\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6023",leadTitle:null,fullTitle:"Advances in Titration Techniques",title:"Advances in Titration Techniques",subtitle:null,reviewType:"peer-reviewed",abstract:"In chemistry, titration (a.k.a. titrimetry) is a common laboratory technique used for the determination of the unknown concentration of an analyte. Because of its versatility, the application of various forms of titration can affect nearly all aspects of society. This book is specifically aimed at broadening and deepening the theory and applications of titration. It contains six chapters being organized into three main sections: Volumetric Titration, Isothermal Titration Calorimetry, and Titrimetric Principles in Electrolytic Systems. Each chapter has been well written by internationally renowned experts in the field of chemistry, with mathematical expressions and illustrative examples selectively and logically presented. It is highly recommended for postgraduate students and scientists alike.",isbn:"978-953-51-3524-1",printIsbn:"978-953-51-3523-4",pdfIsbn:"978-953-51-4641-4",doi:"10.5772/66980",price:119,priceEur:129,priceUsd:155,slug:"advances-in-titration-techniques",numberOfPages:218,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"524754234974864053665bb3d4a892a3",bookSignature:"Vu Dang Hoang",publishedDate:"September 27th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/6023.jpg",numberOfDownloads:11671,numberOfWosCitations:4,numberOfCrossrefCitations:16,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:17,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:37,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 24th 2016",dateEndSecondStepPublish:"December 15th 2016",dateEndThirdStepPublish:"March 13th 2017",dateEndFourthStepPublish:"June 11th 2017",dateEndFifthStepPublish:"August 10th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"199907",title:"Associate Prof.",name:"Vu Dang",middleName:null,surname:"Hoang",slug:"vu-dang-hoang",fullName:"Vu Dang Hoang",profilePictureURL:"https://mts.intechopen.com/storage/users/199907/images/system/199907.jpg",biography:"Vu Dang Hoang completed his Ph.D. in Pharmaceutics at the University of Strathclyde, UK, in 2005 and conducted Postdoctoral research at the Ecole Nationale d'Ingenieurs des Techniques des Industries Agricoles et Alimentaires, France, in 2006. He has been lecturing at the Department of Analytical Chemistry and Toxicology, Hanoi University of Pharmacy, Vietnam, since 2007. He became an associate professor in the field of drug quality control in 2015. His research interests include physicochemical characterization of topical drug delivery systems and chemometrics-based methods for the analysis of drugs in pharmaceutical dosage forms and biological fluids.",institutionString:"Hanoi University of Pharmacy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Hanoi University of Pharmacy",institutionURL:null,country:{name:"Vietnam"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"486",title:"Wet Chemistry",slug:"wet-chemistry"}],chapters:[{id:"55458",title:"The Conditions Needed for a Buffer to Set the pH in a System",doi:"10.5772/intechopen.69003",slug:"the-conditions-needed-for-a-buffer-to-set-the-ph-in-a-system",totalDownloads:1632,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"It is a known fact that buffer systems are widely used in industry and in diverse laboratories to maintain the pH of a system within desired limits, occasionally narrow. Hence, the aim of the present work is to study the buffer capacity and buffer efficacy in order to determine the useful conditions to impose the pH on a given system. This study is based on the electroneutrality and component balance equations for a mixture of protons polyreceptors. The added volume equations were established, V, for strong acids or bases, as well as the buffer capacity equations with dilution effect, β\ndil, and the buffer efficacy, ε, considering that the analyte contains a mixture of the species of the same polyacid system or of various polyacid systems. The ε index is introduced to define the performance of a buffer solution and to find out for certain, whether the buffer is adequate or not to set the pH of a system, given the proper conditions and characteristics.",signatures:"Norma Rodríguez‐Laguna, Alberto Rojas‐Hernández, María T.\nRamírez‐Silva, Rosario Moya‐Hernández, Rodolfo Gómez‐Balderas\nand Mario A. Romero‐Romo",downloadPdfUrl:"/chapter/pdf-download/55458",previewPdfUrl:"/chapter/pdf-preview/55458",authors:[{id:"29229",title:"Dr.",name:"Maria-Teresa",surname:"Ramírez-Silva",slug:"maria-teresa-ramirez-silva",fullName:"Maria-Teresa Ramírez-Silva"},{id:"101040",title:"Prof.",name:"Alberto",surname:"Rojas-Hernández",slug:"alberto-rojas-hernandez",fullName:"Alberto Rojas-Hernández"},{id:"101057",title:"Prof.",name:"Rosario",surname:"Moya-Hernández",slug:"rosario-moya-hernandez",fullName:"Rosario Moya-Hernández"},{id:"101059",title:"BSc.",name:"Norma",surname:"Rodríguez-Laguna",slug:"norma-rodriguez-laguna",fullName:"Norma Rodríguez-Laguna"},{id:"202559",title:"Prof.",name:"Rodolfo",surname:"Gómez-Balderas",slug:"rodolfo-gomez-balderas",fullName:"Rodolfo Gómez-Balderas"},{id:"202560",title:"Prof.",name:"Mario A.",surname:"Romero-Romo",slug:"mario-a.-romero-romo",fullName:"Mario A. Romero-Romo"}],corrections:null},{id:"55246",title:"The Kjeldahl Titrimetric Finish: On the Ammonia Titration Trapping in Boric Acid",doi:"10.5772/intechopen.68826",slug:"the-kjeldahl-titrimetric-finish-on-the-ammonia-titration-trapping-in-boric-acid",totalDownloads:3078,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Kjeldahl method using concentrated boric acid is a common practice in many laboratories. A thorough study of the titration with hydrochloric acid of ammonia trapped in a solution of boric acid is made in an attempt to explain the fundamentals of a widely applied standard method. A new potentiometric method for the determination of the end point in the Kjeldahl titrimetric finish is proposed based on the linearization of the titration curve of the ammonia‐boric acid system. The method is strictly based on mole and charge balances, and no approximations are made in deriving the equations. The proposed method has proved very accurate when applied to synthetic titration curves and data. Some problems, however, are experienced in the practice, because the behavior of the experimental system studied is far from the expected one on the basis of the theoretical model. However, a slight modification of the devised method has been applied to the experimental titration of ammonia with hydrochloric acid, in boric acid as trapping solution, getting good results.",signatures:"Julia Martín, Lucía Fernández Sarria and Agustín G. Asuero",downloadPdfUrl:"/chapter/pdf-download/55246",previewPdfUrl:"/chapter/pdf-preview/55246",authors:[{id:"190870",title:"Dr.",name:"Agustín G.",surname:"Asuero",slug:"agustin-g.-asuero",fullName:"Agustín G. Asuero"},{id:"190871",title:"Dr.",name:"Julia",surname:"Martín",slug:"julia-martin",fullName:"Julia Martín"},{id:"203184",title:"Ms.",name:"Lucía",surname:"Fernández Sarria",slug:"lucia-fernandez-sarria",fullName:"Lucía Fernández Sarria"}],corrections:null},{id:"55373",title:"Intersecting Straight Lines: Titrimetric Applications",doi:"10.5772/intechopen.68827",slug:"intersecting-straight-lines-titrimetric-applications",totalDownloads:1690,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Plotting two straight line graphs from the experimental data and determining the point of their intersection solve a number of problems in analytical chemistry (i.e., potentiometric and conductometric titrations, the composition of metal-chelate complexes and binding interactions as ligand-protein). The relation between conductometric titration and the volume of titrant added lead to segmented linear titration curves, the endpoint being defined by the intersection of the two straight line segments. The estimation of the statistical uncertainty of the end point of intersecting straight lines is a topic scarcely treated in detail in a textbook or specialized analytical monographs. For this reason, a detailed treatment with that purpose in mind is addressed in this chapter. The theoretical basis of a variety of methods such as first-order propagation of variance (random error propagation law), Fieller’s theorem and two approaches based on intersecting confidence bands are explained in detail. Several experimental systems described in the literature are the subject of study, with the aim of gaining knowledge and experience in the application of the possible methods of uncertainty estimation. Finally, the developed theory has been applied to the conductivity measurements in triplicate in the titration of a mixture of hydrochloric acid and acetic acid with potassium hydroxide.",signatures:"Julia Martin, Gabriel Delgado Martin and Agustin G. Asuero",downloadPdfUrl:"/chapter/pdf-download/55373",previewPdfUrl:"/chapter/pdf-preview/55373",authors:[{id:"190870",title:"Dr.",name:"Agustín G.",surname:"Asuero",slug:"agustin-g.