Markers used for characterization of DC subtypes in mice and men
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"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:"6086",leadTitle:null,fullTitle:"Dependability Engineering",title:"Dependability Engineering",subtitle:null,reviewType:"peer-reviewed",abstract:"The new technology and system communication advances are being employed in any system, being more complex. The system dependability considers the technical complexity, size, and interdependency of the system. The stochastic characteristic together with the complexity of the systems as dependability requires to be under control the Reliability, Availability, Maintainability, and Safety (RAMS). The dependability contemplates, therefore, the faults/failures, downtimes, stoppages, worker errors, etc. Dependability also refers to emergent properties, i.e., properties generated indirectly from other systems by the system analyzed. Dependability, understood as general description of system performance, requires advanced analytics that are considered in this book. Dependability management and engineering are covered with case studies and best practices. The diversity of the issues will be covered from algorithms, mathematical models, and software engineering, by design methodologies and technical or practical solutions. This book intends to provide the reader with a comprehensive overview of the current state of the art, case studies, hardware and software solutions, analytics, and data science in dependability engineering.",isbn:"978-1-78923-259-2",printIsbn:"978-1-78923-258-5",pdfIsbn:"978-1-83881-282-9",doi:"10.5772/68108",price:119,priceEur:129,priceUsd:155,slug:"dependability-engineering",numberOfPages:234,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"e8fbd4b0feef5494393639fa03a0f718",bookSignature:"Fausto Pedro García Márquez and Mayorkinos Papaelias",publishedDate:"June 6th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6086.jpg",numberOfDownloads:13358,numberOfWosCitations:8,numberOfCrossrefCitations:19,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:23,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:50,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 6th 2017",dateEndSecondStepPublish:"March 27th 2017",dateEndThirdStepPublish:"November 19th 2017",dateEndFourthStepPublish:"December 19th 2017",dateEndFifthStepPublish:"February 19th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",middleName:null,surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez",profilePictureURL:"https://mts.intechopen.com/storage/users/22844/images/system/22844.jpeg",biography:"Fausto Pedro García Márquez has been a full professor at the University of Castilla–La Mancha (UCLM), Spain, since 2013. He is an honorary senior research fellow at Birmingham University, UK, and a lecturer at the Postgraduate European Institute. From 2013 to 2014, Dr. Márquez was a senior manager at Accenture. He obtained his European Ph.D. with a maximum distinction. He has been awarded several prizes, including the Runner (2020) and Advancement Prizes (2018) for Management Science and Engineering Management; First International Business Ideas Competition Award (2017); Runner (2015), Advancement (2013), and Silver (2012) Prizes from the International Society of Management Science and Engineering Management (ICMSEM); and Best Paper Award, Renewable Energy (2015). He has published more than 150 papers in reputable journals. He is the author and editor of thirty-one books and five patents. He is an editor for five international journals and a committee member of more than forty international conferences. He has been the principal investigator for four European projects, six national projects, and more than 150 projects for universities and companies. His main interests are artificial intelligence, maintenance, management, renewable energy, transport, advanced analytics, and data science. He is an expert in the European Union in AI4People (EISMD), and ESF. He is also the director of the Ingenium Research Group.",institutionString:"University of Castile-La Mancha",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"11",totalChapterViews:"0",totalEditedBooks:"11",institution:{name:"University of Castile-La Mancha",institutionURL:null,country:{name:"Spain"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"200725",title:"Dr.",name:"Mayorkinos",middleName:null,surname:"Papaelias",slug:"mayorkinos-papaelias",fullName:"Mayorkinos Papaelias",profilePictureURL:"https://mts.intechopen.com/storage/users/200725/images/system/200725.jpeg",biography:"Dr Mayorkinos Papaelias (Ph.D. in Metallurgy, Chartered Engineer – Greece, Member of the Technical Chamber of Greece) is a Senior Lecturer in NDT and Condition Monitoring at the School of Metallurgy and Materials at the University of Birmingham, currently leading the NDT and Condition Monitoring Research Group. He has been involved as technical coordinator or scientific consultant in several FP6, FP7 and H2020 collaborative research projects primarily focusing on renewable energy sources and transport. Apart from the EC research projects carried out by Dr Papaelias have been funded by the EPSRC, the National Structural Integrity Research Centre, industry and UK government. He is the author or co-author of more than 110 journal and national and international conference papers in NDT and condition monitoring and has edited 3 books on the subject. He is also a Member of the International Society for Condition Monitoring, currently chairing the Education Committee. He is also a Member of the BINDT Working Group on Acoustic Emission. Dr Papaelias regularly authors articles for industrial magazines.",institutionString:"Birmingham University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Birmingham",institutionURL:null,country:{name:"United Kingdom"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"123",title:"System Engineering",slug:"system-engineering"}],chapters:[{id:"61193",title:"Introductory Chapter: Introduction to Dependability Engineering",doi:"10.5772/intechopen.77013",slug:"introductory-chapter-introduction-to-dependability-engineering",totalDownloads:973,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Fausto Pedro García Márquez and Mayorkinos Papaelias",downloadPdfUrl:"/chapter/pdf-download/61193",previewPdfUrl:"/chapter/pdf-preview/61193",authors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez"},{id:"200725",title:"Dr.",name:"Mayorkinos",surname:"Papaelias",slug:"mayorkinos-papaelias",fullName:"Mayorkinos Papaelias"}],corrections:null},{id:"57514",title:"Modeling Strategies to Improve the Dependability of Cloud Infrastructures",doi:"10.5772/intechopen.71498",slug:"modeling-strategies-to-improve-the-dependability-of-cloud-infrastructures",totalDownloads:985,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Cloud computing presents some challenges that need to be overcome, such as planning infrastructures that maintain availability when failure events and repair activities occur. Cloud infrastructure planning that addresses the dependability aspects is an essential activity because it ensures business continuity and client satisfaction. Redundancy mechanisms cold standby, warm standby and hot standby can be allocated to components of the cloud infrastructure to maintain the availability levels agreed in service level agreement (SLAs). Mathematical formalisms based on state space such as stochastic Petri nets and based on combinatorial as reliability block diagrams can be adopted to evaluate the dependability of cloud infrastructures considering the allocation of different redundancy mechanisms to its components. This chapter shows the adoption of the mathematical formalisms stochastic Petri nets and reliability block diagrams to dependability evaluation of cloud infrastructures with different redundancy mechanisms.",signatures:"Erica Teixeira Gomes de Sousa and Fernando Antonio Aires Lins",downloadPdfUrl:"/chapter/pdf-download/57514",previewPdfUrl:"/chapter/pdf-preview/57514",authors:[{id:"206249",title:"Dr.",name:"Erica",surname:"Sousa",slug:"erica-sousa",fullName:"Erica Sousa"},{id:"221478",title:"Dr.",name:"Fernando Antonio",surname:"Lins",slug:"fernando-antonio-lins",fullName:"Fernando Antonio Lins"}],corrections:null},{id:"57887",title:"Continuous Anything for Distributed Research Projects",doi:"10.5772/intechopen.72045",slug:"continuous-anything-for-distributed-research-projects",totalDownloads:988,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"International research projects involve large, distributed teams made up from multiple institutions. These teams create research artefacts that need to work together in order to demonstrate and ship the project results. Yet, in these settings the project itself is almost never in the core interest of the partners in the consortium. This leads to a weak integration incentive and consequently to last minute efforts. This in turn results in Big Bang integration that imposes huge stress on the consortium and produces only non-sustainable results. In contrast, industry has been profiting from the introduction of agile development methods backed by Continuous Delivery, Continuous Integration, and Continuous Deployment. In this chapter, we identify shortcomings of this approach for research projects. We show how to overcome those in order to adopt all three methodologies regarding that scope. We also present a conceptual, as well as a tooling framework to realise the approach as Continuous Anything. As a result, integration becomes a core element of the project plan. It distributes and shares responsibility of integration work among all partners, while at the same time clearly holding individuals responsible for dedicated software components. Through a high degree of automation, it keeps the overall integration work low, but still provides immediate feedback on the quality of the software. Overall, we found this concept useful and beneficial in several EU-funded research projects, where it significantly lowered integration effort and improved quality of the software components while also enhancing collaboration as a whole.",signatures:"Simon Volpert, Frank Griesinger and Jörg Domaschka",downloadPdfUrl:"/chapter/pdf-download/57887",previewPdfUrl:"/chapter/pdf-preview/57887",authors:[{id:"207473",title:"Dr.",name:"Jörg",surname:"Domaschka",slug:"jorg-domaschka",fullName:"Jörg Domaschka"},{id:"207474",title:"MSc.",name:"Frank",surname:"Griesinger",slug:"frank-griesinger",fullName:"Frank Griesinger"},{id:"207475",title:"BSc.",name:"Simon",surname:"Volpert",slug:"simon-volpert",fullName:"Simon Volpert"}],corrections:null},{id:"56668",title:"Software Fault Injection: A Practical Perspective",doi:"10.5772/intechopen.70427",slug:"software-fault-injection-a-practical-perspective",totalDownloads:1702,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Software fault injection (SFI) is an acknowledged method for assessing the dependability of software systems. After reviewing the state-of-the-art of SFI, we address the challenge of integrating it deeper into software development practice. We present a well-defined development methodology incorporating SFI—fault injection driven development (FIDD)—which begins by systematically constructing a dependability and failure cause model, from which relevant injection techniques, points, and campaigns are derived. We discuss possibilities and challenges for the end-to-end automation of such campaigns. The suggested approach can substantially improve the accessibility of dependability assessment in everyday software engineering practice.",signatures:"Lena Feinbube, Lukas Pirl and Andreas Polze",downloadPdfUrl:"/chapter/pdf-download/56668",previewPdfUrl:"/chapter/pdf-preview/56668",authors:[{id:"206579",title:"M.Sc.",name:"Lena",surname:"Feinbube",slug:"lena-feinbube",fullName:"Lena Feinbube"},{id:"207021",title:"Prof.",name:"Andreas",surname:"Polze",slug:"andreas-polze",fullName:"Andreas Polze"},{id:"210445",title:"M.Sc.",name:"Lukas",surname:"Pirl",slug:"lukas-pirl",fullName:"Lukas Pirl"}],corrections:null},{id:"60190",title:"Stochastic Reward Net-based Modeling Approach for Availability Quantification of Data Center Systems",doi:"10.5772/intechopen.74306",slug:"stochastic-reward-net-based-modeling-approach-for-availability-quantification-of-data-center-systems",totalDownloads:1245,totalCrossrefCites:5,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Availability quantification and prediction of IT infrastructure in data centers are of paramount importance for online business enterprises. In this chapter, we present comprehensive availability models for practical case studies in order to demonstrate a state-space stochastic reward net model for typical data center systems for quantitative assessment of system availability. We present stochastic reward net models of a virtualized server system, a data center network based on DCell topology, and a conceptual data center for disaster tolerance. The systems are then evaluated against various metrics of interest, including steady state availability, downtime