Classification of key components of EVs by their main categories.
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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We have refined our understanding of the etiology and pathogenesis for both peripheral and central nervous system diseases, and developed new therapeutic approaches towards these diseases. Peripheral neuropathy is a common disorder seen by many specialists and can pose a diagnostic dilemma. Many etiologies, including drugs that are used to treat other diseases, can cause peripheral neuropathy. However, the most common cause is Diabetes Mellitus, a disease all physicians encounter. Disability due to peripheral neuropathy can be severe, as the patients suffer from symptoms daily. This book addresses the advances in the diagnosis and therapies of peripheral neuropathy over the last decade. The basics of different peripheral neuropathies is briefly discussed, however, the book focuses on topics that address new approaches to peripheral neuropathies.",isbn:null,printIsbn:"978-953-51-0066-9",pdfIsbn:"978-953-51-6823-2",doi:"10.5772/1276",price:119,priceEur:129,priceUsd:155,slug:"peripheral-neuropathy-advances-in-diagnostic-and-therapeutic-approaches",numberOfPages:220,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"85bc0ed7d22628f9365150affc7fcb05",bookSignature:"Ghazala Hayat",publishedDate:"February 29th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/768.jpg",numberOfDownloads:42137,numberOfWosCitations:4,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:2,hasAltmetrics:1,numberOfTotalCitations:11,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 2nd 2011",dateEndSecondStepPublish:"March 2nd 2011",dateEndThirdStepPublish:"July 7th 2011",dateEndFourthStepPublish:"August 6th 2011",dateEndFifthStepPublish:"December 4th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"85341",title:"Dr.",name:"Ghazala",middleName:null,surname:"Hayat",slug:"ghazala-hayat",fullName:"Ghazala Hayat",profilePictureURL:"https://mts.intechopen.com/storage/users/85341/images/3587_n.jpg",biography:"Ghazala Hayat is a professor of Neurology & Psychiatry at the St. Louis University, USA. She is also the director of Neuromuscular, Clinical Neurophysiology services and Clinical Neurophysiology fellowship.\nAfter graduating from the King Edward Medical College in Pakistan, prof. Hayat received her training in neurology, neuromuscular disorders and neurophysiology at the Medical College Virginia, USA.\nProf. Hayat is board certified in neurology, electrodiagnostic medicine, neuromuscular medicine and clinical neurophysiology. Her interests include peripheral neuropathies, compressive neuropathies, neuromuscular junction disorders and electrodiagnostic studies. She has published on various topics in her area of expertise. Prof. Hayat is a fellow of American Academy of Neurologists, American Association of Neuromuscular disorders & Electrodiagnostic medicine. She was nominated for America’s Best Doctors 2007-2012.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1056",title:"Neurology",slug:"neurology"}],chapters:[{id:"29738",title:"Etiological Role of Dynamin in Charcot-Marie-Tooth Disease",doi:"10.5772/29046",slug:"etiological-role-of-dynamin-in-charcot-marie-tooth-disease",totalDownloads:2072,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Kohji Takei and Kenji Tanabe",downloadPdfUrl:"/chapter/pdf-download/29738",previewPdfUrl:"/chapter/pdf-preview/29738",authors:[{id:"76334",title:"Prof.",name:"Kohji",surname:"Takei",slug:"kohji-takei",fullName:"Kohji Takei"}],corrections:null},{id:"29739",title:"Predictors of Chemotherapy-Induced Peripheral Neuropathy",doi:"10.5772/27563",slug:"predictors-of-chemotherapy-induced-peripheral-neuropathy",totalDownloads:3528,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:null,signatures:"Yuko Kanbayashi and Toyoshi Hosokawa",downloadPdfUrl:"/chapter/pdf-download/29739",previewPdfUrl:"/chapter/pdf-preview/29739",authors:[{id:"70650",title:"PhD.",name:"Yuko",surname:"Kanbayashi",slug:"yuko-kanbayashi",fullName:"Yuko Kanbayashi"},{id:"73399",title:"Prof.",name:"Toyoshi",surname:"Hosokawa",slug:"toyoshi-hosokawa",fullName:"Toyoshi Hosokawa"}],corrections:null},{id:"29740",title:"Targeting Molecular Chaperones in Diabetic Peripheral Neuropathy",doi:"10.5772/27836",slug:"targeting-molecular-chaperones-in-diabetic-peripheral-neuropathy",totalDownloads:1981,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Chengyuan Li and Rick T. 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Dooly",slug:"gerard-dooly",email:"Gerard.Dooly@ul.ie",position:null,institution:null}]}},chapter:{id:"63471",slug:"review-of-liquid-filled-optical-fibre-based-temperature-sensing",signatures:"Fintan McGuinness, Gabriel Leen, Elfed Lewis, Gerard Dooly, Daniel Toal\nand Dinesh Babu Duraibabu",dateSubmitted:"May 22nd 2018",dateReviewed:"August 1st 2018",datePrePublished:"November 5th 2018",datePublished:"April 24th 2019",book:{id:"8271",title:"Applications of Optical Fibers for Sensing",subtitle:null,fullTitle:"Applications of Optical Fibers for Sensing",slug:"applications-of-optical-fibers-for-sensing",publishedDate:"April 24th 2019",bookSignature:"Christian Cuadrado-Laborde",coverURL:"https://cdn.intechopen.com/books/images_new/8271.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"220902",title:"Dr.",name:"Christian",middleName:null,surname:"Cuadrado-Laborde",slug:"christian-cuadrado-laborde",fullName:"Christian Cuadrado-Laborde"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"27036",title:"Dr.",name:"Daniel",middleName:null,surname:"Toal",fullName:"Daniel Toal",slug:"daniel-toal",email:"daniel.toal@ul.ie",position:null,institution:null},{id:"85846",title:"Prof.",name:"Elfed",middleName:null,surname:"Lewis",fullName:"Elfed Lewis",slug:"elfed-lewis",email:"Elfed.Lewis@ul.ie",position:null,institution:{name:"University of Limerick",institutionURL:null,country:{name:"Ireland"}}},{id:"259703",title:"Dr.",name:"Dinesh Babu",middleName:null,surname:"Duraibabu",fullName:"Dinesh Babu Duraibabu",slug:"dinesh-babu-duraibabu",email:"dineshbabu.duraibabu@ul.ie",position:null,institution:{name:"University of Limerick",institutionURL:null,country:{name:"Ireland"}}},{id:"269578",title:"Dr.",name:"Gabriel",middleName:null,surname:"Leen",fullName:"Gabriel Leen",slug:"gabriel-leen",email:"Gabriel.Leen@ul.ie",position:null,institution:null},{id:"269579",title:"M.Sc.",name:"Fintan",middleName:null,surname:"McGuinness",fullName:"Fintan McGuinness",slug:"fintan-mcguinness",email:"Fintan.McGuinness@ul.ie",position:null,institution:null},{id:"269580",title:"Dr.",name:"Gerard",middleName:null,surname:"Dooly",fullName:"Gerard Dooly",slug:"gerard-dooly",email:"Gerard.Dooly@ul.ie",position:null,institution:null}]},book:{id:"8271",title:"Applications of Optical Fibers for Sensing",subtitle:null,fullTitle:"Applications of Optical Fibers for Sensing",slug:"applications-of-optical-fibers-for-sensing",publishedDate:"April 24th 2019",bookSignature:"Christian Cuadrado-Laborde",coverURL:"https://cdn.intechopen.com/books/images_new/8271.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"220902",title:"Dr.",name:"Christian",middleName:null,surname:"Cuadrado-Laborde",slug:"christian-cuadrado-laborde",fullName:"Christian Cuadrado-Laborde"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11510",leadTitle:null,title:"New Trends in Electric Machines - Technology and Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"\r\n\tElectric machines represent one of the most important technological pillars in the development of modern societies. Their use is widely extended in multiple rotatory-based applications, initially in industry, but in energy and transport sectors later. For this reason, the research and developments around electric machines are in constant evolution. In this regard, scientific and technological efforts are continuously being applied in their three main aspects, that is (i) design, including thermal, electromagnetic, and mechanical features, (ii) supervision, comprising instrumentation, sensors development, processing, manufacturing, and testing, and (iii) control and drives, encompassing advanced control strategies and fault-tolerant approaches. Each field of application has its specifications in terms of power rate, speed, torque, efficiency, or performance, among others. This leads to constant advancements seeking optimal electric machines applied to new requirements of Industry 4.0, Electric vehicle or Renewables technologies. This book intends to gather an updated and comprehensive outlook on the scientific and technologic novelties around electric machines from their technology and application points of view.
