These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
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This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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The present theme of this book is concomitant with the lithographic ways and means of deposition, optimization parameters and their wide technological applications. This book consists of six chapters comprehending with eminence of lithography, fabrication and reproduction of periodic nanopyramid structures using UV nanoimprint lithography for solar cell applications, large-area nanoimprint lithography and applications, micro-/nanopatterning on polymers, OPC under immersion lithography associated to novel luminescence applications, achromatic Talbot lithography (ATL) and the soft X-ray interference lithography. Individual chapters provide a base for a wide range of readers from different fiels, students and researchers, who may be doing research pertinent to the topics discussed in this book and find basic as well as advanced principles of designated subjects related to these phenomena explained plainly. The book contains six chapters by experts in different fields of lithographic fabrication and technology from over 15 research institutes across the globe.",isbn:"978-1-78923-031-4",printIsbn:"978-1-78923-030-7",pdfIsbn:"978-1-83881-293-5",doi:"10.5772/intechopen.68234",price:119,priceEur:129,priceUsd:155,slug:"micro-nanolithography-a-heuristic-aspect-on-the-enduring-technology",numberOfPages:134,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"c94caf617c31b349bd3d9dd054a022a3",bookSignature:"Jagannathan Thirumalai",publishedDate:"May 2nd 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6124.jpg",numberOfDownloads:8315,numberOfWosCitations:15,numberOfCrossrefCitations:12,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:25,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:52,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 21st 2017",dateEndSecondStepPublish:"July 12th 2017",dateEndThirdStepPublish:"October 8th 2017",dateEndFourthStepPublish:"January 6th 2018",dateEndFifthStepPublish:"March 7th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"99242",title:"Prof.",name:"Jagannathan",middleName:null,surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai",profilePictureURL:"https://mts.intechopen.com/storage/users/99242/images/system/99242.png",biography:"Dr. J. Thirumalai received his Ph.D. from Alagappa University, Karaikudi in 2010. He was also awarded the Post-doctoral Fellowship from Pohang University of Science and Technology (POSTECH), Republic of Korea, in 2013. He worked as Assistant Professor of Physics, B.S. Abdur Rahman University, Chennai, India (2011 to 2016). Currently, he is working as Senior Assistant Professor of Physics, Srinivasa Ramanujan Centre, SASTRA Deemed University, Kumbakonam (T.N.), India. His research interests focus on luminescence, self-assembled nanomaterials, and thin film opto-electronic devices. He has published more than 60 SCOPUS/ISI indexed papers and 11 book chapters, edited 4 books and member in several national and international societies like RSC, OSA, etc. Currently, he served as a principal investigator for a funded project towards the application of luminescence based thin film opto-electronic devices, funded by the Science and Engineering Research Board (SERB), India. As an expert in opto-electronics and nanotechnology area, he has been invited as external and internal examiners to MSc and PhD theses, invited to give talk in some forum, review papers for international and national journals.",institutionString:"SASTRA University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"10",totalChapterViews:"0",totalEditedBooks:"6",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"751",title:"Nano Electronics",slug:"nano-electronics"}],chapters:[{id:"58555",title:"Introductory Chapter: The Eminence of Lithography—New Horizons of Next-Generation Lithography",doi:"10.5772/intechopen.70725",slug:"introductory-chapter-the-eminence-of-lithography-new-horizons-of-next-generation-lithography",totalDownloads:894,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Jagannathan Thirumalai",downloadPdfUrl:"/chapter/pdf-download/58555",previewPdfUrl:"/chapter/pdf-preview/58555",authors:[{id:"99242",title:"Prof.",name:"Jagannathan",surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai"}],corrections:null},{id:"58220",title:"Fabrication and Replication of Periodic Nanopyramid Structures by Laser Interference Lithography and UV Nanoimprint Lithography for Solar Cells Applications",doi:"10.5772/intechopen.72534",slug:"fabrication-and-replication-of-periodic-nanopyramid-structures-by-laser-interference-lithography-and",totalDownloads:1415,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:0,abstract:"In this chapter, the fabrication and replication of periodic nanopyramid structures suitable for antireflection and self-cleaning surfaces are presented. Laser interference lithography (LIL), dry etching, wet etching, and UV nanoimprint lithography (UV-NIL) are employed for the fabrication and replication of periodic nanopyramid structures. Inverted nanopyramid structures were fabricated on Si substrates by LIL and subsequent pattern transfer process using reactive ion etching, followed by potassium hydroxide (KOH) wet etching. The fabricated periodic inverted nanopyramid structures were utilized as a master mold for the nanoimprint process. The upright nanopyramid structures were patterned on the OrmoStamp-coated glass substrate with high fidelity in the first nanoimprint process. In the second nanoimprint process, inverted nanopyramid structures were replicated on the OrmoStamp-coated substrate using the fabricated upright nanopyramid glass substrate as a mold. The replicated inverted nanopyramid structure on resist-coated substrate was faithfully resolved with the high accuracy compared to original Si master mold down to nanometer scale. Both upright and inverted nanopyramid structures can be utilized as surface coatings for light trapping and self-cleaning applications for different types of solar cell and glass surfaces.",signatures:"Amalraj Peter Amalathas and Maan M. Alkaisi",downloadPdfUrl:"/chapter/pdf-download/58220",previewPdfUrl:"/chapter/pdf-preview/58220",authors:[{id:"6368",title:"Prof.",name:"Maan",surname:"Alkaisi",slug:"maan-alkaisi",fullName:"Maan Alkaisi"},{id:"207012",title:"Dr.",name:"Amalraj",surname:"Peter Amalathas",slug:"amalraj-peter-amalathas",fullName:"Amalraj Peter Amalathas"}],corrections:null},{id:"58424",title:"Large-Area Nanoimprint Lithography and Applications",doi:"10.5772/intechopen.72860",slug:"large-area-nanoimprint-lithography-and-applications",totalDownloads:2069,totalCrossrefCites:6,totalDimensionsCites:12,hasAltmetrics:1,abstract:"Large-area nanoimprint lithography (NIL) has been regarded as one of the most promising micro/nano-manufacturing technologies for mass production of large-area micro/nanoscale patterns and complex 3D structures and high aspect ratio features with low cost, high throughput, and high resolution. That opens the door and paves the way for many commercial applications not previously conceptualized or economically feasible. Great progresses in large-area nanoimprint lithography have been achieved in recent years. This chapter mainly presents a comprehensive review of recent advances in large-area NIL processes. Some promising solutions of large-area NIL and emerging methods, which can implement mass production of micro-and nanostructures over large areas on various substrates or surfaces, are described in detail. Moreover, numerous industrial-level applications and innovative products based on large-area NIL are also demonstrated. Finally, prospects, challenges, and future directions for industrial scale large-area NIL are addressed. An infrastructure of large-area nanoimprint lithography is proposed. In addition, some recent progresses and research activities in large-area NIL suitable for high volume manufacturing environments from our Labs are also introduced. This chapter may provide a reference and direction for the further explorations and studies of large-area micro/nanopatterning technologies.",signatures:"Hongbo Lan",downloadPdfUrl:"/chapter/pdf-download/58424",previewPdfUrl:"/chapter/pdf-preview/58424",authors:[{id:"6642",title:"Prof.",name:"Hongbo",surname:"Lan",slug:"hongbo-lan",fullName:"Hongbo Lan"}],corrections:null},{id:"58772",title:"Micro/Nano Patterning on Polymers Using Soft Lithography Technique",doi:"10.5772/intechopen.72885",slug:"micro-nano-patterning-on-polymers-using-soft-lithography-technique",totalDownloads:1365,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Microfabrication is essential in the field of science and technology. The development and innovations in this field are already prominent in the society through microelectronics and optoelectronics. The lithography or transfer of pattern to the substrate/surface of a layer is an important process step in microfabrication and is usually carried out with photolithography. Though photolithography is a well-established technique, it suffers from drawbacks such as limited feature size due to optical diffraction, requirement of high-energy radiation for small features, and high-cost involvement for sophisticated instruments. Also, it cannot be applied to nonplanar surfaces. Soft lithography is complement to photolithography which overcomes the above-mentioned drawbacks. Soft lithography is a simple and inexpensive method, and also, it suits to wide range of materials and very large surface areas. High-quality micropatterns or nanopatterns can be made using a patterned elastomeric stamp. This article briefly describes the various soft lithography techniques to obtain high-resolution structures for nanofabrication.",signatures:"Sujatha Lakshminarayanan",downloadPdfUrl:"/chapter/pdf-download/58772",previewPdfUrl:"/chapter/pdf-preview/58772",authors:[{id:"220545",title:"Dr.",name:"Sujatha",surname:"Lakshminarayanan",slug:"sujatha-lakshminarayanan",fullName:"Sujatha Lakshminarayanan"}],corrections:null},{id:"59996",title:"EUV/Soft X-Ray Interference Lithography",doi:"10.5772/intechopen.74564",slug:"euv-soft-x-ray-interference-lithography",totalDownloads:1023,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Based on the coherent radiation from an undulator source, extreme UV interference lithography (EUV-IL) technology is considered as the leading candidate for future nodes of high-volume semiconductor manufacturing. The throughput of this technique is much higher than that of traditional lithography methods such as e-beam lithography (EBL) and laser interference lithography (LIL). Different types of interference schemes based on reflection mirrors and transmission diffraction masks have been described in this chapter. Achromatic