Percentage of TAR10 and ATR49 triplets in various taxa independently of the V-R size.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"7181",leadTitle:null,fullTitle:"Erythrocyte",title:"Erythrocyte",subtitle:null,reviewType:"peer-reviewed",abstract:'Red blood cells constitute approximately 40% of the total amount of blood and 99% of shaped elements of blood. Their major function is oxygen transportation and this makes erythrocytes "the basis of life." However, as readers will see in this book, erythrocytes have a lot of different, important functions in our body. With this book, it is planned to collect current information related to "erythrocytes." The book has been divided into two sections. The first section includes information about the roles of erythrocytes in the physiological and pathophysiological processes. The second section includes information on the future perspectives of erythrocytes like their therapeutic applications in medicine. This book will be a stepping stone for scientists who are rapidly advancing their science journey.',isbn:"978-1-78984-210-4",printIsbn:"978-1-78984-209-8",pdfIsbn:"978-1-78984-693-5",doi:"10.5772/intechopen.73981",price:119,priceEur:129,priceUsd:155,slug:"erythrocyte",numberOfPages:176,isOpenForSubmission:!1,isInWos:1,hash:"267d215004c995048557176978208b15",bookSignature:"Anil Tombak",publishedDate:"October 23rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7181.jpg",numberOfDownloads:5755,numberOfWosCitations:8,numberOfCrossrefCitations:9,numberOfDimensionsCitations:15,hasAltmetrics:1,numberOfTotalCitations:32,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 20th 2018",dateEndSecondStepPublish:"November 7th 2018",dateEndThirdStepPublish:"January 6th 2019",dateEndFourthStepPublish:"March 27th 2019",dateEndFifthStepPublish:"May 26th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"202814",title:"Associate Prof.",name:"Anil",middleName:null,surname:"Tombak",slug:"anil-tombak",fullName:"Anil Tombak",profilePictureURL:"https://mts.intechopen.com/storage/users/202814/images/system/202814.jpeg",biography:"Assoc. Prof. Dr. Anil Tombak, MD, was born on April 25, 1976.\nHe graduated from Gazi Anatolian High School in 1994, and\nthen from Çukurova University Medical Faculty in 2000. Subsequently, he was trained at Mersin University Medical Faculty\nInternal Medicine Department, and after internal medicine\nspecialization became a fellow of hematology at the same university. He became a hematologist in 2013 while still working\nat Mersin University Medical Faculty, Department of Internal Medicine—Hematology, Mersin, Turkey. He has performed research in several fields, and has more\nthan 50 publications in (inter)national journals and numerous papers in scientific\nconferences. He has received several awards and is a member of the Turkish Society\nof Hematology. Dr. Tombak is married and has two children.",institutionString:"Mersin University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Mersin University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"183",title:"Hematology",slug:"hematology"}],chapters:[{id:"68721",title:"Introductory Chapter: Erythrocytes - Basis of Life",doi:"10.5772/intechopen.88847",slug:"introductory-chapter-erythrocytes-basis-of-life",totalDownloads:401,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Anil Tombak",downloadPdfUrl:"/chapter/pdf-download/68721",previewPdfUrl:"/chapter/pdf-preview/68721",authors:[{id:"202814",title:"Associate Prof.",name:"Anil",surname:"Tombak",slug:"anil-tombak",fullName:"Anil Tombak"}],corrections:null},{id:"67667",title:"Erythrocyte Morphology and Its Disorders",doi:"10.5772/intechopen.86112",slug:"erythrocyte-morphology-and-its-disorders",totalDownloads:800,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Ademola Samson Adewoyin, Oluwafemi Adeyemi, Nosimot Omolola Davies and Ann Abiola Ogbenna",downloadPdfUrl:"/chapter/pdf-download/67667",previewPdfUrl:"/chapter/pdf-preview/67667",authors:[{id:"281974",title:"Dr.",name:"Ademola Samson",surname:"Adewoyin",slug:"ademola-samson-adewoyin",fullName:"Ademola Samson Adewoyin"},{id:"304907",title:"Dr.",name:"Oluwafemi",surname:"Adeyemi",slug:"oluwafemi-adeyemi",fullName:"Oluwafemi Adeyemi"},{id:"304908",title:"Dr.",name:"Nosimot Omolola",surname:"Davies",slug:"nosimot-omolola-davies",fullName:"Nosimot Omolola Davies"},{id:"304909",title:"Dr.",name:"Ann",surname:"Abiola Ogbenna",slug:"ann-abiola-ogbenna",fullName:"Ann Abiola Ogbenna"}],corrections:null},{id:"67065",title:"Red Blood Cells Actively Contribute to Blood Coagulation and Thrombus Formation",doi:"10.5772/intechopen.86152",slug:"red-blood-cells-actively-contribute-to-blood-coagulation-and-thrombus-formation",totalDownloads:450,totalCrossrefCites:3,totalDimensionsCites:3,signatures:"Ingolf Bernhardt, Mauro C. Wesseling, Duc Bach Nguyen and Lars Kaestner",downloadPdfUrl:"/chapter/pdf-download/67065",previewPdfUrl:"/chapter/pdf-preview/67065",authors:[{id:"205405",title:"Prof.",name:"Ingolf",surname:"Bernhardt",slug:"ingolf-bernhardt",fullName:"Ingolf Bernhardt"},{id:"299027",title:"Dr.",name:"Lars",surname:"Kaestner",slug:"lars-kaestner",fullName:"Lars Kaestner"},{id:"303082",title:"Dr.",name:"Duc Bach",surname:"Nguyen",slug:"duc-bach-nguyen",fullName:"Duc Bach Nguyen"},{id:"303083",title:"Dr.",name:"Mauro C.",surname:"Wesseling",slug:"mauro-c.-wesseling",fullName:"Mauro C. Wesseling"}],corrections:null},{id:"67465",title:"Who Is Balancing: Is It RBC or Acid-Base Status?",doi:"10.5772/intechopen.84768",slug:"who-is-balancing-is-it-rbc-or-acid-base-status-",totalDownloads:424,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"T. Rajini Samuel",downloadPdfUrl:"/chapter/pdf-download/67465",previewPdfUrl:"/chapter/pdf-preview/67465",authors:[{id:"279821",title:"Dr.",name:"T. Rajini",surname:"Samuel",slug:"t.-rajini-samuel",fullName:"T. Rajini Samuel"}],corrections:null},{id:"65673",title:"Red Blood Cells as Redox Modulators in Hemolytic Anemia",doi:"10.5772/intechopen.84498",slug:"red-blood-cells-as-redox-modulators-in-hemolytic-anemia",totalDownloads:559,totalCrossrefCites:1,totalDimensionsCites:3,signatures:"Eitan Fibach and Mutaz Dana",downloadPdfUrl:"/chapter/pdf-download/65673",previewPdfUrl:"/chapter/pdf-preview/65673",authors:[{id:"83134",title:"Prof.",name:"Eitan",surname:"Fibach",slug:"eitan-fibach",fullName:"Eitan Fibach"},{id:"280928",title:"Dr.",name:"Mutaz",surname:"Dana",slug:"mutaz-dana",fullName:"Mutaz Dana"}],corrections:null},{id:"65133",title:"Interplay between Erythrocyte Peroxidases and Membrane",doi:"10.5772/intechopen.83590",slug:"interplay-between-erythrocyte-peroxidases-and-membrane",totalDownloads:726,totalCrossrefCites:0,totalDimensionsCites:2,signatures:"Daniela Melo, Susana Rocha, Susana Coimbra and Alice Santos Silva",downloadPdfUrl:"/chapter/pdf-download/65133",previewPdfUrl:"/chapter/pdf-preview/65133",authors:[{id:"56251",title:"Prof.",name:"Alice",surname:"Santos Silva",slug:"alice-santos-silva",fullName:"Alice Santos Silva"},{id:"66774",title:"Prof.",name:"Susana",surname:"Coimbra",slug:"susana-coimbra",fullName:"Susana Coimbra"},{id:"280442",title:"MSc.",name:"Daniela",surname:"Melo",slug:"daniela-melo",fullName:"Daniela Melo"},{id:"280443",title:"Dr.",name:"Susana",surname:"Rocha",slug:"susana-rocha",fullName:"Susana Rocha"}],corrections:null},{id:"67156",title:"Effects of Therapeutic and Toxic Agents on Erythrocytes of Different Species of Animals",doi:"10.5772/intechopen.85865",slug:"effects-of-therapeutic-and-toxic-agents-on-erythrocytes-of-different-species-of-animals",totalDownloads:588,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Saganuwan Alhaji Saganuwan",downloadPdfUrl:"/chapter/pdf-download/67156",previewPdfUrl:"/chapter/pdf-preview/67156",authors:[{id:"266889",title:"Associate Prof.",name:"Saganuwan",surname:"Alhaji Saganuwan",slug:"saganuwan-alhaji-saganuwan",fullName:"Saganuwan Alhaji Saganuwan"}],corrections:null},{id:"64230",title:"The Biology and Therapeutic Applications of Red Blood Cell Extracellular Vesicles",doi:"10.5772/intechopen.81758",slug:"the-biology-and-therapeutic-applications-of-red-blood-cell-extracellular-vesicles",totalDownloads:743,totalCrossrefCites:4,totalDimensionsCites:5,signatures:"Daniel Xin Zhang, Theodoros Kiomourtzis, Chun Kuen Lam and Minh T.N. Le",downloadPdfUrl:"/chapter/pdf-download/64230",previewPdfUrl:"/chapter/pdf-preview/64230",authors:[{id:"267051",title:"Dr.",name:"Minh T.N.",surname:"Le",slug:"minh-t.n.-le",fullName:"Minh T.N. Le"},{id:"276896",title:"Dr.",name:"Daniel Xin",surname:"Zhang",slug:"daniel-xin-zhang",fullName:"Daniel Xin Zhang"},{id:"276897",title:"Mr.",name:"Theodoros",surname:"Kiomourtzis",slug:"theodoros-kiomourtzis",fullName:"Theodoros Kiomourtzis"},{id:"276898",title:"Mr.",name:"Chun Kuen",surname:"Lam",slug:"chun-kuen-lam",fullName:"Chun Kuen Lam"}],corrections:null},{id:"65464",title:"Application of Red Cell Membrane in Nanobiotechnology",doi:"10.5772/intechopen.84274",slug:"application-of-red-cell-membrane-in-nanobiotechnology",totalDownloads:497,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Insu Kim, Gyudo Lee and Dae Sung Yoon",downloadPdfUrl:"/chapter/pdf-download/65464",previewPdfUrl:"/chapter/pdf-preview/65464",authors:[{id:"180553",title:"Prof.",name:"Dae Sung",surname:"Yoon",slug:"dae-sung-yoon",fullName:"Dae Sung Yoon"},{id:"280027",title:"Dr.",name:"Gyudo",surname:"Lee",slug:"gyudo-lee",fullName:"Gyudo Lee"},{id:"280035",title:"Mr.",name:"Insu",surname:"Kim",slug:"insu-kim",fullName:"Insu Kim"}],corrections:null},{id:"65276",title:"The Influence of the Golden Ratio on the Erythrocyte",doi:"10.5772/intechopen.83682",slug:"the-influence-of-the-golden-ratio-on-the-erythrocyte",totalDownloads:579,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Marcy C. Purnell and Risa D. Ramsey",downloadPdfUrl:"/chapter/pdf-download/65276",previewPdfUrl:"/chapter/pdf-preview/65276",authors:[{id:"278362",title:"Ph.D.",name:"Marcy C.",surname:"Purnell",slug:"marcy-c.-purnell",fullName:"Marcy C. Purnell"},{id:"288727",title:"Prof.",name:"Risa D.",surname:"Ramsey",slug:"risa-d.-ramsey",fullName:"Risa D. Ramsey"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"6905",title:"Blood Groups",subtitle:null,isOpenForSubmission:!1,hash:"545ab2a5b402edec6332c7d632eba398",slug:"blood-groups",bookSignature:"Anil Tombak",coverURL:"https://cdn.intechopen.com/books/images_new/6905.jpg",editedByType:"Edited by",editors:[{id:"202814",title:"Associate Prof.",name:"Anil",surname:"Tombak",slug:"anil-tombak",fullName:"Anil Tombak"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6273",title:"Thrombocytopenia",subtitle:null,isOpenForSubmission:!1,hash:"182f67f8c83b1d8897447f05207feae9",slug:"thrombocytopenia",bookSignature:"Pankaj Abrol",coverURL:"https://cdn.intechopen.com/books/images_new/6273.jpg",editedByType:"Edited by",editors:[{id:"90782",title:"Dr.",name:"Pankaj",surname:"Abrol",slug:"pankaj-abrol",fullName:"Pankaj Abrol"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7845",title:"Platelets",subtitle:null,isOpenForSubmission:!1,hash:"d33b20516d6ff3a5b7446a882109ba26",slug:"platelets",bookSignature:"Steve W. Kerrigan",coverURL:"https://cdn.intechopen.com/books/images_new/7845.jpg",editedByType:"Edited by",editors:[{id:"73961",title:"Dr.",name:"Steve W.",surname:"Kerrigan",slug:"steve-w.-kerrigan",fullName:"Steve W. Kerrigan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8450",title:"Beta Thalassemia",subtitle:null,isOpenForSubmission:!1,hash:"976f72013cd8e78d8f65bfb1f51f0146",slug:"beta-thalassemia",bookSignature:"Marwa Zakaria and Tamer Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/8450.jpg",editedByType:"Edited by",editors:[{id:"187545",title:"Prof.",name:"Marwa",surname:"Zakaria",slug:"marwa-zakaria",fullName:"Marwa Zakaria"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7125",title:"Iron Deficiency Anemia",subtitle:null,isOpenForSubmission:!1,hash:"25d82a6ea6c9d80b195bb40aad06be49",slug:"iron-deficiency-anemia",bookSignature:"Luis Rodrigo",coverURL:"https://cdn.intechopen.com/books/images_new/7125.jpg",editedByType:"Edited by",editors:[{id:"73208",title:"Prof.",name:"Luis",surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7086",title:"Hemophilia",subtitle:"Recent Advances",isOpenForSubmission:!1,hash:"2c281207a3bce680f1a7efbb87ff791c",slug:"hemophilia-recent-advances",bookSignature:"Pankaj Abrol",coverURL:"https://cdn.intechopen.com/books/images_new/7086.jpg",editedByType:"Edited by",editors:[{id:"90782",title:"Dr.",name:"Pankaj",surname:"Abrol",slug:"pankaj-abrol",fullName:"Pankaj Abrol"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6634",title:"Homeostasis",subtitle:"An Integrated Vision",isOpenForSubmission:!1,hash:"3731dfa513781db054545963a4394938",slug:"homeostasis-an-integrated-vision",bookSignature:"Fernanda Lasakosvitsch and Sergio Dos Anjos Garnes",coverURL:"https://cdn.intechopen.com/books/images_new/6634.jpg",editedByType:"Edited by",editors:[{id:"117630",title:"Dr.",name:"Fernanda",surname:"Lasakosvitsch Castanho",slug:"fernanda-lasakosvitsch-castanho",fullName:"Fernanda Lasakosvitsch Castanho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"66065",slug:"corrigendum-to-eating-disorders-as-new-forms-of-addiction",title:"Corrigendum to: Eating Disorders as New Forms of Addiction",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/66065.pdf",downloadPdfUrl:"/chapter/pdf-download/66065",previewPdfUrl:"/chapter/pdf-preview/66065",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/66065",risUrl:"/chapter/ris/66065",chapter:{id:"52200",slug:"eating-disorders-as-new-forms-of-addiction",signatures:"Francisco J. Vaz-Leal, María I. Ramos-Fuentes, Laura Rodríguez-\nSantos and M. Cristina Álvarez-Mateos",dateSubmitted:"April 9th 2016",dateReviewed:"August 12th 2016",datePrePublished:null,datePublished:"February 1st 2017",book:{id:"5372",title:"Eating Disorders",subtitle:"A Paradigm of the Biopsychosocial Model of Illness",fullTitle:"Eating Disorders - A Paradigm of the Biopsychosocial Model of Illness",slug:"eating-disorders-a-paradigm-of-the-biopsychosocial-model-of-illness",publishedDate:"February 1st 2017",bookSignature:"Ignacio Jauregui-Lobera",coverURL:"https://cdn.intechopen.com/books/images_new/5372.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"55769",title:"Prof.",name:"Ignacio",middleName:null,surname:"Jáuregui Lobera",slug:"ignacio-jauregui-lobera",fullName:"Ignacio Jáuregui Lobera"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"188555",title:"Prof.",name:"Francisco J.",middleName:null,surname:"Vaz-Leal",fullName:"Francisco J. Vaz-Leal",slug:"francisco-j.-vaz-leal",email:"fjvazleal@gmail.com",position:null,institution:null},{id:"188719",title:"Dr.",name:"María Cristina",middleName:null,surname:"Álvarez Mateos",fullName:"María Cristina Álvarez Mateos",slug:"maria-cristina-alvarez-mateos",email:"cristinaalvarezmateos@gmail.com",position:null,institution:null},{id:"195142",title:"Dr.",name:"Laura",middleName:null,surname:"Rodríguez Santos",fullName:"Laura Rodríguez Santos",slug:"laura-rodriguez-santos",email:"laura@unex.es",position:null,institution:null},{id:"195143",title:"Dr.",name:"María I",middleName:null,surname:"Ramos Fuentes",fullName:"María I Ramos Fuentes",slug:"maria-i-ramos-fuentes",email:"miramos@unex.es",position:null,institution:null}]}},chapter:{id:"52200",slug:"eating-disorders-as-new-forms-of-addiction",signatures:"Francisco J. Vaz-Leal, María I. Ramos-Fuentes, Laura Rodríguez-\nSantos and M. Cristina Álvarez-Mateos",dateSubmitted:"April 9th 2016",dateReviewed:"August 12th 2016",datePrePublished:null,datePublished:"February 1st 2017",book:{id:"5372",title:"Eating Disorders",subtitle:"A Paradigm of the Biopsychosocial Model of Illness",fullTitle:"Eating Disorders - A Paradigm of the Biopsychosocial Model of Illness",slug:"eating-disorders-a-paradigm-of-the-biopsychosocial-model-of-illness",publishedDate:"February 1st 2017",bookSignature:"Ignacio Jauregui-Lobera",coverURL:"https://cdn.intechopen.com/books/images_new/5372.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"55769",title:"Prof.",name:"Ignacio",middleName:null,surname:"Jáuregui Lobera",slug:"ignacio-jauregui-lobera",fullName:"Ignacio Jáuregui Lobera"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"188555",title:"Prof.",name:"Francisco J.",middleName:null,surname:"Vaz-Leal",fullName:"Francisco J. Vaz-Leal",slug:"francisco-j.-vaz-leal",email:"fjvazleal@gmail.com",position:null,institution:null},{id:"188719",title:"Dr.",name:"María Cristina",middleName:null,surname:"Álvarez Mateos",fullName:"María Cristina Álvarez Mateos",slug:"maria-cristina-alvarez-mateos",email:"cristinaalvarezmateos@gmail.com",position:null,institution:null},{id:"195142",title:"Dr.",name:"Laura",middleName:null,surname:"Rodríguez Santos",fullName:"Laura Rodríguez Santos",slug:"laura-rodriguez-santos",email:"laura@unex.es",position:null,institution:null},{id:"195143",title:"Dr.",name:"María I",middleName:null,surname:"Ramos Fuentes",fullName:"María I Ramos Fuentes",slug:"maria-i-ramos-fuentes",email:"miramos@unex.es",position:null,institution:null}]},book:{id:"5372",title:"Eating Disorders",subtitle:"A Paradigm of the Biopsychosocial Model of Illness",fullTitle:"Eating Disorders - A Paradigm of the Biopsychosocial Model of Illness",slug:"eating-disorders-a-paradigm-of-the-biopsychosocial-model-of-illness",publishedDate:"February 1st 2017",bookSignature:"Ignacio Jauregui-Lobera",coverURL:"https://cdn.intechopen.com/books/images_new/5372.