Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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With innovations on the horizon, the future of wearable devices will go beyond answering calls or counting our steps to providing us with sophisticated wearable gadgets capable of addressing fundamental and technological challenges. This book investigates the development of wearable technologies across a range of applications from educational assessment to health, biomedical sensing, and energy harvesting. Furthermore, it discusses some key innovations in micro/nano fabrication of these technologies, their basic working mechanisms, and the challenges facing their progress.",isbn:"978-1-78984-497-9",printIsbn:"978-1-78984-496-2",pdfIsbn:"978-1-83880-342-1",doi:"10.5772/intechopen.77458",price:119,priceEur:129,priceUsd:155,slug:"wearable-devices-the-big-wave-of-innovation",numberOfPages:144,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"46b13f25dc9a1576e355717c903d81bc",bookSignature:"Noushin Nasiri",publishedDate:"December 4th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7654.jpg",numberOfDownloads:10643,numberOfWosCitations:16,numberOfCrossrefCitations:27,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:34,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:77,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 25th 2018",dateEndSecondStepPublish:"December 17th 2018",dateEndThirdStepPublish:"February 15th 2019",dateEndFourthStepPublish:"May 6th 2019",dateEndFifthStepPublish:"July 5th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"234150",title:"Dr.",name:"Noushin",middleName:null,surname:"Nasiri",slug:"noushin-nasiri",fullName:"Noushin Nasiri",profilePictureURL:"https://mts.intechopen.com/storage/users/234150/images/system/234150.jpg",biography:"Dr Noushin Nasiri is the head of NanoTech Laboratory at the\nSchool of Engineering, Macquarie University, Sydney, Australia. Her research team focuses on the multiscale engineering of\nadvanced nanomaterials and devices for medical, energy, and environmental applications. Her research lies at the intersection of\nscience, technology, and engineering, as she works on fabricating\nfingertip-sized nanostructured sensors capable of measuring\nUV dosage absorbed by skin to improve sun safety and prevent skin cancer, detecting disease biomarkers through analysing human breath, and monitoring levels of\nenvironmentally important gases.\nOutside the lab, Dr Nasiri is a professional science communicator and her research\nhas been recognized with several prestigious talks including TEDx Sydney in 2017,\nTEDx Macquarie University in 2019, and TEDx Bligh Street in 2020.",institutionString:"Macquarie University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Macquarie University",institutionURL:null,country:{name:"Australia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1364",title:"Emerging Technologies",slug:"emerging-technologies"}],chapters:[{id:"69186",title:"Introductory Chapter: Wearable Technologies for Healthcare Monitoring",doi:"10.5772/intechopen.89297",slug:"introductory-chapter-wearable-technologies-for-healthcare-monitoring",totalDownloads:827,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:null,signatures:"Noushin Nasiri",downloadPdfUrl:"/chapter/pdf-download/69186",previewPdfUrl:"/chapter/pdf-preview/69186",authors:[{id:"234150",title:"Dr.",name:"Noushin",surname:"Nasiri",slug:"noushin-nasiri",fullName:"Noushin Nasiri"}],corrections:null},{id:"67018",title:"Noninvasive Acquisition of the Aortic Blood Pressure Waveform",doi:"10.5772/intechopen.86065",slug:"noninvasive-acquisition-of-the-aortic-blood-pressure-waveform",totalDownloads:1157,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Blood pressure reflects the status of our cardiovascular system. 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Second, finding appropriate materials, configurations and placements of electrodes is of interest. Third, the results of modelling and simulations are discussed for obtaining the best sensitivity and stability of the measurement procedures. Finally, the discussion on the provided provisional experiments evaluates the obtained results. The conclusions are drawn together with the need for further development.",signatures:"Mart Min, Hip Kõiv, Eiko Priidel, Ksenija Pesti and Paul Annus",downloadPdfUrl:"/chapter/pdf-download/67018",previewPdfUrl:"/chapter/pdf-preview/67018",authors:[{id:"62780",title:"Prof.",name:"Mart",surname:"Min",slug:"mart-min",fullName:"Mart Min"},{id:"299121",title:"MSc.",name:"Hip",surname:"Kõiv",slug:"hip-koiv",fullName:"Hip Kõiv"},{id:"299122",title:"MSc.",name:"Ksenija",surname:"Pesti",slug:"ksenija-pesti",fullName:"Ksenija Pesti"},{id:"299123",title:"MSc.",name:"Eiko",surname:"Priidel",slug:"eiko-priidel",fullName:"Eiko Priidel"},{id:"299124",title:"Dr.",name:"Paul",surname:"Annus",slug:"paul-annus",fullName:"Paul Annus"}],corrections:null},{id:"67016",title:"Wearable Skin-Worn Enzyme-Based Electrochemical Devices: Biosensing, Energy Harvesting, and Self-Powered Sensing",doi:"10.5772/intechopen.85459",slug:"wearable-skin-worn-enzyme-based-electrochemical-devices-biosensing-energy-harvesting-and-self-powere",totalDownloads:1865,totalCrossrefCites:5,totalDimensionsCites:5,hasAltmetrics:1,abstract:"Integrating enzymes with wearable electrochemical systems delivers extraordinary functional devices, including biosensors and biofuel cells (BFCs). Strategies employing enzyme-based bioelectronics represent a unique foundation of wearables because of specific enzyme recognition and catalytic activities. Therefore, such electrochemical biodevices on various platforms, e.g., tattoos, textiles, and wearable accessories, are interesting. However, these devices need effective power sources, requiring combining effective energy sources, such as BFCs, onto compact and conformal platforms. Advantageously, bioenergy-harvesting BFCs can also act as self-powered sensors, simplifying wearable systems. Challenges pertaining to energy requirements and the integration of biocatalysts with electrodes should be considered. In this chapter, we detail updated advancement in skin-worn devices, including biosensors, BFCs, and self-powered sensors, along with engineering designs and on-skin iontophoretic strategies to extract biofluids. Crucial parameters including mechanical/material aspects (e.g., stretchability), electrochemistry, enzyme-related views (e.g., electron shuttles, immobilization, and behaviors), and oxygen dependency will be discussed, along with outlooks. 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The automatic detection of breathing patterns is equally important in other respiratory rehabilitation therapies, for example, magnetic resonance exams for respiratory triggered imaging, and synchronized functional electrical stimulation. In this context, the goal of many research groups is to create wearable devices able to monitor breathing activity continuously, under natural physiological conditions in different environments. Therefore, wearable sensors that have been used recently as well as the main signal processing methods for breathing analysis are discussed. The following sensor technologies are presented: acoustic, resistive, inductive, humidity, acceleration, pressure, electromyography, impedance, and infrared. 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Smartphones are becoming increasingly popular, both in formal and informal educational environments. This chapter discusses the benefits and obstacles in using smartphones as an assessment tools and it compares the achievement of exams delivered via smart phones to paper-based exams. 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\r\n\tAutism spectrum disorders (ASD) are neurodevelopmental disorders with peculiar biology and genetics with still unclear etiology. ASD represents a relevant and impacting disease with increasing worldwide prevalence. The scope of the present book is to improve the global knowledge in the ASD field with a particular interest in the new clinical and therapeutic trends.
\r\n
\r\n\tThe book's contents will be written by multiple authors and edited by experts (s) in the field. Authors are not limited in terms of topic but are encouraged to present a chapter proposal that best suits their current research efforts. We accept scientific papers which can be presented as original research papers and review papers. The required length of the full chapters is 10-20 pages, and the chapters should be original works (not republished).
\r\n
\r\n\tAs a self-contained collection of scholarly papers, this book will target an audience of practicing researchers, academics, Ph.D. students, and other scientists. This book will be published as an Open Access publication allowing for unrestricted online access to all chapters with no subscription fees.
",isbn:"978-1-83768-343-7",printIsbn:"978-1-83768-342-0",pdfIsbn:"978-1-83768-344-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"934f063be3eacb5dd0902ae8bc622392",bookSignature:"Associate Prof. Marco Carotenuto",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11588.jpg",keywords:"Diagnosis, Epidemiology, Autism Genetic Testing, Autism Candidate Genes, Autism Epigenetics, Environmental Risk Factors, Neurochemistry of Autism, Brain Structure, Brain Connectivity, MRI, fMRI, Neurophysiology of Autism",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 8th 2022",dateEndSecondStepPublish:"July 6th 2022",dateEndThirdStepPublish:"September 4th 2022",dateEndFourthStepPublish:"November 23rd 2022",dateEndFifthStepPublish:"January 22nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Associate Professor of Child and Adolescent Neuropsychiatry at Università degli Studi della Campania Luigi Vanvitelli in Italy and Chief of the Clinic of Child and Adolescent Neuropsychiatry whose main research areas are child neurology, pediatric sleep disorders, polysomnography, pediatric primary headaches, and pediatric rehabilitation.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"305627",title:"Associate Prof.",name:"Marco",middleName:null,surname:"Carotenuto",slug:"marco-carotenuto",fullName:"Marco Carotenuto",profilePictureURL:"https://mts.intechopen.com/storage/users/305627/images/system/305627.jpg",biography:"Marco Carotenuto is Associate Professor of Child and Adolescent Neuropsychiatry at Università degli Studi della Campania Luigi Vanvitelli in Italy and Chief of the Clinic of Child and Adolescent Neuropsychiatry. 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1. Introduction
Direct repair is defined as the elimination of DNA and RNA damage using chemical reversion that does not require a nucleotide template, breakage of the phosphodiester backbone or DNA synthesis. As such, the process of direct repair is completely error-free, granting a major advantage in preservation of genetic information. In mammalian cells, direct repair is utilized to repair specific types of DNA and RNA damage caused by ubiquitous alkylating agents. Only two major types of proteins conduct direct repair in mammalian cells, O6-methylguanine-DNA methyltransferase (MGMT or AGT) and ALKBH family Fe(II)/α-ketoglutarate dioxygenases (FeKGDs). In humans and mice, a single direct repair methyltransferase protein exists, MGMT. In contrast, ALKBH FeKGDs represent a family of nine homologs with conserved active site domains. Although the biochemical function of a number of ALKBH proteins and their biological roles require further investigation, several directly repair alkylation damage in DNA and RNA at base-pairing sites.
2. Direct repair substrates—DNA and RNA alkylation damage
Exposure to alkylating agents is major cause of DNA and RNA damage, generating adducts that can compromise genomic integrity. As a result, repair of alkylation adducts is mediated by a variety of DNA repair pathways, some with overlapping substrate specificity. However, direct DNA repair proteins utilize unique mechanisms to specifically eliminate damage at base-pairing sites. The frequency and site of DNA and RNA damage occurrence is dependent on the source and type of alkylating agent exposure, as discussed in this section.
3. Sources of alkylation damage
Alkylating agents are present environmentally and also generated within the cell via oxidative metabolism. They modify DNA and RNA, forming adducts that disrupt replication and transcription, trigger cell cycle checkpoints, and/or initiate apoptosis. If left unrepaired, some adducts formed by alkylation damage can be cytotoxic and/or mutagenic [1-3].
Environmental alkylating agents fall into two primary groups, nitrosoureas that generate primarily O-alkylations and methanesulfonates that cause mostly N-alkylations [1, 3] (Figure 1). These exogenous alkylating agents are present in air, water, plants and food, in the form of nitrosamines, chloro- and bromomethane gases, myosamines and halocarbons [4]. There are also industrially produced alkylating agents, including various chemotherapeutic agents [5, 6].
Figure 1.
Examples of nitrosourea and methanesulfonate alkylating agents. (A) Nitrosourea, SN1, alkylating agents. Abbrevations are as follows: methylnitrosourea (MNU); ethylnitrosourea (ENU); 1,3-bis (2chloroethyl)-1-nitrosourea (BCNU); N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea- (CCNU); N-methyl-N-nitro-N-nitrosoguanidine (MNNG); N-ethyl-N-nitro-N-nitrosoguanidine (ENNG). (B) Methanesulfonate, SN2, alkylating agents. Abbrevations are as follows: dimethylsufate (DMS); diethylsulfate (DES); methylmethanesulfonate (MMS); ethylmethanesulfonate (EMS). [14]
Enzymes involved in cellular metabolism are responsible for the majority of endogenous alkylating agent damage. Nitrosating agents are generated, resulting in amine nitrosation, and reactive oxygen species (ROS), which cause lipoperoxidation [7]. Additionally, a family of S-adenosyl methionine (SAM) methyltransferase enzymes is involved in more than 40 metabolic reactions using SAM as a methyl donor to modify nucleic acids, proteins and lipids [8, 9]. Four of those SAM methyltransferase enzymes participate in DNA and RNA modification in mammalian cells. DNMT1, DNMT3A, and DNMT3B catalyze methyl group transfer at the C5 position of cytosine in DNA CpG sequences [10], whereas TRDMT1 (DNMT2) methylates the C5 position of cytosine 38 in aspartic acid tRNA [11].
3.1. Types of alkylating agents
Alkylating agents can be categorized by their method of activation. Some alkylating agents react directly with DNA and do not require any activation, whereas many alkylating agents, including many carcinogens, must undergo metabolic activation by the cytochrome P450 system to generate reactive species capable of modifying DNA [3, 12, 13]. In addition, alkylating agents are electrophilic compounds that possess either one or two reactive groups that can interact with the nucleophilic centers of DNA and RNA bases. Alkylating agents that can only react with one nucleophilic center are mono-functional, whereas bi-functional agents can react with two sites in DNA or RNA [1, 13]. Alkylating agents that are mono-functional primarily transfer alkyl groups to ring nitrogens, while agents that react in a bi-functional manner not only react with ring nitrogens, but can form cyclized DNA bases, by reacting with exocylic nitrogen and oxygen groups [13] (Figure 2). In addition to methylating agents, larger alkylating agents also modify nucleic acids—bi-functional ethylating agents can form exocyclic ethano and etheno adducts at nitrogen and oxygen molecules in all DNA and RNA bases. Additionally, bi-functional alkylating agents can produce DNA inter- and/or intrastrand cross-links [13]. Some alkylating agents also react at phosphate residues to generate phosphotriesters, leading to potential single-strand breaks [13] (Figure 2). Two main pathways, characterized as SN1 or SN2, are defined based on the kinetics of the alkylation reaction, leading to the above mentioned modifications of DNA and RNA bases [2].
Figure 2.
(A) Purple arrows indicate sites in DNA most often methylated by SN1 alkylating agents. Green arrows indicate sites commonly modified by SN2 alkylating agents, orange arrows indicate sites in single-stranded DNA. Blue arrows indicate exocyclic amino groups important in formation of cyclized DNA adducts. The location of the major and minor grooves in DNA are indicated. “R” is the attachment of the base to the deoxyribose and phosphodiester backbone. (B) Modified phosphodiester isoforms in the DNA backbone. SN1 alkylating agents generally form more phosphotriester products than SN2 agents. [2,14]
SN1 agents act via a two step reaction involving a unimolecular nucleophilic substitution with a rate-limiting step that generates an intermediate carbonium ion electrophile that reacts with nucleophilic DNA sites. Thus, the reaction kinetics depend only on the formation of the carbonium ion intermediate (first-order). The triganol planar conformation of the sp2 hybridized carbon generated in the carbocation intermediate permits nucleophilic attack from either side, yielding a racemic mixture of reaction products at chiral centers [13] (Figure 3). Though agents that react via an SN1 mechanism produce both N- and O-alkylations, increased amounts of modified oxygens are generated, compared to agents that react via an SN2 mechanism.
Figure 3.
SN1 and SN2 nucleophilic substitution reactions. (A) Example of an SN1 reaction. SN1 reactions are dependent on formation of a carbonium ion intermediate that rate-limiting. Product chiral centres are a racemic mixture because the intermediate can be attacked by either side. (B) Example of an SN2 reaction. Both reactants are required and there is direct attack by the nuclephile in SN2 reactions. Chirality is maintained since a transition state is formed with the chiral center. [2,14]
In contrast, SN2 reaction mechanisms depend on both the alkylating agent and its target to define the kinetics (second-order). Using a one step reaction where both the electrophile and nucleophile are involved in the transition state, SN2 alkylating agents proceed with direct attack by the nucleophile on an electron deficient center. The nucleophile attacks from the back of the electrophile, forming the carbon-nucleophile bond and breaking the carbon-leaving group bond. Simultaneous backside, nucleophilic attack and leaving group departure cause the incoming group to replace the leaving group. Because a transition state is formed with the chiral center, chirality is maintained, leading to a stereocenter (inversion) configuration [13] (Figure 3). Alkylating agents that react via an SN2 mechanism cause primarily N-alkylations.
3.2. DNA and RNA alkylation damage
Modification sites of DNA bases are the same for all alkylating agents and include all the exocyclic nitrogens and oxygens, as well as ring nitrogens without hydrogen. Though all DNA nucleobase oxygen or nitrogen atoms can be alkylated, the type and frequency of specific damage varies depending on the type of alkylating agent, the structure of the substrate, and the position of the damage site [13] (Table 1). Generally, alkylation damage at nitrogen molecules is less mutagenic than oxygen, though both types of alkylation damage are cytotoxic and genotoxic [14].