Talbot lithography (ATL) and the soft X-ray interference lithography (SXIL) with different photon energies have also been developed to produce highly dense, high-resolution periodic nanostructures. Two scan-exposure techniques, one is the method employing the broadband Talbot effect and the other based on the multi-grating EUV-IL with an order sorting aperture (OSA), have been used to obtain periodic nanostructures over large areas. Applications of EUV-IL on EUV-resist testing and nano-science have been illustrated.",signatures:"Shumin Yang and Yanqing Wu",downloadPdfUrl:"/chapter/pdf-download/59996",previewPdfUrl:"/chapter/pdf-preview/59996",authors:[{id:"208197",title:"Dr.",name:"Yanqing",surname:"Wu",slug:"yanqing-wu",fullName:"Yanqing Wu"},{id:"237489",title:"Dr.",name:"Shumin",surname:"Yang",slug:"shumin-yang",fullName:"Shumin Yang"}],corrections:null},{id:"58480",title:"Optical Proximity Correction (OPC) Under Immersion Lithography",doi:"10.5772/intechopen.72699",slug:"optical-proximity-correction-opc-under-immersion-lithography",totalDownloads:1552,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"As advanced technology nodes continue scaling down into sub-16 nm regime, optical microlithography becomes more vulnerable to process variations. As a result, overall lithographic yield continuously degrades. Since next-generation lithography (NGL) is still not mature enough, the industry relies heavily on resolution enhancement techniques (RETs), wherein optical proximity correction (OPC) with 193 nm immersion lithography is dominant in the foreseeable future. However, OPC algorithms are getting more aggressive. Consequently, complex mask solutions are outputted. Furthermore, this results in long computation time along with mask data volume explosion. In this chapter, recent state-of-the-art OPC algorithms are discussed. Thereafter, the performance of a recently published fast OPC methodology—to generate highly manufactured mask solutions with acceptable pattern fidelity under process variations—is verified on the public benchmarks.",signatures:"Ahmed Awad, Atsushi Takahashi and Chikaaki Kodaman",downloadPdfUrl:"/chapter/pdf-download/58480",previewPdfUrl:"/chapter/pdf-preview/58480",authors:[{id:"220602",title:"Dr.",name:"Ahmed",surname:"Awad",slug:"ahmed-awad",fullName:"Ahmed Awad"},{id:"227583",title:"Prof.",name:"Atushi",surname:"Takahashi",slug:"atushi-takahashi",fullName:"Atushi Takahashi"},{id:"227584",title:"Dr.",name:"Chikaaki",surname:"Kodama",slug:"chikaaki-kodama",fullName:"Chikaaki Kodama"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5348",title:"Luminescence",subtitle:"An Outlook on the Phenomena and their Applications",isOpenForSubmission:!1,hash:"d982c49fed4423a0ea7367af4f917b82",slug:"luminescence-an-outlook-on-the-phenomena-and-their-applications",bookSignature:"Jagannathan Thirumalai",coverURL:"https://cdn.intechopen.com/books/images_new/5348.jpg",editedByType:"Edited by",editors:[{id:"99242",title:"Prof.",name:"Jagannathan",surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6489",title:"Light-Emitting Diode",subtitle:"An Outlook On the Empirical Features and Its Recent Technological Advancements",isOpenForSubmission:!1,hash:"20818f168134f1af35547e807d839463",slug:"light-emitting-diode-an-outlook-on-the-empirical-features-and-its-recent-technological-advancements",bookSignature:"Jagannathan Thirumalai",coverURL:"https://cdn.intechopen.com/books/images_new/6489.jpg",editedByType:"Edited by",editors:[{id:"99242",title:"Prof.",name:"Jagannathan",surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6242",title:"Hydroxyapatite",subtitle:"Advances in Composite Nanomaterials, Biomedical Applications and Its Technological Facets",isOpenForSubmission:!1,hash:"6a18a9b6617ae6d943649ea7ad9655cc",slug:"hydroxyapatite-advances-in-composite-nanomaterials-biomedical-applications-and-its-technological-facets",bookSignature:"Jagannathan Thirumalai",coverURL:"https://cdn.intechopen.com/books/images_new/6242.jpg",editedByType:"Edited by",editors:[{id:"99242",title:"Prof.",name:"Jagannathan",surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5699",title:"Thin Film Processes",subtitle:"Artifacts on Surface Phenomena and Technological Facets",isOpenForSubmission:!1,hash:"164177fc1e3eca542ebad5fd34a79d1e",slug:"thin-film-processes-artifacts-on-surface-phenomena-and-technological-facets",bookSignature:"Jagannathan Thirumalai",coverURL:"https://cdn.intechopen.com/books/images_new/5699.jpg",editedByType:"Edited by",editors:[{id:"99242",title:"Prof.",name:"Jagannathan",surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9414",title:"Advances in Condensed-Matter and Materials Physics",subtitle:"Rudimentary Research to Topical Technology",isOpenForSubmission:!1,hash:"3aebac680de7d3af200eadd0a0b2f737",slug:"advances-in-condensed-matter-and-materials-physics-rudimentary-research-to-topical-technology",bookSignature:"Jagannathan Thirumalai and Sergey Ivanovich Pokutnyi",coverURL:"https://cdn.intechopen.com/books/images_new/9414.jpg",editedByType:"Edited by",editors:[{id:"99242",title:"Prof.",name:"Jagannathan",surname:"Thirumalai",slug:"jagannathan-thirumalai",fullName:"Jagannathan Thirumalai"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3635",title:"Polymer Thin Films",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"polymer-thin-films",bookSignature:"Abbass A Hashim",coverURL:"https://cdn.intechopen.com/books/images_new/3635.jpg",editedByType:"Edited by",editors:[{id:"6700",title:"Dr.",name:"Abbass A.",surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. 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1. Introduction
Robert Koch discovered the acid-fast bacterium that is the pathogenic germ of tuberculosis (TB) in 1882 [1]. TB is a major public health problem in the world and the leading cause of death from a single infectious agent. The World Health Organization estimates that one third of the world’s population is infected with Mycobacterium tuberculosis, and annually reports the global burden of the disease caused by TB. Over 8 million new cases and nearly 1.5 million deaths from TB occur each year, presenting a significant threat to the world health [2]. The pathogenicity of mycobacteria is related to their ability to evade being ingested by macrophages, produce latent infection, and induce delayed-type hypersensitivity lesions such as granulomas. Moreover, the global spread of multi- and extensively drug-resistant TB (MDR-TB and XDR-TB, respectively) and the number of immunocompromised hosts, including victims of the human immunodeficiency virus (HIV) epidemic, are important problems [3].
The mycobacteria include the TB-causative acid-fast bacteria that are widely pathogenic to humans: M. tuberculosis,\n\t\t\t\tM. avium-intracellulare complex (MAC), M. leprae, and M. bovis, the source of the only available TB vaccine, Bacillus Calmette Guérin (BCG). The acid-fast bacteria are rich in lipids, and many mycoloyl glycolipids, such as cord factor/trehalose-6,6’-dimycolate (TDM), phenolic glycolipid (PGL), sulfolipid (SL), glycopeptidolipid (GPL), phosphatidylinositol mannoside (PIM), lipomannan (LM), and lipoarabinomannan (LAM), are distributed in the cell wall [4-7]. Among them, glycolipids specific to the mycobacteria play a key role in the pathogenesis, because mycobacteria have large amounts of lipids that possess pleiotropic activities. The complex interaction between a range of mycobacterial components and the host cause the pathogenesis.
In this review, the distribution of major glycolipids in several Mycobacteria and structural analyses using mass spectrometry (MS) are described. MS and MS/MS are useful to analyze the glycosyl linkage, composition, and sequence of the sugar moiety. These results make it possible to discuss the heterogeneity and biosynthesis of glycolipids, and host responses to them. We hope that this review will promote better understanding of the structure-function relationships of glycolipids and open new avenues for prevention of infectious diseases.
2. Distribution of glycolipids and phospholipids in mycobacteria
The cell envelope surrounds the cytoplasm and is important for bacterial physiology and protection of microorganisms from their environment. Unlike other pathogenic microbes, the cell envelope of the acid-fast bacteria, including mycobacteria, is wax-like. The characteristic component is mycolic acids (MAs) which are α-branched β-hydroxy fatty acids (FAs), and have species-specific carbon-chain lengths and subclasses (α, methoxy, keto, dicarboxy, epoxy, etc.). The total lipid fraction was extracted with chloroform/methanol (3:1 and 2:1 v/v) and developed by two-dimensional thin-layer chromatography (TLC). Many glycolipids and phospholipids were detected, as shown in Fig. 1. Some glycolipids, such as cord factor/TDM and trehalose 6-monomycolate (TMM), exist ubiquitously in mycobacteria, and other glycolipids, including SLs and penta-acyl trehalose, exist only in virulent strains [8]. In general, the mycobacterial species have heterogeneous compositions and concentrations of glycolipids. According to current models of the mycobacterial cell envelope, which are ultimately based on an idea of Minnikin [9], arabinogalactan-attached MAs are believed to form one highly-arranged leaflet of a second membrane-like structure adjacent to the cell-wall skeleton (CWS). Complemented by other lipids forming the outer leaflet, this structure represents a very hydrophobic barrier that is responsible for the resistance to certain drugs [10]. The free glycoconjugates of MA, in particular TMM and cord factor/TDM, appear to be more difficult to localize, and occasionally they are described or depicted as distributed on the cell surface or buried more deeply in the cell envelope. A proposed structure of the mycobacterial cell envelope is shown in Fig. 2 [4, 11, 12].
Figure 1.
TLC of total lipids derived from Mycobacterium tuberculosis Aoyama B strain.
Figure 2.
Schematic representation of mycobacterial cell envelope.
3. Host responses to mycobacterial glycolipids
Mycobacteria are intracellular pathogens. Mycobacterial infection has dual consequences for the host: development of inflammatory lesions and clearance of the pathogen. Genetic regulation and expression of cell-mediated immunity and delayed-type hypersensitivity play critical roles in the outcome. Cell-mediated immunity participates in host defense, whereas delayed-type hypersensitivity is involved in the development of granulomatous inflammation. After invasion to the host cell, the mycobacteria multiply inside macrophages. The mechanism of pathogenesis is focused on evading the host’s killing system and induction of delayed-type hypersensitivity [13]. Certain cell wall glycolipids, such as cord factor/TDM, SL, and LAM [5-7], are involved in the host-pathogen interaction, and induce the primary host immune responses.
