Load applied to the actuator section at each wind speed when the rudder angle is 20 deg.
\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6935",leadTitle:null,fullTitle:"Toward Super-Creativity - Improving Creativity in Humans, Machines, and Human - Machine Collaborations",title:"Toward Super-Creativity",subtitle:"Improving Creativity in Humans, Machines, and Human - Machine Collaborations",reviewType:"peer-reviewed",abstract:"What is super creativity? From the simple creation of a meal to the most sophisticated artificial intelligence system, the human brain is capable of responding to the most diverse challenges and problems in increasingly creative and innovative ways. This book is an attempt to define super creativity by examining creativity in humans, machines, and human-machine interactions. Organized into three sections, the volume covers such topics as increasing personal creativity, the impact of artificial intelligence and digital devices, and the interaction of humans and machines in fields such as healthcare and economics.",isbn:"978-1-78985-910-2",printIsbn:"978-1-78985-909-6",pdfIsbn:"978-1-78985-911-9",doi:"10.5772/intechopen.73466",price:119,priceEur:129,priceUsd:155,slug:"toward-super-creativity-improving-creativity-in-humans-machines-and-human-machine-collaborations",numberOfPages:110,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"98c0eed8bde901e69239d5217d9be28d",bookSignature:"Sílvio Manuel Brito",publishedDate:"January 29th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/6935.jpg",numberOfDownloads:6162,numberOfWosCitations:0,numberOfCrossrefCitations:3,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:7,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:10,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 21st 2018",dateEndSecondStepPublish:"June 11th 2018",dateEndThirdStepPublish:"August 10th 2018",dateEndFourthStepPublish:"October 29th 2018",dateEndFifthStepPublish:"December 28th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"170935",title:"Ph.D.",name:"Sílvio Manuel",middleName:"Da Rocha",surname:"Brito",slug:"silvio-manuel-brito",fullName:"Sílvio Manuel Brito",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9HrQAK/Profile_Picture_2022-04-25T07:50:04.png",biography:"Silvio Brito holds a degree in human resources management and work psychology from ISLA, a master’s degree in management in the area of organizational behavior from the Lusíada University, and a Ph.D. degree in psychology from the University of Extremadura, Spain. He is an effective member of the Portuguese Society of Psychology, INFAD (Spain), and CITUR (Portugal), as well as an investigator of Psyche EX (Spain), a member of the chair of Entrepreneurs (Spain), and the founder and general secretary of AFIDE (Spain). He teaches Human Resources at the Polytechnic Institute of Tomar (Portugal) and a master’s course in Portugal and abroad. He is also a member of its jury commissions in Portugal and abroad, and an advisor on several scientific research papers. He has published several scientific, national, and international publications in the field of human resources, management, and psychology. He is an investigator member of the Human Talent Research Group of Organizational Behaviour and Human Resources.",institutionString:null,position:null,outsideEditionCount:null,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"569",title:"Intelligent System",slug:"human-computer-interaction-intelligent-system"}],chapters:[{id:"67510",title:"Introductory Chapter: Super Creativity—Mind, Men, and Machine",doi:"10.5772/intechopen.86358",slug:"introductory-chapter-super-creativity-mind-men-and-machine",totalDownloads:733,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Sílvio Manuel da Rocha Brito",downloadPdfUrl:"/chapter/pdf-download/67510",previewPdfUrl:"/chapter/pdf-preview/67510",authors:[{id:"170935",title:"Ph.D.",name:"Sílvio Manuel",surname:"Brito",slug:"silvio-manuel-brito",fullName:"Sílvio Manuel Brito"}],corrections:null},{id:"65968",title:"The Aha! Moment: The Science Behind Creative Insights",doi:"10.5772/intechopen.84973",slug:"the-aha-moment-the-science-behind-creative-insights",totalDownloads:1069,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:1,abstract:"Insight, often referred to as an “aha moment,” has been defined as a sudden, conscious change in a person’s representation of a stimulus, situation, event, or problem. Recent advances in neuroimaging technology and neurophysiological techniques have allowed researchers an opportunity to hone in on the neural circuitry that governs insight, a phenomenon that has been theorized about by cognitive psychologists for over a century. Studies show that insight is not a sudden flash that comes from nowhere, but in fact is the result of the unconscious mind piecing together loosely connected bits of information stemming from prior knowledge and experiences and forming novel associations among them. This conceptualization of insight naturally gives rise to comparisons between insight and creativity. Creativity, however, involves many cognitive processes, occurring in many regions of the brain and thus cannot be laterally localized as insight can. Thus, creativity is not considered synonymous with insight; however, insight can certainly result in creative solutions during creative problem solving.",signatures:"Wesley Carpenter",downloadPdfUrl:"/chapter/pdf-download/65968",previewPdfUrl:"/chapter/pdf-preview/65968",authors:[{id:"261212",title:"Dr.",name:"Wesley",surname:"Carpenter",slug:"wesley-carpenter",fullName:"Wesley Carpenter"}],corrections:null},{id:"65636",title:"Crowdsourcing in the Fashion Industry",doi:"10.5772/intechopen.84607",slug:"crowdsourcing-in-the-fashion-industry",totalDownloads:1001,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In today’s cutthroat competitive world of fashion, flexibility and adaptability are essential elements for a company to survive in this industry. As such, there is a growing interest for open innovation and crowdsourcing as tools that might boost the competitiveness in the industry. By embracing open innovation, the use of external knowledge to emphasize internal creativity and expand market influence, industries can reach beyond their own internal resources and develop better ideas, faster and at a lower cost. The fashion industry is no exception. Specifically, crowdsourcing is lowering the fashion industry’s barriers to entry and giving the public an opportunity to not just shape a brand but also determine the trends of an entire sector. This chapter aims at analyzing the features, the pros, and the cons of crowdsourcing in the fashion industry focusing on the perspectives of both the companies and the customers.",signatures:"Luigi Nasta and Luca Pirolo",downloadPdfUrl:"/chapter/pdf-download/65636",previewPdfUrl:"/chapter/pdf-preview/65636",authors:[{id:"168999",title:"Dr.",name:"Luca",surname:"Pirolo",slug:"luca-pirolo",fullName:"Luca Pirolo"},{id:"262571",title:"Ph.D.",name:"Luigi",surname:"Nasta",slug:"luigi-nasta",fullName:"Luigi Nasta"}],corrections:null},{id:"68964",title:"From Individual Creativity to Team-Based Creativity",doi:"10.5772/intechopen.89126",slug:"from-individual-creativity-to-team-based-creativity",totalDownloads:803,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Supporting the development of creative competency is important for the actual challenges of the society. However, creativity has been mainly approached in an individual way, without considering the specificities of team-based creativity processes. In this chapter, we establish the differences between creativity as an individual approach and creativity as a collaborative process. Then we discuss creativity from the perspective of the leaners’ and teachers’ attitudes. Subsequently, we discuss the concept of the margin of creativity in different learning activities. We finalize this chapter by discussing digital uses that can support creativity in team-based contexts.",signatures:"Margarida Romero",downloadPdfUrl:"/chapter/pdf-download/68964",previewPdfUrl:"/chapter/pdf-preview/68964",authors:[{id:"234717",title:"Prof.",name:"Margarida",surname:"Romero",slug:"margarida-romero",fullName:"Margarida Romero"}],corrections:null},{id:"66138",title:"Shared Futures: An Exploration of the Collaborative Potential of Intelligent Machines and Human Ingenuity in Cocreating Value",doi:"10.5772/intechopen.85054",slug:"shared-futures-an-exploration-of-the-collaborative-potential-of-intelligent-machines-and-human-ingen",totalDownloads:1081,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"This chapter reports on the exploratory study that aimed at better understanding the conditions under which the combined capabilities of intelligent technologies and human ingenuity could be harnessed to create new efficiencies. The study was conducted within a university setting as universities should model how future societies ought to look like and drive societal change. As the new digital society 5.0 takes shape, the time has come to critically probe one aspect of society 5.0, the leveraging of human-machine collaborations to generate unique ideas and convert them into tangible results. The sequential mixed methods’ approach together with a sociocultural lens was used to investigate the ideal university conditions that could foster human-machine collaborations in value cocreation. Nineteen Senior Scandinavian and South African managers were interviewed to elicit their views on how human-machine collaborations could be harnessed to cocreate value within complex university settings. Entrenched cultures, policies, systems, and multiple stakeholder interests which complex into rules and routines mostly define university mores. These university mores are often impervious to rapid newness and radical change. Fifteen advanced undergraduates at one South African university also participated in a quasi-experimentation that investigated team formation and team development within the context of human-machine collaborations.",signatures:"Teboho Pitso",downloadPdfUrl:"/chapter/pdf-download/66138",previewPdfUrl:"/chapter/pdf-preview/66138",authors:[{id:"259594",title:"Dr.",name:"Teboho",surname:"Pitso",slug:"teboho-pitso",fullName:"Teboho Pitso"}],corrections:null},{id:"65524",title:"Diginalysis: The Man-Machine Collaboration in Music Analysis",doi:"10.5772/intechopen.84355",slug:"diginalysis-the-man-machine-collaboration-in-music-analysis",totalDownloads:600,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The digital technology of the twenty-first century has put man and machine in the center stage where electronic generation, production and manipulation of the musical sound are the norm. The dynamics of the century have made time more elusive and patience more diminutive. Time and patience are vital for any form of successful exercise in music analysis. The intricacies of applying logic to resolve complex musical structures, facts, propositions, and concepts into their elements demand more than technical know-how; they demand a lot of time and patience. With the continued fleeing of time and patience, mechanical accuracy in music analysis would need a full-blown computer-driven “diginalysis.” However, inherent limitations of the computer in music analysis, such as decoding the composer’s ideologies, necessitate human-machine collaboration. An in-depth descriptive survey has shown that this effective collaboration between man and machine will