Common alkylations generated by exogenous alkylating agents include O6-alkylguanine and O4-alkylthymine adducts, as well as N7-alkylguanine, N3-alkyladenine, N1-alkyladenine, and N3-alkylcytosine [13] (Figure 1). Moreover, the frequency of each adduct type depends on whether the DNA and RNA substrates are single- or double-stranded [13] (Table 1). For instance, nitrogen molecules involved in DNA base-pairing are less vulnerable to alkylation damage than the same base nitrogens in a single-stranded region arising during replication and transcription.
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t
\n\t
Table 1.
% of Total DNA alkylation adduct formation in single- and double-strand DNA. Modifications following SN2 alkylating agent methylmethanesulfonate (MMS) or SN1 alkylating agent treatments methylnitrosourea (MNU) or ethylnitrosourea (ENU). Sites where % alkylation is undetermined are indicated as (--) [13].
4. Direct repair proteins
Numerous cellular mechanisms have evolved to deal with various types of DNA damage and each DNA repair pathway is important to maintain genomic integrity. However, most repair mechanisms require DNA synthesis and therefore an intrinsic risk of causing mutation in executing the repair. In contrast, direct repair proteins, MGMT and ALKBH family proteins employ direct reversal mechanisms that result in complete restoration of DNA bases and are thus error-free mechanisms. Moreover, MGMT, ALKBH2, and ALKBH3 repair endogenous and exogenous DNA and RNA alkylation damage at critical base-pairing sites, facilitating proper replication of genetic information or transcription. This section will discuss each of these direct DNA repair enzymes in detail.
Figure 4.
Major mechanisms of alkylation adduct repair. Direct repair pathways are indicated in green. Base and nucleotide excision repair pathways are indicated in blue [2,14].
4.1. Mechanisms of alkylation repair
Multiple mechanisms are employed to rid the genome of alkyl adducts, thereby preventing detrimental effects within the cell (Figure 4). Mismatch repair (MMR), base excision repair (BER) and nucleotide excision repair (NER) and direct repair (DR) pathways all participate in alkylation damage repair [15-24]. Specifically, BER and NER repair small alkylated base damage including 7-methylguanine (7-meG) and 3-methyladenine (3-meA) DNA adducts [25]. Although BER repairs the majority of small alkylated base damage (methyl and ethyl adducts) the NER system can also remove small, as well as bulky adducts larger than ethylated bases [24, 26]. As an alternative to NER, incomplete BER repair intermediates can be processed by homologous recombination (HR) [27]. However, BER, NER and HR repair pathways generate strand breaks during repair of alkyl adducts and could introduce mutations or rearrangements [28]. On the contrary, DR mechanisms, provided by methyltransferase MGMT and ALKBH homologs, eliminate alkylation damage at DNA base-pairing sites, including O6-methylguanine (O6-meG), 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) and do not require a nucleotide template, result in phosphodiester backbone breakage, nor do they require DNA synthesis.
In mammals, methylguanine DNA methyltransferase (MGMT or AGT), can repair two types of DNA adducts: O6-methylguanine (O6-meG) and O4-methylthymine (O4-meT). O6-meG adducts in DNA are extremely mutagenic [29, 30] and also block DNA polymerase extension, which is generally associated with cytotoxicity [31, 32]. The primary mutations observed when there is a failure to repair O6-meG adducts prior to replication are G:CA:T transitions, whereas a failure to repair O4-meT results primarily in T:AC:G transition mutations [29]. In mammals, elimination of O6-meG by MGMT is preferred over O4-meT, but the respective efficiency of each type of reversion is species dependent [29, 33-37].
Removal of O6-meG and O4-meT modifications are achieved via a one-step methyltransferase reaction, wherein MGMT accepts the alkyl adduct from the modified oxygen molecule, onto an internal residue, directly restoring the DNA base and inactivating the protein [38] (Figure 5). In addition to methyl groups, several other alkyl-adducts can also be transferred from guanine to MGMT, including ethyl-, propyl- butyl-, benzyl- and 2-chloroethyl-. However, the efficiency of the reaction is decreased for alkyl adducts greater than methylated bases [39]. Once modified, the protein is targeted for elimination via the proteasome [40].
4.2.1. Protein structure/active site organization
Alkyltransferase proteins are found in eukaryotic and prokaryotic organisms and have been identified in as many as 100 organisms [41]. Though sequences are not highly conserved between human MGMT and Eubacterial, Archea, and Eukaryotic DNA methyltransferase enzymes, structural domains and active site residues are almost identical [42-46].
Figure 5.
Methylguanine methyltransferase (MGMT) activity. (A) MGMT DNA repair substrates (B) MGMT repair reaction. Transfer of the methyl group (orange) from the damaged DNA base to the internal Cys145 (light green) is a suicide reaction, inactivating MGMT. [14]
In human MGMT, a conserved α/β roll structure, containing a three-stranded, anti-parallel β-sheet, followed by two helices, make up the N-terminus (residues 1-85). The MGMT C-terminus (residues 86-207) contains a short, two-stranded, parallel β-sheet, four α-helices and a 310 helix [42, 47]. Found only in humans, a zinc ion stabilizes the interface between the N- and C-termini, binding Cys5, Cys24, His29 and His85 in a tetrahedral conformation to bridge three strands of the N-terminal β-sheet with the coil preceding the 310 helix in the C-terminus [47].
The conserved active site cysteine motif (-PCHR-) is located in the C-terminus contained within the DNA binding channel, and the helix-turn-helix (HTH) DNA binding motif. Residues Try114-Ala121 form the first helix of the HTH motif and residues Ala127-Gly136 form the second, “recognition” helix, which interacts with DNA. Linked by an Asn-hinge (Asn137) that stabilizes the over-lapping turns by binding Val139, Ille143 and the Cys145 thiol, the -PHCR- active site is located near the “recognition” helix [42, 47, 48].
The active site of human MGMT is composed of at least ten residues that participate in substrate binding, enzyme structure and alkyl transfer. Residues Val155-Gly160 and Met134 generate a hydrophobic cleft in the active site loop, while residues Tyr114, His146, Val148, Ser159, and Glu172 participate in active site coordination and alkyl group transfer to residue Cys145. Not unexpectedly, mutation of residue Cys145 results in elimination of alkyl group transfer, however substrate binding is unaffected [49] (Figure 6).
Figure 6.
Structure of human MGMT (PDBid1QNT). The N-termianl p-sheet and C-terminal 310 helix of the α/β roll structure, conserved in AGT proteins are indicated. In humans, a zinc ion stabilizes interaction of MGMT N-and C-termini [46].
4.2.2. Substrate recognition/repair mechanism
In repair, MGMT is unique in that one molecule is responsible for the removal of one O6-meG or O4-meT adduct. Unlike most enzymes with the capacity to catalyze multiple reactions, MGMT catalyzed reactions are stoichiometric and capable of only a single repair reaction [50]. As a result, removal of O6-meG and O4-meT alkyl adducts is dependent on both MGMT and the substrate concentrations (second-order reaction).
The recognition of guanine and thymine base methylation is accomplished by a highly conserved amino acid structure. The hydrophobic cleft of the active site loop and -PCHR- motif within the binding channel allow MGMT to bind to the minor-groove of DNA using residues Ala126, Ala127, Ala129, Gly131, and Gly132, of the HTH “recognition” helix [51, 52], which is followed by necessary conformational changes to orient the damaged base within the active site.
Identified based on bacterial Ada homology and human MGMT structures, following substrate recognition, the target base is repaired using a base flipping mechanism [53-58]. In the MGMT repair reaction, the damaged base undergoes a residue Tyr114-mediated, sterically enforced 3’ phosphate rotation into the active-site pocket. The hydrophobic cleft formed by the active site loop easily accepts the extra-helical base, causing the DNA minor groove to widen [51]. The arginine finger residue, Arg128, intercalates between the DNA bases and interacts with the unpaired cytosine, via a charged hydrogen bond [55], maintaining an appropriate DNA duplex conformation (Figure 6).
Once bound within the MGMT active site, numerous residues participate in the methyltransferase reaction. A hydrogen bond network, conserved in AGTs, is formed between Glu172, His146, water and Cys145. His146 acts as a water-mediated base that deprotonates Cys145, converting Cys145 to a cystine thiolate anion and generating an imidazolium ion that is stabilized by Glu172 [35, 59]. Residues, Val148 and Cys145 carbonyls accept guanine exocyclic amine hydrogen bonds and nitrogen atoms of residues Tyr114 and Ser159 donate protons to N3 and O6 of O6-meG, respectively. The deprotonated Tyr114 residue abstracts a proton from Lys165, simultaneously transferring the alkyl group from the O6 position of guanine to the thiolate anion of the Cys145 residue [35]. Transfer of the alkyl group generates a thioether, S-alkylcysteine, and results in complete restoration of the guanine base, as well as irreversible inactivation of the methyltransferase enzyme (Figure 5). While many DNA repair proteins have a specific requirement for double-stranded DNA, MGMT can also bind to single-stranded DNA [60].
4.2.3. Gene expression/protein regulation
Removal of O6-meG modifications by MGMT has a major role in cell cycle checkpoint control, proliferation, and differentiation [61]. As a result, MGMT is a house-keeping gene that is expressed in all tissues; though expression varies depending on cell type [62]. MGMT expression in an individual cell or tissue type is dependent on a variety of factors, including numerous types of stimuli and promoter regulator elements. However, the relationship between factors that mediate MGMT expression and the regulation of its function is not well-understood. The lack of understanding regarding the consequences of MGMT regulation is illustrated by the fact that MGMT expression is silenced in some cancers, but expression is up-regulated in others [62, 63].
MGMT is a single gene on chromosome 10q26, spanning approximately 300kb [64]. The gene has five exons, but the first is non-coding [65, 66]. The promoter of MGMT is a non-TATA-box promoter that contains a GC-rich CpG island of 780 bp that includes 97 CpG dinucleotides [67]. CpG islands are commonly associated with promoter regions of constitutively expressed genes, from which transcription is initiated from a single promoter site [68-70]. Additionally, the promoter contains six transcription consensus binding sites (SP1, AP1, and AP2), three upstream and three downstream of the transcription start site, a glucocorticoid-responsive element, and a 3’ enhancer element [62, 67, 69, 71]. Though unmethylated in normal cells, promoter CpG island methylation-induced silencing of MGMT is found in various cancer types and MGMT-deficient cell lines and is one mechanism that regulates MGMT expression [72-76]. However, whether MGMT promoter methylation disables transcription factor binding or contributes to chromatin reorganization remains uncertain [71, 75].
In addition to numerous transcription factor binding sites that surround the MGMT promoter transcription start site, the MGMT promoter CpG islands exhibit a chromatin structure that mediates interaction with transcription factors. The MGMT gene is organized around five or more nucleosomes in a manner that positions 300 bp region of the promoter sequence, which contains known MGMT transcription factor binding sites, so that it does not lie within the nucleosomes, and therefore does not maintain a higher-order chromatin structure [62, 72, 77]. Such nucleosomal positioning facilitates an “open” stretch of DNA that enables constitutive interaction of transcription factors with the promoter.
Methylation of the CpG island surrounding the transcription factor binding sites contributes to lack of transcription factor binding, but could also effect nucleosomal positioning of the MGMT promoter [62, 71], suggested by histone H3 Lys9 (H3K9) di-methylation, exhibited in relationship to MGMT silencing [78, 79]. Further, deacetylation of histones H3 and H4 could also be associated nucleosome organization that is more condensed, resulting in transcription inactivation. Therefore, the chromatin structure of the MGMT promoter, as well as CpG island methylation, mediate transcription factor access to the promoter and are important for MGMT expression.
4.2.4. Protein localization and cell type dependence
Immunofluorescence studies indicate MGMT nuclear localization at discrete nuclear regions [80]. Although a nuclear localization signal (NLS) for MGMT has not been identified, the small size of MGMT, 23 kDa, may not require an active translocation signal to traverse nuclear pores [53]. However, a –PKAAR- sequence within the DNA binding domain of MGMT is necessary for DNA interactions to facilitate nuclear retention [81]. The highest MGMT expression levels are found in the liver, where high levels of endogenous nitrosating agents are present, but MGMT is also expressed at high levels in the lung, kidney and colon. MGMT expression is heterogeneous in the brain and the lowest levels are observed in the pancreas, hematopoietic cells, lymphoid tissues [62, 67, 82-86].
4.2.5. Post-translational modification
Once MGMT has transferred a methyl group to its Cys145 residue, no further reactions are catalyzed, so the protein must be eliminated. The degradation of MGMT is an ubiquitination-dependent process that has been evaluated using inactivation of the protein by O6-BzG, BCNU, or NO-generating agents at position Cys145 [40, 87, 88]. Conformational changes in the protein structure after alkyl group transfer target MGMT for ubiquitination and proteasomal degradation [40, 89]. Two sites within MGMT, Lys125 and Lys178, have been identified as ubiquitination targets in B lymphocyte (NCI-H929) or 293T, and myeloid (MV4-11) cells, respectively. Additionally, examination of potential MGMT modification sites using predictive software also identifies Lys104 as an ubiquitination target. Furthermore, predictions also indicate post-translational modification sites for methylation (Arg128, Arg135), acetylation (Lys8, 125, 178, 193), and sumoylation (Lys75, 205, 18, 107), as well as numerous phosphorylation sites (Ser36, 56, 130, 182, 202, 206, 208; Thr37; Tyr91, 115) [90-93], which all merit further consideration. Notably, phosphorylation of residues Thr10 and Thr11 was also noted in HeLa cells [92], and phosphorylation of Ser201 is observed in B lymphocyte cells (DG75 and GM00130), KGI myeloid cells, and HeLa cervical cancer cells. Importantly, crystallographic data suggests that modification of Ser201 could disrupt interaction with DNA [48, 51, 55].
In mammals, repair of cytosine and adenine base methylation at base-pairing positions is specifically associated with the AlkB family dioxygenase proteins [92, 94-96]. Discovered first in Escherichia coli (E. coli) in 1983 [96] alkylation protein B (AlkB) belongs to a super-family of Fe(II)/α-ketoglutarate-dependent dioxygenases (FeKGDs), with roles in histone demethylation [97-99], proline hydroxylation [95] and in the case of AlkB, the ability to directly remove alkyl adducts generated in DNA residues as a result of exposure to SN2 alkylating agents [94, 100]. Originally predicted to act on 1-methyladenine (1-meA) and 3-methylcytosine (3-meC), bacterial AlkB has been shown to repair a variety of DNA and RNA adducts, including 1-meA, 3-meC, 1-meG, 3-meT, 1-etA, as well as aromatic ethyl, 3-etC, and etheno adducts, 1,N6-ethenoadenine (εA) and 3,N4-ethenocytosine (εC) [94, 100-108] (Figure 7).
Figure 7.
ALKBH protein substrates. (A) DNA methyl adducts repaired by ALKBH proteins. (B) DNA etheno adducts repaired by ALKHB proteins.
Using bioinformatics, nine human ALKBH family enzymes, ALKBH1-8 and FTO, were identified, of which only four have been reported to have DNA repair activity, ALKBH1 – ALKBH3 and FTO [109, 110]. Though all of the ALKBH homologs contain conserved catalytic domain residues, none entirely encompass the enzymatic activity of AlkB [15, 103, 104, 111-114]. Removal of alkyl adducts from DNA is only accomplished by three ALKBH proteins, ALKBH1-3, known to remove 1-meA and 3-meC adducts. However, ALKBH1 is reportedly a mitochondrial protein [115], therefore in the nucleus ALKBH2 and ALKBH3 proteins are employed to remove specific adducts in single- or double-stranded DNA or in RNA [104]. Lesions that are repaired by ALKBH proteins generally interfere with base-pairing and block replication and transcription, triggering cell cycle checkpoints and apoptosis [92, 95, 96, 110, 115]. In E. coli AlkB mutants, as well as in Alkbh2- or Alkbh3-deficient mouse embryonic fibroblasts, cells exhibit increased sensitivity to alkylating agents, particularly the SN2 type, and increased mutant frequency [101, 116-119].