",isbn:"978-1-83969-852-1",printIsbn:"978-1-83969-851-4",pdfIsbn:"978-1-83969-853-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"f57b5e35a1bf18acd4fd0d41fe59f49c",bookSignature:"Dr. Miguel Delgado Prieto, Dr. José Alfonso Antonino-Daviu and Dr. Roque A. Osornio-Rios",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11510.jpg",keywords:"Efficiency, Instrumentation and Measurement, Signal Processing, Fault Detection and Identification, Parameter Estimation, Sensorless, Adaptive, Fault-Tolerant Strategies, Electric Vehicle, Industry 4.0, Renewables, Complex Systems",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 29th 2022",dateEndSecondStepPublish:"May 27th 2022",dateEndThirdStepPublish:"July 26th 2022",dateEndFourthStepPublish:"October 14th 2022",dateEndFifthStepPublish:"December 13th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"An enthusiastic researcher in predictive maintenance applications applied to industry 4.0, electric vehicle, and energy sectors, IEEE senior member and researcher and technology transfer manager in national and international consortiums. Dr. Delgado Prieto was awarded the Top 1% reviewers in Engineering award in 2018 and top reviewers for the Polytechnic University of Catalonia award in 2017.",coeditorOneBiosketch:"An active researcher with over 200 publications, and a high h index(37), previously affiliated with the Helsinki University of Technology, Michigan State University, Korea University, and Université Claude Bernard Lyon1. Dr. Antonino-Daviu was the recipient of the Second Prize Paper Award of the IEEE IAS Electric machines Committee in 2013 and he was awarded the Best Paper Award in the conferences IEEE ICEM in 2012, IEEE SDEMPED in 2011, and Best Session Paper Award in ICELIE in 2013.",coeditorTwoBiosketch:"A consolidated researcher in hardware signal processing and mechatronics, with over 200 publications and a high h index(30), Fellow of the Mexican Academy of Engineering, and recipient of the National Award in Investigation 2016 for Mexican Academy of Science and IEEE Senior Member.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"234568",title:"Dr.",name:"Miguel",middleName:null,surname:"Delgado Prieto",slug:"miguel-delgado-prieto",fullName:"Miguel Delgado Prieto",profilePictureURL:"https://mts.intechopen.com/storage/users/234568/images/system/234568.jpeg",biography:"Dr. M. Delgado-Prieto was born in Barcelona, Spain, in 1983. He received the M.S. and Ph.D. degrees in Electronics Engineering from the UPC, Barcelona, Spain, in 2007 and 2012, respectively. In 2008 he joined the MCIA Research Center of the UPC. In 2021 he joined the Automatic Control Department of the UPC as Assistant Professor. His activity includes research, technology transfer and project management on condition based monitoring and internet of things for the transport, industry and energy sectors, trough national and international cooperation with companies, research centers and universities. His research interests include condition monitoring, predictive maintenance, fault detection algorithms, machine learning, signal processing methods and embedded systems.",institutionString:"Universitat Politècnica de Catalunya",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Universitat Politècnica de Catalunya",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"451997",title:"Dr.",name:"José Alfonso",middleName:null,surname:"Antonino-Daviu",slug:"jose-alfonso-antonino-daviu",fullName:"José Alfonso Antonino-Daviu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003Le3vQQAR/Profile_Picture_2022-03-15T10:01:33.png",biography:"Jose Antonino-Daviu (S’04-M’08-SM’12) was born in Valencia, Spain, in 1976. He received his M.Sc. and Ph. D. degrees in Electrical Engineering, both from the Universitat Politècnica de València, Valencia, Spain in 2000 and 2006, respectively and the Ms. Degree in Business Administration and Management from the Universitat de València, Valencia, Spain, in 2012. He worked for IBM, being involved in several international projects. He is currently Associate Professor in the Department of Electrical Engineering of the Universitat Politècnica de València, where he develops his docent and research work. He is also Secretary of the mentioned Department.",institutionString:"Universitat Politècnica de València",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Universitat Politècnica de València",institutionURL:null,country:{name:"Spain"}}},coeditorTwo:{id:"165604",title:"Dr.",name:"Roque A.",middleName:null,surname:"Osornio-Rios",slug:"roque-a.-osornio-rios",fullName:"Roque A. Osornio-Rios",profilePictureURL:"https://mts.intechopen.com/storage/users/165604/images/system/165604.jpeg",biography:"Dr. Roque A. Osornio Rios received the Ph.D. degree in mechatronics from the Autonomous University of Queretaro, Queretaro, Mexico, in 2007. Dr. Osornio-Rios is a National Researcher level 2 with the Mexican Council of Science and Technology, CONACYT. He is currently a Head Professor with the University of Queretaro, Mexico. He is advisor to more than 80 theses, and a coauthor of more than 100 technical papers published in international journals and conferences. His fields of interest include hardware signal processing and mechatronics. Dr. Osornio-Rios is fellow of the Mexican Academy of Engineering. He is part of the editorial board of Journal and Scientific and Industrial Research.",institutionString:"Autonomous University of Queretaro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453622",firstName:"Tea",lastName:"Jurcic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"tea@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"10198",title:"Response Surface Methodology in Engineering Science",subtitle:null,isOpenForSubmission:!1,hash:"1942bec30d40572f519327ca7a6d7aae",slug:"response-surface-methodology-in-engineering-science",bookSignature:"Palanikumar Kayaroganam",coverURL:"https://cdn.intechopen.com/books/images_new/10198.jpg",editedByType:"Edited by",editors:[{id:"321730",title:"Prof.",name:"Palanikumar",surname:"Kayaroganam",slug:"palanikumar-kayaroganam",fullName:"Palanikumar Kayaroganam"}],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:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],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"}},{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:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53914",title:"Acne-Associated Syndromes",doi:"10.5772/65635",slug:"acne-associated-syndromes",body:'\nAcne vulgaris is a common chronic inflammatory disease of the pilosebaceous unit. Acne is typically thought as an adolescent disease but it is also seen in adulthood anymore [1].
\nAlthough there are lots of studies about the pathogenesis of acne, all pathogenetic factors are not known very well. Four main pathways are described in acne pathogenesis: increased sebum production, abnormal keratinization,
Herein, we aim to mention about acne-associated syndromes and their clinical and pathogenetic features.
Polycystic ovary syndrome (PCOS) is an ovarian disease characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries. It is one of the most common endocrinopathy that affects 4–12% of women of reproductive age [5].
\nIts etiology is unknown, but it was first described by Drs Irving Stein and Michael Leventhal in 1935. They discovered polycystic ovaries in seven patients who had anovulation during surgery and described this disorder as the name of Stein-Leventhal syndrome [6]. Later diagnostic criteria were developed.