collapse time and energy by providing immediate feedback, technical accuracy and dependable results.",signatures:"Ikenna Emmanuel Onwuegbuna",downloadPdfUrl:"/chapter/pdf-download/65524",previewPdfUrl:"/chapter/pdf-preview/65524",authors:[{id:"262464",title:"Dr.",name:"Ikenna Emmanuel",surname:"Onwuegbuna",slug:"ikenna-emmanuel-onwuegbuna",fullName:"Ikenna Emmanuel Onwuegbuna"}],corrections:null},{id:"69425",title:"The Machine-Human Collaboration in Healthcare Innovation",doi:"10.5772/intechopen.88951",slug:"the-machine-human-collaboration-in-healthcare-innovation",totalDownloads:877,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The biopharma industry is in crisis, demonstrated by unsustainable research and development (R&D) costs. In parallel, the healthcare system suffers from skyrocketing costs, driven by the prevalence of chronic diseases and increased life expectancy. Innovative technologies have the potential to alleviate challenges both in the biopharma R&D model and in healthcare. This chapter considers how Big Data analysis based on artificial intelligence and machine learning offer opportunities to drive greater efficiency across the entire R&D value chain, enhance the quality of assets produced, and improve the time and cost to bring products to market. We also consider the unique challenges that arise with the integration of these fields into healthcare and medicine, specifically, the initially high costs when new medical and healthcare technologies are brought to the marketplace; widening socioeconomic health inequalities due to high marketplace costs; and unique methodological challenges presented by cross industry innovation, research, development, and implementation.",signatures:"Neta Kela-Madar and Itai Kela",downloadPdfUrl:"/chapter/pdf-download/69425",previewPdfUrl:"/chapter/pdf-preview/69425",authors:[{id:"268981",title:"Ph.D.",name:"Neta",surname:"Kela-Madar",slug:"neta-kela-madar",fullName:"Neta Kela-Madar"},{id:"309674",title:"Dr.",name:"Itai",surname:"Kela",slug:"itai-kela",fullName:"Itai Kela"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6389",title:"Entrepreneurship",subtitle:"Trends and 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Shahjahan Kabir",dateSubmitted:"March 6th 2021",dateReviewed:"March 17th 2021",datePrePublished:"June 10th 2021",datePublished:"December 22nd 2021",book:{id:"11571",title:"Cereal Grains",subtitle:"Volume 2",fullTitle:"Cereal Grains - Volume 2",slug:"cereal-grains-volume-2",publishedDate:"December 22nd 2021",bookSignature:"Aakash Kumar Goyal",coverURL:"https://cdn.intechopen.com/books/images_new/11571.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"97604",title:"Dr.",name:"Aakash K.",middleName:null,surname:"Goyal",slug:"aakash-k.-goyal",fullName:"Aakash K. Goyal"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"338812",title:"Dr.",name:"M. Akhlasur",middleName:null,surname:"Rahman",fullName:"M. Akhlasur Rahman",slug:"m.-akhlasur-rahman",email:"akhlas08@gmail.com",position:null,institution:null},{id:"340364",title:"Dr.",name:"Hasina",middleName:null,surname:"Khatun",fullName:"Hasina Khatun",slug:"hasina-khatun",email:"hasinabrri09@gmail.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"340367",title:"Dr.",name:"Hosneara",middleName:null,surname:"Hossain",fullName:"Hosneara Hossain",slug:"hosneara-hossain",email:"shimulbrri@gmail.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"340368",title:"Dr.",name:"M. Ruhul Amin",middleName:null,surname:"Sarker",fullName:"M. Ruhul Amin Sarker",slug:"m.-ruhul-amin-sarker",email:"mrasbrri@yahoo.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"340369",title:"Dr.",name:"Khandakar M.",middleName:null,surname:"Iftekharuddaula",fullName:"Khandakar M. Iftekharuddaula",slug:"khandakar-m.-iftekharuddaula",email:"kiftekhar03@yahoo.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"352116",title:"Mr.",name:"M. Ruhul",middleName:null,surname:"Quddus",fullName:"M. Ruhul Quddus",slug:"m.-ruhul-quddus",email:"rquddus265@gmail.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"352118",title:"Dr.",name:"M. Shahjahan",middleName:null,surname:"Kabir",fullName:"M. Shahjahan Kabir",slug:"m.-shahjahan-kabir",email:"kabir.stat@gmail.com",position:null,institution:{name:"Bangladesh Rice Research Institute",institutionURL:null,country:{name:"Bangladesh"}}}]},book:{id:"11571",title:"Cereal Grains",subtitle:"Volume 2",fullTitle:"Cereal Grains - Volume 2",slug:"cereal-grains-volume-2",publishedDate:"December 22nd 2021",bookSignature:"Aakash Kumar Goyal",coverURL:"https://cdn.intechopen.com/books/images_new/11571.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"97604",title:"Dr.",name:"Aakash K.",middleName:null,surname:"Goyal",slug:"aakash-k.-goyal",fullName:"Aakash K. Goyal"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11267",leadTitle:null,title:"Human Sexuality",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tHuman sexuality plays a major role in everyone's life. Regardless, whether we are young or old, man or woman, American or Japanese, it is an integral part of what we do and who we are.
\r\n\r\n\tThe book will focus on the following aspects:
\r\n\r\n\t1) Human Cycle Response cycle and sex education.
\r\n\t2) Human sexual disorders in males and females.
\r\n\t3) Psychological aspects of the human sexual response cycle and its disorders.
\r\n\t4) The therapeutic aspects.
\r\n\tThe human sexual response cycle and human sexual behavior are interrelated. How this inter-relationship and its association to normal sexual health need to be delineated. In a world torn between sex and sexually transmitted disease, clear-cut scientific information in the form of a monograph is required to educate.
\r\n\r\n\tHuman sexuality, gender identity, and sexuo-erotic orientation play great roles in human health and disease. Sex education is the need of the hour and a reflection will be timely.
",isbn:"978-1-80355-151-7",printIsbn:"978-1-80355-150-0",pdfIsbn:"978-1-80355-152-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"13af09c4cf93ae89789a3db597972cf6",bookSignature:"Dr. Dhastagir Sultan Sheriff",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11267.jpg",keywords:"Master and Johnson's Cycle, Sex Education, Premature Ejaculation, Orgasmic Disorders, Sexual Aversion Disorders, Dyspareunia, Vaginismus, Sex Hormones, Sexually Transmitted Diseases, Impotence, Low Libido, Blood Analyses",numberOfDownloads:106,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 18th 2021",dateEndSecondStepPublish:"March 3rd 2022",dateEndThirdStepPublish:"May 2nd 2022",dateEndFourthStepPublish:"July 21st 2022",dateEndFifthStepPublish:"September 19th 2022",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Sheriff is a life counselor, sex educationist, and researcher with over 35 years of teaching experience, five authored books, and editorials written in the British Journal of Sexology and the Journal of Royal Society of Medicine. Dr. Sheriff is a life member of the European Society for Human Reproduction, and Early Human Development, American Association of Clinical Chemistry, Association of Physiologists and Pharmacologists of India, and a member of the National Academy of Medical Sciences.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"167875",title:"Dr.",name:"Dhastagir Sultan",middleName:null,surname:"Sheriff",slug:"dhastagir-sultan-sheriff",fullName:"Dhastagir Sultan Sheriff",profilePictureURL:"https://mts.intechopen.com/storage/users/167875/images/system/167875.jpg",biography:"Dhastagir Sultan Sheriff is a life member of the European Society for Human Reproduction and Early Human Development, Association of Physiologists and Pharmacologists of India, member of the National Academy of Medical Sciences, New Delhi, and resource person for UNESCO for Medical and Bioethics. Dr. Sheriff has authored five books including a textbook on medical biochemistry with additional interest in human sexology. He had editorials written in the British Journal of Sexology, Journal of Royal Society of Medicine, Postgraduate Medicine, and Scientist. 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That immunotherapy is an appropriate approach in T1D is convincingly supported by findings that point to a pathogenesis with close involvement of the immune system. Autoantibodies and T-cells reactive to islet-derived self-antigens in humans and in animal models, HLA alleles that are associated with susceptibility to the disease and partial amelioration after systemic immune suppression all indicate that a therapy for T1D will need to have a component that focuses on the immune system.
The aim of any immunotherapy is to influence or reset pathogenic components or processes in the immune system. Fulfillment of this aim requires targeting of these components and an ideal therapy will minimize the impact on the healthy necessary aspects of the immune system while maximizing the effect on its aberrant aspects. This is a demanding and perhaps not fully achievable goal since we are dealing with a system where intervention directed at any one component will not necessarily remain localized but will have the potential to extend to other components.
Immunological interventions may be divided into two basic groups, namely active and passive. In the latter approach the experimenter or clinician provides the targeting reagents, for example antagonists or monoclonal antibodies binding surface receptors of immune cells. In this case the effects usually last as long as the experimental compound is present to block or dampen the targeted processes. However, there are examples where effects are induced that persist beyond the withdrawal of the targeting compound. In the former approach targeting is achieved by indirect means. Here the experimental compound, for example a potential autoantigen is administered as a vaccine either together with an adjuvant or via a specific ‘tolerogenic’ route. As a consequence the immune system itself generates the targeting response. In contrast to passive approaches effects induced by vaccination take longer to become manifest and it is possible that they persist far beyond the point of vaccine administration because immunological memory may have been generated.
From the definition and characterization of aberrant immune processes to preclinical studies on new therapeutics, the NOD mouse model and its derivatives remain the most important tool for the development of the basic concepts that underlie the understanding of T1D. That human and mouse T1D must differ in important aspects is obvious simply by comparing the lifespan of a human with that of a mouse as well as the fact that NOD mice are inbred while humans are not. The importance of the NOD mouse model lies in its usefulness to generate the essential conceptual understanding that allows comparison and identification of how the disease process in humans differs from that of the mouse. In this regard the NOD mouse model acts as a reference point and guidepost. Where the aim is to understand the pathogenic process that manifests as T1D, insight into the differences between the disease in the human and in the mouse is itself important scientific knowledge. Furthermore, given the relative ease with which mouse models can be genetically manipulated it is not necessary to proceed from mouse to human. The direction can be reversed by introducing human genetic susceptibility elements into mouse models allowing the investigation of how these elements contribute to T1D.