-asuero",fullName:"Agustín G. Asuero"},{id:"190871",title:"Dr.",name:"Julia",surname:"Martín",slug:"julia-martin",fullName:"Julia Martín"},{id:"203670",title:"Mr.",name:"Gabriel",surname:"Delgado Martín",slug:"gabriel-delgado-martin",fullName:"Gabriel Delgado Martín"}],corrections:null},{id:"56309",title:"Determination of Thermodynamic Partial Properties in Multicomponent Systems by Titration Techniques",doi:"10.5772/intechopen.69706",slug:"determination-of-thermodynamic-partial-properties-in-multicomponent-systems-by-titration-techniques",totalDownloads:1295,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Thermodynamic experimental techniques using titration are usually employed to study the interaction between solutes in a diluted solution. This chapter deals with the underlying thermodynamic framework when titration technique is applied with densimetry, sound speed measurement and isothermal titration calorimetry. In the case of partial volumes and partial adiabatic compressibilities, a physical interpretation is proposed based upon atomic, free volume and hydration contributions.",signatures:"Mónica Corea, Jean-Pierre E. Grolier and José Manuel del Río",downloadPdfUrl:"/chapter/pdf-download/56309",previewPdfUrl:"/chapter/pdf-preview/56309",authors:[{id:"14299",title:"Dr.",name:"Jose Manuel",surname:"del Río",slug:"jose-manuel-del-rio",fullName:"Jose Manuel del Río"},{id:"137775",title:"Prof.",name:"Jean-Pierre",surname:"Grolier",slug:"jean-pierre-grolier",fullName:"Jean-Pierre Grolier"},{id:"140717",title:"Dr.",name:"Monica",surname:"Corea",slug:"monica-corea",fullName:"Monica Corea"}],corrections:null},{id:"55881",title:"Principles of Titrimetric Analyses According to Generalized Approach to Electrolytic Systems (GATES)",doi:"10.5772/intechopen.69248",slug:"principles-of-titrimetric-analyses-according-to-generalized-approach-to-electrolytic-systems-gates-",totalDownloads:2405,totalCrossrefCites:9,totalDimensionsCites:8,hasAltmetrics:0,abstract:"The generalized equivalent mass (GEM) concept, based on firm algebraic foundations of the generalized approach to electrolytic systems (GATES) is considered, and put against the equivalent “weight” concept, based on a “fragile” stoichiometric reaction notation, still advocated by IUPAC. The GEM is formulated a priori, with no relevance to a stoichiometry. GEM is formulated in unified manner, and referred to systems of any degree of complexity, with special emphasis put on redox systems, where generalized electron balance (GEB) is involved. GEM is formulated on the basis of all attainable (and preselected) physicochemical knowledge on the system in question, and resolved with use of iterative computer programs. It is possible to calculate coordinates of the end points, taken from the vicinity of equivalence point. This way, one can choose (among others) a proper indicator and the most appropriate (from analytical viewpoint) color change of the indicator. Some interpolative and extrapolative methods of equivalence volume Veq determination are recalled and discussed. The GATES realized for GEM purposes provides the basis for optimization of analytical procedures a priori. The GATES procedure realized for GEM purposes enables to foresee and optimize new analytical methods, or modify, improve, and optimize old analytical methods.",signatures:"Anna Maria Michałowska‐Kaczmarczyk, Aneta Spórna‐Kucab and\nTadeusz Michałowski",downloadPdfUrl:"/chapter/pdf-download/55881",previewPdfUrl:"/chapter/pdf-preview/55881",authors:[{id:"35273",title:"Prof.",name:"Tadeusz",surname:"Michalowski",slug:"tadeusz-michalowski",fullName:"Tadeusz Michalowski"},{id:"203867",title:"Dr.",name:"Anna Maria",surname:"Michałowska-Kaczmarczyk",slug:"anna-maria-michalowska-kaczmarczyk",fullName:"Anna Maria Michałowska-Kaczmarczyk"},{id:"203868",title:"Dr.",name:"Aneta",surname:"Spórna-Kucab",slug:"aneta-sporna-kucab",fullName:"Aneta Spórna-Kucab"}],corrections:null},{id:"55742",title:"A Distinguishing Feature of the Balance 2∙f(O)−f(H) in Electrolytic Systems: The Reference to Titrimetric Methods of Analysis",doi:"10.5772/intechopen.69249",slug:"a-distinguishing-feature-of-the-balance-2-f-o-f-h-in-electrolytic-systems-the-reference-to-titrimetr",totalDownloads:1571,totalCrossrefCites:6,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The balance 2∙f(O)−f(H) provides a general criterion distinguishing between electrolytic redox and non-redox systems of any degree of complexity, in aqueous, non-aqueous and mixed-solvent media. When referred to redox systems, it is an equation linearly independent on charge (ChB) and elemental/core balances f(Yg) for elements/cores Yg ≠ H and O, whereas for non-redox systems, 2∙f(O)−f(H) is linearly dependent on these balances. The balance 2∙f(O)−f(H) formulated for redox systems is the primary form (pr-GEB) of the generalized electron balance (GEB) as the fundamental equation needed for resolution of these systems. Formulation of GEB for redox systems needs no prior knowledge of oxidation numbers for all elements of the system. Any prior knowledge of oxidation numbers for all elements in components forming a redox system and in the species of the system thus formed is not necessary within the Approach II to GEB. Oxidants and reductants are not indicated. Stoichiometry and equivalent mass are redundant concepts only. The GEB, together with charge balance and concentration balances for elements ≠ H and O, and the complete set of independent equations for equilibrium constants form an algorithm, resolvable with use of an iterative computer program. All attainable physicochemical knowledge can be included in the algorithm. Some variations involved with tests of possible reaction paths for metastable systems can also be made. The effects of incomplete physicochemical knowledge on the system can be also tested. One of the main purposes of this chapter is to provide the GEB formulation needed for resolution of redox systems and familiarize it to a wider community of chemists.",signatures:"Anna Maria Michałowska-Kaczmarczyk, Aneta Spórna-Kucab and\nTadeusz Michałowski",downloadPdfUrl:"/chapter/pdf-download/55742",previewPdfUrl:"/chapter/pdf-preview/55742",authors:[{id:"35273",title:"Prof.",name:"Tadeusz",surname:"Michalowski",slug:"tadeusz-michalowski",fullName:"Tadeusz Michalowski"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6697",title:"Chemometrics and Data Analysis in Chromatography",subtitle:null,isOpenForSubmission:!1,hash:"513cf51c1f8851d3a5fde73daa281571",slug:"chemometrics-and-data-analysis-in-chromatography",bookSignature:"Vu Dang Hoang",coverURL:"https://cdn.intechopen.com/books/images_new/6697.jpg",editedByType:"Edited by",editors:[{id:"199907",title:"Associate Prof.",name:"Vu Dang",surname:"Hoang",slug:"vu-dang-hoang",fullName:"Vu Dang Hoang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5725",title:"Applications of the Voltammetry",subtitle:null,isOpenForSubmission:!1,hash:"36586695f01005ffab50415baba4de15",slug:"applications-of-the-voltammetry",bookSignature:"Margarita Stoytcheva and Roumen Zlatev",coverURL:"https://cdn.intechopen.com/books/images_new/5725.jpg",editedByType:"Edited by",editors:[{id:"170080",title:"Dr.",name:"Margarita",surname:"Stoytcheva",slug:"margarita-stoytcheva",fullName:"Margarita Stoytcheva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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Germline DNA is a constitutional DNA because it is related to the DNA of tissues derived from reproductive cells, i.e., egg or sperm that is derived from stem cells, and incorporated into the DNA of each cell of the body of the offspring. Therefore, the mutated parental germline DNA can be passed to the offspring.
Germline DNA can be extracted from bone marrow or peripheral blood nuclear cells.
Key Point 2|Somatic DNA.