\nThe National Institutes of Health (NIH), the Rotterdam, and the Androgen Excess Society Criteria are used for the diagnosis of PCOS [7, 8]. Nowadays, NIH criteria are the preferred diagnostic criteria in adolescents [9].
\nNIH criteria are the presence of oligoovulation or anovulation and biochemical or clinical signs of hyperandrogenism [9]. Before the diagnosis with using these criteria, some conditions must be excluded that result in anovulation and hyperandrogenism, such as congenital adrenal hyperplasia, Cushing’s syndrome, and androgen secreting tumors [9]. Thyroid disease, hyperprolactinemia must also be excluded.
\nAlthough pathogenesis of PCOS is not understood very well, it is thought that hormonal pathways contribute to this process. The pulse frequency of gonadotropin-releasing hormone (GnRH) increases in PCOS and stimulates to the anterior pituitary gland to secrete luteinizing hormone (LH) more than follicle-stimulating hormone (FSH), resulting in an increased ratio of LH to FSH. The increase in LH relative to FSH stimulates the ovarian theca cells to synthesize androstenedione. Consequently, the net ovarian androgen production increases [10]. Insulin has also a role in the pathogenesis of PCOS by stimulating the ovarian theca cell to secrete androgens as LH and also inhibits hepatic production of sex hormone binding globulin (SHBG). As a result, free and total androgen level increases.
\nObesity is another component of this syndrome and contributes pathogenesis via insulin resistance [10].
\nInsulin resistance and hyperandrogenism are responsible for the cutaneous involvement of PCOS. Insulin resistance causes acanthosis nigricans (AN), and hyperandrogenism leads to hirsutism, acne, oily skin, seborrhea, and hair loss (androgenic alopecia). It is estimated that 72–82% of women with PCOS have cutaneous signs [11]. PCOS has also multisystemic effects and is associated with lots of diseases including infertility, endometrial cancer, obesity, depression, sleep-disordered breathing/obstructive sleep apnea (OSA), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), type 2 diabetes mellitus (T2DM), and cardiovascular diseases [9]. Patients with PCOS are usually first seen by a dermatologist. Because of the above comorbidities, dermatologists should know the diagnosis and clinical findings of PCOS very well.
\nCutaneous findings in women with PCOS are related to abnormalities of the pilosebaceous unit. Increased androgen levels activate abnormal development of the pilosebaceous unit, and hirsutism, acne or androgenic alopecia. Androgenic alopecia is luckily rare among women with PCOS because of its complex etiology. Acanthosis nigricans (AN) and skin tags are the other skin disorders in PCOS [12].
\nAlthough acne, hirsutism, and AN were the most common skin manifestations, hirsutism and AN were the most sensitive for PCOS diagnosis [13]. In previous reports, the range of acne prevalence in PCOS is 15–95%. While hirsutism affects 5–15% of women in the general population, previous reports showed hirsutism prevalence between 8.1 and 77.5% in women with PCOS. In patients with PCOS, hirsutism is also a sign of metabolic abnormalities [13].
\nAN is also associated with substantial metabolic dysfunction (increased insulin resistance, glucose intolerance, body mass index, and dyslipidemia).
\nTherefore, the presence of AN and hirsutism should warn us regarding a patient’s potential metabolic risk factors. A broad range in the prevalence of AN among women with PCOS (2.5% in the United Kingdom, 39 5.2% in Turkey, 16 and 17.2% in China) were observed [13].
\nAlthough patients with PCOS frequently refer to dermatologists with cutaneous concerns, it is important to educate them about the metabolic and fertility-related implications of PCOS.
\nHormonal therapy (combination estrogen and progesterone oral contraceptives, antiandrogens: spironolactone, cyproterone acetate, drospirenone, flutamide, and inhibition of peripheral androgen conversion: finasteride), insulin-sensitizing agents (metformin, thiazolidinediones), and nonhormonal therapy (standard acne, hirsutism, androgenetic alopecia therapy) are treatment options [14].
\nPharmacologic treatment is not every time necessary for all patients with PCOS. Mild forms of hirsutism, acne, and androgenetic alopecia may be controlled with standard nonhormonal agents and life style changes (weight loss, diet, exercise, glucose control) [14].
Hyperandrogenism-insulin resistance-acanthosis nigricans syndrome (HAIR-AN syndrome) is a subphenotype of polycystic ovary syndrome. It is clinically characterized by acne, obesity, hirsutism, and acanthosis nigricans. It usually manifests in early adolescence. Although etiology is not known very well, genetic, environmental factors, and obesity are estimated to cause HAIR-AN syndrome. The primary abnormality in patients with HAIR-AN syndrome is thought to be severe insulin resistance. In those patients, insulin levels increase and stimulate the overproduction of androgens in the ovaries [15].
\nPatients may also present with amenorrhea and signs of virilization. Although adrenal function is normal, the levels of insulin, testosterone, and androstenedione may be high. Adolescents with HAIR-AN syndrome usually have normal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) but the ratio of LH to FHS is usually more than one [16].
\nClinical findings are related to insulin resistance and hyperandrogenism so patients first refer to dermatologist, endocrinologist, or gynecologist with hyperandrogenism signs (hirsutism, androgenic alopecia, male body habitus acne, menstrual dysfunction, increased libido, clitorimegaly) or insulin resistance signs (polydipsia, polyuria (often subclinical), acanthosis nigricans, skin tags, and obesity [17] (Figure 1).
Acanthosis nigricans,
Polycystic ovary syndrome (71–86%), congenital hyperplasia of the adrenal (3–10%), adrenal and ovarian tumors (0.3%), and idiopathic hirsutism (10%) are, respectively, the most common reasons of hyperandrogenism. Except those, HAIR-AN syndrome should also keep in mind as a reason of hyperandrogenism that is seen in almost 5% of females with hyperandrogenism [18].
\nFor HAIR-AN syndrome diagnosis and follow-up, in addition to history and physical examination, a complete blood cell count, thyroid screen, serum prolactin, glucose and insulin measurements, serum electrolyte, and lipid panel should be evaluated [17] because Cushing’s syndrome, Hashimoto’s thyroiditis, Grave’s disease, and congenital adrenal hyperplasia may accompanied with HAIR-AN syndrome [4]. To investigate the origin of hyperandrogenism, total testosterone, levels of 17-hydroxyprogesterone, dehydroepiandrosterone sulfate (DHEAS), levels of luteinizing and follicle-stimulating hormones, and morning cortisol after a low dose of dexamethasone should be analyzed [17].
\nHigh level of DHEAS should warn us about the possibility of an androgen-producing tumor of the adrenal gland. Increased 17-hydroxyprogesterone is usually seen in congenital adrenal hyperplasia. Patients with Cushing’s syndrome have elevated levels of circulating androgen, and abnormal secretion of cortisol. In those, increased basal levels of cortisol and failure of suppression after stimulation with dexamethasone are observed. In polycystic ovarian syndrome, LH/FSH ratio is usually >2.5 (may see in normal patients as well). Although there is not an underlying virilizing tumor (ovarian or adrenal) in HAIR-AN syndrome, plasma testosterone level is high [19].
\nIn the treatment, lifestyle changes like exercise, lower-calorie diet rich in fiber and protein are advised to patients. Metformin can also be prescribed. Other choices are estroprogestatif pills and antiandrogens [20].
SAHA syndrome was first described in 1982, characterized by seborrhea, acne, hirsutism, and androgenetic alopecia [21]. The SAHA syndrome is classified into four types: idiopathic, ovarian, adrenal, and hyperprolactinemic [21], and it can be associated with polycystic ovaries, cystic mastitis, obesity, insulin resistance, and infertility [4, 21].
