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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Hodges",dateSubmitted:"June 21st 2018",dateReviewed:"October 22nd 2018",datePrePublished:"December 31st 2018",datePublished:"February 19th 2020",book:{id:"8295",title:"Landscape Reclamation",subtitle:"Rising From What's Left",fullTitle:"Landscape Reclamation - Rising From What's Left",slug:"landscape-reclamation-rising-from-what-s-left",publishedDate:"February 19th 2020",bookSignature:"Luis Loures",coverURL:"https://cdn.intechopen.com/books/images_new/8295.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"108118",title:"Dr.",name:"Luis",middleName:null,surname:"Loures",slug:"luis-loures",fullName:"Luis Loures"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"264298",title:"Dr.",name:"Jason",middleName:null,surname:"Gordon",fullName:"Jason Gordon",slug:"jason-gordon",email:"jason.gordon@uga.edu",position:null,institution:{name:"University of Georgia",institutionURL:null,country:{name:"United States of America"}}}]},book:{id:"8295",title:"Landscape Reclamation",subtitle:"Rising From What's Left",fullTitle:"Landscape Reclamation - Rising From What's Left",slug:"landscape-reclamation-rising-from-what-s-left",publishedDate:"February 19th 2020",bookSignature:"Luis Loures",coverURL:"https://cdn.intechopen.com/books/images_new/8295.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"108118",title:"Dr.",name:"Luis",middleName:null,surname:"Loures",slug:"luis-loures",fullName:"Luis Loures"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11601",leadTitle:null,title:"Econometrics - Recent Advances and Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tAcademicians and policy-makers are always searching for new econometric methods to answer specific policy questions. More importantly, the advent in the advances of computing power has enabled more advanced econometric techniques to be computed with ease. Econometrics uses statistical methods and real-world data to predict and establish specific trends within economics and other social sciences.
\r\n\r\n\tThis volume attempts to explore the practical aspects of econometrics to economics, and other social sciences that use econometric methods. This volume is expected to cover a broad range of topics that include but are not limited to spatial econometrics, time series, forecasting, and machine learning, This volume hopes to attract dynamic stochastic general equilibrium (DSGE) models which are gaining prominence in applied macroeconomics. This proposed volume could serve as a reference for academicians, researchers, policy-makers, graduate students, and very abled undergraduate students who are seeking current research on the various applications of econometrics as used in research and to answer specific policy questions.
",isbn:"978-1-80356-525-5",printIsbn:"978-1-80356-524-8",pdfIsbn:"978-1-80356-526-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"bc8ab49e2cf436c217a49ca8c12a22eb",bookSignature:"Dr. Brian Sloboda",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11601.jpg",keywords:"Bayesian, Spatial Durbin Models, Spatial Autocorrelation, Spatial Panel Regression, Forecasting Models, Cointegration, Dynamic Factor Modes, State-Space Models, Causality, Clustering, Dynamic Stochastic General Equilibrium (DSGE), Loss Curves",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 9th 2022",dateEndSecondStepPublish:"May 13th 2022",dateEndThirdStepPublish:"July 12th 2022",dateEndFourthStepPublish:"September 30th 2022",dateEndFifthStepPublish:"November 29th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A mission-driven educator with expertise in Applied Econometrics, Regional Economics, and Labor Economics. Also, a skilled communicator who excels at interacting with students and motivating them to achieve their educational and career goals.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"452331",title:"Dr.",name:"Brian",middleName:null,surname:"Sloboda",slug:"brian-sloboda",fullName:"Brian Sloboda",profilePictureURL:"https://mts.intechopen.com/storage/users/452331/images/system/452331.jpg",biography:"Professional Profile Accredited as an Accredited Professional Statistician™ (PSTAT) by the American Statistical Association (ASA). Reaccredited through Aug.2022.\n\nComputer-proficient researcher skilled in statistical and econometric software, including E-Views, STATA, SPSS, and SAS Studio®. Working knowledge of MATHLAB and Dynare.\n\nResearch Fellow, Global Labor Organization (GLO), Oct.2017 to present\nAcademic and Professional Profiles \nResearch gate Profile:https: // www. researchgate. net/ profile/ Brian_ Sloboda\nORCID:https: // orcid. org/ 0000-0003-0007-1725\nGoogle Scholar Profile https: // scholar. google. com/ citations? user= RSLTrCsAAAAJ&hl= en\nEducation: Ph.D. Economics, Southern Illinois University at Carbondale,1997.\nThesis: The Economic Impact of Southern Illinois University on the State of Illinois: The Human Capital Approach\nM.S. Economics, Southern Illinois University at Carbondale,1992.\nB.A. Economics, Rowan University,1990.Minor: Mathematics.\nFields of Interest: Regional Economics, Economic Growth, Labor Economics, Economic and Statistical Education",institutionString:"University of Maryland, Global Campus",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"7",title:"Business, Management and Economics",slug:"business-management-and-economics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429339",firstName:"Jelena",lastName:"Vrdoljak",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429339/images/20012_n.jpg",email:"jelena.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"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"}],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"}],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. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],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"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3569",title:"Biodegradation",subtitle:"Life of Science",isOpenForSubmission:!1,hash:"bb737eb528a53e5106c7e218d5f12ec6",slug:"biodegradation-life-of-science",bookSignature:"Rolando Chamy and Francisca Rosenkranz",coverURL:"https://cdn.intechopen.com/books/images_new/3569.jpg",editedByType:"Edited by",editors:[{id:"165784",title:"Dr.",name:"Rolando",surname:"Chamy",slug:"rolando-chamy",fullName:"Rolando Chamy"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"45076",title:"Developmental Pathways in CAVD",doi:"10.5772/54356",slug:"developmental-pathways-in-cavd",body:'Calcific Aortic Valve Disease (CAVD) occurs in >2% of the population over 65 years of age and often leads to valvular stenosis that necessitates valve replacement [1]. CAVD is a progressive disease, often manifesting first as aortic valve sclerosis and later developing into stenosis and valve dysfunction [2]. The specific molecular and cellular mechanisms of CAVD initiation and advancement are not well defined, and inhibitors of CAVD progression have not been identified. The current standard of treatment for CAVD is aortic valve replacement [3]. Presently, there are no pharmacologic-based treatments for CAVD, and new therapeutic approaches for CAVD are needed. The majority of aortic valves that are replaced have congenital malformations, such as bicuspid aortic valve (BAV), establishing a link between valve development and disease mechanisms [4].
The molecular mechanisms of CAVD include activation of signaling pathways implicated in both heart valve development (valvulogenesis) and bone development (osteogenesis) [5-8]. These include activation of regulators of progenitor specification, cell proliferation, and differentiation. Heart valves and bone are complex connective tissues with compartmentalized ECM produced by specialized cell types. Over the past several years, extensive progress has been made in defining molecular regulatory mechanisms in heart valve and bone development (Reviewed in [8-10]). Strikingly, regulatory pathways that control development of cartilage, tendon and bone also are active in developing valves [8, 11]. In addition, recent studies have reported induction of molecular regulators of valvulogenesis and osteogenesis in CAVD [7, 12-14]. However, it is not known if these developmental mechanisms have reparative functions or contribute to the progression of CAVD.
Here we review molecular mechanisms of valve and bone development as they relate to molecular mechanisms of CAVD. Recent studies have provided evidence for the involvement of specific regulatory pathways in CAVD as activators or inhibitors of disease progression. Additional research in animal models and human patient specimens is necessary to determine the detrimental molecular regulatory pathways that promote CAVD progression and also beneficial pathways that potentially inhibit CAVD. In the future, manipulation of these pathways could be exploited therapeutically in the treatment of patients with CAVD or with aortic valve sclerosis that precedes calcification.
Valve development begins with the formation of endocardial cushions in the atrioventricular (AV) canal and outflow tract (OFT) of the primitive heart tube, which occurs at embryonic day (E)9-10 in mice, E3 in chickens, and E31-35 in humans [8]. The first evidence of endocardial cushion formation is the separation of the endocardium and overlying myocardium in the AV canal by expansion of the cardiac jelly through increased expression of hyaluronan (Figure 1) [15]. These swellings are invested with mesenchymal cells that arise from endothelial-to-mesenchymal transformation (EMT) of the endocardium [16]. Similar swelling and induction of EMT occur approximately a day later in the cardiac OFT cushions that will contribute to the semilunar valves [17]. Endocardial EMT is induced by signaling molecules, including bone morphogenetic proteins (BMPs), emanating from the adjacent myocardium in the AVC and OFT [8, 18-20]. Once established, the endocardial cushions expand through increased extracellular matrix (ECM) production and cell proliferation of mesenchymal and endothelial cells. The AV cushions subsequently fuse to separate right and left cardiac channels. In addition, lateral cushions are induced in the AV sulcus that will give rise to the mural leaflets of the mitral and tricuspid valves [21]. Neural crest cells (NCCs) migrate into the cushions of the cardiac OFT, contributing to the septum between the aortic and pulmonic roots and also to the morphogenesis of individual semilunar valve leaflets [21, 22]. At this point, distinct primordia of individual valve leaflets become apparent and proliferation of valve interstitial cells (VICs) is reduced [23]. Valve morphogenesis occurs with elongation and thinning of the valve primordia, in addition to ECM remodeling and stratification. In general, the development of the AV and semilunar (SL) valves is similar, but there are some differences in the sources of cells and structure of the resulting leaflets [8, 10, 11, 24]. In mature SL and AV valves, the ECM is stratified into collagen-rich fibrosa, proteoglycan-rich spongiosa, and elastin-rich (atrialis-ventricularis) layers oriented relative to blood flow [24].
The primary embryonic source of adult semilunar valve interstitial cells is the endothelial-derived cells of the endocardial cushions, that arise as a result of EMT as determined by Tie2-Cre lineage tracing in mice [23, 25]. Since the cardiac OFT is derived from the secondary heart field (SHF), semilunar VICs derived from OFT endocardium also are SHF-derived [20, 26]. NCC-derived cells are present in adult mouse semilunar valve leaflets as demonstrated by cell lineage tracing with Wnt1-Cre [27]. These cells are predominant throughout the aortic and pulmonic valve leaflets, but are enriched in the leaflets adjacent to the aorticopulmonary septum, which also is derived from NCCs [21, 28]. NCCs are required for semilunar valve morphogenesis and remodeling, likely by providing signals necessary for cell lineage differentiation and leaflet maturation [29, 30]. Another potential source of VICs is the epicardium, which contributes cells to the parietal leaflets of AV valves [31]. However, epicardial-derived cells (EPDCs) have not been not reported to contribute to the semilunar valves, based on Wt1-Cre fatemapping studies [31, 32]. Recent studies have reported that bone marrow-derived stem cells (BMSCs) are present in the developing and mature semilunar valves [33, 34]. Additional work is necessary to determine if these cells have lineages and functions distinct from the predominant endocardial cushion-derived or neural crest-derived VICs. It is possible that valve cell lineages derived from different developmental sources have distinct functions in normal and diseased aortic valves, but this has not yet been demonstrated. The sources of increased proliferative cells in diseased valves are relatively unknown, but could be any of these embryonic sources or, alternatively, an infiltrating cell type.
Several transcription factors have been implicated in various processes of endocardial cushion formation and EMT (reviewed in [8, 35]). Notch pathway function in EMT is dependent on the transcription factor RBPJ, which activates expression of the bHLH transcription factor
Additional regulatory pathways control heart valve ECM remodeling and compartmentalization. Loss of NFATc1 results in defective remodeling of the AV and SL valves in mice, with embryonic lethality by E14.5 [45, 46]. EMT occurs with loss of NFATc1, but valve primordia fail to remodel and mature ECM molecules are not expressed in null mice or in cultured VICs with inhibition of receptor activator of nuclear factor κ-B ligand (RANKL) or calcineurin signaling upstream of NFATc1 activation [45, 47]. In addition to being required for endocardial cushion mesenchymal proliferation, Sox9 also promotes cartilage-like ECM gene expression in valve progenitor cells [48]. In late stage mouse embryos, loss of Sox9 in remodeling valves results in reduced proteoglycan expression, and Sox9 haploinsufficiency in adults leads to valve calcification [40, 49]. Conversely, the bHLH transcription factor Scleraxis, critical for tendon development, promotes expression of elastic/tendon-like matrix genes in cultured valve progenitor cells [48]. Loss of Scleraxis in mice is not lethal, but heart valve defects similar to myxomatous valve disease occur in these animals [50]. Little is known of the transcriptional regulatory mechanisms that control the development of the valve fibrosa layer, which is most critically involved in CAVD.