What are the possible targets for an immune intervention? Systemic immune suppression represents a very broad targeting approach and thus causes the most pronounced ‘collateral damage’. Since T1D is survivable without any immunotherapy at all this approach is problematic because of its side effects. Nevertheless studies testing these therapies have been performed. On the next level of specificity therapies exist that do not target the entire immune system but rather its major components. Therapies directed against T- or B-cells have been successfully tested in mouse models and are now in the process of clinical evaluation. Here initial findings indicate that some of these therapies have positive effects without inducing pronounced adverse responses. Increasing specificity further, we reach the area of the so-called antigen specific therapies. Here not all T- or B-cells are targeted but only those that recognize a given islet autoantigen. This is the area where active immunotherapy is applied by vaccinating with an islet autoantigen. It is hoped that exposing the immune system in a ‘tolerogenic’ way to autoantigens induces effects that suppress or re-regulate T-cells with specificity for the appropriate self-antigen. This approach has had some success in the NOD mouse model, however clinical trials in patients with recent onset of T1D conducted so far have had less promising outcomes. The lack of success may have to do with observations coming from the NOD mouse model where the majority of the tested autoantigens and routes of administration are only clinically effective if the antigen is administered well before T1D has become overt. It appears therefore that this type of intervention should be undertaken preventively to fully exploit its potential. There is a further level of specificity where targeting is directed against T-cell receptors of autoreactive T-cells. In this approach the vaccine antigen is the recombinant receptor of the self-reactive T-cell and the resulting immune response blocks activation of, or possibly eliminates, that T-cell. This approach has not been tested in T1D but has proved to be partially successful in models of other autoimmune diseases. Therapies that apply a different perspective of the immune system include administration of reagents that can block certain cytokine receptors or administration of cytokines presumed to exert dampening effects. Here specificity is defined by the targeted cytokine receptor, which does not need to be restricted to a particular cell type and consequently the question of unwanted side effects becomes relevant. These therapies also represent one approach that allows targeting of the innate component of the immune system, which like the adaptive part plays a role in the pathogenesis of T1D.
These diverse therapeutic approaches demonstrate that it is possible to develop useful means of targeting immune dysfunction in T1D on all levels of specificity. However, it is our view that currently available therapies represent only a small fraction of what is possible because our understanding of the pathogenesis of T1D is still in its infancy, despite the vast increase in knowledge gained over recent decades. The review below focuses on interventions that have been translated -mostly from the NOD mouse model- to humans either at risk of developing T1D or already suffering from the disease. It does not discuss the large number of potential interventions that have shown promise in preclinical studies of T1D performed again mostly in NOD mice.
It must be kept in mind that pancreatic islets are not simply an aggregation of specialized cells that produce insulin and other endocrine hormones. Rather each islet represents a micro organ with well-developed anatomical structure, innervation and, as an endocrine gland, a sophisticated blood supply. As with any other organ in the body there is a large margin of safety allowing for considerable functional impairment and damage to occur before the onset of overt clinical signs of organ failure. This margin of safety is of course a great benefit for the individual. However, in terms of immune therapeutic intervention this also means that once organ failure has become overt (i.e when diabetes is diagnosed clinically) a large proportion of the organ has been destroyed and the residual mass can restore euglycemia only under ideal conditions - that is the restoration of complete and lasting immune tolerance to islets. In other words an immune therapy that begins after the diagnosis of T1D is unlikely to be sufficient on its own to restore euglycemia. If permanent restoration of euglycemia is the aim then therapies that are initiated after diagnosis of T1D will need to contain a component that addresses regeneration/re-growth of pancreatic islets. If the view of pancreatic islets as (micro) organs is adopted then the chances of successful re-growth of human islets may be limited. This also means that for immune therapies that are initiated after diagnosis of T1D the aims need to be set lower than full restoration of euglycemia and permanent insulin independence. These therapies therefore aim at maintaining residual islet mass that still exists after diagnosis of T1D and that can persist for years or even decades after disease onset. Parameters such as improved glycemic control, a decrease in the dose of exogenous insulin needed and maintenance or slower decrease of C-peptide levels measure success of these therapies. Although these aims are less glorious than independence from exogenous insulin they are nevertheless worthy of pursuit and can mean significant improvement in the quality of life of the treated patients.
That treatment with antibodies directed against CD3, a component of T-cell receptor complex, might have potential in the treatment of autoimmune disease was evident since the discovery
Among immune therapies with broader specificity applied to patients with T1D the treatment with anti CD3 antibodies has been tested most extensively despite side effects such as ‘cytokine storm’ and a selection of recently evaluated trials is summarized below.
All anti CD3 treatments have been given to patients with recent onset of T1D and in accordance with the constraints outlined above, statistically significant increases in the reversal of disease i.e. full independence from exogenous insulin within the study time frame are not observed. However, differences between treatment and placebo groups have been observed and most prominently where results of patient subpopulations are analyzed. This was shown in a trial that observed treated patients and the placebo group for up to four years after treatment with a humanized anti CD3 antibody which was given over a period of six consecutive days. Statistically significant reduction in daily insulin needs vs. the corresponding placebo group were reported for patients whose residual beta cell function at baseline was above the median of all patients as well as for patients whose age was below the median age. These patients also had a slower decrease in C-peptide levels than the placebo group i.e. their residual beta cell function was maintained for longer than that of the placebo group. Levels of HbA1c (glycated hemoglobin) were also positively affected by the treatment but this occurred again only in younger patients [5; 6]. The dependency of treatment efficacy on age and on the residual beta cell mass (correlated to the time interval between diagnosis of T1D and treatment start) was also observed in a recent published study that compared different dose regimens of an anti CD3 antibody [7]. The fact that anti CD3 treatment was more effective in younger patients was explained by the age-dependency of the insulitis process. Islet inflammation was detected in children but rarely in adolescents and adults. Furthermore, late onset T1D patients are presumed to suffer from a less severe form of the disease. Therefore a more pronounced loss of residual beta cell function was observed in the younger placebo subgroup compared to the older placebo subgroup and the effect of the anti CD3 treatment consequently became more clearly visible in younger patients[6].
Side effects induced by the treatment with anti CD3 antibody occurring in most patients are transient and are in accordance with the mechanism of action of this approach. Fever, which might be explained by the ‘cytokine storm’ triggered by the antibody treatment, a syndrome similar to acute mononucleosis correlating with an increase in EBV copies which may be a result of the activation-induced T-cell death upon anti CD3 administration are some of the adverse events reported for this treatment. Lymphomas as consequence of the anti CD3 treatment have not been observed.
While it has been established in the mouse that T-cells are necessary and sufficient to cause the disease the role of B-cells in the pathogenesis of T1D is more indirect. Islet antigen self-reactive T-cells both of the helper and cytotoxic type from diabetic NOD mice can transfer the disease to NOD-SCID recipients whereas B-cells are unable to do so. The contribution of B-cells to the pathogenesis of human T1D is likely also to be more indirect. This is suggested by a report of a child with X-linked agammaglobulinemia who developed T1D [8]. Nevertheless, B-cells must participate in the pathogenesis of T1D because it is possible to prevent the disease by B-cell depletion and it has been shown that B-ells are necessary for the initiation of insulitis in the NOD mouse [9; 10]. B-cells are very efficient antigen presenting cells particularly after they have been activated, which could occur in the accumulation of inflammatory cells in the islets during the pathogenesis of T1D. The rationale for the use of B-ell depletion in humans would therefore be a reduction of antigen presentation, which would result in less T-cell activation and an attenuated inflammatory process. It could also include the elimination of cytokines produced by B-cells that might be damaging to the islets and reduce further recruitment of immune cells to the islets. It is also possible that depletion of B-cells with an antibody initiates complex mechanisms similar to those thought to underlie the effects of treatment with anti CD3 antibody.
Targeting of B-cells is achieved by an antibody against the CD20 molecule, a cell surface phosphoprotein that is expressed during the mid-stages of B-cell development but which does not occur on hematopoietic stem cells or normal plasma cells [11]. Anti CD20 antibody is approved for the treatment of B-cell lymphomas and was used in a study of patients with recent onset of T1D (median time interval between diagnosis of T1D and first infusion 81 days). Four consecutive infusions were given over an interval of 22 days. The results of this trial assessed 12 month after study begin resemble those obtained by anti CD3 treatment- slower decrease of C-peptide levels, lower levels of glycated hemoglobin and lower requirement for exogenous insulin in the treated vs. the placebo group. Although not statistically significant, subgroup analysis again tended to suggest a better response in children and adolescents. Side effects included fever, rash and pruritus as consequence of the ‘cytokine storm’ (or cytokine release syndrome) triggered by the first injection of the antibody. Again these effects were transient and did not reappear when subsequent doses of the anti CD20 antibody were administered [12].
It is not known whether the effects of T- or B-cell targeting with antibodies can be prolonged or increased if the treatment is given repeatedly or if T-and B-cell targeting are combined. The guess here is that an increased risk of adverse side effects might counterbalance positive effects gained by repeated or combined administration of T or B-cell depleting antibodies and/or that repeated administration become less efficient because the immune system activates counteracting mechanisms.
Before reviewing antigen specific immunotherapies two studies with very broad targeting of the immune system shall be mentioned. In one study peripheral hematopoietic stem cells of patients with recent onset of T1D were mobilized, harvested and frozen before immune ablation was achieved by administration of high dose cyclophosphamide and anti thymocyte globulin. The previously harvested hematopoietic stem cells were then infused. During the time needed for the immune system to regenerate extensive supportive care including antibacterial, antiviral and antifungal prophylaxis as well as patient isolation in rooms equipped with air filters was required. This approach resulted in reversal of T1D in the majority of the patients. 12 of the 23 patients participating in this trial became independent from exogenous insulin and this state lasted for 14 to 53 months while 8 patients relapsed and resumed insulin use at low doses [13]. In the insulin-independent group C-peptide levels at 24 and 36 months post transplantation of stem cells had increased while values of glycated hemoglobin had decreased significantly compared to pre transplantation values. The rationale for this study was the possible reconstitution of immune tolerance after an ‘immunologic reset’ by high dose immunosuppression followed by autologous hematopoietic stem cell transplantation [14]. However, it is known from the NOD mouse that the self-reactive tendency of the immune system cannot be eliminated permanently by this approach. Once the immune system has regenerated autoimmune responses are eventually re-established and islet destruction resumes. This process is reflected by the prolonged but not permanent state of independence from exogenous insulin experienced by the majority of the treated patients in this trial. The results of this study raise the questions whether the increase in C-peptide levels and independence from exogenous insulin was due to a process of regeneration of islets or due to an attenuation of the inflammatory environment the islets were exposed to. Since the majority of the insulin-free patients discontinued insulin use between 3 days before stem cell transplantation (i.e. during the process of immune ablation) and 34 days after transplantation of stem cells it is reasonable to assume that the latter mechanism was dominant at least initially because this time span would appear to be too short to allow extensive regeneration of islets. There was however one patient who achieved insulin independence 610 days after stem cell transplantation and in this case regeneration of islets may have played a role and it is possible that this process also contributed during later stages to the increased C-peptide levels observed in the patients with long term independence from exogenous insulin. If attenuation of the inflammatory environment that islets are exposed to is an important early effector mechanism and if insulitis in humans is predominantly found in children but seldom in adolescents and adults then this approach would be expected to work best in children with recent onset of T1D. However none of the patients in this study was younger than 14 years and therefore the best possible effect might not have been achieved.
