Digital Commons Network^™

A Pilot Genome-Wide Association Study Meta-Analysis Of Gastroparesis, Leticia Camargo Tavares, Tenghao Zheng, Madeline Kwicklis, Emily Mitchell, Anita Pandit, Suraj Pullapantula, Cheryl Bernard, Maris Teder-Laving, Francine Z Marques, Tonu Esko, Braden Kuo, Robert J Shulman, Bruno P Chumpitazi, Kenneth L Koch, Irene Sarosiek, Thomas L Abell, Richard W Mccallum, Henry P Parkman, Pankaj J Pasricha, Frank A Hamilton, James Tonascia, Matthew Zawistowski, Gianrico Farrugia, Madhusudan Grover, Mauro D'Amato

Faculty, Staff and Students Publications

BACKGROUND: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.

OBJECTIVE: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed.

METHODS: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on …

A Pancreatic Player In Dementia: Pathological Role For Islet Amyloid Polypeptide Accumulation In The Brain, Angelina S Bortoletto, Ronald J Parchem

Faculty, Staff and Students Publications

Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia. While multiple factors contribute to this predisposition, one of these involves the increased secretion of amylin, or islet amyloid polypeptide, that accompanies the pathophysiology of type 2 diabetes mellitus. Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia, including Alzheimer’s disease and vascular dementia, but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear. In this review, we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage, ultimately leading to …

Mammalian Aging Driven By Transcription Going Awry, Brenna S Mccauley, Weiwei Dang

Faculty, Staff and Students Publications

The mechanisms that underlie increased cryptic transcription during senescence and aging have been poorly understood. Sen et al. recently identified cryptic transcription start sites (cTSSs) and chromatin state changes that may contribute to cTSS activation in mammals. Their results indicate that enhancer-promoter conversion may drive cryptic transcription in senescence.

Neurodevelopmental Deficits And Cell-Type-Specific Transcriptomic Perturbations In A Mouse Model Of Hnrnpu Haploinsufficiency, Sarah A Dugger, Ryan S Dhindsa, Gabriela De Almeida Sampaio, Andrew K Ressler, Elizabeth E Rafikian, Sabrina Petri, Verity A Letts, Jiajie Teoh, Junqiang Ye, Sophie Colombo, Yueqing Peng, Mu Yang, Michael J Boland, Wayne N Frankel, David B Goldstein

Faculty, Staff and Students Publications

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory …

Bioresorbable Mesenchymal Stem Cell-Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation In A Rat Model Of Chronic Kidney Disease, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Jossana A Damasco, Andrea Cortes, Huckie C Del Mundo, Erin Marie D San Valentin, Carleigh Klusman, Gino Martin Canlas, Francisco M Heralde, Rony Avritscher, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Students Publications

Bioresorbable perivascular scaffolds loaded with antiproliferative agents have been shown to enhance arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). These scaffolds, which can mimic the three-dimensional architecture of the vascular extracellular matrix, also have an untapped potential for the local delivery of cell therapies against NIH. Hence, an electrospun perivascular scaffold from polycaprolactone (PCL) to support mesenchymal stem cell (MSC) attachment and gradual elution at the AVF's outflow vein is fabricated. Chronic kidney disease (CKD) in Sprague-Dawley rats is induced by performing 5/6th nephrectomy, then AVFs for scaffold application are created. The following groups of CKD rats are …

Molecular Insights Using Spatial Transcriptomics Of The Distal Lung In Congenital Diaphragmatic Hernia, Krithika Lingappan, Oluyinka O Olutoye, Abiud Cantu, Manuel Eliezer Cantu Gutierrez, Nahir Cortes-Santiago, J D Hammond, Jamie Gilley, Joselyn Rojas Quintero, Hui Li, Francesca Polverino, Jason P Gleghorn, Sundeep G Keswani

Faculty, Staff and Students Publications

Abnormal pulmonary vascular development and function in congenital diaphragmatic hernia (CDH) is a significant factor leading to pulmonary hypertension. The lung is a very heterogenous organ and has marked cellular diversity that is differentially responsive to injury and therapeutic agents. Spatial transcriptomics provides the unmatched capability of discerning the differences in the transcriptional signature of these distinct cell subpopulations in the lung with regional specificity. We hypothesized that the distal lung parenchyma (selected as a region of interest) would show a distinct transcriptomic profile in the CDH lung compared with control (normal lung). We subjected lung sections obtained from male …