Several essential embryonic signaling pathways have been implicated in endocardial cushion formation and EMT (Table 1) (reviewed in [8]). Transforming growth factor (TGF)β signaling was the first pathway implicated in endocardial cushion formation and is required for EMT in chicken and mouse embryonic systems (reviewed in [16]). BMP signaling from the myocardium is required in endothelial cells for the initiation of EMT in the AV canal, and BMP2 and 4 are the predominant ligands involved in endocardial cushion development [18-20]. Notch signaling also is required for EMT as described above. Moreover, Notch signaling is required for expression of TGFβ ligands and receptors, in addition to activating BMP signaling, which promotes mesenchymal cell invasion [36, 51]. Likewise, vascular endothelial growth factor (VEGF) signaling promotes endocardial cushion endothelial cell proliferation and EMT [47, 52]. Furthermore, targeted mutagenesis of β-catenin has implicated Wnt/β-catenin signaling in endocardial cushion EMT and mesenchymal proliferation [53, 54]. Thus multiple pathways are involved in endocardial cushion EMT and mesenchymal cell proliferation. However, the intersection and specific cellular functions of these pathways have not been fully determined.
\n\t\t\t\t | \n\t\t|||
\n\t\t\t | Role in valvulogenesis | \n\t\t\tRole in osteogenesis | \n\t\t\tRole in CAVD | \n\t\t
VEGF | \n\t\t\tEMT, endothelial proliferation | \n\t\t\tangiogenesis | \n\t\t\tangiogenesis | \n\t\t
Notch | \n\t\t\tEMT | \n\t\t\tInhibit OB differentiation | \n\t\t\trepresses calcification | \n\t\t
TGFβ | \n\t\t\tEMT | \n\t\t\tbone homeostasis | \n\t\t\tpromotes VIC calcification | \n\t\t
FGF | \n\t\t\tpromotes tenascin expression | \n\t\t\tOB proliferation, differentiation | \n\t\t\tblocks VIC calcification | \n\t\t
BMP | \n\t\t\tEMT, PG expression | \n\t\t\tpromotes OB specification | \n\t\t\tactive in CAVD | \n\t\t
Wnt/β-catenin | \n\t\t\tEMT, fibrosa expression | \n\t\t\tpromotes OB differentiation | \n\t\t\tactive in CAVD | \n\t\t
RANKL | \n\t\t\tECM remodeling | \n\t\t\tOC differentiation | \n\t\t\tpromotes VIC calcification | \n\t\t
\n\t\t\t\t | \n\t\t|||
\n\t\t\t | Role in valvulogenesis | \n\t\t\tRole in osteogenesis | \n\t\t\tRole in CAVD | \n\t\t
Twist1 | \n\t\t\tECC proliferation, migration | \n\t\t\trepresses differentiation | \n\t\t\tactive in CAVD | \n\t\t
Msx2 | \n\t\t\tEMT, proliferation | \n\t\t\tpresent in progenitors, OB | \n\t\t\tactive in CAVD | \n\t\t
Sox9 | \n\t\t\tproliferation, PG expression | \n\t\t\tprogenitor proliferation, cartilage differentiation | \n\t\t\tactive in CAVD inhibits calcification | \n\t\t
NFATc1 | \n\t\t\tendothelial proliferation, ECM remodeling | \n\t\t\tpromotes OC differentiation promotes OB differentiation | \n\t\t\treported in CAVD | \n\t\t
Runx2 | \n\t\t\tnot present | \n\t\t\tpromotes OB differentiation | \n\t\t\tactive in CAVD | \n\t\t
Osterix | \n\t\t\tnot present | \n\t\t\tpromotes OB differentiation | \n\t\t\treported in CAVD | \n\t\t
Signaling pathways and transcription factors involved in valvulogenesis, osteogenesis, and CAVDa, b
aPlease see text for details and references. bAbbreviations used: CAVD=calcific aortic valve disease; ECM=extracellular matrix; EMT=endothelial to mesenchymal transition; OB=osteoblast; OC=osteoclast; PG=proteoglycan; VIC=valve interstitial cell.
Many of the signaling pathways important for endocardial cushion formation also have later functions in valve lineage diversification, remodeling, and stratification. However, these functions have been difficult to elucidate due to limitations of available genetic tools and critical requirements for these same regulatory pathways in endocardial cushion formation. BMP signaling, as indicated by phosphorylation of the intermediate signaling molecules Smad1/5/8, is active throughout endocardial cushion mesenchymal cells, is associated with mesenchymal cell proliferation [55], and also is active later in valve cell lineage diversification [48].
The later stages of heart valve development are characterized by leaflet elongation, ECM remodeling, and stratification, all of which are critical for mature valve structure and function [24]. Limited information is available on the regulation of these processes, but several regulatory pathways have been implicated in late valve remodeling and morphogenesis. Strikingly these same pathways have been implicated in adult CAVD (see below). RANKL, expressed by valve endothelial cells, promotes ECM remodeling and Cathepsin K (Ctsk) expression by NFATc1 in a mechanism partially conserved with osteoclast differentiation and function [11, 47, 61]. The signaling mechanisms that control stratification and ECM organization of the valve leaflets are relatively unknown. Notch signaling is localized on the ventricularis surface of the remodeling aortic valve in mice [62], and Wnt/β-catenin signaling is active throughout aortic valve primordia at late gestation and in a subpopulation of VICs after birth [60]. Likewise, Wnt signaling promotes expression of fibrosa genes
Bicuspid aortic valve is arguably the most common congenital heart malformation with an incidence of 1-2% in the US adult population [63]. BAV often does not often manifest in valve dysfunction in early life, but malformed aortic valves are predisposed to calcification. Strikingly, the majority of stenotic aortic valves that are replaced in adults are congenitally malformed [4]. However, the molecular and cellular mechanisms of BAV are not well defined. In humans, mutations in
The mature valve leaflets are composed of stratified ECM with layered compartments of fibrillar collagen, proteoglycan, and elastin (Figure 1) (reviewed in [10, 69]). During heart valve remodeling, there is little proliferation of VICs, but the cells are highly synthetic and produce multiple ECM proteins of the mature leaflets [24, 44]. The distinct layers of matrix are integral to heart valve function and confer specific biomechanical properties to the valve leaflets [69]. The regulatory mechanisms for ECM remodeling and stratification are not well defined but are relevant to heart valve disease mechanisms. Periostin is required for collagen remodeling, and loss of periostin in mice leads to adult valve malformations and cardiac dysfunction [70, 71]. Likewise, mutations in
Many osteogenic regulatory interactions identified in developing bone also are active in CAVD (Table 1). The regulatory hierarchies and ECM composition of the developing valves, most notably the collagen rich fibrosa layer, are similar to those observed in osteoblast precursor cells [43]. Both the bone substratum and valve ECM are composed primarily of fibrillar collagen. Thus, it is not surprising that there are extensive similarities in their composition and developmental regulation. Normally, heart valves do not progress to mineralization, but striking similarities have been identified between osteogenic pathways that regulate bone mineralization and CAVD mechanisms [7]. Thus the molecular understanding of normal development of bone has clear implications for pathogenic mechanisms of connective tissue mineralization, including CAVD.
The osteogenic precursors of the developing axial skeleton and long bones of the limbs are derived primarily from paraxial mesoderm of the developing somites and also lateral plate mesoderm, the main source of cardiac precursor cells [76, 77]. Additional progenitors of the craniofacial skeleton are derived from cranial neural crest [78]. Most axial skeletal elements develop by endochondral bone formation that occurs through a cartilage intermediate [76, 77]. Alternatively, the craniofacial bones of the skull form through membranous ossification in which condensed osteogenic progenitors differentiate directly into bone and do not go through a cartilage intermediate [76]. The osteochondroprogenitors present in the axial and appendicular skeletal elements develop into both bone and cartilage lineages [77, 79, 80]. Extensive research over the past several years has defined transcriptional regulatory mechanisms and signaling events that control the development of cartilage and bone (Figure 2) [79, 80].
Hierarchies of signaling pathways and transcription factors regulate the differentiation of chondrogenic and osteogenic progenitor cells during skeletal development. Early osteochondrogenic progenitor cells express BMPs, Twist1, Msx1/2, and Sox9. Wnt/β-catenin signaling promotes pre-osteoblast differentiation while inhibiting chondrocyte differentiation. In contrast, Notch signaling promotes cartilage differentiation and inhibits osteoblast differentiation. BMP signaling is further required for osteocyte differentiation in the final stages of bone maturation. Sox5, 6, and 9 are transcription factors crucial for maintaining the chondrogenic lineage, whereas, Runx2, Osx, and ATF4 are transcription factors necessary for osteoblast and osteocyte differentiation and maturation. Many of these factors are also expressed during calcific aortic valve disease and have been implicated in pathologic calcification. Please see text for details and references. Activating factors are shown in green, inhibitory factors are shown in red, and signaling pathways are indicated in blue.
Mature cartilage is composed predominantly of chondroitin sulfate proteoglycans that provides cushioning and flexibility to cartilaginous structures [77, 81]. In addition, the proteoglycan-rich ECM is angiostatic and mature cartilage is avascular [81]. Interestingly, the predominant proteoglycan composition and lack of vasculature also are features of the mature aortic valve leaflet spongiosa layer [82]. Likewise, the cartilage ECM inhibits mineralization, and a similar role has been hypothesized for the proteoglycan-rich matrix of the aortic valve [49]. During normal axial bone development, osteoblasts from the laterally placed periostium differentiate into trabecular bone, and secondary ossification centers at the ends of the bone displace the growth plate hypertrophic cartilage [79, 80]. During bone differentiation, hypertrophic cartilage cells must die for mineralization to occur in a process of endochondral ossification, which could be related to dystrophic mechanisms of CAVD [79, 80].
Bone cell lineage maturation goes through multiple stages defined by molecular regulatory mechanisms that also are active in valve development and disease processes [80]. Osteochondroprogenitor cells express several mesenchymal transcription factors, including Twist1, Msx2, and Sox9, that also are predominant in valve progenitor cells and diseased aortic valves [79]. Immature pre-osteoblasts express high levels of fibrillar type 1 collagen, in addition to periostin, osteonectin, and osteopontin, similar to normal differentiated VICs [43, 60]. Differentiated osteoblasts are not yet mineralized but express the transcription factor Runx2, in addition to osteocalcin and bone sialoprotein involved in bone mineralization and also in valve calcification, [7, 80]. Later stage osteoblasts and osteocytes express the transcription factor Osterix (Osx), which is regulated by Runx2 and is required for mature bone formation [83]. Bone mineralization occurs with the deposition of calcium phosphate and hydroxyapatite by osteocytes and is dependent on Runx2 and Osx function [80]. Bone homeostasis is maintained throughout life by the osteogenic activity of osteocytes and bone resorption activity of osteoclasts [80].