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"55769",title:"Prof.",name:"Ignacio",middleName:null,surname:"Jáuregui Lobera",slug:"ignacio-jauregui-lobera",fullName:"Ignacio Jáuregui Lobera"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"2989",leadTitle:null,title:"Miniinvasive Face and Body Lifts",subtitle:"Closed Suture Lifts or Barbed Thread Lifts",reviewType:"peer-reviewed",abstract:"The biggest buzz in the facial and body lifting beautification and rejuvenation category is by far around mini-invasive scarless techniques. They are presented by suture and thread lifts. Both suture and thread lift techniques have many unique properties. For example, young patients do not want to be scarred with classic open face liftings. Also, for Asians, Afro-Americans, and Latino-Americans, who have higher percentage of keloids, these are the preferred non-scarring cosmetic surgery methods. Scarless mini-invasive lifting techniques, such as suture and thread lifts, need proper explanation and public access. This will be the first scientific book that could clear the false public belief that transcutaneous suture and thread lifts are one and the same method.",isbn:null,printIsbn:"978-953-51-1196-2",pdfIsbn:"978-953-51-7182-9",doi:"10.5772/2654",price:139,priceEur:155,priceUsd:179,slug:"miniinvasive-face-and-body-lifts-closed-suture-lifts-or-barbed-thread-lifts",numberOfPages:374,isOpenForSubmission:!1,hash:"7e9600ab8fe9125b2c41161d2ee91ff3",bookSignature:"Nikolay Serdev",publishedDate:"October 2nd 2013",coverURL:"https://cdn.intechopen.com/books/images_new/2989.jpg",keywords:null,numberOfDownloads:71642,numberOfWosCitations:3,numberOfCrossrefCitations:10,numberOfDimensionsCitations:16,numberOfTotalCitations:29,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 25th 2012",dateEndSecondStepPublish:"February 15th 2012",dateEndThirdStepPublish:"June 15th 2012",dateEndFourthStepPublish:"August 19th 2012",dateEndFifthStepPublish:"November 18th 2012",remainingDaysToSecondStep:"9 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"32585",title:"Dr.",name:"Nikolay",middleName:null,surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev",profilePictureURL:"https://mts.intechopen.com/storage/users/32585/images/1704_n.jpg",biography:"Prof. Dr. Nikolay Serdev, MD, PhD is a renowned cosmetic surgeon. He has trained hundreds of doctors globally in minimally invasive aesthetic surgery and medical procedures as well as in his author techniques. \nHe is the creator of Scarless Serdev Suture® lifts of face and body and pioneer in many other mini-invasive cosmetic surgery techniques: ultrasound liposculpture of face, body and leg elongation and beautification; T-excision and columella sliding in rhinoplasty; non-surgical body contouring; and their combination with his own suture to facial rejuvenation, beautification and tissue volumising. He is also a world authority in ultrasound-assisted (VASER) body contouring and has trained doctors from around the world in its basic and advanced techniques. \nDr. Serdev is Honorary professor at the New Bulgarian University in Sofia and director of its program of qualification in Aesthetic Surgery. He divides his time between his clinic, the University and short travels for international meetings, live surgery demonstrations and hands-on courses in countries of all continents. \nHe is editor and author of several comprehensive textbooks in the field of Cosmetic and Plastic Surgery, including Liposuction, Sutures Lifts on Face and Body Areas, Thread vs Suture lift techniques, Rhinoplasty and has authored many chapters in aesthetic surgery and medicine books, as well as original papers in medical journals.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"20",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"National Center of Infectious and Parasitic Diseases",institutionURL:null,country:{name:"Bulgaria"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1143",title:"Cosmetic Surgery",slug:"cosmetic-surgery"}],chapters:[{id:"45713",title:"Serdev Sutures® in Upper Face: Brow and Temporal Lift; Glabella Muscle Ligation",slug:"serdev-sutures-in-upper-face-brow-and-temporal-lift-glabella-muscle-ligation",totalDownloads:6044,totalCrossrefCites:0,authors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"45712",title:"Serdev Sutures® in Middle Face",slug:"serdev-sutures-in-middle-face",totalDownloads:4115,totalCrossrefCites:0,authors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"45711",title:"Serdev Sutures® in Lower Face and Neck",slug:"serdev-sutures-in-lower-face-and-neck",totalDownloads:2920,totalCrossrefCites:0,authors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"45710",title:"Serdev Sutures® Lifts in Body Areas",slug:"serdev-sutures-lifts-in-body-areas",totalDownloads:3640,totalCrossrefCites:0,authors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"45725",title:"Percutaneous Suspension Sutures to Change the Nasal Tip",slug:"percutaneous-suspension-sutures-to-change-the-nasal-tip",totalDownloads:3993,totalCrossrefCites:1,authors:[{id:"157270",title:"Dr.",name:"Desmond",surname:"Fernandes",slug:"desmond-fernandes",fullName:"Desmond Fernandes"}]},{id:"45719",title:"Chin Enhancement Using Serdev Suture: Five Case Reports",slug:"chin-enhancement-using-serdev-suture-five-case-reports",totalDownloads:2059,totalCrossrefCites:0,authors:[{id:"151252",title:"Dr.",name:"Meity",surname:"Hidayani",slug:"meity-hidayani",fullName:"Meity Hidayani"}]},{id:"45722",title:"Serdev Technique for Cervicoal Flaccidity and Mandibular Definition Utilizing “Serdev Sutures”",slug:"serdev-technique-for-cervicoal-flaccidity-and-mandibular-definition-utilizing-serdev-sutures-",totalDownloads:2467,totalCrossrefCites:0,authors:[{id:"150342",title:"Prof.",name:"Roberto",surname:"Tullii",slug:"roberto-tullii",fullName:"Roberto Tullii"}]},{id:"45718",title:"Suture Lifting and Liposculpture Integration in the Creation of Facial Esthetic Harmony",slug:"suture-lifting-and-liposculpture-integration-in-the-creation-of-facial-esthetic-harmony",totalDownloads:2247,totalCrossrefCites:0,authors:[{id:"151273",title:"Dr.",name:"Ronald",surname:"Feiner",slug:"ronald-feiner",fullName:"Ronald Feiner"},{id:"151341",title:"Dr.",name:"Chedly",surname:"Bouzouaya",slug:"chedly-bouzouaya",fullName:"Chedly Bouzouaya"}]},{id:"45723",title:"The Holistic Scarless Rejuvenation of the Face",slug:"the-holistic-scarless-rejuvenation-of-the-face",totalDownloads:3584,totalCrossrefCites:1,authors:[{id:"157271",title:"Dr.",name:"Desmond",surname:"Fernandes",slug:"desmond-fernandes",fullName:"Desmond Fernandes"}]},{id:"45708",title:"Midface Thread Lifting: Method of Internal Suturing",slug:"midface-thread-lifting-method-of-internal-suturing",totalDownloads:3589,totalCrossrefCites:1,authors:[{id:"149988",title:"PhD.",name:"Marlen",surname:"Sulamanidze",slug:"marlen-sulamanidze",fullName:"Marlen Sulamanidze"},{id:"151927",title:"Dr.",name:"George",surname:"Sulamanidze",slug:"george-sulamanidze",fullName:"George Sulamanidze"}]},{id:"45714",title:"Mastopexy ‒ How to Reach Consistent Results ‒ New Methods",slug:"mastopexy-how-to-reach-consistent-results-new-methods",totalDownloads:2068,totalCrossrefCites:0,authors:[{id:"149988",title:"PhD.",name:"Marlen",surname:"Sulamanidze",slug:"marlen-sulamanidze",fullName:"Marlen Sulamanidze"}]},{id:"45715",title:"Morphological Foundations of Facelift Using APTOS Filaments",slug:"morphological-foundations-of-facelift-using-aptos-filaments",totalDownloads:1847,totalCrossrefCites:0,authors:[{id:"149988",title:"PhD.",name:"Marlen",surname:"Sulamanidze",slug:"marlen-sulamanidze",fullName:"Marlen Sulamanidze"}]},{id:"45724",title:"Experience in Preventive Measures and Treatment of Complications at Face and Neck Thread Rejuvenation",slug:"experience-in-preventive-measures-and-treatment-of-complications-at-face-and-neck-thread-rejuvenatio",totalDownloads:3524,totalCrossrefCites:0,authors:[{id:"149988",title:"PhD.",name:"Marlen",surname:"Sulamanidze",slug:"marlen-sulamanidze",fullName:"Marlen Sulamanidze"}]},{id:"45716",title:"New Method of Face Elastic Thread Lift",slug:"new-method-of-face-elastic-thread-lift",totalDownloads:6167,totalCrossrefCites:0,authors:[{id:"149988",title:"PhD.",name:"Marlen",surname:"Sulamanidze",slug:"marlen-sulamanidze",fullName:"Marlen Sulamanidze"},{id:"151944",title:"Dr.",name:"Constantin",surname:"Sulamanidze",slug:"constantin-sulamanidze",fullName:"Constantin Sulamanidze"}]},{id:"45721",title:"Minimally Invasive Face and Neck Lift Using Silhouette Coned Sutures",slug:"minimally-invasive-face-and-neck-lift-using-silhouette-coned-sutures",totalDownloads:6279,totalCrossrefCites:4,authors:[{id:"151254",title:"Dr.",name:"Peter",surname:"Prendergast",slug:"peter-prendergast",fullName:"Peter Prendergast"}]},{id:"45709",title:"T3 - Soft Face Lift by Suspension Surgery",slug:"t3-soft-face-lift-by-suspension-surgery",totalDownloads:5219,totalCrossrefCites:0,authors:[{id:"151322",title:"Prof.",name:"Pier Antonio",surname:"Bacci",slug:"pier-antonio-bacci",fullName:"Pier Antonio Bacci"}]},{id:"45720",title:"Correction of Face Involutional Changes by Method of Light Lift Elegance Thread Reinforcement",slug:"correction-of-face-involutional-changes-by-method-of-light-lift-elegance-thread-reinforcement",totalDownloads:2862,totalCrossrefCites:0,authors:[{id:"151605",title:"Dr.",name:"Svetlana",surname:"Shostak",slug:"svetlana-shostak",fullName:"Svetlana Shostak"}]},{id:"45717",title:"Experience in the Use of Barbed Threads and Non-Barbed Serdev Sutures in Face and Body Lift – Comparison and Combination",slug:"experience-in-the-use-of-barbed-threads-and-non-barbed-serdev-sutures-in-face-and-body-lift-comparis",totalDownloads:9040,totalCrossrefCites:3,authors:[{id:"151562",title:"Dr.",name:"Vilma",surname:"Padin",slug:"vilma-padin",fullName:"Vilma Padin"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"24368",firstName:"Ana",lastName:"Pantar",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/24368/images/4736_n.jpg",email:"ana.p@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"330",title:"Advanced Techniques in Liposuction and Fat Transfer",subtitle:null,isOpenForSubmission:!1,hash:"b46d7571b3a7f78d03a83f809c7a637f",slug:"advanced-techniques-in-liposuction-and-fat-transfer",bookSignature:"Nikolay Serdev",coverURL:"https://cdn.intechopen.com/books/images_new/330.jpg",editedByType:"Edited by",editors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5110",title:"Miniinvasive Techniques in Rhinoplasty",subtitle:null,isOpenForSubmission:!1,hash:"795ab5e7adfc30a3907f52b636c45029",slug:"miniinvasive-techniques-in-rhinoplasty",bookSignature:"Nikolay Serdev",coverURL:"https://cdn.intechopen.com/books/images_new/5110.jpg",editedByType:"Edited by",editors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}],productType:{id:"3",chapterContentType:"chapter",authoredCaption:"Authored by"}},{type:"book",id:"7047",title:"Botulinum Toxin",subtitle:null,isOpenForSubmission:!1,hash:"2a6791462a0bbc32c6da3218dcf5ac28",slug:"botulinum-toxin",bookSignature:"Nikolay Serdev",coverURL:"https://cdn.intechopen.com/books/images_new/7047.jpg",editedByType:"Edited by",editors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5346",title:"Body Contouring and Sculpting",subtitle:null,isOpenForSubmission:!1,hash:"79bcaa74382f64066fe10bf59e89be6d",slug:"body-contouring-and-sculpting",bookSignature:"Nikolay P. Serdev",coverURL:"https://cdn.intechopen.com/books/images_new/5346.jpg",editedByType:"Edited by",editors:[{id:"32585",title:"Dr.",name:"Nikolay",surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"797",title:"Rhinoplasty",subtitle:null,isOpenForSubmission:!1,hash:"81bc805ee420b3b2f35cc0a009b6566c",slug:"rhinoplasty",bookSignature:"Michael J. Brenner",coverURL:"https://cdn.intechopen.com/books/images_new/797.jpg",editedByType:"Edited by",editors:[{id:"63530",title:"Dr.",name:"Michael",surname:"Brenner",slug:"michael-brenner",fullName:"Michael Brenner"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editedByType:"Edited by",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7836",title:"The Art of Body Contouring",subtitle:null,isOpenForSubmission:!1,hash:"983c155c9b836c8e4947bb3946694bc9",slug:"the-art-of-body-contouring",bookSignature:"Alexandro Aguilera",coverURL:"https://cdn.intechopen.com/books/images_new/7836.jpg",editedByType:"Edited by",editors:[{id:"162339",title:"Dr.",name:"Alexandro",surname:"Aguilera Salgado",slug:"alexandro-aguilera-salgado",fullName:"Alexandro Aguilera Salgado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"60263",title:"True Mitochondrial tRNA Punctuation and Initiation Using Overlapping Stop and Start Codons at Specific and Conserved Positions",doi:"10.5772/intechopen.75555",slug:"true-mitochondrial-trna-punctuation-and-initiation-using-overlapping-stop-and-start-codons-at-specif",body:'\n
Transfer RNAs are key partners in the ribosome-translation machinery. Generally, they are composed of c.70–90 nucleotides (nts). Moreover, they are the most abundant nucleic acid species, constituting up to 10% of all cellular RNAs [1]. Therewith, the number of tRNA molecules is, e.g., about 2 × 105 in Escherichia coli and 3 × 106 in yeast cell [2]. Due to their anticodon, they read genetic information on mRNAs and deliver codon specified amino acids attached to their distal 3′-extremity for peptide bond synthesis on the ribosome. In this sense, tRNA is a key molecule which makes it possible to pass from a covalent bond between a RNA and an amino acid (fossil trace of the RNA world to the RNA/protein world transition) to peptide bonds (RNA/protein world). Genes specifying tRNAs (noted trn) are present in prokaryotic and nuclear genomes and in most of the DNAs of organelles (chloroplasts and mitochondria). Usually, tRNAs have a characteristic canonical cloverleaf secondary structure made up of the aminoacyl acceptor-stem and the D-arms (as it contains dihydrouridine), anticodon-arms, and T-arms (for the sequence TΨC where Ψ is pseudouridine), the hairpins, or “arms” consisting of a stem (helicoidal region in 3D) ending in a loop (Figure 1). The lengths of each arm, as well as the loop “diameter,” vary from the tRNA type and from species to species. Furthermore, deduced trn sequences and even sequenced mature tRNAs exhibit reduced D-arms or T-arms or even lacking at least one of them, and in the extreme situation such as in Enoplea (nematodes) mitochondrial (mt)-trn genes are totally armless [3]. However, around 90% of the mt-tRNAs fold into the canonical cloverleaf structure [4]. In all the genetic systems, the tRNAs can carry a myriad of idiosyncratic posttranscriptional chemical modifications (e.g.,
Typical cloverleaf secondary structure of a metazoan mt-ss-tRNA (left) with 3D image of an L-shaped tRNA (right). In 2D structure, the standard numbering was applied [5]. The first two nucleotides of the variable region and those of the D-loops and T-loops were represented by circles. The diagonal dashed line indicates the approximate separation between the “top half” and the “cherry-bob”/“bottom half”. Nucleotide types were given for UAG10 and AUG49 triplets, the discriminator base (which is preferentially an A), and the CCA tail at the 3′-end. Short lines connect nucleotides forming Watson-Crick pairing within stems. Coloring: acceptor-stem in purple, D-arm in red, anticodon-arm in blue with the anticodon in black, T-arm in green, and CCA tail in orange. The yellow segments represented respectively in descending order of size, the variable region (connector 2), the connector 1 and the nt 26. 3D structure reproduced with the kind permission of Prof. N.R. Voss (Roosevelt University, Ill.) https://commons.wikimedia.org/wiki/File:3d_tRNA.png.
The ribosome allows the best possible spatial arrangement of the various partners and ensures catalysis, but the adaptor molecule which acts as a link between codes of mRNA and amino acids of polypeptides is the tRNA. In order to fill this major role, tRNAs have two distinct characteristics corresponding to two different genetic codes, the anticodon and the operational codes. The latter which is mainly embodied in the acceptor-stem allows to bind covalently and with high specificity an amino acid to a tRNA, a reaction catalyzed by a specific aminoacyl-tRNA synthetase (aaRS) [6]. The operational code might have actually predated the “classic” code associated with anticodons [7]. Moreover, the tRNAs exhibit diversity in uniqueness, all of them must be similar for entering the ribosome machinery; therefore, they generally look structurally homogeneous, especially in their secondary and tertiary structures even if “non-classical” tRNAs are known [3]. Moreover, cloverleaf structure and especially the tertiary interaction network governing the L-shaped tRNA architecture imply conserved and semiconserved bps and nts. On the other side, each type of tRNA structures must interact specifically with aaRSs and posttranscriptional modification enzymes, which implies that parts of their sequences and of their structures (as the V-R size) allow to distinguish them.