4.3.1. Protein structure/active site organization
Similar to MGMT, the sequences of human ALKBH proteins do not contain a high percentage of sequence homology in regions other than active sites and conserved domains, but do have conserved secondary structures [109, 110, 114, 120-122]. In AlkB family proteins, the catalytic core is composed of three major components, the double-stranded β-helix (DSBH), the nucleotide recognition lid (NRL) and the N-terminal extension (NTE) (Figure 8). The DSBH is comprised of eight β-strands in the C-terminal portion that form two β-sheets to create a central core jelly-roll fold. Within the major and minor β-sheets of the DSBH lie conserved catalytic residues RxxxxxR and HxDxnH, respectively [120, 121, 123]. The HxD dyad is near the amino terminal end and is located in a flexible loop that follows the first strand, stacking with the minor β-sheet. The carboxy-terminal histidine of the conserved HxDxnH residues is associated with the beginning of the sixth strand and together these residues coordinate iron (His171, Asp173 and His236—Alkbh2; His191, Asp193 and His258—Alkbh3) [114, 120, 121, 123, 124]. The histidine and aspartic acid residues (Asp248 and Asp254—ALKBH2; Asp269 and Asp275—ALKBH3), conserved in the DSBH minor β-sheet, coordinate Fe(II), α-ketoglutarate and the DNA or RNA repair substrate within the catalytic core. A conserved Arg residue in the C-terminal β-strand (Arg254—ALKBH2 and Arg275—ALKBH3) sets AlkB family proteins apart from other α-ketoglutarate-dependent dioxygenases within the Fe(II)/α-ketoglutarate dioxygenase superfamily, forming the base of the substrate binding pocket [110, 120, 121, 123].
Figure 8.
Structure of human AlkB homolog DNA repair proteins. Two looped structures (flip1 and flip2) generated by anti-parallel β-sheets create the nucleotide recognition lid (NRL) and are involved in DNA base flipping. (A) Structure of ALKBH2 (PDBid3BTX). ALKBH2 double-strand DNA substrate specificity is facilitated by residues in loops L1 and L2. (B) Structure of ALKBH3 (PDBid2IUW). β -sheets 4 and 5 form the β-hairpin motif in ALKBH3. Part of loop 1, involved in ALKBH substrate specificity, was omitted due to electron density problems. [121]
The N-terminal extension (NTE) and Nucleotide Recognition Lid (NRL) are formed by the β-hairpin motifs that extend from the DSBH jelly-roll, forming a substrate binding groove that covers the active site until bound. Ninety residues are contained within two looped structures, forming “flips” that lie between a single β-sheet and two α-helices in the N-terminal portion of the catalytic core [120, 121]. Secondary structures are of similar size, but possess different characteristics important for substrate specificity and DNA activity. In ALKBH2, the first flip is 20 residues that make up a β-hairpin and short α-helix, creating a hydrophobic binding groove. In contrast, the first flip in ALKBH3 is a β-hairpin made up of 17 residues that form a hydrophilic, positively charged binding groove, more suitable for single-stranded DNA or RNA substrates [15, 120]. The characteristics of the second flip are also unique. Flip two of ALKBH2 spans 24 residues that is made up of three β-sheets, with numerous sites for DNA substrate interaction. The orientation of the three β-sheets, which fold back towards the C-terminal end of the first α-helix, is also unique only to ALKBH2 [114, 121]. However, flip 2 of ALKBH3 is only 12 residues and contains a single β-sheet [114]. The N-terminal regions of each ALKBH homolog are more variable and hypothesized to play roles in sub-cellular sorting and protein-protein interactions [114, 115] (Figure 8).
In addition to the conserved catalytic dioxygenase residues, some human ALKBH proteins also contain additional catalytic residues and domains [104, 109, 110, 113, 125] (Figure 9). Structural analysis of bacterial AlkB and human ALKBH homologs provides insight into substrate preferences and repair capabilities. For instance, ALKBH2 contains three unique motifs that facilitate enhanced activity on double-stranded DNA [121]. A long, flexible β-sheet hairpin loop that contains DNA binding residues Arg198, Gly204 and Lys205, a short loop that contains the RKK motif (Arg241-Lys243) and an aromatic finger residue (Phe102) are used to make contacts with both DNA strands, rotate and take the place of the damaged base in duplex DNA molecules. On the other hand, the number and organization of the catalytic domains in ALKBH3 result in differential manipulation of the DNA backbone, explaining the preference for single-strand substrates. Lack of an aromatic finger residue and RKK motif in ALKBH3, the damaged base is squeezed on either side, forcing it to rotate, and the immediate 5’ and 3’ bases to stack against one another. However, structural analysis of ALKBH3 has identified residue Arg122, specifically the arginine side chain length, as important for double-stranded DNA substrate activity, possibly mimicking the base-flipping and stacking activities of ALKBH2 residue Phe102 [114, 121].
Unfortunately, extensive biochemical analysis or structural studies have not been conducted on ALKBH homologs 4-8. However, it is apparent that differences in the number and organization of catalytic residues, as well as secondary structures play a large role in the diversity of ALKBH family protein substrate specificities and enzymatic activities [113]. For instance, although single- or double-strand DNA repair activity has not been established for ALKBH8, the presence of RNA binding and methyltransferase domains in ALKBH8 (Figure 9) suggested that this homolog plays a role in maintenance of methylation patterns. Investigation of such activities led to the identification of ALKBH8 tRNA methyltransferase activity, necessary in the biogenesis of wobble uridine modifications utilized in translational decoding [126, 127].
Figure 9.
AlkB family protein domain alignment. Conserved amino acid sequences and domain function are indicated. The total number of amino acids is indicated to the right of each homolog. [110,113,125]
4.3.2. Substrate recognition/repair mechanism
Initially, it was predicted that AlkB family proteins directly repaired alkylation adducts by hydroxylating methyl groups and removing the resultant hydroxymethyl groups via an oxidative reaction that directly restores the undamaged base [94, 109, 112, 124, 128, 129]. However, specific investigation of the AlkB family dealkylation mechanism [130] determined that the direct repair reaction mediated by AlkB family proteins involves several intermediate steps that had not yet been identified. Regardless, dealkylation catalyzed by AlkB and its human homologs occurs via transformation of α-ketoglutarate into succinate, formaldehyde release, and restoration of the undamaged base [94, 100, 111, 130, 131] (Figure 10).
Figure 10.
ALKBH protein repair reactions. (A) ALKBH methyl adduct repair reaction. (B) ALKBH ethyl adduct repair reaction. (C) ALKBH etheno adduct repair reaction. Repair of ethyl and etheno adducts requires the same co-factors, but displaces acetaldehyde or water and glyoxal as byproducts of the repair reaction, respectively, instead of formaldehyde [100,102,103]
First, Fe(II) and three water molecules must be coordinated within the conserved catalytic core, stimulating α-ketoglutarate (KG) binding in the catalytic pocket. Binding of α-KG into the catalytic pocket chelates Fe(II) by displacing two water molecules to create the Fe(II)/α-KG active-site complex. Ligation of dioxygen to the Fe(II) molecule displaces the remaining water molecule, generating a ferric-superoxido species that undergoes self-redox and nucleophilic attack on the α-keto group. This nucleophilic attack is necessary to decarboxylate α-KG, releasing succinate and generating a ferryl-oxo intermediate. Reorientation of this intermediate facilitates removal of a hydrogen atom from the methyl adduct. Finally, radical rebound hydroxylation of the methylene group results in decomposition of the hydroxymethyl nucleobase, yielding formaldehyde and the repaired nucleobase. Though two co-factors were noted initially, α-ketoglutarate and Fe(II), ascorbate also plays a role, helping to convert the Fe(III) to Fe(II), thereby regenerating the original oxidative state of iron in the Alkbh proteins that permits enzymatic cycling [94, 111, 112, 122, 124, 130].
The major methylated bases repaired by ALKBH proteins are 1-methyladenine (1-meA) and 3-methylcytosine (3-meC), however homologs have also been reported to repair ethylated, and some etheno and exocyclic bases [102-105, 107, 131, 132]. Similar mechanisms are proposed for repair of ethano and exocyclic etheno (ε) adducts, though the final steps of these reactions result in release of acetylaldehyde and glycol, respectively [130] (Figure 10). However, additional biochemical studies are needed to confirm these mechanisms in similar detail to removal of methyl adducts from DNA.
4.3.3. Gene expression/protein regulation
Human AlkB DNA repair homologs, ALKBH2 and ALKBH3 are single genes on chromosomes 12q24 and 11p11, respectively. Expression of human AlkB homologs has been reported in a variety of normal tissue samples, including ALKBH homologs 4-8, despite the lack of DNA repair activity in the literature [133]. Expression of ALKBH family proteins varies depending on cell types. Protein expression levels in the various tissue types vary depending on the homolog evaluated. Little is known of ALKBH protein regulation mechanisms and is an area in need of further study.
4.3.4. Protein localization and cell type dependence
Differences amongst AlkB homolog proteins in their biological roles are partially ascribed to their sub-cellular localizations. ALKBH2 and ALKBH3 homolog proteins are expressed at the highest levels in the testis and ovary, however detectable expression of all AlkB homolog proteins is exhibited in the spleen, pancreas, lung, kidney, prostate and brain [133]. Although ALKBH1 activity is confined to mitochondria [115], immunofluorescence imaging indicates that the protein is cytoplasmic and nuclear [133]. Similarly, AlkB homolog proteins ALKBH3, 4, 6, and 7 are also present in the nucleus and cytoplasm [133], though ALKBH3 is the only homolog reported to possess repair activity [1, 104, 111]. Localization of ALKBH3 in both the nucleus and cytoplasm are consistent with identified interactions with helicase enzymes to facilitate DNA repair [134] and roles in mRNA repair [131]. ALKBH2 is present only in the nucleus and exhibits diffuse as well as localized, punctate staining, supporting pre-established co-localization with PCNA at replication foci during S phase [111, 131, 133], suggesting a role in replication- and transcription-related repair, as well as genome maintenance. On the contrary, AlkB homolog proteins ALKBH5 and 8 are present only in the cytoplasm [133], which supports known ALKBH8 tRNA methyltransferase activity [126, 127].
4.3.5. Post-translational modification
Unlike MGMT, ALKBH proteins are not suicide enzymes and a single protein can catalyze multiple direct repair reactions, requiring only ascorbate to regenerate the Fe(II) active site center [135]. Therefore, immediate degradation of ALKBH proteins following repair is not required, as it is for MGMT. Other possible post-translational modifications in ALKBH2 and ALKBH3 include candidate sites for phosphorylation and acetylation. Mass-spectrometric analysis of a curated database of cell lines revealed that both ALKBH2 and ALKBH3 proteins undergo post-translational modification of specific residues present in various cancer types [92].
Post-translational modifications curated for ALKBH2 include acetylation of residue Lys34 and Lys104 in various colorectal cancer cell types (HCT116, HT29, XY3-92-T and XY3-68-T), as well as phosphorylation of residue Thr252 in esophageal cancer cell line XY2-E111N [92]. Though the exact effects of these modifications are unknown, it is important to state that Lys34 is within the variable region of the N-terminus that is thought to provide protein specificity. Similarly, Lys104 is between two residues that make contact with the complimentary DNA strand during double-strand DNA repair and Thr230 is a residue in the most C-terminal α-helix of the active site [92]. Examination of potential ALKBH2 modification sites using predictive software shows possible post-translational modification sites for methylation (Arg128, 135), sumoylation (Lys75, 205), and ubiquitination (Lys104), along with other possible phosphorylation sites (Ser36, 56, 130, 182, 202, 206, 208; Thr37; Tyr91, 115) [90-93]. All of those possible post-translational modifications merit further consideration.
Post-translational modifications were also present in ALKBH3, corresponding to various disease states. Phosphorylation of Thr126 and Tyr127 residues in the β-hairpin of the NRL, as well as residue Try229 in the ALKBH3 active site, was present in acute myelogenous, chronic myelogenous and/or T-cell leukemia [92]. Additionally, phosphorylation of Tyr127 was exhibited in lung and non-small cell lung cancer cell lines. Phosphorylation of residue Tyr143, which precedes the first residue of the second β-hairpin in the NRL, was also noted in the gastric carcinoma cell line MKN-45, as well as phosphorylation of residues T212 and T214, within the ALKBH3 active site, was found in liver cancer tissue samples [92]. Examination of potential ALKBH3 modification sites using predictive software shows possible post-translational modification sites for acetylation (Lys43, 116, 219, 220), and sumoylation (Lys57, 236), along with other possible phosphorylation sites (Ser32, 50, 187, 192, 208, 265; Thr29, 41; Tyr78, 127, 229) [90-93]. All of those possible post-translational modifications merit further consideration.
5. Biological significance of direct repair in mammalian cells
Normal cells depend on direct repair to eliminate damage that is possibly cytotoxic or mutagenic. Our knowledge of the biological significance of direct repair proteins in mammalian cells is based on the evaluation of effects on cell cytotoxicity, replication, transcription and subsequent mutagenic consequences observed in the absence of each protein of interest. Recent investigations performed in model system organisms, most prominently in mice, to assess the impact of the absence of Mgmt or Alkbh family proteins will be highlighted in this section. These studies also provide insight into the function and importance of direct repair proteins in humans.
5.1. Knock-out animal models
It is important to remember that a number of DNA repair systems are implicated in the elimination of DNA lesions formed by exposure to alkylating agents. Therefore, dysfunction of repair systems can lead to pathologies that include cancer development. However, without use of a model organism to assay the effects, the consequences to the organism as a whole cannot be assessed. Knock-out animal models are a valuable tool for understanding the overall physiological effects of genes on an organism, and provide insight into disease research and therapeutic development.
Murine Mgmt models have been studied by multiple groups to evaluate sensitivity to alkylating agents commonly used in chemotherapeutics [5, 6, 82, 86, 136-139]. Though Mgmt repairs DNA damage that is known to be mutagenic, Mgmt-deficient mice surprisingly lack any overt phenotype. However, these mice are significantly more sensitive to treatment with N-methyl-N-nitrosourea (MNU), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)3-nitrosourea (ACNU), streptozotocin, temozolomide, and dacarbazine alkylating agents [5, 136, 137, 139-142]. Mgmt knock-out mice treated with various chemotherapeutic agents also show ablation of hematopoietic tissues at the stem cell level [38, 141, 143] and are prone to development of thymic lymphomas [144]and lung adenomas [82, 138, 144, 145]. Similarly, mouse embryonic stem (ES), embryonic fibroblasts (MEFs) and bone marrow cells deficient in Mgmt also exhibit a significant increase in sensitivity (~10-fold) to MNU and BCNU [83, 141, 146]. However, mice heterozygous for Mgmt do not display a significant reduction in survival following treatment with nitrosoureas or increased tumorigenesis, compared to their wild-type counterparts.
Although in vitro DNA repair activity has been established for ALKBH1, studies conducted in murine models lacking Alkbh1 suggest roles involved in transcription. Mice deficient in Alkbh1 exhibit apoptosis in adult testis, sex-ratio distortion and unilaterial eye defects, as well as impaired differentiation of specific trophoblast lineages in the developing placenta [147, 148]. Though the specific activity and function of ALKBH1 remains to be determined, ALKBH1 biological roles seem linked to spermatogenesis and embryonic development.
On the other hand, Alkbh2- and/or Alkbh3-deficient murine models do not manifest any obvious phenotype or histopathological changes [116, 119, 132]. However, over time mice lacking Alkbh2 accumulate significant levels of 1-meA, confirming a role in removing endogenous DNA alkyl adducts. In a recent study, Alkbh2,Alkbh3,Aag knock-out mice (Aag also known as Mpg, a DNA glycosylase in the BER pathway) were viable, but underwent rapid death when exposed to a chemically-induced colitis treatment [119]. Similarly, primary mouse embryonic fibroblasts (MEFs) derived from mice lacking functional Alkbh2 exhibited significantly increased cytotoxicity and mutagenesis following exposure to the SN2 alkylating agent methyl methanesulfonate (MMS) [116, 118, 119]. Survival of Alkbh3-deficient MEFs exposed to MMS was reduced by ~50% compared to wild type MEF sensitivity, though mutant frequency did not significantly increase [116].
5.2. Replication and transcription defects
Though not all lesions generated by exposure to alkylating agents cause defects in replication and transcription, DNA and RNA adducts that are specifically removed via a direct repair mechanism interfere with replication and transcription machinery. The presence of O6-meG in DNA impedes polymerization by DNA and RNA polymerases [31, 32, 149, 150]. Polymerase beta (β), involved in base excision repair (BER) of alkylation adducts, is completely blocked by O6-meG adducts [150]. Polymerase delta (δ) is able to replicate past, but insertion of the correct base opposite O6-methylguanine is very inefficient. However, these adducts can be bypassed using polymerase eta (η) [149], a member of the Y-family DNA translesion synthesis (TLS) polymerases, but TLS polymerases are notorious for being error-prone. Interestingly, when replicating past O6-meG DNA adducts, TLS polymerase, Polη is twice as efficient at inserting cytosines opposite O6-meG as replicative polymerase, Pol δ [32].
1-meA and 3-meC lesions that are repaired by Alkbh2 and Alkbh3 are at DNA base-pairing positions and hinder proper base insertion [101]. During replication, this can lead to arrest of nucleotide synthesis, resulting in replication fork collapse [151]. Similarly, 1-meA and 3-meC adducts can also cause stalling of transcription. Correspondingly, Alkbh2 co-localizes with replication foci during S-phase [111, 131, 133] and Alkbh3 has a role in removal of alkyl adducts from mRNA [1, 15, 108, 115, 131, 152]. However, a TLS polymerase that is linked to 1-meA and/or 3-meC DNA adduct bypass has not been identified.