and downtime cost, and sensitivity analysis.",signatures:"Tuan Anh Nguyen, Dugki Min and Eunmi Choi",downloadPdfUrl:"/chapter/pdf-download/60190",previewPdfUrl:"/chapter/pdf-preview/60190",authors:[{id:"23044",title:"Prof.",name:"Dugki",surname:"Min",slug:"dugki-min",fullName:"Dugki Min"},{id:"23045",title:"Prof.",name:"Eunmi",surname:"Choi",slug:"eunmi-choi",fullName:"Eunmi Choi"},{id:"226196",title:"Prof.",name:"Tuan Anh",surname:"Nguyen",slug:"tuan-anh-nguyen",fullName:"Tuan Anh Nguyen"}],corrections:null},{id:"58392",title:"Reliability and Aging Analysis on SRAMs Within Microprocessor Systems",doi:"10.5772/intechopen.72779",slug:"reliability-and-aging-analysis-on-srams-within-microprocessor-systems",totalDownloads:993,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The majority of transistors in a modern microprocessor are used to implement static random access memories (SRAM). Therefore, it is important to analyze the reliability of SRAM blocks. During the SRAM design, it is important to build in design margins to achieve an adequate lifetime. The two main wearout mechanisms that increase a transistor’s threshold voltage are bias temperature instability (BTI) and hot carrier injections (HCI). BTI and HCI can degrade transistors’ driving strength and further weaken circuit performance. In a microprocessor, first-level (L1) caches are frequently accessed, which make it especially vulnerable to BTI and HCI. In this chapter, the cache lifetimes due to BTI and HCI are studied for different cache configurations, namely, cache size, associativity, cache line size, and replacement algorithm. To give a case study, the failure probability (reliability) and the hit rate (performance) of the L1 cache in a LEON3 microprocessor are analyzed, while the microprocessor is running a set of benchmarks. Essential insights can be provided from our results to give better performance-reliability tradeoffs for cache designers.",signatures:"Taizhi Liu, Chang-Chih Chen and Linda Milor",downloadPdfUrl:"/chapter/pdf-download/58392",previewPdfUrl:"/chapter/pdf-preview/58392",authors:[{id:"209988",title:"Dr.",name:"Taizhi",surname:"Liu",slug:"taizhi-liu",fullName:"Taizhi Liu"},{id:"216579",title:"Dr.",name:"Chang-Chih",surname:"Chen",slug:"chang-chih-chen",fullName:"Chang-Chih Chen"},{id:"216580",title:"Dr.",name:"Linda",surname:"Milor",slug:"linda-milor",fullName:"Linda Milor"}],corrections:null},{id:"58523",title:"Advances in Engineering Software for Multicore Systems",doi:"10.5772/intechopen.72784",slug:"advances-in-engineering-software-for-multicore-systems",totalDownloads:1085,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The vast amounts of data to be processed by today’s applications demand higher computational power. To meet application requirements and achieve reasonable application performance, it becomes increasingly profitable, or even necessary, to exploit any available hardware parallelism. For both new and legacy applications, successful parallelization is often subject to high cost and price. This chapter proposes a set of methods that employ an optimistic semi-automatic approach, which enables programmers to exploit parallelism on modern hardware architectures. It provides a set of methods, including an LLVM-based tool, to help programmers identify the most promising parallelization targets and understand the key types of parallelism. The approach reduces the manual effort needed for parallelization. A contribution of this work is an efficient profiling method to determine the control and data dependences for performing parallelism discovery or other types of code analysis. Another contribution is a method for detecting code sections where parallel design patterns might be applicable and suggesting relevant code transformations. Our approach efficiently reports detailed runtime data dependences. It accurately identifies opportunities for parallelism and the appropriate type of parallelism to use as task-based or loop-based.",signatures:"Ali Jannesari",downloadPdfUrl:"/chapter/pdf-download/58523",previewPdfUrl:"/chapter/pdf-preview/58523",authors:[{id:"232074",title:"Dr.",name:"Ali",surname:"Jannesari",slug:"ali-jannesari",fullName:"Ali Jannesari"}],corrections:null},{id:"57619",title:"Modeling Quality of Service Techniques for Packet-Switched Networks",doi:"10.5772/intechopen.71499",slug:"modeling-quality-of-service-techniques-for-packet-switched-networks",totalDownloads:933,totalCrossrefCites:5,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Quality of service is the ability to provide different priorities to different applications, users or dataflows, or to guarantee a certain level of performance to a dataflow. The chapter uses timed Petri nets to model techniques that provide the quality of service in packet-switched networks and illustrates the behavior of developed models by performance characteristics of simple examples. These performance characteristics are obtained by discrete-event simulation of analyzed models.",signatures:"Wlodek M. Zuberek and Dariusz Strzeciwilk",downloadPdfUrl:"/chapter/pdf-download/57619",previewPdfUrl:"/chapter/pdf-preview/57619",authors:[{id:"146442",title:"Dr.",name:"Wlodek",surname:"Zuberek",slug:"wlodek-zuberek",fullName:"Wlodek Zuberek"},{id:"211502",title:"Dr.",name:"Dariusz",surname:"Strzeciwilk",slug:"dariusz-strzeciwilk",fullName:"Dariusz Strzeciwilk"}],corrections:null},{id:"58120",title:"Discretization of Random Fields Representing Material Properties and Distributed Loads in FORM Analysis",doi:"10.5772/intechopen.71500",slug:"discretization-of-random-fields-representing-material-properties-and-distributed-loads-in-form-analy",totalDownloads:944,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The reliability analysis of more complicated structures usually deals with the finite element method (FEM) models. The random fields (material properties and loads) have to be represented by random variables assigned to random field elements. The adequate distribution functions and covariance matrices should be determined for a chosen set of random variables. This procedure is called discretization of a random field. The chapter presents the discretization of random field for material properties with the help of the spatial averaging method of one-dimensional homogeneous random field and midpoint method of discretization of random field. The second part of the chapter deals with the discretization of random fields representing distributed loads. In particular, the discretization of distributed load imposed on a Bernoulli beam is presented in detail. Numerical example demonstrates very good agreement of the reliability indices computed with the help of stochastic finite element method (SFEM) and first-order reliability method (FORM) analyses with the results obtained from analytical formulae.",signatures:"Ireneusz Czmoch",downloadPdfUrl:"/chapter/pdf-download/58120",previewPdfUrl:"/chapter/pdf-preview/58120",authors:[{id:"207743",title:"Dr.",name:"Ireneusz",surname:"Czmoch",slug:"ireneusz-czmoch",fullName:"Ireneusz Czmoch"}],corrections:null},{id:"58612",title:"Energy Savings in EAF Steelmaking by Process Simulation and Data-Science Modeling on the Reproduced Results",doi:"10.5772/intechopen.72780",slug:"energy-savings-in-eaf-steelmaking-by-process-simulation-and-data-science-modeling-on-the-reproduced-",totalDownloads:1106,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Electric-Arc-Furnace (EAF)-based process route in modern steelmaking for the production of plates and special quality bars requires a series of stations for the secondary metallurgy treatment (Ladle-Furnace, and potentially Vacuum-Degasser), till the final casting for the production of slabs and blooms in the corresponding continuous casting machines. However, since every steel grade has its own melting characteristics, the melting (liquidus) temperature per grade is generally different and plays an important role in the final casting temperature, which has to exceed by somewhat the melting temperature by an amount called superheat. The superheat is adjusted at the ladle-furnace (LF) station by the operator who decides mostly on personal experience but, since the ladle has to pass from downstream processes, the liquid steel loses temperature not only due to the duration of the processes till casting but also due to the ladle refractory history. Simulation software was developed in order to reproduce the phenomena involved in a meltshop and influence downstream superheats. Data science models were deployed in order to check the potential of controlling casting temperatures by adjusting liquid-steel exit temperatures at LF.",signatures:"Panagiotis Sismanis",downloadPdfUrl:"/chapter/pdf-download/58612",previewPdfUrl:"/chapter/pdf-preview/58612",authors:[{id:"35901",title:"Dr.",name:"Panagiotis",surname:"Sismanis",slug:"panagiotis-sismanis",fullName:"Panagiotis Sismanis"}],corrections:null},{id:"61341",title:"Use of Renewable Energy for Electrification of Rural Community to Stop Migration of Youth from Rural Area to Urban: A Case Study of Tanzania",doi:"10.5772/intechopen.74956",slug:"use-of-renewable-energy-for-electrification-of-rural-community-to-stop-migration-of-youth-from-rural",totalDownloads:1512,totalCrossrefCites:2,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Rural electrification is the key in developing countries to encourage youth and skilled personnel to stay in rural for production activities. Lack of grid network in Tanzania currently discourages youth and skilled personnel to live in rural areas. Tanzania has diverse renewable energy which needs to be developed for electricity generation. Most of these sources are found in rural areas but they are not developed and grid network are not extended because of low population density. The government has put in place policy which encourages small power producers to develop renewable energy resources. Energy produced would be sold to the community directly or to the government owned company for grid integration. This paper discussed three major renewable energy sources such as wind, solar and hydro power. Electrifying rural areas will encourage youth to reside in their communities and engaging themselves in production activities like farming and livestock keeping. Also communication among communities and networks between rural - urban would be improved. Establishment of small industries would lead more farm products and earn more money. Therefore, the strong links between rural - urban communities would be strengthened; hence youth migration would be stopped naturally.",signatures:"Urbanus F Melkior, Josef Tlustý and Zdeněk Müller",downloadPdfUrl:"/chapter/pdf-download/61341",previewPdfUrl:"/chapter/pdf-preview/61341",authors:[{id:"216197",title:"Dr.",name:"Zdenek",surname:"Muller",slug:"zdenek-muller",fullName:"Zdenek Muller"},{id:"216199",title:"Prof.",name:"Josef",surname:"Tlusty",slug:"josef-tlusty",fullName:"Josef Tlusty"},{id:"235183",title:"Mr.",name:"Urbanus F.",surname:"Melkior",slug:"urbanus-f.-melkior",fullName:"Urbanus F. Melkior"}],corrections:null},{id:"57878",title:"Time Series and Renewable Energy Forecasting",doi:"10.5772/intechopen.71501",slug:"time-series-and-renewable-energy-forecasting",totalDownloads:895,totalCrossrefCites:2,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Reliability is a key important criterion in every single system in the world, and it is not different in engineering. Reliability in power systems or electric grids can be generally defined as the availability time (capable of fully supplying the demand) of the system compared to the amount of time it is unavailable (incapable of supplying the demand). For systems with high uncertainties, such as renewable energy based power systems, achieving a high level of reliability is a formidable challenge due to the increased penetrations of the intermittent renewable sources such as wind and solar. A careful and accurate planning is at the utmost importance to achieve high reliability in renewable energy based systems. This chapter will assess wind-based power system’s reliability issues, and provide a case study that proposes a solution to enhance the reliability of the system.",signatures:"Mahmoud Ghofrani and Anthony Suherli",downloadPdfUrl:"/chapter/pdf-download/57878",previewPdfUrl:"/chapter/pdf-preview/57878",authors:[{id:"183482",title:"Dr.",name:"Mahmoud",surname:"Ghofrani",slug:"mahmoud-ghofrani",fullName:"Mahmoud Ghofrani"},{id:"216997",title:"Mr.",name:"Anthony",surname:"Suherli",slug:"anthony-suherli",fullName:"Anthony Suherli"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"120",title:"Digital Filters",subtitle:null,isOpenForSubmission:!1,hash:"10692f498575728ddac136b0b327a83d",slug:"digital-filters",bookSignature:"Fausto Pedro García Márquez",coverURL:"https://cdn.intechopen.com/books/images_new/120.jpg",editedByType:"Edited 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\r\n\tThe book aims to collect the state of the art of techniques and technologies for monitoring lentic and lotic environments so important for the ecological role they perform.