Peptides and proteins with a wide range of antigenic moieties are recognized by the host immune system using major histocompatibility complex (MHC) class I or II. The recognition of lipids is important for host defense against mycobacterial infection as well as other antigenic responses. Several bacterial lipid antigens are recognized by specific T cells. MA derived from mycobacteria is a lipid antigen that stimulates CD1b-restricted T cells [14, 15]. Other immunogenic mycobacterial glycolipids, glucose-6-monomycolate (GMM), PIM, and LAM, are available for loading onto CD1 molecules and recognized by specific T cells [16, 17].
4. Mycoloyl glycolipids
Acid-fast bacteria produce several mycolyl glycolipids that are composed of sugar and MA. The carbon-chain lengths and subclasses of MAs are species-specific. Nocardia, Rhodococcus, and Diezia species have short carbon-chain length MAs, and the subclass is mainly the α type. MAs of Mycobacterium species have long carbon-chains and are of various subclasses (α, methoxy, keto, dicarboxy, and epoxy types). In general, the average number of carbons in MAs increases from Dietzia, Rhodococcus, Nocardia, and Gordona to Mycobacteria. The Mas are extracted with n-hexane or chloroform after alkaline-hydrolysis of heat-killed bacteria, and the subclasses are detected by using TLC developed with methyl ester derivatives (Fig. 3). The molecular species of the MA subclasses are determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) using an Ultraflex II (Bruker Daltonics, Billerica, MA, USA) with 10 mg/ml 2,5-dihydroxybenzoic acid (DHB) in chloroform-methanol (1:1, v/v) as a matrix, and analyzed in Reflectron mode with an accelerating voltage operating in positive mode at 20 kV (Fig. 4). The MAs with short carbon-chains can be analyzed by using gas-chromatography mass spectrometry GC/MS. The trimethylsilyl derivatives of MA methyl esters are volatile, and the GC/MS spectra show specific fragment patterns that are assigned to detailed structures (Fig. 5), although the MAs with long carbon chains are difficult to vaporize and detect by GC/MS [18-20]. In addition, MAs are analyzed by using high performance liquid chromatography (HPLC) [21]. The resolution of HPLC is poor compared to that of GC/MS. GMM, fructose-6-monomycolate (FMM), and mannose-6-monomycolate (MMM) are produced by acid-fast bacteria cultured with their respective carbon source: glucose, fructose, and mannose. The structures are composed of MAs attached to glucose, fructose, and mannose, respectively, at the C6 position [20, 22]. Recently, it was reported that M. tuberculosis produces GMM by transferring MA to glucose from cord factor/TDM, and thus evades the host immune system [23]. The molecular weights of mycoloyl glycolipids are measured by MALDI-TOF MS, and this information makes it possible to determine the combination of MA subclasses [24]. Cord factor/TDM is probably the most prominent and best-studied MA-containing compound of mycobacteria, and shows pleiotropic activities, including the development of granulomatous inflammation, anti-tumor immune response, and adjuvant effects based on the induction of proinflammatory and type 1 helper T cell (Th1)-related cytokines from host cells [25-27]. We demonstrated that administration of cord factor/TDM could induce delayed-type hypersensitivity-like lesions and foreign-body granulomas in euthymic and athymic mice, regardless of preimmunization with mycobacteria and cord factor/TDM. In fact, preimmunized mice challenged with cord factor/TDM developed more severe lesions than unimmunized mice. At the active lesion, CC-chemokines attracting monocytes, proinflammatory cytokines, and immunoregulatory cytokines were found. The inflammatory and cytokine responses were augmented in immunized mice challenged with cord factor/TDM. As a result, cord factor/TDM can induce both foreign body-type (nonimmune) and hypersensitivity-type (immune) granulomas by acting as a nonspecific irritant and T-cell-dependent antigen, and both nonimmune and immune mechanisms participate in granulomatous inflammation induced by mycobacterial infection [13, 28]. Moreover, rhodococcal cord factor/TDM induced milder granulomatous lesions than a mycobacterial one, implying that the proinflammatory responses induced by cord factor/TDM are in proportion to the carbon-chain length and subclasses of MAs in addition to carbon species [20, 29]. Recently, it was clarified that macrophage-inducible C-type lectin (mincle) is an essential receptor for cord factor/TDM [30]. Mincle is a receptor for sugar, and our previous result showed that the proinflammatory responses are MA-dependent. I expect the discovery of other unknown receptors for cord factor/TDM in addition to mincle.
Figure 3.
TLC of mycolic acid methyl esters derived from Mycobacterium, Rhodococcus, and Dietzia species.
Figure 4.
MALDI‐TOF MS spectra of mycolic acid methyl ester subclasses from M. tuberculosis H37Rv.
Figure 5.
Total ion chromatogram and mass spectrum of mycolic acid trimethylsilyl derivatives from R. equi.
5. Glycopeptidolipid (GPL)
GPLs are produced by MAC, M. scrofulaceuem, M. chelonae, M. fortuitum, and M. smegmatis. Structurally, a GPL is composed of two parts, a common tetrapeptido-amino alcohol core and a serotype-specific oligosaccharide (OSE) elongated from 6-deoxy-talose (6-d-Tal). D-phenylalanine-D-allo-threonine-D-alanine-L-alaninol (D-Phe-D-allo-Thr-D-Ala-L-alaninol), which is modified with an amido-linked 3-hydroxy or 3-methoxy C26-C34 FA at the N-terminal of D-Phe; D-allo-Thr and terminal L-alaninol are further linked to a 6-d-Tal and 3,4-di-O-methyl rhamnose (3,4-di-O-Me-Rha), respectively [31]. This portion is common to all serotypes, and is called the serotype-nonspecific GPL (apolar GPL), which exhibits antigenicity [11]. Serotype-specific GPLs (polar GPLs) are further glycosylated with a variable haptenic OSE at 6-d-Tal. We determined the structures of the serotype 7, 13, and 16 GPLs and identified the gene clusters completing the OSE biosynthesis [32-34]. In addition, two methyltransferase genes of serotype 7- and 12-specific GPL biosynthesis were characterized [35]. The standard technique to classify MAC strains has employed serologic typing based on the OSE residue of the GPL. Recently, the biosynthetic pathway of various haptenic OSEs has been explored, and the genes encoding the pathways have been identified and characterized [36-38]. At present, 31 distinct serotype-specific polar GPLs have been identified biochemically, and the complete structures of 17 GPLs are defined [12, 33]. The GPL present on the cell wall is considered to affect colony morphology. The MAC colony phenotype spontaneously changed from a smooth to a rough type, and this was due to a mutation lacking GPLs [39, 40]. The polar GPLs produced by MAC species are of particular interest because they are considered to be correlated with the physiology of the bacteria and the host responses to MAC infection, for example, colony morphology, sliding motility, biofilm formation, immune modulation, and virulence [40-43].
We have demonstrated the applicability of serodiagnosis of MAC pulmonary diseases using the GPL and GPL core antigens, and have also shown that the levels of GPL and GPL core antibodies reflect disease activity [44-46]. The GPLs are produced by MAC species but are absent in M. tuberculosis, making it possible to distinguish MAC from tuberculous mycobacteria [44, 47]. An anti-GPL antibody is produced in the sera of patients and the level reflects the extent of disease, which is useful in diagnosis and treatment [48, 49]. GPLs are one of the immunologically active molecules characteristic of MAC, and serotype-specific GPLs participate in the pathogenesis and immunomodulation in the host [50, 51]. It has been reported that the GPL core plays a role in suppression of mitogen-induced blastogenic response in spleen cells [52]. In addition, the immunomodulating activity of GPL on macrophage functions is serotype-dependent [53]. The serotype 4 GPL promotes phagocytosis and inhibits phagosome-lysosome (P-L) fusion, whereas the GPLs of serotypes 9 and 16 exhibit no effect on phagocytosis and P-L fusion. The serotype 8 GPL shows concomitant stimulation of both phagocytosis and P-L fusion. Because the GPL core, but not OSE, is common in all serotypes, the OSE of GPL may be involved in the mechanism of inhibition of P-L fusion, which is mediated through mannose receptors of macrophages [54]. The serotype 4 GPL inhibits the lymphoproliferative response to mitogens [51]. Thus, host responses to GPLs vary with the MAC serotype. It is reported that the uptake by and growth in macrophages of a MAC mutant with a gene in the GPL synthesis pathway inactivated by a transposon insertion were decreased [55]. The pathogenicity of GPL may comprise both a common peptide core and an OSE elongated from 6-d-Tal. The GPL is a pleiotropic molecule and participates in the pathogenesis of MAC disease. Elucidation of the structure-activity relationship of GPL is required for a better understanding of the pathogenesis.
6. Structural analysis of GPL
The polar GPL is species-specific in the portion of the OSE. MS is very useful to analyze the structure of OSE sequences and linkage positions in addition to total molecular weight. In this review, I describe detailed methods and results of structural analyses of some GPLs. The procedure for structural analysis of OSE is summarized in Fig. 6.
Figure 6.
Procedure for structural analyses of OSE.
6.1. Preparation of GPL
MAC was grown on Middlebrook 7H11 agar (Difco Laboratories, Detroit, MI, USA) with 0.5% glycerol and 10% Middlebrook OADC enrichment (Difco) at 37°C for 2-3 weeks. Heat-killed bacteria were sonicated, and total lipids were extracted with chloroform-methanol (2:1, v/v). The total lipids were hydrolyzed with 0.2 N sodium hydroxide in methanol at 37°C for 2 h, followed by neutralization with 6 N hydrochloric acid. Alkaline-stable lipids were partitioned by a two-layer system with chloroform-methanol (2:1, v/v) and water. The organic phase was evaporated and precipitated with acetone to remove any acetone-insoluble components. The supernatant was partially purified with a Sep-Pak Silica Cartridge (Waters Corporation, Milford, MA, USA). The GPL was completely purified by preparative TLC of silicagel G (Uniplate; 20 × 20 cm, 250 µm; Analtech, Inc., Newark, DE, USA). The TLC plate was developed with chloroform-methanol-water (65:25:4 and 60:16:2, v/v), until a single spot was obtained.