5.3. Cell cytotoxicity
Treatment with alkylating agents introduces a variety of adducts into DNA and RNA (Figure 2, Table 1). In the absence of direct repair proteins, those lesions can lead to cell death or damage tolerance, which allows for cell survival, but can introduce mutations into the genome that could have detrimental effects [101, 116, 142, 153]. As exhibited in Mgmt- and Alkbh-deficient murine models, lack of direct repair proteins correlates with a significant increase in cell death following treatment with SN1 or SN2 alkylating agents, respectively [116, 118, 140, 141].
5.4. Mutagenesis
When a modified nucleoside can form at least two hydrogen bonds, transcription and replication templates and translation of messengers are active [13]. O6-meG, 1-meA, and 3-meC are all involved in DNA base-pairing. Modification at O6-meG and 3-meC still allow for formation of two hydrogen bonds, while 1-meA results in only a single hydrogen bond between paired bases [13]. However, the exocyclic amino group of 1-meA can rotate so that both amino group hydrogen molecules can generate the necessary base-pairing bonds, though a slight distortion of the double-strand DNA helix does occur [13]. The addition of a methyl group to O6-G, N1-A, or N3-C interferes with normal replication, and could recruit DNA translesion synthesis (TLS) polymerases to bypass the DNA adducts. The size and organization of the Y-family TLS polymerase active sites is variable and allows for accommodation of numerous adducts. However, not only are TLS polymerases inherently error-prone [154, 155], the number and type of hydrogen bonds that can be made with the modified bases has been altered. Those factors can produce insertion of an erroneous base during bypass that accompanies replication or transcription.
O6-meG mutagenicity has been established in bacterial and mammalian systems [29, 30]. O6-meG is mutagenic and primarily gives rise to G:C→A:T mutations. A mis-insertion of thymine is thought to occur due to mis-identification of O6-meG as adenine, as hydrogen bonding can occur with the N1 and exocyclic amino group of O6-meG [13].
Unfortunately, studies evaluating the mutagenicity of a site-specific 1-meA, 3-meC, 1-meG, or 3-meT adducts have not been conducted in mammalian systems, but studies in E. coli, show that 1-meA adducts are only slightly mutagenic, whereas 3-meC, 1-meG, and 3-meT adducts are much more mutagenic [101]. Work evaluating the anti-mutagenic role of Alkbh2 and Alkbh3 in a murine model showed increased mutant frequency, specifically for mouse embryonic fibroblast (MEF) cells deficient in either Alkbh2 or Alkbh3 [116]. Those Alkbh-deficient cells exhibited increased amounts of C:G→A:T C:G→T:A mutations, respectively. Additionally, when treated with MMS, Alkbh2-deficient MEFs displayed an increased frequency of C:G→T:A and T:A→A:T mutations. Similarly, Alkbh3-deficient MEFs also exhibited an increased frequency of T:A→A:T mutations, as well as an increased frequency of A:T→G:C mutations, in response to MMS treatment. Like O6-meG, misidentification of the modified DNA bases due to the presence of two sites for hydrogen bond formation could arise if 1-meG or 3-meC is recognized as thymine and an adenine is paired with the two remaining hydrogen bond acceptors. Furthermore, T:A→A:T mutations could arise if 3-meT becomes recognized as adenine and a thymine is paired via hydrogen bonds between thymine O4 and O2 and adenine N-3 exocyclic amino group nitrogen. It is likely that 1-meA is rarely mutagenic in E. coli, deficient in AlkB, because 1-meA can utilize the C6 exocyclic amine and N7 as an alternative binding site providing two sites for hydrogen bond formation with thymine N-7 and O4 molecules, using Hoogsteen base-pairing [156].
6. Medical significance of direct repair proteins in humans
Genetic and epigenetic controls that regulate MGMT, ALKBH2, and ALKBH3 gene expression and influence how these proteins directly repair DNA are critical factors that can lead to a better understanding of cancer development. In addition, comprehension of factors that cause variations in the direct DNA repair activities of cancer cells will provide important progress toward formulating cancer therapeutics that target MGMT or ALKBH proteins. Understanding the impact of direct DNA repair proteins will eventually result in treatments that can be tailored to achieve better therapeutic results or to predict treatment and/or disease outcomes.
6.1. Epigenetic and transcriptional regulation
Epigenetic modifications are stable alterations of DNA that are heritable in the short term, but do not involve mutations of the DNA itself, and are mediated by DNA methylation and histone modifications. The stable alterations that are involved in epigenetics have a major role in exerting control on gene expression. Endogenous cell signaling as well as external influences, including diet and other life style choices, can alter gene expression mediated by changes in epigenetic modifications [157, 158]. Methylation of cytosines at transcription factor recognition sites can interfere with binding and/or function and repress transcription of that gene [159, 160]. Alternatively, protein recruitment that binds methyl CpG islands can block transcription machinery or alter chromatin structure [161, 162]. Transcriptional silencing also is connected to histone deacetylation [163, 164]. Methyl CpG binding domain (MBD) family proteins direct histone deacetylases to remove acetyl groups from lysines in the amino terminal histone tails, stabilizing DNA-histone interactions, and condensing chromatin so that transcription factor binding sites are inaccessible.
Though unmethylated in normal cells, transcriptional silencing of MGMT, associated with promoter CpG island methylation has been reported in a variety of cancer cell types and MGMT-deficient cell lines [82, 138]. Additionally, in a glioma mouse model a subpopulation of glioma cells with stem cell properties were identified [165] that are capable of re-establishing tumor growth following temozolomide treatment. Although Mgmt promoter CpG methylation or protein levels were not determined in that study, when MGMT transcript levels were evaluated in glioma patients [166], those with MGMT CpG promoter methylation had increased response to temozolomide, but also maintained a subset of glioma cells with stem cell-like character and MGMT promoter methylation. Interestingly, mRNA levels of DNMT1 and DNMT3b methyltransferases are increased in a number of human glioma patients, but there does not appear to be a link to MGMT expression levels [167]. Moreover, MGMT promoter CpG methylation levels and DNA methyltransferase levels alone do not account for patient response to alkylating agent therapy. However, whether MGMT promoter methylation disables transcription factor binding or contributes to chromatin reorganization remains uncertain [71, 72, 74]. Therefore, regulation of MGMT expression is still unclear and merits intense scrutiny.
The inability to establish direct connections among MGMT expression, CpG methylation, and response to alkylating agent therapy indicates that other mechanisms contribute in regulating MGMT levels. Studies evaluating MGMT expression and microRNAs in patient samples have established a modest inverse correlation between the levels of MGMT transcript and miR-181d [168]. Moreover, expression of mi-181d in A1207 glioblastoma cells, results in abnormal sensitivity to temozolomide. However, expression of MGMT cDNA, restores the survival to levels close to that of the A1207 parental line. These results suggest that identification of other miRNAs involved in regulating MGMT expression will help elucidate the mechanisms that control the gene transcript levels.
In addition to control at the DNA and transcript levels, histone modifications can also control the epigenetic state and direct expression. Acetylated histone H3 and H4 levels also increase in cell lines expressing MGMT, compared to cell lines deficient in MGMT [169], which would facilitate nucleosomal positioning that enables transcription factor interactions. Further, binding of MBD proteins in the MGMT promoter of was greater in MGMT-silenced cells, implicating MBD proteins in recruitment of histone deactylases that remove lysine acetylation from the amino-terminal tails of histones H3 and H4, resulting in more condensed chromatin and transcription inactivation [73, 79, 170]. Therefore, epigenetic and/or enzymatic CpG island methylation at the MGMT promoter influences transcription factor access, as well as chromatin structure that are important for MGMT expression.
ALKBH2 and ALKBH3 both have CpG islands in their promoters, but epigenetic regulation and/or gene silencing has not been reported for either homolog. However, mutations that alter protein expression have been observed [171], but it is likely that methylation of CpG islands near any of the seven transcription factor binding sites in the promoter of ALKBH2 or the single transcription factor binding sites within the promoter region of ALKBH3, would repress transcription factor binding and possibly gene expression. Because data on the function of ALKBH promoters are less abundant compared to those available for the MGMT promoter, examination of the promoter function for those genes is an area that would benefit from further investigation.
6.2. Links to cancer
Dysregulation of numerous DNA repair pathways are involved in tumor development, progression, diagnosis, treatment and prognosis, including direct DNA repair proteins [82, 159, 172-179]. Over-expression of direct repair proteins is generally associated with a protective effect against cell death that would otherwise be induced by alkylating agent treatment. However, down-regulation or silencing of direct repair protein expression is associated with increased mutagenesis that precedes tumorgenesis. Therefore expression profiles could be used to predict potential resistance or enhanced sensitivity to therapeutics.
MGMT has been implicated in many types of human tumors. Numerous MGMT polymorphisms have risk associations with breast, lung, colon, and head and neck cancers [63, 82, 180-186]. Decreased MGMT expression is also found in glioma, lymphoma, retinoblastoma, breast (including triple-negative breast cancer) and prostate cancer [82, 138, 187] [188]. Moreover, lack of MGMT is associated with enhanced outcomes using alkylating agent therapies [5, 62, 67, 82, 86, 138, 139, 180, 181, 183, 189]. Though MGMT silencing occurs in a variety of tumor types, increased levels have also been observed in non-Hodgkin lymphoma, myeloma and glioma, as well as in some colon, pancreatic, breast, and lung cancers [63, 183, 184].
Mutations in ALKBH2 and 3 have been associated with an enhanced expression of these proteins in glioma cells and pediatric brain tumors [171, 190]. Similarly, over-expression of ALKBH3 has been associated with human rectal carcinoma [191] and prostate cancer, as well as, lung adenocarcinoma and non-small-cell lung cancer [134] [192]. On the contrary, down regulation of ALKBH2 has been observed in gastric cancer, promoting growth of gastric cancer cells [193]. Although down regulation of ALKBH2 in gastric cancer cells caused increased proliferation, ALKBH2 silencing in H1299 lung cancer cells had the opposite effect, increasing cisplatin sensitivity. Similarly, ALKBH3 silencing induced senescence and sensitivity to alkylating agents in human adenocarcinoma and prostate cancer cells [134, 193]. Therefore, further study of the role of ALKBH2 and 3 in both normal and tumor cells is necessary to elucidate their biological role(s).
6.3. Therapeutic targets
Understanding the mechanism of proteins involved in various DNA repair pathways is crucial for developing new chemotherapeutic targets and eventually new drugs. DNA alkylating agents and ionizing radiation (IR) are often used as chemotherapeutic treatments because of ability to control the dose administered and area of treatment, as well as the major cytotoxic effects of both agents at high doses. However, in addition to generation of cytotoxic adducts that cause apoptosis, alkylating agents and IR also form adducts that can be mutagenic and as a result can cause initiation of secondary cancers. Although DNA repair deficiencies are associated with increased cancer risk and formation, cancer cells proficient in DNA repair can reduce therapeutic efficacy. Currently, combination cancer treatment regimens are being explored that utilize chemotherapy or IR and target specific DNA repair proteins with pharmacological agents to enhance treatment efficacy and eliminate resistance to treatment regimens exhibited in some patients [189].
6.3.1. MGMT
Chemotherapeutic drugs such as temozolamide (TMZ) and bis-(2-chloroethyl)-nitrosourea (BCNU) generate some lesions repaired via the direct methyltransferase mechanism. Combination treatment with MGMT inhibitors prevents repair and resistance to methylating and chloroethylating agents [1, 38, 137] and has also been shown to reverse cisplatin drug resistance [194].
Understanding cellular regulation of MGMT expression will allow for selective down regulation and sensitization of tumors to alkylating agent chemotherapies. Studies have evaluated manipulation of MGMT expression and protein levels. Initial experiments evaluating MGMT inhibitors identified O6-benzyl guanine (BG) as an efficacious inhibitor of MGMT activity, a single, micromolar dose depleting greater than 99% of MGMT activity in human cells for 24-hours following drug removal [195]. Moreover, treatment with BG lacks any mutagenic or cytotoxic effects [195-197]. Clinical trials combining BG and BCNU treatment have been conducted in colon cancer, sarcoma, melanoma and myeloma, as well as studies evaluating combination of BG and TMZ [138]. Since synthesis of BG, additional BG-like inhibitors have been developed [196], including O6-(4-bromothenyl) guanine, which has been evaluated in patients with glioma [187]. Similarly, targeting of MGMT along with combination of platinum drugs, including cis- and carboplatinum [198], as well as topoisomerase I inhibitors has been investigated in various clinical trials [86].
Another approach to regulate MGMT that holds great, essentially untapped therapeutic potential is strategies utilizing RNA interference-mediated gene silencing to target MGMT [168, 199, 200]. For instance, if anti-sense molecules can specifically target MGMT mRNA translation, and degradation is also inhibited, depletion of MGMT is sustainable for long periods of time [62]. As seen in glioblastoma patients, expression levels of various miRNA markers correlate with prognosis [168, 199, 200]. Therefore, one potential new treatment could use miRNAs, such as miR-181d, to decrease MGMT levels, thus increasing sensitivity to alkylating agents [168]. Similarly, targeting regions of the MGMT promoter that is accessible to transcription factors could interfere with binding and down-regulate MGMT transcription. However, non-specific targeting of MGMT inhibitors in all cells increases chemotherapeutic toxicity. Therefore, mutant forms of MGMT that are resistant to BG-like inhibitors are also being evaluated to limit myelosuppression, affording hematopoietic progenitor cells protection from BG and BCNU or temozolomide treatment [201-204].
6.3.2. Alkbh homologs
Similar to MGMT, the role of ALKBH2 and ALKBH3 in repair of DNA alkylation damage at base-pairing sites is anti-carcinogenic. However, investigations indicate that over-expression of ALKBH proteins in various cancer cell lines shields those cells against methylating agent toxicity and would thereby protect against some chemotherapeutic treatments [134, 171, 192]. Additionally, because loss of ALKBH2 and/or ALKBH3 leads to disruption of replication, inhibition of ALKBH2 and/or ALKBH3 is a strong target for the development of novel chemotherapeutic agents. Some specific inhibitors of these proteins have already been identified [135, 205, 206], as well as generic α-KG/dioxygenase inhibitors including dimethyl oxalylglycine (DMOG) and α-ketoglutarate derivatives such as oxoglutarate. Studies have addressed the application of DNA aptamers as inhibitors of ALKBH proteins [207]. However, to date no studies have been conducted in mammalian models that evaluate the combination of ALKBH inhibitors with chemotherapeutic alkylating agents.