\r\n\r\n\tThe knowledge relating to the chemical, physical and biological characteristics of the still or slow-moving waters - the so-called "lentic environments": lakes, swamps, ponds - but also fresh and salty waters, are to be deepened. Contributions related to their interaction with lotic waters - streams, rivers - will also be well appreciated. All those elements useful to represent the quality of these environments will be considered and treated also in relation to the ecological role they play.
\r\n\r\n\tStudies based on observations made and aimed at forecasting transformations (understood as the evolution of environments over time) will be collected. We also want to collect contributions relating to the influence of the surrounding environment such as those due to human disturbance or even to causes of natural origin. In addition, also studies relating to the management of inland waters and related indicators to identify the more common problems of pollution. Finally, we also want to collect contributions relating to best practices (the most significant experiences, procedures, actions, or in any case those that have allowed the best results to be obtained in relation to the conservation of these environments) through intelligent, low-cost systems.
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It has long been assumed that atherogenesis could be simply explained by lipid accumulation in the vessel wall leading to endothelial dysfunction with adverse vascular wall remodelling. However, over the last decade, a number of studies have clearly demonstrated that lipids are not the whole story in the pathogenesis of atherosclerosis. Accumulating evidence has shown that inflammation and the immune system play a major role in the initiation, progression and destabilization of atheromata [1,2,3,4]. Mainly innate immunity pathways have long been believed to contribute to atherogenesis, and special attention has been given to macrophages, because these effector cells are important for intracellular lipid accumulation and foam cell formation [5]. Yet, although macrophages constitute the largest cell population, other immune cell subsets, namely dendritic cells (DCs) and T cells, can also be found within atherosclerotic plaques and seem to participate in immune responses during atherogenesis.
DCs are the pacemakers of the immune system. These professional antigen-presenting cells play a key role in inducing adaptive immune responses on the one hand, and are critically involved in promoting and maintaining immune tolerance on the other [6]. They originate from hematopoietic stem cells in the bone marrow and circulate as precursors in the blood stream, taking residence in target tissues at sites of potential antigen entry. Within blood vessels [7] and other tissues, they give rise to immature interstitial DCs that act as sentinels, which continuously and efficiently sample the antigenic content of their microenvironment. In the steady state, immature DCs capture harmless self-antigens in the absence of inflammatory signals. They might enter the regional lymph nodes to present the self-antigen to naïve or resting T cells, which will be deleted by apoptosis, silenced by the induction of anergy or primed to become regulatory T cells [8]. In contrast, when infection and tissue damage occur, immature DCs take up antigens in the presence of inflammatory signals, which evokes activation and functional transformation into mature DCs. Meanwhile, they exit the non-lymphoid tissues to migrate via afferent lymph vessels to lymphoid tissues, where they completely mature. Mature DCs present short peptide fragments, which are bound to the surface molecules CD1 or major histocompatibility complex (MHC)-I or MHC-II. Consequently, they activate (naïve) T and B lymphocytes that recognize the presented antigen [9]. Morphological changes occur as well during the DC life cycle: DC precursors are often small, round-shaped cells that turn into larger cells with an irregular (star-like) shape and cytoplasmic protrusions (dendrites) as the cell matures, while migrating DCs are also called veiled cells, as they possess large cytoplasmic \'veils\' rather than dendrites [10].
Following the first observation of DCs in human arteries in 1995 [11], numerous studies suggest that these cells presumably play a crucial role in directing innate or adaptive immunity against altered self-antigens present in atherosclerosis. Localization of DCs nearby vasa vasorum allows monitoring of the major access pathways to the vessel wall and screening of the tissue environment for the appearance of exogenous and endogenous stressors [12]. Once sufficiently activated, DCs in the arterial wall might present the (modified auto-) antigens, such as oxidized epitopes on apoptotic cells, oxidized low density lipoproteins (oxLDL) or heat shock proteins (Hsp) to T cells and initiate inflammatory responses.
Many (auto-)antigens are involved in atherogenesis, both endogenous and exogenous. Here, we summarize some of the best-studied endogenous self-antigens in relation to DC function.
OxLDL is one of the best-studied antigens in atherogenesis. It is considered as a ‘neoantigen’, i.e. a self-antigen that has the potential to provoke an auto-immune response upon modification, but that is tolerated by the immune system in its normal (unmodified) form [13]. It has already been shown that oxLDL can induce differentiation of monocytes into phenotypically abnormal cells, when it is added to monocytes during the early stages of differentiation [14]. These cells have functional characteristics of DCs, such as decreased endocytosis capacity, increased ability to stimulate T cell proliferation and secretion of IL-12, but not IL-10. These findings were consistent with our own study (unpublished data), which showed that monocytes differentiated (at least partly) into DCs, when they were incubated with oxLDL. This was evidenced by a pronounced decrease in the expression of CD14, a typical monocyte/macrophage marker, and increased expression of CD1a, which is mainly expressed on cortical thymocytes and DCs, and CCR-6, a receptor for CCL20 that is expressed by resting T cells and DCs (figure 1).
Apart from the induction of monocyte differentiation into DCs, oxLDL can also activate DCs, as demonstrated by several
Cell morphology pointed to DC maturation as well: oxLDL-stimulated monocyte-derived DCs became more elongated and were arranged in clusters, when compared to unstimulated monocyte-derived DCs. The arrangement in clusters was also more pronounced when cells were stimulated with 50 µg/mL oxLDL as compared to cells stimulated with the lower concentration of oxLDL (10 µg/mL) (figure 4; own unpublished data). Alderman et al. [15] compared the effects of mildly, moderately and highly oxidized LDL and reported a significant upregulation of DC activation markers, including HLA-DR, CD40 and CD86 when cells were incubated with highly oxidized LDL. Furthermore, highly oxidized LDL increased DC-induced T cell proliferation. However, high concentrations of highly oxidized LDL (100 µg/mL) inhibited DC function through increased DC apoptosis [15]. In contrast, another study demonstrated that oxLDL did not trigger maturation of immature DCs [14]. This seems to be a discrepancy, but can easily be explained by a concentration-dependent effect of oxLDL. Perrin-Cocon and colleagues [14] varied the oxLDL concentrations between 2.5-10.0 µg/mL, which could have been insufficient to obtain monocyte-derived DC maturation. Also Zaguri et al. [16] observed no effect of 10 µg/mL oxLDL on CD86, CD83, and CCR-7 expression on DCs, whereas all those activation markers were upregulated with higher concentrations of oxLDL (50-100 µg/mL). Finally, Nickel et al. [17] reported maturation and differentiation of DCs by 10 µg/mL, but he investigated other phenotypic outcomes, such as the expression of scavenger receptors LOX1 and CD36, the mannose receptor CD205 and the activation of the nuclear factor kappa B (NF-κB) pathway.
Beta2-glycoprotein I (β2-GPI) is a plasma protein involved in the haemostatic system that has been detected in carotid atherosclerotic lesions [18]. A previous study in mice showed that the transfer of lymphocytes obtained from β2-GPI-immunized LDLr-/- mice into syngeneic mice resulted in larger fatty streaks within the recipients compared with mice that received lymphocytes from control mice [19]. From that study, it appeared that T cells specific for β2-GPI are able to increase atherosclerosis, suggesting that β2-GPI is a target auto-antigen in atherosclerosis [19].
