Sequence similarities of human nerve tissue proteins with human virulent factors. Multiple alignments obtained in a single BLAST search could result in identities of the amino acids or substitutions of the amino acids in the same peptide region.
\r\n\tAnimal food additives are products used in animal nutrition for purposes of improving the quality of feed or to improve the animal’s performance and health. Other additives can be used to enhance digestibility or even flavour of feed materials. In addition, feed additives are known which improve the quality of compound feed production; consequently e.g. they improve the quality of the granulated mixed diet.
\r\n\r\n\tGenerally feed additives could be divided into five groups:
\r\n\t1.Technological additives which influence the technological aspects of the diet to improve its handling or hygiene characteristics.
\r\n\t2. Sensory additives which improve the palatability of a diet by stimulating appetite, usually through the effect these products have on the flavour or colour.
\r\n\t3. Nutritional additives, such additives are specific nutrient(s) required by the animal for optimal production.
\r\n\t4.Zootechnical additives which improve the nutrient status of the animal, not by providing specific nutrients, but by enabling more efficient use of the nutrients present in the diet, in other words, it increases the efficiency of production.
\r\n\t5. In poultry nutrition: Coccidiostats and Histomonostats which widely used to control intestinal health of poultry through direct effects on the parasitic organism concerned.
\r\n\tThe aim of the book is to present the impact of the most important feed additives on the animal production, to demonstrate their mode of action, to show their effect on intermediate metabolism and heath status of livestock and to suggest how to use the different feed additives in animal nutrition to produce high quality and safety animal origin foodstuffs for human consumer.
",isbn:"978-1-83969-404-2",printIsbn:"978-1-83969-403-5",pdfIsbn:"978-1-83969-405-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8ffe43a82ac48b309abc3632bbf3efd0",bookSignature:"Prof. László Babinszky",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10496.jpg",keywords:"Technological Feed Additives, Feed Industry, Quality of Compound Feed, Non-Antibiotic Growth Promoter, Product Quality, Additive Enzymes, Digestibility of Nutrients, NSP Enzymes, Farm Animals, Livestock, Immunity, Microbiome",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 24th 2020",dateEndSecondStepPublish:"December 22nd 2020",dateEndThirdStepPublish:"February 20th 2021",dateEndFourthStepPublish:"May 11th 2021",dateEndFifthStepPublish:"July 10th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Professor Emeritus from the University of Debrecen, Hungary who authored 297 publications (papers, book chapters) and edited 3 books. Member of various committees and chairman of the World Conference of Innovative Animal Nutrition and Feeding (WIANF).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.jpg",biography:"László Babinszky is Professor Emeritus of animal nutrition at the University of Debrecen, Hungary. From 1984 to 1985 he worked at the Agricultural University in Wageningen and in the Institute for Livestock Feeding and Nutrition in Lelystad (the Netherlands). He also worked at the Agricultural University of Vienna in the Institute for Animal Breeding and Nutrition (Austria) and in the Oscar Kellner Research Institute in Rostock (Germany). From 1988 to 1992, he worked in the Department of Animal Nutrition (Agricultural University in Wageningen). In 1992 he obtained a PhD degree in animal nutrition from the University of Wageningen.He has authored 297 publications (papers, book chapters). He edited 3 books and 14 international conference proceedings. His total number of citation is 407. \r\nHe is member of various committees e.g.: American Society of Animal Science (ASAS, USA); the editorial board of the Acta Agriculturae Scandinavica, Section A- Animal Science (Norway); KRMIVA, Journal of Animal Nutrition (Croatia), Austin Food Sciences (NJ, USA), E-Cronicon Nutrition (UK), SciTz Nutrition and Food Science (DE, USA), Journal of Medical Chemistry and Toxicology (NJ, USA), Current Research in Food Technology and Nutritional Sciences (USA). From 2015 he has been appointed chairman of World Conference of Innovative Animal Nutrition and Feeding (WIANF).\r\nHis main research areas are related to pig and poultry nutrition: elimination of harmful effects of heat stress by nutrition tools, energy- amino acid metabolism in livestock, relationship between animal nutrition and quality of animal food products (meat).",institutionString:"University of Debrecen",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Debrecen",institutionURL:null,country:{name:"Hungary"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"25",title:"Veterinary Medicine and Science",slug:"veterinary-medicine-and-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"185543",firstName:"Maja",lastName:"Bozicevic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/185543/images/4748_n.jpeg",email:"maja.b@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:"7144",title:"Veterinary Anatomy and Physiology",subtitle:null,isOpenForSubmission:!1,hash:"75cdacb570e0e6d15a5f6e69640d87c9",slug:"veterinary-anatomy-and-physiology",bookSignature:"Catrin Sian Rutland and Valentina Kubale",coverURL:"https://cdn.intechopen.com/books/images_new/7144.jpg",editedByType:"Edited by",editors:[{id:"202192",title:"Dr.",name:"Catrin",surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],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:"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:"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:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.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:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],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:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57607",title:"Bioinformatics as a Tool to Identify Infectious Disease Pathogen Peptide Sequences as Targets for Antibody Engineering",doi:"10.5772/intechopen.71011",slug:"bioinformatics-as-a-tool-to-identify-infectious-disease-pathogen-peptide-sequences-as-targets-for-an",body:'\nBioinformatics is the application of techniques derived from disciplines such as applied mathematics, computer science, and statistics to analyze and interpret biological data. In this chapter, you will learn how to use bioinformatic techniques to identify pathogen virulence factor (VF) peptide sequence similarities to human nerve tissue proteins and then how to identify target peptides that could form the basis for engineering recombinant antibodies. Also, wet experiments could be conducted on the identified overlapping sequences to help us to single out target antibodies to be tested for tissue culture studies [1, 2]. The most ideal targeted peptide sequences for antibody engineering are those physiologically relevant, easy to access, and comprise amino acid sequence regions which have high specificity in pathogenic steps and reduced amino acid string length.
\nThe accessibility to the extensive genomic and proteomic databases and the availability of tools to compare and evaluate the information have given rise to a new interdisciplinary field that combines biology and computer science [3]. Bioinformatics conceptualizes physical and chemical biology in terms of macromolecules and then applies “informatics” techniques (derived from disciplines such as applied mathematics, computer science, and statistics) to assimilate and organize the information associated with these molecules, on a large scale [4]. Bioinformatics is an exciting and exploratory method for peptide discovery in antibody engineering and development of antimicrobial therapies and vaccination strategies [5].
\nThere is significantly growing evidence that a number of neurodegenerative diseases are a result of the association of host cell proteins with viral and bacterial infectious agents [6]. When pathogenic micro organisms such as bacteria, viruses, parasites, or fungi cause an infectious disease, there are many molecular interactions between the host-pathogen proteins and host peptides [7] through all the stages of the disease whether incubation, prodromal illness, decline, and convalescence. There is much experimental evidence identifying the virulence factors (VF) of pathogen and host components such as receptors and tissue-specific proteins [8, 9]. Though the pathogenic pathway of the infectious agent in various host tissues is unknown, many of these processes are suspected to be attributable to the yet undiscovered role of molecular mimics identified in pathogenic microorganisms and its corresponding host tissue proteins. The sequence and structural similarities between the pathogenic VF protein and nerve peptides could impact either directly or indirectly the pathogenesis of the infectious disease [10, 11, 12]. It could contribute to molecular mimicry, steric hindrance, receptor binding, cell signaling, and autoantibody production events (involved in neuro degeneration) in the host.
\nLeprosy patients with peripheral nerve damage develop autoimmunity to myelin P0 (nerve protein). The above conclusion was drawn by gathering known scientific evidence that are as follows: (1) labeling and binding studies found that Mycobacterium leprae (bacterium causing leprosy) binds to myelin P0 [13]; (2) clinical studies confirmed the production of autoantibodies as a response of the bacterium to interact with myelin P0 [14, 15]; and (3) bioinformatics searches identified sequences and structural similarities between M. leprae and the immunoglobulin regions of myelin P0 [16].
\nIdentification of molecular mimics in pathogen-host peptide sequences is one approach to identify target peptides for antibody engineering. There are about 180 extensive biological databases to retrieve information on sequence and functional aspects of biological molecules. The updated list is available in Nucleic Acids Research [17].
\nThis section teaches you how to conduct a search for proteins present in a target host, how to obtain its amino acid sequence/s from the existing databases, how to compare the sequence/s of the host protein to that of the pathogen protein, and finally how to interpret the results based on existing evidential data. In our case study, we identify the virulence factor peptide sequence similarities of a few selected infectious agents with human nerve tissue proteins for selecting peptides to engineer antipeptide antibodies which recognizes corresponding host/viral proteins.
\n63 proteins were extracted from the Human Protein Atlas Database that were enriched and enhanced in the nervous tissue as observed by immunehistochemistry (Figure 1).
\nTo conduct a search for human proteins in the nervous tissue, access the website (
Conducting a search on the Human Protein Atlas Database.
Manual protein selection was carried out based on their tissue expression (enriched and enhanced) and also on immunohistochemistry evidence (Figure 2).
\nConducting an advanced search on the Human Protein Atlas Database.