\nReduced bacterial and most organelle genomes do not encode the full set of 32 tRNA species required to read all triplets of the standard genetic code according to the conventional wobble rules. Superwobbling where a single tRNA species contains modifications of the anticodon-loop, such as an hypermodified uridine at the wobble position 34 of the anticodon, reads all 4 nts at third codon position and has been suggested as a possible mechanism for how reduced tRNA sets may be functional [8]. Indeed, many metazoan mtDNAs have only a total of 22 tRNAs, apparently sufficient to recognize all codons (two tRNAs each for serine and leucine and one tRNA for each of the other 18 amino acids). However, superwobbling induces a reduced translational efficiency, which could explain why most organisms have adopted pairs of isoaccepting tRNAs over the superwobbling mechanism [9]. Moreover, e.g., in Cnidaria (sea anemones, corals, etc.) or Chaetognatha (marine invertebrates), current mtDNAs have lost several of their trn genes, and the absence of an apparently full set of mt-trn genes has also been mentioned [10]. Studies have investigated the fate of missing tRNAs and their corresponding aaRSs [11], and in many cases, the lost tRNAs are functionally replaced by imported nucleus-encoded tRNAs [10]. However, recent search strategies suggest that efficient reanalyzes detect several tRNA-like structures (TLS), which can be efficient tRNAs [12].
\nCompared to mitochondria found in other eukaryotic kingdoms, those of metazoa are massively reduced in their genetic structure [4]. Their mtDNA is a short, circular molecule that generally contains about 13 intronless, protein-coding genes, all of which are involved in aerobic respiration (also called oxidative phosphorylation) [13]. Moreover, the coding sequences of genes are usually separated by at most a few nts and long polycistronic precursor transcripts may be processed into mature mRNA and rRNA by precise cleavage of the 5′ and 3′-termini of the flanking tRNAs. This processing, which is known as the tRNA punctuation model [14], is mediated by RNase P and Z endonucleases, respectively [15]. However, this model is not always applicable, genes are not bound by trn genes or these latter may not be involved in the processing of precursor RNAs. Besides, in several taxa mt-mRNAs, rRNAs and even tRNAs may be oligoadenylated or polyadenylated [16]. This has numerous consequences with potentially dual and opposite roles: this promotes transcript stability or offers a target for initiating degradation. Overlapping genes on the same DNA strand occur throughout metazoa [17]. Therefore, the termination points of the protein-encoding genes could be difficult to infer as stop codons (generally UAA or UAG) may be absent. It is accepted that abbreviated stop codons (U or UA) are converted to UAA codons by polyadenylation after transcript cleavage, and this has been confirmed by analyzes of transcripts in some cases [18]. Sometimes, the initiation codon may also not have been detected. For several protein-encoding genes, the question of a possible overlapping with adjacent downstream or upstream trn genes is often raised [19]. Moreover, overlaps between adjacent mt-trn genes are frequent, but it is out of our topic [19, 20].
\nIncidentally, in 2004, searching for chaetognath mt-trn genes [21], it was observed that tRNAs bear nt triplets corresponding to stop or start codons at precise conserved positions, and this constitutes the original topic of this chapter.
\nMost of the research was done in two databases which include primary sequences and graphical representations of tRNA 2D structures, tRNAdb (
Visual observations of tRNA deduced 2D structures suggested that nt triplets which could correspond to stop or start codons seemed to be particularly represented at specific positions. The UAR (R for purine) triplets at position 8–10 in the standard numbering and therefore will be named UAR10, whereas the potential initiation codons whose last nt is at the position 49 will be called AUR49 (Figure 1). We chose to number the codons only according to their last nt because the nt 47 is frequently missing in the metazoan mt-tRNAs. Analyzes focus on DNA; hence, these are usually annotated TAR or ATR instead of UAR or AUR. All the tRNAs which bear one or both of these codons are named ss-tRNAs (ss for stop and start) or ss-trn for the corresponding genes. Using tRNAdb and mitotRNAdb databases, these triplets’ frequencies were investigated in different taxa including nuclear and organelle genomes for eukaryotes (Table 1). Excluding taxa for which the number of trn genes is too low for statistical analysis, TAR10 always occurs at high frequencies, whether in prokaryotic, nuclear, or organelle genomes. Values range from 41.1% for fungi to 81.6% for pseudocoelomates. In all the taxa and all tRNA species combined, the percentage of TAG10 triplets is always significantly higher than those of TAA10. The differences are very important in prokaryotic and nuclear genomes, since the percentage of TAA10 is always less than 1, while that of TAG10 is at least 40%. Within the organelle genomes, the difference is smaller but can vary by a factor of 2.5–22.
\nPercentage of TAR10 and ATR49 triplets in various taxa independently of the V-R size.
Metazoan taxa are in italics. Abbreviation: Nb, number of trn genes. TAR + ATR for % of trn genes bearing the two types of triplet. * Mitochondria.
As the TAR10 triplet (principally TAG) is present in at least 40% of the trn genes for all taxa and genomic systems combined, it could have been present in trn genes of the Last Unicellular Common Ancestor (LUCA), which presumably lived some 3.5–3.8 billion years ago [24]. It is probably an ancestral character which was present in proto-trn sequences. As the percentage of TAA10 strongly increases in trn genes of organelles, one can ask whether this character was not already present in their bacterial ancestor. It is now assumed that despite their diversity, all mitochondria derive from an endosymbiotic α-proteobacterium which has been integrated into a host cell related to Asgard Archaea approximately 1.5–2 billion years ago [25]. However, the earliest fossils possessing features typical of fungi date to 2.4 billion years ago [26]. Moreover, the eukaryotic cells would be chimeras constituted of an archaebacterium and one or more Eubacteria [27]. In addition, all current models for the origin of eukaryotes suggest that the eukaryotic common ancestor had mitochondria. Therefore, as the level of TAA10 is very low in trn genes of α-proteobacteria, it could therefore be a derived trait that may be related to the increase in AT% in mtDNA and/or recognition constraints by mt-aaRSs and modification enzymes. Similarly, it is generally accepted that all chloroplasts and their derivatives are derived from a single cyanobacterial ancestor [28], and in current cyanobacteria, the respective percentage of TAG10 and TAA10 triplets are 62.5 and 3.6, respectively. The increase in the percentage of TAA10 characterizes organelles.
\nIn all the taxa for all tRNA species combined, the ATR49 triplets are always present in smaller numbers than TAR10. Moreover, their numbers are negligible except in organelle genomes, mainly mitochondria. The low level of ATR49 triplets in Pseudocoelomata is due to the frequent absence of T-arm in their mt-tRNAs. In mitochondria, in some taxa, the frequency of ATG49 is higher than of ATA49, while in others, the opposite occurs. The variability is not surprising, given approximately 2 billion years of mtDNA evolution [29]. It must be noted that the nt G is overrepresented at the 5′-end of the 5′-acceptor- and D-stems, quite often at the 5′-end of the T-stem but rarely at the equivalent position of the anticodon-stem. In taxa where the percentage of ATA49 is higher than those of ATG49, G is most often not the nt majority at the 5′-end of the T-stem. Moreover, differences between the relative percentages of ATG49 and ATA49 could be due, at least in part, to variations in the AT% in organelle DNAs. The percentage of ATR49 is very low in α-proteobacteria and weaker in this last taxon compared to all Proteobacteria or Eubacteria, and it is also very weak in cyanobacteria, and so the significant rate of ATR49 triplets would seem to be a derived condition of organelle DNAs rather than a conserved primitive state lost in current prokaryotes. This trait probably appeared during the transition from endosymbiotic bacterium to permanent organelle that implied massive evolutionary changes including genome reduction, endosymbiotic and lateral gene transfers, and emergence of new genes and the retargeting of proteins [25]. The timing of the mt-endosymbiosis and of the proto-mitochondria to mitochondria transition is uncertain, but one might trace the origin of the ATR49 triplets between at least the first eukaryotic common ancestor (FECA) and the last eukaryotic common ancestor (LECA). A second event occurred, at least, in the mitochondria of the ancestors of Opisthokonta (i.e., Metazoa and Fungi), which would have led to a net increase in numbers of ATR49. ATR49 means that the last two nts of the V-R are AT. It turns out that this mainly concerns the mt-trn genes, whose V-R has only 4 nts, which are almost exclusively present in the Fungi/Metazoa clade.
\nThere are large differences in the frequencies of the TAR10 and ATR49 triplets depending on the species of trn genes (Table 2) and taxa (data not shown), and the selective variations in some taxa suggest that the increase in frequency for some types of triplets would be much more recent than mentioned above; in addition, decreases are also observed. There are, however, very conservative trends such as the presence of ATR49 triplets in genes specifying tRNA-Ala. Analyzes on mt-trn genes of Deuterostomia for which a great number of sequences for each type are available (from 1085 to 1382) show that only the tRNA-Cys and tRNA-Glu species have intermediate TAR10 percentages (Table 2). In all other tRNA species, the values are extreme, 9 and 10 tRNA species with values ranging from 0.4 to 9.8% or greater than 82.4%, respectively (Table 2). In contrast, half of the tRNA species have low ATR49 percentages (≤ to 10.8), and for only four types percentages are ≥77.8. There would also be a tendency suggesting that tRNA species with very high or very low percentages of TAR10 most often have low ATR49 (the tRNA species with the 7 highest and the 8 lowest TAR10 percentages exhibit 10 out of 11 of the lower percentages for ATR49).
\nPercentages of TAR10 and ATR49 by mt-trn gene species in Deuterostomia.
The trn genes are represented by three-letter codes of amino acids. The tRNAs are ordered by decreasing TAR10 percentages. The percentage values ≥ to 77.8, between 17.0 to 56.5 and ≤ to 10.8 are underlined in yellow, blue, and green, respectively.
In order to investigate possible implications of TAR10 and ATR49 triplets in translation, analyzes were performed in GenBank using as keywords: “TAA stop codon is completed by the addition of 3\' A residues to the mRNA”, “alternative start codon” or “start codon not determined” and mitochondrion (or mitochondrial DNA) complete genome. Then, it was researched whether upstream (for start codon) or downstream (for stop codon) of the protein-encoding gene was a trn gene. When a trn gene was found, TAR10 or ATR49 triplets were searched, and the same investigation was then made in conspecific mt-genomes. Using this strategy, these triplets have been only found in metazoan mtDNAs, in which overlapping mt-trn genes have long been known.
\nAn example of putative uses of TAR10 triplets as stop codons is presented in Table 3 for a subclass of parasitic flatworms (Platyhelminthes : Eucestoda). Their mt-genetic code has only UAG and UAA as stop codons, avoiding possible bias due to use of other types of termination codons. In 51 among 66 complete mt-genomes, the first in-frame potential stop codon of the cox1 gene is in the downstream trnT gene (24 cases with TAG10 suggesting a 10 nt overlap between cox1 and trnT genes). Authors considering that this long overlap would be impossible have proposed a number of alternative options favoring overlap avoidance (e.g., [30]). (1) cox1 might use an earlier atypical stop codon. (2) The 3′-end of the cox1 mRNA could have an abbreviated stop codon (U or UA instead of UAG10) upstream the trnT gene which is completed by polyadenylation. (3) If in the potential long transcript, the cleavage would occur just after G10, the cox1 mRNA would end with the complete UAG10 as stop codon and the first 10 nts of the trnT gene would be added by an unknown editing process. (4) The trnT gene would be shorter in its 5′-end lacking the nts from 1 to 8 or 9, e.g., this has been proposed for the mt-trnT of Cyclophyllidea (Echinococcus granulosus, Hymenolepis diminuta, and Taenia crassiceps). If the full stop codon is used, then there is only a single nt (G10) overlap between cox1 and trnT. Moreover, if the end of the cox1 gene is at the level of T9, the stop codon would complete by polyadenylation; whereas if the protein gene has a complete stop codon, the nt G10 would be added by edition. In the alternative structures, the D-arm is absent, whereas it is typical for this tRNA in digeneans (a class of Platyhelminthes) and in other phyla. However, mt-trnT genes issuing from Cyclophyllidea for which the first potential stop codon is at different positions (upstream or downstream the trnT gene, or in this last gene but upstream or downstream TAG10 or at this last position) exhibit similar secondary structures, including a D-arm. In addition, the high level of nt conservation in the 5′-end of the trnT genes of cestoda (i.e., G1, G2, T7, T8, A9, G10, T11, T12 and A14) suggests strongly that the 5′-acceptor-stem and the D-stem are under positive selection. All this implies that the hypothesis of D-armless tRNAs is, according to us, improbable.
\nPosition of the first complete in-frame stop codon of the cox1 gene versus the following trnT gene in Cestoda (Platyhelminthes).
Species names are followed by their accession number(s). *: sequences for which the authors of these latter considered that there was an abbreviated stop codon and this latter was upstream the trn sequence. Symbols: X TAR10 was the first in-frame putative stop codon; §, $, & and μ, the putative stop codon was upstream the trn gene (tg), in the tg but upstream or downstream TAR10 or nts 8–10, downstream the tg, respectively. Abbreviations: P. c., Pseudanoplocephala crawfordi; Proteoce., Proteocephalidea; stop cod., putative stop codon according to the authors of the sequences.
Concerning the putative ATR49 start codon, in GenBank, the number of complete mt-genomes found using the keywords previously mentioned was relatively low; moreover, in some cases, the upstream gene encoded a protein, specified a rRNA and/or there was only one mention for a given taxon. A significant example within Deuterostomia (frogs) is presented in Table 4. In the superfamily Hyloidea, the ATA49 triplet is frequently the first potential complete start codon at the level of the gene pair encoding and specifying NAD1 and tRNA-Leu2, respectively. In two families (Bufonidae, Hylidae), for all the sequences (16 belonging to 14 different species), the first ATR triplet found in frame in the ORF of the nd1 gene is ATA49. For four sequences belonging to three other frog families, the ATR49 triplet is missing from the trnL2gene; moreover, an ATA triplet is integrally present in the V-R of the trnL2 gene of Heleophryne regis, but it is not in frame with the following gene. For these last four cases, the authors of the sequences proposed alternative start codons. This seems obligatory, but this has not been experimentally verified. For several authors who have sequenced parts of mtDNAs of Hylidae, the nd1 gene would start at ATA49 for about 140 sequences (e.g., Roelants and Bossuyt [31]).
\nPosition of the first putative start codon of the nad1 gene versus the upstream gene specifying tRNA-Leu2 in Hyloidea, a superfamily of frogs.
X: ATA49 as the first putative in-frame start codon. *: “start codon not determined” according to the authors of the sequences. Alternative start codons are given by the authors of the sequences. §: alternative start codon in the trn gene. Abbreviations: Dendro, Dendrobatidae; Cerato., Ceratophryidae; Heleo., Heleophrynidae.
In the two studied taxa, Blast analyzes of the NCBI ESTs and SRA (SequenceRead Archive) databases have been performed, but no result supports the proposed hypotheses: transcripts starting at an ATR49 or terminating at a TAR10 were not found. However, for each taxon, few mt-transcripts occur, and fully matured transcripts are even rarer.
\nForemost, biases in the search strategy cannot be excluded, but the important point to note is that mt-genomes of animals, fungi, protists, and plants differ drastically in all major characteristics including gene content and large size variation. Generally, metazoans have ultra-compact mtDNAs (from c.10,000 to c.50,000 bp); usually, nonfunctional sequences are rapidly eliminated, and there are short intergenic regions and frequent overlaps [13]. However, nonbilaterian mt-genomes have higher variation in size, gene content, shape, and genetic code [32]. The mtDNA size range is from 30,000 to 90,000 bp in fungi, and generally, intergenic regions are relatively long. A broader range of mtDNA size is found in higher plants (from 0.2 × 106 to about 11.3 × 106 bp [33]), and the largest known mt-genome in this lineage exceeds sizes of reduced bacterial and nuclear genomes [34]. The increased sizes of plant mtDNAs are mostly due to noncoding DNA sequences, large inserted nuclear regions, and many introns and not to a large increase in gene numbers. The nuclear-derived sequences amount to up nearly half of their size as in melon [35], and so presence of mt-trn genes with nuclear origin cannot be excluded. Although not directly correlated, intergenic distances are generally much higher in larger genomes, reducing the number of overlaps. In addition, the situation of plant mt-tRNAs is very complex. Indeed, they contain few “native” tRNAs expressed from true mt-trn genes. They possess “chloroplast-like” trn genes inserted into the mtDNA. They compensate the loss of mt-trn genes by importing several nucleus-encoded tRNAs [36]. In addition, most often in plants, the standard code applies to the reading of organelle genomes, even if ATA is frequently used as start codon. Metazoan mt-genomes are generally small, very constrained and exhibit several gene overlaps between trn and protein-encoding genes or between trn genes. Their tRNAs have sequence and structural peculiarities and tend to shortening [19]. Our exploration is not exhaustive, but this might explain the presence of putative stop or start codons specifically within mt-ss-trn genes of this taxon.
\nOne may wonder why the hypotheses concerning the TAR10 and ATR49 triplets were not proposed before? At least, the presence of these characteristic triplets could have been observed by some authors but considered as having no connection with the translation of neighboring protein genes. Among the first sequenced and the most studied were mt-genomes of Homo sapiens (J01415) and Mus musculus (J01420). In these latter, no putative start or stop codon occurs at these positions within trn sequences adjacent to protein genes (data not shown).