6.2. Preparation of OSE moiety
β-Elimination of the GPL was performed with alkaline borohydride, and the OSE elongated from D-allo-Thr was released [34, 56]. The GPL was stirred in a solution of equal volumes of ethanol and 10 mg/ml sodium borodeuteride in 0.5 N sodium hydroxide at 60°C for 16 h. The reaction mixture was decationized with Dowex 50W X8 beads (Dow Chemical Company, Midland, MI, USA), and evaporated under nitrogen to remove boric acid. After partition into two layers of chloroform-methanol (2:1, v/v) and water, the upper aqueous phase was recovered and evaporated, and the OSE was purified as an oligoglycosyl alditol.
6.3. Molecular weight of intact GPL
The molecular species of the intact GPL was determined by MALDI-TOF MS. One µg of the GPL dissolved with chloroform-methanol (2:1,v/v) was applied to the target plate, and 1 µl of 10 mg/ml DHB in chloroform-methanol (1:1, v/v) was added as a matrix. The intact GPL was analyzed in the Reflectron mode with an accelerating voltage operating in positive mode at 20 kV [57]. The peak ions of intact GPL were detected in sodium adduct form, [M+Na]+ as the main molecular-related ion; representative spectra of some GPLs are shown in Fig. 7. The mass numbers identified the proposed structures of each GPL.
Figure 7.
MALDI-TOF MS spectra of representative GPLs.
6.4. Glycosyl sequences of OSE.
The molecular weight of the OSE portion is measured by MALDI-TOF MS. The OSE and 10 mg/ml DHB were dissolved in ethanol-water (3:7, v/v) and applied to the target plate according to the method for intact GPL. To determine the glycosyl sequence of the OSE, MALDI-TOF MS/MS analysis of the oligoglycosyl alditol from the OSE was performed. The spectrum afforded the molecular ion [M+Na]+, together with the characteristic mass increments in the series of glycosyloxonium ions formed on fragmentation at each glycosyl linkage from both terminal sugars to their opposites, respectively. It was shown the representative assignments of intact serotype 13 GPL and its OSE with the proposed structure in Fig. 8.
Figure 8.
MALDI-TOF MS and MS/MS spectra of serotype 13 GPL. The molecular weight of the intact GPL was detected as m/z 1897 for [M+Na]+ and fixed the proposed structure. The MS/MS spectra clearly show that the each ion was assigned to the fragmentation at each glycosyl linkage from both terminal sugars to their opposites, respectively.
6.5. GC/MS of carbohydrates
To determine the glycosyl composition and linkage position, GC/MS of partially methylated alditol acetate derivatives was performed. Perdeuteromethylation was conducted by the modified procedure of Hakomori [34, 58]. The OSE was dissolved with a mixture of dimethylsulfoxide and sodium hydroxide, followed by the addition of deuteromethyl iodide. After stirring at room temperature for 15 min, the reaction mixture was separated by a two-layer system of water and chloroform. The chloroform-containing perdeuteromethylated OSE layer was collected, washed twice with water, and evaporated completely. Partially deuteromethylated alditol acetate derivatives were prepared from perdeuteromethylated OSE by hydrolysis with 2 N trifluoroacetic acid at 120°C for 2 h, reduction with 10 mg/ml sodium borodeuteride at 25°C for 2 h, and acetylation with acetic anhydride at 100°C for 1 h [34, 59]. GC/MS was performed using a fused capillary column (SP-2380 and Equity-1; 30 m, 0.25 mm ID, Supelco, Bellefonte, PA). The linkage positions were acetylated, and no related positions were previously deuteromethylated. The linkage positions were assigned by the fragmentation patterns of partially deuteromethylated alditol acetate derivatives and retention time of the peaks. The representative fragmentation patterns of partially methylated alditol acetate derivatives are shown in Fig. 9.
Figure 9.
Representative mass spectrum of partially deuteromethylated alditol acetate derivatives.
6.6. Nuclear magnetic resonance (NMR) of GPL
The OSE was dissolved in deuterium oxide. To define the anomeric configurations of each glycosyl residue, 1H and 13C nuclear magnetic resonance (NMR) was employed. Both homonuclear correlation spectrometry (COSY) and 1H-detected [1H, 13C] heteronuclear multiple-quantum correlation (HMQC) were performed as described previously [34, 56]. The 1H NMR and 1H-1H homonuclear COSY analyses of the OSE derived from the GPL revealed distinct anomeric protons with corresponding H1-H2 cross-peaks in the low-field region, and the chemical shift and coupling constant are indicative of α-anomers and a β-hexosyl unit, respectively.
7. Biosynthesis gene of GPL
7.1. Isolation of cosmid clones carrying rtfA gene and sequence analysis
First, we constructed the M. intracellulare cosmid library. Genomic DNA of MAC was prepared by mechanical disruption of bacterial cells, which was accomplished by homogenizing a bacterial pellet with glass beads in phosphate-buffered saline, followed by phenol-chloroform extraction, and precipitation with ethanol. Genomic DNA fragments randomly sheared to 30–50 kb fragments during the extraction process were fractionated and electroeluted from agarose gels using Takara Recochip (Takara, Kyoto, Japan). These DNA fragments were rendered blunt-ended using T4 DNA polymerase and dNTPs, followed by ligation to dephosphorylated arms of pYUB412 (XbaI-EcoRV and EcoRV-XbaI). After in vitro packaging using Gigapack III Gold extracts (Stratagene, La Jolla, CA, USA), recombinant cosmids were introduced into the E. coli STBL2 [F–mcrA\n\t\t\t\t\tD (mcrBC-hsdRMS-mrr) endA1 recA1 lon\n\t\t\t\t\tgyrA96 thi\n\t\t\t\t\tsupE44 relA1 l- D (lac-proAB)]. PCR was used to isolate cosmid clones carrying the rhamnosyltransferase (rtfA) gene with primers rtfA-F (5’-TTTTGGAGCGACGAGTTCATC-3’) and rtfA-R (5’-GTGTAGTTGACCACGCCGAC-3’). RtfA encodes an enzyme responsible for the transfer of Rha to 6-d-Tal in the OSE [38, 60]. We isolated the cosmid clones #49 (accession no. AB274811) and #253 (accession no. AB355138), which are responsible for the biosynthesis of GPL 7 and 16, respectively. The insert of a cosmid clone was sequenced using a BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA) and an ABI Prism 310 gene analyzer (Applied Biosystems). The putative function of each open reading frame (orf) was identified by similarity searches between the deduced amino acid sequences and known proteins using BLAST (http://www.ncbi.nlm.nih.gov/BLAST/) and FramePlot (http://www.nih.go. jp/~jun/cgi-bin/frameplot.pl), and the DNASIS computer program (Hitachi Software Engineering, Yokohama, Japan). The similarity of protein sequences of each ORF was compared to those of serotype 2, 4, 7, and 16 GPLs, and the genetic maps for GPL biosynthetic cluster are summarized in Fig. 10 [32, 36, 61]. The OSE of serotype 1 GPL produced by M. avium serotype 1 strain is composed of α-L-Rha-(1→2)-6-d-L-Tal, which is the core OSE of all serotypes [12]. M. avium serotype 1 strain (NF113) was transformed with pYUB412-cosmid clone #253 containing the serotype 16-specific gene cluster. The transformant produced a serotype 16 GPL with a different Rf value on TLC compared to serotype 1 GPL. The molecular weights of intact GPLs and the fragment patterns of their OSEs were completely equivalent to the serotype 16 GPL. Next, we identified some orf functions of #253. We hypothesized that orf1, 16, and 17 in #253 were correlated with the glycosyltransferase by the similarity of ORF sequences, in addition to rtfA. They were compared to the productive GPLs of serotype 1 transformants inserted with the combination of orf1, 16, and 17. We determined that orf1, 17, and 16 were responsible for the elongation from 6-d-Tal-Rha to 6-d-Tal-Rha-Rha-Rha-Rha, and that these glycosyltransferases operated in this order, as shown in Fig. 11. After the elongation of an OSE, the OSE may be modified by aminotransferase, methyltransferase, and acyltransferase, and serotype 16 GPL may be completed.
Figure 10.
Comparison and overview of genetic maps of GPL biosynthetic cluster. (A), M. avium strain 724 (serotype 2, accession no. AF125999); (B), M. avium strain A5 (serotype 4, accession no. AY130970); (C), M. intracellulare ATCC 35847 (serotype 7, accession no. AB274811); (D), M. intracellulare ATCC 13950T (serotype 16, accession no. AB355138).
Figure 11.
Proposed elongation of OSE in serotype 16 GPL.
7.2. Native conformation of GPL and host response
The native GPL was purified without alkaline treatment. The native GPLs were detected on TLC as several spots that expanded broadly and had different Rf values from that of the alkaline-treated GPL (Fig. 12). Alkaline treatment converged these spots into one spot. It was reported that the native GPLs were modified by several O-acetylations in the OSE portion and the alkaline treatment removed the acetylated groups [23, 33]. We are now analyzing in detail the positions and numbers of O‐acetylations in the OSE by using MALDI-TOF MS/MS.
Figure 12.
TLC of some native GPL fractions (non-alkali-treated).