\nIn the pathogenesis of SAHA, increased androgen synthesis in adrenals and ovaries, disturbed peripheral metabolism of androgens, or induction of metabolism and activation of androgens in the skin may play important role [4].
\nApproximately 20% of the patients have all four major signs of SAHA syndrome. Seborrhoea is observed in all of patients, androgenetic alopecia is seen in 21% of the patients, and acne in 10% and hirsutism in 6% of the patients [4].
\nThe management of disorder resembles HAIR-AN and PCOS [22].
Apert syndrome is a rare congenital type I acrocephalosyndactyly syndrome (acrocephalosyndactyly type I). It was first described in 1906 by the French physician Eugène Apert, characterized by the premature fusion of the craniofacial sutures and syndactyly of the hands and feet [23].
\nThe syndrome is inherited in an autosomal dominant fashion, a rare congenital disease. It is caused by a genetic mutation in the FGFR2 gene, and approximately 98% of all patients have specific missense mutations of FGFR2 [24].
\nFGFR2 is responsible for the development of embryonic skeleton, epithelial structures, and connective tissue [25]. Craniofacial deformities, hypertelorism, dental and palatal abnormalities, proptosis of the eyes, different skeletal deformities, hydrocephalus, abnormal brain development, mental retardation, blindness, cardiovascular, urogenital, gastrointestinal, respiratory, and skin abnormalities can be seen in patients with Apert syndrome [25].
\nDermatologic associations of Apert syndrome was not known when first described in 1906 [26]. In 1970, Solomon first reported the dermatologic manifestation of this disorder, which is severe acneiform lesions [27]. The other skin manifestations are hyperhidrosis, hypopigmentation, and hyperkeratosis of plantar surfaces [27].
\nIn this syndrome, the pathogenesis of acne is not understood very well but increased fibroblast growth factor receptor-2 (FGFR2)-signaling is suspected to be of pathophysiological importance in acne vulgaris because it was reported that in skin cultures, keratinocyte-derived interleukin-1α stimulated fibroblasts to secrete FGF7 which stimulated FGFR2b-mediated keratinocyte proliferation [28]. In acne pathogenesis, increased levels of interleukin-1α (IL-1α) are seen in comedones, and an important pro-inflammatory cytokine stimulates keratinocyte proliferation, hyperkeratinization, and decreased desquamation of comedo formation [28]. Patients with Apert syndrome usually have oily skin. Moderate to severe acne, occurring in childhood or early adolescence, affecting the forearms, which is an unusual site for conventional acne, is often observed [23, 28]. Comedones, papules, pustules, furunculoid cysts, and scars as seen in conglobate acne can be seen. It is very difficult to treat, and often unresponsive to therapy but good response to oral isotretinoin [23, 26, 28].
\nAlthough isotretinoin therapy has good treatment option, it has serious adverse effects such as teratogenicity, hepatic dysfunction, elevation of cholesterol and triglyceride levels, visual changes, pseudotumor cerebri, musculoskeletal pain, hyperostosis, mucocutaneous dryness, and dryness of the eyes. Therefore, the risk/benefit ratio in treatment of acne lesions with isotretinoin in children with Apert syndrome should be evaluated well [26].
SAPHO syndrome was first defined in 1987 by Chamot et al. and its characteristic clinical findings are synovitis, acne, pustulosis, hyperostosis, and osteitis [29]. The etiology is controversial [30]. Although infections (Propionibacterium acnes, Corynebacterium sp.), seronegative spondyloarthropathies (psoriasis, sacroiliitis, enthesitis, inflammatory bowel disease, axial involvement), genetic factors, and stress were responsible for the pathogenesis, those are only hypothesis [30].
\nPropionibacterium acnes is estimated to play a pathogenic role in SAPHO syndrome. Productions of microbial determinants of P. acnes stimulate innate immune response through TLR-2. TLR-2 induces inflammatory cytokines via NF-jB and mitogen-activated protein kinase pathway [31]. Recent reports also showed that SAPHO syndrome had similar features with other autoinflammatory disease. IL-1β, TNF-α, and IL-8 were suggested to be important in the pathogenesis of SAPHO [32].
\nTwo cohort studies investigated genes PSTPIP2, LPIN2, NOD2, PSTPIP1, and PTPN22, but did not show causal mutations. Therefore, SAPHO syndrome is thought as a polygenic disease [33].
\nSAPHO syndrome is a rare disease so usually misdiagnosed because this syndrome have similar clinical features with infectious discitis, seronegative SpA, and psoriatic arthritis (PsA), and skin and bone lesions may appear at different times [34].
\nStandard diagnostic criteria are also controversial such as etiology. The commonly used diagnostic criteria of SAPHO syndrome: (i) local bone pain with gradual onset; (ii) multifocal lesions, especially in the long, tubular bones and spine; (iii) failure to culture an infectious microorganism; (iv) a protracted course for several years with exacerbations and improvement with anti-inflammatory drugs; and (v) neutrophilic skin eruptions, mostly palmoplantar pustulosis (PPP), nonpalmoplantar pustulosis, psoriasis vulgaris, or severe acne [30] (Figure 2).
Pustular psoriasis,
The skin manifestations are those of different neutrophilic dermatoses. PPP is the most common skin involvement, including pustular psoriasis, representing 50–75% of all dermatologic manifestations, psoriasis vulgaris may also be seen among the dermatologic manifestations of SAPHO. One fourth of patients have acne conglobata and fulminans with men clearly predominating [34]. Hidradenitis suppurativa may also be seen.
\nPG, Sweet’s syndrome, and Sneddon-Wilkinson disease are the other rare cutaneous manifestations. IBD especially Crohn’s disease may also be accompanied with SAPHO syndrome [34].
\nThe most of author agree about that SAPHO could be classified within the spectrum of autoinflammatory diseases. Therefore, intra-articular or systemic corticosteroids, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, cyclosporine, and leflunomide are the treatment options but there are no randomized controlled clinical trials for the treatment. Doxycycline can also be thought as a treatment option for P. acnes eradication [33] Infliximab (INFX), an anti-TNF-α monoclonal antibody, has been showed effective for the treatment SAPHO patients especially unresponsive or refractory to conventional drugs. In recent case series, remarkable improvement of bone, joints, and skin inflammatory manifestations was observed with Infliximab (INFX) therapy. In resistant SAPHO cases, the IL-1 antagonist anakinra can be also tried [35, 36].
PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne) is an autosomal dominant, autoinflammatory disorder. PAPA syndrome was first described as a hereditary disease in 1997 [37]. There is a PSTPIP1/CD2BP1 mutation on chromosome 15q that causes an increased binding affinity to pyrin and induces the assembly of inflammasomes [37]. The caspase, a protease, is activated and converts inactive prointerleukin (IL)-1 beta to its active isoform IL-1 beta. Overproduction of IL-1 beta induces to release pro-inflammatory cytokines and chemokines. Those are responsible for the recruitment and activation of neutrophils, leading to a neutrophil-mediated inflammation [38].
\nPAPA syndrome is usually presents with severe self-limiting pyogenic arthritis in early childhood. Pyoderma gangrenosum (Figure 3) and nodular-cystic acne may be seen around puberty and adulthood [37]. Pathergy test is positive in PAPA syndrome and clinically appears as pustule formation followed by ulceration [34]. There is not a diagnostic test but acute phase reactants and white blood cell count may be elevated because of systemic inflammation [34].
Pyoderma gangrenosum,
Arthritis usually gives good response to therapy with corticosteroids. Pyoderma gangrenosum is treated with topical or systemic immunosuppressant drugs. In addition, a few reports showed that anti-TNF-α and anti-IL-1 agents are effective in the treatment [39].
