Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\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:"4588",leadTitle:null,fullTitle:"New Discoveries in Embryology",title:"New Discoveries in Embryology",subtitle:null,reviewType:"peer-reviewed",abstract:"Animal individual life begins as combination of sperm and oocyte, which results in the embryogenesis from ovum fertilization to fetal stage. Embryology has become one central discipline for many modern biotechnologies. Although this subject has been studied for more than a century, new discoveries appear continuously. This book contains some new discoveries and updates some theories and technologies in animal and human embryology. Major content include new findings in gamete biology, new theories and discoveries in embryo implantation by three-dimensional imaging technology and new concept and actual application of embryology. Thus, this book will greatly update knowledge in embryology field and provide some basic theories and technologies for animal scientists and breeders as well as embryologists and anthropologists.",isbn:null,printIsbn:"978-953-51-2182-4",pdfIsbn:"978-953-51-5410-5",doi:"10.5772/59218",price:119,priceEur:129,priceUsd:155,slug:"new-discoveries-in-embryology",numberOfPages:268,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"2d40aace9724b9c451a8d8168acd0169",bookSignature:"Bin Wu",publishedDate:"October 21st 2015",coverURL:"https://cdn.intechopen.com/books/images_new/4588.jpg",numberOfDownloads:21251,numberOfWosCitations:36,numberOfCrossrefCitations:36,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:61,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:133,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 17th 2014",dateEndSecondStepPublish:"October 8th 2014",dateEndThirdStepPublish:"January 4th 2015",dateEndFourthStepPublish:"February 3rd 2015",dateEndFifthStepPublish:"March 5th 2015",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"108807",title:"Ph.D.",name:"Bin",middleName:null,surname:"Wu",slug:"bin-wu",fullName:"Bin Wu",profilePictureURL:"https://mts.intechopen.com/storage/users/108807/images/system/108807.jfif",biography:"Bin Wu, Ph.D., HCLD is currently a scientific laboratory director at Arizona Center for Reproductive Endocrinology and Infertility, USA. He received his training in genetics and reproductive biology at the Northwest Agricultural University in China and Cornell University, New York and post-doctor training at University of Guelph, Canada. He was promoted as a professor at the Northwest Agricultural University. As an embryologist, he later joined in the Center for Human Reproduction in Chicago. Dr. Wu has membership for many professional associations, such as American Society for Reproductive Medicine; International Embryo Transfer Society; Society for the Study of Reproduction; American Association of Bioanalysts and European Society of Human Reproduction and Embryology. Also, he has obtained some significant research awards from these professional associations.",institutionString:"Arizona Center for Reproductive Endocrinology and Infertility",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"5",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"398",title:"Embryology",slug:"human-genetics-embryology"}],chapters:[{id:"48736",title:"Sperm DNA Fragmentation and Its Relation With Fertility",doi:"10.5772/60825",slug:"sperm-dna-fragmentation-and-its-relation-with-fertility",totalDownloads:2487,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Sperm DNA integrity is vital for successful fertilization, embryo development, pregnancy, and transmission of genetic material to the offspring. DNA fragmentation is the most frequent DNA anomaly present in the male gamete that has been associated to poor semen quality, low fertilization rates, impaired embryo quality, and preimplantation development and reduced clinical outcomes in assisted reproduction procedures. This work summarizes the causes of fragmentation in the spermatic DNA, and its relation with seminal parameters, male aging, and results in assisted reproduction procedures.",signatures:"Javier García-Ferreyra",downloadPdfUrl:"/chapter/pdf-download/48736",previewPdfUrl:"/chapter/pdf-preview/48736",authors:[{id:"173256",title:"Ph.D.",name:"Javier",surname:"García-Ferreyra",slug:"javier-garcia-ferreyra",fullName:"Javier García-Ferreyra"}],corrections:null},{id:"48488",title:"Reactive Oxygen Species (ROS) and Male Fertility",doi:"10.5772/60632",slug:"reactive-oxygen-species-ros-and-male-fertility",totalDownloads:2387,totalCrossrefCites:15,totalDimensionsCites:26,hasAltmetrics:0,abstract:"Oxidative energy production is inevitably associated with the generation of reactive oxygen species (ROS), excessive concentrations of which can lead to cellular pathology. A free radical may be defined as any molecule that has one or more unpaired electrons. The superoxide anion, the hydroxyl radical, and the hypochlorite radical are some of the highest reactive radicals of oxygen. Owing to their high reactivity and to their capability of initiating an uncontrolled cascade of chain reactions, ROS produce extensive protein damage and cytoskeletal modifications and inhibit cellular mechanisms. Aerobic organisms are equipped with a powerful battery of mechanisms that protect them from the adverse effects of lipid peroxidation (LPO) and other manifestations of oxygen toxicity. Defective sperm function frequently causes male infertility, due to abnormal flagella movement, failure to recognize the zona, and inhibition of sperm-oocyte fusion. ROS are fundamental mediators of physiological sperm function, such as signal transduction mechanisms that have an effect on fertility. ROS can have positive effects on sperm and the concentration functions depending on the nature and the concentration of the ROS involved. They are necessary in regulating the hyperactivation and the ability of the spermatozoa to undergo acrosome reaction. An increased amount of superoxide anion (O2-) is one of the first steps required by the spermatozoa for induction and development of hyperactivation and capacitation. Numerous studies have shown that oxidative stress plays an important role in the pathophysiology of infertility and assisted fertility. The paternal genome is of primary importance in the normal embryo and fetal development. ROS-induced sperm damage during sperm translation, such as signal transduction through the seminiferous tubules and epididymis, is one of the most important mechanisms leading to sperm DNA damage. Male germ cells are extremely vulnerable to oxidative stress as the sperm membrane is rich in unsaturated fatty acids and lacks the capacity for DNA repair. Spermatozoa are particularly susceptible to ROS-induced damage because their plasma membranes contain large quantities of polyunsaturated fatty acids (PUFA) and their cytoplasm contains low concentrations of the scavenging enzymes. Many clinical and research institutes are investigating the usefulness of antioxidant supplementation and their role in prevention of the infertility problems. Incubation under oxygen in vitro was detrimental to human spermatozoa, decreasing motility and viability. Since then, many reports have associated ROS with impaired sperm function, including decreased motility, abnormal morphology, and decreased sperm-egg penetration. Increasing knowledge of the mechanisms whereby ROS and endogenous antioxidant systems influence reproductive processes can assist to optimize the application of exogenous antioxidants to fertility treatment.",signatures:"Simona Tafuri, Francesca Ciani, Eugenio Luigi Iorio, Luigi Esposito\nand Natascia Cocchia",downloadPdfUrl:"/chapter/pdf-download/48488",previewPdfUrl:"/chapter/pdf-preview/48488",authors:[{id:"32033",title:"Dr.",name:"Natascia",surname:"Cocchia",slug:"natascia-cocchia",fullName:"Natascia Cocchia"},{id:"117666",title:"Prof.",name:"Francesca",surname:"Ciani",slug:"francesca-ciani",fullName:"Francesca Ciani"},{id:"173334",title:"Prof.",name:"Simona",surname:"Tafuri",slug:"simona-tafuri",fullName:"Simona Tafuri"},{id:"173338",title:"Prof.",name:"Luigi",surname:"Esposito",slug:"luigi-esposito",fullName:"Luigi Esposito"},{id:"173431",title:"Prof.",name:"Eugenio Luigi",surname:"Iorio",slug:"eugenio-luigi-iorio",fullName:"Eugenio Luigi Iorio"}],corrections:null},{id:"48988",title:"Influence of ROS on Ovarian Functions",doi:"10.5772/61003",slug:"influence-of-ros-on-ovarian-functions",totalDownloads:1936,totalCrossrefCites:6,totalDimensionsCites:12,hasAltmetrics:0,abstract:"High level of ROS (Reactive Oxygen Species), due to an increased production of oxidant species and/or a decreased efficacy of antioxidant system, can lead to oxidative stress (OS) an emerging health risk factor involved in the aging and in many diseases, either in humans or in animals. ROS are a double-edged sword – they serve as key signal molecules in physiological processes, but also have a role in pathological processes involving the female reproductive tract.",signatures:"Francesca Ciani, Natascia Cocchia, Danila d’Angelo and Simona\nTafuri",downloadPdfUrl:"/chapter/pdf-download/48988",previewPdfUrl:"/chapter/pdf-preview/48988",authors:[{id:"32033",title:"Dr.",name:"Natascia",surname:"Cocchia",slug:"natascia-cocchia",fullName:"Natascia Cocchia"},{id:"117666",title:"Prof.",name:"Francesca",surname:"Ciani",slug:"francesca-ciani",fullName:"Francesca Ciani"},{id:"173334",title:"Prof.",name:"Simona",surname:"Tafuri",slug:"simona-tafuri",fullName:"Simona Tafuri"},{id:"173336",title:"Prof.",name:"Danila",surname:"D'Angelo",slug:"danila-d'angelo",fullName:"Danila D'Angelo"}],corrections:null},{id:"48397",title:"A Novel Concept of Fundus-Ovary-Salpinx-Para-Aorta Implantation Promoting Unit during Human Embryo Implantation",doi:"10.5772/60634",slug:"a-novel-concept-of-fundus-ovary-salpinx-para-aorta-implantation-promoting-unit-during-human-embryo-i",totalDownloads:1519,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Human embryo implantation is mainly regulated by the endocrine system. Since the ovary, fallopian tube, and fundus can directly communicate through the mesosalpinx and ovarian ligament, the local concentration of progesterone in the pathway of the developing embryo is considered to be higher than in systemic blood circulation. The immune system promotes embryo implantation by stimulating progesterone production of the ovary and by inducing endometrial differentiation. The recognition of the developing embryo in the fallopian tube by the immune system is achieved through the para-aortic lymph nodes. On the basis of the above evidence, the autologous immune cells activated in vitro were demonstrated to improve clinical pregnancy rates in patients with repeated implantation failures. In addition, the autonomic nerve system that innervates the fundus, the ovary, and the fallopian tube from the para-aortic region is proposed to regulate the environment of the pathway of the developing embryo. From these findings, we suppose that a unique unilateral functional unit to promote human embryo implantation exists in the pathway of the developing embryo including the para-aortic regions and propose naming this novel functional unit the Fundus-Ovary-Salpinx-Para-aorta Implantation Promoting unit (FOSPa-IP unit).",signatures:"Hiroshi Fujiwara, Yoshihiko Araki, Shigeru Saito, Kazuhiko Imakawa,\nSatoru Kyo, Minoru Shigeta, Masahide Shiotani, Akihito Horie and\nTakahide Mori",downloadPdfUrl:"/chapter/pdf-download/48397",previewPdfUrl:"/chapter/pdf-preview/48397",authors:[{id:"91187",title:"Dr.",name:"Hiroshi",surname:"Fujiwara",slug:"hiroshi-fujiwara",fullName:"Hiroshi Fujiwara"},{id:"132580",title:"Dr.",name:"Yoshihiko",surname:"Araki",slug:"yoshihiko-araki",fullName:"Yoshihiko Araki"},{id:"132581",title:"Dr.",name:"Kazuhiko",surname:"Imakawa",slug:"kazuhiko-imakawa",fullName:"Kazuhiko Imakawa"},{id:"177873",title:"Dr.",name:"Shigeru",surname:"Saito",slug:"shigeru-saito",fullName:"Shigeru Saito"},{id:"177874",title:"Dr.",name:"Satoru",surname:"Kyo",slug:"satoru-kyo",fullName:"Satoru Kyo"},{id:"177875",title:"Dr.",name:"Minoru",surname:"Shigeta",slug:"minoru-shigeta",fullName:"Minoru Shigeta"},{id:"177876",title:"Dr.",name:"Masahide",surname:"Shiotani",slug:"masahide-shiotani",fullName:"Masahide Shiotani"},{id:"177877",title:"Dr.",name:"Akihito",surname:"Horie",slug:"akihito-horie",fullName:"Akihito Horie"},{id:"177878",title:"Dr.",name:"Takahide",surname:"Mori",slug:"takahide-mori",fullName:"Takahide Mori"}],corrections:null},{id:"49200",title:"Human Embryology",doi:"10.5772/61453",slug:"human-embryology",totalDownloads:3534,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:1,abstract:"The