The importance of Toll-like receptor (TLR)-mediated responses has been studied in tuberculous infections. Means et al. reported that M. tuberculosis activated both TLR2 and TLR4, whereas heat-killed M. tuberculosis and MAC activated only TLR2 [62]. It was observed that MyD88- and TLR2-deficient mice have increased susceptibility to MAC infection compared to TLR4-deficient and wild-type mice [63]. These lines of evidence suggest that TLRs are related to host recognition of the MAC components containing GPLs and affect MAC infections. To clarify the host recognitions of GPLs via TLRs, we stimulated HEK-blue-2, and -4 cells (InvivoGen, San Diego, CA, USA) with native and alkaline-treated GPLs. HEK-blue-2 and -4 cells are HEK293 cells stably transfected with multiple genes for recognition of TLR2 and TLR4 (including the co-receptors MD2 and CD14). The native GPL significantly activated HEK-blue-2 cells in a dose-dependent manner, but HEK-blue-4 cells did not respond (Fig. 13). The alkaline-treated GPL without O-acetylation did not activate either HEK-blue-2 or -4 cells. Re-acetylated alkaline-treated GPLs with O-acetyl groups substituted for all hydroxy groups of the OSE activated HEK-blue-2 cells, although the level of activation was lower than that of the native form. Moreover, we confirmed that only the native GPL stimulated mouse bone marrow-derived macrophages via TLR2 by using C57BL/6 and TLR2 knockout mice. Brennan and Goren first proposed that de-acetylated GPLs as alkaline-stable lipids, made it possible to classify serotyping [12, 31]. Schorey and colleagues clarified that serotype 1 and 2 GPLs can function as TLR2 agonists and promote macrophage activation in a TLR2 and MyD88-dependent pathway [64, 65]. They reported that the acetylated and methylated groups of GPLs were necessary for GPL-TLR2 interaction as a molecular requirement. Taken together with our results, native GPLs are a TLR2 agonist, and it may be important for GPL-TLR2 interaction to balance the hydrophobicity and hydrophilicity of the GPL molecules.
Figure 13.
Native GPLs activate cells through TLR2.
8. Sulfolipid (SL)
Mycobacterial SLs are classified into three types by the number of attached short acyl chains. SL-1 is the predominant type, and SL-2 and -3 are intermediate types. The structure of SL-1 was identified as 2-palmitoyl(stearoyl)-3-phthioceranoyl-6,6’-bis-hydroxyphthioceranoyl-trehalose-2’-sulfate [66, 67]. The presence of SLs in mycobacteria is strain-specific. Several studies have demonstrated a significant relationship between SL-1 and virulence, such as the amount of SL-1 biosynthesis in virulent strains, and the inhibition of P-L fusion in macrophages by SL-1. SL-1 modulates superoxide release and secretion of interleukin (IL)-1β and tumor necrosis factor (TNF)-α by blocking activation of human macrophages and neutrophils [68, 69]. In contrast to these studies, it has been reported that pks2 disruption and SL-1 deficiency do not significantly affect the replication, persistence, and pathogenicity of M. tuberculosis in mice, guinea pigs, or cultured macrophages [70, 71]. The pathogenicity of SL-1 is controversial. SL-1 does not induce granulomatous inflammation, but rather inhibits it and the release of TNF-α induced by cord factor/TDM [72]. SL-1 could contribute to virulence at an early stage of mycobacterial infection by counteracting the immunopotentiating effect of cord factor/TDM. On the other hand, it is reported that SL-3, 2-palmitoyl(stearoyl)-3-hydroxyphthioceranoyl-trehalose-2’-sulfate, is mainly recognized by CD1b-restricted T cells as a lipid antigen. The other tetraacylated and triacylated SLs (SL-1 and -2) were unable to stimulate diacylated SL (SL-3)-specific T cell clones, which implies that immunogenic SL-3 are not generated inside the antigen-presented cells [73]
SLs of M. tuberculosis have been implicated in the virulence of this organism by inhibiting the P-L fusion in macrophages, thus probably promoting the intracellular survival of M. tuberculosis, but the pathogenic role remains controversial. The gene, pks2, responsible for SL synthesis was identified and disrupted [74]. The pks2 mutant defective in an early step of SL biosynthesis had no obvious growth defect in infected mice. By contrast, growth of a strain lacking MmpL8, a transporter of SL in M. tuberculosis, was highly attenuated in a mouse model of tuberculosis [70]. Although initial replication rates and containment levels of the MmpL8 mutant were identical, compared with the wild type, a significant attenuation of the mutant strain in time-to-death was observed. Early in infection, differential expression of cytokines and cytokine receptors revealed that the mutant strain less efficiently suppresses key indicators of a Th1-type immune response, suggesting an immunomodulatory role for SLs in the pathogenesis of tuberculosis [75].
Recently, Kummer et al. demonstrate that PapA2 and PapA1 are responsible for the sequential acylation of SL1 biosynthesis. Disruption of papA2 and papA1 in M. tuberculosis confirmed their essential role in SL-1 biosynthesis and their order of action. BALB/c mice infected by aerosol with wild-type, ∆papA2, and ∆papA1 mutants showed no significant difference in the ability of the bacteria to grow or persist through the time to death of the mice. The loss of SL-1 did not appear to affect bacterial replication or trafficking. They suggested that the functions of SL-1 are specific to human infection [76].
9. Phenolic glycolipid (PGL)
The glycosylated phenolphthiocerol dimycocerosates (PDIM), so‐called PGLs, are produced by a limited group of mycobacterial species, and most of them are pathogenic in humans [77]. PGL is distributed in M. leprae as a unique antigen, and inhibits the lymphoproliferative responses and suppresses monocyte oxidative responses [78-80]. It has also shown that disruption of PGL synthesis results in loss of the virulent phenotype without significantly affecting the bacterial load during disease in experimental models using mice and rabbits, and loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines in vitro [81, 82]. A PGL purified from M. leprae has been used as antigen in an enzyme-linked immunosorbent assay. Antibodies directed against the lipid were detected in sera of leprosy patients but not in sera from uninfected controls or patients infected with other mycobacteria, including M. tuberculosis. The antibody response distinguished between the M. leprae lipid and the structurally related PGL from M. kansasii. Similar to serodiagnosis of MAC disease using GPL, this assay based on PGL antigen has considerable potential as a specific serodiagnostic test for infection with M. leprae [83, 84].
We determined the structure of the PGL derived from BCG (Tokyo 172 strain). The PGL produced by BCG is a so-called mycoside B (PGL-BCG), and its sugar moiety is different from that of the PGL produced by M. tuberculosis (PGL-tb). The PGL-BCG has only a 2-O-Me-Rha branch elongated from the phenol moiety, although PGL-tb has it elongated to three sugar residues [85]. The composition of the PDIM in PGL is similar in both species. The MALDI-TOF MS spectrum of PGL-BCG showed m/z 1531 and other mass units at 14 Da intervals for [M+Na]+ as molecule-related ions in positive mode (Fig. 14). In addition, the MS/MS spectrum showed fragment ion peaks m/z 1371 based on the elimination of methyl-deoxysugar; m/z 1135, 1093, based on the elimination of the C26:0, C29:0 FAs; m/z 696 based on the elimination of both C26:0 and C29:0 FAs; and m/z 535 for the phenol phthiocerol that eliminated methyl-deoxysugar and C26:0, C29:0 FAs (Fig. 14).
Reed et al. demonstrated that PGL-tb inhibits the innate immune response. Loss of PGL-tb was responsible for an increase in the release of TNF-α and IL-6 and IL-12 in vitro, and the PGL-tb-deficient mutant showed a phenotype with low virulence/pathogenicity [81]. The composition of the PDIM in PGL-BCG is similar to that in PGL-tb. Although purified PGL molecules by themselves had no effect on the activation of macrophages in vitro, we found that PGL suppressed the activation of murine bone marrow-derived macrophages elicited by total lipids. It is considered that the PGL may have a competitive inhibitory effect or mask the active site of other TLR2 agonistic lipid components, and decrease their activity.
10. Phosphatidylinositol mannoside (PIM), lipomannan (LM), and lipoarabinomannan (LAM)
PIMs and their multiglycosylated counterparts, LMs, and LAMs, are complex lipoglycans that are found ubiquitously in the envelopes of all mycobacterial species. Their structures originate from a phosphatidyl-myo-inositol (MPI) anchor, which is mannosylated to generate LM and further arabinosylated to give LAM [86]. The non-reducing termini of the arabinosyl side chains can be substituted by capping motifs, and LAMs are classified into three families. LAMs from slow growing mycobacteria bearing mannose caps, i.e. mono- or (α1→2)-di- or trimannoside units, are designated as ManLAMs. In contrast, LAMs from fast growing mycobacteria capped by phospho-myo-inositol units and not capped at all, are termed PILAM and AraLAM, respectively [87]. LAMs and LMs exhibit a broad spectrum of immunomodulatory activities, including the ability to modulate the production of macrophage-derived Th1 pro-inflammatory cytokines, most commonly TNF-α and IL-12. The ManLAM from M. tuberculosis is involved in the inhibition of phagosome maturation, apoptosis, and IFN-γ signaling in macrophages and IL-12 secretion of dendritic cells. ManLAMs contribute an immunosuppressive effect to the persistence of slow-growing mycobacteria in humans. In contrast, PILAMs are able to induce the release of a variety of proinflammatory cytokines. Recently it was reported that LMs from both pathogenic and nonpathogenic mycobacterial species, independent of their origin, are potent stimulators of TNF-α, IL-8, and IL-12, and activate macrophages via TLR2 [88-90]. The ManLAM/LM balance might be important to host immune responses against mycobacteria.
Figure 14.
MALDI-TOF MS and MS/MS spectra of PGL derived from BCG Tokyo 172 strain, and proposed structure.
PIMs are composed of a phsophatidylinositol and mannose moieties. PIMs have 4–6 mannoses, the third and fourth of which are acylated in some cases. PIM2 containing two mannoses, a main component of mycobacterial cell walls, is highly immunogenic. Several biological functions have been recently attributed to PIMs. PIM2 was shown to recruit natural killer T cells, which play a role in the local granulomatous response [91, 92]. PIMs activate cells via TLR-2 [93]. PIM6 as well as the ManLAMs from M. leprae and M. tuberculosis are presented by antigen-presenting cells in the context of CD1b [17]. The phosphatidylinositol moiety plays a central role in the process of binding PIMs and ManLAMs to CD1b proteins.