The 2017 American College Of Cardiology/American Heart Association Hypertension Guideline And Blood Pressure In Older Adults, Michael C Wang, Lucia C Petito, Lindsay R Pool, Kathryn Foti, Stephen P Juraschek, John W Mcevoy, Vijay Nambi, Mercedes R Carnethon, Erin D Michos, Sadiya S Khan

Faculty, Staff and Students Publications

Introduction: The 2017 American College of Cardiology/American Heart Association blood pressure guideline redefined hypertension and lowered the blood pressure treatment target. Empirical data on the guideline's impact are needed.

Methods: Data were analyzed from Atherosclerosis Risk in Communities study participants who attended baseline pre-guideline (2016-2017) and post-guideline (2018-2019) visits with baseline systolic blood pressure between 120 and 159 mmHg. Participants were grouped according to baseline systolic blood pressure by change in classification under the new guideline as follows: not reclassified (120-129 mmHg), reclassified to Stage 1 hypertension (130-139 mmHg), and reclassified to Stage 2 hypertension (140-159 mmHg). Means and 95% …

Seminar: Extracellular Vesicles As Mediators Of Environmental Stress In Human Disease, Vrinda Kalia, Andrea A Baccarelli, Christine Happel, Jonathan A Hollander, Anne Marie Jukic, Kimberly A Mcallister, Ramkumar Menon, Bruce A Merrick, Aleksander Milosavljevic, Lingamanaidu V Ravichandran, Matthew E Roth, Anita Subramanian, Frederick L Tyson, Leroy Worth, Daniel T Shaughnessy

Faculty, Staff and Students Publications

Background: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress.

Objectives: This seminar addresses the application …

Hmg-Coa Reductase Inhibitors For Traumatic Brain Injury, Kalman Katlowitz, Shankar Gopinath, Jovany Cruz Navarro, Claudia Robertson

Faculty, Staff and Students Publications

Traumatic brain injuries (TBIs) are associated with high morbidity and mortality due to both the original insult as well as the destructive biological response that follows. Medical management aims to slow or even halt secondary neurological injury while simultaneously laying the groundwork for recovery. Statins are one class of medications that is showing increased promise in the management of TBI. Used extensively in cardiovascular disease, these drugs were originally developed as competitive inhibitors within the cholesterol production pipeline. They are now used in diverse disease states due to their pleiotropic effects on other biological processes such as inflammation and angiogenesis. …

Neuromodulation For Adjunctive Treatment In Postmastectomy Pain Syndrome, Kennedy Kirkpatrick, Jay D Shah, Krishna Shah

Faculty, Staff and Students Publications

Postmastectomy pain syndrome (PMPS) affects nearly half of patients who undergo mastectomy to treat breast cancer. As the survival rate of breast cancer increases with advancements in treatment, the incidence of PMPS is also increasing. Patients with PMPS can experience unrelenting, chronic pain refractory to traditional management with oral pharmacotherapy in conjunction with nonpharmacologic treatment (physical therapy, transcutaneous electrical nerve stimulation (TENS)). Neuromodulation is an emerging treatment modality for numerous chronic pain conditions. This case report highlights the tremendous success of spinal cord stimulator placement for a patient with PMPS.

Structural Biology Of Mcr-1-Mediated Resistance To Polymyxin Antibiotics, Isabel Cristina Materon, Timothy Palzkill

Faculty, Staff and Students Publications

Polymyxins, a last resort antibiotic, target the outer membrane of pathogens and are used to address the increasing prevalence of multidrug-resistant Gram-negative bacteria. The plasmid-encoded enzyme MCR-1 confers polymyxin resistance to bacteria by modifying the outer membrane. Transferable resistance to polymyxins is a major concern; therefore, MCR-1 is an important drug target. In this review, we discuss recent structural and mechanistic aspects of MCR-1 function, its variants and homologs, and how they are relevant to polymyxin resistance. Specifically, we discuss work on polymyxin-mediated disruption of the outer and inner membranes, computational studies on the catalytic mechanism of MCR-1, mutagenesis and …

