Selvin, Vijay Nambi, Aaron Folsom, Gerardo Heiss, Faiez Zannad, Thomas Mosley, Salim S Virani, Josef Coresh, Eric Boerwinkle, Bing Yu, Jonathan W Cunningham, Amil M Shah, Scott D Solomon, James A De Lemos, Ron C Hoogeveen, Christie M Ballantyne

Faculty, Staff and Students Publications

Membrane-bound angiotensin-converting enzyme 2 is important in regulation of the renin-angiotensin-aldosterone system, but the association of cleaved soluble ACE2 (sACE2) with cardiovascular disease (CVD) is unclear. We evaluated the association of sACE2 with cardiac biomarkers, structure, and function and cardiovascular events in the Atherosclerosis Risk in Communities Study. sACE2 was measured in a subset of 497 participants (mean age 78±5.4 years, 53% men, 27% black); Cox regression analyses assessed prospective associations of sACE2 with time to first CVD event at median 6.1-year follow-up. sACE2 was higher in men, blacks, and participants with prevalent CVD, diabetes, or hypertension. Higher sACE2 levels …

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 …

The Small Gtpase Rab-35 Facilitates The Initiation Of Phagosome Maturation And Acts As A Robustness Factor For Apoptotic Cell Clearance, Ryan Haley, Zheng Zhou

Faculty, Staff and Students Publications

We recently identified the novel function of the small GTPase RAB-35 in apoptotic cell clearance in Caenorhabditis elegans, a process in which dying cells are engulfed and degraded inside phagosomes. We have found that RAB-35 functions in two separate steps of cell corpse clearance, cell corpse recognition and the initiation of phagosome maturation. During the latter process, RAB-35 facilitates the removal of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) from the membranes of nascent phagosomes and the simultaneous production of phosphatidylinositol-3-P (PI(3)P) on these same membranes, a process that we have coined the PI(4,5)P2 to PI(3)P shift. RAB-35 also promotes the recruitment of the …

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 …

T-Cell Activation Profiles Distinguish Hemophagocytic Lymphohistiocytosis And Early Sepsis, Vandana Chaturvedi, Rebecca A Marsh, Adi Zoref-Lorenz, Erika Owsley, Vijaya Chaturvedi, Trung C Nguyen, Jordana R Goldman, Michael M Henry, Jay N Greenberg, Stephan Ladisch, Michelle L Hermiston, Michael Jeng, Ahmed Naqvi, Carl E Allen, Hector R Wong, Michael B Jordan

Faculty, Staff and Students Publications

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation that has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. Although clinical similarities between these syndromes suggest similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T-cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T-cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38high/HLA-DR+ effector cells, with activation of CD8+ T …

Medical School To Residency: How Can We Trust The Process?, Gary L Beck Dallaghan, Irene Alexandraki, Jennifer Christner, Meg Keeley, Sorabh Khandelwal, Beat Steiner, Paul A Hemmer

Faculty, Staff and Students Publications

Background To say that the transition from undergraduate medical education (UME) to graduate medical education (GME) is under scrutiny would be an understatement. Findings from a panel discussion at the 2018 Association of American Medical Colleges Annual meeting entitled, "Pass-Fail in Medical School and the Residency Application Process and Graduate Medical Education Transition" addressed what and when information should be shared with residency programs, and how and when that information should be shared. Materials and Methods Over 250 participants representing UME and GME (e.g. leadership, faculty, medical students) completed worksheets addressing these questions. During report-back times, verbal comments were transcribed …

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 …

Sirt3 Is Required For Liver Regeneration But Not For The Beneficial Effect Of Nicotinamide Riboside, Sarmistha Mukherjee, James Mo, Lauren M Paolella, Caroline E Perry, Jade Toth, Mindy M Hugo, Qingwei Chu, Qiang Tong, Karthikeyani Chellappa, Joseph A Baur

Children’s Nutrition Research Center Staff Publications

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for …

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 …

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 …

Cell Signaling Regulation In Salivary Gland Development, Akiko Suzuki, Kenichi Ogata, Junichi Iwata

Faculty, Staff and Student Publications

The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian salivary gland development, particularly on the differentiation of acinar, ductal, and myoepithelial cells. We discuss recent studies that provide conceptual advances in the understanding of the molecular mechanisms of salivary gland development. In addition, we describe the organogenesis of submandibular glands (SMGs), model systems used for the study of SMG development, and the key signaling pathways as well as cellular processes involved in salivary gland development. The findings from the recent studies elucidating the identity of …

Hypoxia-Inducible Factor–1Α–Dependent Induction Of Mir122 Enhances Hepatic Ischemia Tolerance, Cynthia Ju, Meng Wang, Eunyoung Tak, Boyun Kim, Christoph Emontzpohl, Yang Yang, Xiaoyi Yuan, Huban Kutay, Yafen Liang, David R Hall, Wasim A Dar, J Steve Bynon, Peter Carmeliet, Kalpana Ghoshal, Holger K Eltzschig

Faculty, Staff and Student Publications

Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction …

Hypoxia-Inducible Factor-Dependent Induction Of Myeloid-Derived Netrin-1 Attenuates Natural Killer Cell Infiltration During Endotoxin-Induced Lung Injury, Nathaniel K Berg, Jiwen Li, Boyun Kim, Tingting Mills, Guangsheng Pei, Zhongming Zhao, Xiangyun Li, Xu Zhang, Wei Ruan, Holger K Eltzschig, Xiaoyi Yuan