7. Summary
Direct repair proteins represent a unique class of enzymes that remove DNA damage without a dependence on DNA synthesis. In the future, better comprehension of how these proteins function and are produced in cells will lead to understanding their roles in formation of mutations that cause cancer. Eventually, that knowledge will foster the development of drugs to target these proteins and/or to regulate their expression to improve patient outcomes.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/44566.pdf",chapterXML:"https://mts.intechopen.com/source/xml/44566.xml",downloadPdfUrl:"/chapter/pdf-download/44566",previewPdfUrl:"/chapter/pdf-preview/44566",totalDownloads:3415,totalViews:684,totalCrossrefCites:1,totalDimensionsCites:4,totalAltmetricsMentions:1,introChapter:null,impactScore:1,impactScorePercentile:46,impactScoreQuartile:2,hasAltmetrics:1,dateSubmitted:"April 17th 2012",dateReviewed:"October 16th 2012",datePrePublished:null,datePublished:"May 22nd 2013",dateFinished:"May 7th 2013",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/44566",risUrl:"/chapter/ris/44566",book:{id:"3302",slug:"new-research-directions-in-dna-repair"},signatures:"Stephanie L. Nay and Timothy R. O‘Connor",authors:[{id:"155613",title:"Dr.",name:"Timothy",middleName:null,surname:"O\\'Connor",fullName:"Timothy O\\'Connor",slug:"timothy-o'connor",email:"toconnor@coh.org",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"City Of Hope National Medical Center",institutionURL:null,country:{name:"United States of America"}}},{id:"157190",title:"BSc.",name:"Stephanie",middleName:null,surname:"Nay",fullName:"Stephanie Nay",slug:"stephanie-nay",email:"snay@coh.org",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Direct repair substrates—DNA and RNA alkylation damage",level:"1"},{id:"sec_3",title:"3. Sources of alkylation damage",level:"1"},{id:"sec_3_2",title:"3.1. Types of alkylating agents",level:"2"},{id:"sec_4_2",title:"3.2. DNA and RNA alkylation damage",level:"2"},{id:"sec_6",title:"4. Direct repair proteins",level:"1"},{id:"sec_6_2",title:"4.1. Mechanisms of alkylation repair",level:"2"},{id:"sec_7_2",title:"4.2. Methyl Guanine Methyl Transferase (MGMT) proteins",level:"2"},{id:"sec_7_3",title:"4.2.1. Protein structure/active site organization",level:"3"},{id:"sec_8_3",title:"4.2.2. Substrate recognition/repair mechanism",level:"3"},{id:"sec_9_3",title:"4.2.3. Gene expression/protein regulation",level:"3"},{id:"sec_10_3",title:"4.2.4. Protein localization and cell type dependence",level:"3"},{id:"sec_11_3",title:"4.2.5. Post-translational modification",level:"3"},{id:"sec_13_2",title:"4.3. Alkbh Fe(II)/α-ketoglutarate-dependent dioxygenases",level:"2"},{id:"sec_13_3",title:"4.3.1. Protein structure/active site organization",level:"3"},{id:"sec_14_3",title:"4.3.2. Substrate recognition/repair mechanism",level:"3"},{id:"sec_15_3",title:"4.3.3. Gene expression/protein regulation",level:"3"},{id:"sec_16_3",title:"4.3.4. Protein localization and cell type dependence",level:"3"},{id:"sec_17_3",title:"4.3.5. Post-translational modification",level:"3"},{id:"sec_20",title:"5. Biological significance of direct repair in mammalian cells ",level:"1"},{id:"sec_20_2",title:"5.1. Knock-out animal models",level:"2"},{id:"sec_21_2",title:"5.2. Replication and transcription defects",level:"2"},{id:"sec_22_2",title:"5.3. Cell cytotoxicity",level:"2"},{id:"sec_23_2",title:"5.4. Mutagenesis",level:"2"},{id:"sec_25",title:"6. Medical significance of direct repair proteins in humans",level:"1"},{id:"sec_25_2",title:"6.1. Epigenetic and transcriptional regulation",level:"2"},{id:"sec_26_2",title:"6.2. Links to cancer",level:"2"},{id:"sec_27_2",title:"6.3. Therapeutic targets",level:"2"},{id:"sec_27_3",title:"6.3.1. MGMT",level:"3"},{id:"sec_28_3",title:"6.3.2. Alkbh homologs",level:"3"},{id:"sec_31",title:"7. 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ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer. British Journal of Cancer. 2011:1-7.'},{id:"B193",body:'Wu SS, Xu W, Liu S, Chen B, Wang XL, Wang Y, et al. Down-regulation of ALKBH2 increases cisplatin sensitivity in H1299 lung cancer cells. Acta Pharmacologica Sinica. 2011:1-6.'},{id:"B194",body:'Qiu YY, Mirkin BL, Dwivedi RS. Inhibition of DNA methyltransferase reverses cisplatin induced drug resistance in murine neuroblastoma cells. Cancer Detect Prev. 2005;29(5):456-63.'},{id:"B195",body:'Dolan ME, Mitchell RB, Mummert C, Moschel RC, Pegg AE. Effect of O6-benzylguanine analogues on sensitivity of human tumor cells to the. Cancer Res. 1991;51(13):3367-72.'},{id:"B196",body:'Chae MY, Swenn K, Kanugula S, Dolan ME, Pegg AE, Moschel RC. 8-Substituted O6-benzylguanine, substituted 6(4)-(benzyloxy)pyrimidine, and. J Med Chem. 1995;38(2):359-65.'},{id:"B197",body:'Dolan ME, Pegg AE, Dumenco LL, Moschel RC, Gerson SL. Comparison of the inactivation of mammalian and bacterial O6-alkylguanine-DNA. Carcinogenesis. 1991;12(12):2305-9.'},{id:"B198",body:'Sato K, Kitajima Y, Nakagawachi T, Soejima H, Miyoshi A, Koga Y, et al. Cisplatin represses transcriptional activity from the minimal promoter of the. Oncol Rep. 2005;13(5):899-906.'},{id:"B199",body:'Lakomy R, Sana J, Hankeova S, Fadrus P, Kren L, Lzicarova E, et al. MiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients. Cancer Sci. 2011;102(12):2186-90.'},{id:"B200",body:'Zinn P, Sathyan P, Mahajan B, Bruyere J, Hegi ME, Majumder S, et al. A Novel Volume-Age-KPS (VAK) Glioblastoma Classification Identifies a Prognostic Cognate microRNA-Gene Signature. PLoS One. 2012;7(8):e41522.'},{id:"B201",body:'Chinnasamy N, Rafferty JA, Hickson I, Lashford LS, Longhurst SJ, Thatcher N, et al. Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis. Gene Ther. 1998;5(6):842-7.'},{id:"B202",body:'Hickson I, Fairbairn LJ, Chinnasamy N, Lashford LS, Thatcher N, Margison GP, et al. Chemoprotective gene transfer I: transduction of human haemopoietic progenitors. Gene Ther. 1998;5(6):835-41.'},{id:"B203",body:'Koc ON, Reese JS, Davis BM, Liu L, Majczenko KJ, Gerson SL. DeltaMGMT-transduced bone marrow infusion increases tolerance to O6-benzylguanine. Hum Gene Ther. 1999;10(6):1021-30.'},{id:"B204",body:'Reese JS, Koc ON, Lee KM, Liu L, Allay JA, Phillips WP, Jr., et al. Retroviral transduction of a mutant methylguanine DNA methyltransferase gene into. Proc Natl Acad Sci U S A. 1996;93(24):14088-93.'},{id:"B205",body:'Karkhanina AA, Mecinovic J, Musheev MU, Krylova SM, Petrov AP, Hewitson KS, et al. Direct analysis of enzyme-catalyzed DNA demethylation. Anal Chem. 2009;81(14):5871-5.'},{id:"B206",body:'Woon EC, Demetriades M, Bagg EAL, Aik WS, Krylova SM, Ma JHY, et al. Dynamic combinatorial mass spectrometry leads to inhibitors of a. J Med Chem. 2012;55(5):2173-84.'},{id:"B207",body:'Krylova SM, Koshkin V, Bagg E, Schofield CJ, Krylov SN. Mechanistic studies on the application of DNA aptamers as inhibitors of. J Med Chem. 2012;55(7):3546-52.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Stephanie L. Nay",address:null,affiliation:'
Irell and Manella Graduate School of Biological Sciences, USA
Department of Cancer Biology, Beckman Research Institute, Duarte, CA, USA
'},{corresp:null,contributorFullName:"Timothy R. O‘Connor",address:null,affiliation:'
Department of Cancer Biology, Beckman Research Institute, Duarte, CA, USA
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1. Introduction
The leather sector is regarded in most African countries as a major economy driver that highly contributes to a country’s economic growth by means of employment opportunities and foreign cash inflow. The leather sector includes tannery, footwear, leather gloves, and leather goods and garment subsectors. Leather by itself requires high care during the different phases of production, storage, and transportation. Hence, the issue of quality in leather manufacturing process is of paramount importance as most defects in leather and leather products are irreversible. Rework or correction of incurred damages during production of leather, leather goods, and garment leads to higher labor costs and sometimes to rejection of the products. Therefore, the implementation of quality control (QC) concepts in every production step is associated with a valuable impact on the finished products so that defect-free products reach end users.
Most of the Ethiopian companies specializing in the leather sector prefer visual inspections and simpler physical testing methods to control product quality. This preference may work for the local market as the latter may not draw too much focus on quality aspects due to it being less aware for various quality dimensions. However, for penetrating and competing on an international level, special privileges such as African Growth Opportunity Act (AGOA) from importing countries or producing goods with the required quality and at a competitive price are required. Nonetheless, consistent with descriptive statistics results, econometric findings also reveal that exporting firms were found rather less efficient compared to those which are either powerless or have totally given up looking for the international market with respect to income and market sustainability. Once basic international standards are met and market access is established through various mechanisms including participation in trade fairs, the use of the internet, and buyer contacts, exporting companies have continued to benefit from the market due to the natural superiority of Ethiopian leather in terms of fineness, thickness, flexibility, strength, and compactness of texture, according to UNCTAD (2000) [1].
But this is not true for export markets. All leather and leather products-related quality standards need to be implemented which in turn includes, but may not be limited to, physical and/or chemical testing and inspections. In a perfectly competitive market setup consisting of a high number of buyers and sellers (also referred to as a thick market), price signals would reward high quality, and hence, producers and traders of substandard quality would either be driven out of the market or would be relegated to a distinct low-quality-oriented market [2].
This chapter provides a background on quality control aspects for the production of leather products that directly reach end users. It covers quality control aspects applicable to leather products and goods and the garment manufacturing subsector.
1.1 Aims and objectives
The objective of this chapter is to provide a background on quality control aspects required in the production of leather products. In doing so, this research work aims to address the significance of quality control and quality aspects in the leather products manufacturing subsector.
2. Literature review
Quality is an absolute term. Concepts of quality and quality control with regard to the manufacture of leather goods and garments need to be viewed in accordance with the policies of the relevant specialty industries. The outcome thereof in conjunction with the application of quality control concepts listed herein will serve as the basis for supervisors, team leaders, and even operators in those companies with advanced know-how to the parameters, check points, and control mechanisms so that defect-free products will reach end users.
Most Ethiopian leather and leather products manufacturing firms had implemented various quality-related improvement tools and systems including, ISO 9001:2018, Environmental Management Systems (EMS ISO 14001:2018, Occupational Health and Safety Management Systems ISO 45001:2018), and a plethora of other quality management systems (QMSs) in order to enhance their local and global competitions. For instance, (ELICO) Ethiopian Leather Industries Company PLC, Pittards Glove Manufacturing Factory PLC, Modern Zege leather products and footwear Industry PLC had implemented these systems [3].
Therefore, they will be able to acquire and maintain quality concepts, agreed quality standards and procedures, and introduce quality control/quality assurance (QA) to organizational staff/personnel. Furthermore, they will apply these parameters in leather goods and garment production, identify accompanied issues, and provide related documents to employees in accordance with the organization policy.
To implement quality standards, the basic conditions of the customer are (a) the purpose and (b) the selling price of the product or service.
These basic conditions can be resolved in to the following 10 detailed conditions:
specifications of dimensions,
operating characteristics,
life and reliability objectives,
safety requirements,
relevant standard,
engineering,
manufacturing and quality costs,
production conditions,
field installation,
maintenance and service objectives,
energy utilization and material conservation factors,
environmental and other side effects, and
cost of operation or use
2.1 Concept of quality
Quality is the totality of features and characteristics of a product or service that affect its ability to satisfy the specified or implied needs of a customer. Quality consistency requires from users to concentrate on the process rather than on the product alone. Quality gurus define quality as “conformance to requirement” and “fitness for use” [4]. Good quality will automatically result in productivity improvement. It is the author’s view that the best policy should be to do the things right first time.
Quality helps determine a firm’s success in a number of ways:
customer loyalty: satisfied customers return, make repeat purchases, and recommend the product or service to others,
strong brand reputation for quality: retailers want to stock the product; improved quality leads to fewer returns and replacements which in turn lead to reduced costs attracting thus and retaining good staff.
The term “Quality” can be measured aspects such as failure or reject rates, level of product returns, customer complaints, customer satisfaction, customer loyalty, evident from repeat purchases, or renewal rates and employee health and well-being.
2.2 Quality parameters
Quality is measured in a relative manner. It depends on how the user perceives or the way he/she get satisfied with that product/service. Once a product/service is accepted to customers, it can pull more new customers and may be produced/delivered in greater numbers, affecting in turn costs that are reduced and sales which will be increased. But, as quality has no universal meaning, the way users perceive it varies. Some users may like the performance or the reliability, while others may be happy with esthetic features and so on. What is reliable for a user may not be true for another. Hence, quality is an important factor which customers look for in a product or service in order to be rewarded with total satisfaction. Some of the important quality factors/parameters that customer considers in a product or services as stated by some quality gurus are listed as follows.
2.2.1 Dimensions (parameters) of quality
Performance: it evaluates if the product does the intended (planed or proposed) job or if the service delivered meets intended objective. Potential costumers usually evaluate a product to determine if it will perform certain specific functions and how well it will do them. For example, the production of a document holder or a leather bag with multifunction pockets would fall within this category.
Reliability: it indicates a product’s failure rate. Different products may need repair over their service life. The leather machineries should be also reliable so as to increase productivity, i.e. when leather garments are produced, greater attention ought to be placed during, e.g. the stitching procedure. As the needle is typically of a cutter edge type, sometimes it stitches the component by cutting the part. So, if proper stitching is not done, the product is either repaired or rejected.
Durability: it shows the duration that the product is expected to last for. This is the effective service life of the product that customer wants over a long period of time, e.g. a customer that orders a leather jacket may expect this to last for at least 5 years.
Serviceability: this parameter stands for how easy the product may be repaired. There are many industries where the customer’s view of quality is directly influenced by how quickly and economically a repair or routine maintenance activity can be accomplished’ in this case-study, dyeing or changing color of the leather jacket after a number of uses can be an example for this.
Esthetics: this dimension shows what the product looks like externally. This is the visual appeal of the product, often taking into account factors such as style, color, shape, packaging alternatives, and other sensory features.
Features: it means what features the product possesses. Usually, customers associate high quality with products that have added features (such as special color, design, handles, and decorations), which go beyond the basic performance of the competition.
Conformance: it is used to evaluate if the product or service conforms to the specification. This means, if it is developed based on a performance specification; will it actually perform as specified? If it is developed based on a design specification, does it possess all of the features defined?
Perceived quality: The product or service may possess adequate or even superior dimensions of quality but still fall victim to negative customer or public perceptions. As an example, a high-quality product may get the reputation for being low quality based on poor service by installation or field technicians. If the product is not installed or maintained properly, and fails as a result, the failure is often associated with the product’s quality rather than the quality of the service it receives.
2.3 Quality control and quality assurance
Quality control (QC) is a procedure or a set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer. While quality assurance (QA) is defined as a procedure or set of procedures projected to ensure that a product or service under development (before the work is complete, as opposed to afterward) meets specified requirements. QA is sometimes expressed together with QC as a single expression. There is plenty of quality control types. The following are used in the leather-related production controls [5].
Quality control of incoming material:
Ensuring the right materials are available in the right quantity at the right time.
Based on quality requirements, the purchase information such as specification, packing instruction, and transportation instruction should be clearly identified.
For example, in the garment industry for finished leather, the parameters such as color fastness, light fastness, tensile strength and softness need to be checked.
Physical characteristics such as lining, tensile strength and color fastness need to be checked. After finalizing the parameters to be assessed for each incoming material, the standards need to be met for each parameter of each incoming material.
Process control:
Process control (PC) can be defined as any activity that adds value to the product to be supplied or the service to be rendered. The term “process” in the leather garments manufacturing industry may include – but not be limited to – unit processes such as cutting, assembling and stitching, and finishing. According to the process control steps, the parameters for each process need to be identified first. For example, in assembling and stitching, the needle to be used, i.e. the needle number and needle point have an influence on the final product. Further, the thread used in bobbin (lower thread) and the sewing machine (top thread) also affects the quality of the final product.
Process control is carried out by the following steps:
Identification of process control parameters,
Establishing the standards for each parameter of each process (internal process control standard/working standard for process control),
Product refers to the physical output produced by supplying in the inputs or raw materials and carrying out any production process. The final product is what is dispatched to the customer or the end users. Apart from this, there are components sometimes referred to as intermittent products. For a leather garment manufacturer, these are prepared sleeves, pockets, collars, etc. Therefore, the output after each operation or process is an intermediate product. Product control generally refers to the control of the final product. Control of intermediate products is equally essential. This is due to the fact that in each stage the product quality is ensured so as to produce the final product of desired quality [6].
2.4 Quality inspection and testing
Quality inspection: Industrial activities which ensure that manufactured products, individual components, and multicomponent systems are adequate for their intended purpose. Whereas inspection is the activity of examining the product or its components to determine if they meet the design standards, testing is a procedure in which the item is observed during operation in order to determine whether it functions properly for a reasonable period of time under given stress conditions. Inspection and testing are performed before, during, and after manufacturing to ensure that the quality level of the product is within acceptable design standards.
There are also various types of inspections. The following categories are used in leather goods and garment production:
Incoming materials inspections: checking the quantity (finished leather, accessories, etc.), quality, rejection allowances, verification as per purchase order, lead time, etc.
First-article inspections: QC inspects first-article samples prior to volume production. This verifies that product specifications are being met and avoids unnecessary re-engineering work later.
In-process inspections: these on-site inspections evaluate samples of the products selected during the manufacturing process. This confirms the quality of the product and allows any necessary changes to be addressed early on reducing, hence, rework time and costs.
Pre-shipment inspections: during a pre-shipment inspection, engineers verify that finished goods conform to set specifications.
Sample inspections: samples are taken from inspection lots for end user evaluation, laboratory testing, or customer approval randomly, and processing QC can help for inspection. After this type of inspection, one can offer rapid service at a very affordable rate.
