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      The EDN2 rs110287192 gene polymorphism is associated with paratuberculosis susceptibility in multibreed cattle population

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          Abstract

          Paratuberculosis (pTB), also known as Johne's disease (JD), is a contagious, chronic, and granulomatous inflammatory disease of the intestines of ruminants which is caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection, resulting in billions of dollars in economic losses worldwide. Since, currently, no effective cure is available for MAP infection, it is important to explore the genetic variants that affect the host MAP susceptibility. The aim of this study was to analyze a potential association between EDN2 synonymous gene mutations ( rs110287192, rs109651404 and rs136707411), that modifies susceptibility to pTB. EDN2 rs110287192, rs109651404 and rs136707411 mutations were genotyped in 68 infected and 753 healthy animals from East Anatolian Red crossbred, Anatolian Black crossbred and Holstein breed cattle by using Custom TaqMan SNP Genotyping Assays. For pTB status, serum antibody levels S/P ≥ 1.0 were assessed in carriers of the different EDN2 genotypes. EDN2 rs110287192 mutation showed a significant association with bovine pTB (adj. p < 0.05). For rs110287192 locus, the odd ratios for GG and TG genotypes versus TT genotypes were 1.73; (95% CI = 0.34–8.59) and 0.53 (95% CI = 0.12–2.37) respectively, which indicated that proportion of TG heterozygotes were significantly higher in control animals as compared to pTB animals. On the other hand, while rs136707411 mutation showed a suggestive association with pTB status in the examined cattle population (nominal p < 0.05); no association was detected between rs109651404 genotypes and pTB status. Selecting animals against rs110287192-GG genotype may decrease the risk of pTB in cattle of the Bos taurus taurus subspecies.

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          Most cited references32

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          Endothelin

          The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.
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            Regulation of blood pressure and salt homeostasis by endothelin.

            Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.
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              Survival and dormancy of Mycobacterium avium subsp. paratuberculosis in the environment.

              The survival of Mycobacterium avium subsp. paratuberculosis was studied by culture of fecal material sampled at intervals for up to 117 weeks from soil and grass in pasture plots and boxes. Survival for up to 55 weeks was observed in a dry fully shaded environment, with much shorter survival times in unshaded locations. Moisture and application of lime to soil did not affect survival. UV radiation was an unlikely factor, but infrared wavelengths leading to diurnal temperature flux may be the significant detrimental component that is correlated with lack of shade. The organism survived for up to 24 weeks on grass that germinated through infected fecal material applied to the soil surface in completely shaded boxes and for up to 9 weeks on grass in 70% shade. The observed patterns of recovery in three of four experiments and changes in viable counts were indicative of dormancy, a hitherto unreported property of this taxon. A dps-like genetic element and relA, which are involved in dormancy responses in other mycobacteria, are present in the M. avium subsp. paratuberculosis genome sequence, providing indirect evidence for the existence of physiological mechanisms enabling dormancy. However, survival of M. avium subsp. paratuberculosis in the environment is finite, consistent with its taxonomic description as an obligate parasite of animals.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Methodology
                Role: Funding acquisitionRole: Methodology
                Role: ValidationRole: Writing – review & editing
                Role: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Methodology
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 September 2020
                2020
                : 15
                : 9
                : e0238631
                Affiliations
                [1 ] Department of Animal Science, Faculty of Agriculture, Erciyes University, Kayseri, Turkey
                [2 ] Department of Veterinary Microbiology & Pathology, Washington State University, Pullman, WA, United States of America
                [3 ] Department of Genetics, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey
                [4 ] Animal Disease Research Unit, Agricultural Research Service, U.S. Department of Agriculture, Pullman, WA, United States of America
                [5 ] Center for Reproductive Biology, Washington State University, Pullman, WA, United States of America
                [6 ] Department of Animal Science, Washington State University, Pullman, WA, United States of America
                [7 ] Department of Microbiology, Erciyes University, Faculty of Veterinary Medicine, Kayseri, Turkey
                Bangladesh Agricultural University, BANGLADESH
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-5894-5072
                Article
                PONE-D-20-15004
                10.1371/journal.pone.0238631
                7470282
                32881967
                cd46e0c1-f4ac-4e6f-a0ea-22143f90a816

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 19 May 2020
                : 20 August 2020
                Page count
                Figures: 0, Tables: 2, Pages: 9
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004410, Türkiye Bilimsel ve Teknolojik Araştirma Kurumu;
                Award ID: 218O128
                Award Recipient :
                This research was financially supported by the Turkish Research Council (Türkiye Bilimsel ve Teknolojik Araştirma Kurumu (TÜBİTAK)) grant number 218O128 to MUC and the funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Agriculture
                Animal Management
                Livestock
                Biology and Life Sciences
                Genetics
                Single Nucleotide Polymorphisms
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Variant Genotypes
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Genotyping
                Research and Analysis Methods
                Molecular Biology Techniques
                Genotyping
                Biology and Life Sciences
                Zoology
                Animal Diseases
                Paratuberculosis
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Bovines
                Cattle
                Biology and Life Sciences
                Zoology
                Animals
                Vertebrates
                Amniotes
                Mammals
                Bovines
                Cattle
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Ruminants
                Cattle
                Biology and Life Sciences
                Zoology
                Animals
                Vertebrates
                Amniotes
                Mammals
                Ruminants
                Cattle
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Autoimmune Diseases
                Crohn's Disease
                Biology and Life Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Crohn's Disease
                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Crohn's Disease
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Inflammatory Bowel Disease
                Crohn's Disease
                Biology and Life Sciences
                Veterinary Science
                Veterinary Diseases
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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