Another category of auto-antigens that have been implicated in atherosclerosis are the stress-induced heat shock proteins (HSPs) [22]. HSPs are responsible for the repair or degradation of denatured proteins and, by maintaining protein conformation, they enhance the cell’s ability to survive under conditions of metabolic or oxidative stress [23]. The mRNA expression level of several HSPs, including HSP40 and HSP70, has been shown to be significantly increased in carotid endarterectomy specimens as compared to healthy arteries [24]. HSP70 seems to be homogenously distributed throughout the intima and media in healthy aortas, and a strong increase in its immunostaining intensity is observed in aortic atherosclerotic plaques [25]. They appear to stimulate an immune response leading to the development and progression of atherosclerosis [26]. A number of studies indicate that HSPs are associated with DC function and might trigger DC activation and maturation. DCs seem to overexpress HSP70 in atherosclerotic plaques and the latter protein is presumably an important trigger for DC activation [27]. Gp96 (of the HSP90 family) and HSP70 have indeed been shown to stimulate bone marrow-derived DCs
Atherosclerosis is a disease that is associated with strong oxidative stress, and the creation of neo-epitopes is one of the consequences of this situation. As mentioned in section 2, the presence of reactive oxygen species (ROS) in atherosclerotic plaques may lead to the formation of oxLDL and oxidized β2-GPI, which might affect DC phenotype and function. Indeed, oxidative stress has been shown to alter the capacity of antigen-presenting cells to process antigens and to initiate a primary T-cell response. In this respect, it is interesting to unravel whether DCs show phenotypic adaptations in order to function under oxidative stress situations. In a recent study, we demonstrated that DCs appear to be resistant to the detrimental effects of oxidative stress. We showed by confocal live cell imaging that monocyte-derived DCs, which were generated as described earlier [31], were better capable of neutralizing ROS induced by tertiary-butylhydroperoxide (
As discussed above, DCs process and present self and foreign antigens to T cells and are therefore important inducers of adaptive immune responses. However, ‘the’ DC does not exist, as DCs comprise a network of subsets that are phenotypically, functionally, and developmentally distinct [40,41]. It is essential to understand the diversity in DC subtypes to target DCs for immunomodulating therapies. Most studies on DC subsets have been performed in mice, because lymphoid tissue is easier to obtain from mice than from humans. Mature mouse DCs are identified based on their expression of the integrin alpha X chain CD11c, the costimulatory molecules CD40, CD80 and CD86, and high surface levels of the antigen-presenting molecule MHC II [42,43,40]. The T cell markers CD4 and CD8 (in the form of a αα-homodimer) are also expressed on mouse DCs, and can be used to distinguish different subtypes [44]. In general, three DC subsets can be characterized in mouse lymphoid tissue (table 1): 1) CD8α+ CD4- DCs; 2) CD8α- CD4+ DCs; and 3) CD8α- CD4- DCs [44]. The CD8α+ CD4- DCs are mainly localized in the T cell areas of lymphoid organs, whereas the CD8α- CD4+ DCs are found in the marginal zones. Yet, upon stimulation by microbial products, such as lipopolysaccharide, the latter can also migrate to the T cell zones [45,46]. Other markers that can be used to further subdivide mouse DC subsets include the integrin alpha M chain CD11b and the endocytosis receptor CD205 (DEC205). The CD8α+ CD4- DCs are also CD205+ CD11b- and they are mainly present in the thymus, and at moderate levels in lymph nodes [40]. Lymph nodes further contain, in contrast to spleen, CD8α- CD4- CD11b+ CD205mid DCs which are considered as the mature form of tissue interstitial DCs [40,42,43] (table 1). Another DC subtype, which is langerinhigh CD11b+ CD8αlow CD205high, is only found in skin-draining lymph nodes and considered as the mature form of epidermal Langerhans cells. These cells are also positive for MHC II and CD40, CD80 and CD86, suggesting that they are fully activated [42].
The numerous DC subtypes in mouse lymphoid organs are all able to present antigens to T cells, however, they differ in other aspects of DC-T cell communication [40]. CD8α+ DCs mainly induce Th1/Th17-polarizing cytokine responses in CD4+ effector T cells, whereas CD8α- DCs are able to induce Th2-biased cytokine responses [47,48,49,50]. CD8α+ DCs also seem to be specialized for the uptake and cross-presentation of exogenous antigens on MHC I and consequently stimulate CD8+ cytotoxic T cells, whereas CD8α- DCs mainly stimulate CD4+ T helper cells [51,52].
It has to be noticed that the association between mouse and human DC subsets remains elusive, making translation of the above-mentioned findings difficult. One of the major barriers in comparing mouse and human DC subsets is the lack of CD8α expression on human DCs [53]. As a result, it remains unclear which subtype represents the human equivalent of mature mouse CD8α+ DCs. Another important barrier is that most human studies are performed on blood, due to the limited availability of human spleen tissue. Moreover, human blood DCs are mainly immature and heterogeneous in their expression of a range of markers. It might be that part of the heterogeneity reflects differences in the maturation or activation state of DCs, rather than that they all represent separate sub-lineages. Yet, one subtype that is similar to its mouse counterpart is the human Langerhans cell, which expresses CD1a and langerin and is characterized by the presence of Birbeck granules [40].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|
\n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
cDCs | \n\t\t\tlymphoid organ-resident cDC | \n\t\t\tCD8α+ CD4- CD205+ CD11b-\n\t\t\t | \n\t\t\tlineage- HLA-DR+ CD11c+ CD1b/c+\n\t\t\t | \n\t\t
CD8α- CD4+\n\t\t\t | \n\t\t\tlineage- HLA-DR+ CD11c+ CD141+\n\t\t\t | \n\t\t||
CD8α- CD4- CD205mid CD11b+\n\t\t\t | \n\t\t\tlineage- HLA-DR+ CD11c+ CD16+\n\t\t\t | \n\t\t||
circulating cDC | \n\t\t\tCD8α- CD11b+ CD11chigh\n\t\t\t | \n\t\t\tCD1c+ CD11c+\n\t\t\t | \n\t\t|
CD8α+ CD205+ CD11c+\n\t\t\t | \n\t\t\tCD141+ CD11c+ XCR1+\n\t\t\t | \n\t\t||
pDCs | \n\t\t\tlymphoid organ-resident pDC | \n\t\t\t\n\t\t\t | CD11c- CD304+\n\t\t\t | \n\t\t
circulating pDC | \n\t\t\tPDCA-1+ CD11c+ CD11b-\n\t\t\t | \n\t\t\tCD303+ CD304+ CD123+\n\t\t\t | \n\t\t|
\n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|
Activated (mature) DCs | \n\t\t\tCostimulatory molecules | \n\t\t\tCD40 CD80 CD86 | \n\t\t|
Activation molecules | \n\t\t\tCD83 | \n\t\t
Markers used for characterization of DC subtypes in mice and men
cDC = conventional dendritic cell, pDC = plasmacytoid dendritic cell
lineage = cocktail of CD3, CD14, CD16, CD19, CD20, CD56; CD1c = BDCA-1; CD303 = BDCA-2; CD141 = BDCA-3; CD304 = BDCA-4
BDCA = blood dendritic cell antigen
In human blood, the first made classification is often the distinction between plasmacytoid (p)DCs, and myeloid or conventional DCs (cDCs) (table 1). Freshly isolated pDCs resemble plasma cells and have a morphology typical of that of large, round cells with a diffuse nucleus and few dendrites. These type I IFN-producing cells (IPCs) are specialized in innate antiviral immune responses by producing copious amounts of type I interferons. pDCs express CD303 (blood dendritic cell antigen (BDCA) 2), CD304 (BDCA 4) and CD123 (IL 3Rα), whereas cDCs are characterized by their expression of CD1c (BDCA 1) and CD11c [54] (table 1). In addition, pDCs and cDCs also express different sets of Toll-like receptors (TLRs). In brief, pDCs express mainly TLR7 and TLR9, whereas cDCs exhibit strong expression of TLR1, TLR2, TLR3, TLR4, and TLR8. Accordingly, pDCs mainly recognize viral components with subsequent production of a large amount of IFN-α. In contrast cDCs recognize bacterial components and produce pro-inflammatory cytokines such as IL-12p70, TNF-α, and IL-6 [54,7].
Furthermore, cDCs and pDCs also differ in migration behaviour. Generally it is assumed that myeloid (m)DCs are the conventional DCs that infiltrate peripheral tissues, while pDCs migrate directly from the blood into lymphoid organs [54]. Finally, a small third population of blood DCs expressing CD11c and BDCA-3 (CD141) but not BDCA-1, CD123 or BDCA-2 can be distinguished (table 1). Of particular importance is their superior antigen cross-presentation capacity and expression of the XC chemokine receptor 1 (XCR1), suggesting that they represent the human counterpart of mouse CD8α+ DCs. They emerge as a distinctive myeloid DC subset that is characterized by high expression of TLR3, production of IL-12 and IFN-β, and a superior capacity to induce T helper-1 cell responses, when compared to BDCA-1+ mDCs [54,7].
Only in a few recent studies, human DCs have been isolated from lymphoid tissues, which allow direct comparison with mouse DC subtypes. Mittag and colleagues [41] identified four DC subsets in human spleen that resemble DCs found in human blood. These include three cDC subtypes and one pDC subtype (table 1). The cDCs are all negative for lineage markers and positive for HLA-DR and CD11c, and they differ in their expression of CD1b/c (= BDCA-1), CD141 (= BDCA-3) and CD16. The pDCs express high levels of CD304 (= BDCA-4), but not CD11c [41]. Moreover, the hallmark functions of mouse CD8α+ DC subsets, which include IL-12p70 secretion and cross-presentation, appeared to be not restricted to the equivalent human CD141+ cDCs as thought earlier, but shared by CD1b/c+ and CD16+ DC subsets [41].