\nIn the living world, many nucleic sequences with secondary structures playing a physiological role involving stop and/or start codons have been discovered. Some representative examples are briefly presented here. (1) The tropism switching of the bacteriophage BPP-1 is mediated by a phage-encoded diversity-generating retroelement, which introduces nt substitutions in a gene that specifies a host cell-binding protein (Mtd) [37]. The nt substitutions are introduced in a variable repeat located at the 3′-end of this gene. Two nts after this region, the UAG stop codon is present, and its last nt is situated at the 5′ beginning of the 5′-stem of a hairpin. Both the UAG codon and hairpin are required for phage tropism switching. (2) Programmed translational bypassing is a process, whereby ribosomes “ignore” a substantial interval of mRNA sequence. In a bacteriophage T4 gene, bypassing requires translational blockage at a “takeoff codon” immediately upstream of the UAG stop codon, and both codons are in the 5′-stem of a hairpin; moreover, this region is mobile [38]. (3) The operon flgFG of the bacterium Campylobacter jejuni can encode two genes (flgF and flgG). Its expression in E. coli produces a fusion protein probably due to ribosomal frameshifting (translational hopping) [39]. The putative hop region contains, among others, a hairpin beginning by the last nt of the UAA stop codon of the first mRNA. The AUG start codon of the second gene is in the loop of the following hairpin. (4) In Eubacteria, riboswitches are regulatory segments of DNA or mRNA that can bind a small molecule (the effector), which repress or activate their cognate genes at transcriptional and/or translational levels. In the riboflavin and cob operons, conformational changes can form a stem loop which sequesters the translational start site, consisting of the Shine-Dalgarno (SD) sequence plus start codon thus preventing gene translation [40]. (5) Bacterial transfer-messenger RNAs (tmRNAs) have dual TLS and mRNA-like properties. They rescue stalled ribosomes on mRNAs lacking proper translational stop signal; the tRNA-like structure acts first as an alanine-tRNA, and then the short mRNA reading frame is translated and the product is released [41]. This trans-translation terminates at the stop codon terminating the tmRNA reading frame. This stop can be in a little loop or totally or partially integrated in the stem of a hairpin-like structure. In eukaryotes, structurally reduced tmRNAs (no mRNA-like domain) rarely occur in chloroplasts [42] and in mt-genomes (in Jakobids, presumably close to the most ancient living eukaryotes with bacterial-like mt-genome) [41]. Moreover, tmRNA TLSs function even without any canonical initiation factors. These examples show that start or stop codons located in hairpin may have various functions, as we suggest for TAR10 and ATR49.
\nAncient tRNAs probably had diverse functions in replication and proto-metabolism before protein translation [43] and modern tRNAs have also various functions in all the living organisms [1]. These functions include cell wall synthesis, protein N-terminal modification, nutritional stress management, porphyrin biosynthesis (heme and chlorophyll), lipid remodeling, and initiation of retrovirus reverse transcription. Accumulating experimental evidence suggests also that they have important regulatory roles in translation, viral infections, and tumor development (reviewed in [44]). Mt-tRNAs interfere with a cytochrome c-mediated apoptotic pathway and promote cell survival [45] and function as replication origins [46]. Moreover, nuclear-tRNA abundance and modifications are dynamically regulated, and tRNAs and their tRNA-derived RNA fragments (tRFs) are centrally involved in stress signaling and adaptive translation [47, 48]. This suggests that the choice of cleavage sites of mRNA transcripts with or not part of the neighboring ss-tRNA could be dynamic and also respond to environmental changes. Some of the noncanonical translation functions of tRNAs can also be driven or enhanced by their ability to adopt different complex three-dimensional structures, and these conformational changes can be linked to functional states [49]. Moreover, the tRNA multifunctionality has also been considered to be, at least in part, random due to the high amount of tRNA species within the cell [1]. In addition, the mt-trn genes represent natural pause sites for replication forks and could also prone double-strand breaks [50], and their role, as “punctuation signals,” for processing of mtDNA polycistronic transcripts has already been mentioned.
\nEnormous numbers of tRFs in all domains of life were found in the last decade [44]. In the plant Arabidopsis thaliana, nucleus-, plastid-, and mt-encoded tRNAs can produce tRFs [36]. The tRFs are not randomly degraded tRNAs. Experiments showed several functions including regulation of tumor development and viral infections [44]. Degradations resulting from cleavages at TAR10 and ATR49 triplets could produce a conformation exhibiting two loops linked by a forked-stem structure, roughly resembling a pair of cherries, so called “cherry-bob” (Figure 2). Our hypothesis predicts this structure which however has never been observed [51].
\n2D “cherry-bob”/“bottom half” structure. AUG/UAG triplets are discussed in text. Colors as Figure 1.
Metazoan mt-genomes are believed optimized for rapid replication and transcription. Potentially, TAG10 and ATR49 make transcription/translation more complex but perhaps more efficient. Examples in the Section 3.2 (i.e., Eucestoda) suggest mt-overlaps appeared 100s millions of years (MY) ago, enabling co-evolution between protein-encoding genes and those specifying tRNA.
\nOverlaps involve numerous constraints for genes including sequence bias. Constraints are probably less stringent for trn genes, which can evolve rapidly because relatively standard secondary structure coupled with a specific anticodon might suffice for tRNA function [52]. Incomplete cloverleaf structures may also be repaired post-transcriptionally [53].
\nAlternative processing might be possible for the production of either a supposed complete mRNA or a complete tRNA. In the first case, the synthesis of new complete mRNAs could be promoted by high mitosolic tRNA numbers. Moreover, amino acid starvation can regulate mt-tRNA levels [54]. However, if mt-tRNAs already present are not destroyed, translation would not immediately stop because mt-tRNA half-life which is lower than that of their cytosolic counterparts can nevertheless exceed 10 h [54]. Moreover, aberrant mt-tRNAs can be corrected by RNA editing during or after transcription, and this process appeared independently several times in a wide variety of eukaryotes [5]. As an extreme example, due to large overlaps between trn genes, up to 34 nts are added post-transcriptionally during the editing process to the mt-tRNA sequences encoded in an onychophora species, rebuilding the acceptor-stem, the T-arm, and in some extreme cases, the V-R and even a part of the anticodon-stem [55]. In that species, several edition types must be combined, including template-dependent editing [55]. This last example suggests that complete tRNA could be restored after a cleavage just upstream of ATR49. However, edition of parts of the 5′-end of tRNAs seems more problematic. Besides, mRNAs with upstream or downstream ss-tRNA can form a partially double strand region with a homologous ss-tRNA at the level of the acceptor-stem. This might induce mRNA degradation via antisense mechanisms. In bacteria, uncharged tRNAs cause antisense RNA inhibition [56], and small interfering cytosolic tRNA-derived RNAs exist [57]. Modifications (methylation, edition, etc.) of incomplete tRNAs generated after cleavages of polycistronic transcripts at TAR10 or ATR49 triplets would indicate regulatory functions.
\nPutative use of TAR10 or ATR49 triplets affects protein length. When in frame, this could generate a protein at least 3 or 9 amino acids longer, respectively. Extension length depends on positions of upstream stop codons completed by polyadenylation and/or on downstream (alternative) initiator codons. Not only complete proteins may be functional. Depending on cleavage positions in polycistronic transcripts, consequences may be neutral, disadvantageous, or favorable in specific contexts. In yeast, extended proteins can increase fitness under stress conditions [58]. In addition, in bacteria and in organelles, alternative initiation codons decrease efficiency [5], and it must be noted that ATR49 triplets are “canonical” start codons.
\nIn other conditions, incomplete mRNAs could be favored. Mitosolic mRNA accumulations can be due to lack of translation because of tRNA paucity. Thus, high mRNA levels might indirectly promote cleavage of entire tRNA transcripts while reducing the synthesis of new functional mRNAs and favoring translation of those which are already present into proteins. Presence/absence of hairpins involving stop or start codons might regulate translation. This regulation could involve proteins that stabilize the hairpins or posttranscriptional modifications. Moreover, translational products of “incomplete” mRNAs might have housekeeping functions.
\nRegulation of alternative processing producing either complete tRNAs or complete mRNAs requires elucidation. Factors, probably proteins, need characterization. Note that metazoan mt-atp8 and atp6 genes overlap (mainly by 10 bp in vertebrates) and are transcribed as joint bicistronic transcript [59]. This proven overlap is inherent to mt-metabolism. Hence, similar overlaps assumed for TAR10 triplets are plausible.
\nOverlap conservation might reflect the need to produce bicistronic transcripts (5′-tRNA-mRNA-3′ or 5′-mRNA-tRNA-3′) or functional constraints at protein level (i.e., preserving specific amino acid patterns upstream or downstream the ORF). When overlap regions have conserved, amino acid sequences at the protein N- or C-terminal functional constraints at protein level for overlaps are probable [19]. In viruses, mutation rates are low in DNA regions coding for multiple protein products in separate reading frames (called overprinted genes) because point mutations compatible with functional products from all frames are rare. In these regions, the frame is said “close off.” Partial overlap between protein-encoding genes and ss-trn genes would present similar situations explaining greater conservation of extremities of protein and tRNA sequences when the corresponding genes overlap. This lock almost only concerns the ss-tRNA’s “top half,” limiting changes in the region interacting with many processing enzymes. The ss-trn genes could also regulate translation upstream, bicistronic mRNA/ss-tRNA transcripts could be more stable, and likewise, ss-trn genes could also play roles in replication and transcription.
\nMethylation is much rarer in mt- than nuclear-DNA [60]. However, these might occur at trn genes (particularly around TAR10 and ATR49) and might have deleterious consequences especially because differential mtDNA methylations are linked to aging and diseases (including diabetes and cancers) [60]. Methylation of nts of UAR10 and AUR49 is known as those of A9 and G10 which can be important for correct tRNA foldings [61]. We are unaware whether posttranscriptional modifications occur on bicistronic mt-transcripts containing complete or partial tRNAs. This would be worth investigating including possible consequences on maturation and translation.
\nSeveral codon-amino acid reassignments are known, mainly from mitochondria [62, 63]. In 11 different mt-genetic codes, UGA stops code for tryptophan and AUA codes for methionine instead of isoleucine in 8 and 5 mt-genetic codes, respectively [63]. Both reassignments avoid potential errors along traditional wobble rules. Reassigning UGA-stop to UGA-Trp fits the “capture” hypothesis, and UGA codons mutate first to synonymous UAA codon in AT-rich mt-genomes. Then, UGA reappears occasionally by mutations, free for “capture” by an amino acid, like Trp [64]. AUA is frequently used as alternative initiation codon. Its reassignment to internal sense Met codon could also have evolved in AT-rich genomes. Moreover, the standard genetic code assigns six codons to arginine, whereas two would fit arginine’s relatively low frequency in current proteins [65]. In 8 out of 11 mt-codes, different strategies reduce Arg codons to four, AGR reassignments to other amino acids (in six genetic codes), lack of two Arg codons (CGA and CGC yeast mt-code), and AGR as terminators in vertebrates. These AGR codons were believed mt-stop codons since early vertebrate evolution [66]. However, at least in humans, AGRs are not recognized terminators [67], suggesting that AGRs have no assignment. Hence, the vertebrate mt-genetic code could be the most optimized known genetic code (that of yeast was not retained because four Leu codons were reassigned to Thr). Characteristics of the nt triplets at the position 8–10 and ending at position 49 should be analyzed for each mt-genetic code.
\nVarious models could explain tRNA origins (see reviews [68, 69, 70]). The modern tRNA cloverleaf structure might result from direct duplication of primordial RNA hairpins (e.g., [68]). However, studies lend strong support to the “two halves” hypothesis [43], in which tRNAs consist of two coaxially stacked helices with presumed independent structural and functional domains. These correspond to the “top half” containing the acceptor-stem and the T-arm and the “bottom half” with the D-arm and anticodon-arm (Figure 1). The 2D representation of the latter corresponds to the “cherry-bob” structure (Figure 2). The “top half” of modern tRNA embeds the “operational code” in the identity elements of the acceptor-stem that interacts with the catalytic domain of specific aaRSs and is recognized by RNases P and Z and the CCA-adding enzyme (therefore mainly RNA end processing reactions) [70, 71]. This domain also interacts with translation elongation factor Tu and one rRNA subunit [71]. The importance of this domain in most macromolecular interactions involving tRNAs (including in vitro even when it is detached from the “bottom half”) suggests that these half’s specificities were established before the tRNA’s “bottom half,” presumably incorporated later [72]. Growing evidence for tRNA elements involved in both RNA and DNA replication with the 3′-end playing a determinant role has led to the idea that the “top half” initially evolved for replication in the RNA world before the advent of protein synthesis [73]. The supposed evolutionarily recent tRNA “bottom half” provides genetic code specificity. This suggests late implementation of the standard genetic code and late appearance of interactions between the tRNA “bottom half” and ribosomes [74]. Whether the “bottom half” derived from a loop or extra loop belonging to the “top half” or was an independent structural and functional domain that was subsequently incorporated into the “top half” remains unresolved [71]. Some authors suggest independent evolutionary origins [71, 72].
\nThe study of ss-tRNAs suggests a model partially explaining canonical tRNA origins (Figure 3). The DNA region specifying the “bottom half” would be integrated in a sequence that can specify the “top half” but at the junction between the parts corresponding to the 3′-end of the 5′-acceptor stem and the 5′-end of the 5′-T-stem.
\nProposed model for the origin of genes specifying tRNAs with canonical cloverleaf structure. It can be summarized by insertion (follow the arrow) of the region specifying the “bottom half” into those specifying the “top half”. Here, the entire TAG10 triplet presumably belonged to the “bottom half” region as well as the first 2 nts of ATG49. Colors as Figure 1.
On the other hand, the “bottom half”/“cherry bob” structure could also be integrated at RNA level, either in the RNA world by intermolecular RNA-RNA recombination or template switches or later with retrotranscription events. Fujishima and Kanai [70] also proposed an equivalent model where a long hairpin corresponding to about the “top half” region merged with a viral RNA element corresponding to the “bottom half” to give the TLS found in modern viral genomes (who however possessed a pseudoknotted acceptor-stem). Besides, rare pre-tRNA molecules from the three domains of life exhibit an intron. The intron’s origin is debated. The “introns-early” scenario assumes most of them were lost during evolution, and the opposite scenario theorizes that introns were inserted into some trn genes after their emergence [75]. To date, our hypothesis would rather favor the second scenario, even though it could be considered that the “cherry bob” structure could be an ancestral intron becoming unspliceable.
\nIn tRNAs, the two first nts of both UAR10 and AUR49 belong to connector 1 and 2, respectively. They are thus at the junction between the top and bottom halves and are very close physically in the 3D structure (Figure 1). The belonging of some of the nts of the TAR10 and ATR49 triplets to either of the two parts is not discussed here because the theoretical model of Figure 3 is applicable independently of “bottom half” extremities. However, as the V-R is important for aminoacylation [76], ATR49 triplets could rather integrally belong to the “top half.” The tRNA L-shape is stabilized by various tertiary interactions of the V-R with the D-arm and between the D- and T-loops. Nucleotides of the connectors form contacts with the D-arm, and in some tRNAs, the G10 can establish potential tertiary interactions with a nt of the V-R upstream the putative start codon [77]. At least in cytosolic tRNAs, frequently U8 and sometimes U48 form noncanonical pairs. Moreover, generally, base pair 15–48 is more conserved in mt-tRNAs than 8–14, and this is probably due to the fundamental role played by the first in maintaining the tRNA L-shape [5]. UAR10 and AUR49 had to play first only a role in the L-shaped tertiary structure of tRNAs, and their implication as codons, if it exists, would be only a derived character. It was hypothesized that DNA punctuation evolved from 2D structures signaling polymerization initiation, termination, and/or processing to linear sequence motifs, which further evolved to translational signals [78]. In ss-tRNA, UAR10 triplet probably already plays a structural role in proto-tRNAs, whereas AUR49 would have appeared only during the evolution of organelle tRNAs and was related to L-shaped tertiary structures of organelle tRNAs and due to severe genome reduction and extreme base compositions. The opposite hypothesis would imply that the AUR49 triplet would have been a plesiomorphic character counter-selected in large genomes but kept in certain bacterial genomes up to mt-ancestors.
\nSome authors have hypothesized that tRNAs may be the precursors of mRNAs, rRNAs (and therefore proto-ribosomes), and also of the first genomes. Several suggested similar origins for tRNA and rRNA [79]. Analyzes of sequences and secondary structures of ribosome suggested that the ribosomal peptidyl transferase center (PTC) which forms peptide bonds between adjacent amino acids originates from fused proto-tRNAs [80]. Strikingly, the ribosome is a ribozyme, since only RNA catalyzes peptide bond formation [81]. Otherwise, current eubacterial rRNAs themselves could encode several tRNAs [82] and chaetognath 16S rRNA genes appear as tRNA nurseries [12] (or the opposite). Eubacterial 5S rRNAs contain TLSs similar to alanine and arginine tRNAs [82], exhibiting tRNA-like 2D structures [83]. Some suggest that rRNAs are fused tRNA molecules [80].
\nMolecular biology dogmatically assumes that “tRNA genes are of course entirely noncoding” [84]. But in 1981, Eigen and Winkler-Oswatitsch suggested that in the RNA world to the RNA/protein world transition, ancestral tRNAs were mRNAs [85]. Assuming that the first mRNAs had been recruited from proto-tRNAs, it follows that TLSs were inside viral and cellular mRNAs [86]. Self-recognition between tRNA-like mRNAs and canonical cloverleaf tRNAs could stabilize these molecules and produce proto-proteins [87]. The first proteins potentially emerged from junctions of ancestral tRNAs, and among the modern proteins, the only polymerase which matched with tRNAs translated like a mRNA was the RNA-dependent RNA polymerase [87]. Otherwise, eubacterial rRNAs could also encode several active sites of key proteins involved in the translation machinery [82]. Then, analyzes of sequences and secondary structures of ribosomes suggested that these derived from tRNAs also functioned as a protogenome [82]. The very parsimonious syncretic model “tRNA core hypothesis” assumes that some proto-tRNAs were classical tRNAs and also functioned as rRNAs and mRNAs, a self-recognition between these molecules allowed to obtain proto-proteins [88].
\nAssuming that the ATR49 triplets are a primitive character lost during the first genome expansions and that they could already act as an initiation codon seems too speculative, but RNA structures having characteristics of ss-tRNAs could have accumulated many advantages in the RNA/protein world. Structures with both start and stop codons partially in a stem-loop (as ss-tRNA), constituting basic signals for translation, could be a missing link of the RNA world hypothesis. Furthermore, in these proto-tRNAs, 3D structures could act as initiation and termination signals before the emergence of standard codons. Moreover, mRNAs in the form of ss-tRNA or a combination of several of these molecules would have been relatively stable. The cloverleaf structure could facilitate its entry into the PTC, and then interactions with other factors could allow a short region to be in linear form and thus could be read. Upstream and downstream of the linear region, the arrangement in hairpins protected the proto-mRNA from degradation during its reading, and as soon as a long enough region was read, it could take again its original 3D structure. Otherwise, circular proto-mRNAs derived from ss-tRNA-like molecules could not be excluded, although the hypothesis of circular tRNA-like ancestor (“proto-tRNA”) was first proposed by Ohnishi in 1990 [89]. Furthermore, nuclear-encoded mt-tRNAs of Kinetoplastid protists are imported into the mitochondrion, and circularized mature tRNA molecules are produced probably by mt-endogenous RNA ligase activity (in vivo or during mt-isolation) [90]. Moreover, in red and green algae and possibly in one Archaea, the maturation of permuted trn genes, in which the sequences encoding the 5′-half and 3′-half of the specific tRNA are separated and inverted on the genome, needs the formation of a characteristic circular RNA intermediate which after cleavage at the acceptor-stem generates the typical cloverleaf structure with functional termini [91]. If in a ss-tRNA with a T-loop of 7 nts, the nt72 is ligated to the nt1; this creates a small ORF starting with a start codon (AUR49), which potentially codes for a peptide of 12 amino acids if UAR10 is used as stop codon. However, the circularization could be done elsewhere than at levels of nts 72 and 1. Thus, UAR10 would not be in frame, and therefore, this could allow the synthesis of smaller or longer peptides. To date, the formation of this type of structure and its translation remains hypothetical; however, experimental data shown that circular RNAs can be translated in prokaryotic and eukaryotic systems in the absence of any particular element for internal ribosome entry as SD sequence, poly-A tail, or cap structure [92]. Therefore, the evolutionary advantage of a circular proto-mRNA is also posited to be the simplicity of its replication mechanism and not be able to be degraded by the extremities that do not have one.