International standards are preferred to be used for testing leather products, especially in the garment industry. Table 1 shows this standard.
No.
Items
Standard
1
Elastic tapes
IS 9686
2
Metal buckles
IS 96986:1980
3
Threads
IS 1376/1803
4
Leather garment sizing system
IS 10397
5
Metallic slide fastener
IS 3148:1983
6
Garment quality guide
IS 12675
7
Leather for garments
IS 12718
8
Fur leather
IS 3840/2961
9
Fusible lining
IS 12806
10
Zip fasteners
IS 8894/3184/4829
Table 1.
Standards related to leather garments industry and related items.
Source: Leather Industry Development Institute, Advanced Garment Production, Level IV Training Materials, June 11, 2016.
3. Results and analysis
3.1 Leather goods common quality parameters
In addition to the eight quality parameters of any product like durability, feature, performance, conformity, esthetics, serviceability, perceived quality, and reliability, there are also other leather goods-specific quality parameters.
3.2 Most commonly used types of testing
Leather testing: it includes wet rub fastness, dry rub fastness, tool test, stress strain test, and plaster test fastness.
Leather goods and garments testing: it encompasses handbags and small luggage, wherein the strength – say – of strap fastenings is an important consideration in the quality assessment of handbags and luggage. A large number of companies in Ethiopia are able to carry out all strength tests utilizing state-of-the-art equipment to assess the risk of strap failures, whether at fastenings (e.g. buckles) or where the strap is attached to the body of the item itself. The other one is the leather belt testing, from an assessment of the components of a belt for labeling purposes. Also, specialty companies can perform further tests in order to satisfy all clients’ requirements such as the color fastness (wet and dry rub fastness test) to tarnishing of buckles and metal components, to ensure the products are fit for the purpose they are intended for.
A few examples of tests used in leather products manufacturing firms are as follows:
Smell test: the smell test is an important part of every inspection. To avoid illegal toxins, the most reliable way to check it is to perform chemical tests as per ASTM D1296 in an accredited Leather Industry Development Institute (LIDI) laboratory.
Function test: the objective is to check if the product works as designed or anticipated. In the case of the leather bag, an inspector will wear it and test the zippers’ direction and strength.
Color fastness check on leather: excessive dye may be rubbed off during a color fastness check. On leather, this is a frequent problem. The test may be repeated 10 times with a dry cloth and 10 times with a wet cloth.
Abuse and fatigue tests: pulling on straps and zippers with stronger-than-usual force helps to understand the manufacturing quality of leather bags.
Seam strength test for leather bags: this test is similar to the abuse test but focuses on the seams. It uses a tension gauge to check seam strength.
Load test: the inspector loads the leather bag with weights (depending on the model between 2 and 20 kg for backpacks (bag type) most of the time. Then the bag is lifted at least 20 times and is hanged on a hook for 4 h. This is an internal company policy similar to that of color fastness check.
Zipper twisting test: this type of test is used to check both the strength of the zipper and the seams holding it in the open middle and closed position. The QC pulls the zipper sideways for 10 s in each direction. Low-quality zippers tend to open and bend beyond repair. Extensive laboratory equipment test products (e.g. opening and closing zippers 5000 times) could be used also. However, most of small and medium leather products manufacturing companies use the manual test.
Carton humidity check: This test is performed in order to assess the behavior of the product in rainy conditions, while avoiding the buildup of mold or fungus, aiming at maintaining a humidity level below 12%. In particular, during the rainy season, the inspector should check the humidity of the export cartons with a humidity tester. As such, it ought to be ensured that sufficient desiccant (calcium oxide absorb water) is placed in the right spots.
3.3 Factors that influence the quality of leather goods and garments
Factors that influence quality aspects make bags and garments good and/or cheap. The following aspects are commonly experienced in leather products manufacture:
3.3.1 Designs and materials
The design room is where quality starts in leather goods manufacturing companies. Bag design is a system, which is not only the combination of the technique, knowledge, and the art, but also the connection of design and craft from the choice of the theme to grasp the inspiration and the accomplishment of the finished product. Through the design effect of a product, a bag or a garment should become a bridge between designers, technicians, and consumers. In that sense, it would be common language among them. The designers should identify the materials like type of leathers, accessories, colors, and hardware that will be used in the production process. A well-designed bag or a garment should include all information about its design. As an example, a good leather goods design should have at least the following information:
leather type (color, thickness, and feeling),
origin (cow, sheep, goat, buffalo, etc.)
reinforcement (EVA sheet, water proof, fusing, foam, etc.),
lining (velvet, cotton fabric, nylon, and polyester),
accessories (eyelet and rivet),
zipper, in terms of size (3, 5, and 8 mm), finishing (silver, gold, and bronze), and type (metallic, plastic chain, and plastic molded),
stitching (seam type and seam length per centimeter),
thread size (for needle thread and bobbin thread), type (cotton, nylon, polyester, silk, and polyester spun cotton), each dimension, (volume, height, and base, handling length, and width),
edge finishing (raw edge, folded, and edge color) and hard ware’s (buckle, color, and adjustable size) [7].
3.3.2 Material selection
Material selection refers to the materials selected for the manufacture of – say – a bag including the hardware and the accessories, as well as the processes involved.
3.3.3 Pattern making and cutting
The pattern making, which is also referred to as a sample making process is an important aspect and is regarded as a bridge of transforming the graphic designs into the products. The maximum permissible error (acceptable level) of pattern is 1/32 inches (1 inch error of 32 inches length), as by reference to any bag, or in accordance with international standards, such as SATRASumm, which is an industry standard package concerning the efficient cutting of leather and synthetic materials. In pattern making, usually major parts (shape and size of the bag) are made first, and then relatively smaller parts are followed and so on.
3.3.3.1 Fixing product size standards
Unlike leather garment and foot wear products, leather bags have no fixed specifications such as height, depth, and width and may therefore be easy to categorize as small bags, medium bags, and large bags. One could remember Galileo Galilei’s quote: “Measure what can be measured, and make measurable what cannot be measured.” From a quality management point of view, this means that “we cannot manage what we cannot measure.” In short, the clearer the specification, the better the possibility of creating and delivering quality products.
3.3.3.2 Construction
Construction is the matter of how everything or patterns have been put together. Figure 2 shows pattern alignment variations.
Figure 2.
Pattern alignment variations: (a) and (b).
3.3.3.3 Technology
The manufacturing process is a key factor to leather products’ quality. A different technology represents a different style of leather products. The quality of bags is as good as the people that make it. That is why the best stitchery, leather workers, and quality control technician or experts are required. In order to have best-quality products and workers, it is important to put a lot of resources into training or hiring the most qualified staff and paying them well fostering their commitment and creative minds.
3.4 Defects in goods and garments manufacturing
3.4.1 Defects and their types
Defects are deviations/nonconformities of processes, products, or materials from the requirements/standards. Causes of defects may be man-made (assignable causes) or common/natural causes. Assignable causes can be removed, while common causes can only be reduced. For example, a poorly build knife maybe a cause for cutting defects/human fault, while loose leather is a cause for less durability of the garments.
3.4.2 Methods of identifying and isolating faulty pieces
Defects in the cutting section can be identified by various bodies operating therein that are briefly presented as follows:
Cutting supervisors: they are the cutting supervisors that issue leather from raw material store where defects like loose leather, under substance, wrong color/shape, poor nap on nubuck, poor color fastness, and poor knife can be visually identified, and the leather is thereafter sorted accordingly. Only leather bundles that meet specifications are issued and allocated among cutting operators by the supervisors.
Cutting operators: they can identify during cutting minor defects like grains not matched pair wise, wrong direction of cutting, cuts/flaws in component, open defect, wrong size cut, and color variations to name but a few. These operators, in addition to cutting operations, have the responsibility to take care of component quality. As such, items ought to be cut in line with the parameters stated earlier and the data be posted to the operators.
Defects in the stitching (sewing) section can be identified by various bodies operating therein.
Bench workers can identify defects like notch marks not matched, edge folding inaccurate, improper alignment, wrong components placement, too much hammering, and too much glue.
Stitching operators: they can identify minor defects like uneven stitching length, skipped stitches, stitches not locked at the end, wrong needle/thread used, stitches too far or too close to the edge, stitches not as per the marking, broken stitches, top tension tight, and seam puckering.
Possible defects during the final inspection stage may be:
trimming,
thread burning,
glue erasing,
leaving uneven stitching length,
pattern vs. assembly correspondence,
measurement and alignment,
grain structure checking,
component checking,
color and size matching,
ironing dimension,
seem puckering,
proper feeding system,
thread tension,
leaving broken stitches and skipped stitches,
stitches too far or too close to the edge,
top tension tight, thickness, and not ±0.2 mm allowances [8].
3.5 Part five: Finishing in leather products manufacturing
Finishing is the final process given to a garment or goods in order to achieve good appearance, desirable feel and look and to impart some important, and durable and functional properties.
3.5.1 Classification of finishing
Finishing in leather products manufacturing can be classified according to the nature of the finish such as Kawabata’s Evaluation System for Fabric-KES-FB and the degree of performance (ISO11644:2009). Figure 3a and b show these classifications.
Figure 3.
Classifications based on (a) the nature of finish (KES-FB) and (b) the degree of performances as per ISO11644:2009.
3.5.2 Edge coloring
Sand edges: this is done by using emery paper to sand the edges and to arrange many belts/straps of the same size side by side on a flat table and sand simultaneously. This will ensure that all the leather layers are even and square and that any residual glues or finishes have been removed. Figure 4 shows edge coloring in industry.
Figure 4.
Edge coloring in practical.
Applying color: this is done either by using a machine or manually. For manual operation, the use of dye box like Fiebing’s dye will make it simpler. Keeping the dyed edge by facing up for air-drying before applying on the opposite edge is worthy. After the other side got dried, one can paint the opposite one and keep the same way one has done previously. It can also be applied during the second round if necessary. This method is used everywhere globally even though manual coloring is preferably practical in Ethiopian leather products manufacturing firms. Figure 5 indicates the application of color with the aid of a machine.
Figure 5.
Applying color with machine.
Applying filler: the leather filler paste is a white compound that can be air- or heat-dried and requires re-coloring with a leather repair pigment after its application. The leather filler remains flexible, durable, and natural to the existing leather surface. It is used to fill the edge surface and results in smoothness to the edge’s surface (see Figure 6).
Figure 6.
Leather filler paste.
Wet and soap: the edge of the leather can be wetted using a sponge or piece of trimmed woolskin. The outcome will be a slick/polished rounded edge.
Burnishing: this is accomplished by briskly rubbing the canvas against the edge of the belt until the edge is smooth. A canvas wrapped around a motorized wood burnishing wheel which speeds up the process could be used herein. However, care should be taken not to over-burnish, which will result in a rough edge.
Hand burnishing: this is done by means of a clean cloth that rubs the edges removing hence, any residual dye and determining thus, if the second coat is necessary.
Polish: at this point, paraffin is applied to the edge of the belt and burnished again and again. Denim works well here if burnishing is done by hand. Once one is satisfied with the finish, one can polish to a high luster with a dry cloth [9].
Finish: after the edges are polished, final finish is applied.
3.5.3 Trimming: Hand trimming and trimmer machine
It is preferred to use thread trimmer machines as it reduces trimming costs, increases production, uses unskilled help, eliminates scissor damage, keeps trimming area clean, and reduces cleanup cost. One can choose between different clipper blades and motor control for diverse material. Scissors can be used for trimming (Figure 7).
Figure 7.
Scissors for trimming.
Thread burning: it can be manual with a candle or by means of soldering iron (Figure 8).
Figure 8.
Soldering iron used for thread burning.
4. Discussion
The quality control concept is very useful especially for exports of branded products. Apart from the general knowledge and experience of the author in the sector, secondary sources were used from institutions such as the Ethiopian Leather Industry Development Institute (LIDI), Ethiopian Leather Industry Associations, and medium- and large-scale leather products manufacturers. The LIDI laboratory was accredited from SANAS (South African National Accredited System) so as to support the leather sector with various laboratory testing (i.e. physical, mechanical, and chemical) services in 2012. Furthermore, the LIDI laboratory was also accredited from the Ethiopian National Accreditation Office (ENAO) in the same year.
With this responsibility, LIDI has been serving Ethiopian leather manufacturing firms by laboratory testing, technical training, quality management system (QMS), and quality control and quality assurance tools implementations. Under the Twinning program, which was made between LIDI and the Federal Democratic Republic of Ethiopia, FDRE, Ministry of Industry on Ethiopian side, and CSIR – Central Leather Research Institute-Council of Scientific and Industrial Research, India, in association with Footwear Design and Development Institute (FDDI), India, LIDI’s R&D laboratory state of the art was created to meet the requirements and demands of leather and leather products in order to meet and ensure international quality standards [10].
Most of leather goods and garment manufacturing companies in Ethiopia use smell test, function test, and color fastness check on leather accepting it as internal company policy, as it matches with some of global/international standards in this aspect (ASTM D1296, ISO 11640, ISO 11641, SLF 401, IUP 470).
Apart from common quality parameters, there are also other leather goods-specific quality parameters. Items made from real leather or imitations, such as PU, which are very popular, should be treated accordingly. However, leather goods and garment manufacturing companies prefer to use simpler (by observation and manual tests) methods, whereas other manufacturers in footwear subsectors could use more test methods as per international standards in order to check, for example, grain structure, thickness, apparent density, shrinkage, flex resistance, water resistance, and so on as per ISO 2589:2002, ISO 2420, ISO 5402, ISO 3380, ISO 5403. That is because, footwear products are highly vulnerable to damage, and hence, their suitability to use needs to be assured before reaching the end users. Table 2 provides a summary of physical testing standards for leather that could be recommended by the author to be used so as to improve productivity and reduce defect rates, rework, and waste.
S.No.
Types of test
Test method
1
Determination of thickness
ISO 2589:2002
2
Determination of apparent density
ISO 2420
3
Determination of tensile strength and percentage elongation
ISO 3376
4
Determination of tearing load (single and double)
SO3377---1/3377---2
5
Determination of distension and strength of grain ball burst
ISO 3378
6
Determination of flex resistance by flexometer method
ISO 5402
7
Determination of shrinkage temperature up to 1150°C
ISO 3380
8
Water absorption (Kubelka) after 2 and 24 h
SATRA TM/ISO SLP 19
9
Determination of water resistance test for light leather
ISO 5403
10
Determination of water resistance of heavy leather
ISO 5404
11
Determination of water vapor permeability
ISO 14268
12
Determination of cold crack resistance leather finish
SLP 34
13
Determination of sole/upper adhesion tester
Internal
14
Measurement of shoe flex (walk meter)
Internal
15
Determination of dry heat resistance of leather
Internal
16
Determination of adhesion of leather finish
SLF 11
17
Color fastness to artificial light (xenon)
SLF 401
18
Determination of fastness to water spotting
ISO 11642
19
Color fastness to perspiration
ISO 11641
20
Determination of fastness of leather finish to (to and from rubbing)
ISO 11640
21
Determination of fastness to ironing (fastness to heat)
IUP 470
22
Determination of static water absorption
ISO 2417
Table 2.
Leather physical testing.
Source: Leather Industry Development Institute’s Physical Laboratory, March 23, 2016.
Regarding the effect of human factors in product quality, it is the author’s view that most quality problems are caused primarily by a lack of interest or care on the part of the worker in the production department. However, it is usually not only the worker who is responsible for this but also the conditions necessary to carry out the work correctly often do not exist. For example, instructions may be inadequate, the incoming material may be defective, the machines may not be capable of producing goods of the required quality, and proper conditions for conducting inspection of the product are not given to the workers, and so on. The study done by joint consultancy of Ethio-Indian twinning project in collaboration with the Leather Industry Development Institute (LIDI) and the Footwear Design and Development Institute (FDDI) of India approves this fact [11]. Figure 4 (in Section 4.1) shows that inadequate instructions, which accounts for about 28% caused the rest effects. Effective understanding of the worker to the instructions in every step of production will surely lead to more pleasant effects on the product quality. However, although workers may not have control over these factors, they may though lead to defective work. Figure 9 shows Pareto analyses of one factory.
Figure 9.
Result of Pareto analysis for ELICO-universal leather products unit. Source: Twinning report [11].
In Japan, it is generally believed that 40% of quality problems are caused by poor product design, 30% of quality problems are due to wrong or defective materials being purchased from suppliers, and the remaining 30% are due to errors made during the manufacturing process [12]. One could argue that any other quality problems in manufacturing are caused in equal proportion by managers (by not providing adequate training for workers) and by workers (by not paying adequate attention to machine settings).
Regarding defects observed in goods and in garments manufacturing listed in the following section are common examples of deficiencies in leather products manufactured in Ethiopia:
Sewing defects: open seams, wrong stitching techniques, non-matching threads and missing stitches, improper creasing of the garment, erroneous thread tension and raw edges are some of the sewing defects which can affect the garment quality adversely. Firms mitigate these types of defects by providing continuous on-the-job trainings for sewing operators.