The list of selected proteins are as follows: agrin (AGRN_HUMAN, O00468), calbindin (CALB1_HUMAN, P05937), n-chimaerin (CHIN_HUMAN, P15882), secretogranin-2 (SCG2_HUMAN, P13521), neuromodulin (NEUM_HUMAN, P17677), kinesin (KIFC1_HUMAN, Q9BW19), tau (TAU_HUMAN, P10636), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CN37_HUMAN, P09543), myelin-associated glycoprotein (MAG_HUMAN, P20916), myelin P0 (MYP0_HUMAN, P25189), myelin P2 (MYP2_HUMAN, P02689), oligodendrocyte-myelin glycoprotein (OMGP_HUMAN, P23515), brain-derived neurotrophic factor (BDNF_HUMAN, P23560), ciliary neurotrophic factor (CNTF_HUMAN, P26441), neurotrophin-3 (NTF3_HUMAN, P20783), beta-nerve growth factor (NGF_HUMAN, P01138), nestin (NEST_HUMAN, P48681), neurofilament heavy polypeptide (NFH_HUMAN, P12036), neurogranin (NEUG_HUMAN, Q92686), voltage-dependent T-type calcium channel subunit alpha-1G (CAC1G_HUMAN, O43497), hippocalcin (HPCL1_HUMAN, P37235), neurocalcin-delta (NCALD_HUMAN, P61601), recoverin (RECO_HUMAN, P35243), bombesin receptor subtype-3 (BRS3_HUMAN, P32247), kininogen-1/bradykinin (KNG1_HUMAN, P01042), calcitonin (CALC_HUMAN, P01258), cholecystokinin (CCKN_HUMAN, P06307), galanin peptides (GALA_HUMAN, P22466), pro-neuropeptide Y (NPY_HUMAN, P01303), neurotensin/neuromedin N (NEUT_HUMAN, P30990), protein S100-B (S100B_HUMAN, P04271), synapsin-1 (SYN1_HUMAN, P17600), probable tubulin polyglutamylase (TTLL1_HUMAN, O95922), myelin basic protein (MBP_HUMAN, P02686), protein phosphatase 1 regulatory subunit 1B (PPR1B_HUMAN, Q9UD71), Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2_HUMAN, Q99490), cathepsin L2 (CATL2_HUMAN, O60911), D(1A) dopamine receptor (DRD1_HUMAN, P21728), BDNF/NT-3 growth factors receptor (NTRK2_HUMAN, Q16620), melanoma-associated antigen E1 (MAGE1_HUMAN, Q9HCI5), microtubule-associated protein 6 (MAP6_HUMAN, Q96JE9), protocadherin alpha-12 (PCDAC_HUMAN, Q9UN75), carboxypeptidase E (CBPE_HUMAN, P16870), Down syndrome cell adhesion molecule (DSCAM_HUMAN, O60469), dyslexia-associated protein KIAA0319 (K0319_HUMAN, Q5VV43), uncharacterized protein KIAA1211-like (K121L_HUMAN, Q6NV74), microtubule-associated protein 1B (MAP1B_HUMAN, P46821), neuronal calcium sensor 1 (NCS1_HUMAN, P62166), neurofilament light polypeptide (NFL_HUMAN, P07196), receptor expression-enhancing protein 2 (REEP2_HUMAN, Q9BRK0), secretogranin-3 (SCG3_HUMAN, Q8WXD2), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL_HUMAN, P09936), galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 (B3GA1_HUMAN, Q9P2W7), beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GN1_HUMAN, Q00973), caprin-2 (CAPR2_HUMAN, Q6IMN6), dopamine beta-hydroxylase (DOPO_HUMAN, P09172), FAM81A (FA81A_HUMAN, Q8TBF8), mitogen-activated protein kinase 10 (MK10_HUMAN, P53779), N-terminal EF-hand calcium-binding protein 1 (NECA1_HUMAN, Q8N987), neuroligin-3 (NLGN3_HUMAN, Q9NZ94), protein kinase C and casein kinase substrate in neurons protein 1 (PACN1_HUMAN, Q9BY11), sodium channel protein type 7 subunit alpha (SCN7A_HUMAN, Q01118), and clathrin coat assembly AP180 (AP180_HUMAN, O60641). The biological accepts of the proteins have been derived from the information presented in UniProt database for each protein [18, 19, 20].
\nFASTA formats for each of the above proteins were retrieved from NCBI PubMed. The FASTA format is a text-based format obtained from the PubMed search and represents either nucleotide sequences or peptide sequences (Figure 3).
\nUpon accessing the website, select the database in which the search is to be conducted (e.g. Protein). Type the name of the protein and its species in brackets into the search text box provided (e.g. Agrin (Homo sapiens)) and click on the search button.
\nConducting a search on the PubMed database.
List of available sequenced protein information.
The protein with the highest number of amino acids is chosen. Click on the hyperlinked protein to access its gene bank. Upon reaching the gene bank of the selected protein, click on the hyperlinked FASTA (Figures 4, 5 and 6).
\nGene information of agrin.
FASTA format of agrin.
Obtain the FASTA format by copying all the information (Starting from the > symbol).
\nAll the FASTA formats of the human proteins are saved in a sequence on Microsoft Notepad (Figure 7).
\nFASTA formats of the 63 proteins in sequence.
Pathogen-protein mimics, nerve protein sequences were BLAST (Basic Local Alignment Search Tool; Version 2.7.1; e-value ≤0.01) [21] against a pathogen genome (Figure 8).
\nAccess the BLAST website at
BLAST home page.
The pathogen genome sequences that were compared with the human nerve proteins are as follows: HIV (Tax ID: 11,676), Polio (Tax ID: 138,950), Japanese Encephalitis (Tax ID:64,320), M. leprae (Tax ID: 1769), Human herpes virus 1 (Tax ID: 10,298), Human herpes virus 2 (Tax ID: 10,310), Rabies virus (Tax ID: 11,292), Zika virus (Tax ID: 64,320), Corona virus (Tax ID: 11,118), Varicella zoster virus (Tax ID: 10,335).
\nSelect program PSI BLAST as the BLAST algorithm for a more position-sensitive search. It looks deeper into the database to best match to your query. Click on the BLAST button and wait for the results. Take screen shots of your result and also download the provided excel format (Figure 9).
\nBLAST search.
BLAST results of nerve proteins showing similarity to pathogen proteins.
The output of the BLAST identified the significant peptide sequence similarities between the human protein and its pathogenic counterpart Figure 10. These peptide sequence similarities are identified by amino acid positions, in which amino acids exist in single-letter codes. The BLAST provides us with the number of sequence similarities between the pathogenic genomic sequence and its host proteins. It also identifies viral counterpart peptides and the region of similarity on the host proteins.
\nFurther interpretations of the results can be made by referring to the Uniprot database to obtain the biological and functional aspects of the host and the pathogen proteins (Figures 11 and 12).
\nUniProtKB screenshot showing the biological and functional data of the human protein.
Uniprot screenshot showing the biological and functional data of the viral protein.
The results show a number of sequence similarities existing between host proteins and various pathogen proteins. The maximum number of peptide sequence similarities were found between host protein caprin-2 which had 495 similarities with polio; neurogranin had 230 similarities with HHV2; secretogranin-3 had 221 similarities with Japanese encephalitis; agrin had 212 similarities with varicella; caprin-2 had 198 similarities with rabies virus; galanin peptides had 87 similarities with Zika virus; kinesin had 54 similarities with HIV; neurofilament heavy polypeptide had 46 similarities with corona virus; neurogranin had 39 similarities with HHV1; and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase had 21 similarities with M. leprae.
\nThis method identifies significant virulent factors which have sequence similarities to human nerve tissue proteins. The nerve proteins that exhibited sequence similarities with four or more pathogenic virulent factors are displayed in Table 1. All 63 proteins are found to have sequence similarities with M. leprae proteins.
\nS. No | \nQuery No. | \nProteins | \nHIV | \nPolio | \nJE | \nHHV 1 | \nHHV 2 | \nM. leprae | \nCorona | \nZika | \nRabies | \nVericella | \n
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | \nO00468 | \nAgrin | \n0 | \n0 | \n4 | \n0 | \n0 | \n6 | \n1 | \n0 | \n1 | \n212 | \n
2 | \nP17677 | \nNeuromodulin | \n1 | \n1 | \n0 | \n1 | \n3 | \n6 | \n28 | \n1 | \n0 | \n75 | \n
3 | \nQ9BW19 | \nKinesin | \n54 | \n1 | \n0 | \n0 | \n0 | \n9 | \n0 | \n0 | \n0 | \n0 | \n
4 | \nP10636 | \nTau protein | \n0 | \n1 | \n0 | \n0 | \n14 | \n5 | \n9 | \n0 | \n0 | \n19 | \n
5 | \nP25189 | \nMyelin protein P0 | \n2 | \n0 | \n0 | \n1 | \n22 | \n7 | \n1 | \n0 | \n0 | \n0 | \n
6 | \nP23515 | \nOligodendrocyte-myelin glycoprotein | \n0 | \n2 | \n0 | \n1 | \n0 | \n9 | \n0 | \n0 | \n1 | \n23 | \n
7 | \nP48681 | \nNestin | \n0 | \n0 | \n3 | \n2 | \n0 | \n8 | \n2 | \n30 | \n0 | \n22 | \n
8 | \nP04271 | \nProtein S100-B | \n0 | \n26 | \n0 | \n2 | \n11 | \n7 | \n0 | \n0 | \n0 | \n12 | \n
9 | \nP17600 | \nSynapsin-1 | \n0 | \n1 | \n7 | \n11 | \n2 | \n13 | \n0 | \n0 | \n5 | \n0 | \n
10 | \nP02686 | \nMyelin basic protein | \n0 | \n0 | \n0 | \n0 | \n2 | \n9 | \n4 | \n3 | \n0 | \n5 | \n
11 | \nQ16620 | \nBDNF/NT-3 growth factors receptor | \n0 | \n0 | \n0 | \n23 | \n8 | \n11 | \n0 | \n0 | \n1 | \n15 | \n
12 | \nQ5VV43 | \nDyslexia-associated protein KIAA0319 | \n0 | \n0 | \n0 | \n37 | \n21 | \n5 | \n5 | \n0 | \n2 | \n1 | \n
13 | \nP07196 | \nNeurofilament light polypeptide | \n0 | \n0 | \n0 | \n1 | \n1 | \n2 | \n4 | \n0 | \n0 | \n77 | \n
14 | \nQ8WXD2 | \nSecretogranin-3 | \n3 | \n5 | \n221 | \n0 | \n10 | \n8 | \n0 | \n0 | \n9 | \n0 | \n
15 | \nQ00973 | \nBeta-1,4 N-acetylgalactosaminyltransferase 1 | \n1 | \n29 | \n0 | \n1 | \n2 | \n8 | \n0 | \n0 | \n0 | \n0 | \n
Sequence similarities of human nerve tissue proteins with human virulent factors. Multiple alignments obtained in a single BLAST search could result in identities of the amino acids or substitutions of the amino acids in the same peptide region.