\nBesides, the fusion of tRNA-like mRNA and a classical tRNA could be at the origin of the ancestors of tmRNAs, and it can be mentioned just for guidance that the size of the tag peptide encoded by bacteria is of the same order of magnitude as those corresponding to putative translation of a ss-tRNA from the ATR49 triplet. Moreover, evolution of self-charging proto-tRNAs may also be selected [93], it has even been proposed that the activity of the juxtaposed 2′/3′-OHs of the tRNA A76 ribose qualifies tRNA as a ribozyme [94] and some RNAs (the early tRNA adaptor) must have had the ability to undergo 3′-aminoacylation. It has also been previously shown that many hairpin-structured RNAs bear ribozyme activity. These catalyze self-cleavage and ligation reactions [95]. In addition, it remains possible that circular ss-tRNAs with amino acid-anchored structure could be at the origins of tmRNAs. Indeed, two-piece bacterial tmRNAs (e.g., in α-proteobacteria) are encoded by a circularly permuted gene sequence implying that pre-tmRNA is processed, and that the two pieces are held together by noncovalent interactions. Moreover, in line with an α-proteobacterial origin of mitochondria, probable mt-encoded circular permuted tmRNA genes have been found in the oomycete (water mold) Phytophthora sojae and in the jakobid Reclinomonas americana [96]. A proto-trnA gene could be at the origin of modern tmRNAs [41]. Metazoan mt-trnA genes combine the highest levels of TAR10 and ATR49 triplets (>95% for each), but in the prokaryotic world, if the rate of TAG10 is always higher than 91%, only one ATR49 occurs in Eubacteria and none in Archaea.
\nStudies strongly suggest that the tRNA cloverleaf structure unfolded prior to the appearance of a fully functional ribosomal core, making it one of the most ancient RNAs of the RNA world [70, 97] or even the oldest [98]. Though the “RNA-world” hypothesis is well accepted, the successive events leading to the emergence of different partners playing a role in translation and the involvement of tRNAs in this evolution are highly controversial coveted field [99]. However, some hypotheses as the “tRNA core” [88] strongly suggest that tRNAs would be at the origin of the primitive genetic material and gave rise to mRNA and rRNA, as well as the conformational structure of the first proto-ribozymes. The base module being a pleiofunctional RNA that can adopt the cloverleaf structure is found today in various sequences without direct link with translation. One may conclude that “one should not change a winning secondary structure.” In a precellular context, a molecule with ss-tRNA characteristics (small ORF associated with cloverleaf structure) would be advantageous. Putatively, ss-tRNA-like molecules cumulating both tRNA and mRNA functions would have been the first molecules on Earth to support nonrandom protein synthesis.
\nThe antiquity of ss-tRNAs can be discussed, and it is very likely that the TAR10 (and especially TAG) triplets played very early a critical role in the tertiary folding of some tRNAs. Their implication in translation termination would be an exaptation where firstly, they were part of a structural signal. Origin of ATR49 triplets is less clear perhaps tracing to the first endosymbiosis. Hence it would be apomorphic (derived character). Analyzes by taxa and tRNA species suggest a nonhomogeneous evolution. At the beginning of the RNA/protein world, it has quickly become essential to start peptide synthesis at particular codons and one cannot exclude that ATR49 was an ancestral state which would have not been retained as intergenic spaces increased. Analyzes of known tRNAs of α-proteobacteria and cyanobacteria could suggest that in organelles, ATR49 triplets would have been selected with genome reduction. Organelle genomes may be under increased pressure for size reduction with resulting overlaps (see, [100]). However, several features strongly suggest that overlapping genes are not a direct mechanism to substantially reduce genome size. Gene overlaps allow mtDNA genome compaction while avoiding the loss of tRNA genes [53]. Nevertheless, overlaps may allow a more efficient control in the regulation of gene expression, the regulatory pathways are simplified, and the number of proteins (and genes) required decreases [100]. Among others, short antiparallel overlaps may be involved in antisense regulatory mechanisms. Consequently, genomes with compact sizes enable putatively less flexible but more efficient physiologies.
\nThe selection of tRNAs had to be done mainly on two seemingly opposite criteria, stability and plasticity, making it a kind of Swiss army knife of the RNA world. This explains that beyond their central role in protein synthesis, tRNAs have many other crucial functions. To date, it can be hypothesized that ss-tRNAs might regulate gene expression, stress responses, and metabolic processes. Indeed, in silico analyzes allowed to speculate that several overlapping sequences may code simultaneously for mRNAs and tRNAs in most of the metazoan mt-genomes. These overlaps can have a variable (sometimes large) number of nts; however, when annotating their genomes, several authors voluntarily underestimated the number and the size of overlaps, speculating that there would be upstream abbreviated stop codons or downstream alternative start codons but most often without any direct demonstration so far. However, the high number of possible overlaps on the same strand in which the first in-frame complete stop codon or standard start codon are located at specific positions in the sequences of trn genes (TAR10 and ATR49, respectively) strongly suggest an exclusive relationship between obtaining tRNAs and translation of mRNAs and/or the development of repair system to keep the two genes functional due in some cases to co-evolution during several hundred MY. We can therefore speculate that ss-trn genes could allow true tRNA punctuation and initiation. Noted that ss-tRNAs seem to be hybrid molecules which would contain three essential coding or decoding informations in the form of nt triplets (i.e., anticodon and stop/start codons) which are all at least in part integrated into stem or loop; moreover, after the ATR49, nt triplets play the role of internal sense codons. To date, it is unclear what biochemical mechanism would allow to choose between different alternate cleavage sites, leading to the complete tRNA rather than to the mRNA or vice versa, but reduced/expanded proteins can be functional, and various processes including editing suggest this also for incomplete tRNAs. Hence, despite lacking experimental evidence, TAR10 and ATR49 triplets have probable roles, including regulation. Future analyzes of the processed bicistronic transcripts (tRNA/protein-encoding or the contrary) are required. Moreover, even if mt-trn genes are most often expressed at very low levels [53], only direct sequencing of tRNAs can validate transcription, epitranscriptomic maturation and can pinpoint nt modifications including post-transcriptionally edited positions. Purified native, or even synthetic, tRNAs should also be tested for their in vitro activity to confirm the functionality of aberrant transcripts. Similar experiments must be made on the flanking mRNAs and their products. If as we think, ss-tRNAs could play regulatory roles, initially experiments should compare stress and nonstress conditions.
\nHere, the bias for metazoan mtDNA does not allow for a complete picture of variation in the entire eukaryotic world, and protist mt-genomes should also be considered. Special attention should also be paid to noncanonical base pairings potentially formed by UAR10 and AUR49 nts, in perspective with tRNA structure and V-R length. Accounting for TAR10 and ATR49 triplet presences in the algorithms predicting tRNAs could improve mt-genome annotations, reducing numbers of false positives and negatives, and more accurately determine tRNA termini while accounting tRNA species, taxa, and genomic systems.
\nMtDNA plays a central role in apoptosis, aging, and cancer [13]. Moreover, mt-diseases are among the most common inherited metabolic and neurological disorders [101]. In addition, as new functions and new mechanisms of action of tRNAs are continuously discovered [1] and as ss-trn genes could affect the cellular dynamic during normal and stress conditions leading to pathologies, potential subtleties of action and regulation of these genes and products should be more thoroughly investigated.
\nThe authors declare no potential commercial or financial conflicts of interest.
Myxomatous mitral valve disease (MMVD) accounts for 75–80% of heart diseases in dogs and is more prevalent in small and elderly dogs [1, 2]. Due to similarities to human mitral valve prolapse (MVP), it gains huge interest in veterinary and human cardiologists. MMVD and MVP are characterized by progressive myxomatous degeneration of atrioventricular valves and subsequent mitral regurgitation (MR) [3], causing left atrial (LA) and left ventricular (LV) volume overload and left-sided congestive heart failure (CHF) [4]. Although there are many similarities in both diseases (e.g. macroscopic and microscopic pathology, strong genetic background, marked effect of age on prevalence and severity, slow progression), discrepancies in these two diseases (e.g. much more prevalent in dogs than in humans, less prone to develop endocarditis in dogs, less prominent systolic clicks in dogs) exist [5].
\nAlthough there are many diagnostic methods for MMVD, the standard transthoracic echocardiographic examination is a gold standard test for diagnosis and prognosis of MMVD and MVP in dogs and humans, respectively. The echocardiography is non-invasive and enables the clinicians to detect the mitral valve (MV) lesions, to evaluate MR severity, and to assess its impact on cardiac remodeling, myocardial function, left ventricular filling pressures, as well as pulmonary arterial pressure [6, 7, 8, 9, 10, 11]. However, conventional ultrasound imaging modalities such as two-dimensional (2D), M-mode, color Doppler, pulse-wave (PW), and continuous-wave (CW) Doppler echocardiography may not be enough to precisely evaluate the severity of mitral valve diseases and to monitor disease progression. Advanced ultrasound technologies such as tissue Doppler imaging (TDI), strain and strain rate imaging, and two-dimensional speckle tracking echocardiography (STE) gain popularity in veterinary and human cardiologists because these technologies can assess and monitor global and regional myocardial function more precisely [12], although those require more expensive ultrasound machine and training.
\nHuman MVP causing MR is divided into two groups: primary (i.e. structural intrinsic valvular disease) and secondary (i.e. nonstructural functional MR caused by non-mitral valve diseases). Like dogs, causes of primary MR are degenerative diseases on the mitral valve, such as Barlow, fibroelastic degeneration, Marfan, Ehlers-Danlos, and annular calcification, although rheumatic disease and toxic valvulopathy can also cause MR in humans [13]. Severity of MR in humans is graded qualitatively (e.g. mitral valve morphology, color flow MR jet, flow convergence zone, CW signal of MR jets), semi-quantitatively (e.g. vena contracta [VC] width, pulmonary vein flow, mitral inflow, TVI mit/TVI Ao), and quantitatively (effective regurgitant orifice area [EROA], regurgitant volume [R Vol]) [13]. LV and LA size and the systolic pulmonary arterial pressure are also used to determine the severity of CHF caused by MR.
\nAlthough the severity MR and CHF in dogs with MMVD are being evaluated as similar to human cardiology, the veterinary cardiologists are more focused on the severity of cardiac remodeling (e.g. LA and LV dilation) and cardiac dysfunction caused by MR, because surgical restoration of defected mitral apparatus is rarely done in dogs. Therefore, the echocardiographic indices related to MR severity (e.g. MV morphology, flow convergence zone) are not routinely assessed in dogs with MMVD.
\nThe chapter reviews conventional echocardiographic indices being used for diagnosis and prognosis of canine MMVD to provide a better understanding of the similarities and discrepancies between canine MMVD and human MVP to veterinary and human cardiologists and researchers.
\nEchocardiography is a gold standard test in the assessment and management of humans and dogs with MR. Although color flow MR jets and CW signal of MR jets are useful for detecting MR, a more quantitative approach is required for determining the severity of MR in humans and dogs.
\nAlthough quantitative assessment of MR (e.g. EROA and R Vol) is being used for grading the severity of MR in humans [13], it is rarely used in canine practice, because it requires more time-consuming interrogation and is often hard to define the location of EROA and flow convergence shape in dogs with MR [14]. Therefore, canine study, especially in practice, focuses more on the semi-quantification of MR (e.g. the maximal ratio of the regurgitant jet area signal to LA area [ARJ/LAA ratio] and vena contracta).
\nThe ARJ/LAA ratio can be easily obtained with the color Doppler imaging (CDI) method and showed good repeatability and reproducibility in dogs [15, 16]. MR can be graded as mild (<30%), moderate (30–70%), or severe (>70%), based on the ARJ/LAA ratio on the CDI study in dogs with MMVD (Figure 1A) [15, 16]. Unfortunately, the ARJ/LAA ratio can be affected by many intrinsic factors (e.g. SAP, LA pressure, the spatial orientation of MR jet) and extrinsic factors (e.g. pulse repetition frequency and gain settings) [17]. Several studies found the ARJ/LAA ratio was not closely correlated with the severity of MMVD in dogs, especially in dogs with American College of Veterinary Internal Medicine (ACVIM) B2 and C [18, 19].
\n(A) Semi-quantification of mitral regurgitation (MR). The maximal ratio of the regurgitant jet area signal to the left atrial area (ARJ/LAA ratio) was obtained from a left apical four-chamber view. The ARJ (1.12 cm2)/LAA (2.12 cm2) of this case was 53%, indicating moderate MR. (B) the vena contracta diameter from a left apical four-chamber view (VCL) was measured as the diameter of the narrowest point of the mitral regurgitation jet, downstream of the region of proximal flow convergence.
The vena contracta is the narrowest width of the MR jet that occurs at or just downstream from the regurgitant orifice and can reflect the severity of MR (obtained from measuring the regurgitant orifice size by the CDI study) (Figure 1B) [17]. Although it requires less time-consuming interrogation and is technically easier to obtain, this method is prone to errors, especially in dogs having dynamic regurgitant orifices [14]. Several studies found the VC and VC-derived variables were closely correlated with the severity of MR and survival time in dogs with MMVD [20, 21, 22]. One study found the mean (±SD) diameter of the mitral regurgitation vena contracta in a right parasternal long-axis (RPLx) view (VCR:Ao) and a left apical four-chamber view (VCL:Ao) indexed to aortic diameter were 0.21 ± 0.14 and 0.24 ± 0.12, respectively, in dogs with MMVD [21]. Furthermore, the VCL:Ao > 0.24 was closely correlated with survival time (hazard ratio 4.87) [21].
\nThe measurement of the flow convergence area by proximal isovelocity surface area (PISA) is a gold standard method to quantify the MR jet in humans [13]. Although one study found the PISA method was repeatable and reproducible in awake dogs [16], it is more time-consuming and requires several precautions to obtain the optimal acquisition of the flow convergence images in dogs with MMVD [14]. The regurgitation fraction (RF) obtained by the PISA can be used for determining the severity of MR in dogs (e.g. mild if <30%, moderate if 30–75%, and severe if >75% of RF). Several studies found the RF was closely correlated with the severity of MMVD and other echocardiographic variables (e.g. LA/Ao and systolic PA pressure) [16, 23, 24]. However, one study found the MR quantification of the PISA method showed a wide range of RF (~33% asymptomatic MMVD dogs had moderate to severe RF) and thus is not routinely done in canine practice [16].
\nChronic and hemodynamically significant MR can cause LA and LV volume overload, leading to subsequent LA and LV enlargement. The severity of LA and LV remodeling can be assessed by LA to aortic root ratio (LA/Ao), indexed LA diameter (iLA), LV end-diastolic internal dimension to aortic root ratio (LVID/Ao), and normalized LV end-diastolic internal dimension (nLVID).
\nEstimation of LA diameter is one of the best predictors of outcome in dogs with MMVD [25, 26]. It also enables to make a decision for the initiation of medication in dogs with preclinical MMVD (ACVIM B1 and B2) and to estimate the risk for development of left-sided CHF [27, 28]. Hemodynamically significant chronic MR generally induces LA volume overload and thus leads to increase in LA volume [29].
\nIn dogs with MMVD, MR causes LA and LV dilation, and thus the assessments of LA and LV chamber dimensions enable clinicians to predict the progression of MMVD and risk of CHF [27, 30, 31, 32, 33]. One study evaluated the linear dimensions of the LA, LV, and Ao from the right parasternal long-axis view in dogs with MMVD and found that the mean (standard deviation; SD) for LA/LV, LV/Ao, and LA/Ao in dogs with MMVD were 1.1 (±0.09), 2.7 (±0.5), and 3.0 (±0.5), respectively, compared with 1.0 (±0.05), 2.1 (±0.2), and 2.1 (±0.1), respectively, in healthy control dogs [34]. This study showed good applicability and repeatability of the LA/LV, LV/Ao, and LA/Ao for assessing LV and LA enlargement in dogs with MMVD [34].
\nConventional echocardiographic marker assessing LA enlargement is LA/Ao at the aortic root level of LV short-axis plane (Figure 2A and B). The degree of LA dilation is closely related to the progression of CHF and survival time in both symptomatic and asymptomatic dogs with MMVD [23, 25, 35]. One study enrolled in 558 dogs with MMVD found LA/Ao > 1.7 was the only significant prognostic index among echocardiographic indices [25]. Although the LA/Ao is a major echocardiographic index for determining the degree of LA dilation, the method for measuring the diameter of Ao is not standardized. The first method assessing LA size [36] was as follows: step 1 measures the internal short-axis diameter of the Ao along the commissure between the noncoronary and right coronary aortic valve cusps on the first frame after aortic valve closure and step 2 measures the internal short-axis diameter of the LA in the same frame in a line extending from and parallel to the commissure between the noncoronary and left coronary aortic valve cusps to the distant margin of the left atrium (Figure 2A). However, many other studies used a different way of measurement (the second method), i.e. measuring the internal short-axis diameter of the Ao along the commissure between the noncoronary and left coronary aortic valve cusps on the first frame after aortic valve closure (Figure 2B). Our study found the Ao diameters measured by the first method were longer than those measured by the second method. Therefore, the LA/Ao measured by the first method was smaller [37]. Because the LA/Ao is a major echocardiographic index for selecting MMVD study groups for drug trials and clinical trials, the standardization of measurement of Ao diameter is required in the future study.
\nThe method for measurement of left atrial to aortic root ratio (LA/Ao). (A) A LA/Ao obtained from a right parasternal short axis (LA/AoSx) by method 1 (see text). (B) A LA/Ao obtained from a right parasternal short axis (LA/AoSx) by method 2 (see text). (C and D) A LA/Ao obtained from a right parasternal long axis (LA/AoLx). For LA diameter (C), the measurement was made at end-systole 1 to 2 frames before the opening of the mitral valve leaflets. The measurement bisects the atrium extending from the mid-atrial septum in the near field to the bright pericardial echo of the LA lateral wall in the far field and is roughly parallel to the mitral annulus. For Ao diameter (D), the measurement of the aortic valve was made between the opened aortic valve leaflets in an early systolic frame when the Ao diameter is the greatest.