The clinical trial of pyoderma gangrenosum, acne conglobata, and hidradenitis suppurativa was described as PASH syndrome by Braun-Falco et al. in 2012. PASH syndrome clinically resembles pyoderma gangrenosum, acne conglobata, and pyogenic arthritis (PAPA) syndrome, but arthritis is not observed [40].
\nThe molecular basis of PASH syndrome is not known very well. It is accepted as autoinflammatory disease. PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne), PAPASH (pyogenic arthritis and PASH), and PASH (pyoderma gangrenosum, acne conglobata and hidradenitis suppurativa) syndromes clinically have similar components. The absence of pathogenic mutations in the PSTPIP1 gene may be used for distinguishing this syndrome from other AIDs [41, 42]. Although a genetic mutation was not discovered clearly in PASH syndrome, in some case series, NCSTN gene, NOD (nucleotide-binding oligomerization domain) genes, the immunoproteasome, and MEFV mutations were reported in PASH syndrome [41, 42].
\nSystemic corticosteroids, traditional antineutrophilic agents (dapsone and colchicine), and metformin may be tried at first but standard therapy options for autoinflammatory diseases are not usually enough to treat patients with PAPA and PASH syndrome whereas anti-TNF therapies and anti-IL-1 therapy are promising new treatment options for drug resistant cases [43].
Extracellular vesicles (EVs), phospholipid bilayer-enclosed vesicles consisting of proteins, lipids and nucleic acids, were once thought of as merely how cells may discard their waste materials and debris. However, recent discoveries have proven them to be indispensable to cells even in normal physiological functions and as diagnostic biomarkers for various diseases [1]. EVs are secreted by various cells and can be isolated from diverse biological sources like saliva, breast milk and blood serum [2].
Over the years, EVs have been researched as promising diagnostic biomarkers for pathological conditions. This is because their concentration and composition correlate with disease progression, a unique characteristic that sets them apart from other types of paracrine secretions [3, 4]. EVs have also been explored as possible carriers for drug delivery. Recent studies have shown promising results regarding the utilisation of EVs as drug delivery systems (DDSs) to treat various conditions, such as cardiovascular diseases [2, 5], osteoporosis [2, 6] and brain tumours [2, 7]. In light of this, EVs are seen as a more desirable strategy for drug delivery compared to other conventional nanoparticles like liposomes, micelles and polymeric nanoparticles [8, 9]. Conventional DDSs have been extensively used for their ability to protect drugs from inactivation in the external environment. However, plasma proteins risk adsorbing onto the surfaces of these non-EV nanoparticles upon injection into the body, making them an easy target of immune cells and decreasing their uptake by their target cells [10]. Although these nanoparticles may undergo modification to avoid immune cell removal, they still lack biocompatibility due to their non-biological origins. EVs, on the other hand, can evade phagocytosis by immune cells naturally, in addition to being highly selective for designated target sites, due to their biological origins and cell-specific surface properties inherited from the parent cells that secrete them.
Although EVs are promising in their diagnostic and therapeutic applications, it is still unclear whether they can cross membranes like the blood-brain barrier (BBB) naturally or when genetically modified, or only when the membranes become more permeable in certain conditions like injury [11, 12]. Furthermore, the uptake of EVs by target cells is still not fully understood at a microscopic level, be it
Classified by their biogenesis, size, morphology and function, there are three main EV categories—exosomes, microvesicles and apoptotic bodies (Figure 1) [16, 17, 18].
Biogenesis, size, morphology and function of exosomes, microvesicles and apoptotic bodies. (A)
Although exosomes, microvesicles and apoptotic bodies are distinct from one another, there is a partial overlap among their respective size range and composition. Although many different methods have been previously deployed to isolate EVs from their sample sources (a notable example being ultracentrifugation in isolating and purifying exosomes and microvesicles [19, 20, 21, 22]), these methods are unable to provide an accurate attribution of unique characteristics to each EV category. This is due to the complex nature of EVs, such that different size ranges can be derived from the same EV source depending on the isolation technique used [23]. As such, this review will mainly elaborate on EVs in general, unless otherwise stated.
Apart from biogenesis, size and morphology, each EV category possesses its own unique set of key proteins, lipids and nucleic acids (Table 1). Being able to differentiate EV categories based on their key components is vital in understanding their specific roles in both normal and pathological conditions. In general, all EVs possess cell adhesion proteins [13, 14, 17, 18, 24, 25, 26, 27, 28], heat-shock proteins [13, 14, 18, 25, 28, 29, 30], biogenesis-associated proteins [13, 14, 17, 18, 24, 25, 28], fusion proteins [13, 14, 18, 25], cell-type specific proteins [13, 14, 18, 27, 28], cytoskeletal proteins [13, 18], signalling molecules [13, 14, 28, 31], enzymes [13, 25, 28], messenger ribonucleic acid (mRNA), micro ribonucleic acid (miRNA), non-coding ribonucleic acid (RNA), phosphatidylethanolamine, sphingolipids and higher levels of phosphatidylserine (PS) than the cell plasma membrane [24, 25, 28, 35].
Components | Exosomes | Microvesicles | Apoptotic bodies | Reference(s) |
---|---|---|---|---|
Proteins | ||||
Tetraspanins | CD9, CD63, CD81, CD37, CD82, CD53, TSPAN 6, TSPAN 8, TSPAN 29, TSPAN 30 | CD40 ligands, CD82 | CD40 ligands, CD82 | [13, 14, 24, 25] |
Cell adhesion proteins | Integrins (integrin-alpha, integrin-beta), selectins (P-selectin), lactadherin, ICAM | integrins, selectins (P-selectin), fibronectin, PECAM-1 | integrins, fibronectin, PECAM-1 | [13, 14, 17, 18, 24, 25, 26, 27, 28] |
Heat shock proteins | Hsc70, Hsp20, Hsp27, Hsp60, Hsp70, Hsp90 | Hsp70, Hsp90 | Hsp70, Hsp90 | [13, 14, 18, 25, 28, 29, 30] |
Biogenesis-associated proteins | ESCRT proteins (Alix, Tsg101), VPS4, clathrin, ubiquitin, syntenin, VPS32, PLD | ESCRT proteins (Alix, Tsg101), VPS4, ERK, PLD | VPS4, ERK, PLD | [13, 14, 17, 18, 24, 25, 28] |
Fusion proteins | Flotillin 1 and 2, annexins, GTPases, Rab GTPases, dynamin, syntaxin | Flotilin-2, Rab GTPases, annexins | Rab GTPases, annexins (Annexin V) | [13, 14, 18, 25] |
Cell-type specific proteins | MHC class I, MHC class II, APP, PMEL, TCR, CXCR4, HSPG, CD86, PrP, WNT | MHC class I, MHC class II, LFA1, CD14 | MHC class I, LFA1, CD14 | [13, 14, 17, 18, 27, 28] |
Actin, tubulin, cofilin | Actin, tubulin | Actin, tubulin | [13, 18] | |
Cytoskeletal proteins | Protein kinases, beta-catenin, 14-3-3, G proteins | ARF6, Rab11, ROCK | ARF6, Rab11, ROCK | [13, 14, 28, 31] |
Signalling molecules | PLA2, peroxidases, pyruvate kinase, enolase, GADPH, ATPases | GADPH | GADPH | [13, 25, 28] |
Other enzymes | Glycoproteins
| Glycoproteins
| [18, 28] | |
Additional proteins | Growth-factors and cytokines
| Growth factors and cytokines | [18, 25] | |
Membrane signalling receptors
| Membrane signalling receptors | |||
Phosphoproteins | High phosphoproteins | [28, 32] | ||
Ribosomal proteins | GTP-binding protein ARF6 | [28, 33] | ||
Lysosomal proteins
| Chemokines | [25] | ||
Lipids | High phosphatidylserine | High phosphatidylserine | [14, 25] | |
Phosphatidylethanolamine | Phosphatidylethanolamine | [24, 25, 28, 32] | ||
Sphingolipids
| Sphingolipids | [18] | ||
High cholesterol | [14, 28, 34] | |||
High diacylglycerol | [14] | |||
Ceramides | [13, 24, 28] | |||
Phosphatidylcholine | [28] | |||
Phosphatidylinositol | [18] | |||
LBPA | [13] | |||
Nucleic acids | mRNA | mRNA | [25, 35] | |
miRNA | miRNA | |||
Non-coding RNA
| Non-coding RNA
| |||
DNA with histones | Chromosomal DNA fragments with histones, chromatin remnants, cytosol portions, degraded proteins, cell organelles |
Classification of key components of EVs by their main categories.