Twist1 is expressed early in the osteochondroprogenitor lineage and inhibits terminal differentiation of cartilage and bone [84]. In preosteoblasts, Twist1 binds to Runx2 and inhibits its transcriptional activation of bone differentiation genes including
Sox9 functions in the expansion of cartilage progenitors and promotes cartilage differentiation, while inhibiting bone differentiation [77, 80]. Sox9 is required for osteochondroprogenitor lineage specification but is not expressed in differentiated osteoblasts [88]. At early stages of cartilage lineage development, Sox9 promotes cell proliferation and later is required for cartilage lineage differentiation [88]. BMP signaling induces
Runx2, originally called Cbfa1, has been defined as a master regulatory gene in bone formation [79, 93]. Gain and loss of function studies in mice demonstrate that Runx2 is both necessary and sufficient for osteoblast differentiation [93]. During bone development, Runx2 directly regulates
NFATc1 is a critical transcription factor in osteoclast differentiation and also has been implicated in osteoblast development [80, 96]. Osteoclasts, derived from a macrophage lineage, have bone resorptive activity and are necessary for bone homeostasis [96]. During osteoclast development, RANKL signaling induces activation of NFATc1, which promotes the transcription of bone matrix remodeling genes including C
Additional transcription factors involved in bone differentiation are not generally found in CAVD, although there are conflicting reports. Most notable is Osx, which is required for terminal differentiation of osteoblasts and mineralization of bone [83]. Osx, promotes expression of
Multiple signaling pathways control the stages of bone cell lineage determination, differentiation and maturation [80, 107]. These include BMP, Wnt, and Notch pathways, also active in developing and diseased heart valves, as well as FGF, hedgehog, insulin-like growth factor (IGF), and retinoic acid (RA) pathways, not yet characterized in heart valve pathogenesis [80]. BMP, Wnt, and Notch pathways are required at multiple stages of osteogenesis and have distinct regulatory interactions that control transcription factor function and cell type-specific gene expression in cartilage and bone cell lineages (Figure 2). In addition, these pathways crosstalk with each other in synergistic and antagonistic regulatory interactions. Strikingly many of these same regulatory interactions occur in heart valve development and pathogenesis (Table 1) [8].
Bone morphogenetic proteins were originally identified based on their ability to induce ectopic bone formation [108]; however, in vivo functions in normal bone development are less clear [109]. In the developing limb buds, BMP signaling has a critical role in mesenchymal condensation, Sox9 activation, and cartilage lineage differentiation [89]. Thus BMP signaling is an important regulator of the earliest stages of skeletal development. Later in differentiating osteoblasts, BMP signaling through Smad1/5/8 phosphorylation (pSmad1/5/8) promotes osteogenic differentiation and calcification [110]. Runx2 directly binds to activated Smads1 and 5 to cooperatively activate osteoblast gene expression in response to BMP signaling [109]. Conditional loss of BMP2 and BMP4 in the osteoblast lineage in mice inhibits late stage differentiation into Osx1-positive osteocytes, and BMP signaling is required for bone homeostasis after birth [80, 109]. Surprisingly, earlier stages of bone lineage development are apparently unaffected with conditional loss of these ligands.
Wnt/β-catenin signaling is required for osteoblast differentiation as demonstrated by loss of osteoblast differentiation with conditional loss of β-catenin in osteochondroprogenitor cells in mice [80]. In addition, loss of β-catenin in pre-osteoblasts leads to ectopic cartilage formation, thus implicating Wnt signaling in osteogenic versus chondrogenic cell fate determination. At a molecular level, Wnt/β-catenin signaling promotes osteoblast lineage differentiation, while inhibiting chondrogenesis, by activating Runx2, while inhibiting Sox9 [77]. In bone lineages, BMP and Wnt signaling act synergistically to promote calcification, although neither pathway alone is sufficient to induce a full osteogenic response [111]. During the initial differentiation of bone progenitor cells, regulatory elements of
Notch activation inhibits osteogenesis through suppression of the Wnt/β-catenin pathway and Runx2 transcription factor activity [94, 113, 114]. Loss of Notch1 or Notch2 function promotes osteoblast differentiation and leads to increased bone mass in mice [115]. Notch pathway activation inhibits the progression of osteoblast differentiation through direct binding of the activated Notch1 intracellular domain (N1ICD) to β-catenin, thereby counteracting Wnt-mediated induction of osteogenesis [113, 114]. In addition, the Notch target gene
The mature aortic valves are comprised of three ECM layers critical for normal leaflet structure and function [24, 44, 117]. Collagen predominates in the fibrosa layer, which is oriented on the opposite side of blood flow, whereas elastin is enriched in the ventricularis layer on the flow side of the valve. Between the fibrosa and ventricularis layers, is the proteoglycan-rich spongiosa layer [24, 44, 117]. This trilaminar ECM arrangement is preserved among species, and lends both strength and elasticity to the aortic valves [24]. In CAVD, the aortic valve becomes thickened and displays extensive ECM remodeling and mineralization [118-121]. Abnormal thickening (aortic valve sclerosis) and calcification of the aortic valve lead to stiffening of the valve leaflets and can reduce the effective valve opening (aortic valve stenosis), which can impede blood flow and lead to clinical symptoms such as syncope and angina [119, 122, 123]. Histologically, human explanted diseased aortic valves have extensive ECM remodeling and elastic fiber fragmentation with evidence of both macroscopic calcific nodule formation as well as microscopic mineral deposits [119].
Changes in the resident VICs are apparent in CAVD. Under normal conditions, aortic VICs are quiescent and non-proliferative [13, 24, 104, 124]. However, in disease, a subset of aortic VICs exhibits features of myofibroblast activation, which is characterized by expression of α-smooth muscle actin (αSMA), MMP13, non-muscle myosin heavy chain (SMemb), and markers of proliferation [13, 104, 119, 124, 125]. In vivo, the factors responsible for inducing myofibroblast activation are not well defined. However, in culture, TGFβ1 stimulation and mechanical strain are potent inducers of VIC myofibroblast activation [125, 126]. Activated VICs also exhibit characteristics of valve and bone precursor cells as they induce expression of the common mesenchymal markers Sox9, Twist1, and Msx2 [13]. Currently it is unknown where the mesenchymal-like cells come from and what role these proliferative cells play in the progression of CAVD pathogenesis.
Valve calcification, apparent as hydroxyapatite deposits on the surface of or within the leaflets, is a prominent feature of CAVD [119, 127, 128]. Histologically, valve calcific nodules are primarily acellular [13, 129]. Although traditionally thought to be a completely passive deposition of mineral, in some cases, valve calcification is coincident with endochondral bone-like and cartilaginous-like nodules [129, 130]. Aortic valve calcification is observed primarily in the regions of the valves exposed to the greatest physical strain, specifically at the hinge region of the valve and along the line of leaflet coaptation [120]. Furthermore, calcification is predominantly found in the fibrosa layer of the diseased valve, which is similar to early bone matrix as it is contains primarily fibrillar collagen [44]. Expression of other bone matrix molecules, such as osteocalcin and osteopontin, are induced during disease [5]. Furthermore, expression of osteogenic factors, such as Runx2, BMP2, and alkaline phosphatase, also is induced in VICs from calcified valves, suggesting that resident VICs may have the potential to undergo osteogenic transdifferentiation and actively contribute to valve calcification (reviewed in [131]).
Extrinsic factors have been implicated in valve calcification. For example, lipid deposition and immune cell infiltration are common histopathological features of CAVD, and it has been proposed that aortic valve calcification occurs by mechanisms similar to arterial calcification in atherosclerosis [119, 132-135]. In addition, altered external physical forces elicit changes in resident VICs, which play an active role in pathological valve calcification [126]. In contrast to VIC response to immune cell infiltration and altered physical forces, cell intrinsic mechanisms may also contribute to valve calcification, as stimulation with factors such as BMP2 or TGFβ1 in cell culture studies can induce VIC calcification in the absence of inflammatory stimulation or altered physical forces [126, 136-138]. Together, these studies suggest that not only is valve calcification an active cell-regulated process, but that many factors likely contribute to progression of calcification during disease. It is also likely that not all CAVD is created equal. Genetic predisposition, the presence of a malformed aortic valve, and other disease comorbidities, such as coronary artery disease, hypertension, and kidney disease, likely affect the pathology and underlying cause of CAVD [64, 139-142].
The mesenchymal markers Twist1, Msx2, and Sox9 are expressed in adult calcific aortic valves in mesenchymal-like activated VICs [12, 13, 106, 143, 144]. As discussed, these genes are expressed in both valve and bone mesenchymal progenitor cells. A recent study has compared gene expression in pediatric versus adult aortic valve disease and shown that the mesenchymal markers Twist1, Msx2, and Sox9 are increased in both [13]. The observation that both pediatric and adult diseased valves have increased expression of the mesenchymal markers suggests that this expression is related to VIC activation and proliferation, which is common to both, and not related to valve calcification, which is found only in advanced adult disease [13]. In both valve and bone progenitors, Twist1, Msx2, and Sox9 induce proliferation and promote a mesenchymal phenotype, thus reactivation in diseased valves is suggestive of a similar role in valve pathogenesis [38, 40-42, 84, 88, 145]. Although it is presumed that resident VICs re-activate these early mesenchymal markers, other possibilities exist. EMT as a mechanism for VIC activation has not been established in CAVD, however, recent studies report EMT-like events in adult valves. Increased cyclic strain and altered hemodynamics, both recognized features of CAVD, can induce EMT in isolated sheep valve endothelial cells [146, 147]. In addition, cultured valve endothelial cells stimulated with TGFβ adapt a mesenchymal-like phenotype and express markers of both endothelial and mesenchymal cells, suggesting that they can undergo EMT [148, 149]. Likewise, disruption of Notch signaling in adult mice induces aortic valve thickening with evidence of endocardial EMT, as indicated by endocardial cells with more pseudopodial projections, loose endocardial cell-cell junctions, and αSMA expression [150]. Additional sources of mesenchymal-like cells have been suggested. For example, circulating bone marrow-derived hematopoietic stem cells have been shown to integrate into the valve interstitium, adapt fibroblast-like characteristics, and surround regions of prominent valve calcification in human end stage CAVD [33, 130, 151]. It is uncertain what role reactivation of the mesenchymal markers Twist1, Msx2, and Sox9 have in potential valve repair mechanisms or in the progression of CAVD. It is possible that adult VICs maintain a certain “mesenchymal-plasticity” and are able to revert back to an early progenitor-like mesenchymal cell during disease. Alternatively, they may be indicators of newly derived VICs arising from EMT or circulating progenitor cell populations in response to disease conditions.
Molecular mechanisms of endochondral ossification and cartilaginous nodule formation are active in CAVD [7, 13]. Studies in human explanted diseased aortic valve tissues have demonstrated increased expression of the osteogenic factors BMP2, TGFβ1, Runx2, osteocalcin (OCN), osteopontin (OPN), osteoprotegerin (OPG), bone sialoprotein (BSP), alkaline phosphatase (ALP), and Osx in disease [5, 13, 106, 118, 137, 152]. At a molecular level, BMP2 signaling is a key inducer of VIC calcification, which is thought to act through p-SMAD1/5/8 and phospho-ERK1/2 signaling to stimulate increases in both Runx2 and OPN expression [138]. Induction of VIC calcification by BMP2 stimulation is highly reminiscent of BMP signaling in bone development, suggesting that some parallels exist between osteogenic bone formation and VIC calcification [9]. Histological studies of explanted human valves further support a role for BMP signaling in valve calcification. Comparison of pediatric diseased valves, which do not acquire calcification, and adult calcified valves demonstrates that increased BMP signaling, evident in p-SMAD1/5/8 activation, is exclusive to adult valves with calcification, indicating that BMP signaling may contribute to valve calcification in human disease [13]. Additionally, TGFβ1 is also a potent inducer of osteogenic-like differentiation of VICs in cell culture, as it stimulates VIC activation and calcification, increases ALP activity, and increases expression of ECM remodeling enzymes [126, 136, 137]. Negative regulators of valve calcification have been demonstrated through in vivo studies. One negative regulator of valve calcification is Notch signaling. Animals haploinsufficient for Notch signaling develop aortic valve calcification with increased BMP signaling and increased expression of Runx2 in the valve leaflets [65, 153]. Studies in isolated aortic VICs further demonstrate that Notch signaling plays an important role in suppressing valve calcification as treatment of VICs with Notch inhibitors induces BMP signaling and subsequent increases in osteogenic gene expression [65, 153]. Another negative regulator of valve calcification is Sox9, which potentially acts through induction of proteoglycan expression, similar to what has been observed in developing cartilage [40, 49]. Conditional heterozygous Sox9 mutant mice develop valve calcification along with increased valve thickness and expression of the osteogenic genes
CAVD has been linked to chronic kidney disease in human patients and animal models [140, 154-157]. A prominent pathological feature of kidney disease is the inability to regulate calcium and phosphate metabolism [158]. Increased blood phosphate levels (hyperphosphatemia) are highly associated with aortic valve sclerosis and valve calcification in humans [140]. Klotho-null mice are a model of accelerated aging that includes development of kidney failure and hyperphosphatemia, along with cardiovascular disease [159-162]. Klotho-null mice exhibit extensive valve annulus calcification with increased expression of osteogenic genes, but minimal CD68 positive macrophage infiltration [73]. Thus, valve calcification in the klotho-null animals parallels bone formation, where increases in crucial osteogenic genes, such as
Atherogenic lipid deposition and inflammation in the valves also has been linked to induction of osteogenic gene expression and disease [163-165]. Rabbit and mouse models of CAVD, induced with hypercholesterolemic or high fat diets, have increased lipid deposition and macrophage infiltration associated with induction of osteogenic markers such as ALP, OCN, OPN, Runx2, and Osx [165-167]. Although osteogenic gene expression is induced in these models, this type of valve calcification closely mimics vascular calcification observed in atherosclerosis, rather than endochondral bone formation, due to the presence of extensive immune cell infiltration [165, 166]. In support, human aortic VICs stimulated with pro-inflammatory mimetics not only induce the expression of inflammatory cytokines, but also induce the expression of osteogenic factors, such as BMP2 and Runx2, again suggesting that this process may be similar to what is occurring in atherosclerotic disease [164, 168]. Based on this evidence, multiple physiologic factors likely contribute to osteogenic gene induction in calcified diseased aortic valves.