Purification And Characterization Of Mitochondrial Mg2+-Independent Sphingomyelinase From Rat Brain, Jong Min Choi, Yongwei Piao, Kyong Hoon Ahn, Seok Kyun Kim, Jong Hoon Won, Jae Hong Lee, Ji Min Jang, In Chul Shin, Zhicheng Fu, Sung Yun Jung, Eui Man Jeong, Dae Kyong Kim

Faculty, Staff and Students Publications

Sphingomyelinase (SMase) catalyzes ceramide production from sphingomyelin. Ceramides are critical in cellular responses such as apoptosis. They enhance mitochondrial outer membrane permeabilization (MOMP) through self-assembly in the mitochondrial outer membrane to form channels that release cytochrome c from intermembrane space (IMS) into the cytosol, triggering caspase-9 activation. However, the SMase involved in MOMP is yet to be identified. Here, we identified a mitochondrial Mg

Insulin Resistance And Insulin Handling In Chronic Kidney Disease, Vishnu P Parvathareddy, Jiao Wu, Sandhya S Thomas

Faculty, Staff and Students Publications

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of …

Current Approaches To Spinal Cord Protection During Open Thoracoabdominal Aortic Aneurysm Repair, Joseph S Coselli, Scott A Lemaire, Vicente Orozco-Sevilla, Ourania Preventza, Marc R Moon, Lauren M Barron, Subhasis Chatterjee

Faculty, Staff and Students Publications

Spinal cord deficit (SCD) is a feared complication after thoracoabdominal aortic aneurysm repair. Vigilant management throughout the perioperative period is necessary to reduce the risk of SCD. Measures for preventing SCD during the intraoperative period include preoperative optimization and recognizing patients at a higher risk of SCD. In this manuscript, we discuss intraoperative adjuncts including utilization of cerebrospinal fluid drainage, left heart bypass, mild hypothermia, selective reimplantation of intercostal and lumbar arteries, and renal and visceral vessel perfusion. From the operative to the postoperative period, careful attention to avoiding hypotension and anemia is important. If SCD is recognized early, therapeutic …

Uncovering The Effects Of Covid-19 On In-Hospital Cardiac Arrest – A Living Systematic Review And Meta-Analysis, Karol Bielski, Michal Pruc, Zubaid Rafique, Frank William Peacock, Jaroslaw Chmielewski, Lech Panasiuk, Lukasz Szarpak, Nicola Luigi Bragazzi, Izabela Chojnowska-Ćwiąkała

Faculty, Staff and Students Publications

Introduction and objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic and had a negative impact on the entire health care system. To understand the effect of COVID-19 on outcomes of in-hospital cardiac arrest (IHCA), a systematic review and meta-analysis of studies was designed to compare the pre- and intra-pandemic periods of adult patients who suffered cardiac arrest, and additionally by performing a sub-analysis related to COVID-19 positive vs. negative patients in the same group of patients.

Material and methods: To evaluate the impact of COVID-19 on IHCA outcomes a systematic review and meta-analysis was performed. Pubmed …

In Vivo Crispr/Cas9 Screening Identifies Pbrm1 As A Regulator Of Myeloid Leukemia Development In Mice, Bin E Li, Grace Y Li, Wenqing Cai, Qian Zhu, Davide Seruggia, Yuko Fujiwara, Christopher R Vakoc, Stuart H Orkin

Faculty, Staff and Students Publications

CRISPR/Cas9 screening approaches are powerful tool for identifying in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which the sequential acquisition of somatic mutations generates clonal diversity. Over time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We, first, modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs, followed by transplantation. We, then, performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and …

Dopamine Signaling From Ganglion Cells Directs Layer-Specific Angiogenesis In The Retina, Justine H Liang, Viktor Akhanov, Anthony Ho, Mohamed Tawfik, Shane P D'Souza, Morven A Cameron, Richard A Lang, Melanie A Samuel

Faculty, Staff and Students Publications

During central nervous system (CNS) development, a precisely patterned vasculature emerges to support CNS function. How neurons control angiogenesis is not well understood. Here, we show that the neuromodulator dopamine restricts vascular development in the retina via temporally limited production by an unexpected neuron subset. Our genetic and pharmacological experiments demonstrate that elevating dopamine levels inhibits tip-cell sprouting and vessel growth, whereas reducing dopamine production by all retina neurons increases growth. Dopamine production by canonical dopaminergic amacrine interneurons is dispensable for these events. Instead, we found that temporally restricted dopamine production by retinal ganglion cells (RGCs) modulates vascular development. RGCs …