It has become clear that DCs, especially DCs from myeloid origin, are very heterogeneous, representing several subtypes with a common origin, but different anatomical locations (lymphoid organs vs. non-lymphoid organs), function and phenotype. Moreover, there is also a very close relationship between myeloid DCs and macrophages (figure 5).
The distinction of the differences between macrophages and the heterogeneous family of DCs is notoriously difficult and complicated by the plasticity of both cell types [55]. Monocytes that exit the blood and enter tissues under inflammatory conditions can differentiate to macrophages, but also to DCs that share several phenotypic features and functions, making it difficult to unambiguously define macrophages and DCs as individual entities [56]. In addition, resting peripheral monocytes, obtained from mouse peritoneal cavity lavage, represent an immature population, capable of further differentiation along either the dendritic or the macrophage pathway, depending on the type of stimuli (cytokines, growth factors) they receive [10]. Furthermore, many DC subsets are not clearly defined and it is absolutely necessary to bear in mind that different groups use different methods to identify and characterize DCs [57]. Often, the starting populations are preselected based on randomly defined expression levels of markers that were believed to be specific for either DCs or macrophages, but are in fact expressed by both [58] (figure 5).
Functional characteristics and surface markers of DCs and macrophages. Increasing evidence demonstrates an enormous overlap between what is considered a \'macrophage\' and a ‘DC\'.
Consequently, confusion in distinguishing between macrophages and DCs has been – at least in part – caused by the use of nonspecific cell surface markers, such as CD11c. In addition, the number of DC and macrophage subpopulations that can be defined is an exponential function of the number of markers that has been examined [59]. Moreover, since each gene/protein has its own intrinsic expression level, the heterogeneity is really unlimited [60]. CD11c, a commonly used DC marker, was already known to be expressed by most tissue macrophages before the use of CD11c-reporter transgenes as markers of DCs, and of CD11c-DTR mice to ‘selectively’ deplete them [59,61]. Other markers that have been used to track macrophages and DCs in mice include F4/80, CD11b and MHC II, but they have also turned out to be nonspecific [57]. Too little attention has been paid to the expression of antimicrobial effector molecules, such as lysozyme, which is highly secreted by monocytes and macrophages, but only weakly expressed, if at all, by DCs [62]. Part of the confusion may also result from the flexibility and plasticity of macrophages and from the presence of resident and migratory activated DCs in the same organ [63].
The confusion could be possibly resolved if the appropriate reflections are considered [57]. For example, the correctness of CD11c to identify DCs depends on the anatomical site in question. In the spleen and lymph nodes, mononuclear phagocytes with high expression levels of CD11c – though not those with low or intermediate CD11c – appear to be DCs rather than macrophages. Accumulating evidence confirms that spleen and lymph node DCs are functionally different from macrophages, do not originate from differentiating monocytes, and share fewer characteristics with monocytes than macrophages [64,65,66]. However, in the lung, high levels of CD11c are expressed on macrophages [67,68], and there are many other anatomical locations apart from the lymphoid organs where macrophages are CD11c-positive. It has been proposed many times that the same set of markers that allows us to discriminate between DCs and macrophages in lymphoid organs, can also be used in non-lymphoid organs, but it has become clear that this assumption is not correct.
Recent
If the distinction between DCs and macrophages cannot be made based on morphological features, can it be based on function? Several criteria to define DCs include the property of DCs to localize in the T cell zone of lymphoid organs where they can stimulate T cells, as well as their ability to migrate and carry antigen [72,73]. In contrast, macrophages are best defined by their phagocytic activity and are generally considered as tissue-resident cells. However, recent studies show that macrophages can also migrate and that Langerhans cells (i.e. DCs from the skin and mucosa that carry large Birbeck granules) are not important for T cell priming [74]. In addition, some macrophage subtypes, such as microglia, show only poor phagocytic capacity [57]. Taken together, there is no good functional criterion to define macrophages and monocyte-derived DCs (figure 5), since they represent not just two different cell populations, but various cell subtypes. As they are derived from a common precursor, it is really hard to fully identify macrophages and DCs as two separate entities.
We and others discovered a profoundly altered circulating DC compartment in patients with coronary artery disease (CAD), the clinical manifestation of atherosclerosis, as compared to healthy donors [75,76,77,78,79,80]. In 2006, we reported for the first time a decrease in circulating DC precursors (BDCA-1+ mDCs, BDCA-2+ pDCs) in CAD patients by flow cytometry. CAD was determined by angiography and defined as more than 50% stenosis in one or more coronary arteries [77]. In parallel, Yilmaz et al. [79] found a marked reduction in mDC precursors in CAD patients, though the decline in pDCs was less pronounced. Next, we studied whether the lower blood DC counts in CAD patients were related to the extent of atherosclerosis (one- versus three-vessel disease) or type (stable versus unstable angina pectoris) of CAD. Again, we observed significantly lower relative and absolute numbers of pDCs and mDCs in patients with coronary atherosclerosis [78]. Interestingly, the overall lineage-negative HLA-DR-positive blood DCs, which also include other blood DCs (such as BDCA-3+) or more mature blood DCs, confirmed the decline of BDCA+ DC precursors. However, the counts of circulating DCs dropped to the same extent in three groups of CAD patients, irrespective of the number (one or three) of affected arteries or the type (stable or unstable) of angina [78]. Consistent with our results, Yilmaz and colleagues [79] reported no differences between clinically stable or unstable CAD. Yet, in a later and more extended study with a cohort of 290 patients, in which a more refined ‘CAD score’ was used to classify patients, they found that the numbers of pDCs, mDCs, and total DCs decreased when the extent of coronary atherosclerosis increased [80].
Besides flow cytometric studies, we performed immunohistochemical analyses demonstrating increased intimal DC counts with evolving plaque stages, in close relationship with lesional T cells [81]. These findings strongly suggest that blood DCs migrate from the circulation to the atherosclerotic lesion, possibly attracted by chemokines produced by the inflammatory infiltrate in the plaque, and subsequently stimulate T cell proliferation [7]. However, it is unlikely that accumulation of DC into a single tissue site is responsible for the major changes in the number of circulating DCs in CAD [12]. Possibly, DCs may leave the blood to migrate into lymphoid tissues in response to systemic inflammatory activation, which redirects trafficking and compartmentalization of antigen-presenting DCs as well as lymphocytes. Indeed, it has been mentioned that DC numbers of lymph nodes attached to atherosclerotic wall segments exceed those in lymph nodes attached to non-atherosclerotic arteries [7]. The declined circulating DC numbers in atherosclerosis might also be the result of impaired differentiation from bone marrow progenitors. Interestingly, we recently showed that plasma Flt3 ligand (Flt3L) concentrations were reduced in CAD patients [75]. Flt3L is a major cytokine involved in both pDC and mDC development from haematopoietic stem cells and their release from the bone marrow [82,83,84]. As plasma Flt3L correlated with blood DC counts, the reduced blood DCs in CAD might be caused by impaired DC differentiation from bone marrow progenitors. Until now, it remains unclear why plasma Flt3L levels are lowered in CAD. Other possible explanations for the decrease of circulating DC subsets in CAD patients include DC activation resulting in enhanced migration or in loss of subset markers, drug-induced changes, or increased DC turnover, and are reviewed elsewhere [7].
The finding that blood DCs are decreased in CAD patients and that atherosclerotic arteries display a marked increase in the number of DCs suggest the involvement of DCs in the pathogenesis of atherosclerosis. Yet, the exact role of DCs in atherogenesis has not been fully clarified. Moreover, increasing evidence points to different behaviour of DC subsets in the initiation and progression of the disease. We have recently demonstrated
Most evidence points to a proatherogenic role for mDCs. Apolipoprotein E (ApoE)/IL-12 double knockout mice develop smaller atherosclerotic lesions than ApoE deficient (ApoE-/-) mice, illustrating the proatherogenic effect of IL-12, which is the main cytokine secreted by mDCs [85]. Moreover, daily IL-12 administration promotes atherosclerosis in ApoE-/- mice [86]. Because mDCs from CAD patients are still able to mature [75], it is plausible that the blood mDCs that are activated by atherosclerosis-favouring factors in the circulation migrate to the atherosclerotic plaque or the lymph nodes attached to the atherosclerotic wall segments. Once arrived, they might initiate and maintain the inflammatory response by continuous T-cell stimulation. Nevertheless, DCs are not only implicated in the immune response in atherosclerosis, they are also involved in cholesterol homeostasis. A recent study using a mouse model in which the receptor for diphtheria toxin was expressed under the CD11c promoter (CD11c-DTR) showed that (transient) depletion of CD11c+ cDCs resulted in enhanced cholesterolaemia [87]. The latter indicates that DCs are important in regulating the accumulation of lipids during the earliest stages of plaque formation. In contrast, enhancement of the life span and immunogenicity of DCs by specific overexpression of the anti-apoptotic gene hBcl-2 under the control of the CD11c promoter was associated with an atheroprotective decrease in plasma cholesterol levels, neutralizing the proatherogenic signature of enhanced T cell activation, a Th1 and Th17 cytokine expression profile, and elevated production of T-helper 1–driven IgG2c autoantibodies directed against oxidation-specific epitopes. -As a net result, there was no acceleration of atherosclerotic plaque progression [87].