As in both heart valve and endochondral bone development, BMP, TGFβ, Notch, and Wnt signaling have been implicated in the progression of CAVD (Figure 2; Table 1). Increased BMP ligand expression, particularly BMP2 and BMP4, has been demonstrated histologically in human explanted calcific aortic valves surrounding and throughout regions of valvular calcification [118, 129]. Furthermore, active BMP signaling, as indicated by pSMAD1/5/8 expression, is present in both human explanted diseased aortic valves and animal models of CAVD [13, 169, 170]. Comparison of pediatric diseased valves void of calcification to heavily calcified adult diseased valves demonstrates extensive ECM remodeling and evidence of VIC activation in both; however, increased pSMAD1/5/8 signaling is exclusive to calcified valves [13]. The observation that pSMAD1/5/8 expression is found only in adult calcified valves is suggestive of a critical role for BMP signaling as an initiating osteogenic factor in CAVD [13]. Furthermore, increased pSMAD1/5/8 expression reportedly localizes to the fibrosa layer of human calcific aortic valves, which is the primary sight of aortic valve calcification [169]. Cell culture studies support this and show that BMP2 stimulation promotes osteogenic-like aortic valve calcification in human aortic VICs by inducing the expression of the osteogenic factors Runx2, OPN, and ALP [138, 171]. Based on this evidence, active BMP signaling may be a potential therapeutic target to treat CAVD, however it has not yet been tested.
TGFβ signaling induces α SMA expression and myofibroblast differentiation of porcine aortic VICs, suggesting that TGFβ promotes VIC activation, potentially in response to physical strain [125, 172]. Furthermore, TGFβ signaling may also have a role in aortic valve calcification, as human explanted calcific aortic valves have increased levels of TGFβ1 expression and ovine aortic VICs in culture calcify in response to TGFβ1 induction [136, 137]. TGFβ signaling has also been linked to both Wnt/β-catenin and FGF signaling pathways in CAVD [173, 174]. Specifically, FGF signals have been shown to induce MAPK signaling, which inhibits aortic VIC αSMA expression and myofibroblast response to TGFβ [174]. In addition, TGFβ stimulation of aortic VICs induces nuclear localization and activation of β-catenin, which promotes VIC myofibroblast differentiation [173]. Although the role of TGFβ in CAVD is not well established in vivo, there is accumulating evidence for a role in VIC activation and calcification from studies in cell culture systems.
Whereas both BMP and TGFβ signaling have been found to induce VIC calcification, Notch signaling has been implicated as a negative regulator of valve calcification. Familial studies demonstrated that Notch1 haploinsufficiency is associated with CAVD and aortic stenosis (AS) [64]. During development, Notch1 is expressed in the endothelial cells lining the aortic valve cusps and is also observed at lower levels in the VICs, and this expression pattern is maintained into adulthood [64, 175]. Histological analysis of human explanted aortic valves demonstrates that activated Notch1 intracellular domain (NICD) expression is dramatically reduced in VICs directly adjacent to regions of aortic valve calcification [175]. This observation is consistent with a mechanism whereby Notch signaling inhibits valve calcification and downregulation of Notch expression promotes valve calcification [175]. The idea that Notch signaling functions as a negative regulator of calcification was originally defined in endochondral bone formation, where downstream effectors of Notch signaling, Hes1 and Hey1, repress Runx2 transcriptional function, leading to expansion of hypertrophic cartilage and impaired osteoblast differentiation [115]. Notch1 heterozygous or RBPJ heterozygous mice develop CAVD, as evidenced by increased aortic valve calcification, and also display significant increases in BMP/pSMAD1/5/8 signaling and Runx2 expression in the aortic valves [65, 153]. Likewise, deletion of RBPJ in adult mice results in increased aortic valve thickness with evidence of VIC proliferation and potentially, endothelial EMT [150]. Together these in vivo studies support the idea that Notch signaling represses BMP expression, thereby indirectly repressing other osteogenic factors [65, 153]. Cell culture studies indicate that Notch inhibition promotes calcification of VICs by repressing chondrogenic genes, including
Wnt/β-catenin signaling is important for osteoblast maturation during embryonic development and contributes to mineralized bone formation (reviewed in [80]). A number of studies have also shown activation of Wnt/β-catenin signaling in aortic valve calcification. Canonical Wnt signaling acts through the frizzled receptors and the Wnt co-receptors Lrp5 and Lrp6, resulting in β-catenin nuclear localization and TCF/LEF1 activation [176]. Human explanted calcific AoVs have increased expression of Lrp5, β-catenin, and Wnt3a ligand as compared to control valves [143]. Increased Wnt signaling in diseased aortic valves also has been observed in multiple animal models of CAVD. Pigs and rabbits maintained on an atherogenic diet develop aortic valve disease and display increased expression levels of β-catenin and Lrp5 receptor [173, 177]. Likewise, in a subset of endothelial nitric oxide synthase (eNOS) deficient mice that develop BAV, expression of Wnt3a ligand and Lrp5 receptor is increased when the animals are fed a high cholesterol diet [178]. Cell culture studies also support the idea that Wnt/β-catenin signaling is important for VIC myofibroblast activation, proliferation, and chondrogenic gene induction. Studies in porcine aortic VICs show that Wnt3a treatment induces significant VIC proliferation and myofibroblast activation [173, 179]. Furthermore, Wnt3a treatment of embryonic chicken aortic VICs results in increased expression of
Diseased aortic valves are characterized by changes in the ECM; in particular, disorganized collagen bundles and extensive elastic fiber fragmentation are observed [181, 182]. Insight into the role of elastin fiber disorganization in the pathogenesis of CAVD has been provided through studies of elastin haploinsufficient mice, which display elastin fiber fragmentation, abnormal ECM remodeling, and increased valve stiffness, suggesting that elastin homeostasis is important for maintaining valve function [72, 183]. Collagen synthesis and remodeling are dramatically increased in CAVD, however, overall collagen content in the valve is actually decreased, suggesting that there is extensive collagen proteolysis during disease [184-186]. In contrast to collagens, expression of proteoglycans, including decorin, biglycan, versican, and hyaluronan, is increased particularly in regions of the diseased valve adjacent to calcific nodules [187]. These changes in ECM composition during CAVD can be compared to matrix remodeling events that occur during valve development and also in bone formation. The decreased collagen content and increased proteoglycan matrix found in CAVD is similar to the primitive ECM characteristic of early valve development [188]. Furthermore, parallels can also be drawn between matrix remodeling in CAVD and bone development. Specifically, matrix remodeling in the immature bone is essential for providing a scaffold upon which the calcified matrix is deposited, and subsequent ECM degradation is essential for expansion of the calcified regions of newly forming bone [189]. The parallels between matrix remodeling in bone development and the disease process of CAVD suggest that valve matrix remodeling may contribute to valvular calcification.
Matrix degradation and remodeling in valvulogenesis, osteogenesis, and CAVD occurs concomitant with increased activity of MMPs and cathepsins, along with increased RANKL signaling. A number of studies have shown significant increases in expression of multiple MMPs, including MMP1, MMP3, MMP7, MMP9, and MMP12, with increased cathepsins B, K, and S in human calcific diseased aortic valves, suggesting that extensive ECM remodeling is a key feature of disease [124, 163, 181, 182, 184, 190]. In bone, RANKL signals through the RANK receptor, which can be inhibited via binding to the soluble receptor OPG, and promotes the expression of proteolytic enzymes, such as MMPs and cathepsin K, through activation of NFATc1 [191, 192]. A similar mechanism has been identified in heart valve remodeling [47, 61]. Comparison of sclerotic diseased aortic valves and advanced stenotic aortic valves determined that OPG levels are significantly higher in sclerotic valves without calcification, whereas RANKL expression is higher in stenotic calcified valves [103, 193]. This study concluded that OPG may be protective against valve calcification, whereas elevated RANKL expression may promote valve calcification by promoting upregulation of matrix remodeling enzymes [103, 193]. Furthermore, treatment of human aortic VICs with RANKL results in increased MMP1 and MMP2 activity with increased VIC proliferation, concomitant with increased calcification and osteogenic gene expression [103, 191]. In addition, NFATc1 expression is increased in human explanted aortic valve leaflets with CAVD [106]. Together, these studies are consistent with signaling events during bone development, namely RANKL activation of NFATc1, stimulating matrix remodeling enzymes, and promoting calcification [192].
A number of other signaling pathways are likely involved in ECM changes that occur during CAVD. In particular, TGFβ1 stimulation of cultured VICs stimulates myofibroblast differentiation, leading to increased levels of αSMA stress fibers in the VICs [125, 172]. It has been suggested that these myofibroblasts then exert a contractile force on the surrounding valve ECM and stimulate rearrangement of the matrix, particularly in fibronectin fibers [125]. Furthermore, TGFβ1 stimulation also induces increased type I collagen production and expression of the matrix remodeling enzymes MMP9 and MMP2 in cultured aortic VICs [136, 172]. These studies indicate that TGFβ1 signaling may be a key factor in ECM-related changes during CAVD pathogenesis. Moreover, Wnt signaling may work in concert with TGFβ1 to induce changes in ECM during CAVD [173]. TGFβ1 stimulation promotes nuclear localization and activation of β-catenin in cultured VICs, and, when combined, Wnt and TGFβ1 signaling dramatically increases myofibroblast activation [173]. In contrast to TGFβ1 and Wnt signaling, FGF signaling may work to inhibit ECM remodeling during valve disease. FGF signaling has been shown to block TGFβ1 induced myofibroblast differentiation and αSMA expression in porcine aortic VICs through activation of phospho-ERK1/2 signaling [174]. In addition, FGF signaling inhibits myofibroblast contraction of a collagen matrix, supporting the idea that FGF signaling blocks TGFβ1 stimulation of matrix-related changes [174]. Many parallels exist between signaling factors involved in ECM changes in development and disease. In particular, RANKL, TGFβ1, Wnt, and FGF signaling have demonstrated roles in ECM production and regulation in both heart valve and endochondral bone formation [8, 76]. The shared signaling pathways in these tissues, both in development and disease, suggest that developmental pathways may be reactivated in CAVD to induce matrix changes characteristic of the disease.