study of human embryology has a very long history. Modern embryology owes its initial development to the key embryo collections that began in the 19th century. The first large collection was that of Carnegie, and this was followed later by the major 7 collections. The second role of the Carnegie collection was for researchers to establish a defined set of Carnegie stages based on embryo morphological features. Today, embryos are imaged three-dimensionally (3D) by a range of imaging modalities including, magnetic resonance microscopy (MRM), episcopic fluorescence image capture (EFIC), phase-contrast X-ray computed tomography (pCT), and optical projection tomography (OPT). Historically, embryo serial images were reconstructed using wax-plate and model techniques. The above new 3D imaging techniques now allow 3D computer reconstructions, analysis, and even 3D printing. This chapter will describe how the classical embryology collections and techniques have developed into today’s imaging and analysis techniques, giving new insights to human embryonic development.",signatures:"Shigehito Yamada, Mark Hill and Tetsuya Takakuwa",downloadPdfUrl:"/chapter/pdf-download/49200",previewPdfUrl:"/chapter/pdf-preview/49200",authors:[{id:"49486",title:"Prof.",name:"Shigehito",surname:"Yamada",slug:"shigehito-yamada",fullName:"Shigehito Yamada"},{id:"90205",title:"Prof.",name:"Tetsuya",surname:"Takakuwa",slug:"tetsuya-takakuwa",fullName:"Tetsuya Takakuwa"},{id:"175453",title:"Dr.",name:"Mark",surname:"Hill",slug:"mark-hill",fullName:"Mark Hill"}],corrections:null},{id:"48369",title:"Novel Cellular and Molecular Interactions During Limb Development, Revealed from Studies on the Split Hand Foot Congenital Malformation",doi:"10.5772/60402",slug:"novel-cellular-and-molecular-interactions-during-limb-development-revealed-from-studies-on-the-split",totalDownloads:1761,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The embryonic development of the limbs is widely used as a paradigm for the comprehension of the cellular processes and molecular mechanisms underlying organogenesis and pattern formation. The chick, mouse and (recently), zebrafish embryos are excellent models, for the ease of experimental manipulation and the availability of several mutant strains with limb malformation defects.",signatures:"Daniele Conte, Luisa Guerrini and Giorgio R. Merlo",downloadPdfUrl:"/chapter/pdf-download/48369",previewPdfUrl:"/chapter/pdf-preview/48369",authors:[{id:"173285",title:"Prof.",name:"Giorgio R.",surname:"Merlo",slug:"giorgio-r.-merlo",fullName:"Giorgio R. Merlo"},{id:"177811",title:"Dr.",name:"Daniele",surname:"Conte",slug:"daniele-conte",fullName:"Daniele Conte"},{id:"177812",title:"Dr.",name:"Luisa",surname:"Guerrini",slug:"luisa-guerrini",fullName:"Luisa Guerrini"}],corrections:null},{id:"48370",title:"Protein Kinase A and Protein Kinase C Connections: What Could Angiogenesis Tell Us?",doi:"10.5772/60401",slug:"protein-kinase-a-and-protein-kinase-c-connections-what-could-angiogenesis-tell-us-",totalDownloads:1514,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The formation of embryonic blood vessels, defined as vasculogenesis, is a complex morphogenetic process ultimately related to tubulogenesis, carried out from in situ differentiation of mesoderm-recruited or proliferated progenitor endothelial cells (angioblasts) to endothelial cells for structuring a primary vascular plexus. Subsequent events involving apoptosis versus cell survival (remodeling) in the vessel network stabilizes the primordial microvasculature, which through the angiogenesis process yields new capillaries by sprouting from the preexisting ones. Methylxanthinic alkaloids such as caffeine (compounds present in a number of beverages consumed worldwide) exert some well-known effects upon heart and other cardiovascular structures, in part, by negatively interplaying with phosphodiesterase (PDEs) enzymes. Once caffeine as well as Ilex paraguariensis (yerba mate) infusion extract have shown to enhance the vessel formation (vasculogenesis and angiogenesis), we discuss the impact afforded by I. paraguariensis constituents on the (PDEs-related) quantities and stability of Protein kinase A (PKA) and Protein kinase C (PKC) enzymes. Besides, the text reflects on a suggested dual roles displayed by PKA and PKC enzymatic pathways in the developmental angiogenic events.",signatures:"Beatriz Veleirinho, Daniela Sousa Coelho, Viviane Polli, Simone\nKobe Oliveira, Rosa Maria Ribeiro-Do-Valle, Marcelo Maraschin and\nPaulo Fernando Dias",downloadPdfUrl:"/chapter/pdf-download/48370",previewPdfUrl:"/chapter/pdf-preview/48370",authors:[{id:"173479",title:"Dr.",name:"Paulo",surname:"Dias",slug:"paulo-dias",fullName:"Paulo Dias"},{id:"173484",title:"Dr.",name:"Beatriz",surname:"Veleirinho",slug:"beatriz-veleirinho",fullName:"Beatriz Veleirinho"},{id:"173485",title:"Dr.",name:"Marcelo",surname:"Maraschin",slug:"marcelo-maraschin",fullName:"Marcelo Maraschin"},{id:"173486",title:"Dr.",name:"Rosa Maria",surname:"Ribeiro-Do-Valle",slug:"rosa-maria-ribeiro-do-valle",fullName:"Rosa Maria Ribeiro-Do-Valle"},{id:"173487",title:"Dr.",name:"Simone Kobe",surname:"Oliveira",slug:"simone-kobe-oliveira",fullName:"Simone Kobe Oliveira"},{id:"173488",title:"BSc.",name:"Daniela Sousa",surname:"Coelho",slug:"daniela-sousa-coelho",fullName:"Daniela Sousa Coelho"},{id:"173489",title:"MSc.",name:"Viviane",surname:"Polli",slug:"viviane-polli",fullName:"Viviane Polli"}],corrections:null},{id:"49198",title:"A Novel Discipline in Embryology — Animal Embryo Breeding",doi:"10.5772/61299",slug:"a-novel-discipline-in-embryology-animal-embryo-breeding",totalDownloads:2457,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The modern animal biotechnologies, such as animal cloning, transgenesis, sex determination, stem cells, designing new livestock, must be performed on animal gametes including sperm and oocytes, and embryos based on embryology theory. Currently, some key biotechnologies in embryology have become the most powerful tool for animal scientists and breeders to improve genetic construction of animal herds. Here, authors put forward a new concept of Animal Embryo Breeding Science to describe this discipline formation, development, and application in animal genetic improvement and breeding. The relationship of embryo breeding with other disciplines has been profiled. Thus, animal scientists and breeders can easily understand and apply embryo breeding theory and related key techniques to accelerate animal improvement speed, to modify genetic construction of animal population, and to design and create new animal individual or breed.",signatures:"Bin Wu, Linsen Zan, Fusheng Quan and Hai Wang",downloadPdfUrl:"/chapter/pdf-download/49198",previewPdfUrl:"/chapter/pdf-preview/49198",authors:[{id:"108807",title:"Ph.D.",name:"Bin",surname:"Wu",slug:"bin-wu",fullName:"Bin Wu"}],corrections:null},{id:"48710",title:"Assisted Reproductive Technologies in Safeguard of Feline Endangered Species",doi:"10.5772/61004",slug:"assisted-reproductive-technologies-in-safeguard-of-feline-endangered-species",totalDownloads:2297,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"The growth of the human population and the escalating consumption of natural resources have reduced wild habitats, modifying the existing balance of biological cycles. Therefore, ex situ conservation efforts have received renewed attention as a potential safeguard for species with an uncertain future in the wild. Most wild felid species are classified as rare, vulnerable, or endangered due to poaching and habitat loss. Any directed action taken by humans to enhance animal reproduction results in assisted reproductive technologies (ART) development. These technologies have been included in programs for the conservation of endangered species. Therefore, ART provide a new approach in the safeguard programs of felid biodiversity. Currently, ART mainly include Artificial Insemination (AI); In Vitro Embryo Production (IVEP) consisting of In Vitro Maturation (IVM), In Vitro Fertilization (IVF), In Vitro Culture (IVC), Embryo Transfer (ET), and Intra Cytoplasmic Sperm Injection (ICSI); gamete/embryo cryopreservation; gamete/embryo sexing; gamete/embryo micromanipulation; Somatic Cell Nuclear Transfer (SCNT); and genome resource banking.",signatures:"Natascia Cocchia, Simona Tafuri, Lucia Abbondante, Leonardo\nMeomartino, Luigi Esposito and Francesca Ciani",downloadPdfUrl:"/chapter/pdf-download/48710",previewPdfUrl:"/chapter/pdf-preview/48710",authors:[{id:"32033",title:"Dr.",name:"Natascia",surname:"Cocchia",slug:"natascia-cocchia",fullName:"Natascia Cocchia"},{id:"117666",title:"Prof.",name:"Francesca",surname:"Ciani",slug:"francesca-ciani",fullName:"Francesca Ciani"},{id:"173334",title:"Prof.",name:"Simona",surname:"Tafuri",slug:"simona-tafuri",fullName:"Simona Tafuri"},{id:"173338",title:"Prof.",name:"Luigi",surname:"Esposito",slug:"luigi-esposito",fullName:"Luigi Esposito"},{id:"175465",title:"Dr.",name:"Lucia",surname:"Abbondante",slug:"lucia-abbondante",fullName:"Lucia Abbondante"},{id:"175843",title:"Prof.",name:"Leonardo",surname:"Meomartino",slug:"leonardo-meomartino",fullName:"Leonardo Meomartino"}],corrections:null},{id:"48499",title:"Antiluteolytic Strategy for Bovine Embryo Transfer Programmes",doi:"10.5772/60425",slug:"antiluteolytic-strategy-for-bovine-embryo-transfer-programmes",totalDownloads:1361,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This paper presents a comprehensive review of the problematic issue of embryonic mortality in cattle and develops possible strategies towards a hormonal antiluteolitic. A recent and extensive investigation using eCG is also described.",signatures:"Néstor Isaías Tovío Luna, Arturo Duica Amaya and Henry Alberto\nGrajales Lombana",downloadPdfUrl:"/chapter/pdf-download/48499",previewPdfUrl:"/chapter/pdf-preview/48499",authors:[{id:"110124",title:"MSc.",name:"Nestor",surname:"Tovio Luna",slug:"nestor-tovio-luna",fullName:"Nestor Tovio Luna"},{id:"122094",title:"MSc.",name:"Arturo",surname:"Duica Amaya",slug:"arturo-duica-amaya",fullName:"Arturo Duica Amaya"},{id:"138223",title:"Dr.",name:"Henry Alberto",surname:"Grajales Lombana",slug:"henry-alberto-grajales-lombana",fullName:"Henry Alberto Grajales Lombana"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5817",title:"Embryo Cleavage",subtitle:null,isOpenForSubmission:!1,hash:"11de486fcf8fe42d4359c65e71a8f1da",slug:"embryo-cleavage",bookSignature:"Bin Wu",coverURL:"https://cdn.intechopen.com/books/images_new/5817.jpg",editedByType:"Edited by",editors:[{id:"108807",title:"Ph.D.",name:"Bin",surname:"Wu",slug:"bin-wu",fullName:"Bin Wu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4594",title:"胚胎移植新进展",subtitle:"Advances in Embryo Transfer",isOpenForSubmission:!1,hash:"32b738c0d0cbce7a61a3ea63b5d43ed0",slug:"advances-in-embryo-transfer-translation-chinese",bookSignature:"Bin Wu",coverURL:"https://cdn.intechopen.com/books/images_new/4594.jpg",editedByType:"Edited by",editors:[{id:"108807",title:"Ph.D.",name:"Bin",surname:"Wu",slug:"bin-wu",fullName:"Bin Wu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1577",title:"Advances in Embryo Transfer",subtitle:null,isOpenForSubmission:!1,hash:"b9d06c4d4736cf2bd3394ce91e8d3031",slug:"advances-in-embryo-transfer",bookSignature:"Bin Wu",coverURL:"https://cdn.intechopen.com/books/images_new/1577.jpg",editedByType:"Edited by",editors:[{id:"108807",title:"Ph.D.",name:"Bin",surname:"Wu",slug:"bin-wu",fullName:"Bin Wu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6977",title:"Embryology",subtitle:"Theory and Practice",isOpenForSubmission:!1,hash:"4620ebf60e92b453c7e4fde00cd94515",slug:"embryology-theory-and-practice",bookSignature:"Bin Wu and Huai L. 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\r\n\tThe importance of education and care in the early stages of life has long been debated and documented. However, in a world that faces ongoing crises and challenges, early childhood education is in a constant quest for pedagogies that respond to acute problems such as:
\r\n
\r\n\ta. Environmental crises which result in food & water shortages \r\n\tb. The growth of digital environments which can educate and empower as well as exploit and destroy (mobile learning, STEM education, tablets, etc.). \r\n\tc. Social, racial, class, and gender-based discriminations that restrict the developmental potential and the prosperity perspectives \r\n\td. Health hazards and illnesses such as the laters COVID-19 pandemic. \r\n\te. Armed conflicts with casualties and displacements of populations seeking refuge \r\n\tf. Lack of physical spaces that will support and nourish development and learning, etc.