\nSomatic DNA is found in all cells of the body (tissues, skin, organs, and blood), except germ cells and embryonic cells, which are the source of gametes. Therefore, a mutation in the somatic DNA is not transmitted to the offspring, but it can lead to the genesis of diseases, especially tumors. So, somatic DNA can be extracted from both tumor (or matched normal) tissue and plasma.
\nThe recognition specificity of different non–self-antigens or defective self-antigens (tumors) by a well-defined B-cell clone does not result from the presence of an extensive number of receptor genes, but rather from immunogenetic mechanisms affecting a limited number of IG genes, including mechanisms of genetic recombination, mutations, deletions or insertions, and gene repair, through very complex regulatory mechanisms that are responsible for a large B-cell repertoire.
\nThis chapter focuses on the molecular description of the immunogenetic mechanisms responsible for the generation of B-cell antigen receptor diversity.
\nIn humans, the immunoglobulin heavy (IGH) locus is present at chromosome 14q32.33, and the IG light lambda (IGL) and kappa (IGK) loci are located at 22q11.2 and 2p11.2, respectively [1]. The immunoglobulin heavy chain variable region (IGH V) gene encodes VH framework regions 1-3 (FR1-3), VH complementarity determining region 1 (CDR1), and VH CDR2, while IGH joining (IGH J) gene encodes VH FR4. VH CDR3 is positioned at the IGH V-IGH D-IGH J junction [2]. The constant sequences of heavy (H) chain are arranged in the following order: μ → δ → γ3 → γ1 → α1 → γ2 → γ4 → ε → α2 in humans (Figure 1), or μ → δ → γ3 → γ1 → γ2b → γ2a → ε → α in mice.
\nThe organization of the IGH chain C-region genes in humans. Eμ: intronic enhancer, S: switch region, IGH: immunoglobulin heavy chain.
Similar to T-cell receptors (TCRs), functional genes of immunoglobulins (Igs) are the result of somatic recombination of DNA containing the relatively limited germinal genetic information, using the so-called V(D)J recombination process that occurs between individual genes (also referred to as gene segments) of the variable domains of the H and L chains (or α, β, γ, and δ chains of TCRs). Each of these genes is present in multiple copies in most antigen receptor loci. The locus of IGH genes (like TCR β and TCR δ loci) contains variable (V), diversity (D), and joining (J) genes, whereas the IGL and IGK loci (like TCR α and TCR γ loci) contain only V and J genes [3]. So, individual V, D, and J genes at the IGH locus, and V and J genes at either the IGL or IGK loci rearrange somatically at the DNA level to generate V-D-J and V-J regions that, after transcription and translation, encode the variable domains of the antibody [4] (for review see [1]).
\nThe ordered model was described by Alt and Baltimore in 1984 [5]. It states that during the V(D)J recombination, rearrangements at the H chain locus occur before those of the L chains.
\nThe sequential recombination refers to the order of the stages of rearrangements from DH to JH occurring before rearrangements from VH to DJH [5]. In contrast, the genes of the TCR δ locus, in the precursors of T-cells, can recombine in any order. In the case of the IGH locus in B-cell precursors (and TCR β locus in T-cell precursors), one of the multiple DH segments (genes) recombines first with one of the multiple JH segments, by deletion of the DNA separating them. Then, one of the VH genes is recombined/juxtaposed with the rearranged DJ site, again by deletion of the intermediate DNA (Figure 2). After recombination, V, D, and J genes form a single exon [3].
\nOrdered rearrangement of gene segments (adapted from [
Like the TCR, B-cell receptor (BCR) diversity results from (i) the choice of segments to recombine, (ii) the “P” junctional variability of the nucleotides at the V-D-J or V-J junction sites between gene segments during rearrangements, (iii) the “N” diversity by insertion or deletion of a nucleotide during recombination under the action of terminal deoxynucleotidyl transferase (TdT), but also from (iv) the recombination between VH genes by substitution of a or part of a second VH gene to an already recombined VH-D-JH segment. The diversity of the B-cell repertoire is also increased by the process of somatic hypermutation (SHM) of IG variable genes. The V(D)J recombination process generates a much greater diversity at the level of the H chain loci compared to those of the L chains, where simply a V region is joined to a J region. Thus, if the human IGH locus contained only about 40 functional VH segments, 27 DH segments, and 6 JH segments, V(D)J recombination would generate about 6480 (40 × 27 × 6) H chains, whereas, human IGK, which contains about 40 Vκ genes and 5 Jκ genes, would give rise to approximately 200 κ chains, following 200 (40 × 5) different combinations. On the other hand, the variability of nucleotides/point mutations can occur at the junction sites, and bases can be lost (by deletion) or added (by insertion), giving additional diversity of the hypervariable CDR3 region of the H and L chains, which is coded by an additional sequence of DNA created by the junction of V, D, and J segments, for the H chain, and V and J segments, for the L chain; such a phenomenon is responsible for the junctional diversity. In total, molecular mechanisms of genetic recombination could result in a potential repertoire of at least 107 antigen-specific recognition sites/receptors. Each clone of such a cell repertoire contains only a few cells that are capable of recognizing only one antigen; exceptionally, a T-cell clone can express two different receptors and can therefore recognize up to two antigens.
\nTwo-thirds of rearrangements produce a nonfunctional allele for at least three main reasons: (i) the reading frame of V and C regions is correctly aligned in only one-third of the cases, (ii) the codons contain three-nucleotide, and (iii) the number of nucleotides inserted or eliminated in the junctions is essentially random.
\nSome loci include only one V, D, or J gene segment. In these cases, all diversity is derived from junctional diversity or subsequent mechanisms of diversity, such as somatic mutation in IG loci, or from gene conversion in IG loci of some species.
\nD and J segments/genes encode amino acid sequences of the third loop of the immunoglobulin domain, which corresponds to the CDR3 region. If they had the same reading frame, recombination can give rise to an IgH chain.
\nThe transcription of the recombined IG gene gives rise to a functional messenger RNA, after elimination of introns, including any J segment/gene located between that which is joined to D and C segments. A similar process takes place in L chain loci.
\nRearrangements require two major steps: double strand-breaks (DSB) and repair of these breaks.
\nBoth recombination-activating gene 1 (RAG-1) and RAG-2 recombinase enzymes, expressed exclusively in developing lymphocytes, are required to generate DSBs [6] at the level of recombinant signal sequences (consensus RSS, recombination sequence signal), flanking all functional V, D, and J gene segments, on the side that will be joined,
Cleavage site of RAG proteins at the V, D, and J gene segments of the IGH locus: RSS positions. RAG: recombination-activating gene, RSS: recombination sequence signal, IGH: immunoglobulin heavy chain locus.
The RSS motifs are composed of a conserved palindromic heptamer and conserved nonamer motifs, separated by an intervening variable-sequence spacer of fixed length corresponding to 12 or 23 nucleotides (the resulting signals are referred to as 12-RSS or 23-RSS, respectively). From the architectural point of view of the H chains, all the V segments are tracked by a 23-RSS (on the 3′ side), the D segments are “framed” (on the 5′ and 3′ sides) by 12-RSS, and the J segments are preceded by 23-RSS (on the 5′ side). Regarding the L chain genes, the V segments are tracked by 23-RSS (on the 3′ side), and the J segments are preceded by 12-RSS (on the 5′ side) [8]. Only dissimilar RSS associations are efficiently recombined. Thus, each recombination that joins two gene segments occurs between 12-RSS and 23-RSS: this is known as the 12/23 rule. In the H chain recombination, the fact that the V and J segments are naturally both flanked by 23 nucleotide spacers (23-RSS), a connection between these two segments is not possible directly, but is done indirectly if they recombine with D elements, which are flanked on both sides by 12-RSS. After 12-RSS recombination with 23-RSS, the intermediate DNA will either be deleted or inverted depending on the orientation of the two signals (Figure 4). RAG-induced DSBs are then resolved by nonhomologous end joining (NHEJ) pathway.
\nRSS motifs. There are two types of RSS, one includes a 12-nucleotide spacer (12-RSS), and the other includes a 23-nucleotide spacer (23-RSS). Both 12-RSS and 23-RSS include a highly conserved palindromic heptamer and nonamer sequences. Bp: base pairs, RSS: recombination sequence signal.
