\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7845",leadTitle:null,fullTitle:"Platelets",title:"Platelets",subtitle:null,reviewType:"peer-reviewed",abstract:"Mammalian platelets are small (2–4 um), discoid, short-lived fragments derived from megakaryocyte precursors. They play a crucial role not only in the formation of a normal hemostatic plug but they also play a key role in a much wider repertoire of physiological processes such as inflammation, innate immunity, cancer, infection, neurobiology, and tissue repair/regeneration. Over three sections, the individual chapters in this book identify one particular aspect of platelet function, dysfunction, or application. As significant advances continue to develop our thinking of the functional role of platelets in health and disease, this book elevates awareness and enthusiasm in further investigating these functions.",isbn:"978-1-83881-115-0",printIsbn:"978-1-83881-114-3",pdfIsbn:"978-1-83881-116-7",doi:"10.5772/intechopen.77663",price:119,priceEur:129,priceUsd:155,slug:"platelets",numberOfPages:178,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"d33b20516d6ff3a5b7446a882109ba26",bookSignature:"Steve W. Kerrigan",publishedDate:"November 11th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/7845.jpg",numberOfDownloads:4666,numberOfWosCitations:4,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:8,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 20th 2019",dateEndSecondStepPublish:"February 12th 2020",dateEndThirdStepPublish:"April 12th 2020",dateEndFourthStepPublish:"July 1st 2020",dateEndFifthStepPublish:"August 30th 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"73961",title:"Dr.",name:"Steve W.",middleName:null,surname:"Kerrigan",slug:"steve-w.-kerrigan",fullName:"Steve W. Kerrigan",profilePictureURL:"https://mts.intechopen.com/storage/users/73961/images/system/73961.jfif",biography:"Professor Steven W. Kerrigan is deputy head of the School of Pharmacy (Research), head of the Cardiovascular Infection Research Group at the Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, and inventor of the sepsis treatment drug InnovoSep. Professor Kerrigan is a graduate of King’s College London, England (Pharmacology), University of Strathclyde, Scotland (Immunopharmacology), and RCSI (Infection and Immunity). His research focuses on understanding the platelet and endothelial response to infection during sepsis. Through research, Professor Kerrigan identified a promising drug target that prevents a wide number of microorganisms (bacteria, fungus, and virus) from causing a dysregulated response in the systemic circulation during sepsis, specifically preventing unwanted platelet and endothelial cell activation. Professor Kerrigan has published extensively in leading high-impact journals in the areas of platelets, endothelial cells, and bloodstream infections, and has attracted more than €6.5 million in grant funding and filed three patent/disclosures. Professor Kerrigan is currently co-chair of the ISTH Scientific Standardization Committee Biorheology (platelets) and member of the European Sepsis Alliance research committee.",institutionString:"RCSI University of Medicine and Health Sciences, Dublin",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"183",title:"Hematology",slug:"hematology"}],chapters:[{id:"71470",title:"Platelet Imaging",doi:"10.5772/intechopen.91736",slug:"platelet-imaging",totalDownloads:596,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The knowledge gained through imaging platelets has formed the backbone of our understanding of their biology in health and disease. Early investigators relied on conventional light microscopy with limited resolution and were primarily able to identify the presence and basic morphology of platelets. The advent of high resolution technologies, in particular, electron microscopy, accelerated our understanding of the dynamics of platelet ultrastructure dramatically. Further refinements and improvements in our ability to localize and reliably identify platelet structures have included the use of immune-labeling techniques, correlative-fluorescence light and electron microscopy, and super-resolution microscopies. More recently, the expanded development and application of intravital microscopy in animal models has enhanced our knowledge of platelet functions and thrombus formation in vivo, as these experimental systems most closely replicate native biological environments. Emerging improvements in our ability to characterize platelets at the ultrastructural and organelle levels include the use of platelet cryogenic electron tomography with quantitative, unbiased imaging analysis, and the ability to genetically label platelet features with electron dense markers for analysis by electron microscopy.",signatures:"Zachary A. Matthay and Lucy Zumwinkle Kornblith",downloadPdfUrl:"/chapter/pdf-download/71470",previewPdfUrl:"/chapter/pdf-preview/71470",authors:[null],corrections:null},{id:"72872",title:"Molecular Aspects of Pathophysiology of Platelet Receptors",doi:"10.5772/intechopen.92856",slug:"molecular-aspects-of-pathophysiology-of-platelet-receptors",totalDownloads:749,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Receptor is a dynamic instrumental surface protein that helps to interact with specific molecules to respond accordingly. Platelet is the smallest in size among the blood components, but it plays many pivotal roles to maintain hemostasis involving its surface receptors. It (platelet) has cell adhesion receptors (e.g., integrins and glycoproteins), leucine-rich repeats receptors (e.g., TLRs, glycoprotein complex, and MMPs), selectins (e.g., CLEC, P-selectin, and CD), tetraspanins (e.g., CD and LAMP), transmembrane receptors (e.g., purinergic—P2Y and P2X1), prostaglandin receptors (e.g., TxA2, PGH2, and PGI2), immunoglobulin superfamily receptors (e.g., FcRγ and FcεR), etc. on its surface. The platelet receptors (e.g., glycoproteins, protease-activated receptors, and GPCRs) during platelet activation are over expressed and their granule contents are secreted (including neurotransmitters, cytokines, and chemokines) into circulation, which are found to be correlated with different physiological conditions. Interestingly, platelets promote metastasis through circulation protecting from cytolysis and endogenous immune surveillance involving several platelets receptors. The updated knowledge about different types of platelet receptors in all probable aspects, including their inter- and intra-signaling mechanisms, are discussed with respect to not only its (platelets) receptor type but also under different pathophysiological conditions.",signatures:"Mrinal K. Poddar and Soumyabrata Banerjee",downloadPdfUrl:"/chapter/pdf-download/72872",previewPdfUrl:"/chapter/pdf-preview/72872",authors:[{id:"318618",title:"Emeritus Prof.",name:"Mrinal K.",surname:"Poddar",slug:"mrinal-k.-poddar",fullName:"Mrinal K. Poddar"},{id:"318620",title:"Dr.",name:"Soumyabrata",surname:"Banerjee",slug:"soumyabrata-banerjee",fullName:"Soumyabrata Banerjee"}],corrections:null},{id:"72248",title:"Procoagulant Platelets",doi:"10.5772/intechopen.92638",slug:"procoagulant-platelets",totalDownloads:593,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"There are two well-known subpopulations of activated platelets: pro-aggregatory and procoagulant. Procoagulant platelets represent a subpopulation of activated platelets, which are morphologically and functionally distinct from pro-aggregatory ones. Although various names have been used to describe these platelets in the literature (CoaT, CoaTed, highly activated, ballooned, capped, etc.), there is a consensus on their phenotypic features including exposure of high levels of phosphatidylserine (PSer) on the surface; decreased aggregatory and adhesive properties; support of active tenase and prothrombinase complexes; maximal generation by co-stimulation of glycoprotein VI (GPVI) and protease-activated receptors (PAR). In this chapter, morphologic and functional features of procoagulant platelets, as well as the mechanisms of their formation, will be discussed.",signatures:"Andaleb Kholmukhamedov",downloadPdfUrl:"/chapter/pdf-download/72248",previewPdfUrl:"/chapter/pdf-preview/72248",authors:[null],corrections:null},{id:"72840",title:"MicroRNAs in Platelets: Should I Stay or Should I Go?",doi:"10.5772/intechopen.93181",slug:"micrornas-in-platelets-should-i-stay-or-should-i-go-",totalDownloads:391,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In this chapter, we discuss different topics always using the microRNA as the guiding thread of the review. MicroRNAs, member of small noncoding RNAs family, are an important element involved in gene expression. We cover different issues such as their importance in the differentiation and maturation of megakaryocytes (megakaryopoiesis), as well as the role in platelets formation (thrombopoiesis) focusing on the described relationship between miRNA and critical myeloid lineage transcription factors such as RUNX1, chemokines receptors as CRCX4, or central hormones in platelet homeostasis like TPO, as well as its receptor (MPL) and the TPO signal transduction pathway, that is JAK/STAT. In addition to platelet biogenesis, we review the microRNA participation in platelets physiology and function. This review also introduces the use of miRNAs as biomarkers of platelet function since the detection of pathogenic situations or response to therapy using these noncoding RNAs is getting increasing interest in disease management. Finally, this chapter describes the participation of platelets in cellular interplay, since extracellular vesicles have been demonstrated to have the ability to deliver microRNAs to others cells, modulating their function through intercellular communication, redefining the extracellular vesicles from the so-called “platelet dust” to become mediators of intercellular communication.",signatures:"Sonia Águila, Ernesto Cuenca-Zamora, Constantino Martínez and Raúl Teruel-Montoya",downloadPdfUrl:"/chapter/pdf-download/72840",previewPdfUrl:"/chapter/pdf-preview/72840",authors:[null],corrections:null},{id:"72919",title:"Bleeding Disorders Associated with Abnormal Platelets: Glanzmann Thrombasthenia and Bernard-Soulier Syndrome",doi:"10.5772/intechopen.93299",slug:"bleeding-disorders-associated-with-abnormal-platelets-glanzmann-thrombasthenia-and-bernard-soulier-s",totalDownloads:599,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Platelets, the smallest cells in the blood, are associated with hemostasis, bowel formation, tissue remodeling, and wound healing. Although the prevalence of inherited platelet disorders is not fully known, it is a rare disease group and is encountered in approximately between 10000 and 1000000. Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are more frequently observed in inherited platelet disorders. In GT, the platelet aggregation stage due to deficiency or dysfunction of the platelet GPIIb/IIIa complex cannot take place. BSS is a platelet adhesion disorder due to the absence or abnormality of GPIb/IX complex on the platelet surface. If there is bleeding after easy bruising, mucous and oral cavities, menorrhagia, tooth extraction, tonsillectomy, or other surgical interventions, inherited platelet dysfunction should be considered if the platelet count is normal while the bleeding time is long. Firstly, other causes should be investigated by making differential diagnosis of GT and BSS. In this chapter, the definition, etiology, historical process, epidemiology, genetic basis, pathophysiology, clinical findings, diagnosis, differential diagnosis, and the follow-up and treatment approach of GT and BSS will be reviewed according to the current medical literature.",signatures:"Muhammet Mesut Nezir Engin",downloadPdfUrl:"/chapter/pdf-download/72919",previewPdfUrl:"/chapter/pdf-preview/72919",authors:[null],corrections:null},{id:"72634",title:"Thrombocytopenia in Neonates",doi:"10.5772/intechopen.92857",slug:"thrombocytopenia-in-neonates",totalDownloads:629,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Thrombocytopenia defined as platelet count below 150,000/μL is not an uncommon event at the neonatal intensive care unit (NICU). In our region we calculated a prevalence of nearly 2 of 1000 live births. Early-onset neonatal thrombocytopenia (NT) occurring within the first 72 hours of life is more common than late-onset NT. Preterm infants are affected more often than term infants and bacterial infection is the most common diagnosis associated with NT. There are a lot of maternal, perinatal, and neonatal causes associated with NT and complications include bleedings with potentially life-threatening intracranial hemorrhage. Alloimmune thrombocytopenia (NAIT) often presents with severe thrombocytopenia (<30,000/μL) in otherwise healthy newborns and needs careful evaluation regarding HPA-1a antigen status and HLA typing. Platelet transfusions are needed in severe NT and threshold platelet counts might be at ≤25,000/μL irrespective of bleeding or not. Immune mediated NT recovers within 2 weeks with a good prognosis when there happened no intracranial hemorrhage. This short review gives an overview on etiology and causes of NT and recommendations regarding platelet transfusions.",signatures:"Bernhard Resch",downloadPdfUrl:"/chapter/pdf-download/72634",previewPdfUrl:"/chapter/pdf-preview/72634",authors:[{id:"66173",title:"Prof.",name:"Bernhard",surname:"Resch",slug:"bernhard-resch",fullName:"Bernhard Resch"}],corrections:null},{id:"72614",title:"Platelet Rich Fibrin (PRF) Application in Oral Surgery",doi:"10.5772/intechopen.92602",slug:"platelet-rich-fibrin-prf-application-in-oral-surgery",totalDownloads:737,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Platelet rich fibrin (PRF) is an autologous biological product which becomes popular day by day and available in a wide variety of fields in medicine. Platelet concentrates which are introduced at the early 90s have evolved over the years. The use such autologous materials have become trendy in recent years to encounter demanding expectations of patients, improve treatment success and maximize patient comfort. Despite its increasing use in dentistry and oral surgery, the most indications and effects are still being discussed. PRF is easily accepted by patients because of its low cost, easy to receive, low donor morbidity, low postoperative complication and infection rate. This biomaterial may be a solution for patients who have strong negative beliefs about the use of allografts and xenografts or who are afraid of complications during the grafting procedure. The objectives of these technologies are to use their synergistic effect to improve the hard and soft tissue regeneration. PRF in oral surgery are used for alveolar bone reconstruction, dental implant surgery, sinus augmentation, socket preservation, osteonecrosis, oroantral fistula closure, struggling with oral ulcers, preventing swelling and edema constitution. This chapter aims to review the clinical applications of platelets in oral surgery and the role of molecular components in tissue healing.",signatures:"Alper Saglanmak, Caglar Cinar and Alper Gultekin",downloadPdfUrl:"/chapter/pdf-download/72614",previewPdfUrl:"/chapter/pdf-preview/72614",authors:[{id:"316384",title:"Dr.",name:"Alper",surname:"Saglanmak",slug:"alper-saglanmak",fullName:"Alper Saglanmak"},{id:"316735",title:"Dr.",name:"Caglar",surname:"Cinar",slug:"caglar-cinar",fullName:"Caglar Cinar"}],corrections:null},{id:"72712",title:"Rapid Cytoreduction by Plateletapheresis in the Treatment of Thrombocythemia",doi:"10.5772/intechopen.93158",slug:"rapid-cytoreduction-by-plateletapheresis-in-the-treatment-of-thrombocythemia",totalDownloads:373,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The objective of this chapter is to provide a systematic overview of current knowledge regarding therapeutic apheresis—primarily therapeutic plateletapheresis (TP)—and to summarize evidence-based practical approaches related to cytapheresis treatment of “hyperthrombocytosis” or “extreme thrombocytosis” (ETC). Our results of platelet (Plt) quantitative/qualitative analyses and evaluation of efficacy of apheresis systems/devices—on the basis of Plt removal and in vivo Plt depletion—will be presented. Our preclinical researches confirmed that in Plt concentrates, the initial ratio of discoid shapes was 70%, spherical 20%, and less valuable (dendritic/balloonized) shapes 10%—with morphological score of platelets (MSP = 300–400). After storage, the ratio of discoid and spherical shapes was decreased, while the less valuable ones progressively increased (MSP = 200). Electron microscopy has shown discoid shapes with typical ultrastructural properties. Spherical shapes with reduced electron density and peripheral location of granules/organelles were detected. Also, dendritic shapes with cytoskeletal “rearrangement,” membrane system integrity damages, and pseudopodia formations were documented. Our clinical study demonstrated that TP was useful in ETC treatment and should help prevention of “thrombo-hemorrhagic” events—until chemotherapy, antiplatelet drugs, and other medication take effect. During TP treatment, Plt count and morphology/ultrastructure were examined. Plt functions by multiplate analyzer were evaluated. We concluded that intensive TP was an effective, safe, and rapid cytoreductive treatment for ET.",signatures:"Bela Balint, Mirjana Pavlovic and Milena Todorovic",downloadPdfUrl:"/chapter/pdf-download/72712",previewPdfUrl:"/chapter/pdf-preview/72712",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"4463",title:"The Non-Thrombotic Role of Platelets in Health and Disease",subtitle:null,isOpenForSubmission:!1,hash:"edb4b5dc59bbc5b361f367d33ff13ba6",slug:"the-non-thrombotic-role-of-platelets-in-health-and-disease",bookSignature:"Steve Kerrigan and Niamh Moran",coverURL:"https://cdn.intechopen.com/books/images_new/4463.jpg",editedByType:"Edited by",editors:[{id:"73961",title:"Dr.",name:"Steve W.",surname:"Kerrigan",slug:"steve-w.-kerrigan",fullName:"Steve W. 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\r\n\tBismuth-based nanostructured materials have received increasing research interest in the past decades, especially for their applications in photocatalysis and electrocatalysis. New bismuth-based nanostructured materials have been fabricated, and their optical and electronic structures can be fine-tuned via various synthetic approaches. These bismuth-based materials have been widely applied in photocatalysis (NOx removal, VOCs purification, CO2 reduction, water splitting, organic pollutants degradation, heavy metals reduction) and electrocatalysis (nitrogen fixation, CO2 reduction, water electrolysis, organic synthesis). The rapid development in this field needs a comprehensive summary to reflect the new advances in recent years. The aim of this project is to invite researchers worldwide to contribute to this field and promote the developments in the synthesis, characterization, structure-property relationship determination, and application of bismuth-based catalysts, proposing organized materials, challenges, and prospects to guide future works. The content of this book could attract broad interest from diverse fields of materials, catalysis, chemistry, environment, medicine, energy, and engineering.
",isbn:"978-1-83768-048-1",printIsbn:"978-1-83768-047-4",pdfIsbn:"978-1-83768-049-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"951c872d9d90e13cfe7d97c0af91845e",bookSignature:"Dr. William Wilson Anku",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11467.jpg",keywords:"Semiconductor, Synthesis, Morphology, Shape Control, Metal Doping, Surface Modification, Catalysis, Photocatalysis, Photoelectrochemical, Nitrogen Fixation, Energy Conversion, Environmental Remediation",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 12th 2022",dateEndSecondStepPublish:"July 13th 2022",dateEndThirdStepPublish:"September 11th 2022",dateEndFourthStepPublish:"November 30th 2022",dateEndFifthStepPublish:"January 29th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"13 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. William Wilson Anku is a Research Scientist at CSIR- Water Research Institute, Accra-Ghana. He has co-authored 37 papers in renowned peer-reviewed scientific publications with over 590 citations resulting in an H-index of 12.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"196465",title:"Dr.",name:"William Wilson",middleName:null,surname:"Anku",slug:"william-wilson-anku",fullName:"William Wilson Anku",profilePictureURL:"https://mts.intechopen.com/storage/users/196465/images/system/196465.jpg",biography:'Curriculum Vitae\n of \nDr William Wilson Anku\n________________________________________\nCSIR- Water Research Institute,\nP. O. Box AH 38, \nAchimota-Accra, Ghana\n\nPrimary Email Address: williamanku85@gmail.com \nAlternate Email Address: williamanku@csir.org.gh \nMobile Numbers: +233547507987/+233577035326 \nGoogle Scholar: https://scholar.google.com/citations?user=tK_Q8UQAAAAJ&hl=en\nORCID: https://orcid.org/0000-0002-5551-6130\nResearchGate: https://www.researchgate.net/profile/William_Wilson_Anku/research\n\nPersonal Information:\nSurname: Anku\nFirst Names: William Wilson\nGender: Male\nCitizenship: Ghanaian\nDate of birth: 20/12/1976\n\nResearch Interests:\n1. Design of nanoparticles with unique structural and physical properties, and the assessment of their structure-property relationships. \n2. Development and evaluation of photocatalytic, ion exchange, adsorption/filtration properties of metal oxide semiconductors and agro-industrial wastes-based nanomaterials for their practical application in water/wastewater treatment \n3. Water/wastewater treatment\t\n\nEducation:\n2015 – 2018: PhD Chemistry, University of Johannesburg, South Africa.\n2005 – 2008: MSc Environmental Science, Kwame Nkrumah University of Science &\n Technology, Ghana.\n1999 – 2003: BSc Chemistry, Kwame Nkrumah University of Science & Technology, Ghana\n1995 – 1997: Secondary School Certificate, Saint Augustine’s College, Cape Coast, Ghana. \n\nEmployment History:\n1.