11. Conclusion
Mycobacterial glycolipids are pleiotropic molecules and play key roles in both microbes and hosts by acting as structural components of cell walls and immunologically active substances. A better understanding of mycobacterial glycolipids will help us develop novel diagnostics, therapeutics, and prophylactics for mycobacterial diseases.
Acknowledgement
This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Japan Health Sciences Foundation.
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Introduction",level:"1"},{id:"sec_2",title:"2. Distribution of glycolipids and phospholipids in mycobacteria",level:"1"},{id:"sec_3",title:"3. Host responses to mycobacterial glycolipids",level:"1"},{id:"sec_4",title:"4. Mycoloyl glycolipids",level:"1"},{id:"sec_5",title:"5. Glycopeptidolipid (GPL)",level:"1"},{id:"sec_6",title:"6. Structural analysis of GPL",level:"1"},{id:"sec_6_2",title:"6.1. Preparation of GPL",level:"2"},{id:"sec_7_2",title:"6.2. Preparation of OSE moiety",level:"2"},{id:"sec_8_2",title:"6.3. Molecular weight of intact GPL",level:"2"},{id:"sec_9_2",title:"6.4. Glycosyl sequences of OSE.",level:"2"},{id:"sec_10_2",title:"6.5. GC/MS of carbohydrates",level:"2"},{id:"sec_11_2",title:"6.6. Nuclear magnetic resonance (NMR) of GPL",level:"2"},{id:"sec_13",title:"7. Biosynthesis gene of GPL",level:"1"},{id:"sec_13_2",title:"7.1. Isolation of cosmid clones carrying rtfA gene and sequence analysis",level:"2"},{id:"sec_14_2",title:"7.2. Native conformation of GPL and host response",level:"2"},{id:"sec_16",title:"8. Sulfolipid (SL)",level:"1"},{id:"sec_17",title:"9. Phenolic glycolipid (PGL)",level:"1"},{id:"sec_18",title:"10. Phosphatidylinositol mannoside (PIM), lipomannan (LM), and lipoarabinomannan (LAM)",level:"1"},{id:"sec_19",title:"11. Conclusion",level:"1"},{id:"sec_20",title:"Acknowledgement",level:"1"}],chapterReferences:[{id:"B1",body:'KochR.1884Aetiologie der Tuberkulose. Mitt. k. Gesundheitsamt. 2188'},{id:"B2",body:'WHO,2011WHO report 2011 Global Tuberculosis Control. http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf.'},{id:"B3",body:'LeeJ. H.AmmermanN. C.NolanS.GeimanD. E.LunS.GuoH.BishaiW. R.2012Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis. Nat. Commun. 3: 753.'},{id:"B4",body:'BrennanP. J.NikaidoH.1995The envelope of mycobacteria. Annu. Rev. 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USA. 9651415146'},{id:"B92",body:'GilleronM.RonetC.MempelM.MonsarratB.GachelinG.PuzoG.2001Acylation state of the phosphatidylinositol mannosides from Mycobacterium bovis bacillus Calmette Guerin and ability to induce granuloma and recruit natural killer T cells. J. Biol. Chem. 2763489634904'},{id:"B93",body:'Jones BW, Means TK, Heldwein KA, Keen MA, Hill PJ, Belisle JT, Fenton MJ,2001Different Toll-like receptor agonists induce distinct macrophage responses. J. Leukoc. Biol. 6910361044'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Nagatoshi Fujiwara",address:null,affiliation:'
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1. Introduction
The foundation of Lean thinking dates back to the 1900s, when Henry Ford, founder of Ford Motor Company, came up with an entire production process relying on interchangeable parts with standard work and moving conveyance for creating a flow production [1]. Melton [2] defines Lean as a revolution indicating that Lean is not just utilizing tools and techniques or making a few changes in processes, rather he defines Lean as a complete change in businesses to observe supply chain operations, managerial decisions, and daily work of employees in an organization. The authors of the book named “The Machine that Changed the World”, which is one of the most influential books implied that the Lean way results in better products at a lower cost as well as encouraging employees to overcome challenges in production processes [3]. Even though Lean manufacturing has first found its roots at Ford, it was later investigated by Toyota Motor Company. The Japanese engineer Taiichi Ohno, who had several visits to Ford factories to observe production processes. However, Taiichi Ohno found some methods implemented at Ford as needing improvements. Therefore, Sakichi Toyoda, his son, Kiichiro Toyoda, and Taiichi Ohno came up with the concept of Lean Manufacturing, which was first called just-in-time (JIT) production [4]. Taiichi Ohno was responsible for implementing the new ideas that evolved into the Toyota Production System (TPS). Then, Taiichi Ohno hired Shigeo Shingo to work on the setup reduction problem at Toyota. Shingo later named this successful process the famous Single Minute Exchange of Dies (SMED) system. This is how production ideas evolved at Toyota leading to technical innovations.
The lean manufacturing concept was first articulated as a shop floor practice to reach higher efficiency in processes being implemented with JIT and Toyota Production System (TPS) [5, 6]. It was also mentioned that Lean manufacturing in the 1980s rather focused on shop floor techniques and inventory reduction as well as value-added processes in the supply chain [7, 8]. Lean manufacturing is now implemented as a popular manufacturing practice in various countries and industries [9]. The ultimate goal intended by Lean organizations is to have a high-quality organization responsive to customer demands with no waste. On the other hand, most manufacturing organizations fail to realize the transformation for Lean due to a range of challenges faced [6]. The majority of the previous studies implied that even though most Lean organizations aim to implement Lean in the best way, they fail at some point as a matter of fact [10, 11]. However, the organizations are still seeking ways to improve their Lean approach and effectively practice Lean methods.
The success of Lean thinking in the manufacturing industry positively affected the construction industry. However, the construction industry is a conservative and fragmented industry, which makes innovations less welcomed by industry practitioners [12]. On the other hand, low productivity rates and intentions to improve workforce efficiency led the construction industry to implement innovative technologies.
The term ‘Lean Construction’ was first articulated by the International Group for Lean Construction (IGLC) in 1993. Glenn Ballard and Greg Howell, the two construction practitioners who first considered Lean in construction projects, started the Lean Construction Institute (LCI) in 1997 to provide and share information about the management of construction projects in the most effective way. They observed that only 50% of the tasks on weekly work plans in construction projects are completed on time by foremen in a given week [13, 14, 15]. They proposed that construction practitioners can avoid these problems with active management of variability, starting with the structuring of the project (temporary production system) and continuing through its operation and improvement” [16]. This indicated that the construction industry is facing similar challenges to the manufacturing industry. Hence, the principles of the TPS and methods of Lean productions started to have been practiced in the industry by adapting them for construction.
Considering the similarity of challenges and need for improvement in both manufacturing and construction, the Lean methods have evolved with the methods for implementing. Hence, the main purpose of this chapter is to provide the background of Lean thinking in both manufacturing and construction along with presenting a bunch of Lean methods, which are widely practiced by industry practitioners. The chapter also mentions how Lean methods in production have changed when they are being implemented in the construction industry.
2. Background of lean production and lean construction: Interaction in terms of tools, techniques, and methods
Due to the quick industrialization after the industrial revolution, the world has become a place, where natural resources are unconsciously consumed and environmental problems increase. All these negative conditions have caused the run out of natural resources, distortion in the ozone layer, decrease in biodiversity, increase in environmental contamination, and global warming. Therefore, the removal of all these problems and negative conditions is one of the most important challenges of today’s world. This leads to a considerable increase in the number of studies regarding the prevention of environmental problems, conscious use of natural resources, and a cleaner and healthier environment to be inherited by the next generations. In this context, Lean is a newly emerging concept for the majority of industry encouraging the effective use of resources. One of the major challenges of today’s world is to execute projects more efficiently with respect to project objectives. At this point, Lean thinking aims to minimize waste while maximizing value to the customer.
Lean Production was the term coined by [17] to refer to Toyota’s offering of high value, low-volume, and cost-competitive production to best address customer desires [18]. After the success of lean production in the automotive industry [19], Toyota’s Lean thinking was applied in other industries. The construction industry produces more waste than any other industry in the entire world [20]. The waste oftentimes occurs in the form of workforce loss, safety breaches, material waste, and low efficiency. To avoid these, Lean construction has proven to be an effective means of production management for project delivery, i.e., designing and building capital facilities. Lean Construction is important in that it adopts the principle of minimizing waste and maximizing value while improving the total project performance per customer expectations. The need behind Lean construction comes from the failure of mass production and the persistence of craft-based production in the construction industry. Due to the changing needs of the customer, Lean construction is essential to provide the desired variety. To minimize waste and maximize value, researchers have previously focused on several different Lean construction methods. For example, it was implied that modular construction is effective in reducing waste and achieving resource efficiency [21]. This study also demonstrated that modular is reusable, which evidences the essential function of modular construction. In another study, it was indicated that there are several waste factors in mid/high-rise building projects and the determination of those waste factors is essential [22]. Therefore, Lean construction has proposed an opportunity for estimating the impacts of waste on overall project performance [23].
Sacks et al. [24] implied the importance of Lean production management systems in reducing waste in construction. Kalsaas [25] highlighted that measurement of waste and workflow is essential for the achievement of continuous improvement in construction projects. El.Reifi et al. [26] emphasized that Lean thinking is essential in the briefing process, where the design team develops their designs with respect to clients’ desires. Fullalove [27] provided that the use of Lean techniques resulted in significant benefits such as an increase in return on investment and efficiency savings in UK road constructions. Marhani et al. [28] indicated that the application of Lean thinking into the construction industry provides a tremendous opportunity for the reduction of waste and an increase in production. Zhao and Chua [29] demonstrated that the reduction of non-value adding activities has a significant contribution to the construction productivity improvement. Aziz and Hafez [30] concluded that lean projects are safer, easier to manage, completed sooner, cost-effective, and are of better quality by referring to the impact of lean in minimizing waste in construction. Boyce [31] investigated the aspects of Lean thinking and concluded that it helps to improve the design phase of complex projects by emphasizing the essential function of a collaborative planning process in highway design. Going Lean is needed for the defective processes in mass production and craft production. Hence, Lean is an effective approach for customer satisfaction and enhanced project performance as previously implied by several studies [32, 33]. However, there is still a need for more effective Lean techniques to be applied in the construction projects especially given that the industry generally is reluctant to embrace and slow to adopt change.