It is not yet clear whether pDCs are proatherogenic or atheroprotective. PDCs might be involved in plaque destabilization, as they have the unique ability of producing large amounts of type I IFNs. This cytokine exerts strong antiviral effects, but more importantly, it induces marked upregulation of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on CD4+ T cells, which might lead to killing of plaque-resident cells, potentially weakening the scaffold of the lesion and rendering the plaque vulnerable [88]. In addition, nucleotides released from necrotic or apoptotic cells can induce IFN-α production by pDCs in the presence of antimicrobial peptides released from inflammatory cells [89]. Plaque-residing pDCs have also been shown to respond to CpGs (containing motifs typically found in microbial DNA) leading to enhanced IFN-α expression. This process amplifies inflammatory TLR-4, TNF-α, and IL-12 expression by mDCs, and correlates with plaque instability [90]. A recent study in ApoE-/- mice reported that administration of a plasmacytoid dendritic cell antigen-1 (PDCA-1) antibody to deplete pDCs protected from lesion formation [91], demonstrating that pDCs indeed exert proatherogenic functions during early lesion formation. In contrast, pDC depletion by administration of the 120G8 monoclonal antibody promoted plaque T-cell accumulation and exacerbated lesion development and progression in LDLr⁻/⁻ mice [92]. PDC depletion was accompanied by increased CD4⁺ T-cell proliferation, IFN-γ expression by splenic T cells, and plasma IFN-γ levels, pointing to a protective role for pDCs in atherosclerosis. Thus, the exact role of pDCs in atherosclerosis remains to be further unravelled.
Until now, it is impossible to fully inhibit the formation or progression of atherosclerotic lesions in the clinic. Current therapies for atherosclerosis (e.g. statins, stent placement) focus on relieving symptoms, and consequently many patients remain at high risk for future acute coronary events. A very effective strategy in other immune-related pathologies is vaccination, where the culprit protein or the weakened/dead version of the micro-organism is injected to the body in order to create a highly specific primary humoral immune-response [93]. New vaccines have recently been developed that deliver relevant antigens and adjuvants to redirect the immune system for the individual’s benefit [94]. Because DCs are the most effective antigen presenting cells that initiate and regulate the immune response, they seem extremely suitable as vaccine basis. On the one hand, they can activate T cells, on the other hand, they can specifically silence unwanted immune reactions by inducing tolerance [95]. They might function as natural adjuvants for the induction of antigen-specific T-cell responses. Approaches using DCs in atherosclerosis immunotherapy may be comparable to those already used for cancer immunotherapy [96,97,98], although a different immune response is required. One approach that is already intensively studied is the immunization with autologous, monocyte-derived DCs from the patient that are loaded with appropriate antigens
In the context of atherosclerosis, immunization of hypercholesterolemic animals with oxLDL or specific epitopes of ApoB100 has already been shown to inhibit atherosclerosis [102,103,104,105,106]. When LDL receptor-deficient (LDLr-/-) rabbits were immunized with malondialdehyde modified LDL (MDA-LDL), a reduction in the extent of atherosclerotic lesions was observed in the aortic tree [102]. These observations were confirmed in LDLr-/- and apolipoprotein E deficient (ApoE-/-) mice [103,104]. Also hypercholesterolemic rabbits that were immunized with oxLDL showed reduced atherosclerotic lesions in the proximal aorta [107]. Possibly, oxLDL-pulsed DCs or DCs pulsed with immunogenic components of oxLDL could be used for vaccination as well, thereby avoiding the side effects of direct vaccination with oxLDL [108]. A series of studies have already used pulsed DCs as an immunotherapy for atherosclerosis in mice, however, results were not always consistent. Repeated injection of LDLr-/- mice with oxLDL-pulsed mature DCs resulted in attenuation of lesion development with a decreased amount of macrophages and increased collagen content, contributing to a more stable plaque phenotype [109]. Moreover, a similar approach was carried out using mice expressing the full-length human ApoB100 in the liver and humanized lipoprotein profiles [110]. Those mice were repeatedly injected with mature DCs that were incubated with IL-10 and ApoB100, prior to the initiation of a Western diet. The immunosuppressive cytokine IL-10 was used to induce tolerogenic DCs [110]. This approach resulted in attenuation of atherosclerotic lesion development in the aorta, which was associated with decreased cellular immunity to ApoB100. Also, decreased Th1 and Th2 responses most likely due to enhanced regulatory T cell (Treg) expansion were observed [110]. In contrast, subcutaneous injection of DCs that were simultaneously pulsed with LPS and MDA-LDL into ApoE-/- mice at frequent intervals during lesion formation caused a significant increase in lesion size in the aortic root [111]. These differential effects may be due to different forms of antigen presentation leading to qualitatively different immune responses. Apart from oxLDL, DCs might also be pulsed
Promising areas for further research to treat immune-mediated diseases, such as atherosclerosis. Immunization of patients with autologous, monocyte-derived DCs that are loaded with appropriate antigens
Another promising area for further research is the development of tolerogenic vaccines for immune-mediated diseases (figure 7). Both foreign and self-antigens can be targets of tolerogenic processes. DCs can be converted to ‘tolerogenic DCs’ by addition of various immunomodulating agents, including IL-10, transforming growth factor-beta (TGF-β) and 1,25-dihydroxyvitamin D3 [8], or they can be generated by using small interfering RNA (siRNA) that specifically targets IL-12p35 gene [112] (figure 7). Tolerogenic DC-based immunotherapy has recently been tested in mice as a possible novel approach to induce immunological tolerance for prevention or treatment of atherosclerosis [110]. Hermansson et al. [110] used IL-10 to induce tolerogenic DCs. Another group showed that oral administration of calcitriol, the active form of vitamin D3, induced the generation of tolerogenic DCs as well as a significant increase in Foxp3+ Tregs in the lymph nodes, spleen, and atherosclerotic lesions of ApoE-/- mice, which resulted in an inhibition of atherosclerosis [113]. This was associated with increased IL-10 and decreased IL-12 mRNA expression. Furthermore, DCs from the calcitriol group showed reduced CD80 and CD86 expression and decreased proliferative activity of T lymphocytes, indicating that tolerogenic or maturation-resistant DCs show some similarities with immature DCs [113]. Hussain and colleagues [114] hypothesized that aspirin may also induce tolerogenic DCs and CD4+ CD25+ FoxP3+ Treg cells activity/augmentation in experimental models of autoimmune atherosclerosis. Aspirin-induced tolerogenic DCs initiated regulatory activity in responder T cells as they showed a decreased expression of costimulatory molecules and an increased expression of immunoglobulin-like transcript 3 (ILT-3), which is a co-inhibitor of T cell activation required to induce Tregs [114,115,116]. Indeed, the presentation of antigen complexes to T cells in the absence of costimulatory signals could lead to anergy or apoptosis of T cells, or the induction of Treg. Therefore, it might also be useful to adjust the expression of costimulatory molecules on pulsed DCs
Generation of tolerogenic DCs to develop tolerogenic vaccines. Tolerogenic DC-based immunotherapy has recently been successfully tested in mice as a possible novel approach to induce immunological tolerance for prevention or treatment of atherosclerosis.
A completely different strategy that might be used in therapeutic intervention implicates the use of DCs to deplete specific immune cells, such as the detrimental Th1 or Th17 cells, in atherosclerosis. The opposite approach has been shown to work in a mouse model of atherosclerosis. Van Es et al. [119] used DCs to deplete atheroprotective Tregs by vaccinating LDLr-/- mice with DCs which were transfected with Foxp3 encoding mRNA. This approach resulted in a cytotoxic T lymphocyte (CTL) response against Foxp3 and a subsequent depletion of Foxp3+ Tregs. Vaccination against Foxp3 aggravated atherosclerosis, it resulted in a reduction of Foxp3+ regulatory T cells in spleen, lymph nodes and circulation, and in an increase in initial atherosclerotic lesion formation. Besides an increase in lesion size, vaccination against Foxp3 also induced a 30% increase in cellularity of the initial lesions, which may indicate an increase in inflammation within the lesions [119].
Another approach for therapeutic intervention against atherosclerosis might involve the direct targeting of DCs
As it is now well accepted that atherosclerosis is an immune-mediated disease, the targeting of its cellular components might open possibilities for new therapeutic strategies to attenuate the progression of the disease. DCs seem to initiate and regulate immune responses in atherosclerosis and they are also involved in controlling cholesterol homeostasis by yet unknown mechanisms. It would be important to identify the pathway(s) through which CD11c+ cells may modulate the levels of plasma cholesterol. One should take into account that DCs represent a very heterogeneous population, with many subsets that have different phenotypes, functions, origin and anatomical distribution. So far, it is unclear if all DCs have equal antigen-presenting capacities, and very little is known about a preferential DC subset that is responsible for T cell-induced inflammation in the vessel wall. Moreover, there is a close relationship between DCs and macrophages, and the distinction between both cell types is even further complicated by their plasticity. Future studies are essential to determine which DC subtypes exert pro- or anti-atherogenic effects. It is crucial to understand the diversity in DC subsets to target DCs for immunomodulation therapies. Furthermore, functional differences between phenotypically similar mouse and human DC subtypes should also be studied. Nevertheless, DC-based vaccination strategies have been proven successful and animal studies provide some promising data for the treatment of atherosclerosis as well. Yet, several issues, such as the most appropriate antigen(s) for loading DCs and the optimal type of DC used for vaccination remain to be further investigated.
This work was supported by the University of Antwerp [GOA-BOF 2407 and TOP-GOA 3018].