Agrin is a heparin sulphate basal lamina glycoprotein with a molecular mass of 217,232 Da. It plays a central role in the formation and maintenance of the neuromuscular junction. It is known to direct events in postsynaptic differentiation. Agrin also induces the phosphorylation and activation of muscle-specific kinase (MUSK), the clustering of Acetyl choline esterase receptor (AChR) in the postsynaptic membrane, regulates calcium ion homeostasis in neurons, and is involved in regulation of neuritis outgrowth [22, 23].
\nAgrin UniProtKB-O00468 (AGRIN_HUMAN) (AA position 1269–1326) (Figure 13) has a similarity to membrane glycoprotein C (Sequence ID: AEW88711.1 AA Position 43–122) of the varicella zoster virus UniProtKB-Q9J3M8 (GE_VZVO) which by its similarity has the potential to bind to the tissue cell receptor. Experimental evidence in epithelial cells shows that the hetero demonization of viral receptors could spread the virus by sorting nascent virion to nerve tissue cell junctions. The virus particles can spread to adjacent cells through interactions with cellular receptors at these cell junctions. The virus at cell junctions spreads extremely rapidly into the tissues [24, 25]. Sequence mimics of agrin to the varicella membrane glycoprotein could have an effect on either
BLAST output of membrane glycoprotein of HHV3 showing similarity to human protein agrin.
Caprin-2UniProtKB-Q6IMN6 (CAPR2_HUMAN) is a protein of molecular mass 68,429 Da. The structure of caprin-2 was found to be similar to the polio and rabies viruses. Caprin-2 (AA position: 136–176) has a similarity to the polyprotein of polio virus UniProtKB– E0WCG5 (E0WCG5_9ENTO) (polyprotein sequence ID: ACZ05040.1 AA position: 1994–2070) (Figures 14 and 15). Caprin-2 (AA position: 13–54) also has a similarity to the phosphoprotein of rabies virus UniProtKB-Q80JL8 (Q80JL8_9RHAB) (phosphoprotein sequence ID: AAO60615.1 AA position 76–110) (Figure 15). Caprin-2 has a significant role in influencing phosphorylation of the Wnt-signaling pathways (PubMed:18,762,581) [27]. Caprin-2 also facilitates LRP6 phosphorylation by CDK14/CCNY during G2/M stage of the cell cycle, which may potentiate cells for transport or translation of mRNAs, modulate the expression of neuronal proteins involved in synaptic plasticity [28], while simultaneously influencing cell cycle signaling and regulation of viral transcription and replication [29, 30].
\nBLAST output of polyprotein of poliovirus showing similarity to human protein caprin-2.
BLAST output of phosphoprotein of rabies virus showing similarity to human protein caprin-2.
2′, 3′-cyclic-nucleotide 3′-phosphodiesterase UniProtKB-P09543 (CN37_HUMAN) is a protein of molecular mass 47,579 Da. 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase (sequence ID: WP_010908292.1 AA position 191–261) has a similarity to thiamin pyrophosphokinase of M. leprae UniProtKB A0A197SEI9 (A0A197SEI9_MYCLR) (AA position: 170–2166) (Figure 16) 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase is involved in RNA metabolism of the myelinating cell, CN37 (2′, 3′-cyclic-nucleotide 3′-phosphodiesterase) is the one of the most abundant myelin protein in nervous system. The sequence similarities identified could impact cell signaling and also regulate energy metabolism [31].
\nBLAST output of thiamin pyrophosphate of Mycobacterium leprae showing similarity to human protein 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase.
Galanin peptide UniProtKB-P22466 (GALA_HUMAN) is a protein of molecular mass 13,302 Da. Galanin (AA position 53–99 position) has a similarity to polyprotein envelope protein E of Zika virus UniProtKB-Q73880 (Q73880_9HIV1) sequence ID: ARB07952.1 (AA position: 729–765) (Figure 17). Galanin is involved in the smooth muscle contraction of the gastrointestinal and genitourinary tract, regulation of growth hormone release, modulation of insulin release, and might also be involved in the control of adrenal secretion [32]. The envelope protein E of the Zika virus is responsible for binding to host cell surface receptors and mediating fusion between viral and cellular membranes. It is synthesized in the endoplasmic reticulum with protein prM and forms a heterodimer. Galanin’s similarity with the ZIKA polypeptide could subsequently affect neural regulation of muscle function and play a role in immune evasion pathogenesis and viral replication [33].
\nBLAST output of polyprotein of Zika virus showing similarity to human Galanin peptide.
Kinesin-like protein KIFC1 UniProtKB-Q9BW19 (KIFC1_HUMAN) is a protein of molecular mass 73,748 Da. Kinesin-like protein (AA position: 411–470) has a similarity to HIV virus envelope glycoprotein UniProtKB-D6QPK9 (D6QPK9_9HIV1) sequence ID:ADG63850.1 (AA position:270–387)(Figure 18). KIFC1 along with microtubules contributes to movement of endocytic vesicles. These similarities could affect viral attachment to the host cell, membrane fusion, and entry into the cell and the nucleus [34, 35].
\nBLAST output of envelope glycoprotein of HIV 1 showing similarity to human kinesin-like protein.
Neurofilament heavy polypeptide UniProtKB-P12036 (NFH_HUMAN) is a protein of molecular mass 112,479 Da. Neurofilament heavy polypeptide (AA position: 819–872) has a similarity to ORF1a UniProtKB-A0A0F6SKM6 (A0A0F6SKM6_9GAMC) of Corona virus sequence ID: AKF17723.1 (AA positions: 890 –1031) (Figure 19) neurofilament of the nerve tissue usually contain three intermediate filament proteins: L, M, and H (NFH-human) which is involved in the maintenance of neuronal caliber. NFH-H has an important function in axon maturation. These similarities could affect viral replication, protein processing, and could generate autoantibody production [36, 37].
\nBLAST output of ORF1 of corona virus showing similarity to human neurofilament heavy polypeptide.
Neurogranin UniProtKB-Q92686 (NEUG_HUMAN) is a protein of molecular mass 7618 Da. The structure of neurogranin at identical regions has a similarity to envelope glycoprotein M of HHV1 and envelope glycoprotein M of HHV2 at partially overlapping positions. Neurogranin (AA position: 38–63) has a similarity to the envelope glycoprotein M of HHV1(UniProtKB-A0A181ZHE7 (A0A181ZHE7_HHV11) (sequence ID: SBO07578.1 AA position: 347–376) (Figure 20). Neurogranin (AA position: 38–64) also has a similarity to the envelope glycoprotein M of HHV2 (UniProtKB-A0A0Y0R357 (A0A0Y0R357_HHV2)) (sequence ID: AMB66044.1 AA position 389–416) (Figure 21). Neurogranin functions as a signaling messenger, a substrate for protein kinase C and has affinity to calmodulin in the absence of calcium. These similarities of HHV1 & 2 with neurogranin could have an interaction with viral transport into the host cell Golgi network and subsequently to the host nucleus [38].
\nBLAST output of envelope glycoprotein of HHV 1 showing similarity to human protein neurogranin.
BLAST output of envelope glycoprotein of human alpha herpes virus 2 showing similarity to human protein neurogranin.
Secretogranin-3 UniProtKB-Q8WXD2 (SCG3_HUMAN) is a protein of molecular mass 53,005 Da. Secretogranin-3 (AA position: 139–190) has a similarity to the polyprotein of Japanese encephalitis virus (UniProtKB-G3LHD8 (G3LHD8_9FLAV) (sequence ID: SBO07578.1 AA position: 2744 to (Figure 22). Secretogranin-3 is a member of the
BLAST output of polyprotein of JE 2 showing similarity to human protein secretogranin-3.
The sequence similarities in agrin,caprin-2,2′,3′-cyclic-nucleotide 3′-phosphodiesterase, galanin peptide, kinesin-like protein, neurofilament heavy polypeptide, neurogranin and secretogranin-3 with its corresponding pathogenic peptide/s could have a number of cellular-level implications which include alternations in receptor binding, signaling/synaptic transmission, metabolic alteration, inflammation, resulting in autoimmunity and consequently neuropathy (Figure 23) [11, 40].
\nA model for the modes of host-pathogen interaction and possible intracellular regulation of metabolic activities.
In conclusion, it is important to conduct bioinformatic searches and design wet experiments with the objective of identifying a vast number of functionally significant peptides for further comparison and study. Bioinformatic search tools and various available databases are to be extensively explored to rapidly develop possible neuroprotective or pathogenic peptide sequences. These peptides can be further explored as targets to generate recombinant antibodies. This exercise can also be used to develop an efficacious and safe vaccine against pathogens that demonstrate no autoimmune cross-reactions. It can also contribute to design peptide/drug molecules to neutralize the effects of neurotoxins. Bioinformatics is the key to open the door of understanding medical and biological processes in the future.
\nWe acknowledge short-term project works of Do Eon Lee of York University, 700 Keele St, Toronto, ON M3 J 1P3, Canada and Logeshwaran Vasudevan of Bharathidasan University, Palkalaiperur, Tiruchirappalli, Tamil Nadu 620024, and Dr Sharon Bushi of Morristown Med CtrIntnlMedcn, 100 Madison Ave, Morristown, NJ 07960 on the preliminary work of nerve protein pathogen similarity searches.
\nDaratumumab is the first fully IgG1K-human monoclonal antibody targeting CD38.CD38, also known as cyclic ADP ribose hydrolase, is a transmembrane glycoprotein expressed on the surface of hematopoietic and non-hematopoietic cell lines.
This protein plays different functions, both on the external and on the inner surface of cells. As a receptor, it takes part into the inflammatory response, stimulating the production of a great variety of cytokines through the interaction with CD31, on the surface of T cells. As enzyme, it is involved in the metabolism of nicotinamide adenine dinucleotide (NAD+), leading to the synthesis of cyclic ADP ribose (cADPR) which regulates cellular calcium trafficking [1].
In the context of bone niche, CD38 expression is very high on the surface of plasma cells. Pioneering studies have shown that this glycoprotein plays a key-role in the oncogenesis of multiple myeloma: increased intracellular levels of NAD+ seem to be associated with a less susceptibility to apoptosis [2] and the synthesis of cADPR favours the escape of tumour cells from the immune system [3]. In vitro, CD38 seems also to be associated with the formation of nanotubes that transfer mitochondria from the stromal cells to myeloma cells, boosting myeloma cell proliferation and survival [4].