Currently, aortic valve replacement surgery is the only effective treatment option for CAVD [122]. There have been numerous studies, which are summarized below, testing the effectiveness of different pharmacotherapies on preventing the progression of AS. Unfortunately, studies on statin therapies, inhibitors of the renin-angiotensin-aldosterone system, and osteoporosis treatments have not been proven to be effective at preventing the symptoms or the progression of CAVD/AS. Following the summary of these studies, additional treatment options, related to the expression of developmental and osteogenic-related genes in CAVD, are discussed.
Lipid deposition and the accumulation of apolipoproteins (Apo) in the aortic valve leaflets have long been associated with CAVD, and many studies have compared the progression of CAVD to atherosclerotic disease [119, 133, 134, 194]. Therefore, it has been hypothesized that cholesterol lowering therapy with statin drugs may be an effective treatment strategy to delay the progression of CAVD. A specialized mouse model called “Reversa” mice develop signs of CAVD when fed a high cholesterol diet, however, when serum cholesterol is lowered via a genetic deletion of the microsomal triglyceride transfer protein (Mttp), reduced levels of aortic valve calcification, as well as decreased expression of the osteogenic markers pSMAD1/5/8, Msx2, Osx, β-catenin, and Runx2, are observed [167, 170]. Thus reducing plasma cholesterol may reduce CAVD pathogenesis, particularly in terms of reducing osteogenic gene expression in the diseased valves. Similarly, statin treatment of human or porcine aortic VICs cultured concomitantly with osteogenic media results in decreased expression of the osteogenic genes ALP, OCN, Lrp5, and OPN, and reduced calcific nodule formation [171, 177, 195]. However, when statin treatment of aortic VICs is initiated after osteogenic transformation or calcific nodule formation, it is ineffective at reducing calcification and expression of osteogenic markers, indicating that statin therapy cannot reverse aortic valve calcification and osteogenic differentiation once it has occurred [195, 196]. Results from animal studies are equally contradictory. Rabbits fed a high cholesterol diet supplemented with atorvastatin have decreased aortic valve thickness, reduced VIC proliferation, and reduced expression of Lrp5, β -catenin, OPN,
Clinicial studies investigating the use of statin therapy in patients with CAVD are also widely contradictory. An early study investigating the use of statin therapy in patients with moderate to severe aortic stenosis (AS) reported that patients treated with statins had less hemodynamic progression of AS over a 2 year time period than patients who were not on statin therapy [198]. In contrast, three larger prospective clinical studies, SALTIRE (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression), SEAS (Simvastatin and Ezetimibe in Aortic Stenosis), and ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin), found that statin therapy was not effective at treating the progression of AS [199-201]. In these trials, three different statin therapies were investigated in patients with mild to moderate AS and it was determined that statin therapy did not alter the progression of CAVD/AS nor prevent outcomes such as the necessity to undergo aortic valve replacement surgery [199-201]. In response to the negative outcomes of these large clinical trials, the use of statin therapy was next investigated in patients with the earliest form of CAVD/AS, aortic valve sclerosis, to determine if statin use could prevent, rather than reverse, AS [202]. In this report, statin therapy was significantly associated with a decreased development of AS and a decreased need for aortic valve replacement surgery, suggesting that statin therapy may be an effective treatment if started at the earliest stages of the disease, prior to any indication of valve calcification [202]. Based on these studies, it can be concluded that in humans, statin therapy is ineffective at preventing the progression of AS and reversing aortic valve calcification. However, statin therapy may be useful at preventing the onset of AS in patients with the earliest stages of aortic valve thickening.
Another potential therapy to prevent the progression of CAVD/AS is the use of the anti-hypertensive angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Currently, ACEIs and ARBs are prescribed to treat hypertension, and function by acting on the renin-angiotensin-aldosterone system to ultimately inhibit the vasoconstrictor effects of angiotensin II [203]. Previous reports have identified the overlapping expression of angiotensin-converting enzyme (ACE) and angiotensin II in calcified human aortic valves surrounding regions of valvular calcification [133]. It has been hypothesized that ACE inhibition may prevent the progression of CAVD by reducing ACE activity in the diseased valve leaflet [204-206]. A study conducted in ApoE knockout mice with induced chronic renal failure concluded that animals treated with the ACEI enalapril had significantly reduced levels of pathologic aortic valve leaflet thickening and valve fibrosis than untreated animals [206]. Similarly, in a rabbit model of CAVD in which the animals were fed a high vitamin D diet, treatment with the ACEI ramipril significantly reduced the progression to AS, improved valve endothelial cell integrity, and reduced aortic valve calcification [205]. It is uncertain how ACE and angiotensin receptor (AR) inhibition would directly affect molecular changes in the valve leaflets. However, in a study of rabbits fed a high cholesterol diet, treatment with the ARB olmesartan decreased the number of α SMA positive myofibroblasts and reduced expression of the osteogenic markers
Clinical studies testing the therapeutic benefits of ACEIs and ARBs in CAVD progression have had mixed results. In human explanted aortic valve tissues, ARB therapy is associated with reduced aortic valve remodeling and calcification [207]. As in animal studies, this histological analysis suggests that AR inhibition may limit aortic valve calcification [207]. In a small pilot clinical study (Symptomatic Cardiac Obstruction – Pilot Study of Enalapril in Aortic Stenosis), use of the ACEI Enalapril was associated with improved clinical symptoms in patients with severe symptomatic AS [208]. The majority of studies investigating the use of ACEIs or ARBs in CAVD/AS with positive outcomes have been retrospective. In three different retrospective studies, ACEI or ARB use in patients with mild to moderate AS was associated with decreased mortality, decreased number of adverse cardiovascular events, slower progression of AS, and less accumulation of valvular calcification [209-211]. Additionally, one prospective study followed a small random population of patients over a 4-year period and reported that the use of ACEIs or ARBs was significantly associated with reduced CAVD/AS disease progression [212]. Together, these studies provide evidence that ACEI and ARB may delay CAVD progression. Conversely, there have also been a number of studies that show no association between ACEI and ARB use and improved outcomes in CAVD progression. The JASS study (Japanese Aortic Stenosis Study) reported that ARB therapy in patients with moderate to severe AS had no beneficial outcomes in CAVD progression, although patients with mild asymptomatic AS had some indication of reduced progression to AS [213]. Furthermore, a large study in patients with very mild asymptomatic AS found that patients on ACEI or ARB therapy had no improvement in the progression of AS compared against a control group [202]. Similarly, a small 2-year study observed no difference in the hemodynamic progression of AS with ACEI use versus non-use [198]. Based on both animal and clinical studies, it is unclear whether ACEI or ARB therapy is an effective treatment option to prevent the progression of CAVD/AS, however there are indications that perhaps this therapy may limit valve calcification [204, 207]. A placebo controlled, blinded trial will be necessary to determine the effectiveness of these therapies in treating CAVD.
Aldosterone is a component of the renin-angiotensin-aldosterone system that plays a key role in the kidney to regulate water and sodium reabsorption and effectively raise blood pressure [203]. Aldosterone-receptor antagonists (ARA) are commonly prescribed for their diuretic effects [203]. Recently, there have been two studies investigating the use of ARAs in the treatment of CAVD/AS. In an animal study, rabbits fed a high cholesterol diet develop aortic valve sclerosis, with thickening of the valve leaflets and microscopic calcific deposits, which was blocked by treatment with the ARA eplerenone [214]. In addition to reducing valve fibrosis and mineralization, evidence of macrophage infiltration was also reduced [214]. Conversely, in a small placebo-controlled human trial of patients with moderate to severe asymptomatic AS, there was no difference in the progression of AS in those patients receiving the ARA eplerenone versus placebo [215]. To our knowledge, no molecular evidence has been reported in studies on ARA therapy in CAVD and it is unknown whether ARA therapy affects myofibroblast activation or osteogenic gene induction. Additional clinical studies will be necessary to determine if ARA use can prevent AS progression if therapy is started in early disease stages.
Bisphosphonates (BP) are a class of drugs that mimic inorganic pyrophosphate and prevent ectopic soft tissue calcification and inhibit bone resorption [216]. In adults, especially women, BPs are commonly prescribed to treat excessive bone resorption associated with osteoporosis [216]. Human aortic VICs, grown on collagen gels in the presence of a specialized thiol bisphosphonate, have decreased ALP activity and reduced cellular aggregation, a step that precedes calcific nodule formation, as compared to cells grown on collagen alone [217]. This study suggests that bisphosphonates may inhibit VIC calcification in vitro and could serve as a potential therapeutic strategy to prevent aortic valve calcification [217]. Due to the ability of BPs to prevent ectopic calcification in bone and the availability of patient populations currently using BPs, a number of studies have investigated the use of BPs in the inhibition of aortic valve calcification. Three small retrospective human studies compared measurements of AS progression over a 2-year period in patients with AS taking BPs versus those not taking BPs [218-220]. The results of these studies suggest a modest reduction in the progression of AS in those patients taking BPs [218-220]. The large MESA study (Multi-Ethnic Study of Atherosclerosis) followed women taking BPs, compared to those not taking BPs, and their development of CAVD/AS over time [221]. The results of this study were mixed and showed that, in older women, BP therapy was associated with a slight benefit in terms of aortic valve calcification, whereas, younger women taking BPs had significantly more progression of aortic valve calcification compared to women not taking BPs [221]. Most recently, a large retrospective study investigated the progression of AS in women with mild to moderate AS over a 5-year period and compared the outcomes in patients on BP therapy versus those not taking BPs [222]. The evidence from this study shows that there was no change in survival, or in the number of aortic valve replacement surgeries, in women taking BPs compared to those not taking BPs, suggesting that BP therapy does not suppress the progression of CAVD/AS [222]. Thus far, the outcomes of the human studies investigating the use of bisphosphonate therapy in CAVD demonstrate that this therapy is ineffective at preventing or delaying the progression of CAVD/AS. To definitively determine whether or not BP therapy is effective at suppressing the progression of CAVD/AS, placebo-controlled prospective studies will be necessary.
Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO) from L-arginine, and eNOS expression has been identified in the endothelial cells lining the aortic valves [68]. eNOS deficiency has been linked to defective aortic valve development, as approximately 50% of eNOS deficient mice develop a bicuspid, rather than tricuspid, aortic valve [68]. eNOS deficient mice with a BAV phenotype fed a high cholesterol diet develop hemodynamic symptoms of AS and also display microscopic mineralization in the aortic valve leaflets, indicating that eNOS activity may be important for suppressing aortic valve calcification [178]. Nitric Oxide deficiency is also an indicator of endothelial cell dysfunction, and systemic endothelial cell dysfunction is prevalent in patients with aortic valve sclerosis/stenosis [223-225]. The uncoupling, or dysfunction, of eNOS results in decreased NO production and increased generation of reactive oxygen species (ROS) [223]. ROS activity is present in calcific lesions of human stenotic aortic valves, and it has been suggested that ROS activity may speed aortic valve calcification [144, 226]. In animal studies, rabbits fed a high cholesterol/high vitamin D diet develop aortic valve thickening, small deposits of valve calcification, and increased ROS activity in cells surrounding regions of valve calcification [226]. Furthermore, ROS activity was co-localized to clusters of cells expressing Runx2 and OPN, suggesting that ROS activity is associated with VICs displaying an osteogenic-like phenotype [226]. In VIC culture studies, TGFβ1 stimulation induces increased ROS activity, along with calcific nodule formation and ALP activity [227]. Increasing the availability of NO, via NO donors such as sodium nitroprusside, partially blocks both nodule formation and ALP activity, suggesting that NO levels are important for reducing ROS and inhibiting calcification in VICs [227]. There have been a number of small clinical studies investigating the levels of the NOS inhibitor, asymmetric dimethylarginine (ADMA), an indicator of endothelial cell dysfunction, in patients with moderate to severe AS [228-230]. In these studies, plasma levels of ADMA are significantly higher in patients with moderate to severe AS, compared to patients with mild AS or no disease, suggesting that NO production is disrupted in CAVD/AS [228-230]. Combined, these studies suggest that increased ROS production is associated with aortic valve calcification and the induction of osteogenic gene expression. Thus, increasing the bioavailability of NO may be a potential therapeutic avenue to block ROS activity, and thereby disease progression, in CAVD.