Abbreviations: ADP: adenosine diphosphate, APP: amyloid-beta precursor protein, ARF: ADP ribosylation factor, CXCR: CXC chemokine receptor, DNA: deoxyribonucleic acid, ERK: extracellular signal-regulated kinase, ESCRT: endosomal sorting complex required for transport, FasL: Fas ligand, GTP: guanosine triphosphate, HSPG: heparan sulphate proteoglycan, ICAM: intercellular adhesion molecule, Lamp: lysosome-associated membrane protein, LFA: lymphocyte function-associated antigen, MHC: major histocompatibility complex, PECAM: platelet endothelial cell adhesion molecule, piwi: P-element induced wimpy testis, PLA2: phospholipase A2, PLD: phospholipase D, PMEL: premelanosome protein, PrP: prion protein, Rab: Ras-associated binding, TCR: T-cell receptor, RNA: ribonucleic acid, ROCK: Rho-associated protein kinase, TSPAN: tetraspanin, Tsg: tumour suppressor gene, VPS: vacuolar protein sorting-associated protein, WNT: wingless/integrated, GADPH: glyceraldehyde 3-phosphate dehydrogenase, TDP: transactive response DNA-binding protein, TfR: transferrin receptor, TGF: transforming growth factor, TNF: tumour necrosis factor.
The distinct protein, lipid and nucleic acid profiles of each category might be correlated with its formation processes and functions. Both exosomes and microvesicles consist of key protein components which are responsible for cell-to-cell communication [18], such as glycoproteins [18, 28], membrane signalling receptors, growth factors and cytokines [18, 25], while apoptotic bodies do not. This is most likely because exosomes and microvesicles are meant to reach target cells, while apoptotic bodies are merely the means for discarding dead cells. Microvesicles and apoptotic bodies consist of other cytoplasmic proteins which seem to be less prominent in exosomes [13]. This might be due to the similar “budding/bulging” nature of the biogenesis of microvesicles and apoptotic bodies from the cytoplasmic membrane directly, a characteristic that differs from the endocytic-driven biogenesis of exosomes. Unlike exosomes and microvesicles, apoptotic bodies are composed of chromosomal deoxyribonucleic acid (DNA) fragments, chromatin remnants, cytosol portions, degraded proteins and cell organelles from dead cells [25, 35], indicative of their role in removing dead cells.
EVs also possess additional key features according to the specific cell line they originate from (Table 2). In general, cancer cells consist of higher levels of sphingolipids, glycerophospholipids, sterol lipids, ceramide, phosphatidic acid and matrix metalloproteinases like a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), while non-cancer cells consist of higher levels of prenol lipids, glycerolipids and fatty acids [24, 83].
EV source | EV source subtype | Component(s) | Reference(s) |
---|---|---|---|
Bacteria | Gram-positive | ABC transporters, mobility-related proteins (FliC, PilQ), multidrug efflux pumps, porins (Omps, OprF, PorA, PorB) | [24, 36] |
Gram-negative | Beta-lactamase, coagulation factor, penicillin-binding protein | [24, 37, 38, 39] | |
Myxobacteria | Chaperonin GroEL1, GroEL2, hydrolase, peptidase | [24, 40, 41] | |
Blood cells | Platelets | CD31, CD41, CD42a, CD62, C-type lectin, CXCR4, GPIIb/IIIa, PF4, SDF-1α | [24, 42, 43, 44] |
Erythrocytes | Glycophorin A, stomatin | [24, 34] | |
Reticulocytes | Galectin-5 | [42, 45] | |
Bone cells | Osteoblasts | Cadherin-11 | [42, 46] |
Cancer cell lines | Breast cancer cells (MM231, MM231LN) | Rab-5b, actin, integrin beta 1, cavolin-1 | [47] |
Breast cancer cells (MCF7) | Actin, Rab-5b | [47] | |
Breast cancer cells (MCF10A) | Integrin beta 1 | [47] | |
Cervical cancer cells (HeLa) | EGF | [42, 48, 49] | |
Colon cancer cells (LIM1863—EpCAM apical exosomes) | CD44, CD46, CD59, CLDN7, EpCAM, HMGB2, HMGB3, Muc-13, sucrase isomaltase | [50] | |
Colon cancer cells (LIM1863—A33 basolateral exosomes) | ADP-ribosylation factor, AP1G1, AP1M1, AP1M2, AP3B1, CLSTN1, CLTA, CLTB, COPB2, EEA1, GPA33, HLA-A, HLA-B, HLA-C, HLA-E, HLA-A29.1, Rab-13, REEP6 | [50] | |
Colorectal cancer cells (CRC line SW403, CRC28462) | Carcinoembryonic antigen, class I HLA | [51] | |
Hepatoblastoma cancer cells (HepG2, K562) | TfR1, TfR2 | [42, 52] | |
Hepatocellular cancer cells (HKCI-C3, HKCI-8, MHCC97L, MIHA) | ADAM10, ARHGEF18, BROX, CAV1, CAV2, CD44, CDC42, CLDN3, EDIL3, EIF4A3, GNA11, GNA13, GNAQ, GNAS, GRB2, MET, RHOG, RRAS, SNTA1, TNFRSF21, TNFAIP2 | [53] | |
Myeloma cancer cells (RPMI-8226, CAG) | Fibronectin | [54] | |
Nasopharyngeal cancer cells (C15) | Galectin-9, LMP1 | [55] | |
Nasopharyngeal cancer cells (C17) | Galectin-9 | [55] | |
Ovarian cancer cells (IGROV1, OVCAR-3) | Beta-actin, EpCAM, hnRNPA1, hnRNPK | [56] | |
Prostate cancer cells (PC3) | Rab-5b, integrin beta 1, cavolin-1 | [47] | |
Prostate cancer cells (PC-3 M-luc) | Rab-5b, actin, Integrin beta 1 | [47] | |
Prostate cancer cells (22Rv1) | Rab-5b, actin | [47] | |
Prostate cancer cells (PNT2) | Actin, integrin beta 1 | [47] | |
Endothelial and epithelial cells | C-type lectin, galectin-3, Muc-1 | [42] | |
Immune cells | B-cells | A2,3-linked sialic acid, CD169 | [42, 57] |
T-cells | CXCR4, SDF-1α | [42, 48, 58, 59] | |
Dendritic cells | FLOT1, galectins, Lamp-1, MFG-E8, MHC class I and II, TNFR1, TNFR2 | [24, 42, 60, 61, 62] | |
Macrophages | C-type lectin, LFA-1 | [42, 63, 64] | |
Natural killer cells | Granzyme B, perforin | [65] | |
Mesenchymal stem cells | Alternative splicing and Golgi apparatus component mRNA encoding transcription factors, CD54, CD73, CD86, CD90, CD105, CD166, MHC class I and II, sialic acids | [24, 28, 42, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75] | |
Milk cells | Bovine milk cells | β-casein, β-lactoglobulin mRNA, CD59, MFG-E8, miR-30a, miR-92a, miR-223, Rab-1b, Rab-11a | [24, 76, 77, 78, 79, 80] |
Human breast milk cells | miR-17, miR-181a | [81] | |
Nervous cells | Astrocytes | MCP-1, MMP3, MMP9, TIMP-1 | [65] |
Microglia | CD13, CD107a, CD107b | [65] | |
Placental cells | MHC class I chain-related proteins A and B, placental alkaline phosphatase, placental leucine aminopeptidase, pregnancy specific glycoprotein 3, RAET1 proteins/ULBP1–5, TGFβ1, TRAIL, trophoblast glycoprotein 5 T4 | [82] |
Classification of additional key components of EVs by their specific cell lines.