Daratumumab binds CD38, killing tumour cells via Fc-dependent immune effector mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [5]. The complement activation seems to be the most effective mechanism used by Daratumumab [6]: the Fc tail of the drug binds the activating factor C1q leading both to ultimate activation of membrane attack complex and to deposition of C3b on the surface of multiple myeloma plasma cells. The activation of membrane attack complex causes osmotic lysis of cells while the deposition of complement factors attracts phagocytic cells. The recruitment of immune effector cells is also boosted by the release of circulating factors such as C3 and C5a (Figure 1).
Mechanism of action of daratumumab. Daratumumab binds CD38, killing myeloma cells via Fc-dependent immune effector mechanisms: CDC, ADCC and ADCP. Daratumumab also inhibits enzymatic activity of CD38, downregulating intracellular Ca2+ trafficking.
The anti-tumour activity of Daratumumab does not depend only on the direct action on plasma cells but also on the interaction with other lymphoid and myeloid cells with a weak expression of CD38: NK cells, B and T regulatory cells and CD8+ effector cells. Krejcik et al. have demonstrated that bone marrow and peripheral blood from patients on treatment with Daratumumab present low levels of regulatory cells and high levels of NK and CD8+ effector cells. This monoclonal antibody may interfere with the immunosuppressive microenvironment in the multiple myeloma bone niche, in favour of major susceptibility for the plasma cells to the NK and CD8+ cells toxicity [7].
Daratumumab is usually administered at the dosage of 16 mg/kg weekly for 8 weeks then every 2 weeks for 16 weeks and every 4 weeks thereafter until progression of disease. The administration on a mg/kg basis is due to the observation that distribution and clearance of daratumumab depends on bodyweight. It seems to be not influenced by age, gender, race, mild renal and liver impairment. To our knowledge, the extra-liver metabolism of daratumumab is the reason for the absence of interactions with other drugs.
The efficacy and safety of this schedule have been demonstrated by two studies involving patients with relapsed/refractory multiple myeloma (RRMM) treated with the anti-CD38 monoclonal antibody as single agent: GEN501 and SIRIUS.
GEN501 was a phase I/II, open-label, multicenter study. In the dose-escalation part, sequential cohorts of patients received intravenous doses of daratumumab ranging from 0.005 to 24 mg/kg, administered over 6–8 h. In the dose-expansion study, in three of the enrolled cohorts, daratumumab was administered based on the findings from the previous part at 8 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression [8].
SIRIUS was a phase II study with two parts. In the first part, the patients were randomized to receive daratumumab 8 mg/kg every 4 weeks or 16 mg/kg weekly for 8 weeks, then every 2 weeks for 16 weeks and every 4 weeks thereafter. In the second part, all patients received daratumumab 16 mg/kg, according to the findings from the first part [9].
Intravenous administration of Daratumumab is associated with several side effects, included infusion-related reactions (see below). Therefore, this formulation requires a very slow infusion rate which may represent a disadvantage for the patient. Sever trials are evaluating the subcutaneous administration as an alternative. In the phase 1b PAVO study, the subcutaneous formulation of the monoclonal antibody was administered in patients with RRMM in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) to depolymerize hyaluronan in the subcutaneous space and increase the absorption rate [10]. This formulation at the dosage of 1800 mg was well tolerated and allowed to obtain similar concentrations and responses to the intravenous administration. Non-inferiority of subcutaneous daratumumab to intravenous formulation has been confirmed by preliminary results of the ongoing phase III trial COLUMBA [11]: enrolled patients with RRMM are randomized to receive either intravenous daratumumab 16 mg/kg or subcutaneous daratumumab 1800 mg. According to these studies, the approval of this formulation by the regulatory bodies is on the agenda.
Approval of daratumumab by regulatory bodies was made possible thanks to clinical trials evaluating its use in RRMM. Patients with RRMM still represent the patients best benefitting from this monoclonal antibody, both as single agent and in combination with other agents (Table 1a).
Trial | Phase | Therapy | Primary outcome |
---|---|---|---|
(a) RRMM | |||
GEN501 | 1/2 | IV daratumumab single agent | evaluation of safety |
SIRIUS | 2 | IV daratumumab single agent | ORR |
PAVO | 1B | SC daratumumab | Maximum ctrough N° of patients with AEs |
COLUMBA | 3 | IV daratumumab vs SC daratumumab | ORR Maximum ctrough |
NCT01615029 | 1 / 2 | DARA-Rd | ORR |
CASTOR | 3 | DARA-Vd vs Vd | PFS |
POLLUX | 3 | DARA-Rd vs Rd | PFS |
(b) NDMM | |||
ALCYONE | 3 | DARA-VMP vs VMP | PFS |
MAIA | 3 | DARA-Rd vs DARA-Rd | PFS |
CASSIOPEIA | 3 | DARA-VTd vs VTd | sCR after consolidation PFS |
GRIFFIN | 2 | DARA-RVd vs RVd | sCR after consolidation |
PERSEUS | 3 | DARA-RVd vs RVd | PFS |
Overview of main trials using Daratumumab in (a) RRMM, (b) NDMM.
RRMM: Relapsed/Refractory Multiple Myeloma, IV: intravenous, SC: subcutaneous, Rd.: lenalidomide-dexamethasone, Vd: bortezomib-dexamethasone, ORR: Overall Response Rate, Maximum CTrough: Maximum Concentration Trough, AEs: Advese Events, PFS: Progression Free Survival, NDMM: Newly Diagnosed Multiple Myeloma, VMP: bortezomib-melphalan-dexamethasone, VTd: bortezomib-thalidomide-dexamethasone, RVd: lenalidomide-botrezomib-dexamethasone, sCR: stringent Complete Response.
GEN501 and SIRIUS are the two main trials who led to approval of monotherapy with daratumumab. Both studies enrolled patients with RRMM: patients in GEN501 had relapsed after or were refractory to ≥2 prior lines of therapy, including inhibitors of proteasome (PIs), immunomodulatory drugs (IMiDs), chemotherapy and autologous stem cell transplantation (ASCT); patients in SIRIUS had relapsed after ≥3 lines of therapy, including a PI and a IMiDs or were double refractory to the most recently received PI and IMiDs. The primary endpoint of GEN501 was evaluation of safety while SIRIUS was designed to first evaluate overall response rate (ORR). Data regarding 148 patients from pooled analysis of the two trials confirmed how daratumumab, at the dosage of 16 mg/kg, is effective and safe in a population of heavily pretreated patients [12]. With a median number of 12 infusions, the ORR was 31.1%. At the time of the analysis, after a median follow-up of 20.7 months, the progression free survival (PFS) was 4 months, with a 12-month PFS rate of 22%. Stratifying the patients by the response according to International Myeloma Working Group, the PFS and the overall survival (OS) went out to be 15 months and not reached respectively for responders, 3 months and 18.5 months for patients with a stable disease or minimal response, 0.9 months and 3.7 months for non-responders. The median duration of response was 7.6 months and it deepened and improved in patients continuing daratumumab.
Efficacy of daratumumab seems to be strengthened by other drugs used for multiple myeloma, given the synergic action on the immune system. As said before, the anti-CD38 may stimulate NK and T-cells, restoring “tumor suppressive immunological surveillance”. Also IMiDs could increase the amount of regulatory cells in the bone niche, through inhibition of some transcriptional factors (Ikaros and Aialos) and the subsequent production of interleukin 2 [13]. Furthermore, some studies show that the main target of daratumumab is upregulated by action of IMiDs [14]. NCT01615029 was the first trial exploring the applicability of these laboratory observations, investigating efficacy of daratumumab in combination with lenalidomide and dexamethasone (Rd) [15]. It was a phase 1/2 study addressed to patients with relapsed multiple myeloma: phase 1 was a dose-escalation study in which the dose of 16 mg/kg for daratumumab was again determined; phase 2 was a dose-expansion study using the recommended dose of the first part. The three drugs were administered in cycle of 28 days: daratumumab was given according to the standard schedule, lenalidomide at 25 mg/day from days 1 to 21 of each cycle and dexamethasone at 40 mg/week. This combination revealed to be safe and very effective: the 18-months PFS rate was 72% and ORR was 81%, in this case too with an improvement of responses in time. To evaluate the advantage of adding daratumumab to a regimen with lenalidomide and dexamethasone, from 2014 to 2015, a phase III, randomized trial was carried out across Europe, Northern America and Asia [16]. The POLLUX trial enrolled 569 patients with multiple myeloma who had received one or more previous lines of therapy: 286 were assigned to the daratumumab group (daratumumab plus lenalidomide and dexamethasone) and 283 to the control group (lenalidomide and dexamethasone). Also in this trial, each cycle was of 28 days, with daratumumab administered according to the usual schedule, lenalidomide at 25 mg/day from days 1 to 21 of each cycle and dexamethasone at a dose of 40 mg weekly. At 12 months, the PFS rate was 83.2% in the daratumumab group vs 60.1% in the control group. In a sub analysis, this extension of PFS in the experimental group went out to be independent from the number of previous lines of therapy and from the previous exposure to lenalidomide, even if the paucity of refractory patients to IMiDs enrolled in this trial may represent a bias. After a follow-up of 13.5 months, progression disease or death occurred in 53 patients in the daratumumab group vs 116 patients in the control arm, with a hazard ratio of 0.37 in favour of the first group. Also in this case, an improvement of deepness of molecular response was observed with continuation of therapy with the monoclonal antibody and it translated in a longer survival. Indeed, 22.4% of patients in the experimental group had results below the threshold for minimal residual disease (MRD), compared to 4.6% in the control group. Neutropenia, diarrhea and infusional reactions were the main adverse events reported in the experimental arm with a higher incidence than in the control group but, in spite of that, the rate of grade 3 and grade 4 infections was not so different. In conclusion, POLLUX trial confirmed the efficacy and safety of adding daratumumab to a regimen with IMiDs and high-dose steroid. Furthermore, the excellent results below the threshold for minimal residual disease suggest that minimal residual disease negativity could represent a goal also for RRMM patients.