Ulcerative colitis (UC) is a chronic disease resulting not only from the abnormal immune response but also from the activation of non-immune cells. Both, immune and non-immune cells are inducing inflammation that causes tissue injury [1, 2]. Platelets (Plt) are now recognized as proinflammatory cells, and aside from their primary role in a hemostasis they also enhance inflammation. The hypercoagulable state exists in the UC patients. Inflammation activates coagulation and coagulation amplifies inflammation [3, 4]. Platelets are unique cells without nucleus that have an important role in hemostasis and thrombosis, with a 5–9-day life span. Platelets have four granule types with stored numerous biologically active substances, such as platelet factor 4, fibrinogen, Von Willebrand factor (vWF), protein S, histamine, prostaglandin E2, platelet growth factor, thromboxane A2, transforming growth factor-beta, coagulation factors, angiogenic and growth factors, β-thromboglobulin, P-selectin (Psel), chemokines, regulated upon activation, normal T cell expressed and presumably secreted (RANTES), monocyte chemotactic protein-1, interleukin (IL) 8 (IL-8), IL-1β, IL-7 [5, 6]. Platelets can interact with many different cells and contribute to vascular inflammation [7]. Platelet factor 4 and β-thromboglobulin are exclusively released from Plt and are increased in the serum of the patients with active UC [8]. Platelet activation is of utmost importance for Plt functioning and is a result of Plt interaction with numerous active molecules. The first step is adhesion to the subendothelial matrix. After that Plt change their shape, resulting in pseudopodia formation [9]. Platelet activation, in the UC patients, takes place in mesenteric microcirculation after exposure to subendothelial collagen, adenosine diphosphate (ADP), arachidonic acid, Plt activating factor, thrombin, fibrinogen, and cytokines from other cells. Upon Plt activation, they degranulate and release a lot of Plt-derived microparticles (PDMP) and preformed mediators and interact with other immune and non-immune cells [10]. The PDMP represent 70–90% of all human cell-derived microparticles and have high procoagulant (due to tissue factor) and proinflammatory potential [11]. They also secrete ADP which in turn bind to the P2Y1 and P2Y12 receptors on the membrane surface of the Plt and amplify initial Plt activation [12].
Upon activation, Plt express receptors on their surface, the most important being glycoprotein IIbIIIA (GPIIbIIIa), CD40 ligand (CD40L), Psel and receptors for cytokines, chemokines, and complement components [13]. A CD40L is a membrane protein, co-stimulatory molecule, presented mostly on the surface of the activated T lymphocyte (T Ly) and activated Plt. Its receptor is CD40, expressed on the surface of the immune cells, endothelial, epithelial cells, Plt, and other mesenchymal cells [14]. After Plt activation, CD40L and Psel are cleaved from the cell surface and secreted in the blood, being called soluble CD40L (sCD40L) and soluble Psel (sPsel). These soluble forms activate other cells, especially endothelial cells, fibroblasts, T Ly, monocyte, neutrophils, and B cells. The CD40/CD40L signaling pathway is a very important pathogenic mechanism in the UC, it amplifies inflammation and activates numerous immune and non-immune cells, including Plt [15, 16]. Platelets are the main source of sCD40L in UC. The number of CD40L positive T Ly and Plt is increased in colonic mucosa [17]. Also, the CD40L-CD40 signaling pathway is responsible for thromboembolic complications in UC patients and inflammation-induced angiogenesis. Platelet dysfunction exists in UC, meaning that Plt are becoming pro-inflammatory cells, and represent a connection between innate and adaptive immunity and between inflammation and coagulation [18].
P-selectin is expressed on the membrane surface of the activated Plt and endothelial cells. P-selectin has the most important function in leucocyte (Le) recruitment, mostly in the colonic mucosa [19]. The level of tissue expression of Psel is in strong positive correlation with the level of inflammation in colonic mucosa [20]. In severe inflammation, there is abundant Psel expression in colonic mucosa. Soluble Psel and sCD40L are excellent biomarkers of Plt activation [21].
Abnormalities seen in UC are: elevated Plt count (>450,000 × 109/L), reduction in mean Plt volume (MPV), increased platelet distribution width (PDW) value, increased plateletcrit value (PCT), increase in granular content, increased Plt activation and aggregation, hyperreactivity to agonist stimulation, such as ADP and collagen. These abnormalities are mediated by IL-6, are not seen in a healthy person, and are more pronounced in UC than in other inflammatory diseases like rheumatoid arthritis. The MPV and PCT show a negative correlation with disease activity [22, 23, 24, 25]. Spontaneous platelet aggregation is observed in more than 30% of UC patients, a phenomenon that is not seen in healthy persons and rarely seen in other inflammatory disorders [26]. Histopathological studies found mesenteric vascular microthrombi to be the first finding in the mucosa of UC patients. Those microthrombi contribute to ischemia. Microthrombi are not found in mesenteric vessels in healthy persons [27]. Activated Plt form aggregates with Le and other Plt, so-called platelet-leukocyte aggregates (PLA) and Plt-Plt aggregates (PPA), via Psel [28]. Platelet-leukocyte aggregate number is increased in serum and colonic tissue of patients with active UC but does not correlate with disease activity, instead, there is a positive correlation with Plt number and serum sPsel concentration. But it is proven that Le within PLA are more active than free Ly or Plt [29]. Platelet-leukocyte aggregate react with endothelial cells, activate them, activate other free Plt and Le. Also, PLA activate endothelial cells more than free cells, leading to increased expression of adhesion molecules thus contributing to inflammation [30]. Increased Plt activation and aggregation, especially spontaneous platelet aggregation, are very much responsible for thrombosis and thromboembolic complications in UC, particularly arterial thrombosis [31, 32].
Platelet to Ly ratio, with cut off value of 175.9 (sensitivity 90.9%; specificity 78.4%; positive likelihood ratio 4.205, 95% confidence interval (95% CI) 2.214–7.894; area under the curve (AUC) 0.897, 95% CI 0.802–0.992) can serve as a biomarker for disease activity in UC, and can help us distinguish UC from healthy controls, that is, to identify UC patients with active disease [33].
We can also use neutrophil to Plt ratio to identify UC patients with active disease, with cut-off point of 14.94 (sensitivity 87.95%; specificity 63.5%) [34].
With the developments in medicine, especially pharmacology, we have a lot of antiplatelet drugs, and the number is constantly increasing [35]. The most important antiplatelet drugs are:
Thienopyridines represent a group of drugs that blocks ADP-mediated Plt aggregation by blocking the P2Y12 receptor on the Plt membrane surface. After Plt activation, ADP is released from Plt and then binds to P2Y12 on Plt surface and amplifies Plt activation, aggregation, degranulation, and procoagulant activity. Two thienopyridines are most important: clopidogrel and prasugrel. They are prodrugs and require biotransformation to become active. Clopidogrel is used for secondary stroke prevention and after coronary stenting (with aspirin). Prasugrel is used for the prevention of thrombosis after percutaneous coronary interventions [36].
Cyclopentyltriazolopyrimidines: ticagrelor. It is an active drug, with a fast onset of action, 30 minutes after ingestion, and it is a reversible P2Y12 receptor antagonist [37].
The ADP receptor antagonists: cangrelor. It has a short action time and it is used preoperatively in patients with atherosclerotic disease [38].
Aspirin or acetylsalicylic acid is the oldest antiplatelet drug that irreversibly inhibition both cyclooxygenase (COX) 1 and 2 and suppresses the production of prostaglandins and thromboxane. Other non-steroidal anti-inflammatory drugs inhibit COX-1 and Plt function, but their effect is short and reversible [39].
Phosphodiesterase inhibitors: dipyridamole that reversibly inactivates platelet cyclic adenosine monophosphate (cAMP)-phosphodiesterase thus increasing cAMP and decreasing Plt activity. Cilostazol is a selective inhibitor of phosphodiesterase type 3 leading to accumulation of cAMP and inhibition of Plt aggregation. It is used for treating peripheral vascular disease [40].
GP IIb/IIIa antagonists are anti-Plt agents that block binding GP IIb/IIIa to fibrinogen and inhibit Plt aggregation. Three agents are now being used: abciximab (monoclonal antibody), and two smaller molecule drugs tirofiban and eptifibatide [41].
Protease-activated receptor-1 (PAR-1) antagonists: a new class of drugs. Vorapaxar inhibits thrombin-related platelet aggregation [42].
They are used to prevent or treat arterial thrombosis.
The most important indications are: acute coronary syndrome, after the percutaneous coronary intervention (PCI) with stenting, acute ischemic stroke, after percutaneous intervention of peripheral arterial disease, stable angina, and primary prevention of coronary artery disease [43].
Not all anti-Plt agents are the same. Some of them affect mostly Plt aggregation, and some of them affect Plt aggregation and degranulation. The most significant contraindication for anti-Plt agents is active bleeding [44].
The most important antiplatelet drugs with the possibility to be used in UC are clopidogrel, ticagrelor, and GP inhibitors.
Clopidogrel is a prodrug, has 50% bioavailability. After biotransformation in the liver, its active metabolite binds to P2Y12 on the Plt surface and irreversibly inhibits ADP-mediated Plt aggregation and Plt activity. Due to the necessity of the liver biotransformation of clopidogrel by cytochrome P450 (CYP) enzymes CYP3A4/3A5, there is potential for drug interactions and therapeutic failure. Some genetic alterations in the CYP2C19 gene can lead to a low Plt response to clopidogrel [45].
Ticagrelor is an orally active drug. It is a reversible antagonist of P2Y12 receptor on surface Plt membrane that inhibits ADP induced Plt aggregation. It is given twice daily. After ingestion, maximal Plt inhibition was measured at 2–4 hours. It almost completely inhibits Plt aggregation. It has faster and more profound action on Plt inhibition than clopidogrel. Its half-life is 7 hours. After P2Y12 inhibition there is decreased Plt degranulation and decreased releasing of bioactive mediators from Plt, and low expression of Psel and CD40L on Plt surface. Ultimately it leads to reduced generation of PLA and PPA which is considered to be the major mechanism responsible for anti-inflammatory effect. It also inhibits the reuptake of adenosine which leads to its accumulation in the extracellular matrix. Major adverse events are bleeding, dyspnea and bradycardia [46].
Glycoprotein inhibitors compete with fibrinogen and VWF for binding to GPIIbIIIa, which represent the final step in Plt aggregation. They are very potent inhibitors of Plt aggregation. Three GP inhibitors are approved in clinical use: abciximab, eptifibatide, and tirofiban. The route of administration for all three drugs is intravenous. Major adverse events are bleeding and thrombocytopenia. They are very potent in inhibiting Plt aggregation but do not have a potent anti-inflammatory effect [47].
Antiplatelet therapy is not a part of standard therapy for treating UC patients, but growing evidence suggest that it is safe in UC and might be useful addition to the standard therapy. I will summarize published results.