\r\n
\r\n\tEducation in the post-modern era strives to address the above issues and develop policies, curricula, methodologies, and strategies to contribute to an environmentally and socially sustainable future. It embraces multiple perspectives and worldviews and seeks to touch on inequalities and discriminations in favor of equity. In this direction, children’s s agency lies at the heart of democratic approaches. Educational processes adopt forms of interactions that actualize learning as “becoming” and place it in a continuum between past, present, and future. This book intends to feature innovative approaches that employ transformative elements (targets, methods, materials, ideas, etc.) and embrace the concept of child development as “becoming” in an ever-changing and challenging world.
\r\n
\r\n\tWe invite authors to contribute original research or research review papers that present innovative approaches addressing personal and social transformation. All aspects of early childhood education will be considered, including research methodology for the early years.
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He graduated from the Physics Department\r\nof the University of Crete and continued his post-graduate studies at the University\r\nParis-7 and University Paris-5 and received his Ph.D. degree at the University Paris 5.\r\nHis research interests include science education in early childhood, science teaching\r\nand learning, e-learning, the use of ICT in science education, and games simulations.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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\n\t\t\t
1. Introduction
\n\t\t\t
Nanowires are especially attractive for nanoscience studies as well as for nanotechnology applications. Nanowires, compared to other low dimensional systems, have two quantum confined directions, while still leaving one unconfined direction for electrical conduction. This allows nanowires to be used in applications where electrical conduction, rather than tunneling transport, is required. Because of their unique density of electronic states, nanowires in the limit of small diameters are expected to exhibit significantly different optical, electrical and magnetic properties from their bulk 3D crystalline counterparts. The increased surface area, very high density of electronic states, enhanced exciton binding energy, diameter-dependent band gap, and increased surface scattering for electrons and phonons are just some of the ways in which nanowires differ from their corresponding bulk materials. Synthesis, characterization and application of nanowires and nanotubes comprise a significant aspect of today’s endeavor in nanotechnology. During recent years, nanowires and nanorods of metallic and semi-conducting materials have drawn a lot of research interest because of their potential applications in diverse fields, for example, nanoelectronics, opto-electronics and sensors (Sarkar et al. 2007; Ratner & Ratner, 2003; Nalwa & Bandhopadhaya, 2003; Dresselhaus et al. 2003).
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Many studies have focused on the fabrication of copper nanowires (Cao & Liu, 2008; Sun Shin et al. 2009; Ingunta et al. 2008; Fang et al. 2007; Motoyama et al. 2005), because of their potential applications in the micro/nanoelectronics industry and, in particular, for interconnection in electronic circuits. Copper is one of the most important metals in modern electronic technology. Many methods have been developed for the fabrication of copper nanowires but template synthesis is considered to be the most suitable and useful for growth of nanowires.
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Template synthesis by electrochemical deposition route is easy, low-cost as well as less cumbersome compared to other fabrication techniques (Sarkar et al. 2007), namely, pulsed laser deposition (PLD), vapour-liquid-solid (VLS) method and chemical vapour deposition (CVD). Another advantage of the electrochemical deposition technique is the possibility of fabricating multi-layered structures within nanowires. By varying the cathodic potentials in the electrolyte which contains two different kinds of ions, different metal layers can be controllably deposited. Electrochemical cell used in electrodeposition of copper into pores of anodic alumina template was fabricated in our laboratory. Morphology of electrodeposited copper nanowires has been studied using Field Emission Scanning Electron Microscopy (FESEM) and crystal structure by XRD analysis. The diameter of nanowires generally depends upon the pore size of template. Anodic alumina discs of 200 nm and polymer membranes of 100 nm pore diameter were selected for this purpose.
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2. Template synthesis of nanowires
\n\t\t\t
Template-based growth is a versatile method of synthesis of metallic and semiconductor nanowires. In template-assisted synthesis of nanostructures, the chemical stability and mechanical properties of the template, as well as the diameter, uniformity and density of the pores are important characteristics to consider. Templates frequently used for nanowire synthesis include anodic alumina (Al2O3), nano-channel glass, ion track-etched polymers and mica films. Porous anodic alumina templates are produced by anodizing pure Al films in various acids, for example, oxalic acid is most commonly used. Under carefully chosen anodization conditions, the resulting oxide film possesses a regular hexagonal array of parallel and nearly cylindrical channels, as shown in Fig. 2(a). The self-organization of the pore structure in an anodic alumina template involves two coupled processes: pore formation with uniform diameters and pore ordering. Depending on the anodization conditions, the pore diameter can be systematically varied from < 10nm up to 200nm with a pore density in the range of 109 to 1011 pores/cm2 (Dingle et al., 1969).
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Template materials must meet certain requirements (Cao & Liu, 2008). First, the template materials must be compatible with the processing conditions. For example, an electrical insulator is required for a template to be used in electrochemical deposition. Template materials should be chemically and thermally inert during the synthesis. Secondly, depositing materials or solution must wet the internal pore walls. Thirdly, for synthesis of nanowires, the deposition should start from the bottom of the template and proceed upwards to the other side. This is known as bottom up technique in nanotechnology.
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Template-based synthesis offers many advantages over other methods of synthesis (Lai & Riley, 2008): (1) It is performed under mild conditions rather than requiring high temperatures, high vacuum or expensive instrumentation; (2) templated electrodeposition has a relatively high growth rate; (3) the morphology of deposited materials depends on the shape of template pores; (4) the dimensions of the materials obtained can be tuned by tuning of the template pore size; (5) two or more components can be easily deposited into the membrane sequentially to form multi-segmented materials or hetero-junctions.
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3. Materials and methods
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The electrodeposition technique used in our experiment (Virk et al., 2010) is similar in principle to that used for the electroplating process. Commercial anodic alumina membranes (AAM) (anodisc 25 made by Whatman) having an average pore diameter of 200 nm, a nominal thickness of 60 µm and a pore density of 109 pores/ cm2, were used as templates. A second set of polymer membrane (Sterlitech USA) of 100 nm pore diameter was selected for the sake of comparison. To achieve uniform deposition of nanowires, templates were cleaned in the ultrasonic bath for 10 minutes. The electrochemical cell, fabricated in our laboratory using Perspex sheets, was washed in double distilled water. A copper rod of 0.8 cm diameter was used as a sacrificial electrode (anode). The cathode consists of copper foil attached to alumina disc by an adhesive tape of good conductivity. Prior to the electro-deposition process, a thin film of copper (0.5 µm) was sputtered onto one side of alumina disc. This metal layer along with adhesive copper tape provides a stable substrate (cathode) for the growth of nanowires. Figure 1(a) illustrates the scheme of this process.
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Polymer membranes can be prepared by irradiation of polycarbonate foils using heavy ion beams (Toimil Molares, 2001). Author has prepared polymer templates, called Ion Track Filters (Virk & Kaur, 1998), using Makrofol N and Kapton after irradiation at the UNILAC (Universal Linear Accelerator) of GSI, Darmstadt, with highly charged heavy ions having kinetic energies in the GeV range and fluences between 106 and 1010 ions/cm2. Due to energy loss through interaction with the target electrons, each ion creates along its trajectory a cylindrical damage zone, a few nanometers in diameter. The damaged material can selectively be removed by chemical etching, resulting in pores of cylindrical geometry. Composition, concentration, and temperature of the etching solution determine the size and geometry of the resulting pores, the pore diameter increasing linearly with the etching time. A 6 N NaOH solution containing 10% methanol at T = 50 0C was used for etching to produce pore diameters between 50 and 200 nm by varying time of etching. A thin gold film was sputtered onto one side of the membrane using Jeol sputter and reinforced by copper foil attached by an adhesive tape of good conductivity to obtain a stable substrate. This serves as a cathode suitable for the growth of the nanowires in polymer template in our two-electrode electrochemical cell. A schematic diagram of the polymer template synthesis process is illustrated in Figure 1(b).
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The electrolyte used had a composition of 20 gm/100ml CuSO4.5H2O + 25% of dilute H2SO4 at room temperature. A high concentration of CuSO4 was used to supply a sufficiently large number of ions inside the pores during the deposition. Sulfuric acid was added to increase the conductivity of the solution and to lower the cathode over-voltage. The electrodeposition was performed at room temperature of 30 0C. The low overvoltages avoided side reactions such as hydrogen evolution. The inter-electode distance was kept 0.5 cm and a current of 2mA was applied for 10 minutes using a regulated power supply. Electrodeposition of copper nanowires depends on many factors, namely, inter-electrode spacing, electrolyte composition, temperature and pH value, current density and time of deposition. The influence of current density, temperature and type of electrolyte on the crystallinity of copper nanowires has been reported elsewhere (Toimil Molares et al., 2001). We studied the effect of current density on electrodeposition of copper nanowires in our experiment.