Previous reports have demonstrated that immune cell infiltration is common in CAVD [119, 132, 135]. Non-steroidal anti-inflammatory drugs (NSAIDS) are commonly used to treat pain and inflammation, and act by inhibiting the enzymes COX1 and/or COX2 [231-233]. These enzymes function by converting arachidonic acid to prostaglandins (PGs) [233, 234]. There has been one study conducted in human aortic VICs, demonstrating that stimulation of VICs with pro-inflammatory mimetics induces the expression of COX2 and the release of prostaglandins [235]. This study suggests that COX2 inhibition may be one way to treat the immune response associated with CAVD [235]. Interestingly, COX2 and PG signaling are also involved in bone formation as well as cellular responses to physical stress and strain, processes that also likely contribute to CAVD (reviewed in [131]). In bone, PG signaling has an anabolic effect, and PG treatment of osteoblast cultures results in increased expression of OCN, BMP2, Runx2, OPN, ALP, and BSP [236-244]. In osteoblast cultures, BMP2 stimulation induces COX2 expression through upregulation of Runx2, which binds to and activates the COX2 promoter [245, 246]. Downstream, PG signaling induces the expression of p38 MAPK through the activation of protein kinase A [243, 247]. Furthermore, fluid shear stress and other physical forces induce COX2 expression in osteoblast-like cells, suggesting that increased COX2 and PG signaling is a cellular response to altered mechanical forces [248, 249]. The combined results of these studies suggest that COX2/PG signaling may be an effective therapeutic target to treat CAVD progression, as COX2/PG signaling plays a role in inflammation, osteogenesis, and cellular response to physical strain, all of which are thought to be pathological mechanisms involved in CAVD [131, 243, 244, 248-251]. It would be interesting to determine whether COX2 inhibition/NSAID use could reduce CAVD progression. However, one caveat is that COX2 inhibitor therapy can be associated with some rare but significant adverse cardiovascular events such as myocardial infarction and stroke [252, 253]. Perhaps therapeutics designed toward downstream targets of PG signaling, such as p38 MAPK, could improve outcomes of CAVD patients without the cardiovascular side effects of selective coxibs [254].
As reviewed above, Notch, Wnt, and BMP signaling have been implicated in the progression of CAVD. Pharmacotherapies designed to act as Wnt and BMP inhibitors, or Notch agonists, could be a potential avenue for new therapeutics to treat the progression of CAVD. BMP signaling is thought to be a specific indicator of aortic valve calcification as active BMP signaling is observed in adult diseased valves with prominent calcification and is not found in pediatric diseased valves void of calcification [13]. Furthermore, BMP2 signaling stimulates VIC calcific nodule formation and induces osteogenic gene expression [138, 171]. It is possible that therapies designed to inhibit BMP signaling will block osteogenic-like calcification in diseased aortic valves. Likewise, inhibition of the Wnt/β-catenin signaling pathway may also serve to reduce aortic valve calcification during disease, which is supported by evidence from animal studies in ApoE knockout mice. When fed an atherogenic diet, ApoE knockout mice reportedly develop aortic valve calcification, however, when the Wnt co-receptor Lrp5 is genetically deleted in these mice, the amount of aortic valve calcification is significantly reduced [180]. Therefore, Wnt inhibition may be another potential therapeutic approach for treating CAVD. Lastly, strategies to maintain Notch signaling in the valves may be another potential way to inhibit calcification in CAVD. Notch inhibition of calcification and osteogenic gene expression has been demonstrated in aortic VICs in culture and reduced Notch signaling in vivo leads to CAVD in mice [65, 153, 175]. Furthermore, Notch1 haploinsufficiency in humans is associated with CAVD, indicating that maintaining Notch signaling is important for valve homeostasis [64]. Thus, therapeutic strategies designed to affect one or more of these pathways may serve to prevent valve calcification in CAVD. A potential limitation of this approach is that BMP, Wnt, and Notch signaling pathways are involved in many homeostatic and disease processes. For example, Wnt signaling is increased in many types of cancer, and all three pathways are involved in bone homeostasis. Therefore the development of therapeutics based on these molecular mechanisms must take into account potential effects on multiple organ systems. Nevertheless, targeted approaches based on these pathways could represent a new therapeutic avenue in the development of pharmacologic based approaches to CAVD.
There are numerous examples of shared molecular pathways between valvulogenesis, osteogenesis, and disease pathogenesis of CAVD. In valvulogenesis, signaling factors involved in early cushion formation, such as BMP, Notch, and Wnt/β-catenin pathways are active in osteogenesis and in CAVD [7-9, 14]. Furthermore, transcription factors expressed in the early valve mesenchyme, such as Twist1, Msx2, and Sox9, can also be found in the primitive condensed bone mesenchyme and in the mesenchymal-like cells identified in diseased aortic valve tissues [8, 13, 80, 255]. In addition to signaling and transcription factors, molecular pathways governing ECM production and remodeling, such as the RANKL – NFATc1 – CtsK pathway are shared amongst valve progenitor, developing bone, and diseased valve tissues [11, 47, 103, 106, 193]. This commonality suggests that the mesenchymal cells found within these tissues are governed by common molecular pathways and that these developmental pathways are reactivated during disease. Additional parallels can be drawn between calcification of the embryonic bone tissues and calcification observed in diseased aortic valves. For example, the endochondral bone factors Runx2, OCN, and BSP are reactivated during aortic valve disease, suggesting that osteogenic molecular pathways are activated during CAVD and may contribute to pathogenic calcification [5, 13, 76, 80, 106, 152]. Effective pharmacological therapies to treat CAVD remain elusive and identifying potential targets for new pharmacotherapies is a priority, as the only effective treatment for CAVD with AS is valve replacement surgery [256]. Studies testing the effectiveness of statin therapy, inhibitors of the renin-angiotensin-aldosterone, and bisphosphonates in slowing the progression of CAVD have been disappointing (see therapeutic section). New therapeutic strategies are needed and, perhaps, targeted inhibition of BMP and Wnt signaling or maintenance of Notch signaling may provide new avenues for potential CAVD treatments.
The use of managed western honey bee (
Even the intensive cultivation of the apple trees shows some problems from the point of view of pollination [27]. The intensification of cultivation has made the survival of local not managed pollinators difficult, especially where the cultivations reach great extents, while at the edge of the cultivated area, near the natural vegetation (woods or grasslands), not managed pollinators can easily satisfy the residual pollination needs. To support the pollination provided by wild pollinators in areas where these do not constitute stable and conspicuous populations, apple producers use the pollination service provided in general by the managed honey bee colonies. We used honey bee colony and beehive as synonyms even if this latter is formed by the colony of honey bees and the hive (box) that contains it.
\nCommercial pollination is a consolidated practice in Val di Non (North Italy), an alpine area specialized in intensive apple cultivation. In this area the pollination contract with the beekeepers is stipulated by the cooperatives to which the farmers confer apples for storage, processing, and marketing. The combined management of the pollination service allows to overcome the technical-economic limit deriving from the typical pulverization of the land structure of the local farms. In order to gather information about beekeepers who support the pollination of the apple orchards in Val di Non, a survey was conducted through a questionnaire. The survey was filled anonymously. Participants were asked questions about some technical-economic and apidological questions concerning mainly migratory beekeeping. The objective of the survey is twofold: on the one hand to verify if there are differences between the answers provided by small- and large-scale beekeeping operations on quantitative aspects, such as the level of bee colony losses in winter and the number of kilometers traveled annually, but also on qualitative aspects such as balancing of bee colonies and the propensity to ensure bee colonies, and on the other hand, to compare the results obtained with those of other surveys on beekeeping. Unfortunately, this comparison will remain confined to a few aspects because many questions we submit to beekeepers are lacking terms of comparison.
\nThe structure of this chapter is the following. After the presentation in Section 2 of the materials and methods of investigation, in Section 3 five economic and five apidological aspects considered worthy of attention will be briefly discussed, not all those considered in the questionnaire, to avoid that the analysis becomes too dispersive. The results obtained will be shown and briefly discussed in Section 4. Section 5 will present some proposals for the future of migratory beekeeping in Val di Non (but not only).
\nThe exploratory survey on beekeepers supporting apple pollination in Val di Non was conducted during the spring 2019 using a special questionnaire. Submitting questionnaires to the beekeepers to collect business information is a fairly common practice. The winter losses of bee colonies [28, 29], the pollination fees [30, 31], and the movement of bee colonies during the year [32, 33] have been surveyed with this instrument.
\nThe associated management of the pollination service in Val di Non facilitated the investigation; in fact, the cooperative managers contacted beekeepers to interview, distribute, and collect questionnaires. Beekeepers filled in a questionnaire with 20 questions: in some cases, the interviewee was asked to provide a dichotomous answer (yes/no) as shown in Table 1, Section 1; in other cases, the questions were multiple choice and the interviewee could choose between several pre-coded answers (Table 1, Section 2); in other cases, the answer was in an open form where the interviewee entered numeric data (Table 1, Section 3).
\n\n | Number of honey bee colonies | \n|||||
---|---|---|---|---|---|---|
\n | 1–80 | \n>80 | \nAll | \n|||
\n | Yes (%) | \nNo (%) | \nYes (%) | \nNo (%) | \nYes (%) | \nNo (%) | \n
Plans honey bee colony movements? | \n93.1 | \n6.9 | \n100. 0 | \n0.0 | \n95.2 | \n4.8 | \n
Interest in ensuring honey bee colonies? | \n63.3 | \n36. 7 | \n92.3 | \n7.7 | \n72.1 | \n27.9 | \n
Balance honey bee colonies? | \n93.3 | \n6.7 | \n100.0 | \n0.0 | \n95.3 | \n4.7 | \n
\n | \n% | \n|||||
Irrelevant | \n34.5 | \n46.2 | \n38.1 | \n|||
Low | \n41.4 | \n46.2 | \n42.9 | \n|||
Significant | \n24.1 | \n7.7 | \n19.0 | \n|||
\n | \n% | \n|||||
<5% | \n92.8 | \n74.6 | \n90.3 | \n|||
5–10% | \n3.6 | \n15.4 | \n7.3 | \n|||
>10% | \n3.6 | \n0.0 | \n2.4 | \n|||
\n | \n% | \n|||||
No | \n10.0 | \n8.3 | \n9.5 | \n|||
Low | \n30.0 | \n25.0 | \n28.6 | \n|||
High | \n60.0 | \n66.7 | \n61.9 | \n|||
\n | \n% | \n|||||
No | \n43.3 | \n38.5 | \n41.9 | \n|||
Yes | \n10.0 | \n30.7 | \n16.3 | \n|||
Do not know | \n47.7 | \n30.8 | \n41.8 | \n|||
Cost of feeding honey bees (€/colony) | \n21.1 | \n14.7 | \n19.1 | \n|||
Kilometers traveled per year | \n3538 | \n13,592 | \n6650 | \n|||
Winter honey bee colony losses (%) | \n12.5 | \n10.3 | \n11.9 | \n
Beekeepers replies to the questionnaire.
A total of 43 completed questionnaires were returned by the beekeepers. However, the number of valid answers varies from question to question. As a whole, the respondent beekeepers, given the stocking density average locally applied to apple orchards, provide almost half of the commercial pollination needs in the area under investigation.