Color defects: this category includes color variations between the sample and the final garment, wrong color combinations, and mismatching dyes’ that should always be avoided. Leather issuers check this in store for every order with the help of leather sorter or in-process quality inspector.
Sizing defects: this refers to wrong gradation of sizes and difference in the measurement of various parts of garment-like sleeves of XL size for a body of L size garment that can deteriorate the garments beyond repair. Though tanneries use leather grading machine during production, Ethiopian leather goods and garment manufacturing firms usually identify and mitigate these defects by cross-checking cut components visually.
Other defects: this group entails broken or defective buttons, snaps, stitches, different shades within the same garment, dropped stitches, exposed notches and raw edges, fabric defects, holes, faulty zippers, loose or hanging sewing threads, misaligned buttons and holes, missing buttons, needle cuts or chews, pulled or loose yarn, stains, unfinished buttonhole, short zippers, inappropriate trimmings, etc. These defects, unless tackled at the very beginning, and/or quality assurance is undertaken in every step, could lead leather products manufacturing companies to be less competitive and affect in turn their existence. Due to globalization and acceptance of Ethiopian leather products to export markets, manufacturers of leather products are obliged to implement various quality improvement tools including QC/QA. Thus, respective process and final quality checking parameters have been posted in front of operators in each section along with visual defective and free cut components. This method encourages operators to think about quality issues in addition to their duties of – say – cutting, table work, sewing, and finishing.
Concerning defect control at the finishing section, various final quality control parameters are used that include trimming, thread burning, glue erasing, pattern vs. assembly correspondence, thread tension, leaving broken stitches and skipped stitches, and stitches too far or too close to the edge.
As for Ethiopian leather products manufacturers, the defect control parameters during the final inspection stage include aspects such as:
leaving uneven stitching length,
measurement and alignment,
grain structure checking,
component checking,
color and size matching,
ironing dimension,
seem puckering,
proper feeding system,
top tension tight and thickness, etc., are inspected prior to this stage.
5. Conclusion and further work
The leather sector’s contribution is very high with respect to export incomes and economic development, especially on creating job opportunities. For instance, according to the Central Statistical Agency (CSA) of Ethiopia, export of leather and leather products, which was US $23 million in 2013, reached US$133 million in 2018. Hence, leather goods and garment to be exported need high care during all manufacturing stages in order to increase competitiveness in the global market.
This book chapter discussed quality control concepts and quality standards for leather goods and garment. In doing so, it highlighted applicable procedures and documents enabling supervisors, quality controllers, and operators in those companies to get detailed knowledge about quality parameters and control mechanisms so that defect-free products reach end users. Furthermore, it will allow readers to familiarize themselves with quality concepts in this sector. It is the author’s view that this research work may prompt readers to confront themselves with quality control aspects and to research more about these aspects in this specialized manufacturing area.
Moreover, leather goods and garment quality parameters and factors that influence the quality of leather goods and garment were included. In addition to the earlier-mentioned ones, commonly occurring defects, methods of identifying and isolating faulty pieces, and some finishing types in leather products production were discussed.
Studying the application of QC/QA on the whole leather sector (leather processing, footwear industry, glove making, and other related subsectors) will be the next tasks of the researchers and book writers. This may include subsector-specific inspection and control mechanisms starting from designing, cutting, table work (preparation), sewing, inspection and testing, packing, and shipping that need to be further analyzed.
Acknowledgments
The author would like to express his gratitude to his wife for her patience and assistance.
Further reading
To get more practical explanation of quality aspects, readers are advised to read of the work of David Garvin (1988) – Eight Dimensions of Quality.
\n',keywords:"quality, quality control, leather goods and garment, defects",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82033.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82033.xml",downloadPdfUrl:"/chapter/pdf-download/82033",previewPdfUrl:"/chapter/pdf-preview/82033",totalDownloads:12,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 15th 2022",dateReviewed:"March 14th 2022",datePrePublished:"May 30th 2022",datePublished:null,dateFinished:"May 30th 2022",readingETA:"0",abstract:"The leather industry is one of the priority sectors that contribute to export income and economic development in the majority of African countries, in terms of creating job opportunities. Leather products need high care during manufacturing because their quality should never be compromised. Quality is a universal term used to evaluate the performance of a product or a service and the acceptance by the customer(s) in terms of customer satisfaction. As such, understanding quality concepts such as quality control (QC), quality standards, procedures, and documents related to leather goods and garment production in accordance with manufacturing company’s policy is deemed useful within the context of this paper. Supervisors, quality controllers, and operators in leather products manufacturing firms need to know required quality parameters and associated control mechanisms so that defect-free products will reach the end users. In order to achieve this, quality-influencing parameters such as performance, reliability, durability, serviceability, esthetics, features, and conformance are measured so as to verify set quality levels. Furthermore, factors that affect the quality of leather goods and garments as well as methods of identifying and isolating common defects and faulty pieces especially in the finishing activities of leather production are included herein. Hence, this paper covers quality control aspects on leather goods observed within the garment manufacturing subsector.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82033",risUrl:"/chapter/ris/82033",signatures:"Abduletif Hebo",book:{id:"11170",type:"book",title:"Quality Control",subtitle:null,fullTitle:"Quality Control",slug:null,publishedDate:null,bookSignature:"Dr. Leo Dimitrios Kounis",coverURL:"https://cdn.intechopen.com/books/images_new/11170.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-991-9",printIsbn:"978-1-80355-990-2",pdfIsbn:"978-1-80355-992-6",isAvailableForWebshopOrdering:!0,editors:[{id:"111582",title:"Dr.",name:"Leo",middleName:"Dimitrios",surname:"Kounis",slug:"leo-kounis",fullName:"Leo Kounis"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Aims and objectives",level:"2"},{id:"sec_3",title:"2. Literature review",level:"1"},{id:"sec_3_2",title:"2.1 Concept of quality",level:"2"},{id:"sec_4_2",title:"2.2 Quality parameters",level:"2"},{id:"sec_4_3",title:"2.2.1 Dimensions (parameters) of quality",level:"3"},{id:"sec_6_2",title:"2.3 Quality control and quality assurance",level:"2"},{id:"sec_7_2",title:"2.4 Quality inspection and testing",level:"2"},{id:"sec_9",title:"3. Results and analysis",level:"1"},{id:"sec_9_2",title:"3.1 Leather goods common quality parameters",level:"2"},{id:"sec_10_2",title:"3.2 Most commonly used types of testing",level:"2"},{id:"sec_11_2",title:"3.3 Factors that influence the quality of leather goods and garments",level:"2"},{id:"sec_11_3",title:"3.3.1 Designs and materials",level:"3"},{id:"sec_12_3",title:"3.3.2 Material selection",level:"3"},{id:"sec_13_3",title:"3.3.3 Pattern making and cutting",level:"3"},{id:"sec_13_4",title:"3.3.3.1 Fixing product size standards",level:"4"},{id:"sec_14_4",title:"3.3.3.2 Construction",level:"4"},{id:"sec_15_4",title:"3.3.3.3 Technology",level:"4"},{id:"sec_18_2",title:"3.4 Defects in goods and garments manufacturing",level:"2"},{id:"sec_18_3",title:"3.4.1 Defects and their types",level:"3"},{id:"sec_19_3",title:"3.4.2 Methods of identifying and isolating faulty pieces",level:"3"},{id:"sec_21_2",title:"3.5 Part five: Finishing in leather products manufacturing",level:"2"},{id:"sec_21_3",title:"3.5.1 Classification of finishing",level:"3"},{id:"sec_22_3",title:"3.5.2 Edge coloring",level:"3"},{id:"sec_23_3",title:"3.5.3 Trimming: Hand trimming and trimmer machine",level:"3"},{id:"sec_26",title:"4. Discussion",level:"1"},{id:"sec_27",title:"5. Conclusion and further work",level:"1"},{id:"sec_28",title:"Acknowledgments",level:"1"},{id:"sec_28",title:"Further reading",level:"1"}],chapterReferences:[{id:"B1",body:'Worku G, UNCTAD. Is the Ethiopian leather industry on the right track? An empirical investigation. Ethiopian Journal of Economics. 2000, 2001;X(2):16'},{id:"B2",body:'Girum A, Florian S. High Hopes and Limited Successes: Experimenting with Industrial Polices in the Leather Industry in Ethiopia. Working Papers. Addis Ababa: Ethiopian Development Research Institute; 2014'},{id:"B3",body:'Annual Leather Sector Performance Report for LIDI. Addis Ababa, Ethiopia: Leather Industry Development Institute; 15 October 2019'},{id:"B4",body:'Juran JM, Blanton GA. Juran’s Quality Handbook. 5th ed. New York: McGraw Hill; 1998. pp. 20-28'},{id:"B5",body:'Alemu T. Leather Goods Design, Manufacturing & Quality Book. Maude Avenue, Sunnyvale, USA: LAP LAMBERT Academic Publishing; 2018. pp. 46-58'},{id:"B6",body:'Application of Quality Standards, College Level-III Training Material. 2019. pp. 15-39. Available from: https://www.elidi.com [Accessed: 2021-06-12]'},{id:"B7",body:'The innovative garment accessories. Available from: https://www.fibre2fashion.com/industry-article [Accessed: 2021-05-10]'},{id:"B8",body:'Engineer’s Manual No. E356-01. p. 23'},{id:"B9",body:'Mechanical finishing, polishing vs. buffing by Pat Wenino. Available from: https://www.pfonline.com [Accessed: 21 September 2021]'},{id:"B10",body:'Leather Industry Development Institute. Compendium of Outcome and Achievements of Twinning Program, 2011-2014. September 16th, 2014'},{id:"B11",body:'Twinning Project. Unpublished Company Report. ELICO Universal Leather Products Factory. 2014'},{id:"B12",body:'Product Quality, A Guide for Small and Medium-Sized Enterprises. Working Paper. Vienna: United Nations Industrial Development Organization; 2006'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Abduletif Hebo",address:"abduinda@gmail.com",affiliation:'
Bio and Emerging Technology Institute, Emerging Technology Center, Reverse Engineering Directorate, Addis Ababa, Ethiopia
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This chapter aims to present the main good practices, challenges, and opportunities related to Industry 4.0 paradigm.",book:{id:"6291",slug:"digital-transformation-in-smart-manufacturing",title:"Digital Transformation in Smart Manufacturing",fullTitle:"Digital Transformation in Smart Manufacturing"},signatures:"Antonella Petrillo, Fabio De Felice, Raffaele Cioffi and Federico\nZomparelli",authors:[{id:"161682",title:"Prof.",name:"Fabio",middleName:null,surname:"De Felice",slug:"fabio-de-felice",fullName:"Fabio De Felice"},{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"},{id:"205141",title:"Dr.",name:"Federico",middleName:null,surname:"Zomparelli",slug:"federico-zomparelli",fullName:"Federico Zomparelli"},{id:"208748",title:"Dr.",name:"Raffaele",middleName:null,surname:"Cioffi",slug:"raffaele-cioffi",fullName:"Raffaele Cioffi"}]},{id:"35715",doi:"10.5772/38693",title:"The Role and Importance of Cultural Tourism in Modern Tourism Industry",slug:"the-role-and-importance-of-cultural-tourism-in-modern-tourism-industry",totalDownloads:41085,totalCrossrefCites:31,totalDimensionsCites:62,abstract:null,book:{id:"2298",slug:"strategies-for-tourism-industry-micro-and-macro-perspectives",title:"Strategies for Tourism Industry",fullTitle:"Strategies for Tourism Industry - Micro and Macro Perspectives"},signatures:"Janos Csapo",authors:[{id:"118766",title:"Dr.",name:"János",middleName:null,surname:"Csapó",slug:"janos-csapo",fullName:"János Csapó"}]},{id:"38973",doi:"10.5772/51460",title:"Risk Management in Construction Projects",slug:"risk-management-in-construction-projects",totalDownloads:102568,totalCrossrefCites:36,totalDimensionsCites:59,abstract:null,book:{id:"2175",slug:"risk-management-current-issues-and-challenges",title:"Risk Management",fullTitle:"Risk Management - Current Issues and Challenges"},signatures:"Nerija Banaitiene and Audrius Banaitis",authors:[{id:"139414",title:"Dr.",name:"Nerija",middleName:null,surname:"Banaitiene",slug:"nerija-banaitiene",fullName:"Nerija Banaitiene"},{id:"149658",title:"Dr.",name:"Audrius",middleName:null,surname:"Banaitis",slug:"audrius-banaitis",fullName:"Audrius Banaitis"}]},{id:"40977",doi:"10.5772/53885",title:"The Emergence of Scientific Reasoning",slug:"the-emergence-of-scientific-reasoning",totalDownloads:4554,totalCrossrefCites:8,totalDimensionsCites:59,abstract:null,book:{id:"654",slug:"current-topics-in-children-s-learning-and-cognition",title:"Current Topics in Children's Learning and Cognition",fullTitle:"Current Topics in Children's Learning and Cognition"},signatures:"Bradley J. Morris, Steve Croker, Amy M. Masnick and Corinne Zimmerman",authors:[{id:"154336",title:"Prof.",name:"Bradley",middleName:null,surname:"Morris",slug:"bradley-morris",fullName:"Bradley Morris"},{id:"154337",title:"Prof.",name:"Steve",middleName:null,surname:"Croker",slug:"steve-croker",fullName:"Steve Croker"},{id:"154338",title:"Prof.",name:"Amy",middleName:null,surname:"Masnick",slug:"amy-masnick",fullName:"Amy Masnick"},{id:"154339",title:"Prof.",name:"Corinne",middleName:null,surname:"Zimmerman",slug:"corinne-zimmerman",fullName:"Corinne Zimmerman"}]}],mostDownloadedChaptersLast30Days:[{id:"58890",title:"Philosophy and Paradigm of Scientific Research",slug:"philosophy-and-paradigm-of-scientific-research",totalDownloads:14074,totalCrossrefCites:9,totalDimensionsCites:17,abstract:"Before carrying out the empirical analysis of the role of management culture in corporate social responsibility, identification of the philosophical approach and the paradigm on which the research carried out is based is necessary. Therefore, this chapter deals with the philosophical systems and paradigms of scientific research, the epistemology, evaluating understanding and application of various theories and practices used in the scientific research. The key components of the scientific research paradigm are highlighted. Theories on the basis of which this research was focused on identification of the level of development of the management culture in order to implement corporate social responsibility are identified, and the stages of its implementation are described.",book:{id:"5791",slug:"management-culture-and-corporate-social-responsibility",title:"Management Culture and Corporate Social Responsibility",fullTitle:"Management Culture and Corporate Social Responsibility"},signatures:"Pranas Žukauskas, Jolita Vveinhardt and Regina Andriukaitienė",authors:[{id:"179629",title:"Prof.",name:"Jolita",middleName:null,surname:"Vveinhardt",slug:"jolita-vveinhardt",fullName:"Jolita Vveinhardt"}]},{id:"74550",title:"School Conflicts: Causes and Management Strategies in Classroom Relationships",slug:"school-conflicts-causes-and-management-strategies-in-classroom-relationships",totalDownloads:2328,totalCrossrefCites:1,totalDimensionsCites:10,abstract:"Conflicts cannot cease to exist, as they are intrinsic to human beings, forming an integral part of their moral and emotional growth. Likewise, they exist in all schools. The school is inserted in a space where the conflict manifests itself daily and assumes relevance, being the result of the multiple interpersonal relationships that occur in the school context. Thus, conflict is part of school life, which implies that teachers must have the skills to manage conflict constructively. Recognizing the diversity of school conflicts, this chapter aimed to present its causes, highlighting the main ones in the classroom, in the teacher-student relationship. It is important to conflict face and resolve it with skills to manage it properly and constructively, establishing cooperative relationships, and producing integrative solutions. Harmony and appreciation should coexist in a classroom environment and conflict should not interfere, negatively, in the teaching and learning process. This bibliography review underscore the need for during the teachers’ initial training the conflict management skills development.",book:{id:"7827",slug:"interpersonal-relationships",title:"Interpersonal Relationships",fullTitle:"Interpersonal Relationships"},signatures:"Sabina Valente, Abílio Afonso Lourenço and Zsolt Németh",authors:[{id:"324514",title:"Ph.D.",name:"Sabina",middleName:"N.",surname:"Valente",slug:"sabina-valente",fullName:"Sabina Valente"},{id:"326375",title:"Prof.",name:"Abílio Afonso",middleName:"Afonso",surname:"Lourenço",slug:"abilio-afonso-lourenco",fullName:"Abílio Afonso Lourenço"},{id:"329177",title:"Dr.",name:"Zsolt",middleName:null,surname:"Németh",slug:"zsolt-nemeth",fullName:"Zsolt Németh"}]},{id:"58969",title:"Corruption, Causes and Consequences",slug:"corruption-causes-and-consequences",totalDownloads:27687,totalCrossrefCites:13,totalDimensionsCites:15,abstract:"Corruption is a constant in the society and occurs in all civilizations; however, it has only been in the past 20 years that this phenomenon has begun being seriously explored. It has many different shapes as well as many various effects, both on the economy and the society at large. Among the most common causes of corruption are the political and economic environment, professional ethics and morality and, of course, habits, customs, tradition and demography. Its effects on the economy (and also on the wider society) are well researched, yet still not completely. Corruption thus inhibits economic growth and affects business operations, employment and investments. It also reduces tax revenue and the effectiveness of various financial assistance programs. The wider society is influenced by a high degree of corruption in terms of lowering of trust in the law and the rule of law, education and consequently the quality of life (access to infrastructure, health care). There also does not exist an unambiguous answer as to how to deal with corruption. Something that works in one country or in one region will not necessarily be successful in another. This chapter tries to answer at least a few questions about corruption and the causes for it, its consequences and how to deal with it successfully.",book:{id:"6487",slug:"trade-and-global-market",title:"Trade and Global Market",fullTitle:"Trade and Global Market"},signatures:"Štefan