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After the electrodeposition was over, copper foil with template-grown nanowires was divided into two parts. One part was kept for study of I-V characteristics in-situ using Dual Source Meter (Keithley Model 4200 SCS) with platinum probes for contacts. The other part was kept immersed in 1 M NaOH for 1 hour in a beaker to dissolve alumina template. The copper nanowires were liberated from the host matrix, washed in distilled water and dried in an oven at 500C for 30 minutes. The cleaned and dried nanowires were mounted on aluminium stubs with the help of double adhesive tape. Field Emission Scanning Electron Microscope (FESEM, Hitachi S-4300) was used to record cross-sectional and lateral views of grown nanowires at an accelerating voltage of 15kV using different magnifications. X-ray Diffraction studies were carried out at Sophisticated Analytical Instruments Facility (SAIF) set up by Punjab University, Chandigarh using X\' Pert PRO (PANanalytical, Netherlands) using Cu Kα radiation.
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Figure 1.
a). A schematic diagram of the template synthesis process (Gao et al., 2002):(a) Anodic alumina template, (b) copper sputtered alumina template, (c) electrodeposited copper nanowires, and (d) copper nanowires after removal of anodic alumina template. (b). Scheme of the polymer template synthesis (Toimil Molares et al., 2001).\n\t\t\t\t\t
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4. Characterization of copper nanowires
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4.1. AFM, SEM and FESEM analysis
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Commercial available templates were examined before their use using Atomic Force Microscope (NT-MDT PR 400 Model) installed in our laboratory and Scanning Electron Microscope (Jeol, JSM 6100) facility of Punjab University, Chandigarh. Atomic force microscopic technique (Menon, 2003) shows the two dimensional surface topology of the anodic alumina template with pores regularly arranged on the surface (Fig. 2a). The pores appear nearly at the centre of each hexagonal cell. After gold sputtering, using Jeol sputter JFC 1100, SEM micrograph (Fig. 2b) shows the geometrical pattern of pores on the alumina surface of anodisc.
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Copper nanowires liberated from AAM were examined under SEM and FESEM under different magnifications. Two sets of templates were used for growth of copper nanowires. In one set, current density was changed intermittently which resulted in non-uniform growth of nanowires. Figure 3 represents the cross-sectional view of copper nanowires of 200nm diameter grown in alumina template. Figure 4(a) shows the SEM image of copper nanowires array in lateral view, grown under constant current conditions. Figure 4(b) represents the FESEM image of copper nanowires fabricated under transient current conditions. Overdeposition of copper is clearly visible towards the tip of nanowires resulting in capping effect. Nanawires are quite uniform with diameter in the range of 200 nm but they are not perfect cylinders. It has been reported (Schonenberger et al., 1997) that pore diameters of commercially available templates vary over a large range. The aspect ratio, that is, the ratio of length to diameter, is on the order of 300.
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Figure 2.
a) AFM image of hexagonal pores of anodic alumina template, (b) SEM image of anodic alumina template pores
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Figure 3.
SEM image of copper nanowires (cross-sectional view, 200 nm dia.)
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Figure 4.
a) SEM image of copper nanowires fabricated under constant current, (b) SEM image of copper nanowires showing capping effect
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Experiment was repeated using polycarbonate membrane with pore diameter of 100 nm as a template and keeping the other conditions identical. The polymer template was dissolved in dichloromethane to liberate copper nanowires from the host matrix. The rest of the procedure is same. Instead of nanowires, we observed under FESEM the exotic patterns in the form of microflowers (Fig. 5) having their petals in nanometer dimension and copper buds (Fig. 6) leading to mushroom effect. Similar results with exotic patterns were reported in our earlier experiment (Virk et al. 2010).
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There is as yet no specific theory to explain exotic patterns developed during electrodeposition of copper in anodic alumina or polymer templates. A speculative explanation (Gao et al., 2002) is provided on the basis of overdeposition. During the growth of copper nanowires in the template pores, the current remains nearly stable until the wires arrive at the template surface. If the electro-deposition process is not stopped at this stage, the current keeps on rising very gradually leading to overdeposition of copper. Flower like morphologies of metal overdeposits have been attributed to the changes in hydrodynamic conditions due to excessive hydrogen evolution during electrodeposition process (Kumar et al., 2008).
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Figure 5.
FESEM micrographs showing flower patterns grown in polymer templates
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Figure 6.
FESEM micrographs showing copper buds grown in polymer templates
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Figure 7.
SEM micrograph of pyramid shaped polycrystalline copper crystals
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We repeated the experiment for 20 nm pore diameter polycarbonate template. The template was not coated with a conducting layer during electrodeposition. It resulted in failure to grow nanowires but the failure of experiment proved to be a blessing in disguise. Instead of copper nanowires, we observed growth of double pyramid shaped copper crystals (Fig. 7). We could not find evidence for this phenomenon in literature. It is anticipated that copper ions from the electrolyte do not enter template pores due to poor conductivity but get deposited on the cathode surface in the form of polycrystalline crystals.
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4.2. X-ray and EDAX analysis
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The characterization techniques that are commonly used to study the crystal structure and chemical composition of nanowires include X-ray diffraction and X-ray energy dispersion analysis (EDAX). Both these techniques have been employed in our analysis. The crystal structure of the double pyramid shaped copper crystals has been determined using X-ray diffraction analysis. XRD spectrum (Fig. 8) shows two prominent peaks corresponding to 2θ = 43.4610 and 50.5803, with d spacing = 2.082 and 1.804, respectively. These peaks reveal the polycrystalline nature of copper crystals, indicating that preferred growth direction of crystals is the (200) plane. Template based synthesis of single crystal copper nanowires has been reported in literature (Toimil Molares, 2001; Gao et al., 2002; Mingliang et al., 2003) with preferred growth direction along (111) plane, but to the best of our knowledge, there is hardly any report for copper nanowire arrays or copper crystals with a (200) preferred orientation.
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Figure 8.
XRD spectrum of pyramid shaped polycrystalline copper crystals
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The crystallographic structure of copper nanowire arrays was investigated by X-ray diffraction analysis (XRD). For sake of comparison, XRD spectrum of Cu foil used as a substrate was also recorded (Fig. 9). XRD diffractograms were obtained in the 2θ range from 100 to 800 with a step of 0.020, using the Cu Kα radiation source of λ = 1.5406 Å. XRD spectrum (Table 1) shows three prominent peaks corresponding to 2θ = 43.5966, 50.8127 and 74.4331, with d spacing = 2.074, 1.80 and 1.27, and corresponding Miller indices, (111), (200) and (220), respectively. All peaks can be attributed to the cubic form of metallic copper (Ingunta et al., 2008). XRD spectrum of copper nanowires (Fig. 10) shows some interesting results. There are in all 8 peaks in the spectrum; with 2 additional peaks at 2θ = 37.0062 and 54.9761, which are of negligible intensity and may be ignored. Three main peaks are also there as in Fig. 9 but two of them split into double and triple peaks (Table 2), which may be attributed to X-ray scattering at the substrate. These peaks reveal the polycrystalline nature of copper nanowires, the most prominent peak at 2θ = 50.9870, indicating that the preferred growth direction of nanowires is the (200) plane. Due to polycrystalline nature of copper nanowires, the most prominent peak at 2θ = 43.5966 (Fig. 9) shifts to 2θ = 50.9870 (Fig. 10). Template based synthesis of single crystal copper nanowires have also been reported in literature (Gao et al., 2002; Mingliang et al., 2003) with preferred growth direction along (111) plane.
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The average size D of the crystalline grains in the Cu nanowires is calculated using the Debye Scherrer’s formula (Cullity, 1956): D = 0.9 λ / β cos θ, where λ=1.5406 Å is the wavelength of the X-ray radiation used, β is the full width at half maximum (FWHM) of the diffraction peak (0.1224), K, shape factor is assumed to be 0.9 and θ is the Bragg diffraction angle of the most prominent XRD peak. Substituting appropriate values in the formula, the crystallite size value of Cu nanowires comes out to be 1.22 nm. However, the value of crystallite size calculated for Cu foil is exact double, of the order of 2.44 nm.
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\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Pos. [°2Th.]
\n\t\t\t\t\t\t\t
WHM [°2Th.]
\n\t\t\t\t\t\t\t
d-spacing [Å]
\n\t\t\t\t\t\t\t
Rel. Int. [%]
\n\t\t\t\t\t\t\t
Area [cts*°2Th.]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
43.5966
\n\t\t\t\t\t\t\t
0.0612
\n\t\t\t\t\t\t\t
2.07438
\n\t\t\t\t\t\t\t
100.00
\n\t\t\t\t\t\t\t
847.65
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
50.8127
\n\t\t\t\t\t\t\t
0.0816
\n\t\t\t\t\t\t\t
1.79542
\n\t\t\t\t\t\t\t
48.53
\n\t\t\t\t\t\t\t
548.43
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
74.4331
\n\t\t\t\t\t\t\t
0.1428
\n\t\t\t\t\t\t\t
1.27358
\n\t\t\t\t\t\t\t
11.94
\n\t\t\t\t\t\t\t
236.07
\n\t\t\t\t\t\t
\n\t\t\t\t\t
Table 1.
XRD spectrum peaks data of copper film
\n\t\t\t\t
\n\t\t\t\t\t\t
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\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
Pos. [°2Th.]
\n\t\t\t\t\t\t\t
FWHM [°2Th.]
\n\t\t\t\t\t\t\t
d-spacing [Å]
\n\t\t\t\t\t\t\t
Rel. Int. [%]
\n\t\t\t\t\t\t\t
Area [cts*°2Th.]
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
37.0062
\n\t\t\t\t\t\t\t
0.3346
\n\t\t\t\t\t\t\t
2.42724
\n\t\t\t\t\t\t\t
2.29
\n\t\t\t\t\t\t\t
76.37
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
43.4706
\n\t\t\t\t\t\t\t
0.0669
\n\t\t\t\t\t\t\t
2.08010
\n\t\t\t\t\t\t\t
33.59
\n\t\t\t\t\t\t\t
223.69
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
43.8561
\n\t\t\t\t\t\t\t
0.2509
\n\t\t\t\t\t\t\t
2.06270
\n\t\t\t\t\t\t\t
93.99
\n\t\t\t\t\t\t\t
2347.28
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
50.5881
\n\t\t\t\t\t\t\t
0.0816
\n\t\t\t\t\t\t\t
1.80286
\n\t\t\t\t\t\t\t
74.62
\n\t\t\t\t\t\t\t
819.15
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
50.9870
\n\t\t\t\t\t\t\t
0.1224
\n\t\t\t\t\t\t\t
1.78969
\n\t\t\t\t\t\t\t
100.00
\n\t\t\t\t\t\t\t
1646.70
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
51.1172
\n\t\t\t\t\t\t\t
0.1224
\n\t\t\t\t\t\t\t
1.78544
\n\t\t\t\t\t\t\t
87.56
\n\t\t\t\t\t\t\t
1441.89
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
54.9761
\n\t\t\t\t\t\t\t
0.4080
\n\t\t\t\t\t\t\t
1.66889
\n\t\t\t\t\t\t\t
0.75
\n\t\t\t\t\t\t\t
41.24
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t
74.4238
\n\t\t\t\t\t\t\t
0.4080
\n\t\t\t\t\t\t\t
1.27372
\n\t\t\t\t\t\t\t
5.90
\n\t\t\t\t\t\t\t
324.08
\n\t\t\t\t\t\t
\n\t\t\t\t\t
Table 2.