\nThe commercial pollination of the apple orchards in Val di Non is always practiced at the beginning of the migration itinerary of the beekeepers of Northern Italy. In this period of the year, beekeepers are not able to provide data on the loss of honey bee colonies in summer and winter, on the average feeding cost of the honey bee colony. For these aspects, the questionnaire asked the beekeeper to refer to the situation of the previous year (2018) or the last two years or to indicate the expected value under normal conditions. The averages of the continuous variables and the percentages of the answers to the pre-coded questions were calculated. The statistical analyzes of the data collected with the questionnaire are placed, for the peculiarity of the questions set out and for the lack of information on the distribution of the variables, in the context of non-parametric statistics. To process the collected data, the R program, an open source programming language designed specifically for statistical analysis [34], was used. In order to ascertain the effect of the company size, beekeepers were divided into two groups based on the number of bee colonies they managed: a) up to 80 honey bee colonies; and b) more than 80 honey bee colonies.
\nMost apple cultivars require cross-pollination with a compatible pollinizer to increase apple tree yield and fruit quality. Some exceptions to this are the diploid varieties as Golden Delicious, the more cultivated in Val di Non. Although this variety is partially self-fruitful, it will produce better apples with cross-pollination by means of honey bees. This has been observed in Val di Non where, despite being close to vast areas of meadow and wood, the pollination action carried out by wild pollinators is sometimes limited due to the low temperatures of the flowering period. To get the maximum quality of apple production, it is necessary that pollination takes place at the first flowering phase, when 2–4% of the flowers of apple are open (first king flowers). The commercial pollination of the apple tree does not occur in Val di Non simultaneously because the local flowering periods of the apple orchards depend on the altitude and exposure and on the different varieties cultivated. Depending on the altitudinal level, at the same variety, the flowering window is about 14–18 days, while it’s between 5 and 8 days the period of beginning of flowering among the varieties grown on the same altitudinal plane. The honey bee colonies are distributed in orchards to be pollinated in small batches according to precise stocking density, which in the case of apple intensive cultivation is placed in the range 8 ± 4 honey bee colonies per batch. The optimal stocking density varies according to some parameters, in particular the varieties of apples locally grown (few varieties or multi-varieties). Even if one colony per hectare could generally be enough, it is advisable to distribute honey bee colonies at a rate of 1.5 per hectare. The permanence of honey bee colonies for pollination of apple orchards has a theoretical duration of 18 ± 2 days, generally included between the first week of April and May; operatively this period is greatly influenced by the weather pattern [35]. If the first phase of full flowering takes place with very favorable weather for the flight of honey bees, the hives can be transferred to the next site already after 7–10 days.
\nThe problem of the use of pesticides assumes in the case of the Val di Non and, more generally in the alpine territory, a particular connotation due to the blossoming of apple orchards that is strictly correlated to the variation of the elevation. In fact, it may happen that active honey bees on a site where apple orchards are in bloom and therefore pesticide treatments are not yet performed can reach apple orchards located at a lower elevation where the bloom is already over (or is considered such by growers), and therefore the treatments with pesticides have already started. The problem is aggravated by the presence of new apple plants which, especially in the first year of plantation, usually bloom 3–4 weeks later than the others. These young apple trees are often nearby or mixed (in rows) with productive ones and can after that receive pesticides while blooming.
\nThe apple growers of the Val di Non confer (with few exceptions) their production for the subsequent conservation, processing, and marketing to 16 cooperatives associated in turn in a Consortium. The area cultivated with apple trees from the 4000 producers associated with the cooperatives of the Val di Non extends over 6400 ha located at an altitude between 450 and 900 m above sea level (https://www.melinda.it/il-consorzio/il-consorzio.html). In the Val di Non, the average size of the apple orchards owned by single farmers is only 1.6 ha, and the land parcels are so small that they evoke the image of “patches of land.” The management of the pollination service at the farm level would be almost impossible, given that the flight of the honey bee exceeds 1 km and does not respect the boundaries of the land parcels. In these conditions, some farmers may behave as free riders, i.e., wait for others to implement their apple orchard pollination service and then benefit from it free of charge. Acting in this way would get the service without paying the fee; lastly, however, they would compromise, due to the reaction of those who paid for the service, the commercial pollination on the whole area (or almost) reaching a socially inefficient situation. The problem of the free rider found a solution in Val di Non thanks to the coordination function carried out by the farmer cooperatives. The latter, acting as territorial authority, organize the pollination service on behalf of their members: they decide the stocking density to be applied to the apple orchards, settle the payments to beekeepers who have provided honey bee colonies for hire, and divide the cost of the service among the producers in proportion to the pollinated surface. In some areas of the Val di Non, the commercial pollination service is managed by the land improvement consortium to replace the cooperative.
\nThe associated management of the pollination service generates a further economic advantage as it allows to contain the transaction costs [36]. The pollination contract is in fact stipulated by the cooperative without the direct involvement of thousands of farmers.
\nThe most significant economic aspects among those submitted to beekeepers with the questionnaire are the following:
If they plan the movements of honey bee colonies before the start of the migration route. This hypothesis, however plausible it may be, remains to this day unproven.
If they consider the robustness of the honey bee colonies to be relevant in determining the pollination fee of the apple orchards. The effectiveness of the pollination service depends critically to know if the beekeepers who support the pollination of the apple orchards in Val di Non are aware of the need to consider this factor in the calculation of the pollination fee of the commercial pollination service.
What is the average cost borne by the beekeeper for feeding the honey bee colony in order to obtain strong colonies early in the season. The data on the costs of big beekeeping operations for the year 2018 reported by Sumner and Champetier [37] show that the cost of the food purchased suffered a very strong increase compared to 1976.
How many kilometers the beekeeper travels to manage the movements of his bee colonies; this is a significant aspect for measuring the migratory footprint of the beekeeper.
Whether the beekeeper is interested in securing his honey bee colonies. This is an economic aspect of primary importance. In the last few decades, the role of insurance has grown enormously in many productive sectors of alpine agriculture, especially in those afflicted by adverse climatic conditions or plant diseases. Surprisingly, in apiculture the insurance instrument has not found wide applications (at least in Italy) although the effects of climatic adversities have become increasingly evident in the last few years.
The intensification of apple cultivation, even in the Val di Non, has made the survival of local not managed pollinators difficult due to the drastic reduction of the flora capable of supplying pollen and nectar, for the reduction of nesting and overwintering sites for some bees and even more for the use of agrochemicals. The presence of not managed Apoidea is generally very scarce in intensively cultivated areas. Stable populations of Apoidea and other wild pollinators are present only in areas adjacent to meadows, pastures, and forests [38]. However, these populations provide a limited contribution because they have normally reduced mobility, not exceeding 80–100 m of home range. Since the cultivation of the apple tree in Val di Non follows linearly the path of the Noce river forming on the two sides of the river strips of variable width often fragmented by areas of natural vegetation, the presence of not managed pollinators in apple orchards is closely related to their ability to reach them from adjacent areas that depends on the width of these strips. The immediate implication of the peculiar apple orchard cultivation configuration in Val di Non, in relation to the management of the commercial pollination service, is that the stocking density to be applied is not uniform but varies according to the need for integration of “natural” pollination. The choice of stocking density to be applied in order to optimize the pollination of the apple orchards must carefully consider the level of robustness of the honey bee colonies. In fact, the pollination potential of the honey bee colonies depends both on the number of foraging bees as well as on their health status. Each bee is able to make 3–10 daily flights, during which it can visit up to 3000 flowers [39]. Since the health status is difficult to estimate quickly and economically, the pollination contract is limited to prescribing, if provided, the minimum strength (population) of the colonies quantified on the basis of the number of “inhabited” frames/combs.
\nAt the beginning of the spring season, i.e., at the end of the wintering period, honey bee colonies have a poor robustness, and beekeepers must reinforce them with artificial preventive nutrition or enter the market to buy colonies or brood combs. Among the apidological aspects submitted to beekeepers in the questionnaire, the following are the most relevant:
If they proceed to balance the colonies of honey bees before the pollination of the apple orchards.
What is the percentage of losses of bee colonies found in the winter rest period 2017/2018 and 2018/2019.
What is the percentage of losses of bee colonies found in the summer period 2017/2018 and 2018/2019, classifying it as follows: less than 5%, between 5 and 10%, and over 10%.
If they consider that the concentration of bee colonies in the area to be pollinated facilitates the spread of diseases and parasites among bees.
If the use of commercial hybrids (i.e., the so-called Buckfast bees) constitutes an opportunity. Commercial hybrids offer opportunities for their great vigor, for the production of abundant broods, and for the consequent formation of populous honey bee colonies, but they carry with them the risk of not reaching the robustness of the colonies themselves at the beginning of the productive season. Commercial hybrids, strongly selected for the production of honey, find hard to develop their colonies in the early stages of the production season when they are used for pollination of crops.
The responding beekeepers manage on average 93.3 honey bee colonies. Thirty beekeepers have less than 80 honey bee colonies with an average of 27.9. The remaining 13 beekeepers with more than 80 honey bee colonies have an average of 244.2. All beekeepers with less than 80 honey bee colonies have their headquarters in the local area, specifically in the Trentino-Alto Adige region, while the remaining 13 come from other Italian regions. It follows that the size classes and the classes of origin coincide. Overall, the responding beekeepers have in total 4011 honey bee colonies; those from outside the region have only 3175 colonies that are almost 80% of the total number. The “local” beekeepers therefore prevail numerically over the others, but they are minority in terms of colonies of honey bees possessed.
\nWith regard to the economic aspects (see Table 1, Section 1), a clear majority percentage (95.2%) of the responding beekeepers declares that they plan the migration itinerary ex ante. The percentage reaches 100% for the beekeeper with over 80 honey colonies. This result supports the basic assumption of the model of the migratory beekeeper on the planning of the movement sequence at the beginning of the year.
\nMost beekeepers (61.9%) believe that the strength of the honey bee colony should affect highly the pollination fee paid for pollination of the apple tree (see Table 1, Section 2). This percentage is low compared to the importance attributed to balancing the honey bee colonies; it could be distorted due to the convenience of beekeepers with less robust honey bee colonies to declare the parameter irrelevant.
\nThe distance traveled by beekeepers takes into account not only the movements of bee colonies but also the visits to apiaries located at various sites during the season. Responding beekeepers traveled (see Table 1, Section 3) an average of 6650 km during 2018 (both for pollination services and honey production). The distance traveled by beekeepers with less than 80 honey bee colonies is much lower, being on average 3538 km. Beekeeper with more than 80 colonies traveled an average of 13,592 km during 2018. The greater distance traveled by beekeepers belonging to the latter size class finds an easy explanation in their origin from outside the region and in their farm size. The reduced number of kilometers traveled by beekeepers with less than 80 honey bee colonies shows that these beekeepers have a weak migration footprint.
\nThe average annual cost for the honey bee colony feeding stands at 19.1 €/colony, being higher for beekeepers with less than 80 colonies (21.1 €/colony) and minor (14.7 €/colony) for those with a higher number. It is surprising that the big beekeeping operations have a lower average cost for feeding the colony than the small ones. The first possible explanation of the difference is the amount of food provided to honey bees, and the second one is that beekeepers with less than 80 colony pay a higher price because they buy smaller quantities.
\nIn total 72.1% of beekeepers declare an interest in securing honey bee colonies being the 92.3% within the beekeepers belonging to the class with more than 80 colonies. This high percentage is a good starting point to implement an insurance strategy suitable on the needs of beekeepers.
\nRegarding the apidolological aspects, almost all (95.3%) the responding beekeepers balance their honey bee colonies before the apple pollination service. The percentage reaches 100% for beekeepers with more than 80 colonies.
\nThe losses of honey bee colonies suffered in the winter period in the 2-year period 2017/2018 and 2017/2019 amounted to the average of 11.9% (see Table 1, Section 3). This is a lower percentage than that documented by the Coloss survey [29] for European beekeepers, which reached an average of 16.4% during winter 2017/2018 with variations from 2.0 to 32.8% between countries. Beekeepers with a number of colonies greater than 80 undergo winter losses that are lower in percentage (10.3%) than in those with a lower number of colonies (12.5%). This result is aligned with that of the Coloss survey.
\nThe losses of honey bee colonies suffered by beekeepers during the productive, summertime period, with few exceptions, are less than 5% in the area under investigation (seeTable 1, Section 2). The overall average loss of honey bee colonies during the 2-year period considered therefore remains less than 16.9%.