\tResearch Scientist (March 2019-present): CSIR-Water Research Institute, \nAccra-Ghana.\n2.\tPostdoctoral Research Fellow (February 2018 – January 2019): Department of Applied Chemistry, University of Johannesburg, South Africa \n3.\tTeaching Assistant/Tutor (June 2015 – November 2016): Department of Applied Chemistry, University of Johannesburg, South Africa \n4.\tChemistry Tutor (January 2007-September 2014): Effiduase Senior High School, Effiduase-Ashanti (Ghana Education Service).\n\nSupervision of junior researchers at the graduate and postgraduate level:\n1.\tPhD thesis supervision:\n(a) Student Name: Michael Kumi\nInstitution: Department of Applied Chemistry, University of Johannesburg (UJ), South Africa.\nThesis title: Integrated bone and biochar bed for contaminant removal from groundwater. (In progress).\n\n(b) Student Name: George Atongo Atia\n Institution: Department of chemistry, KNUST, Kumasi\n Thesis title: Fabrication of CNTs-metal oxide/polymer chemical sensors for gas sensor\n application and computational studies. (In progress).\n\n2.\tMSc Thesis supervision:\n(a) Student Name: Esther Acheampong \nInstitution: Department of Chemical Engineering, KNUST, Kumasi\n Thesis title: Synthesis of polysulphide intercalated layered double hydroxides for\n adsorption processes. (Completed).\n\n(b)\tStudent Name: Sechaba Menyadi\nInstitution: Department of Applied Chemistry, UJ, South Africa.\nThesis title: Improving the thermoelectric performance of zinc oxide with Al3+, In3+ \nand 2D materials through the formation of superlattice structures. (Completed).\n\n(c)\tStudent Name: Nokuthula Ndaba\nInstitution: Department of Applied Chemistry, UJ, South Africa.\n Thesis title: Isolation and characterization of Drimia delagoensis phytochemicals and\n their application in diabetic foot ulcer treatment. (Completed).\n\nExternal examination of PhD/MSc theses and proposal reviews:\n1.\tExternal examination of a PhD thesis from the Chemical Engineering Department of Vaal University of Technology, South Africa, 2021.\n2.\tExternal examination of PhD thesis from the Physics and Chemistry Departments of Kwame Nkrumah University of Science and Technology, KNUST-Ghana, 2020.\n3.\tReviewer for the 2021-2022 Graduate Women in Science (GWIS) National Fellowship Program of the USA.\n\nScientific Reviewing Activities:\nServing as a reviewer for the following journals:\nACS Applied Materials and Interfaces, ACS Applied Nanomaterials, ACS Industrial and Engineering Chemistry Research, Journal of Dispersion Science and Technology, Journal of Taiwan Institute of Chemical Engineers, Electroanalysis, Journal of Molecular Catalysis A, Inorganic and Nano-Metal Chemistry, Materials Science in Semiconductor Processing, Recent Innovations in Chemical Engineering, Journal of Inorganic and Organometallic Polymers and Materials, International Journal of Biological Macromolecules, Fibers and Polymers, Catalysis letters, Desalination and water treatment, Inorganic and Nano-Metal Chemistry.\n\nProfessional Associations:\n•\tResearch Scientist Association of Ghana\n•\tSouth African Chemical Institute (SACI)\n\nLeadership and volunteering activities:\n•\tVice President of Water Research Institute Branch of Research Staff Association (RSA) of the Council for Scientific and Industrial Research (CSIR), Ghana (2021-2022).\n•\tEditorial board member of RSA-CSIR, Southern Zone (2021/2022).\n•\tEnvironmental Science Department Representative of Graduate Students Association of Ghana: Kwame Nkrumah University of Science and Technology (KNUST) branch (2005-2006).\n•\tVice President of Volta Region Students Association: KNUST branch (2002-2003).\n•\tNational Public Relations Officer of Ghana Students Chemical Society: KNUST branch (2002-2003).\n•\tGeneral Secretary of Volta Region Students Association: KNUST branch (2001-2002).\n•\tVolunteer Teacher at Asukawkaw Senior High School in the Volta Region of Ghana (May-August 2002)\n\nPrizes, awards, fellowships:\n•\tPostdoctoral research fellowship: Faculty of Science, University of Johannesburg, 2018.\n•\tPhD studentship: Faculty of Science, University of Johannesburg, 2015-2018.\n•\tStudents travel fund award: National Research Foundation (NRF) of South Africa, 2016.\n•\tBest poster presenter at the 5th UJ Cross Faculty Symposium held at UJ-Bunting Road Campus, South Africa on 13th October 2015.\n•\tSecond best poster presenter at the 3rd conference on “Emerging Frontiers for Sustainable Water” held at the Protea Hotel Wanderers, in Johannesburg, South Africa from 3-5 August 2015. \n\nPublication Record:\nA.\tBook Chapters\n1.\tOtun, Kabir Opeyemi, Idris Olayiwola Azeez, Onoyivwe Monday Ama, William Wilson Anku, Uyiosa Osagie Aigbe, Kingsley Eghonghon Ukhurebor, and Robert Birundu Onyancha. "Sensing the Presence of Inorganic Ions in Water: The Use of Electrochemical Sensors." In Modified Nanomaterials for Environmental Applications, pp. 65-89. Springer, Cham, 2022.\n2.\tAnku, William Wilson, Onoyivwe Monday Ama, Ikenna Chibuzor Emeji, Uyiosa Osagie Aigbe, Adelaja Otolorin Osibote, Peter Ogbemudia Osifo, and Suprakas Sinha Ray. “Functionalized nanomagnetic materials for environmental applications”. In Functionalized Nanomaterials Based Devices for Environmental Applications, pp. 127-145. Elsevier, 2021.\n3.\tKhoele, Khotso, Onoyivwe Monday Ama, Ikenna Chibuzor Emeji, William Wilson Anku, Suprakas Sinha Ray, David Jacobus Delport, and Peter Ogbemudia Osifo. “Dynamic Degradation Efficiency of Major Organic Pollutants from Wastewater”. Springer, Cham, In book: Nanostructured Metal-Oxide Electrode Materials for Water Purification, pp. 1-18, 2020.\n4.\tAnku, William Wilson, Onoyivwe Monday Ama, Suprakas Sinha Ray, and Peter Ogbemudia Osifo. “Application of Modified Metal Oxide Electrodes in Photoelectrochemical Removal of Organic Pollutants from Wastewater”. Springer, Cham. In book: Nanostructured Metal-Oxide Electrode Materials for Water Purification, pp. 151-166, 2020.\n5.\tWilliam W Anku, Ephraim M Kiarii, Sudheesh K Shukla, and Penny P Govender. “Photocatalytic degradation of pharmaceuticals using graphene based materials”. Springer, Cham. In book: A New Generation Material Graphene: Applications in Water Technology. pp 187-208, 2018.\n6.\tWilliam W Anku, Samuel OB Oppong and Penny P Govender. “Bismuth-based nanoparticles as photocatalytic materials”. InTechOpen. In book: Bismuth: Advanced Applications and Defects Characterization. pp 25-44, 2018.\n7.\tWilliam W Anku, Messai A Mamo and Penny P Govender. “Phenolic compounds in water: sources, reactivity, toxicity and treatment methods”. InTechOpen. In book: Phenolic Compounds-Natural Sources, Importance and Applications. pp. 420-443, 2017. \n\nB.\tPeer-Reviewed Journal Publications \n\n1. Ahiahonu, Elvis K., William W. Anku, Ashira Roopnarain, Ezekiel Green, Penny P. Govender, and Mahloro H. Serepa‐Dlamini. Bioresource potential of Tetradesmus obliquus UJEA_AD: critical evaluation of biosequestration rate, biochemical and fatty acid composition in BG11 media. Journal of Chemical Technology & Biotechnology (2021).\n2. Ahiahonu, Elvis Kodzo, William Wilson Anku, Ashira Roopnarain, Ezekiel Green, Penny Poomani Govender, and Mahloro Hope Serepa-Dlamini. Bioprospecting wild South African microalgae as a potential third-generation biofuel feedstock, biological carbon-capture agent and for nutraceutical applications. Biomass Conversion and Biorefinery (2021): 1-16.\n3. Obiri, Samuel, Gloria Addico, Saada Mohammed, Wilson William Anku, Humphry Darko, and Okrah Collins. Water quality assessment of the Tano Basin in Ghana: a multivariate statistical approach. Applied Water Science 11 (2021): 1-8.\n4. Oppong, Samuel Osei-Bonsu, Francis Opoku, William Wilson Anku, and Penny P. Govender. Insights into the complementary behaviour of Gd doping in GO/Gd/ZnO composites as an efficient candidate towards photocatalytic degradation of indigo carmine dye. Journal of Materials Science 56 (2021): 8511-8527.\n5. Ama Onoyivwe Monday, Khotso Khoele, William Wilson Anku, Suprakas Sinha Ray, Peter Ogbemudia Osifo, and David Jacobus Delport. Synthesis and Application of MnO2/Exfoliated Graphite Electrodes for Enhanced Photoelectrochemical Degradation of Methylene Blue and Congo Red Dyes in Water. Electrocatalysis.11 (2020): 413-421.\n6. Anku, William Wilson, Eric Selorm Agorku, Samuel Osei-Bonsu Oppong, and Anthony Yaw Karikari. "MWCNTs attached neodymium doped-ZnO photocatalysts for efficient removal of dyes from wastewater. SN Applied Sciences. 5 (2020): 1-13.\n7. Karikari Anthony Yaw, Asmah Ruby, Anku, William Wilson, Amisah Steve, Agbo Nelson Wheatson, Telfer C Trevor, Ross, Glenn Lindsay. Heavy Metal Concentrations and Sediment Quality of a Cage Farm on Lake Volta, Ghana. Aquaculture Research. 5 (2020): 2041-2051.\n8. Manyedi, Sechaba, William W. Anku, Ephraim M. Kiarii, and Penny P. Govender. Thermoelectric, Electronic, and Optical Response of Nanostructured Al‐doped ZnO@ 2D‐TiC Composite. ChemistrySelect 5 (2020): 13144-13154.\n9. Renu Kumari, Adeniyi Olugbenga Osikoya Adeniyi Olugbenga Osikoya, Francis Opoku, William Wilson Anku, Sudheesh Kumar Shukla, and Penny Poomani Govender. Composite 2D Nanointerfaces for Electrochemical Biosensing: An Experimental and Theoretical Study. ACS Applied Biomaterials. 12 (2020): 8676-8687.\n10. Onoyivwe Monday Ama, William Wilson Anku, Suprakas Sinha Ray. Photoelectrochemical degradation of methylene blue dye under visible light irradiation using EG/Ag-ZrO2 nanocomposite electrodes. International Journal of Electrochemical Science. 14 (2019) 9982-10001. \n11. Onoyivwe Monday Ama, Khotso Khoele, William Wilson Anku, Suprakas Sinha Ray. Photoelectrochemical Degradation of 4-Nitrophenol using CuOZnO/exfoliated graphite Nanocomposite Electrode. International Journal of Electrochemical Science. 14 (2019) 2893 – 2905.\n12. Ndaba, Nokuthula, Marthe Carine Fotsing, William Wilson Anku, and Penny Poomani Govender. In vitro and in silico studies of the antifungal properties of the bulb and leaves extracts of Drimia delagoensis Baker (Jessop). Advances in Traditional Medicine, (2019): 1-7.\n13. Samuel Osei-Bonsu Oppong, Francis Opoku, William Wilson Anku, Ephraim\nMuriithi Kiarii, Penny Poomani Govender. Experimental and Computational Design of Highly Active Ce–ZrO2–GO Photocatalyst for Eosin Yellow Dye Degradation: The Role of Interface and Ce3+ Ion. Catalysis Letters. (2019) 1-18.\n14. Renu Kumari, Adeniyi Olugbenga Osikoya, Francis Opoku, William Wilson Anku, Sudheesh Kumar Shukla, Penny Govender. Hierarchically assembled Two-dimensional Gold-Boron Nitride-Tungsten Disulphide nanohybrid interface system for electrobiocatalytic applications. Materials chemistry and physics, 226 (2019) 129-140.\n15. Madima Ntakadzeni, William Wilson Anku, Penny Poomani Govender, Leelakrishna Reddy. Mo3S4 nanorod: An effective photocatalyst for the degradation of organic dyes in aqueous solution. Recent innovations in chemical engineering, 12 (2019) 61-9.\n16. Madima Ntakadzeni, William Wilson Anku, Neeraj Kumar, Penny Poomani Govender, Leelakrishna Reddy. Pegylated MoS2 nanosheets: A dual functional photocatalyst for photodegradation of organic dyes and photoreduction of chromium from aqueous solution. Bulletin of Chemical Reaction Engineering & Catalysis, 14 (2019) 142-152.