The assembly between the V, D, and J segments is done according to the sequential model as reported above. The V(D)J recombination mechanisms can be generated experimentally
The kinetics of main rearrangement events are described according to the following steps (Figure 5):
Molecular mechanisms of V(D)J recombination and junctional diversity generation (adapted from [
The junction system comprises a number of ubiquitous repair proteins (present in both B-cells and T-cells), which would allow rearrangement of IG genes in B-cell precursors, but rarely in T-cell precursors, and TCR gene rearrangements in T-cell precursors, but rarely in B-cell precursors. It includes in particular the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase complex (DNA-PKcs), a member of the phosphatidylinositol 3-kinase-related (PIKK) family of protein kinases, composed of a heterodimer of Ku proteins that bind free DNA ends given their strong affinity (Ku70/Ku80 [encoded, respectively, by X-ray cross-complementing gene 5 (XRCC5) and XRCC6 genes in humans, and also called Ku86]) [19], XRCC4, DNA ligase IV and Artemis [3]. TdT is also recruited into the junction system and is involved in the formation of the coding joints, alongside Artemis and DNA-PKcs. Nevertheless, TdT is only rarely recruited into rearrangements that occur during fetal life, so that junctional diversity is limited.
\nIt should be clearly noted that the VH segments are not silent before the V-DJH recombination steps or before their physical juxtaposition with the Eμ enhancer. It has therefore been shown that they undergo active noncoding germline transcription in B-cell precursors. In addition, many other noncoding transcripts appear as rearrangements occur, in order to allow the opening of chromatin, and thus, the targeting and accessibility by RAG-1/RAG-2 complex, as well as the establishment of the three-dimensional structure of the locus considered. From a kinetic point of view, the first noncoding DH transcripts, also referred to as sterile transcripts (to differentiate them from the coding transcripts, which are initiated at the rearranged VDJ segments), are detected before the D-JH rearrangements and are initiated at JH-proximal DH gene (DQ52), which has both promoter and enhancer activities preferentially active in B-cell precursors [20], generating μ0 transcripts, and at downstream of intronic IGH enhancer Eμ, generating Iμ transcripts. Both μ0 and transcripts Iμ are getting spliced and polyadenylated [ 21]. Once the DJH rearrangement is carried out, new noncoding germinal transcripts appear in VH regions (for review, see [21]).
\nEpigenetic modifications are necessary for the positive or negative regulation of the activities of different loci. Indeed, besides the presence of sites sensitive to DNase activity, other conditions, controlled by the activating elements and the promoters of the loci concerned, are necessary to initiate gene rearrangements and are correlated with the opening of chromatin to transcription, such as histone acetylation, DNA demethylation, and transcription itself.
The establishment of loops is necessary to bring into contact the different segments to recombine giving rise to an image of the so-called rosette locus, which represents one of the prerequisites for V(D)J rearrangements [25]. These loops take place through a number of factors, including transcriptional repressor CCCTC-binding factor (CTCF, also known as 11-zinc finger protein), Yin Yang 1 (YY1), a ubiquitously distributed transcriptional repressor/activator factor of a number of promoters, belonging to the GLI-Kruppel class of zinc finger proteins, and paired box 5 (Pax5), which is important regulators in early development, but not late stages of B-cell differentiation. Such different factors and particularly CTCF, by binding to cohesins, regulate the IG loci reorganization and contraction. This contraction/reorganization allows the juxtaposition of different gene segments (in particular the distal V genes) and thus facilitates rearrangements.
\nThe locus nuclear positioning is decisive for the rearrangement. Hence, the IGH locus, anchored
The allelic exclusion of IG of H and L chain genes allows the production of antibodies from a single chromosome located on 14q32.3 for the H chain [26], and one of the two chromosomes located on 2p12 or 22q11.2 for the L chain [27, 28] (respectively, the Lκ and Lλ chains). This phenomenon constitutes genetic basis of monospecificity of B-cells-a central paradigm in explaining the pathogen-specific production of antibodies (Burnet’s clonal selection theory of the adaptive immune system),
During the differentiation of the B-cell, only one fraction of the IG genes, resulting from a first somatic V(D)J recombination on one of the two random chromosomes 14, is functional,
The mechanism of allelic exclusion uses pre-BCR–mediated signals. The pre-BCR consists of the H chain resulting from the productive rearrangement of an allele encoding the μ H chain associated with a pseudo-L chain (surrogate L chain). This chain comprises a V polypeptide (called V pre-B) and a type C polypeptide (called λ5 in mice and λ-like in humans) that associate noncovalently. The signals mediated by this pre-BCR block the accessibility of the RAG recombinases on the second allele of the nonrecombinant μ H chain and redirect them toward the Lκ chain locus to initiate the first recombinations. The formation of a complete BCR combining H and L chain blocks recombinations on other L chain alleles.
\nImportantly, it has been shown, using genetically engineered mice that carry two functional IGH alleles that are completely recombined and different, that the expression of IG loci does not appear to be monoallelic and that B-cells could have the ability to express H chains by both alleles [29] (for review, see [30]).
\nA single B-cell never expresses both a κ string and a λ string. The first recombination attempt for the L chains takes place at one of the two κ genes. In case of failure, the κ gene of the other chromosome 2 or the λ genes is used.
\nThe B-cell that initially produced the IgM isotype will subsequently produce other immunoglobulin isotypes (IgG, IgE, and IgA), thanks to a process termed Ig H chain class switching, isotype switching, or class switch recombination (CSR). Such a phenomenon occurs after activation of a mature B-cell by an appropriate antigen, thereby generating different antibody isotypes that have the same variable domains as the original antibody generated in the immature B-cell during V(D)J rearrangement, but having distinct constant domains in their H chains.
\nCSR is instigated following conversion of deoxycytidines in S regions-a G rich with high density of WGCW (A/T-G-C-A/T) motifs-to deoxyuracil by activation-induced cytidine deaminase (AID) in the IG loci, which is also required for SHM. The presence of deoxyuracil promotes DNA mutagenesis though a subset of DNA repair proteins. Deoxyuracil residues are subsequently removed from DNA by enzymes of the base excision repair (BER) and mismatch repair (MMR) complex MSH2/6 pathways, leading to mutations, single-strand DNA breaks (SSBs), and the DSBs required for CSR. Recall that, in humans, nine functional CH genes are located downstream of the V, D, and J gene segments of antigen receptor loci. The V(D)J segment, initially rearranged in the bone marrow, can be juxtaposed, during B-cell activation, to one of these functional genes coding for another constant domain, depending on antigen and the cytokine milieu, and occurs between DSBs introduced into the donor μ S (Sμ) region and a downstream/acceptor S region located from ∼65 to 160 kb downstream, which can subsequently recombine with an S region farther downstream (for review, see [31, 32, 33]). Finally, Igs resulting from the CSR process have the same specificity for the antigen responsible for the B-cell activation. They have also the same L chains as well as the same variable fragments of the H chains (Figure 6).
\nCSR process. Here is an example of switching to the IgG1 isotype. First, AID induces DSB formation after deamination of Sμ and Sγ1 regions. Subsequently, these two regions recombine by an intrachromosomal deletional recombination, and the expressed VDJ segment associates with the Cγ1 gene. AID: activation-induced cytidine deaminase, CSR: class switch recombination (also called immunoglobulin heavy chain class switching/isotype switching), DSB: double strand-breaks, Eμ: intronic enhancer, S: switch region.
Many resting B-cells, agglutinated around follicular dendritic cells (FDCs), harbor primary follicles. Thus, in the adult spleen, about 80% of B-cells are follicular B-cells.