Abbreviations: ABC: adenosine triphosphate-binding cassette, ADAM: A disintegrin and metalloproteinase domain-containing protein, ADP: adenosine diphosphate, AP: adaptor related protein complex, ARFGEF: Rho/Rac guanine nucleotide exchange factor, BROX: BRO1 domain and CAAX motif containing, CA: carbohydrate antigen, CAV: caveolin, CLDN: claudin, CLSTN: calsyntenin, CLT: clathrin light chain, COP: coatomer protein complex, CXCR: CXC chemokine receptor, EDIL: EGF like repeats and discoidin domains, EEA: early endosome antigen, EGFR: epidermal growth factor receptor, EGF: Epidermal growth factor, EpCAM: epithelial cell adhesion molecule, FLOT: flotillin, GN: guanine nucleotide-binding protein, GP: glycoprotein, GRB: growth factor receptor-bound protein, HLA: human leukocyte antigen, HMG: high-mobility group, HNRNP: heterogeneous nuclear ribonucleoprotein, Lamp: lysosome-associated membrane protein, LDLR: low-density lipoprotein receptor, LDL: low-density lipoprotein, LFA: lymphocyte function-associated antigen, LMP1: Epstein-Barr virus latent membrane protein 1, MAPK: mitogen-activated protein kinase, MCP: membrane cofactor protein, MET: mesenchymal-epithelial transition facror, MFG-E: milk fat globule-EGF factor, MHC: major histocompatibility complex, miRNA: microribonucleic acid, MMP: matrix metalloproteinase, Muc: mucin, PF: platelet factor, RAET: retinoic acid early transcript, Rab: Ras-associated binding, REEP: receptor expression-enhancing protein, RHOG: Ras homolog family member G, RRAS: RAS-related protein R-Ras, SDF: stromal cell-derived factor, SNT: syntrophin, TfR: transferrin receptor, TNF: tumour necrosis factor, TNFR: tumour necrosis factor receptor, TNFRSF: TNF receptor superfamily, TNFAIP: TNF alpha-induced protein, TRAIL: tumour necrosis factor-related apoptosis-inducing ligand, TYRP: tyrosinase-related protein, ULBP: UL16 binding protein.
To reach their target sites, EVs need to overcome various biological barriers (Figure 2). Complementing these barriers are blood vessels (capillaries in particular). EVs can enter and extravasate from these vessels
Biological barriers encountered by extracellular vesicles (EVs). (A)
EVs administered orally need to overcome digestive enzymatic degradation, harsh stomach acidic conditions and the small intestinal barrier before entering the bloodstream for systemic absorption. As milk and plant-derived EVs are delivered into the body naturally
Milk-derived EVs have been shown to withstand acidic and enzymatic conditions [87, 91]. However, their ability to do so might be dependent on the milk source, as EVs from processed milk would have undergone more damage than those from unprocessed milk and hence possess less integrity [87, 92, 93, 94, 95, 96, 97]. Although bovine milk-derived EV surface proteins CD9 and CD81 were found to be partially degraded by acidification at pH 4.6 in one study [98], these findings did not demonstrate whether these EVs can survive stomach acidic conditions, which are usually characterised by a much lower pH. Moreover, the study was focused on evaluating the effectiveness of acidification in ultracentrifugation to isolate EVs. Thus, these conditions would have differed vastly from true gastrointestinal conditions. Although the underlying mechanism is unclear, the ability of both processed and unprocessed milk-derived EVs to withstand harsh conditions might be correlated with milk calcium content [87]. This could be due to the adhering of milk calcium to the surface of EVs, which might strengthen their membrane integrity against acidic and enzymatic degradation. Another hypothesis is that calcium might influence milk-derived EV biogenesis pathways in alveoli cells to increase the expression of certain proteins or transporters in secreted EVs that enable them to withstand gastrointestinal conditions.
Fruit and vegetable-derived EVs have been shown to withstand gastrointestinal conditions and eventually be internalised by rodent intestinal tissue
The placenta supports foetal growth and development while secreting female hormones [106, 107, 108, 109, 110, 111]. The placental barrier (PB) is suggested to be selectively penetrable, given that drugs administered to pregnant women can either cause adverse side effects in both the mother and the fetus or not penetrate the PB at all. It consists of an inner blood-vessel-rich layer with the syncytiotrophoblast facing the bloodstream and an outer layer of trophoblasts [106, 112, 113, 114]. Occurring in large amounts during pregnancy [115, 116], placental exosomes exert their functions during foetal growth and development, being involved in processes like angiogenesis regulation and cell migration [106, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126]. This implies that they can overcome the PB, though the underlying mechanism is unclear. Placental exosomes have also been tested as diagnostic biomarkers for foetal development [106, 115] and gestational diabetes [106, 127].
Although placental EVs may be used to pass through the PB, the use of non-placental EVs to deliver drugs across the PB is a potential area for exploration. The placenta can respond to signals from immune cells and exert an inflammatory response during infection. An
The body is heavily guarded by immune cells responsible for eliminating pathogens and perceived foreign substances. As such, nanoparticles injected into the bloodstream risk being removed by phagocytes of the mononuclear phagocyte system (including those in the liver and spleen), or the adaptive immune system
A recent study on an
The blood-brain barrier (BBB) is characterized by an innermost layer of endothelial cells (which prevents blood and extracellular fluid from mixing), pericytes surrounding the endothelial cells and astrocyte end-feet acting as a sheath in the outermost layer. Though the movement of substances across the BBB is tightly regulated [136], different EVs have been observed to cross the BBB. One study demonstrated the ability of exosomes to carry miR-193b-3p across the BBB to exert an anti-inflammatory effect on rodent brain cells with subarachnoid haemorrhage [137], although the mechanism of crossing was unclear. Other studies involving the BBB in zebrafish showcased the ability of various human breast cancer cell EVs and brain endothelial cell EVs to cross the BBB
Modifications have also been made to EVs to enhance their ability to cross the BBB. In one experiment, after overexpressing the rabies virus glycoprotein (RVG) peptide on their surface, dendritic exosomes became significantly localized in rodents’ brain cells [139]. Mouse L929 fibroblastic cell exosomes loaded with methotrexate and functionalized with LDL peptide in another experiment showed enhanced BBB exosome extravasation in rodents [140]. When miR-210-loaded mesenchymal stromal cell-derived exosomes were coupled with c(RGDyK) peptide in another experiment, they displayed enhanced targeting of rodent ischaemic brain cells, indicating greater angiogenesis and improving animal survival significantly [141]. Another experiment showed that RGE-Exo EVs demonstrated greater accumulation and duration of accumulation in murine glioma tumour cells than free exosomes [142].