To overcome the problem of LA/Ao at the short axis (LA/AoSx), the LA/Ao was also measured at the long axis (LA/AoLx) [34]. The method measuring LA/AoLx standardized and thus minimized the inconsistency of measurement of LA and Ao (Figure 2C and D). Several canine studies found cut-offs for LA/AoLx > 2.6 and LA/AoSx > 1.6 indicate hemodynamically relevant MMVD and timing of therapeutic intervention (e.g. enalapril and pimobendan administration) [27, 33].
\nIndexed LA diameter (iLA) is a good alternative for assessing LA dilation [19]. The iLA is calculated by using the following formula: LA diameter (mm)/(0.795 × body weight [kg])1/3. In this study, the iLA diameter had higher sensitivity and specificity for detecting heart disease (healthy control vs. ACVIM B2), despite lower specificity for detecting heart failure (ACVIM B vs. ACVIM C) in dogs with MMVD. Cut-off for iLA > 12.7 indicates the risk of heart failure (ACVIM C) in dogs with MMVD [19].
\nBecause the actual structure of LA is three-dimensional (3D), the LA dilation may occur in all direction (e.g. cranio-caudal, medio-lateral, and ventrodorsal). Therefore, the degree of LA dilation may be overestimated or underestimated, depending on the direction of LA dilation [38, 39]. For this reason, traditional estimation of LA diameter using 2D assessment of LA with linear methods (e.g. LA/AoSx, LA/AoLx, iLA) may not be enough to provide an accurate and consistent measurement. One study measured the LA volume to detect mild LA enlargement using the three-dimensional echocardiography (3D-EC) and found this method provided a more accurate measurement of LA size than the 2D echocardiography (2D-EC) [40]. Furthermore, the estimation of LA diameter and area by the 2D-EC was shown to have a poor correlation with the 3D-LA volume in humans [41]. However, it is more time-consuming, and substantial off-line analysis is required. Furthermore, the 3D-EC underestimated the LA volumes compared with magnetic resonance imaging (MRI) in human patients [42].
\nThe area-length method (ALM; Figure 3A) or monoplane or biplane Simpson’s modified method of discs (SMOD; Figure 3B) is currently recommended to measure LA area derived from the LA volume [43, 44, 45, 46]. In human, the biplane method from four- and two-chamber views is preferred to measure the LA volume [47]. One study evaluated the difference of LA volume measurement by comparing 3D-LA volume measurement to two different 2D-LA volume measurements (using the SMOD and ALM) [48]. In this study, the SMOD and ALM systematically underestimated the LA volume by 7% and overestimated by 24%, respectively, compared with 3D-LA volume (Figure 3C). One human study also found the SMOD underestimated the LA volume compared to the 3D-LA volume [49]. Therefore, the 2D-SMOD may be a better method for the estimation of LA volume, if the 3D-EC is not available. One study found the LA volume indices including LA maximal volume (LAVmax) and LA minimal volume (LAVmin) using the ALM was useful to predict survival time when cardiac-related death was only considered [50]. In this study, the LAVmax > 3.53 mL/kg indicated high mortality risk in dogs with MMVD.
\nLeft atrial (LA) volume measured for three different methods at a left apical four-chamber view. (A) Area-length method (ALM), (B) Simpson’s modified method of discs (SMOD), (C) real-time three-dimensional echocardiography (RT3DE).
Evaluation of the LA function may help to determine the severity of heart failure in dogs with MMVD [40, 44]. The LA function consists of three components: it acts as a reservoir for pulmonary venous (PV) return during ventricular systole (atrial diastole), as a conduit for the passage of stored blood from LA to LV during early ventricular diastole and diastasis, and as an active pump delivering 15–30% of LV filling during late ventricular diastole (atrial systole) [51]. One study established reference intervals for the LA function using 2D linear and area-based estimates and evaluated the diagnostic value to differentiate dogs with asymptomatic (ACVIM B) from symptomatic (ACVIM C) MMVD [52]. This study evaluated four LA functional indices (Figure 4): the LA expansion index for LA reservoir, the LA active emptying fraction for LA contractile, the LA passive emptying fraction for LA conduit, and the LA total emptying fraction for LA reservoir. This study demonstrated estimates of LA function except LA passive emptying fraction worsened with the severity of heart failure, although these indices were not sensitive enough to differentiate dogs with asymptomatic from symptomatic MMVD [52].
\nTwo-dimensional echocardiographic estimates of left atrial function. (A) the minimal left atrial diameter/area was obtained at the first frame after mitral valve closure (late ventricular diastole), (B) maximal left atrial diameter were obtained at the last frame before opening of the mitral valve (early ventricular diastole), and (C) the mid-left atrial diameter/area was obtained at the onset of the p-wave on the ECG (diastasis). (D) The formula for LA function index.
Chronic and hemodynamically significant MR can lead to the enlargement of the LV dimension. The degree of LV dilation was strongly correlated with the severity of heart failure in dogs with MMVD [53]. The LV internal dimension can be measured from the 2D or M-mode echocardiography by freezing the image at the end-diastole and the end-systole (Figure 5). As described above, the LV internal dimension was significantly larger in dogs with MMVD [34]. However, the LV dimensions noticeably vary among breeds of dogs. Therefore, one study evaluated the allometric scaling of M-mode cardiac measurements in normal adult dogs and found a good correlation between M-mode measurements and BW after logarithmic transformation of the data [54]. Therefore, the M-mode-derived LV internal dimension at systole (LVIDs) and diastole (LVIDd) can be transformed into body weight-indexed (normalized) LV internal dimension using the following formulas to obtain a more accurate estimation of LV dilation in dogs with MMVD:
LV end-diastolic diameter normalized for body weight (LVIDdN) = LVIDd (cm)/weight (kg)0.294\n
LV end-systolic diameter normalized for body weight (LVIDsN) = LVIDs (cm)/weight (kg)0.315\n
Measurement of left ventricular internal dimension. (A) M-mode echocardiography obtained from a right parasternal short axis at the papillary muscle level and (B and C) 2D echocardiography obtained from a right parasternal long axis at systole (B) and diastole (C).
LVIDdN ≥1.7 indicates dogs requiring cardiac medication (>ACVIM B2) [55].
\nSeveral studies also found that body surface area (BSA) indexed LV dimensions including end-diastolic index (EDVI) and end-systolic volume index (ESVI) could detect myocardial systolic dysfunction in dogs with MMVD [10, 11, 56]. The EDVI and ESVI can be obtained by the Teichholz formula [57]:
EDVI = [7 × (LVIDd)3/(2.4 + LVIDd)]/BSA
ESVI = [7 × (LVIDs)3/(2.4 + LVIDs)]/BSA
End-diastolic volume index and end-systolic volume index are obtained by dividing BSA, respectively [57]. Normal values of EDVI and ESVI are <100 and <30 mL/m2, respectively [57]. One study evaluated the diagnostic accuracy of ESVI using two different methods (i.e. the geometric [GM, based on Teichholz formula] and two planimetric methods [PM, Simpson’s derived and area-length methods]) and found that the GM overestimates ESVI in a nonlinear way [11]. However, the ESVI was correlated with the severity of CHF in dogs with MMVD [11]. A recent study also found the EDVI and ESVI obtained from the GM were overestimated and had poor diagnostic values in dogs with MMVD [19]. To overcome this limitation, the veterinary Teichholz formula has been proposed (Table 1).
\n\n | Dog | \n
---|---|
Diastolic volume | \nLVd3 X 7/[2.4 + 3.7 X LVd/(0.795 X W1/3)] | \n
Systolic volume | \nLVs3 X 7/[2.4 + 5.9 X LVs/(0.795 X W1/3)] | \n
Veterinary Teichholz method formulas for dogs.
LVd, Left ventricle end-diastolic diameter (in cm); LVs, left ventricle end-systolic diameter (in cm); W, weight in kilograms. From “Clinical Echocardiography of the Dog and Cat - E-Book (edited by Madron E, Chetboul V and Bussadori C), St Louis: Elsevier; 2016. pp. 115.
Because sole use of LV dimension often leads to the misestimation of LV dilation, the 2D and M-mode-derived LVIDd/Ao ratio is more appropriate and simpler for evaluating the degree of LV enlargement [14]. However, a recent study found the LVIDd/Ao ratio had high specificity and low sensitivity for detecting asymptomatic dogs from healthy control dogs and symptomatic dogs from asymptomatic dogs with MMVD [19].
\nDue to the LV dilation, the sphericity of the LV can be increased. One study revealed a significant decrease in the LV sphericity index in dogs with advanced MMVD [11]. The LV sphericity index can be calculated by the ratio of LV end-diastolic length (at left apical two- or four-chamber plane; Figure 6A) to the M-mode LV end-diastolic diameter (Figure 6B).
\nThe left ventricular (LV) sphericity index was calculated by the ratio of LV end-diastolic length (at left apical four-chamber plane; A) to the M-mode LV end-diastolic diameter (B).
LV systolic function can be reduced on serial 2D-EC in some dogs with MMVD [10], as noticed in human with advanced CHF [58]. However, LV measurement for systolic function often complicates depending on the LV loading condition, and thus fractional shortening (%FS) and LV ejection fractions (%LVEF) are often increased in dogs with advanced MMVD. In many cases of canine MMVD, when cardiac output is reduced with the progression of MMVD, the LV wall motion becomes more hyperdynamic [10]. Therefore, echocardiographic indices with Doppler for assessing LV functions and filling pressures are often ambiguous by age-related impairment of LV relaxation, LA pressure overload by MR, and impact on myocardial tissue velocities by LV loading condition. Therefore, echocardiographic indices for LV systolic and diastolic function often lead to the misinterpretation of LV function.
\nLV remodeling caused by chronic and hemodynamically significant MR is characterized by changes in LV geometry in response to chronic volume overload. The common echocardiographic indices for LV systolic myocardial function are %LVEF and %FS. The EF is the volumetric fraction of blood ejected from the LV in each heartbeat (LVEF = [end-diastolic volume − end-systolic volume]/end-diastolic volume × 100). The %FS is defined by the percent change in the dimension from end-diastole to end-systole (FS% = [LVIDd − LVIDs]/LVIDd × 100) [59]. As discussed earlier, %FS and %LVEF are reduced in human with myocardial dysfunction [58]; they are often increased in dogs with advanced MMVD due to hyperdynamic LV contraction from elevated preload and reduced afterload [19, 56]. Therefore, these two indices do not have good diagnostic value for detecting the progression of heart failure in dogs with MMVD [19].
\nMore advanced Doppler and tissue echocardiographic methods are being used for detecting LV dysfunction in dogs with MMVD to overcome problems encountered with the simple measurement of LV geometry.
\nContinuous-wave Doppler interrogation of MR flow profile can be affected by LA pressure, LV systolic function, and loading condition as well as systemic arterial pressure (SAP) (Figure 7A). Although the peak velocity of MR is closely related to MR fraction in the LA but not related to the severity of MMVD in dogs [19], dogs with LV systolic impairment and high LA pressure (as well as markedly reduced SAP) may have decreased peak MR velocity [14]. This may help to differentiate dogs with end-stage CHF from those with ACVIM C and D MMVD. Asymmetric MR flow profiles and a cut-off sign in mid to late systole are often noticed in dogs with the advanced stage of MMVD and are caused by reduction in MR flow due to high LA pressure (Figure 7B). The dp/dt is the rate of pressure change over time during isovolumic contraction and closely related to LV systolic function in humans (Figure 7A) [60]. However, the dp/dt in dogs with MMVD has limited value, because most MMVD dogs may have high peak velocity and asymmetric MR profiles, regardless of the severity of MMVD [18], although some authors proposed its use for detecting LV systolic function [2].
\nContinuous-wave (CW) Doppler flow profile obtained from dogs with severe mitral regurgitation (MR). (A) The MR peak velocity and pressure gradient were 5.69 m/s and 129.5 mmHg, respectively, in this dog. (B) Asymmetric MR flow profiles and cut-off signs (arrow) in mid to late systole obtained from the advanced stage of mitral valve disease (see text).
Pulse-wave Doppler interrogation of transmitral flow profile is closely correlated with the stage of MMVD in dogs [14, 18, 19]. The transmitral flow profile consists of an early E-peak (rapid LV filling) and a late diastolic A-peak (atrial contraction) and is closely related to diastolic LV function (LV relaxation/compliance, LV volume overload/pressure overload, and recoil) as well as LV filling pressure (Figure 8A) [61, 62]. Although E/A reversal (E/A < 1) is common in the aged canine population, E-peak is higher than A-peak in general canine population (i.e. E/A < 1). One study found 0.87 ± 0.13 m/s (E-peak) and 0.61 ± 0.12 m/s (A-peak) in 100 healthy dogs [63]. A high-velocity E-peak (>1.5 m/s) indicates marked elevation of LA pressure [10] and is correlated with severity of CHF and survival time in dogs with MMVD [18, 19, 23, 25]. Generally, a higher E-peak with a shorter E deceleration time (<80 ms in dogs older than 10–12 years) indicates marked LA pressure overload and non-compliant LV, while an E/A ratio <1 and/or a prolonged E deceleration time indicates impaired relaxation [10]. Because the E-peak velocity is increased with the elevation of LA pressure whereas decreased with impairment of LV relaxation, transmitral flow profile sometimes misleads the severity of LV myocardial dysfunction. However, myocardial and annular velocities are less load-dependent than transmitral flow profile, and thus the E/e (the early longitudinal mitral annular velocity measured by tissue Doppler imaging) ratio is found to better reflect LV filling pressure in dogs with MMVD [61]. A decrease in e-peak at mitral annulus indicates impaired relaxation. One study revealed an E/e ratio >9 was equivalent to >20 mmHg of LA pressure (95% probability in a canine model of acute MR) (Figure 8B) [61]. Furthermore, >12 of E/e along with a high E-peak velocity was able to detect the presence of CHF in this study population [61]. One recent study also demonstrated an E/e cut-off value of 13 identifies CHF with high sensitivity (80%) and high specificity (83%) [64]. Although the e-peak is less affected by LV loading condition, it can be also affected by age and severe LV volume overload, and thus the E/e ratio may have limited value in this situation [14]. Several studies demonstrated E-peak/isovolumic relaxation time (E/IVRT) was correlated with LA pressure and end-diastolic LV pressure in dogs (Figure 8C and D) [62, 65, 66]. The IVRT may be decreased with the elevation of LV filling pressure. One study suggested the E/IVRT ratio >2.5 and an IVRT <45 ms might indicate the presence of CHF in dogs with advanced MMVD [62]. PW Doppler interrogation of the pulmonary venous flow profile gains popularity to determine LA volume and pressure overload by severe MR in humans [67]. However, it has limited value in dogs with MMVD, due to technical difficulty (e.g. PV usually locates at the far-end of an echocardiographic window) and poor-quality PV profiles (e.g. MR flow often enters into the PV) [14]. The LV Tei index (LV Tei = [IVRT + IVCT + LVET]/LVET, IVCT stands for the isovolumic contraction time) is a valuable index for detecting LV systolic and diastolic dysfunction simultaneously in human with CHF (Figure 9) [68]. A human study found shortened LVET/increased LV Tei index in patients with systolic dysfunction and increased mitral valve closure time and Tei index in humans with diastolic dysfunction [69, 70]. One canine study found the LV Tei was closely related to LV dp/dt and was increased with the severity of MMVD [71]. However, in dogs with moderate to severe MR, the IVRT and IVCT are often too short or not detectable [14]. Therefore, the Tei index is rarely used in veterinary fields.
\nTransmitral E/e ratio and E/IVRT (the isovolumic relaxation time). (A and B) Transmitral E-peak obtained from a left apical four-chamber plane and tissue Doppler imaging of lateral e-peak obtained from a left apical four-chamber plane. (C and D) Transmitral E-peak obtained from a left apical four-chamber plane. By moving sampling gate towards the midline of the aorta and mitral annulus, aortic and mitral flows were obtained simultaneously. The IVRT was measured from the end of the aortic flow to the beginning of the mitral E-peak.
Two methods for measuring left ventricular (LV) Tei index. (A) Tissue Doppler imaging at the mitral annulus and (B) Pulse-wave Doppler interrogation at the midline of the aorta and mitral annulus (see Figure 8D for the measurement). (See text for more information).
Pulmonary venous hypertension (PVH) is a common cause of pulmonary hypertension (PH) in dogs and is prevalent in dogs with MMVD, especially in dogs with the advanced stage of CHF [7, 62, 72]. Gold standard methods detecting PH in dogs are Doppler assessment of peak tricuspid regurgitation (TR) and pulmonic regurgitation (PR) jet velocities [7]. One study demonstrated the Doppler evidence of PH was more evidenced in dogs with more advanced MMVD [7]. Another study also found that dogs having moderate to severe PH had a poorer outcome than in MMVD dogs [72].
\nThe peak velocity of TR jet (obtained from either a right parasternal short-axis view or a left parasternal four-chamber view) represents the systolic pulmonary artery pressure (sPAP) if there is no right ventricular outflow tract (RVOT) obstruction [73]. The systolic pulmonary artery pressure can be calculated by applying the modified Bernoulli equation (ΔP = 4 × velocity2) to the peak velocity of TR (Figure 10A) or PR jets (Figure 10B) and adding the right atrial pressure (RAP): ΔP + π right atrium. The estimated right atrial pressure is 5 mmHg in dogs without any evidence of RA dilation; 10 mmHg in dogs with evidence of RA dilation, but no signs of right-sided heart failure (R-HF); and 15 mmHg in dogs with evidence of RA dilation and clinical signs of R-HF. Then mean pulmonary arterial pressure (mPAP) can be calculated using the following equation: mPAP = 0.61 × sPAP +2. In dogs having the only PR, the mPAP can be calculated using the following equation: PR peak pressure gradient + RAP. A mPAP <25 mmHg is considered normal, while mPAP 25–40 (equivalent to 2.8–3.4 m/s of peak TR velocity), 41–55 (3.4–4.3 m/s), and >55 mmHg (>4.3 m/s) are considered mild, moderate, and severe, respectively [73]. Because the peak velocity is closely correlated with the beam alignment of jet, it often underestimates the severity of PH, if the beam is not parallel to jet [18]. Another study also claimed that the Doppler estimation of SAP often overestimated PH in dogs with MMVD [73]. Since some dogs with PH may have no or insufficient Doppler evidence of PH (e.g. TR or PR jets), other echocardiographic evidence of PH should be pursued in dogs having R-CHF signs or persistent coughing [14]. Despite these limitations, canine studies found the SAP showed good prognostic value for detecting the progression of CHF and the survival time in dogs with MMVD [7, 62, 72].