\nA major role is attributed to FDCs, as prominent stromal cell constituents of B-cell follicles. These cells do not express major histocompatibility complex class II (MHC II) molecules nor do they have the capacity to phagocytose and process exogenous antigens for MHC I-restricted presentation [34]. Experiments using cryoimmunogold electron microscopy have demonstrated that the presence of MHC II molecules on their surface is passive and originate from microvesicles/exosomes they are attached to [35]. Additionally, their ontogeny remains controversial. They are not derived from the bone marrow hematopoietic stem cell, but they could originate from local mesenchymal precursors in lymphoid organs [36]. Moreover, FDCs promote the survival and continuous recirculation of naive B-cells and allow for the attraction of activated B-cells, as well as the selective process for affinity maturation within the GC of lymphoid follicles during humoral adaptive/antibody-mediated immune response, allowing activated B-cells to significantly improve the affinity of their BCR. Thus, they have the ability to retain on their Fc receptor (FcR) antigens in native form combined with antibodies (immune complexes [ICs]), for long periods of time, ranging from months to years, thus making them accessible to the centrocytes (CC) that enter light zone (LZ) and result from the proliferation of blasts in the dark zone (DZ; this zone has been designed because it contains a high cell density) (Figure 7).
\nSchematic representation of the organization of the germinal center. The dark zone is occupied mainly by proliferating centroblasts. These are cells in which SHM would take place. After proliferation, B-cells, now called centrocytes, are in the adjacent LZ, which also contains Tfh cells and FDCs. Centrocytes that poorly link the antigen will die by apoptosis. Those that can bind the antigen and receive survival signals from the BCR and Tfh cells can either return to the dark zone for another cycle of proliferation, mutation, and selection or become memory B-cells or plasma cells that migrate to bone marrow to ensure prolonged antibody secretion [
Most protein antigens induce T-dependent (TD) antigen humoral immune responses (responses to T-independent [TI] antigen are not evoked in this chapter). Such responses require cooperation between the antigen-specific B-cell and the T-cell carrying a specific TCR of the same antigen. Nevertheless, the two cell types have different localizations within ganglion, and the probability for a B-cell to meet a T-cell with the same antigen specificity is extremely low and is about \n
The search for the antigen by the appropriate B-cells is done through an immutable path. The blood enables the naive B-cells,
When B-cells expressing antigen-specific BCR encounter the appropriate antigen (acquired from FDCs) in secondary lymphoid organs (SLOs), within lymph nodes for the antigen that is carried into them from the tissues, or within spleen for the antigen that reach it from the bloodstream, they increase the expression of the C-C chemokine receptor type 7 (CCR7) on their surface and migrate to the T/B border [38] (comment in [40]) in the spleen and in the interfollicular region in lymph nodes, after both T-cells and B-cells have been primed with antigen. The activated B-cells follow one of the following two fates to trigger a TD humoral immune response to protein antigen (for review, see [41, 42, 43, 44]):
either they migrate to
or they migrate to a primary
Only CCs that express a high affinity receptor for epitopes of the antigen presented in its native form by the FDCs and that can capture it are selected efficiently. These selected CCs process the antigen and present antigen-derived peptides bound to MHC II molecules to antigen-specific CD4+ Tfh cells, which have been shown to develop immediately from naive CD4+ T-cells during antigen priming by dendritic cells in T-cell zones [46] (comment in [47]). The Tfh cells then give survival and differentiation signals to B-cells, which can then undergo CSR and mature either in LLPCs or in memory B-cells.
\n\n
Following antigenic stimulation, B-cell IG genes undergo SHM and CSR within GCs.
\nThe process of somatic hypermutation-a process targeting the V genes of the H and L chains-is the basis for the antibody affinity maturation. It is induced during humoral responses of conventional B-follicular cells in response to TD antigen. In contrast to the somatic-V(D)J-recombination that takes place in the bone marrow, the SHM process takes place in the SLOs, in the DZ of the GCs, at a stage where the B-cell is called centroblast.
\nSince the specificity and affinity of the BCR/mIg of the B-cell that left the bone marrow, and subsequently the circulating antibody produced, are determined before the encounter with the antigen (antigenic epitope), the phenomenon of SHM occurs in the activated B-cell clone through mutations in the sequence of genes derived from V(D)J somatic recombination, in order to adjust the hypervariable regions to the epitope and thus to modulate/increase the antibody affinity and the effective and adapted recognition of the antigen triggering the humoral immune response. As mentioned above, such a phenomenon participates in the generation of Igs diversity.
\nSHM introduces mutations that replace one or more amino acids in the Ig, producing closely related B-cell clones that differ subtly in terms of antigenic specificity and affinity [48]. Despite recent advances, the molecular mechanisms responsible for them remain little known. Nevertheless, the results of
It corresponds to an adaptive mutagenesis initiated by the action of the enzyme AID, which is expressed solely by the B-cells of the CG [48].
It occurs during an extremely brief stage of differentiation of B-cells at the GCs.
It occurs in the peripheral lymphoid organs in the DZ GC B-cells.
Numerous point mutations are introduced in the hypervariable regions of the BCR or Ig H and L chain V gene following the activation of antigen-specific B-cell clones.
The mutations extend over about 1 kb.
Purine-purine or pyrimidine-pyrimidine mutations are mainly observed; A and G are more often mutated than T and C.
Random mutations can enhance the affinity of the antibodies.
It relates to TD antigen immune responses.
The mutations essentially concern the variable gene and the adjacent 3′ region of the rearranged V(D)J segment.
The mutation domain extends in 3′ from the promoter to the intronic J-C region.
It also affects the DNA flanking the rearranged V gene, but does not generally extend to C region exons.
Mutations are mostly nucleotide substitutions, but insertions and deletions are possible.
SHMs only occur during the secondary response, but not during the primary responses.
The cis sequences of IG locus are indispensable for triggering or regulating the hypermutation process.
There is an important involvement of the IG promoter and enhancer sequences of the IG locus, suggesting a link between transcription and SHM [49].
\n
If the U is targeted by the enzyme uracil-DNA N-glycosylase (UNG), which is usually followed by components of the base-excision repair (BER) pathway (an essential DNA repair pathway), it will be excised, and an abasic site appears in DNA following the action of apurinic/apyrimidinic endonuclease (APE), an enzyme that identifies damaged apurinic/apyrimidinic sites in DNA, cuts the phosphodiester bond in the backbone of the sites, and has critical roles in the base excision pathway. This site will, in turn, be mutagenically replicated by translesion DNA synthesis (TLS) polymerases, leading to a very high error rates.
If the U:G mismatch is recognized by the mismatch repair (MMR) protein pathway, the U:G lesion will be excised by Exonuclease I, resulting in degradation of the DNA strand surrounding the U, then the MSH2/MSH6 heterodimer induces the formation of a gap in the DNA. Unfaithful replication of a DNA strand will take place at the level of the gap by the TLS DNA polymerase eta (pol η), a “wrong” TLS repair polymerase [56] (Figure 8).
DNA deamination model of IG gene diversification by AID during SHM (adapted from [
The frequency of IG region V gene mutations corresponds to approximately one bp change per 1000 bp per gene and per cell division/generation, while that affecting the rest of the cell DNA is much lower, and corresponds to about one bp change per 1010 bp per cell and per division. Of note, there is approximately a 50% chance during each division of B-cells that a mutation leads to a change in BCR, since it is known that each V region is encoded by approximately 360 bp and that approximately ¾ basic changes modify the encoded amino acid [48].
\nThe low affinity of antibodies produced during the primary immune response tends to increase as the immune response progresses, thanks to the numerous point mutations in hypervariable regions of the IG V gene of the antigen-specific B-cell clones.
\nMost mutations have no positive effect on the affinity of BCR or Ig produced, and frequently negatively affect their ability to bind antigen inducing B-cell activation.
\nOf the four types of possible mutations-silent, neutral, deleterious, and positive-only deleterious mutations and positive mutations have an effect on the affinity of the antigen for its appropriate BCR:
The deleterious mutations are responsible for a decrease in the affinity of the antigen for its BCR, but also for the rapid division of B-cells (the expansion would overwhelm the lymphoid tissues), since they can induce modifications of the framework regions and thus disrupt the basic structure of Ig. The many B-cells that carry such mutations will be a target of apoptotic death by a negative selection process, either because they can no longer produce a functional BCR, or because they cannot efficiently internalize antigens through clonally distributed membrane BCRs. These apoptotic cells will invade GC and then be rapidly ingested by resident macrophages, giving rise to tingible body macrophages (TBM), containing dark nuclear debris in their cytoplasm [48].