Given this background, this chapter presents the most applied methods of Lean in the construction industry with inference to Lean production. The construction industry is utilizing most of the Lean techniques developed for manufacturing. Hence, it is essential to present these tools and techniques to guide industry practitioners for the proper implementation of the methods.
3. Lean methods: how tools and techniques are evolved
Lean methods have been heavily implemented in the manufacturing industry. Over time, the efficiency and reliability of the methods have been proven. This encouraged other industries to benefit from Lean methods. Since the construction industry relies on a heavy workforce, it is essential to utilize safer, reliable, and efficient methods and technologies.
In production, it is of utmost importance to eliminate ‘waste’. Waste or ‘muda’ in Japanese is simply defined as anything other than the minimum amount of parts, materials, equipment, and work time specific to production [34]. There are seven waste types defined as overproduction, waiting time, transportation, inventory, processing, motion, and product defects. Lean manufacturing aims to manage processes without waste. However, it was evidenced that several companies are still challenging with staying Lean [35]. Kongguo [36] implied that Lean thinking helps conceive the Lean principles better, which first starts with realizing the customer value and continues with identifying value-added activities, generating flow, implementing the pull system, and sustaining continuous improvement. To improve the efficiency in those, various Lean methods and techniques are developed and practiced in manufacturing organizations. Some of them have been more effective in other industries such as construction.
Below are the widely implemented Lean techniques that have evolved and be used in the construction industry.
3.1 The last planner system (LPS)
LPS was originally developed by Glenn Ballard in 1993 in accordance with Lean construction principles. LPS is a Lean construction tool that focuses on increasing productivity by creating weekly work plans. The weekly plan includes tasks related to work and the individuals executing these tasks are called the Last planners [13]. LPS allows quick monitoring of the work-related issues for all construction personnel. LPS also provides an environment, where mistakes are visible. However, problems might occur, and timely actions are not taken in traditional construction management leading to late delivery of projects [36]. The Last planner is the person, who directly supervises the work. This person is usually responsible for production capability. The Last planner can be anybody like a project engineer, department manager, or foreman [37]. Figure 1 presents the Last Planner System.
Figure 1.
Last planner system (adapted from [38]).
The tasks are split into two as needed and weekly. As needed tasks involve ‘should’ tasks, whereas weekly tasks include ‘can’, will’, ‘did’ tasks. In ‘should’, the tasks include work to be done to reach the determined milestones according to the project plans. These tasks are created from different data such as customer demands, project goals, and information, planner stuff’s former experiences. In ‘can’, the fundamental tasks are reflecting the actual work that is executed with respect to the constraints of the project. In this process, the required materials and labor are ready, where the previous project stage is completed. In ‘will’, the tasks ensure the work to be completed after all constraints are assessed. In ‘did’, the tasks refer to completed work [39].
3.2 5S method
5S is a Japanese method of organizing the workspace in a clean, efficient, and safe manner to create a productive work environment. The 5S is a starting point for any company aiming to be recognized as a responsible and reliable producer [40]. In Japanese, the 5S methodology represents 5 different words, which all start with the letter S. Figure 2 presents these five steps, respectively.
Figure 2.
5S stages.
Sort (Seiri): Sorting is the first stage of 5S. It is the process of sorting out (separating) materials and equipment needed or unneeded. This process might result in fewer complaints, improved communication among employees, and an increase in the quality and efficiency of production. This process allows workers to take the next steps such as tagging the items.
Set in order (seiton): This stage refers to make all equipment needed for production accessible and prepared for use. This step also refers to organize all equipment and material for easy access and facilitation for production. This step requires the work area to be organized for production. A map can be drawn to represent station and equipment places.
Shine (seiso): This step refers to cleaning polluted equipment and work area. Pollution can be detected by sense organs and this might help find out the problem before it occurs. This stage also refers to sweeping everywhere cleanly and taking all kinds of unwanted objects away from the working environment. Thus, abnormalities can be noticed immediately, and the decision to clean materials after separation becomes easier.
Standardize (seiketsu): This stage refers to cleaning and maintaining the arrangement and standardizing that. The main purpose of this step is to fully meet 3S requirements and to detect and eliminate the root cause of problems. The way to ensure these is to constantly check the environment and detect deficiencies.
Sustain/self-discipline (shitsuke): This step encompasses all stages. It includes checking the existing system, training the employees, establishing good communication, and rewarding. The main purpose of this step is to get into the habit of maintaining the correct procedures [41].
3.3 Mistakeproofing (Poka yoke)
“Mistake proofing, or its Japanese equivalent poka-yoke (pronounced PO-ka yo-KAY), is the use of any automatic device or method that either makes it impossible for an error to occur or makes the error immediately obvious once it has occurred” [42]. Mistake proofing is an effective quality control technique to avoid human error, which might cause mistakes or defects [43]. Shingo [44] defines three inspection techniques for quality control, namely the judgment inspection, informative inspection, and source inspection. Judgment inspection is for discovering defects, whereas informative inspection is used to lower defect rates by controlling the process and prevent defects. Source inspection rather searches the conditions that exist for an error-free action.
Poka yokes might be grouped into three as shutdown poka-yoke, control poka-yoke, and warning poka-yoke in terms of their functions. The poka-yoke devices check different and important parameters and detect whether the process has an improper action. This check allows detecting whether the product manufactured has defects or not. The shutdown of poka-yokes constitutes an important part to prevent defects eliminating the possibility of error. The control poka-yoke is built into the production equipment and works as a redactor. When the device finds an unwanted condition that occurred during manufacturing processes, it signals production to avoid defects. The warning poka-yoke warns the operator with either visual symbols or sound signals for errors. The warning poka-yokes rely on human factors, where it is not quite certain to avoid defects in the production processes [45].
Mistake-proofing has six principles namely elimination, prevention, replacement, facilitation, detection, and mitigation. The first four principles intend to prevent the occurrence of human error, whereas the last two principles are to minimize the effects after the occurrence of human error. Figure 3 presents these six principles along with their tasks.
Figure 3.
Mistake proofing principles.
The use of mistake-proofing devices also provides various advantages in terms of safety at the workplace [46]. It is possible to create fail-safe approaches in manufacturing with the use of such tools and devices. Considering the high accident rates in the construction industry, the use of mistake-proofing devices is also effective means of enhancing safety performance and avoiding human errors leading to work-related accidents.
3.4 Visual management
Visual management is a broadly implemented Lean technique in the manufacturing industry. This technique helps to make information visible for all showing the information through visual signals [47]. Visual management has recently been used as a system enabling employees to better understand their role and contribution with respect to organizational values and customer needs. Nevertheless, the critical role of visual management has not yet been understood well by the construction industry. For example, two types of visual means such as 3D and visual planning are utilized in construction design [48]. Visual management helps increase communication, transparency, and stakeholders’ capabilities [49, 50]. Therefore, construction companies must make use of these techniques to provide a better environment for their employees increasing efficiency and productivity.
3.5 Target value design (TVD)
Target Value Design (TVD) is simply defined as “a management practice that steers the design and construction of the project to the customer’s constraints while maximizing the value delivered within those constraints” [51]. TVD is an emerging practice in the U.S. construction industry for cost predictability during design, construction, and delivery. It is adapted from the Target Costing method of manufacturing, which first appeared as a profit planning and strategic management approach in the 1930s [52]. This technique is promising for several benefits for the construction industry, where the companies are still struggling with project constraints such as cost, quality, and time. Therefore, TVD is an effective means of collaborative Lean approach in terms of reducing construction costs [53]. It was further indicated that the systematic application of TVD resulted in significant improvement in project performance based on 12 construction projects, where TVD was introduced. Figure 4 presents the TVD process with respect to construction project phases.
Figure 4.
TVD process scheme [53].
3.6 Value stream mapping (VSM)
Value Stream Mapping is an essential tool to identify and comprehend the productive stream focusing on the identification of waste sources, such as waiting for products and inventories, rework, information lost in the process, non-value-adding activities besides the identification of opportunities for improvement [54]. With VSM, it is possible to improve the information stream in the design process through the inclusion of alternative methods of control. This creates a base for incentives and future actions to generate value [55].
VSM helps visualize the whole rather than isolated parts of the process as well as monitoring the products, documents, and information. It also allows simultaneous visibility of streams of materials and information; visualization of indicators such as throughput time, percentage of value aggregation, lots size, and cycle time for the performance of activities [56].
VSM consists of several steps such as mapping activity for a family of products, defining the current state map of the value stream, and creating the future value stream map, where improvement takes place based on the proper identification of problems [54, 56]. Figure 5 presents the steps for VSM.
Figure 5.
VSM processes.
3.7 5 whys and root cause analysis
5 Whys is a quality management tool of problem-solving aiming to find the root cause of an event [57]. It directs that one needs to ask five times repeatedly to identify the root cause of a problem for the fact that the solution is clear. This procedure aims to eliminate the root cause to prevent its recurrence [58]. Figure 6 shows the 5 Whys procedure for finding the problem’s root cause.
Figure 6.
5 whys analysis procedure.
Considering the risky nature of construction projects, it is of utmost importance to determine the root cause of the problems leading to unwanted situations. Therefore, 5 Whys analysis is an essential method for preventing problems either from occurring or recurring. Therefore, utilizing the 5 Whys method might result in higher efficiency and productivity, where risky conditions are eliminated.