Some in-vitro studies have shown that not only IMiDs but also PIs interact with daratumumab in a synergic way, strengthening its effect. An assay performed by the Dutch group [14] evaluated the rate of lysis in samples of bone marrow mononuclear cells from 16 multiple myeloma patients incubated with medium containing either daratumumab, lenalidomide and bortezomib or just one drug. The rate of lysis went out to be higher in the samples with the addition of daratumumab, showing that not only lenalidomide but also bortezomib enhance the effect of this monoclonal antibody by sensitizing the cells to the antibody-mediated lysis. The “lysis effect” was even better in cells from patients who previously showed refractoriness to IMiDs or IPs, suggesting that immunomodulatory effects of daratumumab may restore host susceptibility to anti-myeloma agents. Based on a phase 1b trial in which daratumumab showed encouraging results in combination with PIs-based regimens in naive patients [17], a phase 3 trial randomized patients with relapsed and/or refractory multiple myeloma to a treatment with only bortezomib and dexamethasone or with the addition of daratumumab [18]. Of 498 patients, 251 were assigned to the daratumumab group and 247 to the control group. Each cycle had a duration of 21 days. Daratumumab was administered at the usual dosage of 16 mg/kg once per week during cycles 1 to 3, once every 3 weeks during cycles 4 to 8 and once every 4 weeks thereafter until toxicity or progression disease. Dexamethasone was given for a total dose of 160 mg per cycle and bortezomib was administered in the subcutaneous formulation at the dosage of 1.3 mg per square meter on days 1, 4, 8 and 11 of cycles 1 to 8. The 12-month rate of PFS was 60.7% in the experimental group and 26.9% in the control group. After a follow up of 7.4 months, progression disease or death occurred in 67 patients in the daratumumab group vs 122 in the control group. Given the results of the interim analysis, the trial was unblended earlier and patients in the control group with a progression disease were offered daratumumab monotherapy. This may represent a bias in the interpretation of all the long-term results. Nevertheless, this trial showed how daratumumab could give an advantage also in combination with PIs-based regimens. The recorded responses are deep and durable. The main adverse events reported in the daratumumab group were thrombocytopenia and infusion-related reactions but none of them led to a treatment discontinuation higher than in the control group.
Fazio et al. performed a multicentre retrospective analysis of patients with relapsed/refractory multiple myeloma treated with IMiDs or IPs-based regimens containing daratumumab in the hospitals of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) network in the Italian region of Lazio [19]. Of 188 patients, sixty-five performed at least one cycle of therapy and were evaluable for hematologic response. The ORR was 81.97%; with four patients (6.56%) achieving a stringent complete response (sCR), 20 (32.79%) patients a complete response (CR), 5 (8.2%) patients a non-complete response (NCR), 13 (21.31%) patients a very good partial response (VGPR) and 8 (13.11%) patients a partial response (PR). After a median follow-up of 8.8 (range 0.23–22.3) months, 50 (42.37%) patients were alive maintaining response, eight (13.11%) patients presented a progression disease and one (1.64%) patients died. The overall survival and progression-free survival were 86.3% (95% CI, 79.2–94) and 70.8% (95% CI, 61.2–82), respectively. The most common grade 3 or 4 hematologic treatment-emergent adverse events (TAEs) included neutropenia, anemia and thrombocytopenia. The most common non-hematologic TAEs, of any grade, were infections, peripheral sensory neuropathy (7.6%) and fatigue (7.6%). Among the cases of infection, 17 (26%) patients presented pneumonia, eight (12%) patients FUO and five (7.7%) patients viral reactivation. Our preliminary results confirm data from POLLUX and CASTOR trial, suggesting that treatment with daratumumab in combination with lenalidomide or bortezomib plus dexamethasone is a highly effective and well-tolerated regimen to be considered for multiple myeloma patients after first relapse.
In the setting of heavily pretreated myeloma patients, daratumumab has shown good results also in association with novel drugs belonging to the last generations of IMiDs and IPs. Both combination of daratumumab with pomalidomide and dexamethasone and with carfilzomib and dexamethasone allowed to obtain deep and durable responses with a tolerable toxicity profile [20, 21]. Therefore, it seems reasonable to use daratumumab in combination with triplets or quadruplets in RRMM to obtain the best response.
Despite improvements in the MM outcome and in the depth and response duration following subsequent lines of therapy, MM remains an incurable disease. It is reasonable to consider allogenic (allo) hematopoietic cell transplantation (HCT) as a treatment strategy for young patients with high-risk disease and an available donor. Allo-HCT is potentially effective by virtue of a graft-versus-myeloma (GvM) effect but currently, there is little available data regarding this treatment [22]. Given the action of daratumumab on the microenvironment, it could be used both to control the graft-versus-host disease and to improve the GvM effect. In the review by Nikolaenko et al., 34 patients treated with daratumumab after aploidentical HCT were evaluated [23]. The ORR after the treatment with the monoclonal antibody was 41%, only five cases of acute GVHD were reported and no cases of chronic GVHD, showing the efficacy of this strategy on a population of high-risk heavily pretreated patients. Based on this little data, we may speculate that the modification of microenvironment induced by daratumumab could be used to “plow the land” for the transplant. To our knowledge, none is known about the use of anti-CD38 as a bridge to the transplant. We recently reported the case of a young patients with relapsed myeloma after the standard induction therapy and a tandem ASCT who underwent 11 cycles of rescue therapy with daratumumab in combination with lenalidomide and dexamethasone, followed by haploidentical transplant. Thanks to this treatment, he achieved a partial response and is now on consolidation with Daratumumab-Rd regimen [24].
More recently, the use of daratumumab has been also explored in the setting of newly diagnosed multiple myeloma (NDMM) patients, showing encouraging results both in the population of transplant eligible patients and in that of transplant ineligible patients. The first results about daratumumab in NDMM patients proceed from a phase 1b study evaluating tolerability and safety of this monoclonal antibody in combination with myeloma backbone regimens: bortezomib-dexamethasone (VD), bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-dexamethasone (VMP), pomalidomide-dexamethasone (PD) [25]. NDMM patients were included in all the arms except the PD one: in the VD and VTD arms the patients were enrolled irrespective of the transplant eligibility, while all patients in the VMP arm were transplant ineligible. In all the four arms, daratumumab was well tolerated and safe (Table 1b).
ALCYONE and MAIA are the two main trials which evaluated the efficacy of adding daratumumab in the standard treatment of untreated patients with multiple myeloma ineligible to transplant. ALCYONE enrolled 706 naive patients randomized to receive VMP alone or with daratumumab [26]. Each cycle had a duration of 42 days. In the control group, all the patients received up to nine cycles of subcutaneous bortezomib, administered at the dosage of 1.3 mg per square meter of body-surface area (twice weekly on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9), oral melphalan (9 mg per square meter, once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg per square meter, once daily on days 1 through 4 of each cycle). In the experimental group, intravenous daratumumab at the usual dose of 16 mg/kg was administered with oral or intravenous dexamethasone at a dose of 20 mg once weekly in cycle 1, every 3 weeks in cycles 2 through 9, and every 4 weeks thereafter until disease progression or toxicity. Dexamethasone at a dose of 20 mg was substituted for prednisone on day 1 of each cycle. At 12 months, the PFS was 86.7% in the daratumumab group vs 76.0% in the control group. At the clinical data cut-off, an event of disease progression or death had occurred in 88 (25.1%) patients in the daratumumab group vs 143 (40.2%) patients in the control group, with a hazard-ratio of 0.50 in favour of the first group. The superiority was even confirmed in the older patients, in those with a poor performance status and worse stage. It seemed to be also independent from impairment of renal and liver function which were quite frequent in the enrolled population. In spite of this general advantage given adding daratumumab, a prespecified subgroup analysis of progression-free survival showed that the D-VMP combination is not so effective in the overcome of the bad prognosis given by the high-risk cytogenetics (defined by t (4;14), t (14;16), del17p). The main adverse effect was represented by infections of the respiratory tract but they were not a cause of discontinuation of treatment. MAIA compared Rd. to daratumumab-Rd [27]. The trial enrolled 737 naïve patients: in cycles of 28 days, all of them received oral lenalidomide 25 mg on days 1 through 21 and oral dexamethasone 40 mg per week, until disease progression or toxicity. In the experimental group, daratumumab was added at a dose of 16 mg/kg once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter. At the median follow-up of 28 months, PFS was not reached in the daratumumab group and was 31.9 months in the control group. Disease progression or death occurred in 97 patients in the experimental group vs 143 in the control group, with a hazard-ratio of 0.56. Also in this trial, the benefit was maintained in older patients with worse performance status but not in the patients with high-risk cytogenetics. Pneumonia was recorded as the most frequent side effect in the experimental group but it did not influence the general outcome. Based on the exciting results of ALCYONE and MAIA, several ongoing trials throughout the world aim to evaluate the benefit of adding both subcutaneous and intravenous daratumumab to the different combinations of drugs used for the induction of multiple myeloma in naïve unfit patients (NCT03993912, NCT03742297, NCT03652064, NCT03217812, NCT04052880, NCT04009109, NCT03695744, NCT02918331). Some of these are designed to study possibility of combining the monoclonal antibody with the newest generations of IMiDs and IPs: NCT4009109 is a phase II trial with two arms based on induction with lenalidomide, ixazomib, daratumumab and dexamethasone; maintenance in arm 1 is with the only lenalidomide, in the arm 2 it is with lenalidomide, ixazomib and daratumumab. Ixazomib is a last-generation IPs which recently received the approval to be used in combination with lenalidomide and steroid in RRMM. The interim analysis of this phase II trial showed an overall response rate (ORR) of 70%, with good molecular response [28].