\n17. S. O.B. Oppong, W. W. Anku, F. Opoku, S. K. Shukla, E. S. Agorku and P. P. Govender. Photodegradation of Eosin Yellow Dye in Water under Simulated Solar Light Irradiation using La-Doped-ZnO Nanostructure Decorated on Graphene Oxide as an Advanced Photocatalyst. ChemistrySelect 3 (2018) 1180-1188.\n18. W. W. Anku, S. K. Shukla and P. P. Govender. Graft gum ghatti caped Cu2O nanocomposite for photocatalytic degradation of naphthol blue black dye. Journal of Inorganic and Organometallic polymers and Materials (2018) 1540-1551.\n19. C.N. Peter, W. W. Anku, R. Sharma, G. M. Joshi, S. K. Shukla, P. P. Govender. N-doped ZnO/graphene oxide: a photo-stable photocatalyst for improved mineralization and photodegradation of organics dye under visible light. IONICS (2018) 327-339.\n20. C.N. Peter, W. W. Anku, S. K. Shukla, P. P. Govender. Theoretical studies of the Interfacial charge transfer and the effect of vdW correction on the interaction energy of non-metal doped ZnO and graphene oxide interface. Theoretical Chemistry Accounts 137 (2018) 75-84.\n21. Renu Kumari, Adeniyi Olugbenga Osikoya, William Wilson Anku, Sudheesh Kumar Shukla, Penny Poomani Govender. Hierarchically assembled two-dimensional hybrid nanointerfaces: A platform for bioelectronic applications. Electroanalysis. Electroanalysis 30 (2018) 2339-2348.\n22. W. W. Anku, S. O. B. Oppong, S. K. Shukla, E. S. Agorku, and P. P. Govender. Cobalt doped ZrO2 decorated multiwalled carbon nanotube: A promising nanocatalyst for photodegradation of indigo carmine and eosin Y dyes. Progress in Natural Science: Materials International 26 (2017) 354-361.\n23. S. O. Oppong, W. W. Anku, S. K. Shukla and P. P. Govender. Synthesis and characterisation of neodymium doped-zinc oxide–graphene oxide nanocomposite as a highly efficient photocatalyst for enhanced degradation of indigo carmine in water under simulated solar light. Research on Chemical Intermediates 43 (2017) 481-501.\n24. W W Anku, S. O. B. Oppong, S K Shukla and P P Govender.Comparative photocatalytic degradation of monoazo and diazo dyes under simulated visible light using Fe3+/C/S doped-TiO2 nanoparticles. Acta Chimica Slovenica 63 (2016) 380-391.\n25. W. W. Anku, S. O. B. Oppong, S. K. Shukla, E. S. Agorku, and P. P. Govender. Chitosan–sodium alginate encapsulated Co-doped ZrO2–MWCNTs nanocomposites for photocatalytic decolorization of organic dyes. Research on Chemical Intermediates 42 (2016) 7231–7245.\n26. W. W. Anku, S. O. B. Oppong, S. K. Shukla, E. S. Agorku, and P. P. Govender. Palladium-doped–ZrO2–multiwalled carbon nanotubes nanocomposite: an advanced photocatalyst for water treatment. Applied Physics A 122 (2016) 579-587.\n27. W W Anku, S. O. B Oppong, S K Shukla and P P Govender. Influence of ZnO concentration on the optical and photocatalytic properties of Ni-doped ZnS/ZnO nanocomposite. Bulletin of Materials Science 39 (2016) 1745-1752.\n28. S. O. B. Oppong, W. W. Anku, S. K. Shukla, E. S. Agorku and P. P. Govender. Photocatalytic degradation of indigo carmine using Nd-doped TiO2-decorated graphene oxide nanocomposites. Journal of Sol-Gel Science and Technology 80 (2016) 38–49.\n29. M. Mzoughi, W. W. Anku, S. O. Oppong, S. K. Shukla, E. S. Agorku and P. P. Govender. Neodymium Doped ZrO2-graphene Oxide Nanocomposites: A Promising Photocatalyst for Photodegradation of Eosin Y Dye. Advanced Materials Letters 7 (2016) 946-950.\n30. S. O.B. Oppong, W. W. Anku, K. S. Shukla and P. P. Govender. Lanthanum doped-TiO2 decorated on graphene oxide nanocomposite: A photocatalyst for enhanced degradation of Acid Blue 40 under simulated solar light. Advance Materials Letters 8 (2016) 432-438.\n\nConference Presentations\n1.\tSession Co-chairs: William Wilson Anku and Saada Mohammed. Session Title: Innovative sample preparation and detection techniques for legacy and emerging pollutants in different environmental matrices. Virtual SETAC Africa 10th Biennial Conference held from 20-22 September 2021.\n\n2.\tW.W. Anku, S.O.B. Oppong, S. K. Shukla, E.S Agorku and P.P. Govender. Hetero-elements doped TiO2 for comparative photocatalytic degradation of monoazo and diazo dyes. SPEA9- 9th European Meeting on Solar Chemistry and Photocatalysis: Environmental Applications. Held in Strasbourg, France from 13th to 17th June 2016. \n\n3.\tW.W. Anku, S.O.B. Oppong, S. K. Shukla, E.S Agorku and P.P. Govender. Cobalt-doped ZrO2 decorated multiwalled carbon nanotube: A promising nanocatalyst for photodegradation of indigo carmine dye. 4th YWP-ZA Biennial Conference and 1st Africawide YWP Conference. Held at the CSIR-Pretoria, South Africa from 16th to 18th November 2015. (Won second best presenter award).\n\n4.\tW.W. Anku, S.O.B. Oppong, S. K. Shukla, E.S Agorku and P.P. Govender. Palladium doped-ZrO2-multiwalled carbon nanotubes nanocomposite as an advanced photocatalyst for water treatment. 5th UJ Cross Faculty Symposium. Held at UJ-Bunting Road Campus on 13th October 2015. (Won best presenter award).\n\n5.\tW.W. Anku, S.O.B. Oppong, S. K. Shukla, E.S Agorku and P.P. Govender. Cobalt-doped ZrO2 decorated multiwalled carbon nanotube: A promising nanocatalyst for photodegradation of indigo carmine dye. UJ Harvest festival. Held on 17 September 2015 in Perskor Building, DFC.\n\n6.\tW.W. Anku, S.O.B. Oppong, S. K. Shukla, E.S Agorku and P.P. Govender. Palladium doped-ZrO2-multiwalled carbon nanotubes nanocomposite as an advanced photocatalyst for water treatment. 3rd conference on Emerging Frontiers for Sustainable Water. Held at the Protea Hotel Wanderers, in Johannesburg, South Africa from 3-5 August 2015.\n\nReferences\n1. Prof Penny Govender\nDirector: Research Capacity Development (RCD)\nPostgraduate School: Research & Innovation, 101, Akanya Building\nAPK campus, University of Johannesburg, South Africa\nTel: 27845002689. Email: pennyg@uj.ac.za\n\n2. Dr. Anthony Yaw Karikari\nDeputy Director: \nCSIR-Water Research Institute, P.O. Box M38, Achimota-Accra, Ghana\nTel: 233208184215, E-mail: aykarikari@hotmail.com\n\n3. Dr Monday Onoyivwe Ama\nResearch Scientist: CSIR-National Centre for Nanostructured Materials,\nMeiring Naude Road Brummeria, Block 19B, Pretoria 0001, South Africa \nTel.: +27733300486, Email: onoyivwe4real@gmail.com',institutionString:"CSIR-Water Research Institute",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"14",title:"Materials Science",slug:"materials-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"440212",firstName:"Elena",lastName:"Vracaric",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/440212/images/20007_n.jpg",email:"elena@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6320",title:"Advances in Glass Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6d0a32a0cf9806bccd04101a8b6e1b95",slug:"advances-in-glass-science-and-technology",bookSignature:"Vincenzo M. 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Proteins, the nanomachines essential to living organisms, have their “manufacturing plan” encoded in their DNA gene sequence [2]. During their synthesis, proteins adopt a specific three-dimensional structure that allows them to perform their functions within the cell. “Seeing” the structure of biological macromolecules, such as proteins or nucleic acids (RNA or DNA), allows researchers to elucidate the mechanisms of live in all organisms, and among many other applications, allows them to design new drugs [3].
\n“Seeing” proteins or nucleic acids in three dimensions, a dream or a reality? Could microscopy, a technic known since more than 350 years that allows to visualize biological cells, be the right approach? Of course, the dimensions of these two objects, macromolecules and cells are very different: The cell size ranges generally from 10 to 100 microns (10−6 m), the dimensions of biological macromolecules, proteins or nucleic acids, are of the order of tens of angstroms (10−10 m) (Figure 1). To reach atomic details, the method of choice is crystallography, whose principle is based on the bombardment by X-ray of crystals composed of biological macromolecules [4].
\nDimension of biological macromolecules represented at the same scale (picture provided by Dr Jérémie Piton). The length of a 60 base pairs DNA double helix is 204 Å.
In only 50 years, crystallography has become the technique of choice for the determination of structures of biological macromolecules at atomic scale, taking advantage of the major advances in the scientific fields as diverse as molecular biology, biochemistry, computer science, physics and more recently robotics. Today, crystallography is able to address the determination of three-dimensional structures of macromolecules more and more complex, more and more quickly. Currently, more than 25 crystal structures are deposited daily in the Protein Data Bank (http://www.rcsb.org) The protein Data Bank (PDB) is a databank that contains 120,262 entries of macromolecules structures (protein, nucleic acids, complexes), 107,455 have been solved by X-ray crystallography (July 2016).
The physical principle of crystallography is based on X-ray diffraction by all the electrons constituting the atoms of all the macromolecules contained in the crystal (Figure 2). The analysis of these diffraction data then allows the crystallographer to calculate the electron density, which is the distribution of the electron cloud of the macromolecule in the crystal. This electron density provided it is sufficiently precise—this preciseness depends on the resolution of the diffraction data—allows the localization of each atom of the molecule, and thus the determination of its coordinates in the three-dimensional space [6].
\nThe principle of crystallography. (A) A monochromatic X-ray beam bombards a crystal frozen in a cryo-loop that rotates on itself. The observed diffraction spots are the result of the impact on the detector of the wave diffracted by the electrons in the crystal. (B) Electron density map of a fragment of a macromolecule is represented (left). The three-dimensional structure of a macromolecule (here a protein) is represented in three ways: all-atoms, backbone and cartoon representation (see
To get this three-dimensional structure, several steps that falls within multiple disciplines are required (Figure 3). Each of these steps represents potential bottlenecks that need to be overcome. These are the production and the purification of the macromolecule, its crystallization, diffraction data collection and processing. Another crucial step is the determination of the phases of the measured signal, absolutely required to calculate the electron density. The last step is the refinement of the built structure, called the model, which will then be interpreted in the context of its biological function. The analysis of the model will thus raise new questions leading to the resolution of other crystal structures, such as structure of a complex between the studied protein and its partners [7]. We will in the following sections describe each of these steps.