Šumah",authors:[{id:"228073",title:"Mr.",name:"Stefan",middleName:null,surname:"Sumah",slug:"stefan-sumah",fullName:"Stefan Sumah"}]},{id:"55499",title:"Human Resources Management in Nonprofit Organizations: A Case Study of Istanbul Foundation for Culture and Arts",slug:"human-resources-management-in-nonprofit-organizations-a-case-study-of-istanbul-foundation-for-cultur",totalDownloads:2399,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The aim of this study is to investigate the efficiency and importance of human resources management in nonprofit organizations. The understanding was included to the literature as personnel management at the beginning of the twentieth century and it turned into an approach as human resources management in the 1980s. It could be observed that many organizations, which deem the human as the most critical stakeholder, adopt a traditional way of personnel management in operating human resources. The employees play a key role in the success of an organization. For this reason, subjects such as recruitment, training, development, career management, performance appraisal, occupational health, and safety are the fundamental functions of human resources management. The study examines to what extent these roles are evaluated through a case study. The subject matter of the study is the most powerful culture and art foundation in Turkey. Compared to many other nonprofit organizations, the foundation actively performs a variety of services within a year worldwide. The fact that the total number of employees might rise up to 800, including the field personnel, indicates the need of a good functioning human resources management. The human resources practices of the foundation are examined and evaluated within that scope.",book:{id:"5826",slug:"issues-of-human-resource-management",title:"Issues of Human Resource Management",fullTitle:"Issues of Human Resource Management"},signatures:"Beste Gökçe Parsehyan",authors:[{id:"189113",title:"Dr.",name:"Beste",middleName:null,surname:"Gokce Parsehyan",slug:"beste-gokce-parsehyan",fullName:"Beste Gokce Parsehyan"}]},{id:"59152",title:"Marketing Strategies for the Social Good",slug:"marketing-strategies-for-the-social-good",totalDownloads:1669,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Social network sites (SNS) have proven to be a good environment to promote and sell goods and services, but marketing is more than creating commercial strategies. Social marketing strategies can also be used to promote behavioral change and help individuals transform their lives, achieve well-being, and adopt prosocial behaviors. In this chapter, we seek to analyze with a netnographic study, how SNS are being employed by nonprofits and nongovernment organizations (NGOs) to enable citizens and consumers to participate in different programs and activities that promote social transformation and well-being. A particular interest is to identify how organizations are using behavioral economic tactics to nudge individuals and motivate them to engage in prosocial actions. By providing an understanding on how SNS can provide an adequate environment for the design of social marketing strategies, we believe our work has practical implications both for academicians and marketers who want to contribute in the transformation of consumer behavior and the achievement of well-being and social change.",book:{id:"6583",slug:"marketing",title:"Marketing",fullTitle:"Marketing"},signatures:"Alicia De La Pena",authors:[{id:"196878",title:"Dr.",name:"Alicia",middleName:null,surname:"De La Pena",slug:"alicia-de-la-pena",fullName:"Alicia De La Pena"}]}],onlineFirstChaptersFilter:{topicId:"4",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83075",title:"Practices and Challenges of Community Services at Debre Markos University, Ethiopia: A Case Study",slug:"practices-and-challenges-of-community-services-at-debre-markos-university-ethiopia-a-case-study",totalDownloads:1,totalDimensionsCites:0,doi:"10.5772/intechopen.105896",abstract:"Universities are the main actors that deliver community service in Ethiopia. Community service is among the three pillars of the university’s business along with teaching and research tasks. Employing a qualitative case study design, this research inspects the practices of community services against the ascribed principles and identifes the pitfalls of community service in Debre Markos University. Both primary and secondary data were collected. Primary data were collected through key informants interviews, semistructured interviews, and non-participant observation. Thirteen participants, five through key informant interview and eight through a semistructured interview were addressed. Participants were purposively selected from both the university and the nearby community. Lecturers, vice-presidents, and directors have participated in the interview. Articles, books, different reports, newspapers, and magazines were reviewed and used as sources of secondary data. Thematic data analysis technique was employed to analyze the primary data, and document analysis was used to analyze the data gained from secondary sources. The results show that, though community service is rendered since 2006 at Debre Markos University, there are still limitations in adhering to the principles of community service. These include shortage of budget, low level of University-Industry Linkage (UIL), less commitment of the staff, and the low level of monitoring and evaluation.",book:{id:"11602",title:"Corporate Social Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11602.jpg"},signatures:"Adane Mengist"},{id:"83053",title:"Apologies in L2 French in Canadian Context",slug:"apologies-in-l2-french-in-canadian-context",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.106557",abstract:"This article presents the results of an analysis of apology strategies in native and non-native French in Canadian context. The data used were obtained through a Discourse Completion Task questionnaire that was completed by a group of native French speakers (FL1) and a group of learners of French as a second language (FL2). The goal was to identify and compare pragmatic and linguistic choices made by both groups when apologizing in three different situations. Several differences and similarities emerged between the two groups regarding the use of exclamations to introduce apologies, direct apologies, indirect apologies, and supportive acts. For instance, it was found that the FL1 speakers used “expressions of regret”, “offers of apology” 15 and “requests for forgiveness” to apologize directly, while the FL2 speaking informants used 16 only “expressions of regret” and “offers of apology”. While the respondents of both groups 17 mostly chose “offers of repair” to apologize indirectly, they displayed divergent preferences 18 regarding the use of other indirect apology strategies. Differences were also documented 19 with respect to the use of intensification devices in direct apologies and the use of supportive acts. Implications of the findings for L2 French pedagogy were also discussed.",book:{id:"11480",title:"Second Language Acquisition - Learning Theories and Recent Approaches",coverURL:"https://cdn.intechopen.com/books/images_new/11480.jpg"},signatures:"Bernard Mulo Farenkia"},{id:"83049",title:"An Ethnographic Study on Sense of a Community: The “Awramba” Experience",slug:"an-ethnographic-study-on-sense-of-a-community-the-awramba-experience",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.105953",abstract:"The study was conducted on “Awramba” Community who are living in “Amhara” region, south “Gondor” Zone, Ethiopia. The general objective of this study was to capture an understanding of sense of community in “Awramba” community. The study tried to answer the following questions: How the community was established? What are the criteria to be part of the community? What are the shared values of social practice that has survived for the test of time? What is the historical background of the “Awramba” Community? The researcher used realist ethnography method to achieve the above objective and to answer the questions. In-depth interview and observational guide techniques were applied to collect reliable data for the study. The observation and in-depth interview data were analyzed qualitatively. The study showed the following themes: Membership criteria of the community are based on adhering to the community norm. They have a strong sense of community based on shared story, cooperative work, marriage and mourning values, religious view, gender equality, commitment to be honest, and solving their problem by themselves. The emotional connection of the “Awramba” community is strengthened by their common celebration of the yearly anniversary of New Year and scheduled meeting.",book:{id:"11429",title:"Sustainability, Ecology, and Religions of the World",coverURL:"https://cdn.intechopen.com/books/images_new/11429.jpg"},signatures:"Nassir-Maru Yesuf"},{id:"83027",title:"Coping Strategies and Meta-Worry in Adolescents’ Adjustment during COVID-19 Pandemic",slug:"coping-strategies-and-meta-worry-in-adolescents-adjustment-during-covid-19-pandemic",totalDownloads:0,totalDimensionsCites:0,doi:"10.5772/intechopen.106258",abstract:"With the beginning of the COVID-19 pandemic, several limitations and stressful changes have been introduced in adolescent’s daily life. Particularly, Italian teenagers were the first among western populations to experience fears of infection, home confinement, and social restrictions due to a long lockdown period (10 weeks). This study explores the role of coping strategies (task-oriented, emotion-oriented, and avoidance coping) and meta-beliefs about worry as vulnerability factors associated with adolescents’ anxiety. A community sample of adolescents (N = 284, aged 16–18 y.o.) answered questionnaires assessing anxiety symptoms (RCMAS-2), meta-cognitive beliefs and processes about worry (MCQ-C), and coping strategies (CISS). Results show that 37% of participants report clinically elevated anxiety. Emotion-centered coping predicted higher anxiety, whereas task-centered coping resulted associated with decreased anxiety. Cognitive monitoring about their own worry contributes, but to a lesser extent, to higher levels of anxiety. The implications for the intervention are discussed, especially the need to enhance the coping skills of adolescents and mitigate the stress of the COVID-19 pandemic, which could last for a long time.",book:{id:"10671",title:"Adolescences",coverURL:"https://cdn.intechopen.com/books/images_new/10671.jpg"},signatures:"Loredana Benedetto, Ilenia Schipilliti and Massimo Ingrassia"},{id:"83023",title:"Gestational Tryptophan Fluctuation Underlying Ontogenetic Origin of Neuropsychiatric Disorders",slug:"gestational-tryptophan-fluctuation-underlying-ontogenetic-origin-of-neuropsychiatric-disorders",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106421",abstract:"Neuropsychiatry underlies personality development and social functioning. Borderline personality disorder exhibits high trait aggression and is associated with tryptophan hydroxylase polymorphisms. The acute tryptophan depletion reduces plasma and cerebrospinal fluid tryptophan availability and brain serotonin concentrations, leading to alterations in personality and trait-related behaviors. Tryptophan is essential for fatal neurodevelopment and immunomodulation in pregnancy. Gestational tryptophan fluctuation induced by maternal metabolic disorders or drug administrations may account for the maternal-fetal transmission determining neurogenesis and microbial development, consequentially shaping the long-standing patterns of thinking and behavior. However, it is not possible to assess the gestational tryptophan exposure effects on fetal brain and gastrointestinal system in humans for ethical reasons. The maternal–fetal microbe transmission in rodents during gestation, vaginal delivery, and breastfeeding is inevitable. Chicken embryo may be an alternative and evidence from the chicken embryo model reveals that gestational tryptophan fluctuation, i.e., exposed to excessive tryptophan or its metabolite, serotonin, attenuates aggressiveness and affects peer sociometric status. This chapter discusses the gestational tryptophan fluctuation as a risk factor of personality disorders in offspring and the prevention of personality disorders by dietary tryptophan control and medication therapy management during pregnancy.",book:{id:"11782",title:"Personality Traits - The Role in Psychopathology",coverURL:"https://cdn.intechopen.com/books/images_new/11782.jpg"},signatures:"Xiaohong Huang, Xiaohua Li and Heng-Wei Cheng"},{id:"83014",title:"Culture: A Pillar of Organizational Sustainability",slug:"culture-a-pillar-of-organizational-sustainability",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.106523",abstract:"Sustainability is a concern that permeates all levels of society and is premised on meeting the needs of the present without compromising the ability of future generations to meet theirs. More recently, policies and research have emerged that guide organizations to align their activities with the broader sustainable development agendas, including cultural issues, not just economic, social, and environmental ones. Culture is the material and immaterial attribute of society. It incorporates social organizations, literature, religion, myths, beliefs, behaviors and entrepreneurial practices of the productive segment, use of technology, and expressive art forms on which future generations depend. Thus, cultural sustainability is a fundamental issue and is configured as the fourth pillar of sustainability, equal to social, economic, and environmental issues, which has to do with the ability to sustain or continue with cultural beliefs and practices, preserve cultural heritage as its entity, and try to answer whether any culture will exist in the future. The importance of cultural sustainability lies in its power to influence people. Their beliefs are in the decisions made by society. Thus, there can be no sustainable development without including culture.",book:{id:"11429",title:"Sustainability, Ecology, and Religions of the World",coverURL:"https://cdn.intechopen.com/books/images_new/11429.jpg"},signatures:"Clea Beatriz Macagnan and Rosane Maria Seibert"}],onlineFirstChaptersTotal:282},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:141,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. 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He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. 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He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"426586",title:"Dr.",name:"Oladunni A.",middleName:null,surname:"Daramola",slug:"oladunni-a.-daramola",fullName:"Oladunni A. Daramola",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Federal University of Technology",country:{name:"Nigeria"}}},{id:"357014",title:"Prof.",name:"Leon",middleName:null,surname:"Bobrowski",slug:"leon-bobrowski",fullName:"Leon Bobrowski",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bialystok University of Technology",country:{name:"Poland"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"354126",title:"Dr.",name:"Setiawan",middleName:null,surname:"Hadi",slug:"setiawan-hadi",fullName:"Setiawan Hadi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Padjadjaran University",country:{name:"Indonesia"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"332603",title:"Prof.",name:"Kumar S.",middleName:null,surname:"Ray",slug:"kumar-s.-ray",fullName:"Kumar S. Ray",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Statistical Institute",country:{name:"India"}}},{id:"415409",title:"Prof.",name:"Maghsoud",middleName:null,surname:"Amiri",slug:"maghsoud-amiri",fullName:"Maghsoud Amiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Allameh Tabataba'i University",country:{name:"Iran"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}}]}},subseries:{item:{id:"1",type:"subseries",title:"Oral Health",keywords:"Oral Health, Dental Care, Diagnosis, Diagnostic Imaging, Early Diagnosis, Oral Cancer, Conservative Treatment, Epidemiology, Comprehensive Dental Care, Complementary Therapies, Holistic Health",scope:"
\r\n\tThis topic aims to provide a comprehensive overview of the latest trends in Oral Health based on recent scientific evidence. Subjects will include an overview of oral diseases and infections, systemic diseases affecting the oral cavity, prevention, diagnosis, treatment, epidemiology, as well as current clinical recommendations for the management of oral, dental, and periodontal diseases.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/1.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11397,editor:{id:"173955",title:"Prof.",name:"Sandra",middleName:null,surname:"Marinho",slug:"sandra-marinho",fullName:"Sandra Marinho",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGYMQA4/Profile_Picture_2022-06-01T13:22:41.png",biography:"Dr. Sandra A. Marinho is an Associate Professor and Brazilian researcher at the State University of Paraíba (Universidade Estadual da Paraíba- UEPB), Campus VIII, located in Araruna, state of Paraíba since 2011. She holds a degree in Dentistry from the Federal University of Alfenas (UNIFAL), while her specialization and professional improvement in Stomatology took place at Hospital Heliopolis (São Paulo, SP). Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). Dr. Marinho's experience in Dentistry mainly covers the following subjects: oral diagnosis, oral radiology; oral medicine; lesions and oral infections; oral pathology, laser therapy and epidemiological studies.",institutionString:null,institution:{name:"State University of Paraíba",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,series:{id:"3",title:"Dentistry",doi:"10.5772/intechopen.71199",issn:"2631-6218"},editorialBoard:[{id:"267724",title:"Prof.",name:"Febronia",middleName:null,surname:"Kahabuka",slug:"febronia-kahabuka",fullName:"Febronia Kahabuka",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZpJQAW/Profile_Picture_2022-06-27T12:00:42.JPG",institutionString:"Muhimbili University of Health and Allied Sciences, Tanzania",institution:{name:"Muhimbili University of Health and Allied Sciences",institutionURL:null,country:{name:"Tanzania"}}},{id:"70530",title:"Dr.",name:"Márcio",middleName:"Campos",surname:"Oliveira",slug:"marcio-oliveira",fullName:"Márcio Oliveira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRm0AQAS/Profile_Picture_2022-08-01T12:34:46.jpg",institutionString:null,institution:{name:"State University of Feira de Santana",institutionURL:null,country:{name:"Brazil"}}}]},onlineFirstChapters:{paginationCount:26,paginationItems:[{id:"83087",title:"Role of Cellular Responses in Periodontal Tissue Destruction",doi:"10.5772/intechopen.106645",signatures:"Nam Cong-Nhat Huynh",slug:"role-of-cellular-responses-in-periodontal-tissue-destruction",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:null,authors:null,book:{title:"Periodontology - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11566.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"82654",title:"Atraumatic Restorative Treatment: More than a Minimally Invasive Approach?",doi:"10.5772/intechopen.105623",signatures:"Manal A. 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