This chapter is based on an evaluation of antiplatelet therapy in patients with UC. We defined key questions as our literature searching algorithm. We searched literature from PubMed according to the adequate MESH terms (“ulcerative colitis,” “platelets,” “antiplatelet therapy,” “P-selectin,” “CD40 ligand,” “ticagrelor,” “clopidogrel,” and “glycoprotein inhibitors”) for the period from 2000 to the present.
The authors conducted an animal study about the usage of antiplatelet agents—ticagrelor and eptifibatide in mice. Forty C57BL/6 mice (inbred females, age: 2–3 months, and average body mass: 20–24 g) were used. The bodyweight of mice was measured every day. Mice were observed for stool consistency and rectal bleeding on a daily basis so that disease activity index (DAI) could be calculated daily as the sum of the weight loss score, the diarrheal score, and the hematochezia score based on the method used by Friedman et al., as shown in Table 1. The DAI was used to assess the severity of colitis [48].
DAI score | |||||
---|---|---|---|---|---|
0 | 1 | 2 | 3 | 4 | |
Weight loss | 0% | 1–5% | 6–10% | 11–20% | >20% |
Stoll consistency | Well-formed pellets | Semi-formed pellets | Liquid stools | ||
Rectal bleeding | Hemoccult negative | Hemoccult positive | Gross bleeding |
Disease activity index (DAI).
Colitis was induced in 30 mice by 5-day drinking water with 3.5% dextran sulfate sodium (DSS) (average molecular weight within the range of 35,000–55,000). All mice developed DSS colitis. After 5 days, DSS-induced mice were divided into three experimental groups, 10 each. The first (I) group, the DSS control group, received no intervention during the subsequent 5 days treatment period. The second (II) group, the ticagrelor treatment (PO) group, received 1 mg (in 0.5 mL) dosages per day of Brilinta® via gastric tube. The third (III) group, the eptifibatide treatment (IP) group, received 150 μg (in 0.2 mL) dosages per day of Integrilin® via intraperitoneal injection. Group of mice (
The primary outcome was bleeding, and the secondary outcomes were changes in platelet count, hemoglobin (Hgb) level, and hematocrit (HCT) level. Complete blood counts were determined for each group at baseline (day 0: before treatment; DSS1, PO1, and IP1 subgroups) and at 1 day after the last dose (day 5; DSS2, PO2, and IP2 subgroups). On day 5, all surviving mice were sacrificed, and an autopsy was performed. The Plt aggregation was measured using a multiplate Plt function analyzer with adenosine diphosphate and thrombin receptor-activating peptide.
Platelet aggregation was measured at baseline, after 2 h, and 24 h of ticagrelor and eptifibatide therapy. An autopsy showed signs of colitis and there was no evidence of recent bleeding in the liver, spleen, central nervous system, or serous cavities of any of the antiplatelet treatment groups. Histological findings of colonic mucosa in all three experimental groups after autopsy were that DSS2, PO2, and IP2 showed mild inflammation and ulceration.
Maximum weight loss was below 15% in all three experimental groups. Hematochezia was observed in all three experimental groups as blood around the anus and present in the sawdust or as hemoccult positive. Blood was seen from the fourth day of the experiment in all three experimental groups.
The DAI score was not significantly different between the three experimental groups (Kruskal-Wallis test;
Significantly lower levels of Hgb and HCT were found in all three experimental groups (PO1, DSS1, PO1, and IP1 vs. control; Kruskal-Wallis test:
Hemoglobin (Hgb) values before initiation of antiplatelet drug administration. Data are presented as mean ± SD. Groups DSS1, IP1, and PO1 represent DSS colitis mice before administration of drugs; K represents the experimental control group. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment.
Hematocrit (HCT) values before initiation of antiplatelet drug administration. Data are presented as mean ± SD. Groups DSS1, IP1, and PO1 represent DSS colitis mice before administration of drugs; K represents the experimental control group. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test:
Platelet (PLT) count for all groups. Data are presented as mean ± SD. Groups DSS1, IP1, and PO1 represent DSS colitis mice before administration of drugs; K represents the experimental control group. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test:
Percent change in values of hemoglobin (Hgb) relative to basal values. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: HGB,
Percent change in values of hematocrit (HCT) relative to basal values. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: HCT,
Percent change in values of platelets (PLT) relative to basal values. Groups DSS2, IP2, and PO2 represent DSS colitis mice after administration of drugs. DSS, dextran sulfate sodium; IP, eptifibatide treatment; PO, ticagrelor treatment (Kruskal-Wallis test: PLT,
The authors concluded that administering eptifibatide and ticagrelor to DSS colitis mice did not cause serious adverse events. There was no significant decrease in Plt count or Hgb and HCT levels, and autopsy found no bleeding into the liver, spleen, serous cavities or intracranially. These observations support the potential use of antiplatelet therapy for treating UC in humans as an addition to the standard therapy. Ticagrelor could be used in the moderate form of UC and eptifibatide in the severe form, together with standard therapy.
The goal of this research was to evaluate the anti-inflammatory effect of clopidogrel on an animal model for Crohn’s disease (TNBS model) and ulcerative colitis (oxazolone induced) in rats. Rats were weighing 150–200 g and were housed in standard conditions, on a standard diet and water ad libitum. Ulcerative colitis was induced by intrarectal administration of oxazolone on first day. Rats were divided into four groups, each consisting of six animals:
The goal of this study was to evaluate the effect of acetylsalicylic acid (ASA) on DSS colitis in mice. Female C57BL/6 mice, average body weight 19–21 g, were divided into three groups:
The aim of this study was to evaluate the role of the CD40-CD40L signaling pathway in intestinal inflammation in DSS colitis in mice and the anti-inflammatory effect of Trapidil (triazolopyrimidine) on intestinal inflammation. Trapidil is an antagonist of platelet-derived growth factor and it was developed to inhibit the response of monocytes to CD40L. They found a 10-fold increase in CD40 expression in endothelial cells in the colon (an important result of CD40-CD40L signaling pathway), increased recruitment of Plt and leukocytes in colonic venules due to CD40-CD40L pathway and significant inhibition of CD40-CD40L signaling pathway with Trapidil [51].
The objective of this study was to evaluate the role of Psel on leukocyte recruitment and the effect of its blockade with an anti-P-sel antibody. They induced DSS colitis in wild type and P-selectin−/− C57BL/6 J mice. Disease activity index, plasma IL-6, length of colon and rectum, histological damage of the colon, and MPO activity of the distal colon were evaluated. Leukocyte-endothelial interaction in colonic venules was assessed using intravital microscopy. Vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 expression on endothelial cells and expression of very large antigen-4 integrin on circulating leukocytes were obtained. They found that Psel has an important role in intestinal inflammation in DSS colitis. Its blockade or genetic deficiency offers protection against DSS colitis. They also found that treatment of DSS colitis with Psel antibody was very potent in reducing DAI, MPO activity, and leukocyte adhesion. The VCAM-1 over-expression in the colon and extracolonic organs and increased level of IL-6 in circulation were observed in P-selectin−/− mice, but not in mice treated with anti-P-sel antibodies. The conclusion was that Psel is a key molecule for the development of DSS colitis and that Psel antibodies administration or genetic deficiency offers protection against DSS colitis by diminishing leukocyte recruitment in the colon [52].
It was a retrospective analysis of 174 patients with pre-existing inflammatory bowel disease, who were taking aspirin, due to cardiac comorbidity, for at least 18 months and did not differ in age, gender, disease duration, smoking status, medication usage, or baseline C-reactive protein. They were looking for the connection between aspirin and inflammatory bowel disease (IBD) related hospitalization/surgery/corticosteroid required during the period of follow-up. Their results indicate that aspirin use did not have a clinical impact on IBD patients [53].
A retrospective analysis of 36 patients with pre-existing IBD (test group), who started on combination therapy of aspirin and clopidogrel for at least 6 months, due to PCI for coronary artery disease. There was a control group with IBD matched for gender and age, not taking antiplatelet therapy. They found no change in frequency of IBD exacerbations between groups, after the initiation of the aspirin and clopidogrel in the test group [54].
After analysis of the PLATO study, the question was raised whether ticagrelor has antibacterial activity in standard anti Plt dosages against Gram-positive bacteria because patients treated with ticagrelor had a lower risk of infection-related death than patients treated with clopidogrel. Authors proved that in vitro ticagrelor has bactericidal activity against all Gram-positive strains tested, including drug-resistant strains glycopeptide intermediate
The author tested the antimicrobial activity of ticagrelor against different types of
The exact pathophysiology of ulcerative colitis is unknown. Except immune cells, it is important to take platelet function into the consideration so we could improve the response rate to the standard therapy in ulcerative colitis patients. Antiplatelet therapy is still not a part of the therapeutic armamentarium for this disease. We have increasing evidence that raises the possibility of using antiplatelet therapy in humans with ulcerative colitis. Antiplatelet therapy in UC is safe and it seems that ticagrelor could be the drug of the first choice.
The authors declare no conflict of interest.
acetylsalicylic acid adenosine diphosphate area under the curve CD40 ligand colon mucosal damage index cyclic adenosine monophosphate cyclooxygenase cytochrome P450 dextran sulfate sodium disease activity index glycoprotein IIbIIIA hematocrit hemoglobin inflammatory bowel disease interleukin leucocyte magnetic resonance imaging mean Plt volume minimal inhibitory concentration myeloperoxidase plateletcrit percutaneous coronary intervention platelet distribution width platelet-leukocyte aggregates platelets P-selectin Plt derived microparticles Plt-Plt aggregates protease-activated receptor-1 regulated upon activation, normal T cell expressed and presumably secreted soluble CD40L soluble Psel T lymphocyte ulcerative colitis vascular cell adhesion protein 1 Von Willebrand factor 95% confidence interval
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:null,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, National University of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013. She relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. She was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently Deputy Principal of the Australian College of Business and Technology – Kandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI) Ambassador to Sri Lanka.",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. Dr. Suzuki currently serves as a visiting researcher at Kogakuin University, Japan, and also a vice president of the Japan Firefly Society.",institutionString:"Kogakuin University",institution:null}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"