\nEchocardiographic evidence of pulmonary hypertension. Continuous-wave Doppler study showing severe tricuspid regurgitation (A) and pulmonic regurgitation (B). (See text for more information).
The 2D-EC evidence of PA/RVOT dilation is the simplest way to detect the existence of PH in dogs with MMVD [35, 74, 75, 76, 77]. Since chronic pressure overload and volume overload in RV can cause RV concentric hypertrophy (thickened RV free wall) and eccentric hypertrophy (RV dilation), respectively, simple 2D measurements of RV free wall thickness and dimension may help to identify dogs with PH [74, 78]. Furthermore, LV eccentricity (obtained from right parasternal short-axis view at papillary level; a ratio of longitudinal to the transverse length of LV chamber; Figure 11C) is also a simple echocardiographic index for detecting the existence of PH in dogs [78]. Two studies found the LV eccentricity becomes <1, as the RV pressure becomes higher than the LV pressure (as commonly seen in dogs with PH) [74, 79].
\n2D echocardiographic interrogation of pulmonary hypertension. (A and B) right pulmonary artery distensibility index (RPADi) is the difference in diameters of the right pulmonary artery (RPA) at systole (A) and diastole (B) obtained from either 2D or M-mode echocardiography at a right parasternal short axis of PA. (C) Left ventricular (LV) eccentricity obtained from right parasternal short-axis view at papillary level (a ratio of longitudinal to the transverse length of LV chamber). (D) The ratio of main pulmonary artery diameter to aortic root diameter obtained at a right parasternal short axis of PA. (See text for more information).
In normal dogs, the diameters of the main pulmonary artery (MPA) are roughly identical, and thus MPA/Ao ratio should be close to 1 (Figure 11D). Therefore, MPA/Ao ratio > 1 indicates the PA dilation meaning the existence of PH, unless there is RVOT obstruction. Many studies revealed the dilation of MPA in dogs with PH [35, 74, 75, 76, 77].
\nRight pulmonary artery distensibility index (RPADi) is the difference in diameters of the right pulmonary artery (RPA) at systole and diastole obtained from either M-mode right parasternal short-axis (Figure 11A and B) or long-axis four-chamber view (Figure 12A) of PA [77, 80]. One canine study suggested that a RPADi <35 is indicative of PH, while values of 28–35, 23–27, and <23 are indicative of mild (30–55 mmHg), moderate (56–79 mm Hg), and severe PH (>79 mm Hg), respectively [80]. Further study also found that the RPADi was closely correlated with the sPAP [77]. However, the reference range of RPADi was significantly different, depending on the echocardiographic views [77, 80].
\n2D and M-mode echocardiographic interrogation of pulmonary hypertension. (A) Right pulmonary artery distensibility index (RPADi) can be obtained from a right parasternal long axis of four-chamber plane (arrow). (B) Right ventricular outflow tract fractional shortening (RVOT-%FS) obtained from M-mode measurement of the RVOT of the right parasternal short-axis view at the level of the aortic root. Tricuspid (TAPSE; C) and mitral (MAPSE; D) annular plane systolic excursion obtained from a left apical four-chamber plane of M-mode echocardiography. (See text for more information).
RVOT-%FS indicates RV systolic function and can be obtained from M-mode measurement of the RVOT of the right parasternal short-axis view at the level of the aortic root using the following formula: ([RVOT dimensions at end-diastole − RVOT dimensions at end-systole]/RVOT dimensions at end-diastole) × 100 (Figure 12B) [81]. One recent canine study found the RVOT-%FS is significantly decreased (<45%) in dogs with PH [82]. However, the RVOT-%FS can be affected by other diseases causing RV systolic dysfunction.
\nTricuspid annular plane systolic excursion (TAPSE) also reflects RV systolic function, which can be significantly affected by RV pressure overload [83]. Recent canine studies found dogs with PH had lower TAPSE, indicating pressure overload in the RV chamber [75, 84]. The TAPSE can be obtained from M-mode echocardiography that aligned the beam to the lateral tricuspid annulus in the left apical long-axis four-chamber view by calculating the maximal and the minimal excursion of lateral tricuspid annulus motion (Figure 12C) as similar to the measurement of mitral annular plane systolic excursion (MAPSE; Figure 12D). However, the TAPSE is influenced from the size of dogs; recent studies used body weight-normalized TAPSE (nTAPSE = TAPSE/[BW(kg)]1/3) and TAPSE to Ao ratio to overcome the influence of body size [82, 85]. The median (range) of nTAPSEs were 0.60 (0.53–0.66) in ACVIM B1, 0.71 (0.64–0.84) in B2, and 0.73 (0.58–0.80) in C and D MMVD dogs [85]. Other study found the TAPSE/Ao ratio was closely correlated with the size of the LA in dogs with MMVD and PH [82]. The TAPSE/Ao ratio <0.65 was indicative of the presence of PH in dogs with MMVD, although it showed low sensitivity for detecting PH [82].
\nSeveral studies evaluated quantitative echocardiographic variables related to PH in humans and dogs [78, 86, 87, 88, 89]. Among those echocardiographic variables, PW Doppler-derived acceleration time to peak PA flow velocity (AT), AT to the ejection time of PA flow ratio (AT/ET) (Figure 13A) [86], the right ventricular Tei index (RV Tei) (Figure 13B and D) [89], and Doppler pulmonic outflow profiles (Figure 13C) [90] are being used to interrogate PH in dogs. One study found AT, AT/ET ratio, and RV Tei index are strongly correlated with sPAP in dogs without detectable PR [35]. Especially, AT/ET ratios ≤0.25 were predictive of PH, whereas AT/ET ratios >0.42 ruled out PH [86]. However, other study found Doppler estimated mPAP was strongly associated with AT and AT/ET, but weakly associated with RV Tei index [90]. Over 50% of dogs in International Small Animal Cardiac Health Council (ISACHC) II and III had equivocal value of AT/ET indicating PH (0.25–0.42) in this study, suggesting low sensitivity for detecting PH, although most dogs having <0.25 had detectible TR or PR on echocardiography, indicating high specificity for detecting clinically significant PH [90]. This study also found Doppler pulmonic outflow profiles were closely associated with severity of PH in dogs with MMVD, since the Doppler pulmonic outflow profiles (type I/II/III) were 18/0/0 in control, 22/5/1 in ISACHC I, 21/24/2 in ISACHC II, and 17/40/4 in ISACHC III MMVD dogs [90]. The PW Doppler-derived echocardiographic variables of PA flow may have limited value in dogs with hyperdynamic RV condition because Doppler pulmonic outflow profiles can be influenced by RV loading conditions and systolic function [90]. Although RV-TDI may not be a direct indicator of PH, it can be used to evaluate RV systolic and diastolic function in PH patients. It can be obtained from the basal segment of the internal mid-portion of the RV wall in the left parasternal long-axis four-chamber view (Figure 13D). One study evaluated the diagnostic value of peak RV myocardial velocities at systole (Stdi), early (Etdi), and late (Atdi) diastole [35]. Also the global TDI index was calculated using the following formula in this study: global TDI index = Stdi × Etdi/Atdi [35]. This study demonstrated the decrement of the global TDI index and Etdi/Atdi in dogs with PH [35]. Furthermore, global TDI index of <11.8 showed sensitivity of 89% and specificity of 90%, while Etdi/Atdi of <1.12 showed sensitivity of 89% and specificity of 93% for detecting PH in the study population [35].
\nPulse-wave and tissue Doppler interrogation of pulmonary hypertension. (A) PW Doppler-derived acceleration time (AT) to peak pulmonary artery (PA) flow velocity (AT), AT to the ejection time (ET) of PA flow ratio (AT/ET). (B) Tissue Doppler-derived right ventricular Tei index (RV Tei), (C) PW Doppler-derived pulmonic outflow profiles, (D) PW Doppler-derived RV Tei index. (See text for more information).
Strain and strain rate imaging is an advanced echocardiographic technique for estimating myocardial segmental deformation, respectively [12, 91]. Myocardial strain (i.e., deformation of a myocardial segment over time; % change from its original dimension) and strain rate (the rate of myocardial deformation; S−1) can evaluate more direct intrinsic myocardial function and are less angle-dependent than TDI-based methods [92, 93, 94]. Strain and strain rate can be obtained from LV, LA, and RV wall using STE, feature-tracking echocardiography (FTE), or color TDI technology in the longitudinal, radial, and circumferential planes (Figure 14) [83]. Speckle tracking can detect the degree of myocardial deformation from the continuous frame-by-frame tracking of speckles (acoustic markers). By tracking these speckles in the myocardium throughout the cardiac cycle, the direction and velocity of myocardial motion can be determined. By comparing the motion of each speckle, the degree of deformation on each segment of the myocardium can be assessed.
\nRepresentative images of left atrial (LA) and ventricular (LV) strain and strain rate imaging for LA and LV deformation analysis in dogs with mitral regurgitation. (A and B) LV (A) and LA (B) strain profiles obtained from GE analysis software algorithm (EchoPAC). (C and D) LV (C) and LA (D) strain profiles obtained from Siemens vector velocity imaging (VVI). (See text for more information).
Although precise assessment of LV systolic dysfunction is critical for therapeutic intervention and prediction of progression of CHF in dogs with MMVD, assessment of LV function using conventional echocardiography is often complicated with loading conditions [95]. Several studies demonstrated strain and strain rate obtained from the 2D-STE were useful to grade the progression of dogs with MMVD [95, 96, 97, 98]. One study claimed the longitudinal strain with the GE analysis software algorithm (EchoPAC) was inconsistent and less repeatable, while radial strain curves from short-axis images were more consistent and more repeatable (Figure 14A and B) [95]. Since the software algorithm for strain is automated, special attention should be focused on “(1) timing of the ECG to select the cardiac cycle and the onset and duration of analysis; (2) tracing of the endocardial border for automated detection; (3) inspecting the region of interest; (4) following the tissue tracking in real-time and slow-motion; and (5) inspecting the generated curves relative to the R-waves and aortic valve closure (AVC)” as described in Smith et al. [95]. A velocity vector imaging (VVI) is another form of strain analysis, which can display tissue velocity as a vector showing the amplitude and direction of the movement (Figure 14C and D) [99].
\nAtrial myocardial deformation profiles estimated by TDI and 2D-STE (e.g. strain and strain rate) have been recently emerged as a good alternative method of exploring LA mechanics in both humans and dogs [100, 101, 102, 103]. Although many drawbacks of this approach were noticed (e.g. suboptimal reproducibility, angle dependence, and the confounding effect of noise artifacts), 2D-STE can be a more advanced angle-independent echocardiographic technique for the direct evaluation of LA function than standard grayscale echocardiographic images [100, 101, 102, 103]. The specific STE variables subject to the LA function include peak atrial longitudinal average strain (PALS), peak atrial contraction average strain (PACS), and contraction strain index (CSI), which reflect the LA function during its reservoir, booster pump phase, and the contribution of LA active contraction to the LV filling phase (Figure 14B) [104]. In humans, LA strain analysis has been useful for grading patients with valvular diseases, atrial fibrillation, or acute coronary disease [105, 106, 107]. However, a recent canine study found the STE variables were not significantly different between ACVIM B1 and B2 groups, although those (especially, PALS) were significantly different between ACVIM B2 and C groups [108]. The use of cut-off for PALS <27.9% enables to perfectly differentiate dogs in ACVIM stage B2 from those in ACVIM stage C with a sensitivity of 100% and specificity of 100% [108]. Another study also demonstrated the STE variables including PALS, PACS, and CSI were significantly decreased with the progression of MMVD [103]. A further study from this study group also found the STE variables (PALS <30% and CSI per 1% increase) were predictors of cardiac death in the univariate analysis [109].
\nSince the RV chamber is crescent-shaped and is wrapped around the LV, precise echocardiographic assessment of RV function is often difficult. The TDI and STE can overcome this limitation as reported in human studies [110, 111]. Recent canine study found the STE on RV was applicable and repeatable in healthy dogs [93]. Furthermore, other study demonstrated the RV longitudinal strain and the dyssynchrony index were significantly different from control dogs [75]. In this study, the global, free wall, and septal RV longitudinal strain in dogs with precapillary PH were significantly lower than those in control, while free wall and septal systolic shortening time strain were significantly slower [75].
\nIn this chapter, we described echocardiographic features of MMVD in dogs along with human echocardiographic criteria of MR. Although there are many similarities for diagnosing and grading the severity of MR in both species, veterinary cardiologists are more focused on the severity of cardiac remodeling and cardiac dysfunction caused by MR, because surgical restoration of defected mitral apparatus is rarely done in dogs. Recent canine studies also found advanced ultrasound technologies, such as strain and strain rate imaging, and two-dimensional speckle tracking echocardiography were also applicable for dogs with MMVD, although more studies are warranted for standardizing the method of assessment in dogs. The authors believe that this chapter would be a valuable reference for veterinary and human cardiologists and researchers for understanding mitral valve disease.
\nThe authors express great gratitude to Siemens Healthineers (Ms. UnWook Park) for technical support and Drs Jae-Min Suhl and Jin-Hee Noh for sharing space and resources for preparing echocardiographic images on this chapter.
\nThere is no conflict for this publication.
IntechOpen publishes different types of publications
",metaTitle:"Types of publications",metaDescription:"IntechOpen publishes different types of publications",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen Edited Volumes are integrated collections of chapters about particular topics that present new areas of research or novel syntheses of existing research and, as such, represent perspectives from various authors.
\\n\\nEdited Volumes can be comprised of different types of chapters:
\\n\\nRESEARCH CHAPTER – A research chapter reports the results of original research thus contributing to the body of knowledge in a particular area of study.
\\n\\nREVIEW CHAPTER – A review chapter analyzes or examines research previously published by other scientists, rather than reporting new findings thus summarizing the current state of understanding on a topic.
\\n\\nCASE STUDY – A case study involves an in-depth, and detailed examination of a particular topic.
\\n\\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\\n\\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
\\n\\nMonographs is a self-contained work on a particular subject, or an aspect of it, written by one or more authors. Monographs usually have between 130 and 500 pages.
\\n\\nTYPES OF MONOGRAPHS:
\\n\\nSingle or multiple author manuscript
\\n\\nCompacts provide a mid-length publishing format that bridges the gap between journal articles, book chapters, and monographs, and cover content across all scientific disciplines.
\\n\\nCompacts are the preferred publishing option for brief research reports on new topics, in-depth case studies, dissertations, or essays exploring new ideas, issues, or broader topics on the research subject. Compacts usually have between 50 and 130 pages.
\\n\\nCollection of papers presented at conferences, workshops, symposiums, or scientific courses, published in book format
\\n"}]'},components:[{type:"htmlEditorComponent",content:"IntechOpen Edited Volumes are integrated collections of chapters about particular topics that present new areas of research or novel syntheses of existing research and, as such, represent perspectives from various authors.
\n\nEdited Volumes can be comprised of different types of chapters:
\n\nRESEARCH CHAPTER – A research chapter reports the results of original research thus contributing to the body of knowledge in a particular area of study.
\n\nREVIEW CHAPTER – A review chapter analyzes or examines research previously published by other scientists, rather than reporting new findings thus summarizing the current state of understanding on a topic.
\n\nCASE STUDY – A case study involves an in-depth, and detailed examination of a particular topic.
\n\nPERSPECTIVE CHAPTER – A perspective chapter offers a new point of view on existing problems, fundamental concepts, or common opinions on a specific topic. Perspective chapters can propose or support new hypotheses, or discuss the significance of newly achieved innovations. Perspective chapters can focus on current advances and future directions on a topic and include both original data and personal opinion.
\n\nINTRODUCTORY CHAPTER – An introductory chapter states the purpose and goals of the book. The introductory chapter is written by the Academic Editor.
\n\nMonographs is a self-contained work on a particular subject, or an aspect of it, written by one or more authors. Monographs usually have between 130 and 500 pages.
\n\nTYPES OF MONOGRAPHS:
\n\nSingle or multiple author manuscript
\n\nCompacts provide a mid-length publishing format that bridges the gap between journal articles, book chapters, and monographs, and cover content across all scientific disciplines.
\n\nCompacts are the preferred publishing option for brief research reports on new topics, in-depth case studies, dissertations, or essays exploring new ideas, issues, or broader topics on the research subject. Compacts usually have between 50 and 130 pages.