The above-mentioned trial could not have been designed as a controlled and blinded study and it is possible that that some of the remissions observed were not related to the treatment but represent spontaneous remissions. However, the close correlation of the observed remissions with the immune ablative treatment and their duration argued for a genuine effect of the treatment. There are results from a double blind and placebo- controlled study applying broad targeting of the immune system with cyclosporine. They show a statistically significant increase in complete as well as complete and partial remissions at the 9th month in the treated vs. placebo group with the effects being more pronounced in the subgroup with whole blood cyclosporine levels of ≥300ng/ml [15].
Certainly immune ablation followed by autologous stem cell transplantation even if it has to be performed only every 3-4 years is not something that could be considered suitable for repeat administration. This also holds in regards to the continued administration of cyclosporine to patients with T1D especially since even a short lasting course of the drug (12.5 +/- 4 months) accelerated the rate of progression of the urinary albumin excretion rate and tended to induce a loss in kidney function [16].
Although it appears from the approaches presented above that the more severe the therapeutic intervention the better its success antigen specific therapies remain attractive conceptually because they allow for an intervention that is more precisely targeted. Rather than targeting all T-cells (or the immune system in its entirety) the idea is to apply an approach that controls only those T-cells that are self-reactive. Here an important question concerns the specificity of the self-reactive T-cells that ‘merit’ control. It is obvious that insulin is considered a major self-antigen as it is the defining protein of the beta cells that are impaired and destroyed during the pathogenesis of T1D. There are many experimental findings that confirm this view such as the presence of anti-insulin autoantibodies as a proven prediction tool for the assessment of diabetes risk in the pre-clinical state. Furthermore, among the group of beta cell proteins that have been studied to date as potential self-antigens insulin is one of the few that fulfills a formal requirement for a beta cell protein to be considered a self antigen: insulin specific T-cell clones and lines derived from NOD mice can reliably transfer diabetes to NOD-SCID recipients. Another question concerns how these self-reactive T-cells can be targeted and here the mechanisms that mediate oral or nasal tolerance offer a possible approach. Oral or nasal tolerance is defined as the specific suppression of cellular and/or humoral immune responses to an antigen by prior administration of the antigen via the oral or nasal route. The mechanisms of oral tolerance are thought to have evolved in order to generate peripheral tolerance to external agents that gain access to the body via a natural route (the digestive or respiratory tract). As consequence these external agents are ‘seen’ by the immune system as internal components that become part of self. Two different but not mutually exclusive mechanisms have been defined that can mediate oral tolerance, depending on the amount of antigen administered orally: Induction/activation of regulatory T-cells has been reported to occur when low doses are given whereas induction of anergy or deletion of T-cells appears to be the main mechanism involved when higher doses are administered [17]. According to this schematic, if insulin specific self-reactive or autoaggressive T-cells were to be targeted, feeding of insulin would result - upon presentation of insulin by specialized gut-associated antigen presenting cells - in the activation of insulin-specific regulatory T-cells in the gut. These T-cells then migrate to the pancreatic lymph nodes where they encounter epitopes derived from endogenous insulin and become reactivated. This leads to the secretion of IL-10 and TGFβ- cytokines, which can attenuate the ongoing inflammatory process. Because it is mediated by cytokines this mechanism would not only target insulin reactive T-cells but would suppress T-cells with other specificities as well. A degree of specificity would be generated because both types of T-cells -autoagggressive and regulatory- would become activated in the same location (pancreatic lymph nodes or islet infiltrates) but not in other sites. This is one reason why antigen specific therapies thought to rely on T-regulatory cells might be better applied before the onset of T1D. Once islets have been destroyed the pancreatic lymph nodes can no longer activate T regulatory cells because beta cell antigens are no longer presented.
Anergy or deletion of insulin reactive T-cells might also be achieved by oral administration of insulin with the latter mechanism potentially leading - through the presence of debris from apoptotic insulin specific T-cells - to the generation of T regulatory cells according to the process discovered to be activated by i.v. administration of anti CD3 antibodies. It should be mentioned in advance, that in the studies administering oral or nasal insulin presented below, parameters that would indicate which, if any, of the proposed mechanism (tolerance/anergy/ activation of T-regulatory cells) had been triggered were not acquired.
Oral administration of insulin has been tested as intervention in patients with recent onset of T1D [18] and oral as well as nasal insulin have been given to persons at risk of developing T1D in order to assess the potential of this approach to prevent or delay the onset of the disease. The ‘Diabetes Prevention Trial-Type 1’ (DPT1) screened first and second-degree relatives of patients with T1D for the presence of islet cell antibodies. Relatives who had anti islet cell and anti insulin antibodies but a normal glucose tolerance and first phase response to intravenous insulin were projected to have a 5-year risk of 26-50%. 372 of these individuals were randomized in the oral insulin study. (DPT1 also included a group of individuals classified as having a risk of greater than 50% who received intravenous instead of oral insulin [19]). The follow-up in the oral insulin study was 4.3 years. During this time there appeared no differences between placebo and control groups. The average proportion of subjects who progressed to diabetes was 6.4% per year in the oral insulin group and 8.2% per year in the placebo group. However, upon subgroup analysis there appeared to be a beneficial effect in those individuals who had a higher anti insulin autoantibody titer (≥80nU/ml, n=263). In this group the proportion who developed diabetes was 6.2% per year in the oral insulin group and 10.4% in the placebo group [20]. This effect became even more pronounced if analysis was confined to those with an anti insulin autoantibody titer of >300nU/ml (n=132] with a projected delay of the disease of almost 10 years [21]. These findings were encouraging but since the subgroup analyses had not been prespecified they could not be considered a positive outcome. Another important result this trial yielded was the confirmation that the parameters used to predict development of T1D in relatives of individuals with the disease were sufficient and accurate. Risk was projected to be 26-50% whereas the actual observed value was 35% over 5 years. Accurate risk prediction is essential for the design of further prevention trials, one of which is currently ongoing and builds on the hypotheses generated by the evaluation of the oral insulin DPT1 trial (better efficiency of the treatment in individuals with higher anti insulin autoantibody titers).
A second prevention trial used nasal instead of oral insulin and a screening and staging approach different from the DPT1. In this case cord blood samples of infants were tissue typed for the presence of the T1D susceptibility allele HLA-DQB1. Carriers of this allele and an additional cohort consisting of their siblings were repeatedly tested for the presence of T1D-associated autoantibodies. Individuals of the two cohorts who were positive for two or more autoantibodies but free of clinical diabetes were invited to participate in the prevention trial. Individuals enrolled in this trial were younger than those in the DPT1 (1.6-5.2 years vs. 7-14 years in the DPT1). 224 individuals of the HLA-DQB1+ cohort and 40 individuals of the sibling cohort were randomized to receive intranasal insulin or placebo with a median duration of the intervention of 1.8 years. This trial failed to demonstrate a positive effect of intranasal insulin in all analyzed groups. The annual rate of progression to diabetes in the HLA-DQB1+ cohort was 16.8% for the group receiving intranasal insulin vs. 15.3% for the placebo group. In the sibling cohort these values were 10.8% vs. 6.0% respectively. In contrast to DPT1 a subgroup analysis of individuals with high anti insulin autoantibody titers did not show any benefit of intranasal administration of insulin. Although this trial failed to demonstrate positive effects of intranasal insulin it showed that by screening for HLA risk alleles a cohort with a disease risk similar to that of first-degree relatives could be identified from the general population [22]. Thus even if these two trials largely failed in their primary aim they nevertheless clearly demonstrated the ability to accurately predict disease risk, which is essential to optimize the timing of preventative therapies.
Besides oral or nasal administration of an autoantigen there is in T1D models another approach to induce tolerance. In this case a candidate autoantigen is injected subcutaneously together with the adjuvant alum. Although using an islet autoantigen as a vaccine to prevent or ameliorate disease might appear strange it has nevertheless been shown in the mouse model of T1D that this approach can be effective. The idea is that such a vaccination either activates regulatory T-cells or that it converts autoaggressive T-cells to a non-destructive phenotype. This approach has been tested in humans with GAD65, which is the 65 kd isoform of the autoantigen glutamic acid decarboxylase. In contrast to the prevention studies with oral and nasal insulin the trials with GAD65 have been conducted in individuals with recent onset of T1D. A phase II trial tested the safety and efficacy of vaccination with human GAD65 in alum (two subcutaneous vaccinations with 20µg GAD one month apart) in patients with recent onset of T1D (n=70). Results of this study were reported 30 months and again 4 years after treatment. Of the subgroups prespecified in the protocol (HLA classification, age, sex, baseline GAD autoantibody levels) only duration of T1D had a significant influence on the efficacy of the vaccination. In the patients vaccinated less than 6 month after diagnosis of T1D both fasting and stimulated C-peptide secretion decreased significantly less in the GAD-alum group than in the placebo group by month 30 and this positive effect was retained at 4 years after treatment. There was no significant difference between the GAD-alum and the placebo group for patients treated 6 month or more after diagnosis. As expected, vaccination with GAD-alum lead to strong increase of the GAD autoantibody titers, which was sustained to month 30 and a neurological assessment was performed because of concerns that this might lead to stiff-man syndrome. However, there were no notable neurological differences between treatment and placebo group. In accordance with the B-cell responses anti GAD cytokine responses assessed in PBMCs of treatment and control groups at 15 months showed a significantly increased release of most of the tested cytokines (IL-5, 10, 13, 17, IFN-γ and TNFα) in the GAD-alum group. Furthermore increased GAD-induced levels of FOXP3, a transcription factor associated with T regulatory cells, was found in the GAD-alum group [23] [24]. Given the findings of this trial a second study (phase III) was conducted, which enrolled patients within 3 month of the diagnosis of T1D. Patients were randomly assigned to receive one of three study treatments: either two (n=108) or four vaccinations with GAD-alum (n=111) or a vaccination with the adjuvant alum alone (placebo group, n=115). This trial with a follow up time of 15 months failed to show improvements in stimulated C-peptide levels after either the two or the four-dose vaccination when compared to the placebo group. Pooling of data from both groups with GAD vaccinations failed to show a significant effect on stimulated C-peptide levels compared to the control group [25].