\nThe main steps of the three-dimensional structure determination of biological macromolecules by crystallography.
The first step, a step that falls within biology and includes molecular biology and biochemistry techniques, is the production of highly pure macromolecule in large quantity. Once the sequence of the macromolecule to be studied has been identified and characterized by bioinformatics analyses, the sequence corresponding to the gene of the macromolecule is cloned in an expression vector and produced classically in a bacterial organism (typically In a aqueous solution containing a buffer, salt and various additives.
The next bottleneck is based on physical chemistry, specifically crystallization which addresses concepts such as solubility of molecules and their transition from soluble state to a solid crystalline ordered state [8]. This step, built on statistical screenings plays with the variation of parameters such as temperature, pH, concentrations of biological macromolecules, as well as nature and concentration of crystallizing agents and various additives [9]. Obtaining a single homogeneous crystal, that result to high quality diffraction data, represents a crucial step in the process of determining a macromolecular structure. In order to increase the success rate, crystallization robots are used today to screen more than several thousands of parameters. The size (from tens to hundreds of microns) and the morphology of the crystals are highly variable (Figure 4) and are not necessarily related to their diffracting power and quality.
\nCrystals of biological macromolecules. Left, a typical crystallization plate used in crystallization robots that allows to screen 96 crystallization conditions. Middle, different crystals of macromolecule. Right, the crystal is shown in its cryo-loop (see Section 2.). The black bar is 100 microns.
The crystals obtained during the previous step are fished using a small loop (Figure 4), cryo-cooled to protect them from radiation damage [10], and then placed into a monochromatic X-ray beam produced by an appropriate source, either a rotating anode generator available in crystallography laboratories or a synchrotron radiation, the latter producing significantly more intense beams [11]. Under these conditions, the waves scattered by the electrons of the macromolecules that are three-dimensionally ordered in the crystal add up in given directions (the diffracted beam is characterized by a structure factor, Figure 7) and generate a diffraction spot on the screen of the detector (Figure 5A). All the spots, regularly spaced, form the diffraction pattern (Figure 5A). This diffraction pattern is reconstituted by using several hundreds of images, each corresponding to an orientation of the crystal that rotates on itself during the measurement of the diffraction data (Figure 2 and Figure 5B). The information contained in each diffraction spot is characterized by the amplitude and the phase of the structure factor characterizing the corresponding scattered wave.
\n\n\nThe three-dimensional distribution of the spots is directly related to the cell parameters, e.g. the three lengths of the parallelepiped that constitutes the volume element (the cell), which is regularly repeated in space (Figure 6) and allows to describe the crystal. The distribution of the spot intensities is directly related to the electron density distribution (the macromolecules) in the cell. Mathematically, this means that the diffraction pattern is the Fourier transform of the electron density (Figure 7).
\n(A) The diffraction pattern (or Fourier transform) of a crystallized molecule generates a three-dimensional spot lattice (bottom), whose background image corresponds to the Fourier transform of a single molecule (top). The amplitude and phase of the diffracted beams are represented by the color brightness and the color hue, respectively (Kevin Cowtan\'s Picture Book of Fourier Transforms (http://www.ysbl.york.ac.uk/~cowtan/fourier/fourier.html). (B) Example of detector image constituting the diffraction pattern. Hundreds of images are usually recorded. The spots at the image edge are high resolution spots, providing the most detailed information.
The macromolecules are ordered in the three directions of space and form the crystal packing (left). The smallest volume that is repeated by translation in all directions of space is the cell (middle and right). It forms a parallelepiped characterized by three vectors named a, b and c.
The electron density contained in one cell can thus be calculated by inverse Fourier transform, a mathematical property of this transformation, provided the amplitude and the phase of all the diffracted beams are known (Figure 7). Whereas the amplitude is directly proportional to the intensity of the diffracted spots, the phase information is not experimentally measurable.
\nIn summary, the crystal “realizes” a Fourier analysis producing diffraction data, and the crystallographer will calculate a Fourier synthesis to get the electron density contained in one cell (Figure 7).
\nSchematic summary of the relationship between the diffraction (structure factors and diffraction spots) and the electron density of the structure three-dimensionally packed in the crystal.
Three main methods exist for the estimation of the phases [12]. We have to remember here that the number of phases to be estimated is typically several tens to hundreds of thousands (the phase of each spot for which the intensity has been measured has to be estimated).
\nThe first method is
The second method is
The third method is
Once a first set of phases is estimated, a first electron density map is calculated. If this map is sufficiently interpretable, the macromolecule can be built step by step in this map (Figure 8). A combination of automated algorithm and manual method available through interactive graphics softwares are used [25], leading to a final model composed of the three-dimensional coordinates of each atom of the cell content constituted by one or several macromolecules.
\n\nFrom that first built model, the diffraction intensities are calculated by Fourier transform and compared to the intensities experimentally measured. This comparison allows the step by step improvement of the model. This cyclical process is called the crystallographic refinement, alternating the search for global minimum of energy functions and manual reconstruction of the model [26].
\nThe calculation of the electron density map (left) allows the building of the atomic model step by step (middle) and leads to the three-dimensional model of the structure (right).
The final step, downstream the structure determination by X-ray diffraction, concerns the interpretation of the structure and its integration into the biological context [27–29]. It consists in the understanding of the structural result as a three-dimensional object and the appreciation of its function at the cellular or evolution level. The description of the interatomic interactions, the secondary structures (Figure 9), the domains and their arrangement that defines the fold or the tertiary structure (Figure 9), as well as the characterization of the shape, the electrostatic properties and the quaternary structure based on the content of the cell in the crystal packing, are often complemented by the study of the macromolecule in solution, to better characterize its oligomeric (Figure 9) and its dynamic behavior, alone or in the presence of interactors, if known. These studies use a variety of biophysical methods, such as mass spectrometry, analytical ultracentrifugation, light scattering, microcalorimetry or surface plasmon resonance (Biacore® technology), etc … [30]. In the case of enzymes, these studies will be coupled with enzymological approaches to determine the activity and the catalytic constants.
\n(A) The protein structures are represented by three modes of representation (see also
An analysis based on bioinformatics tools will allow to place the structure determined in the context of structural and evolutionary knowledge at a given time [31]. The lessons learned from these studies, often of primary importance, provide information including the classification of the structure and its sequence within a family counterparts, on the distribution and evolution of folding in the different domains of life (viruses, bacteria, archaea, eukaryotes), on the possible function when it is unknown, on the catalytic site and its spatial conservation and sequence, on the degree of oligomerization or on the existence of interaction with other partners, proteins, nucleic acids or ligands. A final type of study seeks to place the three-dimensional object into the context of the knowledge on the major biological mechanisms of live, such as knowledge on gene expression with transcriptomics, on complex formation with interactomics, etc … This information will include the characterization of the partners of the studied macromolecule at the scale of the cell or the whole organism.
\n\nAll these steps, from the structure determination to the biological interpretation, far from being the end of the story, are often the beginnings of new structural studies (Figure 3). These can be articulated around analyses of the relative importance of the components of the macromolecule, the aminoacids, by determining the structure of mutants, or the studies of the interactions with partners by determining the structure of macromolecular complexes.
\nThe brain has a remarkably high metabolic rate and thus requires a highly disproportional amount of blood flow. Although its only 2% of body weight, the brain takes up 15–20% of cardiac output [1], making it one of the most highly perfused organs in the human body. This high metabolic rate coupled with its limited capacity for energy storage [2] necessitates heavy reliance on oxidative metabolism and thus requires constant blood flow to maintain nutrient and oxygen supply, remove waste products, and maintain a state of cerebral metabolic homeostasis. Severe underperfusion can quickly result in unconsciousness [3] and if prolonged, death [4]; while chronic mild under perfusion is associated with cognitive decline [5]. In addition to its high perfusion and metabolic rate, the cerebral circulation faces a unique challenge of being enclosed in the skull. This rigid structure prevents the expansion of tissue and extracellular fluid. Swelling within the skull from vasogenic edema leads to an increase in intracranial pressure which in turn can lead to neurologic complications or in more extreme cases death [1]. The unique challenges of the cerebral circulation, including intolerance to ischemia and edema, coupled with the paramount importance of maintaining constant nutrient and oxygen supply to cerebral tissue creates a need for precise regulation of cerebral blood flow and therefore the presence of redundant intrinsic mechanisms for its regulation. The anatomy of the brain vasculature ensures multiple routes for blood and oxygen delivery potentially allowing for perfusion even in cases of a blocked blood vessel [6]; however, acute regulation of flow is done primary by altering the diameter of blood vessels, and thus the resistance to flow. The major mechanisms of local regulation of vascular tone intrinsic to the cerebral vasculature include myogenic, shear, and metabolic based regulation. Although each mechanism has a discrete effect on vascular tone the integration of the different contributors to determine an appropriate level of tone is much more difficult to discern, especially in the cerebral circulation. These complex interactions allow for highly accurate control of cerebral blood flow in addition to protecting vulnerable downstream capillaries from high pressures and flow rates that could otherwise lead to edema; but, they also introduce several potential areas for failure. The intimate interactions of the various mechanisms of regulation of flow mean that the failure of one mechanism has the potential to initiate a cascade of events that results in inappropriate regulation of flow. As such abnormal execution of vascular tone regulation may form the basis of vascular pathologies [7].
One of these pathologies with a significant vascular component associated with impaired cerebral vascular tone regulation is metabolic syndrome (MetS). The incidence and prevalence of MetS is growing in Western society [8, 9, 10] and is contributing to decreased quality of life and increased economic burden. Thus an understanding of how it alters the cerebral circulation is crucial. MetS is categorized by a collection of metabolic risk factors including obesity, hypertension, atherogenic dyslipidemia and impaired glycemic control creating a pro-oxidant pro-inflammatory environment that raises the risk of developing impaired vascular structures and function [11, 12, 13, 14]. These impairments are particularly detrimental when they affect the cerebral circulation and lead to cerebrovascular pathologies such as stroke or transient ischemic attack (TIA) due to the detrimental consequences associated with such events. However, cognitive impairments are not limited to individuals that have experienced an acute ischemic event since even in their absence MetS is strongly associated with impaired cognitive function and decreased quality of life [15, 16, 17, 18]. Therefore preventing their occurrence by protecting the cerebrovasculature from functional and structural decline is paramount. This chapter will present a description of the local mechanisms involved in the regulation of cerebral vascular tone, how they integrate with one another and how they can be compromised in disease. Although impairments to the regulation of cerebral vascular tone are not limited to conditions associated with MetS this discussion will focus on the impact of MetS and its associated risk factors.