\n\nCollection of papers presented at conferences, workshops, symposiums, or scientific courses, published in book format
\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5775},{group:"region",caption:"Middle and South America",value:2,count:5238},{group:"region",caption:"Africa",value:3,count:1721},{group:"region",caption:"Asia",value:4,count:10409},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15805}],offset:12,limit:12,total:118374},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"1",sort:"dateEndThirdStepPublish"},books:[{type:"book",id:"10231",title:"Proton Therapy",subtitle:null,isOpenForSubmission:!0,hash:"f4a9009287953c8d1d89f0fa9b7597b0",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10231.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10652",title:"Visual Object Tracking",subtitle:null,isOpenForSubmission:!0,hash:"96f3ee634a7ba49fa195e50475412af4",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10653",title:"Optimization Algorithms",subtitle:null,isOpenForSubmission:!0,hash:"753812dbb9a6f6b57645431063114f6c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10653.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10655",title:"Motion Planning",subtitle:null,isOpenForSubmission:!0,hash:"809b5e290cf2dade9e7e0a5ae0ef3df0",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10655.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10657",title:"Service Robots",subtitle:null,isOpenForSubmission:!0,hash:"5f81b9eea6eb3f9af984031b7af35588",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10657.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10662",title:"Pedagogy",subtitle:null,isOpenForSubmission:!0,hash:"c858e1c6fb878d3b895acbacec624576",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10662.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10673",title:"The Psychology of Trust",subtitle:null,isOpenForSubmission:!0,hash:"1f6cac41fd145f718ac0866264499cc8",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10673.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10675",title:"Hydrostatics",subtitle:null,isOpenForSubmission:!0,hash:"c86c2fa9f835d4ad5e7efd8b01921866",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10675.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10677",title:"Topology",subtitle:null,isOpenForSubmission:!0,hash:"85eac84b173d785f989522397616124e",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10677.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10678",title:"Biostatistics",subtitle:null,isOpenForSubmission:!0,hash:"f63db439474a574454a66894db8b394c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10678.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10679",title:"Mass Production",subtitle:null,isOpenForSubmission:!0,hash:"2dae91102099b1a07be1a36a68852829",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10679.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10689",title:"Risk Management in Construction",subtitle:null,isOpenForSubmission:!0,hash:"e3805b3d2fceb9d33e1fa805687cd296",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10689.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:6},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:6},{group:"topic",caption:"Business, Management and Economics",value:7,count:4},{group:"topic",caption:"Chemistry",value:8,count:1},{group:"topic",caption:"Computer and Information Science",value:9,count:5},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:3},{group:"topic",caption:"Engineering",value:11,count:4},{group:"topic",caption:"Environmental Sciences",value:12,count:4},{group:"topic",caption:"Immunology and Microbiology",value:13,count:2},{group:"topic",caption:"Mathematics",value:15,count:2},{group:"topic",caption:"Medicine",value:16,count:26},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{group:"topic",caption:"Robotics",value:22,count:4},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1}],offset:12,limit:12,total:81},popularBooks:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5247},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"115",title:"Control Engineering",slug:"engineering-control-engineering",parent:{title:"Engineering",slug:"engineering"},numberOfBooks:47,numberOfAuthorsAndEditors:1132,numberOfWosCitations:1255,numberOfCrossrefCitations:813,numberOfDimensionsCitations:1458,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"engineering-control-engineering",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9287",title:"Control Theory in Engineering",subtitle:null,isOpenForSubmission:!1,hash:"7c584de5f40193b636833aa812dab9d5",slug:"control-theory-in-engineering",bookSignature:"Constantin Volosencu, Ali Saghafinia, Xian Du and Sohom Chakrabarty",coverURL:"https://cdn.intechopen.com/books/images_new/9287.jpg",editedByType:"Edited by",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8347",title:"Computer Architecture in Industrial, Biomechanical and Biomedical Engineering",subtitle:null,isOpenForSubmission:!1,hash:"3d7024a8d7d8afed093c9c79ec31f15a",slug:"computer-architecture-in-industrial-biomechanical-and-biomedical-engineering",bookSignature:"Lulu Wang and Liandong Yu",coverURL:"https://cdn.intechopen.com/books/images_new/8347.jpg",editedByType:"Edited by",editors:[{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7485",title:"Applied Modern Control",subtitle:null,isOpenForSubmission:!1,hash:"c7a7be73f7232e08867ed81bdf9850c6",slug:"applied-modern-control",bookSignature:"Le Anh Tuan",coverURL:"https://cdn.intechopen.com/books/images_new/7485.jpg",editedByType:"Edited by",editors:[{id:"180550",title:"Dr.",name:"Le",middleName:null,surname:"Anh Tuan",slug:"le-anh-tuan",fullName:"Le Anh Tuan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6806",title:"Fuzzy Logic Based in Optimization Methods and Control Systems and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"fedf4479b910cbcee3025e391f073417",slug:"fuzzy-logic-based-in-optimization-methods-and-control-systems-and-its-applications",bookSignature:"Ali Sadollah",coverURL:"https://cdn.intechopen.com/books/images_new/6806.jpg",editedByType:"Edited by",editors:[{id:"147215",title:"Dr.",name:"Ali",middleName:null,surname:"Sadollah",slug:"ali-sadollah",fullName:"Ali Sadollah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6323",title:"PID Control for Industrial Processes",subtitle:null,isOpenForSubmission:!1,hash:"3994459e0812cf44a04b3f6c3e28e9c1",slug:"pid-control-for-industrial-processes",bookSignature:"Mohammad Shamsuzzoha",coverURL:"https://cdn.intechopen.com/books/images_new/6323.jpg",editedByType:"Edited by",editors:[{id:"87344",title:"Dr.",name:"Mohammad",middleName:null,surname:"Shamsuzzoha",slug:"mohammad-shamsuzzoha",fullName:"Mohammad Shamsuzzoha"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6101",title:"Advances in Some Hypersonic Vehicles Technologies",subtitle:null,isOpenForSubmission:!1,hash:"5ecc3136420d6f6cc0de2da29f9d749c",slug:"advances-in-some-hypersonic-vehicles-technologies",bookSignature:"Ramesh K. Agarwal",coverURL:"https://cdn.intechopen.com/books/images_new/6101.jpg",editedByType:"Edited by",editors:[{id:"38519",title:"Prof.",name:"Ramesh K.",middleName:null,surname:"Agarwal",slug:"ramesh-k.-agarwal",fullName:"Ramesh K. Agarwal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6240",title:"Adaptive Robust Control Systems",subtitle:null,isOpenForSubmission:!1,hash:"19601f78e28ac1956912e5eeb6b834ac",slug:"adaptive-robust-control-systems",bookSignature:"Le Anh Tuan",coverURL:"https://cdn.intechopen.com/books/images_new/6240.jpg",editedByType:"Edited by",editors:[{id:"180551",title:"Prof.",name:"Anh Tuan",middleName:null,surname:"Le",slug:"anh-tuan-le",fullName:"Anh Tuan Le"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5823",title:"Recent Developments in Sliding Mode Control",subtitle:"Theory and Applications",isOpenForSubmission:!1,hash:"1075a2f87196085bae2babfac6bc3d52",slug:"recent-developments-in-sliding-mode-control-theory-and-applications",bookSignature:"Andrzej Bartoszewicz",coverURL:"https://cdn.intechopen.com/books/images_new/5823.jpg",editedByType:"Edited by",editors:[{id:"18337",title:"Prof.",name:"Andrzej",middleName:null,surname:"Bartoszewicz",slug:"andrzej-bartoszewicz",fullName:"Andrzej Bartoszewicz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5496",title:"Fault Diagnosis and Detection",subtitle:null,isOpenForSubmission:!1,hash:"9d27af6f557a4c54b28af7072dc3fcb6",slug:"fault-diagnosis-and-detection",bookSignature:"Mustafa Demetgul and Muhammet Ünal",coverURL:"https://cdn.intechopen.com/books/images_new/5496.jpg",editedByType:"Edited by",editors:[{id:"19106",title:"Dr.",name:"Mustafa",middleName:null,surname:"Demetgul",slug:"mustafa-demetgul",fullName:"Mustafa Demetgul"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5486",title:"Quality Control and Assurance",subtitle:"An Ancient Greek Term Re-Mastered",isOpenForSubmission:!1,hash:"549fefebffcb2f610fb669f6eb86c785",slug:"quality-control-and-assurance-an-ancient-greek-term-re-mastered",bookSignature:"Leo D. Kounis",coverURL:"https://cdn.intechopen.com/books/images_new/5486.jpg",editedByType:"Edited by",editors:[{id:"111582",title:"Dr.",name:"Leo",middleName:"Dimitrios",surname:"Kounis",slug:"leo-kounis",fullName:"Leo Kounis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5379",title:"Computer-aided Technologies",subtitle:"Applications in Engineering and Medicine",isOpenForSubmission:!1,hash:"f33a3bdb537f32114b4c1ca6ed3be8dd",slug:"computer-aided-technologies-applications-in-engineering-and-medicine",bookSignature:"Razvan Udroiu",coverURL:"https://cdn.intechopen.com/books/images_new/5379.jpg",editedByType:"Edited by",editors:[{id:"13146",title:"Prof.",name:"Razvan",middleName:null,surname:"Udroiu",slug:"razvan-udroiu",fullName:"Razvan Udroiu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4521",title:"Fuzzy Logic",subtitle:"Tool for Getting Accurate Solutions",isOpenForSubmission:!1,hash:"37b90572d58c2c01bd61c23e908649e2",slug:"fuzzy-logic-tool-for-getting-accurate-solutions",bookSignature:"Elmer P. Dadios",coverURL:"https://cdn.intechopen.com/books/images_new/4521.jpg",editedByType:"Edited by",editors:[{id:"111683",title:"Prof.",name:"Elmer",middleName:null,surname:"Dadios",slug:"elmer-dadios",fullName:"Elmer Dadios"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:47,mostCitedChapters:[{id:"29691",doi:"10.5772/37638",title:"A Real-Time Gradient Method for Nonlinear Model Predictive Control",slug:"a-real-time-gradient-method-for-nonlinear-model-predictive-control",totalDownloads:2163,totalCrossrefCites:47,totalDimensionsCites:60,book:{slug:"frontiers-of-model-predictive-control",title:"Frontiers of Model Predictive Control",fullTitle:"Frontiers of Model Predictive Control"},signatures:"Knut Graichen and Bartosz Käpernick",authors:[{id:"113632",title:"Prof.",name:"Knut",middleName:null,surname:"Graichen",slug:"knut-graichen",fullName:"Knut Graichen"},{id:"139321",title:"MSc.",name:"Bartosz",middleName:null,surname:"Kaepernick",slug:"bartosz-kaepernick",fullName:"Bartosz Kaepernick"}]},{id:"34221",doi:"10.5772/36321",title:"A Mamdani Type Fuzzy Logic Controller",slug:"a-mamdani-type-fuzzy-logic-controller",totalDownloads:11962,totalCrossrefCites:30,totalDimensionsCites:48,book:{slug:"fuzzy-logic-controls-concepts-theories-and-applications",title:"Fuzzy Logic",fullTitle:"Fuzzy Logic - Controls, Concepts, Theories and Applications"},signatures:"Ion Iancu",authors:[{id:"107854",title:"Prof.",name:"Ion",middleName:null,surname:"Iancu",slug:"ion-iancu",fullName:"Ion Iancu"}]},{id:"4579",doi:"10.5772/5812",title:"Cumulative Vehicle Routing Problems",slug:"cumulative_vehicle_routing_problems",totalDownloads:3069,totalCrossrefCites:18,totalDimensionsCites:30,book:{slug:"vehicle_routing_problem",title:"Vehicle Routing Problem",fullTitle:"Vehicle Routing Problem"},signatures:"İmdat Kara, Bahar Yetiş Kara and M. Kadri Yetiş",authors:null}],mostDownloadedChaptersLast30Days:[{id:"62915",title:"Advanced Methods of PID Controller Tuning for Specified Performance",slug:"advanced-methods-of-pid-controller-tuning-for-specified-performance",totalDownloads:2414,totalCrossrefCites:3,totalDimensionsCites:6,book:{slug:"pid-control-for-industrial-processes",title:"PID Control for Industrial Processes",fullTitle:"PID Control for Industrial Processes"},signatures:"Štefan Bucz and Alena Kozáková",authors:[{id:"21933",title:"Ms.",name:"Alena",middleName:null,surname:"Kozakova",slug:"alena-kozakova",fullName:"Alena Kozakova"},{id:"213658",title:"Dr.",name:"Štefan",middleName:null,surname:"Bucz",slug:"stefan-bucz",fullName:"Štefan Bucz"}]},{id:"62600",title:"Introductory Chapter: Which Membership Function is Appropriate in Fuzzy System?",slug:"introductory-chapter-which-membership-function-is-appropriate-in-fuzzy-system-",totalDownloads:1155,totalCrossrefCites:8,totalDimensionsCites:16,book:{slug:"fuzzy-logic-based-in-optimization-methods-and-control-systems-and-its-applications",title:"Fuzzy Logic Based in Optimization Methods and Control Systems and Its Applications",fullTitle:"Fuzzy Logic Based in Optimization Methods and Control Systems and Its Applications"},signatures:"Ali Sadollah",authors:[{id:"147215",title:"Dr.",name:"Ali",middleName:null,surname:"Sadollah",slug:"ali-sadollah",fullName:"Ali Sadollah"}]},{id:"53946",title:"The Evolution of Quality Concepts and the Related Quality Management",slug:"the-evolution-of-quality-concepts-and-the-related-quality-management",totalDownloads:3219,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"quality-control-and-assurance-an-ancient-greek-term-re-mastered",title:"Quality Control and Assurance",fullTitle:"Quality Control and Assurance - An Ancient Greek Term Re-Mastered"},signatures:"Ching-Chow Yang",authors:[{id:"11862",title:"Prof.",name:"Ching-Chow",middleName:null,surname:"Yang",slug:"ching-chow-yang",fullName:"Ching-Chow Yang"}]},{id:"16112",title:"Applications of Adaptive Filtering",slug:"applications-of-adaptive-filtering",totalDownloads:10609,totalCrossrefCites:2,totalDimensionsCites:8,book:{slug:"adaptive-filtering-applications",title:"Adaptive Filtering Applications",fullTitle:"Adaptive Filtering Applications"},signatures:"J. Gerardo Avalos, Juan C. Sanchez and Jose Velazquez",authors:[{id:"26570",title:"MSc",name:"Juan",middleName:"Gerardo",surname:"Avalos",slug:"juan-avalos",fullName:"Juan Avalos"},{id:"67182",title:"Dr.",name:"Juan",middleName:null,surname:"Sanchez",slug:"juan-sanchez",fullName:"Juan Sanchez"},{id:"67184",title:"Dr.",name:"Jose",middleName:null,surname:"Velazquez",slug:"jose-velazquez",fullName:"Jose Velazquez"}]},{id:"53024",title:"Key Aspects for Implementing ISO/IEC 17025 Quality Management Systems at Materials Science Laboratories",slug:"key-aspects-for-implementing-iso-iec-17025-quality-management-systems-at-materials-science-laborator",totalDownloads:1957,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"quality-control-and-assurance-an-ancient-greek-term-re-mastered",title:"Quality Control and Assurance",fullTitle:"Quality Control and Assurance - An Ancient Greek Term Re-Mastered"},signatures:"Rodrigo S. Neves, Daniel P. Da Silva, Carlos E. C. Galhardo, Erlon H.\nM. Ferreira, Rafael M. Trommer and Jailton C. Damasceno",authors:[{id:"20571",title:"Prof.",name:"Erlon H.",middleName:null,surname:"Martins Ferreira",slug:"erlon-h.-martins-ferreira",fullName:"Erlon H. Martins Ferreira"},{id:"145815",title:"Dr.",name:"Rodrigo",middleName:null,surname:"De Santis Neves",slug:"rodrigo-de-santis-neves",fullName:"Rodrigo De Santis Neves"},{id:"145816",title:"Dr.",name:"Carlos",middleName:null,surname:"Eduardo Cardoso Galhardo",slug:"carlos-eduardo-cardoso-galhardo",fullName:"Carlos Eduardo Cardoso Galhardo"},{id:"159056",title:"Dr.",name:"Jailton",middleName:null,surname:"Damasceno",slug:"jailton-damasceno",fullName:"Jailton Damasceno"},{id:"191863",title:"Dr.",name:"Daniel",middleName:"Pereira Da Silva",surname:"Fernandes",slug:"daniel-fernandes",fullName:"Daniel Fernandes"},{id:"191865",title:"Dr.",name:"Rafael",middleName:null,surname:"Mello Trommer",slug:"rafael-mello-trommer",fullName:"Rafael Mello Trommer"}]},{id:"63072",title:"Fuzzy Controller-Based MPPT of PV Power System",slug:"fuzzy-controller-based-mppt-of-pv-power-system",totalDownloads:1225,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"fuzzy-logic-based-in-optimization-methods-and-control-systems-and-its-applications",title:"Fuzzy Logic Based in Optimization Methods and Control Systems and Its Applications",fullTitle:"Fuzzy Logic Based in Optimization Methods and Control Systems and Its Applications"},signatures:"M. Venkateshkumar",authors:[{id:"243101",title:"Dr.",name:"M",middleName:null,surname:"Mven",slug:"m-mven",fullName:"M Mven"}]},{id:"19188",title:"High-Speed and High-Precision Position Control Using a Nonlinear Compensator",slug:"high-speed-and-high-precision-position-control-using-a-nonlinear-compensator",totalDownloads:2409,totalCrossrefCites:3,totalDimensionsCites:3,book:{slug:"advances-in-pid-control",title:"Advances in PID Control",fullTitle:"Advances in PID Control"},signatures:"Kazuhiro Tsuruta, Kazuya Sato and Takashi Fujimoto",authors:[{id:"31823",title:"Prof.",name:"Kazuhiro",middleName:null,surname:"Tsuruta",slug:"kazuhiro-tsuruta",fullName:"Kazuhiro Tsuruta"},{id:"45823",title:"Prof.",name:"Kazuya",middleName:null,surname:"Sato",slug:"kazuya-sato",fullName:"Kazuya Sato"},{id:"45824",title:"Prof.",name:"Takashi",middleName:null,surname:"Fujimoto",slug:"takashi-fujimoto",fullName:"Takashi Fujimoto"}]},{id:"19194",title:"PID Controller Using FPGA Technology",slug:"pid-controller-using-fpga-technology",totalDownloads:15242,totalCrossrefCites:0,totalDimensionsCites:4,book:{slug:"advances-in-pid-control",title:"Advances in PID Control",fullTitle:"Advances in PID Control"},signatures:"Abdesselem Trimeche, Anis Sakly, Abdelatif Mtibaa and Mohamed Benrejeb",authors:[{id:"19211",title:"Prof.",name:"Mohamed",middleName:null,surname:"Benrejeb",slug:"mohamed-benrejeb",fullName:"Mohamed Benrejeb"},{id:"31012",title:"Mr.",name:"Trimeche",middleName:null,surname:"Abdesselem",slug:"trimeche-abdesselem",fullName:"Trimeche Abdesselem"},{id:"57991",title:"Mr",name:"Anis",middleName:null,surname:"Sakly",slug:"anis-sakly",fullName:"Anis Sakly"},{id:"57993",title:"Mr",name:"Abdelatif",middleName:null,surname:"Mtibaa",slug:"abdelatif-mtibaa",fullName:"Abdelatif Mtibaa"}]},{id:"37990",title:"Automation in aviation",slug:"automation-in-aviation",totalDownloads:5933,totalCrossrefCites:11,totalDimensionsCites:13,book:{slug:"automation",title:"Automation",fullTitle:"Automation"},signatures:"Antonio Chialastri",authors:[{id:"116690",title:"Dr.",name:"Antonio",middleName:null,surname:"Chialastri",slug:"antonio-chialastri",fullName:"Antonio Chialastri"}]},{id:"58282",title:"Matlab-Simulink-Based Compound Model Reference Adaptive Control for DC Motor",slug:"matlab-simulink-based-compound-model-reference-adaptive-control-for-dc-motor",totalDownloads:1524,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"adaptive-robust-control-systems",title:"Adaptive Robust Control Systems",fullTitle:"Adaptive Robust Control Systems"},signatures:"Marian Găiceanu",authors:[{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Gaiceanu",slug:"marian-gaiceanu",fullName:"Marian Gaiceanu"}]}],onlineFirstChaptersFilter:{topicSlug:"engineering-control-engineering",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"chapter.detail",path:"/books/mitochondrial-dna-new-insights/true-mitochondrial-trna-punctuation-and-initiation-using-overlapping-stop-and-start-codons-at-specif",hash:"",query:{},params:{book:"mitochondrial-dna-new-insights",chapter:"true-mitochondrial-trna-punctuation-and-initiation-using-overlapping-stop-and-start-codons-at-specif"},fullPath:"/books/mitochondrial-dna-new-insights/true-mitochondrial-trna-punctuation-and-initiation-using-overlapping-stop-and-start-codons-at-specif",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()