The excellent results achieved in the population of unfit NDMM patients led to evaluate the efficacy of daratumumab also in the population of NDMM transplant eligible patients. CASSIOPEIA trial is the first largest study going in this direction: it enrolled 1085 patients across Europe, randomly assigned to the control arm with the use of VTD triplet or to the experimental arm adding daratumumab [29]. All patients received up to four 28-day, pre-transplant induction cycles and two 28-day, post-transplant consolidation cycles of subcutaneous bortezomib (administered according to the usual schedule), oral thalidomide (100 mg daily in all cycles), and oral or intravenous dexamethasone. Daratumumab was administered intravenously at a dose of 16 mg/kg of bodyweight once weekly in induction cycles 1 and 2 and once every 2 weeks during induction cycles 3 and 4 and consolidation. At 100 days post-transplant, the rate of sCR was higher in the daratumumab group than in the control group (29% vs 20%) and this superiority was maintained in older patients, but not in patients with a higher stage disease and a higher risk cytogenetics. Also in this trial the main adverse events were represented by infections but none of them represented a cause of treatment discontinuation. Surprisingly, daratumumab went out to be associated with a reduction of the amount of collected stem cells CD34+ and the subsequent use of plerixafor, even if this aspect did not translate into a worse performance of the transplant. Recently, Voorhees et al. published the results of another study evaluating the use of daratumumab as first line in transplant eligible patients, the GRIFFIN trial [30]. In this phase II randomized trial, 207 enrolled patients received four 21-day induction cycles and two 21-day consolidation cycles of oral lenalidomide (25 mg daily on days 1–14), subcutaneous bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), and oral dexamethasone (VRD), followed by maintenance with lenalidomide until toxicity or progression disease. Patients in the experimental group received daratumumab (16 mg/kg) on days 1, 8, and 15 of cycles 1 through 4 and day 1 of consolidation cycles and of maintenance cycles. After the end of post-transplant consolidation, the primary end-point of sCR was achieved in 42 patients in the experimental group vs 31 patients in the control group. Also the secondary end-points of overall response rate and rate of VGPR or better resulted higher in the daratumumab group. These good results deepened over time. The observed benefit was maintained also in the older population but not again in patients with a higher disease stage and with high-risk cytogenetics. As usually observed, also in this trial the experimental arm recorded a high rate of not statistically significant infections. Several ongoing trials aim to evaluate the use of daratumumab as first-line in transplant eligible NDMM patients: among these, PERSEUS is a promising ongoing phase III trial evaluating efficacy of daratumumab plus VRD vs VRD in terms of PFS, utilizing subcutaneous daratumumab to minimize toxicity. There are also few ongoing trials evaluating induction with daratumumab irrespective of transplant eligibility and some of them are based on MRD-driven therapies (MASTER trial). The results of all these studies are awaited.
Given the promising results in the treatment of multiple myeloma with daratumumab, its use is being investigating also in the treatment of other plasma cell neoplasms, especially immunoglobulin light chain (AL) amyloidosis and smouldering myeloma (SMM).
AL amyloidosis is due to the production of misfolded immunoglobulin light chain by an aberrant plasma-cells clone. This pathologic protein deposits in a variety of organs, usually heart and kidney, causing serious dysfunction. In spite of good results showed by treatment of this disease with PIs and IMiDs [31, 32], there is still a significant proportion of patients that do not respond to these agents. Based on a variety of reports showing safety and efficacy of daratumumab in patients with relapsed/refractory AL amyloidosis [33, 34, 35, 36], some perspective trials have been recently conducted. NCT028441033 is a phase II study led at Boston Medical Center and aimed to evaluate safety and tolerability of daratumumab in a cohort of 25 participants with relapsed/refractory AL amyloidosis. The preliminary results were encouraging, with only infusion reactions being reported as main side effect [37]. The ORR is instead the primary outcome of a multi-center phase II study across France and Italy (NCT02816476): it enrolled 35 patients with AL amyloidosis not in VGPR or better after previous treatment. The preliminary results showed an ORR of 59% with 44% of patients achieving at least a VGPR [38]. These good results are confirmed by a report with the collaboration of our group [39]: 59 patients out of 72 with relapsed/refractory AL amyloidosis achieved a hematologic response after eight infusions of daratumumab, single agent or combined with bortezomib and lenalidomide, and the quality of this response improved with the continuation of therapy. The demonstration of the efficacy of daratumumab in the treatment of AL amyloidosis provided the rationale for exploring its use earlier in the disease course. Hossein Taghizadeh MA et al. presented the case of two patients with advanced cardiac involvement who achieved a normalization of light chain levels within one cycle of therapy with the anti-CD38, without any serious adverse events in spite of the cardiac dysfunction [40]. A phase III trial comparing cyclophosphamide, bortezomib and dexamethasone with or without daratumumab in the first-line treatment of AL amyloidosis has recently completed the enrolment and the results are awaited (NCT03201965).
Smouldering myeloma is defined by a medullar infiltration of clonal plasma-cells ≥10% in the absence of symptoms. According to the Mayo Clinic criteria, M-protein >2 g/dl, medullar infiltration ≥20% and free-light chain ratio > 20 define risk categories. Patients with one, two and three of these criteria are considered to be at low, intermediate and high risk with 5-year progression of 23% in the low risk, 47% in the intermediate risk and 82% in the high risk [41]. However, in spite of the important risk of transformation into symptomatic disease, current guidelines recommend “watch and wait” even in people with high and intermediate risk smouldering myeloma. Since the earlier intervention may delay progression, different studies are evaluating the use of new drugs in this subset of patients. Daratumumab could be the perfect drug, given the efficacy and the tolerability showed in other subsets. Based on the good results of the CENTAURUS trial, a phase II study for patients with intermediate and high risk smouldering multiple myeloma, randomly assigned, in a 1:1:1 ratio, to receive one of three different schedules of daratumumab [42], a phase III trial has been designed (NCT03301220). In this study, patients with high-risk smouldering myeloma are randomized either to receive subcutaneous daratumumab or to be just monitored. Daratumumab is administered according to the usual schedule, until 39 cycles or up to 36 months or until confirmed disease progression or unacceptable toxicity. This study recently completed the enrolment and the results are still awaited but all the most recent findings suggest that the anti-CD38 could be used with safety and efficacy also in smouldering myeloma.
All pivotal studies leading to approval of daratumumab for the treatment of relapsed-refractory or newly diagnosed multiple myeloma showed a slight major susceptibility to infections in the studied populations. This risk seems to be due to the neutropenia and to the impairment of cellular immunity which is a direct consequence of targeting CD38 [43]. In the study by Nahi et al., nine patients out of 23 treated with daratumumab had viral and/or bacterial complications, mainly involving the respiratory tract. In these patients, assessment of circulating lymphocytes indicated a selective depletion of NK cells and viral reactivation after Daratumumab treatment. This finding is in line with data emerging from all the trials using anti-CD38-based regimens and suggest the necessity of screening for cytomegalovirus, Epstein–Barr virus and viral hepatitis before starting the treatment, therefore an adequate antiviral and antibacterial prophylaxis in the treated population. In the consensus document by ESCMID Study Group for Infections in Compromised Hosts (ESGICH), based on the pooled analysis of the two trials GEN501 an SIRIUS, daratumumab is associated also with an increased risk of varicella-zoster virus (VZV) infections, especially in the presence of combination therapy with protease inhibitors and/or corticosteroids [44]. Anti-herpesvirus prophylaxis with (val)acyclovir should be administered to VZV-seropositive patients at least 1 week before starting daratumumab therapy and for at least 12 weeks after its discontinuation. The consensus document also recommends seasonal-influenza vaccination. In the review of the drug conducted under the EMA’s accelerated assessment program for drugs that are of major interest for public health, also thrombocytopenia and anemia are reported as the most common side effects, besides neutropenia [45]. In this same report, half of all patients experienced infusion-related reactions, mainly occurring at the first infusion. These reactions usually presented with nasal congestion, cough, throat irritation, chills, vomiting and nausea. Serious adverse reactions with bronchospasm, dyspnea, laryngeal edema, pulmonary edema and hypoxia have been also reported but in a few cases. Based on this phenomenon, EMA gave indication to premedicate every infusion with antihistamines, antipyretics and corticosteroids. Furthermore, oral corticorsteroids should be taken by all patients on the first and second day after all infusions. Patients on therapy with Daratumumab may present with positive indirect and direct Coombs test, due to the CD38 expression also on the red blood cells. This interference could complicate the safe provision of blood products to people on treatment with this drug. Chapuy et al. demonstrated that this “laboratory side effect” might be solved by incubating red blood cells with dithiothreitol (DTT) or trypsin [46]. These reagents remove the CD38 on the surface of red blood cells, easing routine compatibility testing. Evaluation of disease response in patients with multiple myeloma on treatment with daratumumab could also be complicated by this antibody. Given its proteic nature (IgG1), the drug can be confused with the endogenous monoclonal component during the interpretation of serum immunofixation electrophoresis (IFE). McCudden et al. proposed a daratumumab-specific immunofixation electrophoresis reflex assay (DIRA) using a mouse anti-daratumumab antibody in order to discriminate between endogenous myeloma protein and daratumumab [47]. Both Castor and Pollux trials showed a slight increase of rates of secondary primary cancers in the experimental arms, within 6 months after the initiation of trials [16, 18]. Most of the cases were non-melanocytes related cutaneous tumours and occurred in patients already treated with IMiDs and alkylating agents. Further studies and longer follow-up are needed to clarify the potential carcinogenicity of Daratumumab. Another concern, regarding the use of daratumumab, is due to the expression of CD38 on the surface of CD34+ hematopoietic progenitor cells. This could theoretically translate into a delay in stem cells collection for eligible patients to ASCT on treatment with the monoclonal antibody. Xun Ma et al. conducted an assay in which specimens of mobilized peripheral blood CD34 + cells from myeloma patients were evaluated to determine percentage of CD38 expression and later incubated with daratumumab and complement-rich human serum. First, CD38 is minimally expressed on CD34+ cells, compared to the control cell lines used. Furthermore, CDC did not occur, showing that, in vitro, daratumumab is not toxic to mobilized CD34 + progenitor cells from myeloma patients [48].
Daratumumab has showed proven efficacy and tolerability both in patients with RRMM and with NDMM, as confirmed in all the studies conducted during the last years. A deep and durable response with easy-to-control side effects was obtained using this monoclonal antibody. The revolutionary power of this new drug could be also extended to patients with other plasma cell neoplasms, such as AL amyloidosis and SMM. Given the specific mechanisms of action of daratumumab targeting both clonal plasma-cells and bone-niche microenvironment, further studies are warranted to better understand the correct timing to introduce this monoclonal antibody in the context of a sequential therapy. On a side, the immune-mediated plasma-cell killing, induced by daratumumab in the early phase of treatment, acts as a debulking for the disease; on the other side, the restoration of the immune system may boost other metabolic effects of the monoclonal antibody, in a later phase of therapy, when the control of the disease is better [49]. Based on these hypothesis, the retreatment with daratumumab after a wash-out period may seem reasonable. Therefore, the anti-CD38 is a revolutionary weapon: understanding the best moment to use it in the battle against multiple myeloma is the great challenge of the future.