Apart from surface components, the size of EVs might also be a crucial factor in determining whether EVs can cross the BBB, as deduced from another study where intranasal administration of exosomes to rodent microglial cells
The blood-labyrinth barrier (BLaB) and blood-retinal barrier (BRB) are two other neurological barriers pertaining to the ear and eye, respectively. The BLaB consists of five layers, namely, the blood-endolymph barrier, blood-perilymph barrier, cerebrospinal-fluid-perilymph barrier, middle-ear-labyrinth barrier and endolymph-perilymph barrier [106, 144]. The BRB consists of the retinal vascular endothelium and the retinal pigment epithelium (RPE) [106]. These two barriers share similarities with each other and the BBB, though the number of EV studies on these two barriers is smaller than that involving passage across the BBB [106]. Nevertheless, the utilization of EVs as potential drug carriers targeting the ear and eye with negligible side effects is worth further research, especially when current drug treatments have resulted in adverse side effects [106]. EVs from RPE cells are involved in the progression of age-related macular degeneration
The process of crossing the blood-lymph barrier (BLyB) is regulated by various mechanisms including extravasation, overcoming of the interstitium, diffusion and passage through the mucosal barrier [106, 147]. In addition, the collagen reticular network (RN) hinders soluble substances from passing through [106, 148, 149, 150, 151, 152, 153]. However, EVs possess certain characteristics that enable them to cross the BLyB. For instance, human ovarian cancer cell exosomes were found to be able to travel from the periphery to the lymph node in just a matter of minutes in rodents due to their small size [106, 154], and their lipidic rather than soluble nature seemed to enable them to cross the RN [106, 155].
Although EVs already possess intrinsic advantages that enable them to cross the BLyB, methods like microfluidic surface engineering have been conducted on EVs to modify them further as potential drug carriers for lymphoma treatment or other diseases related to the lymphatic system [106, 156, 157]. A recent study explored the modification of exosomes derived from bovine serum. α-D-mannose was added to the exosomes containing immune stimulators to enable them to interact with the mannose receptors on dendritic cells for uptake, and the exosomes were PEGylated. This has been found to enhance the internalisation of the exosomes by murine dendritic cells and to increase their localisation in the lymph nodes, paving the way for efficient delivery of immune stimulators
Located in the lungs, the blood-air barrier (BAB) possesses characteristics that enable it to guard against pathogenic invasion. For instance, the lung mucosa is a rich source of immune cells [106, 159], and lung epithelial cells can sense a wide range of bacteria and viruses
The nephron’s ability to efficiently filter out waste materials from the blood into the urine is attributed to the high pressure in the glomerulus due to high blood flow, as well as the presence of the glomerular filtration barrier consisting of three layers—fenestrated endothelium, glomerular basement membrane and glomerular epithelium [66, 164, 165, 166]. Despite the tiny pores (2.5–2.8 nm) of the glomerular basement membrane [166, 167] which are smaller than the smallest EVs (30 nm [16, 17, 18]), and the presence of filter proteins lining the slits in the glomerular epithelium [165, 166, 168], the urine is surprisingly a rich source of EVs from both renal and non-renal sources. While the majority of EVs found in urine originate from the kidney, urinary bladder, testis, prostate, epididymis and seminal vesicle [169, 170, 171, 172], studies have also identified EVs from outside the urinary tract, such as those carrying biomarkers of acute myocardial infarction [173]. EVs injected into the bloodstream of rodents in one study were found to accumulate in the kidneys, and eventually the urine, without undergoing degradation, as indicated by their ability to be internalized by HEK293 cells after being retrieved from the urine and introduced to the cells [166]. The presence of EVs in urine might imply that EVs can squeeze through the tiny pores of the glomerular filtration barrier due to their fluid membranes, or undergo mechanisms like transcytosis to reach the glomerular filtrate. It is also logical to deduce that EVs can cross the glomerular filtration barrier better in pathological conditions like diabetic nephropathy when the glomerular filtration barrier becomes more porous due to injury [166].
EVs that eventually reach the target cell has to overcome the plasma membrane, escape the endosome and evade lysosomal degradation to release their cargo into the cytosol (Figure 3).
Internalisation, lysosomal degradation and lysosomal escape mechanisms of extracellular vesicles (EVs) in target cells. Upon reaching the target cell, EVs may be internalised by the cell
The plasma membrane is an intricate structure consisting of various domains formed
EVs can be internalised by target cells
In general, the CME of EVs is initiated through the mediation of lectins, tetraspanins, cell adhesion proteins and other receptor-ligand interactions [18, 179]. For instance, exosomes from macrophages possess C-type lectin, which interacts with the C-type lectin receptor found on dendritic and brain endothelial cells [179, 180]. Galectin-5 on red blood cell (RBC) EVs enables them to be internalised by macrophages [45, 179]. Integrins on tumour EVs have been associated with the uptake of these EVs by lung fibroblasts and liver macrophages [42, 179]. Exosomes and target cells can exploit the interaction between intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) in exosomal uptake [179, 180, 181]. Heparan sulphate proteoglycans on target cells bind to EV fibronectin to facilitate uptake of EVs [54, 179, 182]. The high levels of outward-facing PS on the surface of exosomes also enable the recognition and uptake of these exosomes by antigen-presenting cells
EVs internalised
EVs have also been reported to deliver their cargo into target cells
In providing a recommendation to engineer EVs as DDSs, EV engineering methods to overcome specific barriers can be deployed. Natural evasion of immune cells is a highly favourable quality and should mark all engineered EVs regardless of the barrier(s) they target. CD47, CD24, CD31 and PD-L1 are prominent surface proteins that achieve this quality and should be incorporated into engineered EVs in high amounts if not originally present [129, 130, 131, 132, 133, 134]. Fusing EVs with liposomes to create hybrid DDSs can also increase their drug loading capacity without risking cargo aggregation [198, 199].
The choice of the source of EVs depends on its availability and the ability of its EVs to overcome respective biological barriers associated with the disease. Milk and plant-derived EVs, which are highly available in nature and able to overcome gastrointestinal barriers [76, 77, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105], can be engineered for drug delivery
A summary of the recommendation is shown in Figure 4.
Recommendation on how to engineer extracellular vesicles (EVs) to overcome various biological barriers for drug delivery applications. (1)
Through critically analysing the relationship between the key components of EVs and the biological barriers EVs overcome, this review is the first to put together a recommendation in such a manner (Figure 4) to engineer EVs as suitable DDSs based on various studies. The implementation of EV drug carriers would revolutionise the global worldview of therapeutic treatments, as EVs unlock a whole new realm of endless possibilities in achieving the ideal therapeutic for patients, one of maximum efficacy and biocompatibility with negligible side effects. Even now, efforts have been made to transform the notion of personalised medicine into a reality, and having EVs as fully-approved personalised DDSs is worth pursuing. As past findings are limited due to the complex nature of EVs and various biological membranes, it is hoped that the mechanisms of EVs and their interactions with various biological membranes can continue to be more fully delved into, and that EV engineering can be carried out
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",metaTitle:"IntechOpen events",metaDescription:"In our mission to support the dissemination of knowledge, we travel worldwide to present our publications, authors and editors at international symposia, conferences, and workshops, as well as attend business meetings with science, academia and publishing professionals. We are always happy to host our scientists in our office to discuss further collaborations. Take a look at where we’ve been, who we’ve met and where we’re going.",metaKeywords:null,canonicalURL:"/page/events",contentRaw:'[{"type":"htmlEditorComponent","content":"May 18, 2022 | 1:00 PM - 2:00 PM CEST
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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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