Positive mutations are less common than deleterious mutations and are responsible for increasing antigen affinity for its BCR and improving its binding. The small portion of daughter cells with many nucleotide substitutions in the Ig V region encoding gene that are derived from B-cell clones undergoing such mutations will be positively selected and will therefore have an increased survival rate relative to the cells expressing a low BCR affinity. Positive selection would be a consequence of the accumulation and concentration of many amino acid substitutions in CDRs of the Ig V region, as a result of nucleotide changes that alter amino acid sequences and so the protein structure.
Silent or neutral mutations have no noticeable effect on antigen affinity. They preserve the amino acid sequence and do not alter the structure of proteins and are dispersed throughout the V region [48].
Cell schematic illustrations are adapted from free Servier Medical Art (smart.servier.fr/servier-medical-art).
\nBrain death is defined as permanent cessation of all vital functions of the brain. It is principally established using clinical criteria including coma, absence of brain stem reflexes, and using apnea test. In Canada, two physicians must determine whether particular patient is brain dead or not [1, 2]. The criteria for declaring brain death includes deep unresponsive coma with established etiology, absence of reversible conditions [2]. Absence of brain stem reflexes includes absence of gag, cough, bilateral absence of corneal response, pupillary response to light and vestibule-ocular response, absence of respiratory efforts based on apnea test, and absence of confounding factors [2]. Ancillary imaging tests are necessary in situations when neurological examination or the apnea test cannot be performed or its validity comes into a question [3]. These situations include when patients have resuscitated shock, hypothermia, severe metabolic abnormalities, complex spinal reflexes, peripheral nerve or muscular dysfunctions, high cervical spine injury, craniofacial trauma or if the patient is on sedative drugs such as alcohol, barbiturates, sedatives, and hypnotics.
\nAn ideal ancillary test should not have any false positive results. This is very important in brain death patients. If the ancillary test confirms death, when in fact, patient is not dead, is very dangerous and raises critical social, ethical and legal concerns. The main objective of the ancillary test would be to demonstrate the absence of cerebral electric activity or cerebral circulatory arrest [4]. Based on this, the first type assesses the electrical functions of the brain, and the other type analyses cerebral blood flow in the brain on imaging. Here, we provide description of cerebral blood flow imaging techniques and compare them.
\nYoung and his colleagues described the attributes of an ideal ancillary test [5]. A reliable ancillary test should meet all the criteria mentioned below.
When the test confirms brain death, there should be no one that recovers or have the potential to recover. There should be no false positives.
The test should be independently sufficient enough to establish whether brain death is present or not.
The test should not be susceptible to external or internal confounding factors such as drug effects and metabolic disturbances.
The test should have standardized technology, technique, and classification of results.
The test should be inexpensive, safe, and readily applied. Testing should not be restricted to only few tertiary academic centers. It could be applied with any intensive care unit, and the technique should be mastered without difficulty.
This is considered the gold standard for ancillary imaging test. DSA is the first used modality for determining the cerebral blood flow. It is typically performed with a catheter tip in the aortic arch and contrast injection into each of the four arteries supplying the brain [3]. At least two injections, 20 min apart, must show an absence of filling of four arteries as their course becomes intracranial (Figure 1) [3, 6].
\nDigital subtraction angiography image of a brain dead patient showing no intracranial filling on selective (A) left and (B) right common carotid artery as well as (C) left and (D) right vertebral artery angiograms. These show continued filling of the extracranial arteries including (A) left and (B) right external carotid arteries.
This test is capable of detecting dynamic blood flow in the arteries, veins, and capillaries. The criteria for brain death diagnosis using this method include no intracerebral filling at the level of entry into the skull of carotid or vertebral artery and filling of external carotid arteries. But this method does not have the spatial resolution to distinguish the blood flow in the different parts of the brain such as brainstem. Other disadvantages include transportation of patents to the angio suite; requires expert operator to perform; is invasive; and requires injection of contrast medium that may have a potential risk to the patients with kidney diseases. It can have “stasis filling” due to diffusion of contrast in the static column of blood, which can result in false negatives. Thus, it is an expensive procedure and not readily available in many hospitals and may not be easy to interpret in many healthcare facilities.
\nThis is another gold standard ancillary imaging test for determination of brain death. In this technique, a gamma emitting radioactive tracer is intravenously injected and is detected by a radio counter in the nuclear medicine. One of the radioactive tracers used is Tc99m-DTPA. After bolus intravenous injection of the tracer, brain vascular flow is estimated. DTPA does not have the ability to cross the intact blood brain barrier, so intracranial blood flow is seen in normal patients. However, Tc99m-DTPA tracer has low resolution for brain vascular flow [7]. There are two other radiopharmaceuticals, namely Tc99m-HMPAO (hexamethylpropyleneamine oxime) and Tc99m-ECD (ethyl cysteinate dimer) [8]. Both of them are brain specific, lipophilic and after intravenous injection, they cross the blood brain barrier. Because of this property, they are accumulated proportional to the blood flow in normal gray matter including brain cells of cerebrum, cerebellum, and brainstem [8]. So, it is not only blood flow but also brain parenchyma is seen in the normal functioning brain. In this method, radioactive isotope is injected 30 min after its reconstitution. Images are taken immediately after injection, after 30 min, and finally after 2 hours. If there is no blood flow, there is no accumulation of tracer in the brain and brain looks hollow, this phenomenon is known as “hollow skull” or “empty bulb” sign (Figure 2). These injected radioactive tracer compounds are safe to the patients because they do not interact with their medication and have no associated side effects [8].
\n“Hallow skull”/“empty bulb” sign shown in brain death patient using (A) AP and (B) lateral nuclear scintigraphy imaging. Flow and delayed imaging demonstrated no significant intracranial flow or parenchymal uptake.
Disadvantages of this technique is sometimes posterior fossa may be difficult to visualize, and uptake may be affected by hypothermia and barbiturates [3]. It does not have the spatial resolution to detect isolated brainstem activity. Other disadvantages include associated time delay and availability of this technique. Nuclear scintigraphy requires instrumentation, an experienced radiologist to interpret the test results, and the radioactive tracer used in this test is expensive and requires a trained pharmacist to reconstitute.
\nComputed tomography (CT) was introduced in 1970, since then it has revolutionized the assessment of head injuries including brain death [9]. It is fast, readily available, and requires no contrast medium. It is a standard imaging test for the patients admitted in the hospital because of brain injuries. Plain head CT scan can visualize brain tissue and lesion. It accurately diagnoses skull fractures, intracranial bleeds, brain contusions, and brain herniation. For diagnosis of brain death, a diffuse loss of gray-white mater differentiation needs to be established (Figure 3).
\nPlain head CT image of a brain dead patient showing diffuse loss of gray-white mater differentiation.
Plain head CT has several limitations in assessment of brain death. Plain head CT does not provide functional information of the brain and does not assess intracranial blood flow. Diffuse loss of gray-white mater differentiation is likely a late phenomenon and the inter-rater reliability is poor [10].
\nContrast enhanced CT of head can be acquired to assess brain blood flow but is delayed compared to CT angiography. Contrast-enhanced CT acquisition requires a delay of 5 min, whereas CT angiography requires only 12–16 seconds. This delay makes the contrast-enhanced CT highly susceptible to “stasis filling” of the brain blood vessels. Thus, plain head CT is not very reliable test in determining brain death.
\nCTA is a valuable ancillary imaging technique for intracranial blood flow. CTA was first reported in 1998 as an ancillary test in diagnosing the brain death [11]. According to Dupas et al., in 14 patients who were diagnosed as brain dead using clinical criteria, the results were confirmed to have 100% sensitivity using CTA [11]. CTA is fast, non-invasive, technically noncomplicated, inexpensive, readily and widely available. It is perhaps the most widely available brain blood-flow test. CTA has a high spatiotemporal resolution and is relatively operator independent. Several European countries have adopted CTA as an ancillary test but not the United States [12, 13].
\nThe technique of CTA involves rapid intravenous administration of iodinated contrast followed by volume scanning of the whole brain. For imaging of brain death at least two acquisitions should be performed, 60 seconds apart [9]. Others have proposed at least three acquisitions-arterial phase scanning after 20 seconds and venous phase scanning after 50–60 seconds [4].