The myogenic mechanism which was first described by Bayliss is an intrinsic property of the vascular smooth muscle to respond to changes in intravascular pressure which is independent of other mechanisms of tone regulation including neural, metabolic, and hormonal influences [19]. The intrinsic nature of the myogenic response is supported by its existence in arteries and arterioles that have been sympathetically denervated and had their endothelium removed [20] thus leaving only the vessel itself to initiate and execute the response. The prototypical response of the vascular smooth muscle in response to an increase in intraluminal pressure is initial distension quickly followed by a constriction. The opposite can be said in situations of decreased intraluminal pressure; a fall in intraluminal pressure results in vessel collapse followed by dilation [21]. The myogenic response has several physiological roles including the establishment and maintenance of basal vascular tone (some degree of constriction) so that resistance may be increased or decreased by metabolic vasoconstrictors or vasodilators respectively, in order to regulate tissue perfusion. The establishment and maintenance of this partially constricted state in a pressurized vessel is referred to as myogenic tone. Additionally, the myogenic tone has a role in flow and pressure regulation. It functions by constricting to drop the pressure that reaches the downstream capillaries and protect them from edema or vascular remodeling associated with hypertension in the capillaries [22, 23, 24, 25]. Equally important as protecting from hypertension is the ability of the vasculature to promote flow during low pressure by dilating. This ability to alter diameter over a range of pressures is referred to as myogenic reactivity. Beyond the local implications for the regulation of vascular tone, resistance to flow also has implications for systemic blood pressure since mean arterial pressure is the product of total peripheral resistance and cardiac output. This relationship illustrates system-wide implications of accurate vascular tone regulation. While the myogenic response is present throughout the body in a variety of vessels (arterioles, veins, lymphatic vessels) [26] the aforementioned functions of the myogenic response are particularly important in the cerebral circulation due to the catastrophic outcomes associated with under or over perfusion including unconsciousness and edema respectively. It is therefore not surprising that the most prominent myogenic response is found in the cerebral circulation with arterioles (resistance vessels) having the most pronounced response [1]. It should also be noted that the large arteries feeding the brain have a greater contribution to regulating vascular resistance in the cerebral circulation compared to other vascular beds, again providing evidence for the importance of regulating tone in the cerebral circulation.
A phase model of arterial myogenic behavior is commonly used to describe the response over a range of pressure. In the first phase, there is an initial development of myogenic tone at approximately 40–60 mmHg with increasing pressure up to that point causing passive distension. There is then a phase of myogenic reactivity in the pressure range of 60–140 mmHg and finally a phase of forced dilation at transmural pressures greater than approximately 140 mmHg [27].
Myogenic tone develops at approximately 40–60 mmHg and is characterized by an increase in intracellular Ca2+, of about 200%, followed by a reduction in lumen diameter. This pressure causes cellular deformation, depolarization of the vascular smooth muscle cells (VSMC), and a significant increase in wall tension. Wall tension appears to be the controlled parameter in the myogenic response which is altered during an increase or decrease in transmural pressure. The myogenic response adjusts the diameter of the vessel in an attempt to restore or limit the change in basal wall tension through a negative feedback mechanism [28, 29]. The suggestion that wall tension is the controlled parameter is supported by its correlation with changes in cell calcium and myosin light-chain phosphorylation, a relationship that is not seen with vessel diameter [30, 31].
The mechanism of the myogenic response is attributed to stretch-activated ion channels: including L-type calcium channels, voltage-activated calcium channels and calcium activated potassium channels along with enzymatic mechanisms. Specifically, increased intraluminal pressure causes depolarization of the VSMC membrane and calcium influx by the opening of voltage-gated calcium channels (VGCCs), with the most prominent involvement being from CaV1.2. This influx of Ca2+ leads to increased myosin light-chain (MLC) phosphorylation which promotes increased actin/myosin interaction followed by cross-bridge cycling and cell shortening (vasoconstriction) [7, 24, 32, 33, 34]. The importance of Ca2+ influx in the generation of myogenic tone supported by its complete abolishment under Ca2+ free conditions [32, 35]; this is also a technique frequently used to study the passive mechanical characteristics of vessels to determine the degree of vascular remodeling since the VMSC exhibit a passive response (no force production) its strain is only due to the applied stress applied and the composition of the vessel [36]. Under physiological conditions the magnitude of the constrictor response to increased intraluminal pressure is limited by calcium-activated potassium channels that carry hyperpolarizing current proportional to the intracellular calcium concentration [35]. This negative feedback mechanism is supported by enhanced myogenic constriction being observed following blockade of calcium-activated potassium channel by specific inhibitors of these channels [37, 38, 39]. Additionally, at this pressure of 40–60 mmHg there is an activation of enzymatic systems and a complex interaction between matrix metalloproteins, the extracellular matrix, integrins and the cytoskeleton [40, 41, 42] that contribute to the myogenic reactivity at higher intraluminal pressures within the range of 60–140 mmHg [27]. This myogenic tone phase can also be characterized as the lower limit of autoregulation, which has important physiological implications. Below this pressure blood flow becomes dependent on blood pressure since the vessel cannot further dilate and begins to collapse as the pressure drops below this point [43]. Having an appropriate lower limit becomes especially important in situations of cerebral ischemia to allow restoration of flow in the presence of hypotension.
In this range of intraluminal pressure of 60–140 mmHg where the myogenic tone has already been established increases in pressure generally result in mild constriction and decreased pressure leads to mild dilation. Just as previously discussed for the generation of myogenic tone, increased pressure within this range leads to stretch, depolarization, and constriction of the vascular smooth muscle. However, in the myogenic reactivity phase, there is little change in vessel diameter across the range of pressures along with relatively small increases in Ca2+ (<20%) despite sizable increases in force production [27]. Multiple studies suggest an increased sensitivity to Ca2+ compared to the previous phase in the development of myogenic tone [20, 27, 44, 45, 46, 47, 48]. Increased sensitivity to Ca2+ is achieved by inhibition of myosin light chain phosphatase (MLCP) which promotes the accumulation of phosphorylated LC20 without an accompanying increase in calcium-induced myosin light chain kinase activity [49]. The presence of a contractile mechanism that does not require large variation of calcium, such as altering Ca2+ sensitivity requires less storage and transmembrane shuttling and is therefore advantageous in terms of conserving Ca2+ [35].
There are several proposed mechanisms that regulate Ca2+ sensitivity within this phase including, activation of protein kinase C (PKC), RhoA/Rho kinase pathways, and reactive oxygen species (ROS) [27, 35, 44, 46, 50]. The following studies provide evidence for the aforementioned mechanisms of enhanced Ca2+ sensitivity in this phase of the myogenic response through the utilization of specific inhibitors or transgenic animal models. Inhibition of PKC stops myogenic vasoconstriction in middle cerebral arteries with no impact on pressure-induced Ca2+ elevation [46]. Direct assessment of Ca2+ sensitivity by measuring the Ca2+-tone relationship has consistency found decreased sensitivity during Rho kinase inhibition [20, 45]. ROK has also been reported to trigger smooth muscle depolarization during myogenic constriction and limit the extent of depolarization by opening delayed rectifier potassium channels [51, 52]. Arteries from transgenic animals missing NADPH oxidase function show an absence of myogenic activity [53], while mice deficient in superoxide dismutase, an endogenous antioxidant enzyme that catalyzes the breakdown of superoxide radical to H2O2, acquired enhanced myogenic reactivity [54]. Additional mechanisms that contribute to the myogenic reactivity phase independent of Ca2+ sensitivity include actin cytoskeleton reorganization and thin filament regulation [55, 56].
Although the prototypical response of increased intraluminal pressure is a constriction, at excessively high pressures, beyond the autoregulatory range of approximately 140 mmHg, forced dilation often occurs [57]. This process results in a loss of myogenic tone, and thus results in an increase in vessel diameter, rapid increase in wall tension and significant elevation in Ca2+ (>50%) [27]. Although the name implies a degree of passiveness in the process, forced dilation is likely an active vasodilation involving KCa channels, nitric oxide (NO) and or ROS, which are activated to protect the arterial wall from damage [44, 57]. If the pressure is reduced to within the myogenic reactivity range reestablishment of tone and reduction in Ca2+ is observed.
An increase in flow leads to an increase in a frictional force known as shear that is detected by the endothelial cells lining the vessel lumen as blood moves through a vessel. As such, the magnitude of the shear force is proportional to blood flow. Shear catalyzes physiologically important responses in the cerebral vasculature such as encouraging reperfusion after ischemia, aiding in the hyperemic response to increased metabolic demand, and perhaps protection of downstream capillaries from edema and structural damage. Flow has been found to induce both constrictor and dilator pathways that act on the VSMC and result in a final level of tone taking into account the opposing processes. It is generally accepted that in the peripheral circulation flow leads to dilation; however, in the cerebral circulation the response is more controversial with both constriction and dilation being reported. These opposing observations may be because of a variety of factors including the area of the brain studied, the preparation used or because of interactions with other mechanisms affecting cerebral vascular tone. Within the cerebral circulation, the vertebrobasilar systems appear to elicit flow-mediated dilation, as measured in rats and mice [58] and humans [59]. The increase in flow is sensed by the endothelium, which initiates a negative feedback mechanism in an attempt to decrease the shear stress by dilating. Shear-induced dilation is largely endothelium-dependent and is at least partially mediated by NO [60]. The production of NO is controlled by the enzyme nitric oxide synthase (NOS), particularly endothelial NOS (eNOS), which catalyzes the formation of NO from L-arginine and is itself dependent on phosphorylation by Akt [61, 62]. The NO formed by eNOS then diffuses into the vascular smooth muscle where it activates soluble guanylyl cyclase (sGC) and increases cyclic guanine monophosphate (cGMP) and activating protein kinase G [63, 64]. Activation of protein kinase G opens large-conductance Ca2+-activated K+ (BKCa) channels reducing intracellular Ca2+ which leads to relaxation of the vascular smooth muscle and thus vasodilation [65]. In addition to NO, eNOS can also lead to the formation of H2O2 which may also mediate flow-induced dilation [18]. During enzymatic cycling, eNOS produces oxygen radicals [66, 67] which, in the presence of sufficient antioxidants, are converted into H2O2 that may then, like NO, activate sGC and lead to dilation [68]. Other endothelium-dependent dilators such as prostaglandins do not appear to be involved in shear-induced dilation since the COX inhibitor indomethacin had no effect on the response to flow [60].
Constriction of cerebral vessels has also been reported in cats [69], rats [70] and human isolated cerebral arteries [71]. Constriction appears to predominate within the carotid circulatory area [58] especially when studies using
The differences in observed responses may also be dependent on whether the study was conducted
Although flow induced constriction is not usually seen
In a physiological setting multiple inputs are being processed by the cerebral vasculature leading to the generation of a certain level of tone. Pressure and shear stress exerted by flowing blood are two mechanical stimuli that have been described to play a major role in the regulation of vascular tone [83, 84]. It is therefore important to consider their interaction when determining the resultant effect on vascular tone. At high pressures (around >80 mmHg) cerebral vessels tend to constrict in response to flow [72, 85, 86, 87]. This biphasic response is further supported by findings from Garcia-Roldan and Bevan in isolated rabbit pial arterioles with flow rates from 0 to 20 μL/min at 90 mmHg but did not with the same flow at 60 mmHg [72]. It is interesting that the tipping points for “high” and “low” pressures observed in previous studies are around 80 mmHg since, in resistance arterioles such as the MCA this pressure is commonly measured under physiological conditions. If 80 mmHg is indeed the point where higher pressures lead to constriction and lower to dilation in response to shear the resistance arterioles that are resting around this pressure would have the opportunity to tightly regulate the response to flow and shear thus allowing for precise control of cerebral blood flow. Please see Figure 1 for a schematic representation of how flow and intravascular pressure can impact cerebral vascular tone.