GL and FF have nothing to declare. MTP served as a consultant or on an advisory board for and received honoraria from Janssen-Cilag, Celgene, Bristol-Myers Squibb,Amgen, Takeda and Sanofi.
IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. We uphold a flexible Copyright Policy, guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Monograph",metaDescription:"IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.",metaKeywords:null,canonicalURL:"/page/publication-agreement-monograph",contentRaw:'[{"type":"htmlEditorComponent","content":"When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\\n\\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\\n\\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\\n\\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\\n\\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\\n\\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\\n\\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\\n\\nAUTHOR'S DUTIES
\\n\\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\\n\\nThe Author agrees to:
\\n\\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\\n\\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\\n\\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\\n\\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\nAUTHOR'S WARRANTY
\\n\\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\\n\\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\\n\\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\\n\\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\nTERMINATION
\\n\\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\\n\\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\nIntechOpen’s DUTIES AND RIGHTS
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\\n\\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\nMISCELLANEOUS
\\n\\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\\n\\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\\n\\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\\n\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\n\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\n\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nIntechOpen’s DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\n\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\n\nPolicy last updated: 2018-09-11
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5763},{group:"region",caption:"Middle and South America",value:2,count:5227},{group:"region",caption:"Africa",value:3,count:1717},{group:"region",caption:"Asia",value:4,count:10365},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15784}],offset:12,limit:12,total:118187},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"ebgfFaeGuveeFgfcChcyvfu"},books:[],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:14},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:3},{group:"topic",caption:"Business, Management and Economics",value:7,count:1},{group:"topic",caption:"Chemistry",value:8,count:6},{group:"topic",caption:"Computer and Information Science",value:9,count:7},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:15},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:3},{group:"topic",caption:"Materials Science",value:14,count:5},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:28},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:2},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Social Sciences",value:23,count:2},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:0,limit:12,total:null},popularBooks:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9668",title:"Chemistry and Biochemistry of Winemaking, Wine Stabilization and Aging",subtitle:null,isOpenForSubmission:!1,hash:"c5484276a314628acf21ec1bdc3a86b9",slug:"chemistry-and-biochemistry-of-winemaking-wine-stabilization-and-aging",bookSignature:"Fernanda Cosme, Fernando M. Nunes and Luís Filipe-Ribeiro",coverURL:"https://cdn.intechopen.com/books/images_new/9668.jpg",editors:[{id:"186819",title:"Prof.",name:"Fernanda",middleName:null,surname:"Cosme",slug:"fernanda-cosme",fullName:"Fernanda Cosme"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9660",title:"Inland Waters",subtitle:"Dynamics and Ecology",isOpenForSubmission:!1,hash:"975c26819ceb11a926793bc2adc62bd6",slug:"inland-waters-dynamics-and-ecology",bookSignature:"Adam Devlin, Jiayi Pan and Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/9660.jpg",editors:[{id:"280757",title:"Dr.",name:"Adam",middleName:"Thomas",surname:"Devlin",slug:"adam-devlin",fullName:"Adam Devlin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",middleName:null,surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9043",title:"Parenting",subtitle:"Studies by an Ecocultural and Transactional Perspective",isOpenForSubmission:!1,hash:"6d21066c7438e459e4c6fb13217a5c8c",slug:"parenting-studies-by-an-ecocultural-and-transactional-perspective",bookSignature:"Loredana Benedetto and Massimo Ingrassia",coverURL:"https://cdn.intechopen.com/books/images_new/9043.jpg",editors:[{id:"193200",title:"Prof.",name:"Loredana",middleName:null,surname:"Benedetto",slug:"loredana-benedetto",fullName:"Loredana Benedetto"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5221},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9668",title:"Chemistry and Biochemistry of Winemaking, Wine Stabilization and Aging",subtitle:null,isOpenForSubmission:!1,hash:"c5484276a314628acf21ec1bdc3a86b9",slug:"chemistry-and-biochemistry-of-winemaking-wine-stabilization-and-aging",bookSignature:"Fernanda Cosme, Fernando M. Nunes and Luís Filipe-Ribeiro",coverURL:"https://cdn.intechopen.com/books/images_new/9668.jpg",editors:[{id:"186819",title:"Prof.",name:"Fernanda",middleName:null,surname:"Cosme",slug:"fernanda-cosme",fullName:"Fernanda Cosme"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9660",title:"Inland Waters",subtitle:"Dynamics and Ecology",isOpenForSubmission:!1,hash:"975c26819ceb11a926793bc2adc62bd6",slug:"inland-waters-dynamics-and-ecology",bookSignature:"Adam Devlin, Jiayi Pan and Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/9660.jpg",editors:[{id:"280757",title:"Dr.",name:"Adam",middleName:"Thomas",surname:"Devlin",slug:"adam-devlin",fullName:"Adam Devlin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",middleName:null,surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8098",title:"Resources of Water",subtitle:null,isOpenForSubmission:!1,hash:"d251652996624d932ef7b8ed62cf7cfc",slug:"resources-of-water",bookSignature:"Prathna Thanjavur Chandrasekaran, Muhammad Salik Javaid, Aftab Sadiq",coverURL:"https://cdn.intechopen.com/books/images_new/8098.jpg",editedByType:"Edited by",editors:[{id:"167917",title:"Dr.",name:"Prathna",middleName:null,surname:"Thanjavur Chandrasekaran",slug:"prathna-thanjavur-chandrasekaran",fullName:"Prathna Thanjavur Chandrasekaran"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editedByType:"Edited by",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10432",title:"Casting Processes and Modelling of Metallic Materials",subtitle:null,isOpenForSubmission:!1,hash:"2c5c9df938666bf5d1797727db203a6d",slug:"casting-processes-and-modelling-of-metallic-materials",bookSignature:"Zakaria Abdallah and Nada Aldoumani",coverURL:"https://cdn.intechopen.com/books/images_new/10432.jpg",editedByType:"Edited by",editors:[{id:"201670",title:"Dr.",name:"Zak",middleName:null,surname:"Abdallah",slug:"zak-abdallah",fullName:"Zak Abdallah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9671",title:"Macrophages",subtitle:null,isOpenForSubmission:!1,hash:"03b00fdc5f24b71d1ecdfd75076bfde6",slug:"macrophages",bookSignature:"Hridayesh Prakash",coverURL:"https://cdn.intechopen.com/books/images_new/9671.jpg",editedByType:"Edited by",editors:[{id:"287184",title:"Dr.",name:"Hridayesh",middleName:null,surname:"Prakash",slug:"hridayesh-prakash",fullName:"Hridayesh Prakash"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8415",title:"Extremophilic Microbes and Metabolites",subtitle:"Diversity, Bioprospecting and Biotechnological Applications",isOpenForSubmission:!1,hash:"93e0321bc93b89ff73730157738f8f97",slug:"extremophilic-microbes-and-metabolites-diversity-bioprospecting-and-biotechnological-applications",bookSignature:"Afef Najjari, Ameur Cherif, Haïtham Sghaier and Hadda Imene Ouzari",coverURL:"https://cdn.intechopen.com/books/images_new/8415.jpg",editedByType:"Edited by",editors:[{id:"196823",title:"Dr.",name:"Afef",middleName:null,surname:"Najjari",slug:"afef-najjari",fullName:"Afef Najjari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editedByType:"Edited by",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"343",title:"Seed Technology",slug:"horticulture-seed-technology",parent:{title:"Horticulture",slug:"horticulture"},numberOfBooks:1,numberOfAuthorsAndEditors:27,numberOfWosCitations:24,numberOfCrossrefCitations:33,numberOfDimensionsCitations:82,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"horticulture-seed-technology",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"5218",title:"New Challenges in Seed Biology",subtitle:"Basic and Translational Research Driving Seed Technology",isOpenForSubmission:!1,hash:"cbdf379c83007e5a7341c51bcd02db9a",slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",bookSignature:"Susana Araujo and Alma Balestrazzi",coverURL:"https://cdn.intechopen.com/books/images_new/5218.jpg",editedByType:"Edited by",editors:[{id:"156799",title:"Dr.",name:"Susana",middleName:null,surname:"Araújo",slug:"susana-araujo",fullName:"Susana Araújo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,mostCitedChapters:[{id:"51934",doi:"10.5772/64420",title:"Seed Priming: New Comprehensive Approaches for an Old Empirical