XRD spectrum peaks data of copper nanowires
\n\t\t\t\t
Figure 9.
XRD spectrum of Copper film serving as a substrate
\n\t\t\t\t
Energy dispersive X-ray analysis (EDAX) of Cu nanowires was carried out at FESEM facility of CSIO, Chandigarh to determine chemical composition of nanowires. The spectrum (Fig. 11) reveals 3 peaks of copper with 100% pure copper content and no traces of any impurity in Cu nanowires. It also establishes that multiple XRD peaks are not due to any impurity but due to polycrystalline nature of Cu nanowires.
\n\t\t\t\t
Figure 10.
XRD spectrum of Copper nanowires of 200 nm diameter
\n\t\t\t
\n\t\t\t
\n\t\t\t\t
4.3. I-V Characteristics of copper nanowires
\n\t\t\t\t
I-V properties of aligned copper nanowires have been studied using a current- sensing AFM (Cao et al., 2006). Electronic transport through nanocontacts has been an active research area. The ultimate aim for nanowires is to find applications in the nanoelectronic devices. How can a copper nanowire produce a nonlinear I–V curve? The simplest possibility for observing such a phenomenon is generation of a tunnelling barrier at the wire–lead junction whose effect gradually collapses as a function of increasing bias voltage (Mehrez & Guo, 2004). The nonlinear curves of Cu nanowire arrays may be caused by the existence of impurities (such as oxide) near the wire–lead contact region. Nonlinear phenomena of silver wire and gold wire have also been observed in air (Mehrez & Guo, 2004; Wildoer et al., 1998). It has been demonstrated that the nonlinear I–V characteristic is the basis of functional electronic devices (Itakura et al., 1999).
\n\t\t\t\t
I-V characteristics of copper nanowires were recorded in-situ, as grown in pores of anodic alumina template, using Dual Source Meter (Keithley Model 4200 SCS) with platinum probes for contacts. The combination of copper nanowires on alumina, an insulator, results in the formation of a strange device. I-V plot (Fig. 12) shows some interesting features of a resonating tunneling diode in the forward bias mode but nothing special in the reverse bias mode. The offset in I-V plot around zero voltage may be due to slight non-ohmic characteristic of the contact, or due to quantum confinement behaviour of electrons traversing through copper nanowires.
\n\t\t\t\t
Figure 11.
EDAX spectrum and elemental composition of Copper nanowires
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
5. Conclusions
\n\t\t\t
Our investigations confirm that electrodeposition of copper nanowires in anodic alumina is the simplest route to nanotechnology. The copper nanowires reveal effect of high current density resulting in overdeposition in the form of capped growth, and not as perfect cylinders. The aspect ratio is very high, of the order of 300. XRD analysis shows polycrystalline nature of nanowires and pyramid shaped copper crystals with preferred growth direction in the (200) plane. The crystallite size of nanocrystals in copper nanowires is determined to be 1.22 nm. Overdeposition results in growth of copper buds and beautiful flower patterns. I-V characteristics do not conform to normal p-n junction behaviour and need further investigation. The nonlinear I–V characteristic of the as-synthesized copper nanowire arrays suggests the presence of a potential barrier. Due to high aspect ratio, copper nanowires may be used as field emitters.
\n\t\t\t
Figure 12.
I-V characteristics of copper nanowires grown in-situ in anodic alumina template
\n\t\t\t
Copper oxide nanowire arrays have already found applications in gas sensing, field emission and photovoltaic devices. A recent study (Rathmell et al., 2010) has established that copper nanowires could revolutionize the development and production of low-cost flexible displays, light emitting diodes and thin film solar cells. Copper is 1000 times more abundant than indium or silver, and is 100 times less expensive. As a consequence, films of copper nanowires represent a low-cost alternative to silver nanowires or ITO for use as a transparent electrode.
\n\t\t
\n\t\t
\n\t\t\t
6. Acknowledgements
\n\t\t\t
The authors are thankful to the Principal, DAV Institute of Engineering & Technology, Jalandhar and DAV College Managing Committee, New Delhi for providing research grant to set up Research Centre and Nanotechnology Laboratory. Author wishes to record his appreciation for research assistants and technical staff of Nanotechnology Laboratory in collection of data. He is thankful to Dr Lalit M. Bharadwaj and his team at CSIO, Chandigarh for providing FESEM research facility.
\n\t\t
\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/16379.pdf",chapterXML:"https://mts.intechopen.com/source/xml/16379.xml",downloadPdfUrl:"/chapter/pdf-download/16379",previewPdfUrl:"/chapter/pdf-preview/16379",totalDownloads:6283,totalViews:419,totalCrossrefCites:2,totalDimensionsCites:5,totalAltmetricsMentions:0,impactScore:2,impactScorePercentile:83,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"October 11th 2010",dateReviewed:null,datePrePublished:null,datePublished:"July 18th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/16379",risUrl:"/chapter/ris/16379",book:{id:"514",slug:"nanowires-implementations-and-applications"},signatures:"Hardev Singh Virk",authors:[{id:"24912",title:"Dr.",name:"Hardev",middleName:"Singh",surname:"Virk",fullName:"Hardev Virk",slug:"hardev-virk",email:"hardevsingh.virk@gmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/24912/images/646_n.jpg",institution:{name:"Guru Nanak Dev University",institutionURL:null,country:{name:"India"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Template synthesis of nanowires",level:"1"},{id:"sec_3",title:"3. Materials and methods",level:"1"},{id:"sec_4",title:"4. Characterization of copper nanowires",level:"1"},{id:"sec_4_2",title:"4.1. AFM, SEM and FESEM analysis",level:"2"},{id:"sec_5_2",title:"4.2. X-ray and EDAX analysis",level:"2"},{id:"sec_6_2",title:"4.3. I-V Characteristics of copper nanowires",level:"2"},{id:"sec_8",title:"5. Conclusions",level:"1"},{id:"sec_9",title:"6. Acknowledgements",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCao\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Template-based synthesis of nanorod, nanowire, and nanotube arrays. 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Director Research, Nanotechnology Laboratory,, India
DAV Institute of Engineering and Technology,, India
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Hashim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},onlineFirst:{chapter:{type:"chapter",id:"65340",title:"Engineering of Surface Proteins in Extracellular Vesicles for Tissue-Specific Targeting",doi:"10.5772/intechopen.83537",slug:"engineering-of-surface-proteins-in-extracellular-vesicles-for-tissue-specific-targeting",body:'\n
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1. Introduction
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The transfer of extracellular vesicles (EVs) has emerged in the last two decades as a novel mechanism for intercellular communication. Nomenclature of EVs has by now been agreed to be based on biogenesis pathway. Therefore, EVs budding from plasma membranes are termed ectosomes or microvesicles, while exosomes are formed via the endosomal compartment within multivesicular bodies (MVB) which then are released by their fusion with the plasma membrane. Finally, when blebbing from apoptotic cells, the term apoptotic bodies has been retained [1]. Biomarkers to differentiate these EVs are still questionable, and in general, size is used to differentiate exosomes from ectosomes, while apoptotic bodies are considered to present phosphatidylserine on the outside and thus can be stained by annexin V. Exosomes (40–150 nm in diameter) are produced by formation of endosomal intraluminal vesicles (ILVs) in multivesicular bodies (MVBs) and are secreted by fusion of these vesicles with the plasma membrane [2, 3] (Figure 1).
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Figure 1.
Biogenesis of EVs.
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Since they have been known to mediate directional intercellular transfer of their content, typically proteins, mRNAs, microRNAs (miRNAs) and a variety of non-coding RNAs [4], several studies were oriented towards their application as drugs per se or as therapeutic tool for drug delivery [5]. Their membrane is strongly enriched in sphingomyelin and cholesterol, which contributes to their unique buoyancy coefficient and enables practical isolation from other particles of cellular origin using differential centrifugation methods. Another discernible feature of exosome membranes is that it reflects the composition of the MVB membrane and has a high density of endosomal membrane proteins, such as proteins involved in MVB biogenesis (Alix and TSG101), membrane transport, in particular the components of the endosomal sorting complex required for transport (ESCRT) and most prominently tetraspanin proteins (CD9, CD37, CD53, CD63, CD81, CD82 and CD151) [6, 7]. Some tetraspanins such as CD9, CD81 and CD151 are more broadly expressed, while others are restricted to specific EV subsets [8, 9]. The overexpression of tetraspanins, as shown for CD9, can in several production cell lines enhance the exosome production and, in addition, cause a reduced overall size of the vesicles [10].
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Tetraspanins play an important role in several physiological processes [11] and have been discovered to cooperate in states of health and disease in signal transduction, cellular activation, polarization, motility, adhesion, tissue differentiation, angiogenesis, tumorigenesis and metastasis [12, 13, 14], both by regulating cellular interactions as cell-membrane bound molecules and indirectly through exosomes. They are involved in each step of the metastatic cascade due to their ability to interact with cell surface receptors, adhesion molecules, matrix-remodeling proteases and signaling molecules. In this pathological state, they hence regulate cell proliferation, participate in epithelial-mesenchymal transition, modulate integrin-mediated cell adhesion and mediate the invasion through modulation of angiogenesis, tumor-endothelial cell interactions and regulation of cancer cell migration through the regulation of tumor microenvironment, as well as direct influence on extracellular matrix [15]. In this chapter, we introduce the characteristics of EVs and the engineering approaches aimed at their surface proteins to achieve tissue-specific targeting.
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2. Structure of the tetraspanin proteins
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The rod-shaped structure of a tetraspanin consists of four transmembrane helices that connect the two extracellular loops [16] (Figure 2). The short extracellular loop (SEL), which has not yet been reported to contain any element of a particular secondary structure, is of 12–31 amino acids in length. In the studies oriented towards tetraspanin engineering, the EC1 domain has until now been less addressed due to its lower degree of structural organization. Its replacement for a strand of glycine-serine residues has led to an unusual cell surface expression and a distribution dissimilar to the wild-type parental molecule, which may suggest the importance of this structural subunit for the stability of the membrane-bound tetraspanin [17].
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Figure 2.
Organization of tetraspanin CD81: 4 transmembrane helices (TM) span 2 extracellular loops. Positions of cysteine residues are indicated with yellow dots. Crystal structure of EC2 domain is presented as a cartoon diagram of the dimeric form (PDB: 1G8Q); the conserved three-helix bundle is black and the variable domains C and D are surfaced in blue or green for each protomer. The figure was prepared using PyMOL (PyMOL molecular graphics system, version 1.3 Schrödinger, LLC).