A schematic representation of how intravascular pressure (myogenic), increased lumen flow rates (shear), tissue metabolism and neurovascular coupling can impact cerebral vascular tone regulation.
The mechanical stimuli of pressure and flow are generally thought to be important in setting the basal vascular tone so that metabolic influences are able to cause dilation or constriction depending on the needs of the cerebral tissue [24]. Metabolic control of vascular resistance is of particular importance in the cerebral circulation since cerebral tissue is extremely intolerant to ischemia [88]. As such, the cerebral circulation has a precise and highly localized coupling between the metabolic requirements of cerebral tissue and the magnitude of blood flow by controlling vascular resistance. There are numerous vasoactive metabolites that contribute to the control of cerebral vascular tone including adenosine, CO2, H+, O2 and K+. Increasing concentrations of adenosine, CO2, H+, and K+ and decreased concentration of O2 result in relaxation of VSM and dilation of cerebral resistance vessels. Each metabolite is associated with a cascade of events that ultimately either alters intracellular Ca2+ concentration or Ca2+ sensitivity of the VSM and results in a change in vessel diameter. Although the effects of each metabolite have been well characterized the relative importance of each along with its interaction with each other and other parameters of tone remains an area of further investigation. The discussion below is summarized in Figure 1.
Adenosine has been proposed as being the primary metabolite controlling metabolic regulation of cerebral vascular tone. It is a naturally occurring nucleoside produced as a byproduct of ATP metabolism; thus, its accumulation signals a need for increased blood flow to match the metabolic activity. This relationship with metabolism has widely implicated adenosine in local regulation of cerebral vascular tone during functional hyperemia, ischemia, or whenever PO2 becomes limited [89, 90, 91]. Adenosine has direct effects on the vasculature [92, 93] that can both vasodilate and hyperpolarize VSM and is therefore considered an EDHF [94]. There are four distinct subtypes of adenosine receptors; however, the A2A receptor appears to be of high importance in mediating vasodilation [95, 96, 97]. The A2A receptor is a purinergic P1 receptor that has been confirmed to be present in cerebral microvessels [98, 99, 100, 101] on the VSM cells [102, 103]. It causes dilation in a concentration-dependent manner [101, 104] once bound to the A2A receptor by activation of adenylate cyclase [105] and therefore cAMP [106, 107, 108] which reduces cytosolic calcium and leads to vasodilation. The opening of KATP channels also occurs secondary to the increase in cAMP levels as a result of adenosine binding to its receptors on the cell membrane [109, 110, 111, 112]. The contribution of opening KATP channels to dilation is likely substantial since during blockade of KATP channels with glibenclamide, adenosine-induced dilation was reduced by approximately 50% [113]. Although A2A receptors are generally considered the most important mediators of the effects of adenosine on vascular tone the A2B receptors are also proposed to cause dilation through similar mechanisms as A2A in addition to coupling to Gq proteins to produce Ca2+ mobilization by activation of phospholipase C and mitogen-activated protein kinase activation [98, 114, 115]. In addition to dilating the cerebral vasculature adenosine may also block vasoconstrictive signals in the parenchyma as evidenced by
Similar to many of the other metabolites discussed CO2 tends to increase under conditions of increased metabolism without adequate flow to eliminate it from the area of production and thus its accumulation leads to dilation of the vasculature. High sensitivity to PCO2 is unique to the cerebral circulation [119] causing approximately 3–6% increase and 1–3% decrease in flow per mmHg change in PaCO2 above or below eupnoeic PaCO2 respectively. This high sensitivity is seen throughout the arterial side of the vascular network including the large arteries in the neck [120] and large intracranial arteries [121, 122, 123] to the smallest pial arterioles [124] and parenchymal vessels [125, 126, 127, 128]. There are likely several redundant mechanistic contributors to the sensitivity of the vasculature to PCO2 which may contribute to the debate as to whether the dilation is triggered by increased PCO2 or rather the accompanying increase H+ concentration from the carbonic anhydrase reaction. There is strong support that the change in PCO2 mediates at least in part alterations in cerebral vascular tone locally by changes in perivascular pH [107, 129, 130, 131] as evidenced by acidic and alkaline perfusate administered through an intracranial window. Experiments that have been able to alter pH and PCO2 independently have provided evidence of the dependence of altered pH to initiate a change in cerebral vascular tone [74]. In a cat pial arteriole cranial window preparation, lowering pH along with hypercapnia resulted in no difference in the magnitude of vasodilation when compared to acidic isocapnia [132]. Interestingly, vessel tone was unaltered in response to intraluminal CO2 change, suggesting that a change in superfusate pH is necessary to evoke a change in cerebral vascular tone [107, 133]. This is supported by the findings of unchanged CBF in humans [107] and animals [133] in response to changes in arterial pH, and highly localized pial arteriolar diameter changes in response to the application of acidic/basic solution into the perivascular space [131]. Additionally, when pH is maintained as seen in an experiment with artificial CSF pretreated with sodium bicarbonate, pial vessel dilation is eliminated in response to intraluminal hypercapnia [107, 134] further supporting that a change in superfusate pH is necessary to alter the cerebral vascular tone. In addition to its link with CO2 and H+ through the carbonic anhydrase reaction, there is some evidence that bicarbonate ion may independently influence vascular tone. Having the ability to sense and react to multiple parameters associated with acidosis allows for control of tone in response to not only the pH but also the cause of the disturbance (accumulation of CO2 for instance). In isolated rat basilar arteries reduced [HCO3−]o has been shown to directly increase cerebral vascular tone (with pH maintained at 7.4 and CO2 kept constant at 5%) through the binding of receptor protein tyrosine phosphatase through an endothelium-dependent response [135]. HCO3− may, therefore, stimulate soluble adenylate cyclase activity through a pH-independent mechanism [136]. If this is correct then the modest increase in [HCO3−] during hypercapnia may aid in the dilation response to CO2 but the opposing vasocontractile response to decreases in [HCO3−]o may limits the vasorelaxation caused by a reduction in pH [135]. Limiting vasorelaxation during acidosis is important to lessen the increase in capillary pressure associated with vasorelaxation of upstream arterioles. Hyper-relaxation may overload the capillaries leading to edema and damage thereby worsening the consequences of local inadequate perfusion.
The effects of oxygen are unique in that its availability is required for aerobic metabolism rather than a byproduct like some of the metabolic factors discussed. Therefore it is not surprising that its abundance leads to vasoconstriction and its relative shortage leads to dilation. Although its availability is tightly linked to that of PCO2 and H+ and other metabolic byproducts in a physiological setting, studies have been able to discern its independent effect in the presence of otherwise constant conditions. Data from isolated arteries/arterioles suggest there is in fact an oxygen sensor independent of other vasoactive metabolic byproducts within the vascular wall itself [137, 138, 139, 140, 141, 142]. Once the change in oxygen is sensed there are various mediators of hypoxic dilation including endothelial-derived NO [138, 141], prostanoids [137, 140, 141, 143], 20-HETE [141] and EDHF [139]; however, the contribution of each factor appears to be dependent on the severity of hypoxia [141]. In skeletal muscle, dilation from mild hypoxia (15% O2) was mostly NO-dependent, while moderate (10% O2) was mediated by a combination of increased PGI2 and decreased 20-HETE, and severe (0% O2) was almost entirely accounted for by an increase in PGI2 [141]. In all cases, there appears to be significant involvement by the endothelium to mediate the dilation, which is further supported by a reduction in hypoxic dilation when isolated vessels were exposed to indomethacin (an inhibitor of AA metabolism and thus the production of PGI2) [137, 144, 145] and to a lesser degree by L-NAME (an inhibitor of NO production from NOS) [145]. Therefore, PGI2 is likely a substantial contributor to hypoxic dilation with a lesser but likely still significant role for NO. Human studies measuring CBF with pcMRI, instead of isolated vessel diameter as in the aforementioned studies, with and without administration of L-NAME suggest that hypoxic dilation is highly dependent on NO, with no change from baseline observed in hypoxia when L-NAME was administered [146]. These differences may be because of a species-specific response or differences in
Although K+ is not directly a byproduct of a metabolite pathway it tends to increase in concentration when the frequency of neuronal depolarization is increased, and is therefore indicative of increased metabolism. K+ channels are present in cerebrovascular smooth muscle cells and are important regulators of tone because of their ability to alter membrane potential [148, 149]. Although K+ channels are present through the peripheral vasculature, the cerebral circulation has a unique anatomical feature that allows for intimate interaction of astrocytic endfeet and cerebral vessels. This tight interaction between the astrocytic endfeet and vasculature allows for precise localized changes in blood flow to match the site-specific neural activity in the brain [150, 151]. K+ can therefore be thought of as a direct link between neuronal activity and blood flow. This pairing of neuronal metabolism with appropriate blood flow and is termed neurovascular coupling (NVC). NVC forms the mechanistic basis for neuroimaging techniques that are able to map changes in neuronal activity based on vascular responses such as changes in blood flow or oxygen saturation [152]. As such, an understanding of NVC is not only crucial to understand the regulation of cerebral vascular tone but is also needed to interpret these neuroimaging techniques including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and near-infrared spectroscopy [153].
NVC is dependent on the interactions of the neurovascular unit which is made up of three major components: the vascular smooth muscle, neuron, and astrocyte glial cell. Somewhat surprisingly, the initiation site of neurovascular coupling is at the level of capillaries which then leads to changes upstream; however, once the close anatomical locations of neurons to the capillaries (8–20 μm) are considered this becomes a logical point of initiation [154]. Not only does NVC rely on interactions apart from the vasculature but it also requires several structural components to facilitate cell-to-cell interactions of these different cell types. These components include gap junctions [155, 156], anchoring proteins [157] and specialized ion channels [158] expressed on cell–cell interface membranes. Neurons initiate NVC by generating direct signals that act on the vasculature and indirect signals that are transmitted through astrocytes and lead to increases in intracellular Ca2+ within the astrocyte. This is achieved by the glutamatergic synaptic activity initiating post-synaptic N-methyl-D-receptors (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The increase in intracellular Ca2+ activates Ca2+-dependent enzymes to produce vasodilators. Some of the enzymes activated include neuronal NOS (nNOS) and cyclooxygenase 2 (COX-2) [159, 160]. Glutamate also acts on metabotropic glutamate receptors in astrocytes increasing Ca2+ in these cells and leading to the production of vasoactive metabolites including adenosine, ATP, and K+ that act of the VSMCs [161].