Novel Genetic And Phenotypic Expansion In Gosr2-Related Progressive Myoclonus Epilepsy, Lea Hentrich, Mered Parnes, Timothy Edward Lotze, Rohini Coorg, Tom J De Koning, Kha M Nguyen, Calvin K Yip, Heinz Jungbluth, Anne Koy, Hormos Salimi Dafsari

Faculty, Staff and Students Publications

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age …

Blockade Of Interferon Signaling Decreases Gut Barrier Integrity And Promotes Severe West Nile Virus Disease, Shih-Ching Lin, Fang R Zhao, Hana Janova, Adrian Gervais, Summer Rucknagel, Kristy O Murray, Jean-Laurent Casanova, Michael S Diamond

Faculty, Staff and Students Publications

The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived …

Comparative Genomics Analysis Of Three Conserved Plasmid Families In The Western Hemisphere Soft Tick-Borne Relapsing Fever Borreliae Provides Insight Into Variation In Genome Structure And Antigenic Variation Systems, Alexander R Kneubehl, Job E Lopez

Faculty, Staff and Students Publications

Borrelia spirochetes, causative agents of Lyme disease and relapsing fever (RF), have uniquely complex genomes, consisting of a linear chromosome and both circular and linear plasmids. The plasmids harbor genes important for the vector-host life cycle of these tick-borne bacteria. The role of plasmids from Lyme disease causing spirochetes is more refined compared to RF Borrelia because of limited plasmid-resolved genome assemblies for the latter. We recently addressed this limitation and found that three linear plasmid families (F6, F27, and F28) were syntenic across all the RF Borrelia species that we examined. Given this conservation, we further investigated the three …

Boosting Glycolysis To Combat Fragile Bone In Type 1 Diabetes, Zixue Jin, Brendan Lee

Faculty, Staff and Students Publications

Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji et al.1 show that impaired glucose metabolism in the bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.

Kcnq2/3 Gain-Of-Function Variants And Cell Excitability: Differential Effects In Ca1 Versus L2/3 Pyramidal Neurons, Nissi Varghese, Bruno Moscoso, Ana Chavez, Kristen Springer, Erika Ortiz, Heun Soh, Sabato Santaniello, Atul Maheshwari, Anastasios V Tzingounis

Faculty, Staff and Students Publications

Gain-of-function (GOF) pathogenic variants in the potassium channels KCNQ2 and KCNQ3 lead to hyperexcitability disorders such as epilepsy and autism spectrum disorders. However, the underlying cellular mechanisms of how these variants impair forebrain function are unclear. Here, we show that the R201C variant in KCNQ2 has opposite effects on the excitability of two types of mouse pyramidal neurons of either sex, causing hyperexcitability in layer 2/3 (L2/3) pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. Similarly, the homologous R231C variant in KCNQ3 leads to hyperexcitability in L2/3 pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. However, the effects of KCNQ3 …

Epigenetic Induction Of Smooth Muscle Cell Phenotypic Alterations In Aortic Aneurysms And Dissections, Abhijit Chakraborty, Yanming Li, Chen Zhang, Yang Li, Kimberly R Rebello, Shengyu Li, Samantha Xu, Hernan G Vasquez, Lin Zhang, Wei Luo, Guangyu Wang, Kaifu Chen, Joseph S Coselli, Scott A Lemaire, Ying H Shen

Faculty, Staff and Students Publications

BACKGROUND: Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified.

METHODS: We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis.

RESULTS: Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of …

Specific Polysaccharide Antibody Deficiency, Daniel M Musher

Faculty, Staff and Students Publications

No abstract provided.