3.8 Gemba walks
Gemba is a Japanese word and it stands for the “actual place” [59]. For creating value in the organization, the actual place must enable employees to manufacture with less waste, fewer challenges, less overload, land ess overproduction. At this point, Gemba walks are essential to go and see the current situation and understand the root cause of the problem. In the Lean construction context, walking means “go see, ask why, show respect” [60]. Gemba walks help making the problems visible and create improvement ideas with the proper consideration of the root cause. It also allows collecting data regarding the root cause leading to problems. In the construction industry, it is clear that Gemba walks constitute an important part since the majority of the processes in construction need improvements and require the proper identification of the root cause for problems.
3.9 Daily huddle meetings
Daily huddle meetings take place, where team members are ready to share what they achieved and what they challenge. A huddle meeting can also be organized as a weekly work plan meeting highlighting the completion of assignments for the following week in addition to discussing the work to be done that day [61]. The huddle meetings enhance the job satisfaction of employees while strengthening two-way communication among the team [62]. Daily huddle meetings create an opportunity for employees to involve in discussions and indicate the positive and negative sides of their tasks. The employees also find room for solving problems together during those meetings. These meetings also help detect the causes of accidents, which are associated with poor communication and coordination [63]. Hence, daily huddle meetings must be organized, and employees are encouraged to speak up on the tasks listing good and bad sides.
4. Conclusions
This chapter presented the historical evolution of Lean management and how Lean is adopted in the construction industry. The study presented the core principles of Lean along with the most widely adopted practices. According to the information presented in this chapter, one may advocate that the construction industry still struggling with the adaption of various Lean manufacturing practices into construction. Therefore, it is apparent that more research has to be conducted to provide a guideline for the industry practitioners in terms of benefitting from Lean practices at maximum. On the other hand, the methods, tools, and techniques presented in this chapter are expected to lead industry practitioners in terms of scrutinizing Lean concepts and evaluate those in the context of project conditions. As future work, the efficiency of Lean methods both applied in manufacturing and construction might be compared based on different operating processes.
\n',keywords:"lean manufacturing, productivity, efficiency, lean construction, lean methods",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75657.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75657.xml",downloadPdfUrl:"/chapter/pdf-download/75657",previewPdfUrl:"/chapter/pdf-preview/75657",totalDownloads:340,totalViews:0,totalCrossrefCites:1,dateSubmitted:"November 1st 2020",dateReviewed:"January 25th 2021",datePrePublished:"March 10th 2021",datePublished:"November 3rd 2021",dateFinished:"March 10th 2021",readingETA:"0",abstract:"Lean manufacturing first emerged in the automotive industry. However, low productivity and low efficiency in production are major problems for the majority of industries relying on a heavy workforce. Being one of these, the construction industry suffers from low productivity rates along with inefficient work practices. To prevent those, the industry has shifted its focus from the traditional approach to a more innovative one, which is called Lean construction. Lean construction aims to maximize value while minimizing waste. Therefore, it intends to create safer, smoother, and more efficient processes to eliminate waste. This chapter focuses on Lean construction and highlights the generic Lean tools and techniques practiced in the construction industry indicating its historical journey from Lean manufacturing. The chapter aims to raise awareness towards the efficiency of Lean methods in the construction industry with respect to practices observed in manufacturing.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75657",risUrl:"/chapter/ris/75657",signatures:"Sevilay Demirkesen",book:{id:"10548",type:"book",title:"Lean Manufacturing",subtitle:null,fullTitle:"Lean Manufacturing",slug:"lean-manufacturing",publishedDate:"November 3rd 2021",bookSignature:"Karmen Pažek",coverURL:"https://cdn.intechopen.com/books/images_new/10548.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-150-8",printIsbn:"978-1-83969-149-2",pdfIsbn:"978-1-83969-151-5",isAvailableForWebshopOrdering:!0,editors:[{id:"179642",title:"Prof.",name:"Karmen",middleName:null,surname:"Pažek",slug:"karmen-pazek",fullName:"Karmen Pažek"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"338001",title:"Assistant Prof.",name:"Sevilay",middleName:null,surname:"Demirkesen",fullName:"Sevilay Demirkesen",slug:"sevilay-demirkesen",email:"demirkesen@gtu.edu.tr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Gebze Technical University",institutionURL:null,country:{name:"Turkey"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Background of lean production and lean construction: Interaction in terms of tools, techniques, and methods",level:"1"},{id:"sec_3",title:"3. Lean methods: how tools and techniques are evolved",level:"1"},{id:"sec_3_2",title:"3.1 The last planner system (LPS)",level:"2"},{id:"sec_4_2",title:"3.2 5S method",level:"2"},{id:"sec_5_2",title:"3.3 Mistakeproofing (Poka yoke)",level:"2"},{id:"sec_6_2",title:"3.4 Visual management",level:"2"},{id:"sec_7_2",title:"3.5 Target value design (TVD)",level:"2"},{id:"sec_8_2",title:"3.6 Value stream mapping (VSM)",level:"2"},{id:"sec_9_2",title:"3.7 5 whys and root cause analysis",level:"2"},{id:"sec_10_2",title:"3.8 Gemba walks",level:"2"},{id:"sec_11_2",title:"3.9 Daily huddle meetings",level:"2"},{id:"sec_13",title:"4. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Lean Enterprise Institute (LEI) 2021. 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Application level of lean construction techniques in reducing accidents in construction projects. Journal of Financial Management of Property and Construction.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Sevilay Demirkesen",address:"demirkesen@gtu.edu.tr",affiliation:'
Gebze Technical University, Kocaeli, Turkey
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Various technical variants of this test can detect antigen (native or foreign) or antibody, determine the intensity of the immune response whether pathological or not; the type of induced immune response as well as the innate immunity potential; and much more. These capabilities, as well as the high sensitivity and robustness of the test and a small price, make it possible to quickly and reliably diagnose diseases in most laboratories. Besides, ELISA is a test that is also used in veterinary medicine, toxicology, allergology, food industry, etc. Despite the fact that it has existed for almost 50 years, different ELISA tests with different technical solutions are still being developed, which improves and expands the application of the this exceptional test. The aim of this chapter is to empower the rider to optimize, standardize and validate an enzyme linked immunosorbent assay.",book:{id:"9850",slug:"norovirus",title:"Norovirus",fullTitle:"Norovirus"},signatures:"Rajna Minic and Irena Zivkovic",authors:[{id:"325806",title:"Ph.D.",name:"Irena",middleName:null,surname:"Zivkovic",slug:"irena-zivkovic",fullName:"Irena Zivkovic"},{id:"325839",title:"Dr.",name:"Rajna",middleName:null,surname:"Minic",slug:"rajna-minic",fullName:"Rajna Minic"}]},{id:"56750",title:"Laboratory Approach to Anemia",slug:"laboratory-approach-to-anemia",totalDownloads:6255,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Anemia is a major cause of morbidity and mortality worldwide and can be defined as a decreased quantity of circulating red blood cells (RBCs). The epidemiological studies suggested that one-third of the world’s population is affected with anemia. Anemia is not a disease, but it is instead the sign of an underlying basic pathological process. However, the sign may function as a compass in the search for the cause. Therefore, the prediagnosis revealed by thorough investigation of this sign should be supported by laboratory parameters according to the underlying pathological process. We expect that this review will provide guidance to clinicians with findings and laboratory tests that can be followed from the initial stage in the anemia search.",book:{id:"5942",slug:"current-topics-in-anemia",title:"Current Topics in Anemia",fullTitle:"Current Topics in Anemia"},signatures:"Ebru Dündar Yenilmez and Abdullah Tuli",authors:[{id:"183998",title:"Ph.D.",name:"Ebru",middleName:null,surname:"Dündar Yenilmez",slug:"ebru-dundar-yenilmez",fullName:"Ebru Dündar Yenilmez"},{id:"209103",title:"Prof.",name:"Abdullah",middleName:null,surname:"Tuli",slug:"abdullah-tuli",fullName:"Abdullah Tuli"}]},{id:"33133",title:"Waist Circumference in Children and Adolescents from Different Ethnicities",slug:"waist-circumference-in-children-and-adolescents-from-different-ethnicities",totalDownloads:8023,totalCrossrefCites:4,totalDimensionsCites:7,abstract:null,book:{id:"642",slug:"childhood-obesity",title:"Childhood Obesity",fullTitle:"Childhood Obesity"},signatures:"Peter Schwandt and Gerda-Maria Haas",authors:[{id:"29867",title:"Prof.",name:"Peter",middleName:null,surname:"Schwandt",slug:"peter-schwandt",fullName:"Peter Schwandt"}]},{id:"54411",title:"Isolation and Characterization of Escherichia coli from Animals, Humans, and Environment",slug:"isolation-and-characterization-of-i-escherichia-coli-i-from-animals-humans-and-environment",totalDownloads:6182,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Working on a diverse species of bacteria that have hundreds of pathotypes representing hundreds of strains and many closely related family members is a challenge. 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Some clues on sample and isolate preservation for future use are outlined, and general precautions regarding E. coli handling are also presented to the researcher to avoid improper planning and execution of E. coli-related research. 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A pregnant woman has an increased risk (up to four times) of getting malaria and twice the chances of dying from malaria, compared to a non‐pregnant adult, becuase the immune system is partially suppressed during pregnancy. Malaria in pregnancy not only affects the mother but also has a dangerous sequel for the developing foetus, resulting in premature delivery or intrauterine growth retardation. Diagnosis of malaria in pregnancy remains a challenge due to the low parasite density and placental sequestration of Plasmodium falciparum. Thus, there is an urgent need for new diagnostic methods to detect malarial parasites in the pregnant women. Though antimalarial drugs are available, which can be safely given in the pregnancy, increasing drug resistance of malarial parasite may pose a big problem in the future. In this chapter, we review the burden of pregnancy‐associated malaria (PAM), its pathogenesis, diagnostic issues during pregnancy and recent guidelines for chemoprophylaxsis and treatment.",book:{id:"5270",slug:"current-topics-in-malaria",title:"Current Topics in Malaria",fullTitle:"Current Topics in Malaria"},signatures:"Kapil Goyal, Alka Sehgal, Chander S. 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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\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\t
\r\n
\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\t
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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. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. 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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. 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