\nDiagnostic criteria for brain death using CTA include lack of intracranial arterial contrast opacification. Lack of intracranial contrast opacification can be assessed by 4, 7, and 10 point scales. In 4 point scale, M4 (cortical) segments of middle cerebral artery (MCA) and intracerebral vein (ICV) are evaluated for contrast opacification [11]. The 7 point scale included evaluation of MCA-M4, anterior cerebral artery (ACA), ICV, and great cerebral vein (GCV) [14]. In the 10 point scale, all the seven segments of the 7 point scale plus posterior cerebral artery (PCA) and basilar artery are included [6]. In a recent study, Garret et al. assessed statistical performance of CTA in diagnosing brain death. For all the 18 patients included in the study, CTA had sensitivity of 75%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 33% [15]. Another recent study from Macdonald et al. reported the diagnostic accuracy and inter-rater reliability of different ancillary imaging tests used for brain death in 74 patients. They showed that CTA along with CTP and radionuclide scan had a specificity and positive predictive value of 100% [10]. These results certainly add to the growing medical literature that supports the use of CTA as a reliable ancillary imaging test in confirming the brain death. However, systematic reviews do not support use of CTA as an ancillary imaging test for confirmation of brain death [16, 17].
\nThe disadvantages of CTA are that this is not widely available as a bedside test and patient needs to be transported to imaging facility and this is challenging for an intensive care unit (ICU) patient. However, this can be obviated by the use of portable CT scanners in the future. CTA provides incomplete quantitative measurement of cerebral blood flow due predominantly of “stasis filling” (Figure 4). It is defined as delayed, weak persistent opacification of proximal cerebral arteries. This phenomenon causes a major problem in the development of reliable CTA protocol for the diagnosis of brain death [6]. There is also potential risk of damage to the organs of the brain death patients because of iodinated contrast media used in CTA. However based on the volume of contrast used for CTA, this is rare or negligible [18, 19].
\nAxial CTA images (A, B) in patient with clinically confirmed brain death show contrast opacification of bilateral internal carotid arteries, proximal branches of bilateral middle, and anterior cerebral arteries. None of the two images show opacification of M4 or cortical branches of middle cerebral arteries, distal anterior cerebral artery (ACA), internal and great cerebral vein. There is some opacification of only right posterior cerebral artery. There is continued filling of the extra cranial arteries.
CTP is an advanced CT scan technique that provides both anatomical as well as functional information about the brain. CTP is useful in detecting perfusion even in small vessels such as arterioles, capillaries, and venules [20]. CTP is routinely used for evaluation of cerebral ischemia and vascularization of brain tumors and has the spatial resolution to quantify perfusion in any selected part of the brain [21, 22]. This imaging technique can help in calculation of cerebral blood flow (CBF) and cerebral blood volume (CBV). Normal CBF in the brain is 50–60 ml/100 mg/min and CTP can measure as low as 1.2 ml/100 mg/min [20]. CTP is very sensitive in detecting the blood flow and can detect decreased perfusion as low as 2–3% in CBF and 2% in CBV [23]. In CTP acquisition protocol, patients will undergo whole brain coverage with 80 kVp, 100 mAs resulting in a radiation dose of approximately CT dose index of 189.64 mGy [20]. A minimum scan duration of 60 seconds is recommended to reliably cover the venous phase of the circulation. A total of 40 ml nonionic iodinated contrast medium injected at the rate of 5 ml/seconds, followed by 40 ml of saline flush at the rate of 5 ml/seconds. Regular perfusion analysis is performed if intracranial arteries are seen on the source images [20]. Whole brain death could be seen as no intracranial CBF or CBV (Figure 5). Shankar et al. compared CTP and CTA derived from the CTP for confirmation of brain death in a retrospective review of 11 patients clinically suspected of brain death [20]. CTA showed a sensitivity of 72.7% for 7- and 4-point scales, 81.8% sensitivity for opacification of ICV, and 100% sensitivity for CTP scores in the brainstem [20]. They, for the first time, showed that CTP can be a valuable ancillary tool in early detection of brain death. Recently, Sawicki et al. tested the reliability and diagnostic accuracy of CTP over CTA in determining brain death [24]. For whole brain CTP, they also showed a sensitivity of 100% to confirm the diagnosis of brain death [24]. MacDonald et al. showed similar sensitivity [10].
\nCT perfusion showing no detectable cerebral blood flow (CBF) (A) and cerebral blood volume (CBV) (B) in the whole brain.
CTP can also evaluate brain-stem specific CBF [10, 20]. The concept of isolated brainstem death was first proposed by Shankar et al. in clinically confirmed brain death patients (Figure 6) [20]. Exact pathophysiological mechanism behind isolated brainstem death is not yet known. This is described when in patients with clinically confirmed brain death, there is presence of blood flow in the supratentorial brain and isolated absence of blood flow in the brainstem [10, 20]. Clinical examination does not differentiate between whole brain death and isolated brainstem death. CTP is the first imaging test reported to show the phenomenon of isolated brainstem death [10, 20]. It is suspected that isolated brainstem death is an earlier phenomenon in the process of brain death and may help early declaration of brain death [10]. However, the concept of brainstem death is debatable at the present time, and more studies are needed to establish this phenomenon.
\nCT perfusion showing matched defect on cerebral blood flow (CBF) (A and B) and cerebral blood volume (CBV) (C and D) maps in brainstem only. The supratentorial brain as well as cerebellum showed preserved CBF and CBV.
Like CTA, CTP is a widely available tool and with the availability of automated software, CTP is relatively operator-independent [20]. The advantage of CTP is that it can be performed along with CTA. CTP has a presumed risk of contrast induced renal damage in the patients with kidney disease. But, based on the volume of contrast used for CTP, the chances of nephrotoxicity is very rare or negligible [18, 19].
\nIt is a reliable high-resolution imaging of brain and has been used for imaging for brain death. MRI has an advantage of not requiring nephrotoxic contrast material for demonstration of cerebral blood flow. It is noninvasive and accurate in identifying structural abnormalities in the brain. Common MRI findings in brain death patients are variable edema, diffuse cortical high signal intensity, diffuse cerebral white matter injury, and tonsillar herniation [25, 26]. Lovblad and colleagues demonstrated the usefulness of diffusion weighted imaging (DWI) in the diagnosis of brain death [27]. They reported that apparent diffusion coefficient (ADC) values are reduced in brain death patients when compared to the normal individuals [27]. Using DWI and ADC mapping, it is possible to identify areas of cytotoxic damage and ischemic damage [4]. However, this has not been accepted in the imaging guidelines for brain death. The major disadvantages of this method are the length of the scan time and obtaining MRI on ventilated patients as they may have several contraindications to MRI.
\nIt is a reliable test for cerebral blood flow [28] and can detect intracranial arterial blood flow and flow voids (Figure 7). However, MRA has not yet been proven as an ancillary test in assessing the brain death. Time of flight MRA is relatively immune to “stasis filling” when compared to CTA or DSA. Like any MRI, the patient needs transportation to the radiology department, and the length of time for MRA is longer than that for CTA or CTP. There is requirement of having specialized critical care equipment in a scanner.
\nTime of flight MR angiography image of a brain dead patient showed no intracranial flow but preserved extracranial flow on source image (A), axial (B), and coronal (C) maximum intensity projection images.
MRP is noninvasive and can be used to detect intracranial arterial blood flow. It can also detect perfusion parameters of affected brain tissues such as cerebral blood flow and cerebral blood volume. There are not many reports in the literature that used MR perfusion as an ancillary imaging tool, and more research studies are needed to establish the reliability of this technique in the clinical setting.
\nFor clinical confirmation of brain death, the three essential criteria are apnea, absence of brain stem reflexes, and coma. In situations where brain death cannot be confirmed by one of these clinical tests or there are uncertainties around the reliability of clinical examination, ancillary imaging techniques are required to confirm brain death. We describe different ancillary imaging tests commonly used and reported to confirm the brain death. More research is required to validate these tests to become gold standards in the clinical practice.
\nJai Shankar is the co-PI of ongoing INDEX study for prospective evaluation of CT perfusion for confirmation of brain death.