Faculty, Staff and Student Publications

Sepsis and sepsis-associated lung inflammation significantly contribute to the morbidity and mortality of critical illness. Here, we examined the hypothesis that neuronal guidance proteins could orchestrate inflammatory events during endotoxin-induced lung injury. Through a targeted array, we identified netrin-1 as the top upregulated neuronal guidance protein in macrophages treated with lipopolysaccharide (LPS). Furthermore, we found that netrin-1 is highly enriched in infiltrating myeloid cells, particularly in macrophages during LPS-induced lung injury. Transcriptional studies implicate hypoxia-inducible factor HIF-1α in the transcriptional induction of netrin-1 during LPS treatment. Subsequently, the deletion of netrin-1 in the myeloid compartment (Ntn1

A Phase Ii Study Of Autologous Mesenchymal Stromal Cells And C-Kit Positive Cardiac Cells, Alone Or In Combination, In Patients With Ischaemic Heart Failure: The Cctrn Concert-Hf Trial, Roberto Bolli, Raul D Mitrani, Joshua M Hare, Carl J Pepine, Emerson C Perin, James T Willerson, Jay H Traverse, Timothy D Henry, Phillip C Yang, Michael P Murphy, Keith L March, Ivonne H Schulman, Sohail Ikram, David P Lee, Connor O'Brien, Joao A Lima, Mohammad R Ostovaneh, Bharath Ambale-Venkatesh, Gregory Lewis, Aisha Khan, Ketty Bacallao, Krystalenia Valasaki, Bangon Longsomboon, Adrian P Gee, Sara Richman, Doris A Taylor, Dejian Lai, Shelly L Sayre, Judy Bettencourt, Rachel W Vojvodic, Michelle L Cohen, Lara Simpson, David Aguilar, Catalin Loghin, Lem Moyé, Ray F Ebert, Barry R Davis, Robert D Simari

Faculty, Staff and Student Publications

AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.

METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association …

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. …

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 …

Mechanisms, Diagnosis, Prevention And Management Of Perioperative Opioid-Induced Hyperalgesia, Sylvia H Wilson, Kevin M Hellman, Dominika James, Adam C Adler, Arvind Chandrakantan

Faculty, Staff and Students Publications

Opioid-induced hyperalgesia (OIH) occurs when opioids paradoxically enhance the pain they are prescribed to ameliorate. To address a lack of perioperative awareness, we present an educational review of clinically relevant aspects of the disorder. Although the mechanisms of OIH are thought to primarily involve medullary descending pathways, it is likely multifactorial with several relevant therapeutic targets. We provide a suggested clinical definition and directions for clinical differentiation of OIH from other diagnoses, as this may be confusing but is germane to appropriate management. Finally, we discuss prevention including patient education and analgesic management choices. As prevention may serve as the …

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 …

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 …

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 …

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 …

Guideline-Directed Heart Failure Therapy In Patients After Left Ventricular Assist Device Implantation, Bailey M. Colvin, James C. Coons, Craig J. Beavers

The VAD Journal

Background: Left ventricular assist devices (LVADs) are used as an advanced therapy option for patients with stage D heart failure. These devices provide mechanical unloading of the heart as either a bridge to transplant or recovery, or as destination therapy. In patients with LVADs, there are emerging data on the use of heart failure guideline-directed medical therapy (GDMT) to improve outcomes. This review describes the current evidence available for the use of neurohormonal blocking agents in patients with LVADs.

Methods: Articles were found using PubMed and web searches for heart failure therapies/neurohormonal blockade and LVADs. Studies were included if they …

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 …

On The Application, Reporting, And Sharing Of In Silico Simulations For Genetic Studies, Kaleigh Riggs, Huann-Sheng Chen, Melissa Rotunno, Bing Li, Naoko I Simonds, Leah E Mechanic, Bo Peng

Faculty, Staff and Students Publications

In silico simulations play an indispensable role in the development and application of statistical models and methods for genetic studies. Simulation tools allow for the evaluation of methods and investigation of models in a controlled manner. With the growing popularity of evolutionary models and simulation-based statistical methods, genetic simulations have been applied to a wide variety of research disciplines such as population genetics, evolutionary genetics, genetic epidemiology, ecology, and conservation biology. In this review, we surveyed 1409 articles from five journals that publish on major application areas of genetic simulations. We identified 432 papers in which genetic simulations were used …

Pegylated Arginine Deiminase Depletes Plasma Arginine But Maintains Tissue Arginine Availability In Young Pigs, Mahmoud A Mohammad, Inka C Didelija, Barbara Stoll, Trung C Nguyen, Juan C Marini

Faculty, Staff and Students Publications

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (

Deficiency Of Stat1 In Cd11c+ Cells Alters Adipose Tissue Inflammation And Improves Metabolic Dysfunctions In Mice Fed A High-Fat Diet, Antu Antony, Zeqin Lian, Xiaoyuan Dai Perrard, Jerry Perrard, Hua Liu, Aaron R Cox, Pradip Saha, Lothar Hennighausen, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 …