A third antigen tested for its therapeutic value in human T1D, is the 60kDa heat shock protein (hsp60). While GAD and especially insulin are specifically expressed in pancreatic islets this is not the case for hsp60, which is expressed throughout the body. Although anti hsp60 autoantibodies can be detected in patients at the onset of T1D they are not useful as predictive markers for disease beyond what can be achieved by measuring anti insulin or anti GAD titers. If hsp60 is an autoantigen in T1D and is widely expressed throughout the body one would expect to find inflammation driven by hsp60-reactive T-cells in other organs as well. However this is not the case and raises the question as to whether there are beta cell/islet intrinsic factors that set this site apart immunologically from other parts of the body.
In therapeutic applications hsp60 is not given as a whole protein but as a peptide derived from the native sequence of human heat shock protein 60. The sequence of this peptide was first identified in the NOD mouse with the help of diabetogenic T-cell clones responding to the
Several phase II trials have been conducted with DiaPep277 in patients with T1D. In one of these trials that focused on the changes in immunological parameters after treatment, DiaPep277 was administered subcutaneously in a 10% lipid preparation with the placebo group receiving mannitol in 10% lipid preparation. Three different doses of DiaPep277 were tested (0.2mg, 1mg and 2.5mg). Four injections of the drug or the placebo were given over a timeframe of 12 months and a total of 48 patients were enrolled with onset of T1D between 200 and 800 days before start of treatment. Glucagon-stimulated C-peptide production significantly decreased over 12 months in all groups except the group receiving Diapep277 at 2.5mg. The decrease in C-peptide production over 12 months was significantly less in the 2.5mg than in the placebo group. Absolute daily insulin dosage did not decrease over time in any of the groups [30]. These results are in accordance with an earlier trial that found a significantly higher stimulated C-peptide concentration in the treatment vs. placebo group at 6 and 10 months after start of treatment. This earlier trial also found a significantly reduced insulin requirement at 10 months and observed that individuals with higher C-peptide concentration at the time of initiation of treatment showed better preservation of C-peptide concentrations 10 months later [31]. Therefore the rule that the earlier treatment is started the more efficient it tends to be also applies to this approach. The former study was accompanied by an extensive evaluation of immunological parameters before, during and after treatment. As expected, it was observed that immunological responses were quantitatively and qualitatively highly diverse among the subjects. Nevertheless, after development of new methods to evaluate the results obtained from proliferation and cytokine release experiments, some interesting information could be derived. An IL-10 response but not a proliferative response to DiaPep277 before initiation of treatment, and a decrease or loss of proliferative response subsequent to treatment, appeared to provide a correlate for clinical efficiency. These biomarkers might reflect some kind of tolerance to DiaPep277 (hsp60) and appear to be associated with improved clinical outcome. These findings imply that the status of the immune response prior to therapy may be predictive for treatment outcome. Proliferative responses after treatment with DiaPep277 were frequently specific for hsp60 in that responses to GAD or tetanus toxoid were not or only weakly altered [32]. Treatment with DiaPep277 therefore appeared immunologically effective and specific. One phase III trial with DiaPep277 was recently concluded and awaits publication of the results and another phase III trial is currently underway.
What could be reasons for the limited success of the antigen specific therapies presented above? From a conceptual point of view there is a concern that in these therapies there is always a risk that administration of the candidate autoantigen does not lead to attenuation of the autoimmune reaction but rather leads to its exacerbation. This is especially the case when autoantigens are administered with an adjuvant such as was done in the GAD-alum trials. We have observed while studying the Reg proteins as potential autoantigens in T1D that vaccination of NOD mice with an N-terminal fragment of RegII in alum leads to acceleration of T1D instead of prevention [33]. A similar observation was made in BB rats, which like the NOD mice spontaneously develop T1D. Here insulin given orally with an
The analysis of the trials presented here suggests that treatment efficacy can differ from subgroup to subgroup. This indicates that there might not be a single therapeutic approach that fits all. Rather the observations suggest that it may be necessary to establish an individual profile that goes beyond the standard parameters such as sex, age, family history, time of diagnosis of T1D, HLA type, and autoantibody profile for each person intending to undergo an immune therapeutic intervention. These parameters might include the spectrum of T-cell responses to beta cell autoantigens (in terms of proliferation as well as of cytokine release), characterization of the gut flora [36; 37], imaging of islet inflammation [38] type and time of prior vaccinations and infections, season [25], and might even include psychological parameters such as familial stress levels [39]. As new approaches are translated from the pre clinical stage to individuals at risk of developing T1D or to patients already suffering from the disease the palette of possible interventions will grow more diverse. Obtaining highly differentiated profiles may refine the process of matching the time point and the type of immune intervention to an individual and thus optimize outcome.
Dielectric elastomer actuators (DEAs) are currently used in a variety of applications such as robots and medical devices. Since a DEA is very light and capable of high output, it is expected to be able to control the output of the planetary exploration ship and the solar panels loaded on exploration ships.
We are developing a DEA related to the output and control of Mars probes that observe the surface of Mars. Mars Airplane is a new Mars observation platform that enables a wide range of observations from low altitudes. Since 2010, the Japanese Mars spacecraft working group has been working on the conceptual design of Mars airplanes and various basic researches [1, 2, 3, 4, 5]. Mars exploration is performed with a weight of 6 kg, a wing width of 2.4 m, and a maximum cruising speed of 70 m/s. We are developing such a machine, as shown in Figure 1 [6].
Image of the Mars exploration airplane.
We would like to take this airplane down from the Mars exploration spacecraft with a parachute, disconnect the parachute at a high altitude (30 km) on Mars, control its flight remotely, and then gradually lower the altitude to fly a distance of about 300 km. Therefore, it is necessary to avoid high mountains on flights after the middle stage.
This Martian plane can obtain more detailed data than satellites and can observe a wider range than rovers. Also, one of the unique features of the Mars plane is to observe the formations of the canyons. Satellites cannot see the formation from the sky, and rovers cannot approach them.
Flight exploration by Martian planes has some difficulties, as detailed below:
These planes are not mass-produced and are very expensive due to their special payload and avionics for academic research. In addition to this, Mars planes must be lightweight to fly in the thin atmosphere of Mars. It also has to be fairly lightweight to carry this spacecraft to Mars as well as to even be transported to Mars itself.
DEAs have the potential to be used as actuators for control surfaces (i.e. ailerons, rudder, and elevator) and as a propeller for the Mars airplane, since it is light and has high output and high efficiency. Another advantage of the DEA is that it is linearly driven, making it less susceptible to dust. This research investigated the feasibility of the DEA for the application of control surfaces (i.e., ailerons, rudder, and elevators) on the Mars airplane. A structural model of a wing having the control surface, the DEA, and a linkage was built, and a wind tunnel test of a control surface actuation using a DE actuator was carried out to investigate the feasibility of the DE actuators for the Mars airplane.
The results obtained in this study will be useful not only for the development of Mars exploration airplanes, but also for the structure and aerodynamic design of lightweight airplanes where large aerodynamic deformation is expected. The study also provides valuable examples of some of the expensive custom-made airplanes for academic research, airplanes that are not capable of many flight tests, and airplane development processes for which conducting flight tests are difficult.
To date, various types of soft actuators have been studied, and many functions desirable for different devices have been studied [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. An especially attractive soft actuator is the dielectric elastomer (DE). DEs began to be studied in 1991 by R. Pelrine, S. Chiba et al. [16].
The basic element of a DE is a very simple structure comprised of a thin elastomer sandwiched by stretchable and flexible electrodes (see Figure 2) [24]. When a voltage difference is applied between the electrodes, they are attracted to each other by Coulomb forces leading to a thickness-wise contraction and plane-wise expansion of the elastomer. The typical thickness of the elastomers is about 500 microns to 1 mm. The electrode uses carbon black, CNT, or nano-sized metal. At the material level, the DE actuator has a fast speed of response (over 100,000 Hz), with a high strain rate (up to 680%), as shown in Figure 3, a high pressure, and a power density of 1 W/g [32, 33, 34]. DEs can also be used for pressure-sensors and 3D position-sensors.
Principle of operation of DEs.
Expanding Circular Actuator up to 680.
As shown in Figure 4, recently, DE actuators having only 0.15 g of DE material have been able to lift a weight of 8 kgf easily using the single wall carbon nano tube (SWCNT) electrodes (ZEONANO®-SG101) [33]. With 0.15 g of DEs, it is possible to lift an 8 kg weight by 1 mm or more. Its operating speed is 88 ms.
A DE lifted a 8.0 kgf weight using SWCNTs (ZEONANO®-SG101) (ZEONANO®-SG101 is a single-wall carbon nanotube synthesized by the Super-Growth method. (Diaphragm type DE actuator having a diameter of 8 cm)).
When the DE sheet is rolled, it becomes an actuator that looks like a human muscle. Figure 5 shows the roll actuators with 3-DOF [34]. As shown in Figure 6, a DE can be the arm or leg of a robot. Using five of them, we created a robot that can moves around the surface of Mars [34], so it enables sideways stepping like a crab without turning around, when it collides with wall.
Roll actuator having 3-DOF.
Biologically inspired robots powered by DE rolls.
These roll-type actuators seem to be ideal for moving the antenna or solar panel of a space craft to the correct position and as an actuator for a working robot arm on it. For example, a robot arm is attached to the Japanese experimental module Kibo of the International Space Station (see Figure 7). It is possible to use DEs as the drive source.
International Space Station: Kibo (Japanese experiment module) has a robot arm.
In order to verify the possibility of using a DEA as a surface control actuator for the Mars exploration airplane, a wind tunnel was used to operate with the DEA while receiving wind.
Using a continuously circulating low-speed wind tunnel (see Figure 8) owned by JAXA (Japan Aerospace Exploration Agency), we conducted a verification experiment to verify whether the DEA actuator could be used as a steering actuator under the wind received during flight. The wind tunnel used in this experiment has a measurement section of 2 m x 2 m and a maximum wind speed of 67 m / s (up to 60 m/s during continuous operation using the model).
2 m x 2 m Low-speed wind tunnel.
In the preliminary study, the wind speed was set from 0 m/s to 40 m/s in order to match the actual driving conditions as much as possible. In addition, it was decided to observe the aileron driving state by changing the angle of attack from 0° to ±10° at 5° intervals at each wind speed (Figure 9).
Input parameters.
The structural model of the wing used in the experiment was shaped vertically so that the surface control actuator (in this case, an aileron-like structure) can be driven by the DEA in a limited space in the wind tunnel. The body is shown in Figure 10 [6].
Body used in experiment.