Astrocytes are anatomically well positioned to transmit signals from neurons to the vasculature because of their close proximity to the capillaries; however, in a vascular network both the downstream and upstream vasculature must work in concert in order to effectively regulate blood flow delivery. It appears that endothelial cells provide the crucial role of retrograde propagation of the vasomotor response allowing for coordination between up and downstream vasculature. Endothelial cells can produce numerous metabolites including NO, prostanoids, and endothelin to alter VSMCs constriction. Endothelial intermediate K+ channels (KIR) channels and small conductance K+ channels (KSK) have been implicated as a mechanistic contributor to the propagation of the vasodilatory signal upstream for a synchronized hemodynamic response between the capillaries and arterioles via myoendothelial gap junctions [162]. Secondary to the movement of hyperpolarizing current through gap junctions, K+ efflux from KIR and KSK channels generates what has been described as a “K+ cloud” [163] that also hyperpolarizes neighboring VSMC through both the inducible Na+-K+ electrogenic pump and stimulation of inward rectifying potassium channels in the VSMC of cerebral arteries and arterioles. In both cases, there is a net efflux of K+ from VSMC [164, 165, 166, 167] in conjunction with closed voltage-gated calcium channels and therefore results in the relaxation of the VSMC. The importance of K+ channels in dilating the cerebral vasculature is supported by reduced K+ conductance, depolarization and ultimately constriction seen in experimental inhibition of the channels [163]. For example, 6–10 mM K+ applied to capillaries generated a hyperpolarizing response in endothelial cells which was transmitted upstream to penetrating arterioles hyperpolarizing and relaxing VSMCs [168]. This propagation of the vasodilation signal was blocked with inhibition of KIR with barium or endothelial deletion of KIR1.2 channels, supporting its role transmitting the hyperpolarizing current. Interestingly the capillaries themselves did not dilate to K+ suggesting they act as a sensor detecting the signal for the upstream arterioles to be the effector of the response [161].
Although in a physiological setting K+ tends to lead to vasodilation, the response to K+ may be dependent on the [K+]. In isolated cerebral arterioles low (<7 mM) and moderate (8–15 mM) increases in [K+] result in endothelium-independent dilations and sustained dilation respectively through mechanisms previously discussed [165]. Higher K+ concentrations cause constriction; however, under normal physiological conditions this concentration is not reached and is only seen under pathological processes such as spreading depression and stroke [169, 170]. This response seen in isolated vessel has also been confirmed in vivo [151]. There is a combination of mechanisms at work in response to K+ that may explain the opposing responses to different concentrations. Alone an increase in [K+]o actually tends to depolarize neighboring VSMC resulting in constriction; this response predominates at high [K+]. At low concentrations, the minor increase in [K+]o would by itself lead to constriction but it also stimulates both KIR channels [150, 171, 172, 173, 174] and Na+/K+ ATPase [175, 176, 177] promoting K+ efflux as previously described. This description of the electrophysiology at work in the VSMC is supported by Em measurement in VSMCs when a solution containing [K+] (<20 mM) is applied and produces VSM hyperpolarization, whereas at higher K+ concentrations depolarization predominates [166, 172, 178]. Ultimately the signals generated by neurons, astrocytes, and endothelial cells must be received and integrated into a final level of tone by the VSMCs. A schematic representation of the impact of neurovascular coupling on cerebral vascular tone is presented in Figure 1.
Each component implicated in the regulation of tone has a multitude of signals being produce that is intended to affect a vasomotor response from the VSMCs. Signals from myogenic, shear, metabolic, and neurovascular influences may be additive or opposing in their effect on VSMCs and further combine with one another creating intricate and precise regulation of cerebral vascular tone. It is this intricacy however, that also introduces many possible steps in the pathway for an abnormal response to occur. As such changes to the regulation of tone may form the basis of several pathologies including MetS. The contributing risk factors associated with MetS alter the local regulation of cerebral vascular tone by inducing changes in both the structure and function of the vessels. These risk factors include hypertension, T2DM, and obesity which promote a pro-inflammatory pro-oxidant state. Functionally, MetS is highly linked to increased smooth muscle activation and endothelial dysfunction which has important implications for the ability of a vessel to dilate in response to a multitude of stimuli previously discussed including hypotension, shear, hypoxia, and other metabolic stimuli. Increased myogenic properties are consistently overserved in MetS in multiple vascular beds [179, 180] including in the cerebral circulation [181, 182, 183]. This increase in constriction may be due to both a decrease in buffering capacity from endothelial dysfunction and alterations in the vascular smooth muscle itself [183, 184]. Endothelial dysfunction also has implication for shear-induced dilation since it is highly dependent on NO bioavailability which has consistently been shown to be reduced in MetS. The chronic inflammatory state seen in MetS likely contributes to the reduction in NO bioavailability due to increased scavenging to the produced NO by reactive oxygen species since this reduction in NO bioavailability is consistently reported to evolve in parallel with oxidant stress and the development of a chronic inflammatory state [185, 186]. This is supported by improved dilatory reactivity of MCA with the pretreatment of the cell-permeable superoxide dismutase mimetic TEMPOL in a model of T2DM [145]. Interestingly some studies have actually shown an increase in eNOS expression which may be an attempt to compensate for the increased scavenging; however, they too continue to find reduced dilator reactivity [187].
Aside from reduced NO bioavailability, a shift in arachidonic acid metabolism toward constrictors and away from dilators that are highly responsible for hypoxic dilation has been demonstrated [145]. Thus not only does endothelial dysfunction seen in MetS increase cerebrovascular resistance by decreased dilator metabolite production it may also promote the production of constrictors that exacerbate the impaired dilation capacity of cerebral vessels [184, 188]. A change in sensitivity to various metabolites in addition to their differential production may also contribute to differential vasomotor responses. For example, studies using SNP, an exogenous NO donor, while blocking endogenous NO production by eNOS using L-NAME, found smaller relaxation of the MCA in spontaneously hypertensive rats which was attributed to a decreased expression of soluble guanylate cyclase [189, 190, 191, 192]. In a model of T2DM decreased sensitivity of MCA to the PGI2 analog iloprost was also found suggesting that both decrease production and sensitivity of dilators may be contributing to the impaired dilation of the cerebral circulation in MetS [145].
Impaired dilation in response to exogenous dilator metabolites may also be due to vascular remodeling. Structural changes are an important consideration since even if the smooth muscle of a cerebral vessel is able to relax due to metabolic influences resulting in hyperpolarization, remodeling may prevent an increase in lumen diameter which is ultimately the major contributor to acute changes in resistance and thus the regulator of flow. Hypertension is largely implicated in the thickening of the vascular smooth muscle as well as increasing the ratio of collagen to elastin in the vessel. High intraluminal pressure increases the shear stress exerted on the vascular endothelium which normally could be restored to baseline by NO-induced vasodilation [193, 194, 195]; however, in a disease state with impaired NO production, there is a reduced ability to dilate resulting in endothelial damage and upregulation of atherogenic genes [193, 194, 195]. As a means of protection from chronic increased shear stress and wall tension that may lead to downstream edema cerebral vessels tend to hypertrophy with chronic hypertension, but this protective hypertrophy is also detrimental [188]. Since wall tension is equal to intraluminal pressure X radius and wall stress is wall tension/wall thickness, hypertension-induced hypertrophy and inward remodeling resulting in a decrease in radius and increase wall thickness can normalize both the wall tension and wall stress [188]. Although this remodeling may be protective in regards to increases in pressures and protecting the downstream capillaries from edema it increases the cerebrovascular resistance and limits the dilation reserve during hypotension and therefore presents itself as a right-shift in the autoregulatory range [196, 197]. The development of myogenic tone at higher pressure implies an increased lower limit of autoregulation. This predisposes cerebral tissue to reduced blood flow during hypotension. When pressure drops below the lower limit flow becomes dependent on the passive diameter of the vessel. Not only does an impaired lower limit predispose hypertensive individuals to ischemia but the reduced passive diameter from vascular remodeling further compromises flow to cerebral tissue resulting in hypoxic areas [43].
In addition to hypertrophy and inward remodeling, there is substantial arterial stiffening commonly seen in MetS. The pro-oxidant stress of ROS may interact with components of the perivascular matrix and initiate collagen cross-linking and deposition as well as the breakdown of elastin making the vessel less distensible [198]. This is measured by a left shift in the stress-strain curve of isolated cerebral vessels under passive conditions achieved by using a Ca2+ free solution preventing the development of tone [183]. The stiffening vessel from increased collagen to elastin ratio is made worse by the thickening of vessel walls previously discussed. In a model of T2DM with hypertension significant collagen deposition in addition to medial hypertrophy increasing the wall the lumen ratio and stiffness of the rats MCA [199] was demonstrated while T2DM in the absence of hypertension does not appear to induce structural changes to the cerebral vasculature [145]. This along with data that suggests the increase in arterial stiffness seems to follow a time course similar to that of the onset of hypertension suggests a strong relationship between hypertension and vascular remodeling [200]. Chronic uncontrolled hyperglycemia and inflammation do tend to lead to the development of hypertension and thus contribute to changes in the composition of cerebral vessels and it is likely the combination of both seen in MetS increases the degree to which remodeling occurs. A summary of the impact of disease states on the regulation of cerebral vascular tone is presented in Figure 2.
A schematic representation of how the presence of metabolic syndrome and the major constituent pathologies can impact the integrated regulation of cerebral vascular tone.
In conclusion, the regulation of vascular tone involves a complex set of pathways with myogenic, shear, and metabolic control. The mechanical influences of pressure and flow serve as a stimulus for the myogenic and shear responses to set a basal level of tone over a wide range so that metabolic factors have room to produce vasoactive responses on the vasculature. Due to the paramount importance of precise cerebral blood flow control these mechanisms are particularly pronounced and redundant in the cerebral circulation allowing for greater protection against insufficient perfusion or edema and capillary damage in situations of hypotension and hypertension respectively. However, due to the complexity of these homeostatic blood flow mechanisms there is the potential for the development of a pathological state. MetS presents a constellation of cardiovascular risk factors that are highly linked to the development of such cerebrovascular pathologies increasing the risk of stroke, TIA, and vascular dementia. The risk factors associated with MetS result in vascular remodeling which decreases the lumen size and increases stiffness and when paired with endothelial dysfunction and increased activation of the vascular smooth muscle it promotes increased cerebrovascular resistance. This right shifts the autoregulatory zone of myogenic regulation allowing for enhanced protection from hypertension but leaves cerebral tissue vulnerable to underperfusion. Controlling these risk factors and well as implementing targeted therapeutic strategies aimed at ameliorating the regulation of cerebrovascular tone has the potential to restore function in the cerebral circulation and improve current negative outcomes associated with MetS and cerebrovascular dysfunction.
This work was supported by Canadian Institutes of Health Research #389769 and Natural Sciences and Engineering Research Council (Canada) RGPIN-2018-05450. All figures were created with Biorender.com.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
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