Structure, Function, And Molecular Landscapes Of The Aging Retina, Jeffrey D Zhu, Sharma Pooja Tarachand, Qudrat Abdulwahab, Melanie A Samuel

Faculty, Staff and Students Publications

Because the central nervous system is largely nonrenewing, neurons and their synapses must be maintained over the lifetime of an individual to ensure circuit function. Age is a dominant risk factor for neural diseases, and declines in nervous system function are a common feature of aging even in the absence of disease. These alterations extend to the visual system and, in particular, to the retina. The retina is a site of clinically relevant age-related alterations but has also proven to be a uniquely approachable system for discovering principles that govern neural aging because it is well mapped, contains diverse neuron …

Decoding Depression Severity From Intracranial Neural Activity, Jiayang Xiao, Nicole R Provenza, Joseph Asfouri, John Myers, Raissa K Mathura, Brian Metzger, Joshua A Adkinson, Anusha B Allawala, Victoria Pirtle, Denise Oswalt, Ben Shofty, Meghan E Robinson, Sanjay J Mathew, Wayne K Goodman, Nader Pouratian, Paul R Schrater, Ankit B Patel, Andreas S Tolias, Kelly R Bijanki, Xaq Pitkow, Sameer A Sheth

Faculty, Staff and Students Publications

BACKGROUND: Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis.

METHODS: We recorded high-density neural activity from intracranial electrodes implanted in depression-relevant prefrontal cortical regions in 3 human subjects with severe depression. Neural recordings were labeled with depression severity scores across a wide dynamic range using an adaptive assessment that allowed sampling with a temporal frequency greater than that possible with typical rating scales. We modeled these data using regularized regression techniques with region selection to decode depression severity from …

Speg Interactions That Regulate The Stability Of Excitation-Contraction Coupling Protein Complexes In Triads And Dyads, Chang Seok Lee, Sung Yun Jung, Rachel Sue Zhen Yee, Nadia H Agha, Jin Hong, Ting Chang, Lyle W Babcock, Jorie D Fleischman, Benjamin Clayton, Amy D Hanna, Christopher S Ward, Denise Lanza, Ayrea E Hurley, Pumin Zhang, Xander H T Wehrens, William R Lagor, George G Rodney, Susan L Hamilton

Faculty, Staff and Students Publications

Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) …

Gut Barrier Defects, Intestinal Immune Hyperactivation And Enhanced Lipid Catabolism Drive Lethality In Ngly1-Deficient Drosophila, Ashutosh Pandey, Antonio Galeone, Seung Yeop Han, Benjamin A Story, Gaia Consonni, William F Mueller, Lars M Steinmetz, Thomas Vaccari, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of Pngl in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of Pngl mutants rescued their developmental delay but not …

Shp2 Promotes Sarcoidosis Severity By Inhibiting Skp2-Targeted Ubiquitination Of Tbet In Cd8+ T Cells, Sherly I Celada, Clarice X Lim, Alexandre F Carisey, Scott A Ochsner, Carlos F Arce Deza, Praveen Rexie, Fernando Poli De Frias, Rafael Cardenas-Castillo, Francesca Polverino, Markus Hengstschläger, Konstantin Tsoyi, Neil J Mckenna, Farrah Kheradmand, Thomas Weichhart, Ivan O Rosas, Luc Van Kaer, Lindsay J Celada

Faculty, Staff and Students Publications

Sarcoidosis is an interstitial lung disease (ILD) characterized by IFNγ and TBET dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we report that pharmacological inhibition of phosphorylated SH2 containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFNγ levels, decreases large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8+ T cells. Mechanistically, our findings identified a previously unknown post-translational modification (PTM) pathway in which the E3 F-box …

Description Of A New Pavlovskyella Species (Acari: Argasidae) From Chile, Sebastián Muñoz-Leal, José M Venzal, Alexander R Kneubehl, Job E Lopez, Thiago F Martins, Marcelo B Labruna

Faculty, Staff and Students Publications

Soft ticks (Argasidae) of the Pavlovskyella Pospelova-Shtrom subgenus are important vectors of relapsing fever spirochetes, which are agents of disease globally. South American representatives of the Pavlovskyella subgenus include 3 species: Ornithodoros (Pavlovskyella) brasiliensis Aragão, Ornithodoros (Pavlovskyella) furcosus Neumann, and Ornithodoros (Pavlovskyella) rostratus Aragão. Here, we describe a fourth species based on morphological and mitogenomic evidence of ticks collected in burrows of unknown hosts in central Chile. The larva of the new species separates from other South American soft ticks by the following combination of characters: 13 pairs of dorsolateral setae, dorsal plate hexagonal, hypostome blunt with denticles from apex …