The dimensions of the wings used in this experiment were 168.5 mm wide, 633 mm high and 25 mm thick, and the dimensions of the ailerons were 78.5 mm wide and 633 mm high. The wings and ailerons were made using polycarbonate resin for the frame and ABS resin for the exterior. The bottom of the model was 125 mm in diameter and 757.5 mm in length. The tip and tail are made of ABS resin, and the center is made of acrylic resin. For strength, the parts are reinforced with aluminum. The aileron has a hollow structure, but the total weight was about 5 kg. A DEA to control ailerons was installed inside the body. The DEA and aileron are connected by a link mechanism built into the main body (see Figure 11) [6], and when the DEA is displaced by 2 mm, the aileron moves 20 degrees. The DEA unit for aileron drive has a structure that adopts a diaphragm type with an outer dimension of φ100 mm.
Link mechanism between the body and the measurement equipment.
As shown in Figure 12, a load measuring device other than the main body, a high-voltage power supply, a high-voltage switch, etc. were installed outside the wind tunnel and connected to the main body with a cable so as not to obstruct the air flow in the wind tunnel [6]. A video camera was installed on the ceiling outside the wind tunnel to observe the state of the enclosure, and the images were taken from the observation window.
System diagram of the aileron drive experiment with a DEA.
First, in order to examine the specifications required to control the actuator used to steer the aileron, a load cell was used to measure the load applied to the actuator part at each steering angle. Figure 13 shows the measurement system used for load measurement [6].
Load measurement system using a load cell.
The load cell used for load measurement was mounted at the DEA mounting position of the main body. The maximum load applied to the load cell is 20 kg, and the analog data output from the load cell is converted to digital data by the 24-bit A/D converter IC (HX-711), and the CPU (ATmega328P). A lithium polymer battery (Li-Po) was used as the power source to minimize the effect of noise on the weak signal output from the load cell. In order to shorten the connection distance, the circuit to the CPU was attached to the fuselage. A personal computer for operation and recording was installed outside the wind tunnel, and it was connected by serial communication.
A laser distance sensor (VL50L0X) was also installed to measure the displacement velocity (Figure 14) [6]. Since this laser distance sensor uses I2C for the interface, it is not easily affected by noise and stable measurement is possible. The control was performed by the same CPU (ATmega328P) as the load measurement, and the measurement data was transmitted to the measurement PC by serial communication. Laser distance sensors were installed in the front and rear to observe the movement of ailerons and the DE.
Laser distance sensor system installed inside the body. (a) Mounting location of the laser distance sensor; (b) Laser distance sensor system.
The load was measured by continuously changing the wind speed from 0 m/s to 40 m/s in 5 m/s increments and setting the steering angles to 0, 5, 10, 15, and 20 degrees. When the set wind speed was reached, measurements were taken at each wind speed for about 30 seconds, and the load applied to the actuator section was measured (see Figure 15) [6].
Load applied to the actuator section (by steering angle and wind speed).
In this experiment, it was found that the DEA was loaded with 11.54 kg/f in an environment with a steering angle of 20 degrees and a wind speed of 40 m/s (see Table 1). In order to move the aileron through the link mechanism, a force of about 2.6 kgf is required even in the absence of wind. It was found that a force of about 14.14 kg/f is required to steer 20 degrees in an environment with a wind speed of 40 m/s. It was also confirmed that the wings were deformed from the joint with the airframe at a wind speed of 30 m/s or more. Since the experiment was repeated in such a state and there was a risk of damage to the blade due to fatigue, the aileron drive experiment with the DEA was carried out at a wind speed of 0 m/s to 30 m/s. In order to steer 20 degrees in this environment, a DEA that can obtain a force of about 8.7 kg/f is required.
Wind speed (m/s) | ||||||||
---|---|---|---|---|---|---|---|---|
5 | 10 | 15 | 20 | 25 | 30 | 35 | 40 | |
Load applied to the actuator (kg / f) | 0.12 | 0.37 | 1.12 | 2.30 | 3.90 | 6.10 | 8.72 | 11.54 |
Load applied to the actuator section at each wind speed when the rudder angle is 20 deg.
The load cell mounted for load measurement was replaced with a diaphragm type DEA, and an aileron drive experiment was conducted. Figure 16 shows the state of the DEA mounting.
DEA mounted in the body. (a) Diaphragm type DEA. (b) DEA built into the body.
The DEA unit used had a donut shape with an outer diameter of φ100 mm, a DEA part with an outer diameter of φ80 mm, and a central part of φ50 mm (see Figure 15a). The DEA used a 3 M acrylic sheet (VHB4910) as the main elastomer and SWCNT (SG101) manufactured by Zeon Corporation as the main electrode material. This DEA unit had a displacement performance of 2.0 mm with an applied voltage of DC 3.2 kV under a load of 4.0 kg, and the drive time at this time was about 100 ms. The DEA was driven by a high voltage power supply and a high voltage switch located outside the wind tunnel. The high-voltage power supply installed outside the wind tunnel and the DEA installed in the enclosure are connected by a high-voltage cable with a length of about 6 m. However, due to the low current consumption of the DEA, the maximum voltage drop during driving is 100 V, which is within the range where there is no problem in driving the DEA. The DEA unit consists of four cartridges, and if one of the DEA cartridges fails, the remaining DEA cartridges can drive it.
In this experiment, the wind speed was changed from 0 m/s to 20 m/s every 5 m/s, and the change in wind speed at each wind speed was recorded with a video camera installed on the ceiling of the wind tunnel. The rudder angle was measured by analyzing the recorded video.
In the initial experimental plan, the angle of attack was planned to be changed from −10° to +10° in 5° increments, but the stress applied to the wing was greater than expected, so there was a risk of damage to the skeleton. In order to avoid such an outcome, this time, the angle of attack was set to 0° only, and the wind speed was changed from 0 to 20 m/s at 5 m/s intervals.
Table 2 shows the aileron angle at each wind speed. Figure 17 shows the aileron displacement at each wind speed [6]. Up to a wind speed of 5 m/s, the aileron angle could be obtained up to 20 deg. However, the aileron angle gradually decreased from a wind speed of 10 m/s and reached 4 deg. at a wind speed of 15 m/s.
Wind speed (m/s) | |||||
---|---|---|---|---|---|
0 | 5 | 10 | 15 | 20 | |
Aileron angle (deg.) | 20 | 20 | 9 | 4 | 0 |
Aileron angle at each wind speed.
Aileron displacements at applied voltage DC3,200 V.
Figure 18 shows the aileron drive speed when there is no wind, as measured in the lab. The rudder angle could be moved up to 20° at a speed of about 100 ms, and the same rudder angle and speed could be reproduced even if the drive control was repeated.
Aileron drive speed when there is no wind.
Figure 19 shows the operating speed of the aileron. The displacement speed was measured using a laser distance sensor mounted inside the body. At a wind speed of 5 m/s, it took 250 ms to reach the maximum displacement, but at a wind speed of 10 m/s, it took 300 ms. As described above, since the angle change of the aileron can be easily replaced with the voltage change, the feedback control can be easily performed by changing the voltage applied to the DEA using the voltage change.
Aileron’s operating speed measured by the laser distance sensor. (a) Wind speed of 5 m/s; (b) Wind speed of 10 m/s.
The structural model used this time required a force of 2.6 kg for steering even at a wind speed of 0 m/s. This was a huge loss. It is probable that the maximum aileron angle could not be obtained due to insufficient driving force at a wind speed of 10 m/s. Most of this loss was due to the link mechanism. By increasing the efficiency of the link mechanism, we were able to obtain a maximum displacement of up to 15 m/s even with the same DEA. In the next experiment, we will investigate how much the mechanism can reduce the power consumed by developing a new drive that drives ailerons directly, enabling a simple and practical steering system.
To send a Martian plane to Mars, we need to dramatically reduce the weight of our compact and powerful motors. In addition, a powerful, efficient and responsive motor is essential for long-term flight of the spacecraft on the surface of Mars. Also, the surface temperature of Mars is very low and dust is present. Therefore, the required level of efficiency and responsiveness is very high. In this paper, based on the data obtained in this experiment, we attempted to compare the current level of a DEA with existing motors for these requirements.
First, we will explain the performance of the DE developed for this experiment:
The total weight of the DEA used is 52.8 g, of which 51.8 g is the weight of structures, etc., and the weight of the DEA itself is as small as 0.98 g. This DEA can lift a 4 kgf weight by 2 mm with an applied voltage of 3.3 kV. In order to increase this operating speed, the DE has been strengthened, and the total weight is 0.98 g, which is 98 ms.
Next is a comparison between the DE and existing motors:
From the above data, the power of the DE linear actuator is 0.0074 W per gram. As shown above, the weight including the DE actuator and its associated structure was approximately 53 g. If a similar linear actuator is configured using an existing DC motor of similar weight, the output of the linear actuator is 0.0015 (W). The weight including the DC motor and linear gear is about 95 g. Therefore, the DEA has a working speed per gram that is 4.9 times faster than a linear actuator that uses an existing DC motor. However, in the case of a linear actuator that uses a DC motor, a displacement of 1 mm takes about 200 milliseconds, so the difference in drive time is 9.9 times. In this experiment, we created a DE actuator that can lift a weight of 4 kgf using SWCNT (ZEONANO®-SG101) from Zeon Corporation. However, using high-crystal SWCNTs (extracted in the laboratory of Zeon Corporation under the guidance of Chiba et al.) gives about 1.32 times better results [35]. An SEM photograph of high-crystal CNTs is shown in Figure 20. It is estimated that DE motors using this CNT are about 13.1 times better than existing motors. When using metal CNTs, it is estimated to be twice as high as SWCNTs with high crystallinity. It is expected to be about 27.5 times that of existing motors.
SEM photograph of high-crystal CNT.
In order to explain in more detail the good response of the DE obtained in this research, we compared it with the existing servo motor (which shows better performance than the model airplane used for radio control). The reason we chose the servo motor is that it can be controlled more accurately. The specifications of the servo motor that can obtain the same level of output as the DEA unit used this time are “servo motor (GWS): weight 41 g, torque 4.1 kg/cm, running speed: 270 ms /60 degrees”. In contrast, the DEA used this time weighs 36 g (when four cartridges are built in), is about 13% lighter than the servo motor, and has a drive speed of 98 ms/2 mm, so it can be driven at higher speeds.