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The large extracellular loop (LEL) or extracellular domain 2 (EC2) has on the other hand been well characterized. The crystal structure of CD81 [18] demonstrated the four invariant cysteine resides within EC2 to form the 2 disulfide bridges, as a hallmark stability feature of the conserved tetraspanin fold [8, 19] (Figure 2). Moreover, the topology of several other tetraspanins was predicted by molecular modeling studies in the absence of an available crystal structure, using the CD81 EC2 structure as a template: these were the tetraspanins CD37, CD53, CD82 and CD151 [20, 21]. It has been early established that binding of CD81-specific antibodies depends on the formation of the disulfide bonds [22]. One class of tetraspanins harbors the EC2 composed of five α-helical elements, forming stalk and head elements of a mushroom-like structure, and the second class of tetraspanins is postulated to contain an additional helical element, stabilized with another pair of cysteine residues. The EC2 fold structure is evolutionarily conserved across species for any particular tetraspanin in spite of a high degree of variability at the amino acid level [23], with a subdomain consisting of a three-helix-bundle fold and a second subdomain variable in size among members of the tetraspanin family [18, 20].
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The presence of an energetically unfavorable hydrophobic patch and the dimeric form of CD81 LEL in a crystal hinted at the high likelihood of tetraspanin assembly into dimers or multimers in the cell membrane. As shown later, clustering of tetraspanins leads to the organization of tetraspanin-associated proteins in a tetraspanin web or tetraspanin-enriched microdomain (TEM) [24, 25]. Biologically, such domains induce partitioning of the complexes into lipid rafts and clustering of the lipid rafts [26].
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Apart from the hydrophobic interactions of the extracellular domains, the membrane-proximal cysteines residing in transmembrane domains contribute to the dimer formation and stability of tetraspanins. For the CD9 tetraspanin, it has been demonstrated that these residues are positioned close to the dimerization interface and influence homotypic and heterotypic tetraspanin association depending on their reversible palmitoylation status [27]. Similarly, the mutation of N-terminal and C-terminal transmembrane cysteines to serine eliminated palmitoylation of CD151, which turned out to be deleterious for the assembly with other cell surface proteins, including tetraspanins CD9 and CD63, their organization to TEMs and subsequently their subcellular distribution and cell morphology [28]. At the same time, it had minimal influence on the density of tetraspanin protein complexes and was dispensable for CD151-α3β1 integrin association. Depalmitoylation of CD81 did not impact its surface expression and stability, but rendered it less available for contact with its natural interaction partner CD9 and the relevant epitopes less accessible for binding of structurally dependent antibodies [29].
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The four transmembrane helices of tetraspanin proteins form two largely separated pairs of antiparallel helices: one pair comprises TM1/TM2 and the other TM3/TM4. The two pairs of helices only converge close to the cytoplasmic side of the membrane through contacts between TM2 and TM3. In the recently solved crystal structure of full-length CD81, this cone-like structure has been shown to harbor a binding pocket for cholesterol [30], and mutations within transmembrane domains in certain tetraspanins have been connected with pathological states [31]. The short cytoplasmic tails show no obvious functional significance in signaling processes, suggesting that their signaling competence relies on association with other molecules [32]; nevertheless, its mutation can lead to different assembly with association partners as shown for CD9 [33].
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3. Natural ligands of tetraspanin proteins
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3.1. The tetraspanin web and intertetraspanin contacts
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The ability of members of the tetraspanin family to assemble into a unique biological feature known as tetraspanin-enriched microdomain (TEM) is due to their mutual interactions; however, these structures include also receptors, integrins and signaling molecules such as phosphatidyl-kinase C (PKC) and phosphatidylinositol-4-kinase (PI4K) [9]. These interactions are fundamental for cellular functions such as cell adhesion, proliferation and motility. Interactions between tetraspanin members are important in maintaining the integrity and stability of the tetraspanin web and providing binding sites for different ligands. The multimers of newly synthesized proteins are formed in the Golgi apparatus. The predominantly cross-linked tetraspanin species are homodimers, but also higher order complexes and low amounts of heterodimeric tetraspanins (CD81/CD9, CD9/CD151, CD81/CD151) were identified [27]. It has been suggested that tetraspanin homodimers, formed in the Golgi and present at the cell surface, serve as building blocks in the assembly of higher organized tetraspanin protein complexes. Interestingly, the exosomes originating from cell lines overexpressing CD9 are believed to be enriched in more stable TEMs [10]. Overall, although most tetraspanins can interact with most other tetraspanins, and similarly engage with several other proteins, the nature of these interactions has been until recently classified only according to their stability in the presence of detergents of different stringency, which does not necessarily reflect their significance in the cellular milieu [34]. A thorough characterization of strength and abundance of the interactions between the members participating in a tetraspanin web in a particular cell and physiological situation is therefore needed and will support the understanding of its mediated biological effects. Similarly, most data on tetraspanin functionality come from studies on their localization on cell membranes, while functional data in vesicles are still scarce. Therefore, we here summarize the known cellular functions, while speculating how this might translate to EVs.
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An important step towards the understanding of the specificity of the tetraspanin interactions in TEM has been achieved by delineation of the involved tetraspanin regions by dissecting the model tetraspanin into domains, differently amenable for modification. Early experiments that addressed the relatively unstructured and at the same time antigen-binding competent regions that appeared attractive for mutagenesis resulted in a protein that showed aberrant clustering involving both homo- and heterodimerization of resulting full-length tetraspanins [35], albeit the mutagenesis method employed in this study was a complete deletion of targeted domains. The CD81 D-region was studied in more detail: the CD9 and CD151 tetraspanins were more competent of clustering with CD81 when homologously engrafted with CD81 D-region [36]. When the mutagenized CD81 EC2 molecular subunits were transplanted to other tetraspanins, the extremely flexible conformation of the solvent-exposed D-segment of CD81 EC2 was sufficient to overcome the orientational restrictions to initiate the homotypic contact for dimerization, and this finding has been corroborated with both wet-lab data and the insights from molecular dynamic simulation of the cell membrane-embedded protein [37].
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3.2. Interaction of tetraspanins with integrins and matrix-degrading enzymes: role of tetraspanins in cancer and metastasis
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Important association partners of tetraspanins are the integrins. The role of such complexes in invasive growth in vivo as well as the effect of integrin-mediated binding events on cell proliferation and invasion is well established. Especially, the laminin-binding integrins (α6β4, α3β1, α6β1 and α7β1) exhibit extensive interactions with tetraspanin proteins [12, 38]. The functionality of integrins may depend critically on their interaction of tetraspanins: it has early been described that the remarkably stable association of the tetraspanin CD151 and the integrin α3β1 leads to a high level of activation of cellular PI4K [39]. Further, CD151 interacts directly with the α3 subunit and links it to other tetraspanins, CD9 and CD81. Loss of CD151 abrogates the α3β1 mediated mobility on its ligands, laminin-332 and laminin-551. CD9/CD81 complex may even regulate the integrin-mediated functions independently of CD151 by forming a complex with the integrin and directing the PKCα-α3β1 association [40]. Another example of tetraspanin-integrin association reveals its proangiogenic role through VEGF induction, mediated by cooperation between TM4SF5 and integrin α5 of epithelial cells [41]. Interestingly, removal of CD151 palmitoylation sites did not disrupt the CD151–α6β4 complex in epithelial cells but strongly influenced α6β4-integrin–dependent cell morphology [42]. The rat tetraspanin D6.1A (human homolog is CO-029) was able to induce systemic angiogenesis by initiation of an angiogenic loop that reached organs distant from the tumor, probably due to the abundance of D6.1A in tumor-derived exosomes. This is in line with reports claiming that EVs prepare niches for metastatic tumor cells at tissues distant from the primary tumor [43]. This tetraspanin associates with integrins α3β1, α6β1 and α6β4, as well as with tetraspanins CD9 and CD81, and is similarly to CD151 linked to tumor-promoting activities [44].
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Active complexes of tetraspanins and integrins influence biological processes other than cellular signaling by interacting with cellular metalloproteinases, important players in the remodeling of extracellular matrix. A study of MDA-MB-231 cells, a breast cancer cell line, has indicated that the α3β1-tetraspanin protein complex may be linked to an invasive phenotype of tumor cells via modulation of various signaling pathways, including activation of membrane metalloproteinase-2 (MMP-2), an enzyme associated with invasive migration of the cells, and affecting phosphatidylinositol-3-kinase (PI3K) signaling pathways, which control actin cytoskeleton dynamics [45]. By the incorporation of the members of a disintegrin and metalloproteinase (ADAM) family members the tetraspanins are able to influence the cellular ectodomain cleavage and release activity of these enzymes [46]. The tetraspanins of the TspanC8 group (tetraspanins with 8 cysteines) have a significant impact on the cellular exit and catalytic activity of ADAM10 [47], in particular the activity of Tspan15/ADAM10 promoted N-cadherin cleavage [48, 49, 50]. Different TspanC8/ADAM10 complexes seem to have different substrate specificities [51]. The silencing of CD9 enhanced shedding of ADAM17-substrates TNF-α and ICAM-1 [52].
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Important discovery of the possible consequences of fine differences in composition of TEMs has been delivered by the study of exosomes enriched in Tspan8-α4 complex that were preferentially taken up by the endothelial and pancreatic cells [53]. The fact that such modifications can allow selective targeting in vitro and in vivo holds promise to achieve improved exosomal delivery by engineering of their membrane components.
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3.3. The role of tetraspanins in immune complexes
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In antigen-presenting cells (APCs), tetraspanins integrate into TEMs protein-recognition receptors binding to conserved repeated motifs of microbes, such as Toll-like receptors, and MHCII molecules into tetraspanin web platforms, as well as Fcγ receptor I in phagocytic cells, Fcγ receptor IIb and III upon the activation of macrophages and Fcε receptor I in monocytes and skin-derived dendritic cells [54].
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The particular role of CD81 protein in the formation of specialized microdomains in the plasma membrane of the cells of the immune system was discovered by elucidating its function of recruiting various adhesion molecules, receptors and signaling proteins to the central zone of the immune synapse in T-lymphocytes and APCs [55]. Therefore, it has early been proposed for CD81 to play a key role during antigenic presentation, since it colocalizes with the T-cell receptor/CD3 [56], and CD81 indeed turned out to be a regulator of CD3 clustering and sustained CD3 signaling [57].
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Further, the T-cell side of the immune synapse is densely populated by tetraspanins CD9 and CD151. The abolishment of their expression reduces markers of activation of T-lymphocytes conjugated to the APCs, such as IL-2 secretion and expression of CD69 [58].
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Another role in the immune response of tetraspanin CD81 is amplifying and sustaining B-cell receptor signaling from lipid rafts by ligation to the co-receptor CD19/CD21 complex. The signaling through a variety of cell surface protein complexes implies a role of lipid rafts, again highlighting the ability of tetraspanin to facilitate raft association [9].
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3.4. Tetraspanins in pathogen infection
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Several studies have been oriented towards the research of tetraspanins as ligand molecules for pathogen entry. CD81 has been identified as a ligand for hepatitis C virus (HCV) recognition and viral entry [59]. The ligand for viral glycoprotein E2 is the D-domain of the LEL, a dynamic region positioned within the triple-bundle helix, whose conformation in solution differs substantially from the one suggested by crystal structure. Challenging for structure-based design, this region nevertheless presents an attractive target for design of therapeutically relevant ligands with methods such as NMR [60]. Apart of the EC2 domain, other regions of CD81 have proven important for virus infection. Experimental evidence here was based on the exchange of the structural domains of the molecule with the ones of tetraspanins of different degrees of homology, and it was found that closely related substitutions were more efficient at functional complementation of CD81. Viral entry has been shown to correlate with surface expression of the chimeric protein and to depend on the presence of the cholesterol-coordinating glutamate residue [61]. EWI-2wint, a cleavage form of EWI-2, a member of the immunoglobulin superfamily, has an inhibitory effect on HCV infection by obstructing the interaction between CD81 and HCV E2 [62]. The related factor EWI-F inhibits Plasmodium infection, whereas its silencing increases infection efficiency [63].