Technique",slug:"seed-priming-new-comprehensive-approaches-for-an-old-empirical-technique",totalDownloads:6323,totalCrossrefCites:21,totalDimensionsCites:56,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Stanley Lutts, Paolo Benincasa, Lukasz Wojtyla, Szymon Kubala S,\nRoberta Pace, Katzarina Lechowska, Muriel Quinet and Malgorzata\nGarnczarska",authors:[{id:"94090",title:"Prof.",name:"Stanley",middleName:null,surname:"Lutts",slug:"stanley-lutts",fullName:"Stanley Lutts"},{id:"181730",title:"Prof.",name:"Paolo",middleName:null,surname:"Benincasa",slug:"paolo-benincasa",fullName:"Paolo Benincasa"},{id:"181732",title:"Dr.",name:"Lukasz",middleName:null,surname:"Wojtyla",slug:"lukasz-wojtyla",fullName:"Lukasz Wojtyla"},{id:"181733",title:"Dr.",name:"Szymon",middleName:null,surname:"Kubala",slug:"szymon-kubala",fullName:"Szymon Kubala"},{id:"181734",title:"Mrs.",name:"Katzzarina",middleName:null,surname:"Lechowska",slug:"katzzarina-lechowska",fullName:"Katzzarina Lechowska"},{id:"181735",title:"Dr.",name:"Muriel",middleName:null,surname:"Quinet",slug:"muriel-quinet",fullName:"Muriel Quinet"},{id:"181736",title:"Prof.",name:"Malgorzata",middleName:null,surname:"Garnczarska",slug:"malgorzata-garnczarska",fullName:"Malgorzata Garnczarska"}]},{id:"51881",doi:"10.5772/64791",title:"Recent Advances in Seed Enhancements",slug:"recent-advances-in-seed-enhancements",totalDownloads:3825,totalCrossrefCites:7,totalDimensionsCites:13,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Irfan Afzal, Hafeez Ur Rehman, Muhammad Naveed and Shahzad\nMaqsood Ahmed Basra",authors:[{id:"180245",title:"Dr.",name:"Irfan",middleName:null,surname:"Afzal",slug:"irfan-afzal",fullName:"Irfan Afzal"}]},{id:"51743",doi:"10.5772/64466",title:"Effects of Some Hormone Applications on Germination and Morphological Characters of Endangered Plant Species Lilium artvinense L. Seeds",slug:"effects-of-some-hormone-applications-on-germination-and-morphological-characters-of-endangered-plant",totalDownloads:1533,totalCrossrefCites:2,totalDimensionsCites:5,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Kerim Guney, Mehmet Cetin, Hakan Sevik and Kudret Betül Güney",authors:[{id:"93082",title:"Dr.",name:"Hakan",middleName:null,surname:"Sevik",slug:"hakan-sevik",fullName:"Hakan Sevik"},{id:"166881",title:"Ph.D.",name:"Mehmet",middleName:null,surname:"Cetin",slug:"mehmet-cetin",fullName:"Mehmet Cetin"},{id:"181104",title:"Prof.",name:"Kerim",middleName:null,surname:"Guney",slug:"kerim-guney",fullName:"Kerim Guney"},{id:"181105",title:"Dr.",name:"Kudret Betül",middleName:null,surname:"Güney",slug:"kudret-betul-guney",fullName:"Kudret Betül Güney"}]}],mostDownloadedChaptersLast30Days:[{id:"51934",title:"Seed Priming: New Comprehensive Approaches for an Old Empirical Technique",slug:"seed-priming-new-comprehensive-approaches-for-an-old-empirical-technique",totalDownloads:6319,totalCrossrefCites:21,totalDimensionsCites:56,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Stanley Lutts, Paolo Benincasa, Lukasz Wojtyla, Szymon Kubala S,\nRoberta Pace, Katzarina Lechowska, Muriel Quinet and Malgorzata\nGarnczarska",authors:[{id:"94090",title:"Prof.",name:"Stanley",middleName:null,surname:"Lutts",slug:"stanley-lutts",fullName:"Stanley Lutts"},{id:"181730",title:"Prof.",name:"Paolo",middleName:null,surname:"Benincasa",slug:"paolo-benincasa",fullName:"Paolo Benincasa"},{id:"181732",title:"Dr.",name:"Lukasz",middleName:null,surname:"Wojtyla",slug:"lukasz-wojtyla",fullName:"Lukasz Wojtyla"},{id:"181733",title:"Dr.",name:"Szymon",middleName:null,surname:"Kubala",slug:"szymon-kubala",fullName:"Szymon Kubala"},{id:"181734",title:"Mrs.",name:"Katzzarina",middleName:null,surname:"Lechowska",slug:"katzzarina-lechowska",fullName:"Katzzarina Lechowska"},{id:"181735",title:"Dr.",name:"Muriel",middleName:null,surname:"Quinet",slug:"muriel-quinet",fullName:"Muriel Quinet"},{id:"181736",title:"Prof.",name:"Malgorzata",middleName:null,surname:"Garnczarska",slug:"malgorzata-garnczarska",fullName:"Malgorzata Garnczarska"}]},{id:"51881",title:"Recent Advances in Seed Enhancements",slug:"recent-advances-in-seed-enhancements",totalDownloads:3823,totalCrossrefCites:7,totalDimensionsCites:13,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Irfan Afzal, Hafeez Ur Rehman, Muhammad Naveed and Shahzad\nMaqsood Ahmed Basra",authors:[{id:"180245",title:"Dr.",name:"Irfan",middleName:null,surname:"Afzal",slug:"irfan-afzal",fullName:"Irfan Afzal"}]},{id:"52197",title:"Postharvesting Techniques and Maintenance of Seed Quality",slug:"postharvesting-techniques-and-maintenance-of-seed-quality",totalDownloads:2068,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Zubaida Yousaf, Nadia Saleh, Asba Ramazan and Arusa Aftab",authors:[{id:"180675",title:"Dr.",name:"Zubaida",middleName:null,surname:"Yousaf",slug:"zubaida-yousaf",fullName:"Zubaida Yousaf"}]},{id:"51743",title:"Effects of Some Hormone Applications on Germination and Morphological Characters of Endangered Plant Species Lilium artvinense L. Seeds",slug:"effects-of-some-hormone-applications-on-germination-and-morphological-characters-of-endangered-plant",totalDownloads:1532,totalCrossrefCites:2,totalDimensionsCites:5,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Kerim Guney, Mehmet Cetin, Hakan Sevik and Kudret Betül Güney",authors:[{id:"93082",title:"Dr.",name:"Hakan",middleName:null,surname:"Sevik",slug:"hakan-sevik",fullName:"Hakan Sevik"},{id:"166881",title:"Ph.D.",name:"Mehmet",middleName:null,surname:"Cetin",slug:"mehmet-cetin",fullName:"Mehmet Cetin"},{id:"181104",title:"Prof.",name:"Kerim",middleName:null,surname:"Guney",slug:"kerim-guney",fullName:"Kerim Guney"},{id:"181105",title:"Dr.",name:"Kudret Betül",middleName:null,surname:"Güney",slug:"kudret-betul-guney",fullName:"Kudret Betül Güney"}]},{id:"51388",title:"Seed Germination Technologies for Helophyte Production Used in Wastewater Treatment",slug:"seed-germination-technologies-for-helophyte-production-used-in-wastewater-treatment",totalDownloads:1178,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Trinidad Ruiz-Téllez, Francisco M. Vázquez-Pardo, José Blanco-Salas\nand F. Javier Carbonell-Espín",authors:[{id:"180723",title:"Prof.",name:"Trinidad",middleName:null,surname:"Ruiz Téllez",slug:"trinidad-ruiz-tellez",fullName:"Trinidad Ruiz Téllez"},{id:"181957",title:"Dr.",name:"José",middleName:null,surname:"Blanco Salas",slug:"jose-blanco-salas",fullName:"José Blanco Salas"},{id:"181958",title:"Mr.",name:"Javier",middleName:null,surname:"Carbonell Espín",slug:"javier-carbonell-espin",fullName:"Javier Carbonell Espín"},{id:"181959",title:"Dr.",name:"Francisco María",middleName:null,surname:"Vázquez Pardo",slug:"francisco-maria-vazquez-pardo",fullName:"Francisco María Vázquez Pardo"}]},{id:"51642",title:"Designing Novel Breeding Strategies for Producing High-Oil Crops Based on a Molecular Understanding of Triacylglycerol Metabolism",slug:"designing-novel-breeding-strategies-for-producing-high-oil-crops-based-on-a-molecular-understanding-",totalDownloads:1398,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Masatake Kanai, Shoji Mano, Makoto Hayashi and Mikio Nishimura",authors:[{id:"124407",title:"Dr.",name:"Shoji",middleName:null,surname:"Mano",slug:"shoji-mano",fullName:"Shoji Mano"},{id:"124408",title:"Prof.",name:"Mikio",middleName:null,surname:"Nishimura",slug:"mikio-nishimura",fullName:"Mikio Nishimura"},{id:"181879",title:"Dr.",name:"Masatake",middleName:null,surname:"Kanai",slug:"masatake-kanai",fullName:"Masatake Kanai"},{id:"181882",title:"Prof.",name:"Makoto",middleName:null,surname:"Hayashi",slug:"makoto-hayashi",fullName:"Makoto Hayashi"}]},{id:"52023",title:"Signaling Patterns of Reactive Oxygen Species and Phytohormones During Transition Period of Quiescent Seeds into Metabolically Active Organisms",slug:"signaling-patterns-of-reactive-oxygen-species-and-phytohormones-during-transition-period-of-quiescen",totalDownloads:1319,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Prabhakaran Soundararajan, Abinaya Manivannan and Byoung\nRyong Jeong",authors:[{id:"180921",title:"Prof.",name:"Byoung Ryong",middleName:null,surname:"Jeong",slug:"byoung-ryong-jeong",fullName:"Byoung Ryong Jeong"},{id:"182193",title:"Ph.D. Student",name:"Prabhakaran",middleName:null,surname:"Soundararajan",slug:"prabhakaran-soundararajan",fullName:"Prabhakaran Soundararajan"},{id:"185493",title:"Dr.",name:"Abinaya",middleName:null,surname:"Manivannan",slug:"abinaya-manivannan",fullName:"Abinaya Manivannan"}]},{id:"51923",title:"The Dynamics of Plant Cell Wall In Muro Modifications and its Physiological Implications on Seed Germination",slug:"the-dynamics-of-plant-cell-wall-in-muro-modifications-and-its-physiological-implications-on-seed-ger",totalDownloads:961,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"new-challenges-in-seed-biology-basic-and-translational-research-driving-seed-technology",title:"New Challenges in Seed Biology",fullTitle:"New Challenges in Seed Biology - Basic and Translational Research Driving Seed Technology"},signatures:"Ximena Gómez‐Maqueo and Alicia Gamboa‐deBuen",authors:[{id:"115057",title:"Dr.",name:"Alicia",middleName:null,surname:"Gamboa-De Buen",slug:"alicia-gamboa-de-buen",fullName:"Alicia Gamboa-De Buen"},{id:"181871",title:"Ph.D. Student",name:"Ximena",middleName:null,surname:"Gómez-Maqueo",slug:"ximena-gomez-maqueo",fullName:"Ximena Gómez-Maqueo"}]}],onlineFirstChaptersFilter:{topicSlug:"horticulture-seed-technology",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/188831/palsamy-periyasamy",hash:"",query:{},params:{id:"188831",slug:"palsamy-periyasamy"},fullPath:"/profiles/188831/palsamy-periyasamy",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()