Based on the data obtained, the power consumption of the DE will be explained as follows. The power consumption during driving was measured with a voltage/current monitor of a high-voltage power supply installed outdoors. The wind speed was 5 m/s, the applied voltage was 3.2 kV, and the power consumption was 0.29 W. The current at this time was as small as 0.09 mA, and there was almost no voltage drop or heat generation due to the wiring cable. As mentioned above, one of the features of the DEA is that it consumes less current and can contribute to the weight reduction of the wiring cable, that is, the weight reduction of the main body. The power consumption during driving was measured with a voltage/current monitor of a high-voltage power supply installed outdoors. The wind speed was 10 m/s, the applied voltage was 3.2 kV, and the power consumption was 0.29 W. The current at this time was as small as 0.09 mA, and there was almost no voltage drop or heat generation due to the wiring cable. One of the features of the DEA is that it consumes less current. It can also contribute to the reduction of wiring cables and reduce the weight of the aircraft.
Considering the manufacturing cost of a DE, the weight of the DE including reinforcement is 0.96 g, which is cheaper and lighter than the price of a general existing motor with the same output. The SWCNT used as the electrode material for the DE in this experiment has started being mass produced at ZEON, so it costs about 1,000 yen ($ 9.6) per gram. Also, since the amount used is about 0.1 g, it is 100 yen (9 cents). The 3 M acrylic used for the elastomer is 20 yen per gram, so even if 1 g is used, it costs 120 yen ($ 1.15), which is cheap enough. Also, as mentioned above, the DEA itself is sufficiently lightweight and compact, which is a great advantage when mounted on a rocket.
When the DE is actually transported to Mars, it passes through outer space, so the effects of cosmic rays cannot be ignored. Next year, we plan to conduct a DE exposure test at the International Space Station (ISS: see Figure 7) and observe its effects.
Finally, we will explain the further improvement of the DE. As shown in Figure 4, we succeeded in launching a weight of 8 kg with a DE of 0.15 g. Using this, it will probably be able to move smoothly even in the wind with a higher speed. In this experiment, SWCNT (SG101) was also used, but it has been found also that the use of highly crystallized SWCNTs further improves drive speed and output. Even if the above link mechanism is not improved significantly, wind experiments of 25 m/s or more can be performed. In addition, new acrylics are currently being synthesized by Chiba et al. These acrylics can be used at −40°C to 150°C and may be able to handle even the harsh temperatures found on Mars. Also, due to the sufficient withstand voltage of the film, the control unit of the Mars probe will be developed mainly using this elastomer.
From the above experimental results, it is suitable for controlling the Mars probe because it can output a large amount of DE even with a small number of DEs and has a high operating speed. In addition, DEs are manufactured at low manufacturing cost and can withstand −40°C.
Thus, for the first time in the world, we aim to fly in the atmosphere of Mars. By doing so, we would like to obtain our own Mars observation data such as high-resolution residual magnetic field data and atmospheric data. By establishing this technology, it will lead to the flight of other celestial bodies (Titan, Venus, etc.) that have an atmosphere.
The function of detecting radiation on Mars (particle type, energy range, dose range, etc.) and the function of detecting underground features such as caves and water volume, which are important considerations for Martian colonies, have not been considered in the paper. At this moment, the payload of the airplane is small and we will not able to consider them. As mentioned in the background of DEs, however, the output of the DE has come to lift 8 kg against the weight of the 0.15 g DE. In the near future, we would like to increase the output of the DE, so that a larger payload can be realized.
DEs are also suitable for controlling the solar panels, antenna control, and drive output control of planetary exploration spacecraft.
What we need to know in the future is how well DEs can withstand cosmic rays. As early as next year, we plan to experiment with how a DE behaves in space on the International Space Station.
Recently, more and more research has been aimed at exploring the possibility of applying DEs to frequently used items such as spacesuits, power suits, and robots, and we hope that the results of this research will be valuable.
We would like to thank to Mr. Hiroki Ura and Mr. Takashi Yajima of the Aerodynamics Research Unit, Japan Aerospace Exploration Agency (JAXA)\'s Ministry of Education, Culture, Science and Technology’s Advanced Research Platform Operation Promotion Project “Wind and fluid Engineering Platform” for their enthusiastic support in getting this important data using their wind tunnel.
We also thank Aisin AW Co., LTD. for its financial support and manpower support during measurement in the wind tunnel.
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There are several ways to apply robust optimization and the choice of form is typical of the problem that is being solved. In this paper, the basic concepts of robust optimization are developed, the different types of robustness are defined in detail, the main areas in which it has been applied are described and finally, the future lines of research that appear in this area are included.",book:{id:"6587",slug:"nature-inspired-methods-for-stochastic-robust-and-dynamic-optimization",title:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization",fullTitle:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization"},signatures:"José García and Alvaro Peña",authors:[{id:"227809",title:"Ph.D.",name:"Jose",middleName:null,surname:"Garcia",slug:"jose-garcia",fullName:"Jose Garcia"},{id:"240407",title:"Dr.",name:"Alvaro",middleName:null,surname:"Peña",slug:"alvaro-pena",fullName:"Alvaro Peña"}]},{id:"51131",doi:"10.5772/63785",title:"Survey of Meta-Heuristic Algorithms for Deep Learning Training",slug:"survey-of-meta-heuristic-algorithms-for-deep-learning-training",totalDownloads:3111,totalCrossrefCites:14,totalDimensionsCites:23,abstract:"Deep learning (DL) is a type of machine learning that mimics the thinking patterns of a human brain to learn the new abstract features automatically by deep and hierarchical layers. DL is implemented by deep neural network (DNN) which has multi-hidden layers. DNN is developed from traditional artificial neural network (ANN). However, in the training process of DL, it has certain inefficiency due to very long training time required. Meta-heuristic aims to find good or near-optimal solutions at a reasonable computational cost. In this article, meta-heuristic algorithms are reviewed, such as genetic algorithm (GA) and particle swarm optimization (PSO), for traditional neural network’s training and parameter optimization. Thereafter the possibilities of applying meta-heuristic algorithms on DL training and parameter optimization are discussed.",book:{id:"5165",slug:"optimization-algorithms-methods-and-applications",title:"Optimization Algorithms",fullTitle:"Optimization Algorithms - Methods and Applications"},signatures:"Zhonghuan Tian and Simon Fong",authors:[{id:"1952",title:"Dr.",name:"Simon",middleName:null,surname:"Fong",slug:"simon-fong",fullName:"Simon Fong"},{id:"186166",title:"MSc.",name:"Zhonghuan",middleName:null,surname:"Tien",slug:"zhonghuan-tien",fullName:"Zhonghuan Tien"}]},{id:"51209",doi:"10.5772/62472",title:"A Review and Comparative Study of Firefly Algorithm and its Modified Versions",slug:"a-review-and-comparative-study-of-firefly-algorithm-and-its-modified-versions",totalDownloads:2885,totalCrossrefCites:14,totalDimensionsCites:19,abstract:"Firefly algorithm is one of the well-known swarm-based algorithms which gained popularity within a short time and has different applications. It is easy to understand and implement. The existing studies show that it is prone to premature convergence and suggest the relaxation of having constant parameters. To boost the performance of the algorithm, different modifications are done by several researchers. In this chapter, we will review these modifications done on the standard firefly algorithm based on parameter modification, modified search strategy and change the solution space to make the search easy using different probability distributions. The modifications are done for continuous as well as non-continuous problems. Different studies including hybridization of firefly algorithm with other algorithms, extended firefly algorithm for multiobjective as well as multilevel optimization problems, for dynamic problems, constraint handling and convergence study will also be briefly reviewed. A simulation-based comparison will also be provided to analyse the performance of the standard as well as the modified versions of the algorithm.",book:{id:"5165",slug:"optimization-algorithms-methods-and-applications",title:"Optimization Algorithms",fullTitle:"Optimization Algorithms - Methods and Applications"},signatures:"Waqar A. Khan, Nawaf N. Hamadneh, Surafel L. Tilahun and Jean\nM. T. Ngnotchouye",authors:[{id:"180330",title:"Dr.",name:"Surafel",middleName:null,surname:"Tilahun",slug:"surafel-tilahun",fullName:"Surafel Tilahun"},{id:"180784",title:"Dr.",name:"Waqar Ahmed",middleName:null,surname:"Khan",slug:"waqar-ahmed-khan",fullName:"Waqar Ahmed Khan"},{id:"185148",title:"Dr.",name:"Nawaf",middleName:null,surname:"Hamadneh",slug:"nawaf-hamadneh",fullName:"Nawaf Hamadneh"},{id:"185149",title:"Dr.",name:"Jean M. T.",middleName:null,surname:"Ngnotchouye",slug:"jean-m.-t.-ngnotchouye",fullName:"Jean M. T. Ngnotchouye"}]},{id:"61251",doi:"10.5772/intechopen.76979",title:"A Brief Survey on Intelligent Swarm-Based Algorithms for Solving Optimization Problems",slug:"a-brief-survey-on-intelligent-swarm-based-algorithms-for-solving-optimization-problems",totalDownloads:1603,totalCrossrefCites:8,totalDimensionsCites:12,abstract:"This chapter presents an overview of optimization techniques followed by a brief survey on several swarm-based natural inspired algorithms which were introduced in the last decade. These techniques were inspired by the natural processes of plants, foraging behaviors of insects and social behaviors of animals. These swam intelligent methods have been tested on various standard benchmark problems and are capable in solving a wide range of optimization issues including stochastic, robust and dynamic problems.",book:{id:"6587",slug:"nature-inspired-methods-for-stochastic-robust-and-dynamic-optimization",title:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization",fullTitle:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization"},signatures:"Siew Mooi Lim and Kuan Yew Leong",authors:[{id:"229799",title:"Dr.",name:"Siew Mooi",middleName:null,surname:"Lim",slug:"siew-mooi-lim",fullName:"Siew Mooi Lim"},{id:"231023",title:"Dr.",name:"Kuan Yew",middleName:null,surname:"Leong",slug:"kuan-yew-leong",fullName:"Kuan Yew Leong"}]},{id:"68118",doi:"10.5772/intechopen.88185",title:"Overview of Multi-Objective Optimization Approaches in Construction Project Management",slug:"overview-of-multi-objective-optimization-approaches-in-construction-project-management",totalDownloads:1158,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"The difficulties that are met in construction projects include budget issues, contractual time constraints, complying with sustainability rating systems, meeting local building codes, and achieving the desired quality level, to name but a few. Construction researchers have proposed and construction practitioners have used optimization strategies to meet various objectives over the years. They started out by optimizing one objective at a time (e.g., minimizing construction cost) while disregarding others. Because the objectives of construction projects often conflict with each other, single-objective optimization does not offer practical solutions as optimizing one objective would often adversely affect the other objectives that are not being optimized. They then experimented with multi-objective optimization. The many multi-objective optimization approaches that they used have their own advantages and drawbacks when used in some scenarios with different sets of objectives. In this chapter, a review is presented of 16 multi-objective optimization approaches used in 55 research studies performed in the construction industry and that were published in the period 2012–2016. The discussion highlights the strengths and weaknesses of these approaches when used in different scenarios.",book:{id:"8521",slug:"multicriteria-optimization-pareto-optimality-and-threshold-optimality",title:"Multicriteria Optimization",fullTitle:"Multicriteria Optimization - Pareto-Optimality and Threshold-Optimality"},signatures:"Ibraheem Alothaimeen and David Arditi",authors:[{id:"304595",title:"Dr.",name:"David",middleName:null,surname:"Arditi",slug:"david-arditi",fullName:"David Arditi"},{id:"304596",title:"Dr.",name:"Ibraheem",middleName:null,surname:"Alothaimeen",slug:"ibraheem-alothaimeen",fullName:"Ibraheem Alothaimeen"}]}],mostDownloadedChaptersLast30Days:[{id:"60097",title:"Robust Optimization: Concepts and Applications",slug:"robust-optimization-concepts-and-applications",totalDownloads:2510,totalCrossrefCites:21,totalDimensionsCites:29,abstract:"Robust optimization is an emerging area in research that allows addressing different optimization problems and specifically industrial optimization problems where there is a degree of uncertainty in some of the variables involved. 