\nOnly 19% of interviewed beekeepers consider the risk of spread of honey bee diseases as significant due to the movement and the subsequent concentration of honey bee colonies. This risk is considered irrelevant or low by 92.4% of beekeepers with more than 80 honey bee colonies.
\nTo the question of whether commercial hybrids represent an opportunity, the answers “do not” and “don’t know” are on a par with 41.9 and 41.8%. Only 16.3% of beekeepers believe that commercial hybrids are an opportunity. However, the answers to this question are very different in the two size classes. 30.7% of beekeepers with more than 80 honey bee colonies compared to a meager 10.3% of beekeepers of the other size class believe that commercial hybrids are an opportunity. 47.7% of beekeepers with less than 80 bee colonies and 30.8% of the other size class do not know how to answer this question, demonstrating their lack of knowledge of the subject.
\nThe survey carried out using the questionnaire highlighted some interesting differences between migratory beekeeping implemented in the Val di Non for pollination of apple orchards and the pollination service conducted in other beekeeping contexts such as the USA. The major differences concern the average annual cost for the honey bee colony feeding, the risk of spread of honey bee diseases, and the losses of honey bee colonies suffered in the winter period. These differences derive both from the specific morphological and climatic conditions of the Val di Non and from the main address and the size of the beekeeping operations involved in the pollination service. The Val di Non is a typical alpine valley where the apple orchards are of small extension and the altitudinal variability generates a straightness of blooms. It is therefore necessary to move the honey bee colonies from one site to the next one in rapid succession, and this obviously favors small- and medium-sized, more flexible, and dynamic beekeeping operations.
\nThe average annual cost for the honey bee colony feeding stands in Val di Non at 19.1 €/hive, a value much lower than that reported by Sumner and Champetier [37], equal to 50.21 $/hive, referred, however, to large-scale commercial migratory beekeepers (1000 hive operation) from California. The differences between the two contexts make the data for the cost for the honey bee colony feeding difficult to compare even if they refer to the same year (2018). The small size of beekeeping operations that support the commercial pollination of apple orchards in Val di Non probably favors greater efficiency in the management of honey bee colonies, and, on the other hand, the main production address (honey production) does not allow the use of large artificial feeds before the production season, in order not to contaminate the honey product with noncompliant sugars and not to stimulate swarming.
\nAlmost all the beekeepers that support the commercial pollination of the apple orchards in Val di Non balance their honey bee colonies before the apple pollination. Beekeeping in North America, in particular that aimed at the large-scale pollination service, does not provide for colony balancing, but on the contrary, these, kept in hives of different conception, are divided before the migration. The most common hives used by North American beekeepers are multi-nest body Langstroth hives, while in Italy the most common ones are the Dadant-Blatt hives with single nest body. With these hives the balancing and moderate feeding of the honey bee colonies before their displacement in cultivated agricultural areas are normal in Italy in order to anticipate their demographic development and after that to better perform pollination and honey production.
\nThe risk of spread of honey bee diseases due to the concentration of honey bee colonies is considered irrelevant by beekeepers interviewed above all by those who have more than 80 honey bee colonies. It is a result in contrast with the resonance that this problem has aroused in the USA and Australia. Most likely, the concentration of a few thousand bee colonies in an area of about 6000 ha that develops linearly along the two sides of the Val di Non is not perceived by the responding beekeepers as a real risk of spread of honey bee diseases.
\nThe losses of honey bee colonies suffered in the winter period in the 2-year period 2017/2018 and 2017/2019 assumes a lower average value than that documented by the Coloss survey [33] for European beekeepers. Winter losses are lower in percentage for the large-scale beekeeping operations than in those with a higher number of colonies. The greater distance traveled annually by large beekeeping operations for the transfer of honey bee colonies between forage sites therefore does not exercise the feared negative effect in the opinion of beekeepers who support pollination of the apple orchards in Val di Non.
\nThe pollination of the apple orchards in Val di Non has peculiar characteristics that make it a case of study: the orography and landscape structure could favor the integration between “natural” pollination and “managed pollination”; pollination of apple orchards is managed in a cooperative manner and not by each farmer; and the pollination of the apple tree is also supported by the honey bee colonies managed by small local beekeepers not contractually involved in the pollination service.
\nAmong the economic and apidological aspects covered by the survey on beekeepers who operate the apple pollination service in Val di Non, two deserve to be highlighted for their immediate operational implications:
The robustness of the honey bee colonies is considered, by the majority of interviewed beekeepers, a parameter that must have a large impact on pollination fee, and therefore apple tree pollination service contracts should include clauses that subordinate the level of pollination fee to the robustness of honey bee colonies.
The high propensity of the responding beekeepers to ensure their honey bee colonies are the prerequisite for pushing insurance companies to place on the market “cutoff” policies on the needs of beekeepers, in particular for the coverage of risks of honey bee colony losses and of honey production reduction.
Regarding the future of apple orchard pollination in Val di Non (and not only), it is to be hoped that the value of unmanaged pollinators will be enhanced by means of an integrated crop pollination strategy [40] that includes the protection of plant biodiversity also in agroecosystems and the protection of sensitive sites in view of the reproduction of wild pollinators.
\nNo conflict of interest.
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\n\nTo view current Open Access book projects that are Open for Submissions visit us here.
\n\nNot sure if this is the right publishing option for you? Feel free to contact us at book.department@intechopen.com.
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It is a statistical process that transforms the data containing correlated features into a set of uncorrelated features with the help of orthogonal transformations. Unsupervised machine learning is a concept of self-learning method that involves unlabelled data to identify hidden patterns. PCA converts the data features from a high dimensional space into a low dimensional space. PCA also acts as a feature extraction method since it transforms the ‘n’ number of features into ‘m’ number of principal components (PCs; m < n). Mobile Malware is increasing tremendously in the digital era due to the growth of android mobile users and android applications. Some of the mobile malware are viruses, Trojan horses, worms, adware, spyware, ransomware, riskware, banking malware, SMS malware, keylogger, and many more. To automate the process of detecting mobile malware without human intervention, machine learning methods are applied to discover the malware more precisely. 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As such, we expected salient properties of volatile jumps on the written products/contracts. We found that insurance claims for general insurance quoted products cease to be normal. There exist at times some jumps, especially during holidays and weekends. Such jumps are not healthy to the capital structures of firms, as such they need attention. However, it should be noted that gaps or jumps (unless of specific forms) cannot be hedged by employing internal dynamic adjustments. This means that, jump risk is non-diversifiable and such jumps should be given more attention.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Leonard Mushunje, Chiedza Elvina Mashiri, Edina Chandiwana and Maxwell Mashasha"},{id:"81645",title:"Determining an Adequate Number of Principal Components",slug:"determining-an-adequate-number-of-principal-components",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104534",abstract:"The problem of choosing the number of PCs to retain is analyzed in the context of model selection, using so-called model selection criteria (MSCs). For a prespecified set of models, indexed by k=1,2,…,K, these model selection criteria (MSCs) take the form MSCk=nLLk+anmk, where, for model k,LLk is the maximum log likelihood, mk is the number of independent parameters, and the constant an is an=lnn for BIC and an=2 for AIC. The maximum log likelihood LLk is achieved by using the maximum likelihood estimates (MLEs) of the parameters. In Gaussian models, LLk involves the logarithm of the mean squared error (MSE). The main contribution of this chapter is to show how to best use BIC to choose the number of PCs, and to compare these results to ad hoc procedures that have been used. Findings include the following. These are stated as they apply to the eigenvalues of the correlation matrix, which are between 0 and p and have an average of 1. For considering an additional PCk + 1, with AIC, inclusion of the additional PCk + 1 is justified if the corresponding eigenvalue λk+1 is greater than exp−2/n. For BIC, the inclusion of an additional PCk + 1 is justified if λk+1>n1/n, which tends to 1 for large n. Therefore, this is in approximate agreement with the average eigenvalue rule for correlation matrices, stating that one should retain dimensions with eigenvalues larger than 1.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Stanley L. Sclove"},{id:"81542",title:"On the Use of Modified Winsorization with Graphical Diagnostic for Obtaining a Statistically Optimal Classification Accuracy in Predictive Discriminant Analysis",slug:"on-the-use-of-modified-winsorization-with-graphical-diagnostic-for-obtaining-a-statistically-optimal",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.104539",abstract:"In predictive discriminant analysis (PDA), the classification accuracy is only statistically optimal if each group sample is normally distributed with different group means, and each predictor variance is similar between the groups. This can be achieved by accounting for homogeneity of variances between the groups using the modified winsorization with graphical diagnostic (MW-GD) method. The MW-GD method involves the identification and removal of legitimate contaminants in a training sample with the aim of obtaining a true optimal training sample that can be used to build a predictive discriminant function (PDF) that will yield a statistically optimal classification accuracy. However, the use of this method is yet to receive significant attention in PDA. An alternative statistical interpretation of the graphical diagnostic information associated with the method when confronted with the challenge of differentiating between a variable shape in the groups of the 2-D area plot remains a problem to be resolved. Therefore, this paper provides a more comprehensive analysis of the idea and concept of the MW-GD method, as well as proposed an alternative statistical interpretation of the informative graphical diagnostic associated with the method when confronted with the challenge of differentiating between a variable shape in the groups of the 2-D area plot.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Augustine Iduseri"},{id:"81471",title:"Semantic Map: Bringing Together Groups and Discourses",slug:"semantic-map-bringing-together-groups-and-discourses",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.103818",abstract:"This chapter presents a multivariate analysis method which is developed in two steps using a combination of Hierarchical cluster analysis (HCA) and Factorial Correspondence Analysis (AFC). To explain and describe the steps of the method, we use an application example on a survey dataset from young students in Thessaloniki trying to investigate their behavioral profiles in terms of political characteristics and how these may be affected about their attendance to a civic education course offered by the Political Science department in the Aristotle University of Thessaloniki. The method is explained step by step on this example serving as a manual of its application to the researcher. HCA assigns subjects into cluster membership variables and in the next stage, these new variables are jointly analyzed with AFC. Correspondence analysis manages to extract the dimensions of the phenomenon in the study, explaining the inner antithesis between the categories but also giving the opportunity to visualize the information in a two-dimensional space, a semantic map, making interpretation more comprehensive. HCA is then applied again to the AFC’s coordinates of the categories constructing profiles of subjects, assigning them to the categories of the variables.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Theodore Chadjipadelis and Georgia Panagiotidou"},{id:"81460",title:"Spatial Principal Component Analysis of Head-Related Transfer Functions and Its Domain Dependency",slug:"spatial-principal-component-analysis-of-head-related-transfer-functions-and-its-domain-dependency",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104449",abstract:"In this chapter, the Principal Component Analysis (PCA) was adopted to spatial variation of Head-Related Transfer Function (HRTF) or its corresponding inverse Fourier Transform, called Head-Related Impulse Response (HRIR), in order to compactly represent their spatial variation. This is called the Spatial PCA (SPCA). The SPCA was carried out for a database of HRTFs in all directions by selecting the domain as one of the HRIRs, the complex HRTFs, the frequency amplitudes of HRTFs, log-amplitudes of HRTFs, and complex logarithm of HRTFs. The minimum phase approximation was incorporated for the frequency amplitudes and log-amplitudes of HRTFs. Comparison of the accuracies in both time and frequency domains taking into account their influence on subjective evaluation showed that the log-amplitudes and complex logarithm of HRTFs are suitable for the SPCA of HRTFs.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Shouichi Takane"}],onlineFirstChaptersTotal:18},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:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",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:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"July 5th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:9,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,annualVolume:11418,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,annualVolume:11419,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,annualVolume:11422,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"27",title:"Multi-Agent Systems",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",isOpenForSubmission:!0,annualVolume:11423,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. Barderas",slug:"oxidative-stress-in-cardiovascular-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}}]},overviewPagePublishedBooks:{paginationCount:33,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. 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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. 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Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"17",type:"subseries",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11413,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. 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