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Tetraspanin microdomains have been described to regulate HIV-1 entry, assembly and transfer between the cells [64, 65]. CD81 influences importantly the early stages of virus replication by controlling the stability of HIV-1 restriction factor and consequently the activity of viral reverse transcriptase [66], while CD63 facilitates endocytosis of the HIV receptor CXCR4 [67] as well as supports the replication steps in macrophages [68, 69]. Also Coronaviruses and low-pathogenicity Influenza A viruses utilize TEM domains as entry portals to co-engage with cellular receptors and proteases, which enable viral proteolytic priming [70]. As shown in an in vivo model with CD151 null-mice, this tetraspanin is a critical novel host factor of nuclear export signaling of Influenza A virus, used complementary to the viral nuclear export proteins [71].
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Tspan9 modulates the early endosome compartment to make it more permissive for membrane fusion of early-penetrating viruses, and its depletion strongly inhibits infection by alphaviruses that fuse in early endosomes but does not alter the delivery of virus to early endosomes or change their pH or protease activity [72]. It is unclear, what function then EV-based tetraspanins might have in the context of viral infection, and it might be speculated that cells use EVs to titrate away virus into membrane structures that are unable to provide replication and protein synthesis machineries for the virus. This is supported by the findings that EVs might have anti-influenza infection activity in vitro [73].
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4. Extracellular vesicles as mediators of cell-cell interaction
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4.1. Biological basis for therapeutic applications: EVs as mediators of intercellular interactions
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EVs are secreted by most cell types and are taken up by recipient cells, where their cargo consisting of a cocktail of proteins, mRNAs and non-coding RNAs alters the behavior of the recipient cells in a way that might be even considered similar to hormones or cytokines [74], e.g. in the context of skin or bone cell paracrine signaling [75, 76, 77]. siRNAs (small interfering RNAs) and miRNA-based inhibitors have been recognized as potent novel drug candidates for many years. As EVs can be loaded with different drugs in vitro, they qualify as an attractive drug delivery system. The specificity of the recipient cell targeting in vivo is understood in a limited way only, although there is evidence of accumulation of specific EVs [43]. For example, EVs from human mesenchymal stem cells accumulated in the liver, spleen and sites of acute kidney injury [78]. Such tropism for a specific cell type, a requirement for targeted drug delivery, appears to be determined by surface proteins of the source cells. The composition of EV membrane reflecting the one of their source cell makes these particles non-immunogenic, and their small size allows them to pass the immune surveillance of the host organism [79, 80]. The reported engagement of exosomes in physiological processes in normal and diseased central nervous system makes them attractive vehicles for delivering neurotherapeutic agents across the blood-brain barrier [81, 82, 83]. Nevertheless, their delivery in humans seems so far limited to liver and kidney as they are reported not to reach therapeutic amounts in brain, heart and other tissues due to lack of specific targeting and thus low enrichment of the intended therapeutic ingredient in the target tissue. Modifications of the EV surface membrane to achieve enhanced targeting of a specific cell type are hence a common strategy embodied in several different engineering approaches.
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4.2. Mechanisms of EV entry into the target cell
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When an EV attaches to the target cell surface, it can in some cases activate the cognate receptors without internalization or transfer of the content to the recipient cell via its fusion with the target cell membrane or via endocytosis [84]. Endocytosis is an active process that requires cytoskeletal remodeling dependent on actin dynamics and includes clathrin-dependent endocytosis, phagocytosis and macropinocytosis. The clathrin-dependent endocytosis has been established as cellular entry for EVs based on the experiments with specific inhibitors of this pathway. Additionally, endocytic uptake of EVs can involve lipid rafts, sometimes dependent on caveolin proteins. The size of EVs may be a limiting factor for cellular entry via endocytosis [85]. The EV uptake by phagocytosis was monitored by their high level of accumulation in phagocytic cells and localization into the phagolysosome [86], as well as the identification of the crucial role of the phosphatidylserine binding T-cell immunoglobulin and mucin domain containing (TIM4) receptor for the uptake of exosomes into macrophages [87, 88]. The contribution of macropinocytosis pathway was revealed with studies where exosomal uptake was decreased by the inhibition of cytoskeletal rearrangements that normally lead to membrane ruffles [89], as well as with its promotion caused by the activation of the agonistically acting epidermal growth factor [90].
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5. Molecular engineering to facilitate EV labeling and delivery to target cells
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5.1. Modifications of EV membrane with non-covalent and chemical modifications
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The role of EVs as encapsulated intercellular messengers makes them attractive for development into nanoscale therapeutic agents [91], and therefore, the need of augmenting the interaction with the recipient cell has been widely recognized. The higher rigidity of the membrane of EVs in comparison with their source cells does not appear to obstruct the efficient application of common hydrophobic insertion strategies to EVs. The introduction of small lipophilic ligands, such as membrane dyes, works effectively for their labeling and aids in monitoring in in vitro and in vivo experiments. Furthermore, hydrophobic loading is used for encapsulation of certain drugs and leads to their increased stability and therapeutic effect [92, 93].
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Due to the negative charge on the recipient cells, binding and uptake of EVs were enhanced by increasing the charge interactions with an artificially introduced positive surface potential, as exemplified in their derivatization with cationic lipids [94]. A downside of this method can be that the extremely charged cationic reagents can cause cytotoxicity and the cellular uptake of the modified particles can proceed differently from the usual pathways, which results in an unpredictable cellular fate of the particle and its cargo and possibly its undesired degradation. The innate slightly negative electrostatic potential exhibited by unmodified EVs should contribute to the longer half-life of such particles in vivo as inferred from liposomal studies [95]. Further, the extremes of unbalanced positive charge may negatively impact the storage stability and the application of such reagents in high concentrations.
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As an alternative to other methods, labeling of EV surfaces with fluorescent probes has been achieved using click chemistry without an apparent effect on the size and function of the particles [96]. Nevertheless, there is an immense complexity behind the engineering and downstream methods developed for other biologicals conjugated with small molecules, especially when intended for therapeutic purposes [97, 98].
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The idea of decoration of EV membranes with functional ligands further led to the consideration of receptor binding strategies. Such EV functionalization can readily be achieved by modification of the source cell. A resulting opportunity harvesting the specificity of this approach could also be used as a strategy to eliminate vesicles implicated in pathological processes, such as cancer metastasis, or to neutralize the undesired activity of therapeutically applied vesicles. Transferrin-conjugated superparamagnetic nanoparticles, reactive with surface-expressed transferrin receptor of exosomes, enabled their isolation from blood and endowed the vesicles with superior targeting properties [99]. A robust labeling approach of microvesicles was the expression of biotin acceptor peptide-transmembrane domain (BAP-TM) receptor on the source cells in combination with biotinylation in vivo [100].
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Another example of employing an EV-localizing protein for efficient presentation on the EV surface involved a peptide or a protein fused with the C1C2 domain of lactadherin, which binds to EV outer membrane due to its affinity to phosphatidylserine, strongly enriched in exosome membranes. This method was used to generate antibodies against tumor biomarkers [101] and to increase the host immune response to tumor-associated antigens [102, 103].
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Strong binding of lactadherin to the exosome membrane was also the basis of an efficient labeling protocol utilizing overexpression of a fusion protein composed of Gaussia luciferase and a truncated lactadherin in source melanoma cells. After harvest by ultracentrifugation, the labeled exosomes were successfully used for in vivo biodistribution studies [104].
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5.2. Engineering of tetraspanin proteins for detection and monitoring of EVs
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Regarding the tetraspanins not only as very abundant, but as prominent structural and stability elements of the exosomal membrane, it is sensible to engineer genetic fusions of these proteins enriched in EVs to ensure a high density of the expressed product and optimize the derivatization for the different purposes of engineering: cognate ligand binding, labeling for visualization or isolation, modifying cargo uptake and transfer and stability (Figure 3). Most practically, transgene expression in the parent cell would be induced to deliver EVs enriched in the modified protein. The success of such set-up depends on the understanding of both molecular biology and protein architecture of the targeted species.
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Figure 3.
Main engineering goals utilizing the modification of tetraspanins.
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In one of the pioneering studies, certain sites on the tetraspanin CD63 have been chosen to allow the integration of fluorescent fusion proteins on the extra- and intravesicular side of the exosomal membrane [105]. CD63-GFP fusions have proven valuable reporters in the elucidation of the role of immune synapse in secretion of exosomes from T-cells to APCs and their fusion with recipient cells [106], in determining differential uptake properties of different immune cell subsets for EVs originating from a cancer cell line [107] and in an in vivo study imaging the fate of EVs produced by breast cancer cell line in nude mice [108].
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5.3. Engineering of EV surface proteins for enhanced cell-type specific targeting: introduction of target specificity, stability and improved cargo delivery
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In the pioneering example of derivatization of a protein enriched in exosomal membrane to achieve specific targeting [109], the rabies virus glycoprotein (RVG)-peptide fused with lysosome-associated membrane glycoprotein 2b (Lamp-2b) was used to target exosomes to the central nervous system in an in vivo mouse model. Immature dendritic cells-derived exosomes, enriched in an N-terminal fusion of an αv integrin-specific internalizing RGD-sequence containing peptide with this scaffold, could internalize efficiently into target-positive breast cancer cells [110]. The display of such constructs could be efficiently enhanced by introducing a protective glycosylation motive, which improved the surface expression of exosome-bound N-terminally fused peptides by preventing their acid-mediated proteolysis during endosomal passage and indeed led to a more efficient specific cellular uptake of exosomes engineered in this way [111]. Specific targeting of IL3-receptor overexpressing chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cells has been shown for exosomes armed with a fusion protein of IL3 and Lamp2b and loaded with Imatinib, a tyrosine kinase inhibitor, and led to a the reduction of tumor size in vivo [112]. Exosomes engineered in this way achieved a higher abundance at the tumor site and were hence able to inhibit xenograft growth more efficiently than the active ingredient alone or than loaded control exosomes.
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Glycosylphosphatidylinositol (GPI)-mediated anchoring of the specific targeting unit was demonstrated to be a stable alternative to Lamp2b fusions. EVs expressing GPI-anchored nanobodies, specific to epidermal growth factor receptor (EGFR), displayed enhanced binding to the EGFR-overexpressing cancer cells. This, however, did not lead to an increased uptake, and it was suggested that in this particular biological system not only the affinity but also the density of the targeting ligand must be high enough to induce receptor clustering and subsequent internalization [113]. Exosomes derived from a HEK cell line transfected with a construct of platelet-derived growth factor (PDGF)-anchoring sequence and an EGFR-binding peptide were on the other hand efficient in targeting EGFR-expressing tumors in vivo and reducing their size with delivery of microRNA Let7 [114]. Enhanced uptake has been achieved for EVs enriched in a fusion protein of tetraspanin CD63 and stearylated octaarginine, a representative cell-penetrating peptide, by their ability to induce active macropinocytosis [115].