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In this paper, the basic concepts of robust optimization are developed, the different types of robustness are defined in detail, the main areas in which it has been applied are described and finally, the future lines of research that appear in this area are included.",book:{id:"6587",slug:"nature-inspired-methods-for-stochastic-robust-and-dynamic-optimization",title:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization",fullTitle:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization"},signatures:"José García and Alvaro Peña",authors:[{id:"227809",title:"Ph.D.",name:"Jose",middleName:null,surname:"Garcia",slug:"jose-garcia",fullName:"Jose Garcia"},{id:"240407",title:"Dr.",name:"Alvaro",middleName:null,surname:"Peña",slug:"alvaro-pena",fullName:"Alvaro Peña"}]},{id:"76058",title:"Ultrasonic Detection of Down Syndrome Using Multiscale Quantiser with Convolutional Neural Network",slug:"ultrasonic-detection-of-down-syndrome-using-multiscale-quantiser-with-convolutional-neural-network",totalDownloads:353,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Down Syndrome is a genetic condition that occurs when there is an extra copy of a chromosome 21 in the newly formed fetus. EIF is observed as one of the possible symptoms of DS. But in comparison to the other symptoms like nasal bone hypoplasia, increased thickness in the nuchal fold, EIF is very much less prone to DS. Hence, recommending the pregnant women with EIF to undergo the diagnostic process like amniocentesis, CVS and PUBS is not always a right choice as these diagnostic processes suffer serious drawbacks like miscarriage, uterine infections. This chapter “Ultrasonic Detection of Down Syndrome Using Multiscale Quantiser With Convolutional Neural Network” presents a new ultrasonic method to detect EIF that can cause DS. Ultrasonic Detection of Down Syndrome Using Multiscale Quantiser with Convolutional Neural Network entails two stages namely i) training phase and ii) testing phase. Training phase aims at learning the features of EIF that can cause DS whereas testing phase classifies the EIF into DS positive or DS negative based on the knowledge cluster formed during the training phase. A new algorithm Multiscale Quantiser with the convolutional neural network is used in the training phase. Enhanced Learning Vector Classifier is used in the testing phase to differentiate the normal EIF from EIF causing DS. The performance of the proposed system is analysed in terms of sensitivity, accuracy and specificity.",book:{id:"9965",slug:"computational-optimization-techniques-and-applications",title:"Computational Optimization Techniques and Applications",fullTitle:"Computational Optimization Techniques and Applications"},signatures:"Michael Dinesh Simon and A.R. 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Meta-heuristic aims to find good or near-optimal solutions at a reasonable computational cost. In this article, meta-heuristic algorithms are reviewed, such as genetic algorithm (GA) and particle swarm optimization (PSO), for traditional neural network’s training and parameter optimization. Thereafter the possibilities of applying meta-heuristic algorithms on DL training and parameter optimization are discussed.",book:{id:"5165",slug:"optimization-algorithms-methods-and-applications",title:"Optimization Algorithms",fullTitle:"Optimization Algorithms - Methods and Applications"},signatures:"Zhonghuan Tian and Simon Fong",authors:[{id:"1952",title:"Dr.",name:"Simon",middleName:null,surname:"Fong",slug:"simon-fong",fullName:"Simon Fong"},{id:"186166",title:"MSc.",name:"Zhonghuan",middleName:null,surname:"Tien",slug:"zhonghuan-tien",fullName:"Zhonghuan Tien"}]},{id:"58127",title:"Particle Swarm Optimization Solution for Power System Operation Problems",slug:"particle-swarm-optimization-solution-for-power-system-operation-problems",totalDownloads:1635,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Application of particle swarm optimization (PSO) algorithm on power system operation is studied in this chapter. Relay protection coordination in distribution networks and economic dispatch of generators in the grid are defined as two of power system-related optimization problems where they are solved using PSO. Two case study systems are conducted. The first case study system investigates applicability of PSO on providing proper overcurrent relay settings in the grid, while in the second case study system, the economic dispatch of a 15-unit system is solved where PSO successfully provides the optimum power output of generators with minimum fuel costs to satisfy the load demands and operation constraints. The simulation results in comparison with other methods show the effectiveness of PSO against other algorithms with higher quality of solution and less fuel costs on the same test system.",book:{id:"6363",slug:"particle-swarm-optimization-with-applications",title:"Particle Swarm Optimization with Applications",fullTitle:"Particle Swarm Optimization with Applications"},signatures:"Mostafa Kheshti and Lei Ding",authors:[{id:"120842",title:"Associate Prof.",name:"Mostafa",middleName:null,surname:"Kheshti",slug:"mostafa-kheshti",fullName:"Mostafa Kheshti"},{id:"213017",title:"Prof.",name:"Lei",middleName:null,surname:"Ding",slug:"lei-ding",fullName:"Lei Ding"}]},{id:"51209",title:"A Review and Comparative Study of Firefly Algorithm and its Modified Versions",slug:"a-review-and-comparative-study-of-firefly-algorithm-and-its-modified-versions",totalDownloads:2875,totalCrossrefCites:14,totalDimensionsCites:19,abstract:"Firefly algorithm is one of the well-known swarm-based algorithms which gained popularity within a short time and has different applications. It is easy to understand and implement. The existing studies show that it is prone to premature convergence and suggest the relaxation of having constant parameters. To boost the performance of the algorithm, different modifications are done by several researchers. In this chapter, we will review these modifications done on the standard firefly algorithm based on parameter modification, modified search strategy and change the solution space to make the search easy using different probability distributions. The modifications are done for continuous as well as non-continuous problems. Different studies including hybridization of firefly algorithm with other algorithms, extended firefly algorithm for multiobjective as well as multilevel optimization problems, for dynamic problems, constraint handling and convergence study will also be briefly reviewed. A simulation-based comparison will also be provided to analyse the performance of the standard as well as the modified versions of the algorithm.",book:{id:"5165",slug:"optimization-algorithms-methods-and-applications",title:"Optimization Algorithms",fullTitle:"Optimization Algorithms - Methods and Applications"},signatures:"Waqar A. Khan, Nawaf N. Hamadneh, Surafel L. Tilahun and Jean\nM. T. Ngnotchouye",authors:[{id:"180330",title:"Dr.",name:"Surafel",middleName:null,surname:"Tilahun",slug:"surafel-tilahun",fullName:"Surafel Tilahun"},{id:"180784",title:"Dr.",name:"Waqar Ahmed",middleName:null,surname:"Khan",slug:"waqar-ahmed-khan",fullName:"Waqar Ahmed Khan"},{id:"185148",title:"Dr.",name:"Nawaf",middleName:null,surname:"Hamadneh",slug:"nawaf-hamadneh",fullName:"Nawaf Hamadneh"},{id:"185149",title:"Dr.",name:"Jean M. T.",middleName:null,surname:"Ngnotchouye",slug:"jean-m.-t.-ngnotchouye",fullName:"Jean M. T. 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He collaborates with the Environmental Resources Analysis Research Group (ARAM), University of Extremadura (UEx), Spain; VALORIZA - Research Center for the Enhancement of Endogenous Resources, Polytechnic Institute of Portalegre (IPP), Portugal; Centre for Tourism Research, Development and Innovation (CITUR), Madeira, Portugal; and AQUAGEO Research Group, University of Campinas (UNICAMP), Brazil.",institutionString:"University of Johannesburg, South Africa and WSB University, Poland",institution:{name:"University of Johannesburg",institutionURL:null,country:{name:"South Africa"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:11,paginationItems:[{id:"81920",title:"Rethinking an Approach for Sustainable Globalization",doi:"10.5772/intechopen.105141",signatures:"Parakram Pyakurel",slug:"rethinking-an-approach-for-sustainable-globalization",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:null,authors:null,book:{title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg",subseries:{id:"91",title:"Sustainable Economy and Fair Society"}}},{id:"81297",title:"Legumes Cropping and Nitrogen Fixation under Mediterranean Climate",doi:"10.5772/intechopen.104473",signatures:"Fernando Teixeira",slug:"legumes-cropping-and-nitrogen-fixation-under-mediterranean-climate",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Food Systems Resilience",coverURL:"https://cdn.intechopen.com/books/images_new/10897.jpg",subseries:{id:"91",title:"Sustainable Economy and Fair Society"}}},{id:"81493",title:"Rust Disease Classification Using Deep Learning Based Algorithm: The Case of Wheat",doi:"10.5772/intechopen.104426",signatures:"Shivani Sood, Harjeet Singh and Suruchi Jindal",slug:"rust-disease-classification-using-deep-learning-based-algorithm-the-case-of-wheat",totalDownloads:40,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Food Systems Resilience",coverURL:"https://cdn.intechopen.com/books/images_new/10897.jpg",subseries:{id:"91",title:"Sustainable Economy and Fair Society"}}},{id:"81428",title:"Observatory of Sustainable Development in Postgraduate Study Programs in Baja California",doi:"10.5772/intechopen.104641",signatures:"Rodolfo Martinez-Gutierrez, Maria Marcela Solis-Quinteros, Maria Esther Ibarra-Estrada and Angel Ernesto Jimenez-Bernardino",slug:"observatory-of-sustainable-development-in-postgraduate-study-programs-in-baja-california",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Globalization and Sustainability - 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Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:249,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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