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Intriligator",authors:[{id:"79235",title:"Dr.",name:"Hector",middleName:null,surname:"Perez-De-Tejada",slug:"hector-perez-de-tejada",fullName:"Hector Perez-De-Tejada"}]}],onlineFirstChaptersFilter:{topicId:"101",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"80231",title:"Dark Matter in Spiral Galaxies as the Gravitational Redshift of Gravitons",slug:"dark-matter-in-spiral-galaxies-as-the-gravitational-redshift-of-gravitons",totalDownloads:59,totalDimensionsCites:0,doi:"10.5772/intechopen.101130",abstract:"Several recent attempts to observe dark matter with characteristics similar to atomic or subatomic particles as Weakly Interacting Massive Particles (WIMPs) have failed to detect anything real over a wide energy range. Likewise, considerations of large, non-emitting objects as the source of most dark matter fall short of expectations. Here we consider the possibility that massless gravitons suffering slow redshift may be responsible for the properties of spiral galaxies attributed to dark matter. Particles such as gravitons will be extremely difficult to directly detect; the best we can envision is measuring this influence on stellar and galactic motions. Since the motions of stars and galaxies are non-relativistic, we can apply our idea to describe the expected large-scale motions using only Newtonian mechanics. Using our assumption about the importance of the graviton, we here describe the well-known Tully-Fisher relationship of spiral galaxies without resorting to hypothesizing exotic WIMPs or invoking modifications of Newtonian dynamics (MoND).",book:{id:"10954",title:"Dark Matter - Recent Observations and Theoretical Advances",coverURL:"https://cdn.intechopen.com/books/images_new/10954.jpg"},signatures:"Firmin Oliveira and Michael L. Smith"},{id:"79591",title:"Cosmology and Cosmic Rays Propagation in the Relativity with a Preferred Frame",slug:"cosmology-and-cosmic-rays-propagation-in-the-relativity-with-a-preferred-frame",totalDownloads:64,totalDimensionsCites:0,doi:"10.5772/intechopen.101032",abstract:"In this chapter, cosmological models and the processes accompanying the propagation of the cosmic rays on cosmological scales are considered based on particle dynamics, electrodynamics and general relativity (GR) developed from the basic concepts of the ‘relativity with a preferred frame’. The ‘relativity with a preferred frame’, designed to reconcile the relativity principle with the existence of the cosmological preferred frame, incorporates the preferred frame at the fundamental level of special relativity (SR) while retaining the fundamental space-time symmetry which, in the standard SR, manifests itself as Lorentz invariance. The cosmological models based on the modified GR of the ‘relativity with a preferred frame’ allow us to explain the SNIa observational data without introducing the dark energy and also fit other observational data, in particular, the BAO data. Applying the theory to the photo pion-production and pair-production processes, accompanying the propagation of the Ultra-High Energy Cosmic Rays (UHECR) and gamma rays through the universal diffuse background radiation, shows that the modified particle dynamics, electrodynamics and GR lead to measurable signatures in the observed cosmic rays spectra which can provide an interpretation of some puzzling features found in the observational data. Other possible observational consequences of the theory, such as the birefringence of light propagating in vacuo and dispersion, are discussed.",book:{id:"10954",title:"Dark Matter - Recent Observations and Theoretical Advances",coverURL:"https://cdn.intechopen.com/books/images_new/10954.jpg"},signatures:"Georgy I. Burde"},{id:"78811",title:"Black Holes as Possible Dark Matter",slug:"black-holes-as-possible-dark-matter",totalDownloads:116,totalDimensionsCites:0,doi:"10.5772/intechopen.99766",abstract:"Black holes and Dark matter are two fascinating things that are known very little. They may have non gravitational interactions, but those are definitely extremely feeble in comparison to their gravitational interactions. Nowadays some people think that one may contain the other. In this chapter we will see that some black holes may contain the dark matter. These black holes decay under Hawking radiation, but do not vanish completely. They produce stable end states due to both quantum gravitational effects and thermodynamic reasons. These end states are the replicas of what we call dark matter. We will develop the complete theory for decay of such black holes, starting from some scheme independent assumptions for the quantum mechanical nature of the black holes. We will then consider explicit examples of some black holes to show that they indeed produce replicas of dark matter at their end states. Thus this chapter is going to be a manuscript for theoretical development of black hole decay from a quantum mechanical perspective and its consequences for producing replicas of dark matter.",book:{id:"10954",title:"Dark Matter - Recent Observations and Theoretical Advances",coverURL:"https://cdn.intechopen.com/books/images_new/10954.jpg"},signatures:"Aloke Kumar Sinha"},{id:"78389",title:"Non-Keplerian Orbits in Dark Matter",slug:"non-keplerian-orbits-in-dark-matter",totalDownloads:105,totalDimensionsCites:0,doi:"10.5772/intechopen.99243",abstract:"This paper is concerned with the mathematical description of orbits that do not have a constant central gravitating mass. Instead, the attracting mass is a diffuse condensate, a situation which classical orbital dynamics has never encountered before. The famous Coma Cluster of Galaxies is embedded in Dark Matter. Condensed Neutrino Objects (CNO), which are stable assemblages of neutrinos and anti-neutrinos, are candidates for the Dark Matter. A CNO solution has been attained previously for the Coma Cluster, which allows mathematical modeling of galaxy orbital mechanics within Dark Matter, first reported here. For non-zero eccentricity galaxy orbits, each point along the trajectory sees a different gravitating central mass, akin to satellite orbits inside Earth. Mathematically, the galaxy orbits are non-Keplerian, spirographs.",book:{id:"10954",title:"Dark Matter - Recent Observations and Theoretical Advances",coverURL:"https://cdn.intechopen.com/books/images_new/10954.jpg"},signatures:"Peter D. Morley"},{id:"77754",title:"The Most Probable Cosmic Scale Factor Consistent with the Cosmological Principle, General Relativity and the SMPP",slug:"the-most-probable-cosmic-scale-factor-consistent-with-the-cosmological-principle-general-relativity-",totalDownloads:222,totalDimensionsCites:1,doi:"10.5772/intechopen.99325",abstract:"Current literature on the evolution of the cosmic scale factor is dominated by models using a dark sector, these all involve making many conjectures beyond the basic assumption that the Cosmological Principle selects a space–time metric of the Friedmann–Lemaître–Robertson–Walker type through which ordinary Standard Model of Particle Physics matter moves according to General Relativity. In this chapter a different model is made using the same basic assumptions but without making extra conjectures, it depends on following the idea introduced by Boltzmann that when physically meaningful concepts fluctuate the value which will be observed is the one which has the highest probability. This change removes the mathematically incorrect procedure of averaging the matter density before solving Einstein’s Equation, the procedure which causes the introduction of many of the conjectures. In the non-uniform era the changes are that the evolution of the scale factor is influenced by the formation of structure and removes the conjecture of having to use two inconsistent probability distributions for matter through space, one to calculate the scale factor and one to represent structure. The new model is consistent from the earliest times through to the present epoch. This new model is open and matches SNe 1a redshift data, an observation which makes it a viable candidate and implies that it should be fully investigated.",book:{id:"10954",title:"Dark Matter - Recent Observations and Theoretical Advances",coverURL:"https://cdn.intechopen.com/books/images_new/10954.jpg"},signatures:"Arthur N. James"},{id:"76451",title:"The Case for Cold Hydrogen Dark Matter",slug:"the-case-for-cold-hydrogen-dark-matter",totalDownloads:205,totalDimensionsCites:0,doi:"10.5772/intechopen.97557",abstract:"The novel ‘Cold Hydrogen Dark Matter’ (CHDM) theory is summarized in this chapter. Special attention is paid to the fact that current technology prevents us from directly observing extremely cold ground state atomic hydrogen when it is of sufficiently low density in deep space locations. A number of very recent observations in support of this theory are summarized, including cosmic dawn constraints on dark matter. The importance of the Wouthuysen-Field effect as a probable mechanism for CMB decoupling of hydrogen at cosmic dawn is also stressed. This mechanism does not require a non-baryonic dark matter intermediary. Several predictions for this theory are made for the coming decade of observations and simulations.",book:{id:"10954",title:"Dark Matter - Recent Observations and Theoretical Advances",coverURL:"https://cdn.intechopen.com/books/images_new/10954.jpg"},signatures:"Eugene Terry Tatum"}],onlineFirstChaptersTotal:6},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. 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