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The concept of enhancing the stability of the targeted exosomal surface protein intended for fusion with a targeting agent to allow a higher degree of versatility for their modification for an improved target recognition has raised interest in their engineering at the protein level. A significant increase in thermal stability has been achieved by introduction of additional disulfide bonds in the EC2 of tetraspanin CD81, with the best variant exhibiting a positive shift in the melting temperature for 45°C comparing with the wild-type protein [116]. When engrafted with a human transferrin-receptor specific peptide, the stabilized scaffold exhibited significantly better biophysical properties than the analogously engrafted wild-type protein. In the same study, a mutant has been discovered that exhibits reversible unfolding behavior up to a temperature of 110°C in contrast to the wild-type CD81 EC2, which presents another option for extensive engineering required for directed evolution of tetraspanin proteins towards novel antigen binding.
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Not only can the overexpression of tetraspanins in source cell lines increase the production and stability of exosomes, but also the exosomes engineered to contain adeno-associated viruses (AAVs), designed for improved delivery of genetic material to target cell [100], were superior in their yield and functionality when CD9 was overexpressed in AAV-producer cells [10]. CD9 overexpression has also increased the speed and transduction efficiency of lentiviral gene delivery into numerous cell lines, confirming the important role of this tetraspanin in gene transfer [117].
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The current scope of EV engineering reaches beyond receptor targeting systems and aspires towards modifications with complex modules, assigning them simultaneously with multiple novel functionalities, such as specific recognition as well as enzymatic activity, to enhance their potential therapeutic effect. Recently, regression of orthotopic Her2-positive tumors has been achieved by applying exosomes, able of specific targeting via their surface decoration with a fusion protein of high-affinity anti-Her2 single-chain Fv, and containing mRNA encoding a bacterial enzyme Hchr6, which in the strongly Her2-positive cells catalyzed the conversion of the prodrug CNOB to cytotoxic MCHB [118]. Tetraspanin engineering could support a sophisticated concept to aid intracellular delivery of exosomal cargo proteins, directionally incorporated during vesicle biogenesis [119]. Genes encoding two recombinant proteins, a fusion of photoreceptor cryptochrome 2 (CRY2) and the protein of interest and a fusion of tetraspanin protein CD9 and CRY-interacting basic-helix–loop–helix 1 (CIB1), were co-transfected into a single cell line. The blue light-induced binding of CRY2 and CIB1 enabled docking of CRY2-fused target proteins into nascent exosomes, and in the absence of the blue light, the cargo protein was released into the exosomal lumen. Transfer of Cre recombinase confirmed the efficiency of this system in vitro and in vivo.
\n
\n
\n
\n
6. Conclusions
\n
The tetraspanins, well established as the biomarker proteins of extracellular vesicles, have been addressed for increasing EV stability and improving their function as delivery vehicles, both by assigning them with target recognition properties and modulating their cargo transfer. From the current point of view, the complexity of the tetraspanin-mediated interactions and signaling networks formed in a cell is yet to be discerned. Tetraspanins are known to interact naturally with a plethora of cell surface-bound ligands, which results in potent biological effects conveyed through different pathways; however, systematic evaluation of the affinity of the association with the interaction partners would assist in prediction of the consequential cellular processes as well as in determining optimal choice of the tetraspanin targeted for modification. There are recent reports describing modified tetraspanins mediating both surface protein interactions and an intracellular fusion-mediated enzymatic activity, which underline the feasibility of engineering versatile functions into tetraspanin proteins as fusion partners. The structural details on tetraspanins modified in this way, as well as the read-out revealing their actual behavior in the foreseen role and the influence of such modifications on the fate of an EV preparation, will pave the way into the design and production of EV-based reagents as therapeutics.
\n
\n
Acknowledgments
\n
The financial support by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology and Development is gratefully acknowledged. S.V. was also supported by the PhD program BioToP (Biomolecular Technology of Proteins) funded by the Austrian Science Fund (FWF W1224).
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"extracellular vesicles, exosomes, tetraspanin, tissue-specific targeting, exosomal drug delivery",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65340.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65340.xml",downloadPdfUrl:"/chapter/pdf-download/65340",previewPdfUrl:"/chapter/pdf-preview/65340",totalDownloads:1658,totalViews:38,totalCrossrefCites:3,dateSubmitted:"September 5th 2018",dateReviewed:"December 13th 2018",datePrePublished:"January 28th 2019",datePublished:"August 7th 2019",dateFinished:"January 24th 2019",readingETA:"0",abstract:"Extracellular vesicles (EVs) have in the recent decades gained an important stand as vehicles enabling cell-to-cell transport and communication. With the advanced development towards their clinical use and increasing versatility of potential applications, improving their tissue-specific targeting in order to enhance their functionality in drug delivery opened as a challenging engineering field. In the past, the question of specific intercellular contact has been addressed by decoration of the EV surface with agents able of specific target recognition. An attractive possibility here is the modification of strongly overexpressed EV surface marker proteins towards recognition of target cells. As these proteins are involved in a plethora of biological functions in EV biogenesis, cargo targeting and intercellular transfer, a minimal impact on protein architecture upon modifications is desirable, which would also increase the stability of the exosomal preparation intended for therapeutic use. This chapter focuses on the possibilities of engineering of the EV marker proteins towards antigen-recognition units broadly applicable to endow EVs with tissue-targeting functionality.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65340",risUrl:"/chapter/ris/65340",signatures:"Stefan Vogt, Gerhard Stadlmayr, Johannes Grillari, Florian Rüker and Gordana Wozniak-Knopp",book:{id:"7594",type:"book",title:"Current Topics in Biochemical Engineering",subtitle:null,fullTitle:"Current Topics in Biochemical Engineering",slug:"current-topics-in-biochemical-engineering",publishedDate:"August 7th 2019",bookSignature:"Naofumi Shiomi",coverURL:"https://cdn.intechopen.com/books/images_new/7594.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83881-210-2",printIsbn:"978-1-83881-209-6",pdfIsbn:"978-1-83881-211-9",isAvailableForWebshopOrdering:!0,editors:[{id:"163777",title:"Dr.",name:"Naofumi",middleName:null,surname:"Shiomi",slug:"naofumi-shiomi",fullName:"Naofumi Shiomi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"273010",title:"Dr.",name:"Gordana",middleName:null,surname:"Wozniak-Knopp",fullName:"Gordana Wozniak-Knopp",slug:"gordana-wozniak-knopp",email:"gordana.wozniak@boku.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Natural Resources and Life Sciences",institutionURL:null,country:{name:"Austria"}}},{id:"273012",title:"M.Sc.",name:"Stefan",middleName:null,surname:"Vogt",fullName:"Stefan Vogt",slug:"stefan-vogt",email:"stefan.vogt@boku.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"273013",title:"Dr.",name:"Gerhard",middleName:null,surname:"Stadlmayr",fullName:"Gerhard Stadlmayr",slug:"gerhard-stadlmayr",email:"gerhard.stadlmayr@boku.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"273014",title:"Prof.",name:"Florian",middleName:null,surname:"Rüker",fullName:"Florian Rüker",slug:"florian-ruker",email:"florian.rueker@boku.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"273015",title:"Prof.",name:"Johannes",middleName:null,surname:"Grillari",fullName:"Johannes Grillari",slug:"johannes-grillari",email:"johannes.grillari@boku.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Structure of the tetraspanin proteins",level:"1"},{id:"sec_3",title:"3. Natural ligands of tetraspanin proteins",level:"1"},{id:"sec_3_2",title:"3.1. The tetraspanin web and intertetraspanin contacts",level:"2"},{id:"sec_4_2",title:"3.2. Interaction of tetraspanins with integrins and matrix-degrading enzymes: role of tetraspanins in cancer and metastasis",level:"2"},{id:"sec_5_2",title:"3.3. The role of tetraspanins in immune complexes",level:"2"},{id:"sec_6_2",title:"3.4. Tetraspanins in pathogen infection",level:"2"},{id:"sec_8",title:"4. Extracellular vesicles as mediators of cell-cell interaction",level:"1"},{id:"sec_8_2",title:"4.1. Biological basis for therapeutic applications: EVs as mediators of intercellular interactions",level:"2"},{id:"sec_9_2",title:"4.2. Mechanisms of EV entry into the target cell",level:"2"},{id:"sec_11",title:"5. Molecular engineering to facilitate EV labeling and delivery to target cells",level:"1"},{id:"sec_11_2",title:"5.1. Modifications of EV membrane with non-covalent and chemical modifications",level:"2"},{id:"sec_12_2",title:"5.2. Engineering of tetraspanin proteins for detection and monitoring of EVs",level:"2"},{id:"sec_13_2",title:"5.3. Engineering of EV surface proteins for enhanced cell-type specific targeting: introduction of target specificity, stability and improved cargo delivery",level:"2"},{id:"sec_15",title:"6. Conclusions",level:"1"},{id:"sec_16",title:"Acknowledgments",level:"1"},{id:"sec_19",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Wickman G, Julian L, Olson MF. How apoptotic cells aid in the removal of their own cold dead bodies. Cell Death & Differentiation. 2012;19:735-742. DOI: 10.1038/cdd.2012.25\n'},{id:"B2",body:'Harding C, Heuser J, Stahl P. 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DOI: 10.1038/ncomms12277\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Stefan Vogt",address:null,affiliation:'
acib GmbH (Austrian Centre of Industrial Biotechnology), Austria
Christian Doppler Laboratory for Innovative Immunotherapeutics, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), Austria
Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), Austria
acib GmbH (Austrian Centre of Industrial Biotechnology), Austria
Christian Doppler Laboratory for Innovative Immunotherapeutics, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), Austria
acib GmbH (Austrian Centre of Industrial Biotechnology), Austria
Christian Doppler Laboratory for Innovative Immunotherapeutics, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), Austria
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Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,700 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes that assure your research is made available to the scientific community without delay
\n\t
Personal support during every step of the publication process
\n\t
+184,650 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 175 million downloads
\n
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That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}}]}},subseries:{item:{id:"11",type:"subseries",title:"Cell Physiology",keywords:"Neurodevelopment and Neurodevelopmental Disease, Free Radicals, Tumor Metastasis, Antioxidants, Essential Fatty Acids, Melatonin, Lipid Peroxidation Products and Aging Physiology",scope:"
\r\n\tThe integration of tissues and organs throughout the mammalian body, as well as the expression, structure, and function of molecular and cellular components, is essential for modern physiology. The following concerns will be addressed in this Cell Physiology subject, which will consider all organ systems (e.g., brain, heart, lung, liver; gut, kidney, eye) and their interactions: (1) Neurodevelopment and Neurodevelopmental Disease (2) Free Radicals (3) Tumor Metastasis (4) Antioxidants (5) Essential Fatty Acids (6) Melatonin and (7) Lipid Peroxidation Products and Aging Physiology.
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He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null,series:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261"},editorialBoard:[{id:"186048",title:"Prof.",name:"Ines",middleName:null,surname:"Drenjančević",slug:"ines-drenjancevic",fullName:"Ines Drenjančević",profilePictureURL:"https://mts.intechopen.com/storage/users/186048/images/5818_n.jpg",institutionString:null,institution:{name:"University of 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Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. 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