Correlation between material and process parameters and customers´ demands
\r\n\t
",isbn:"978-1-83768-248-5",printIsbn:"978-1-83768-247-8",pdfIsbn:"978-1-83768-249-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"8bc7ffd7544fff1901301c787e64fada",bookSignature:"Prof. Magdy Elnashar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11998.jpg",keywords:"Preparation, Characterisation, Applications, Immobilised Cells, Biomaterials, Biofibers, Resins, Polysaccharides, Biocomposites in Health Sciences, Biocomposites in the Chemical Industry, Nanobiocomposites, Nano-Composites",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 27th 2022",dateEndSecondStepPublish:"July 29th 2022",dateEndThirdStepPublish:"September 27th 2022",dateEndFourthStepPublish:"December 16th 2022",dateEndFifthStepPublish:"February 14th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"22 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Prof. Magdy Elnashar received his M.Sc. Degree in Chemistry from the Cairo University, Egypt, in 1998, and his Ph.D. Degree in Biochemistry from the University of Leeds (top 100 in the world). He was the head of the Group of Encapsulation and Nanobiotechnology at the Centre of Advanced Sciences in Egypt. Prof. Elnashar has 6 patents, and 11 Awards in teaching, research, and commercialization. His scientific interests include the production of nano to macro beads, biopolymers grafting, and immobilized enzyme",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"12075",title:"Prof.",name:"Magdy",middleName:null,surname:"Elnashar",slug:"magdy-elnashar",fullName:"Magdy Elnashar",profilePictureURL:"https://mts.intechopen.com/storage/users/12075/images/system/12075.jpg",biography:"Prof. Magdy Elnashar was born in Cairo, Egypt in 1972. He recevied his M.Sc. 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His current position is the Head of Biopolymers & Nanobiotechnology Group at the Center of Excellence, National Research Center in Egypt. \nProf. Elnashar’s fields of interest are in the production of Nano to Macro Beads, Biopolymers Grafting, Immobilized Enzymes, Drug Delivery Systems, Nano Magnetic Particles, Diagnostic Kits (Immunology) and Water Purification.",institutionString:"Curtin University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Curtin University",institutionURL:null,country:{name:"Australia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"14",title:"Materials Science",slug:"materials-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466998",firstName:"Dragan",lastName:"Miljak",middleName:"Anton",title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/466998/images/21564_n.jpg",email:"dragan@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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The production costs reduction (minimization of the use of resources) together with best technological exploitation has become the biggest challenge for them to enhance their productivity. This has emerged a new setup wherein increased customization, product proliferation, heterogeneous markets, shorter product life cycle and development time, responsiveness, and other factors are increasingly taking centre stage (Bollinger, 1998). Up to now, the classical meaning of productivity in the production environment is more to minimize or efficient resource utilization but global competition has drastically changed the meaning of this term. Now manufacturers are striving hard to focus their attention towards best technological exploitation of resources to achieve effectiveness. Effectiveness can be defined as the way in which the industry meets the dynamic needs and expectations of customers. The exploitation leads to systematic planning, quick and robust decision making, precise process modelling and above all the intelligent process monitoring and production control through precise and real time information exchange among different agents of the production system. But resources and technologies cannot be fully exploited due to the complexity of the production system and diversified and highly dynamic processes. This in turn also limits the systematic collection, characterization and the effective and efficient exploitation of knowledge for precise system and process adaptation as well as for robust decision making. Productivity is now dependent on the value and the range of the products and services as well as the efficiency with which they are produced and delivered to the system. This is the main aspect of the holistic concept for enhancing productivity. The globalization of the manufacturing industry and the intense competition to lead or survive in the market require a much broader conception of productivity enhancement methodologies either or together employed internally and externally to the industry. A comprehensive picture of these productivity enhancement methodologies in the different sub domain of the whole production system is illustrated in detail in the form of integrated intelligent methodology.
\n\t\t\tThis chapter provides an integrated intelligent methodology for developing a mechanism among different agents of the production system to enhance productivity indirectly. In order to practically demonstrate the mechanism for enhancing productivity, two different application examples from the complete production domain are selected. This domain covers the manufacturing and assembly processes. In manufacturing domain, it is practically investigated the influence of better structuring of knowledge and effective knowledge exchange for the effective optimization of a process chain to produce compressor parts. In joining area, the widespread and systematic knowledge sharing among different agents of the production plant is formulated and implemented to influence productivity through a concept of intelligent production control for joining car body in white parts. The effective knowledge sharing with the process model, automatically updating the influential process parameters for enhancing precision in the process model and achievement of better quality of knowledge guidance for the assembly floor staff is described with the application example of adhesive bonding of car body parts. The investigations and the results from these two distinct examples are merged together to generate the integrated methodology based on intelligent approach for productivity enhancement.
\n\t\t\tFor structuring, characterization and sharing relevant engineering data generated during manufacturing and assembling processes, a technology data catalogue (TDC) is developed. It is used for updating or influencing governing parameters for effective control in the production system. In manufacturing domain, an innovative methodology for process chain optimization is described. In assembly domain, the role of intelligence through knowledge characterization, precise knowledge acquisition for intelligent updating the process models and its use in an automated production setup configuration, on process parameter adaptation and real time corrections for quality assurance is comprehensively described.
\n\t\tCurrently, diversified productivity enhancement methodologies are being practised in the industry. In this regard, two case studies have been carried out to investigate productivity improvement potential in the production domain; this domain covers the manufacturing of aero engines components and the automotive assembly.
\n\t\t\tThe actual state of aero engines is the result of considerable progress in materials, manufacturing and surface technologies supporting and completing the improvements achieved in design, aerodynamics and thermodynamics (Steffens and Wilhelm, 2008). One example is the introduction of the titanium-alloys in the early 1960 that enabled the design of large fan blades and the design of fast rotating high pressure compressor rotors. This means that the maturity in the design has been reached to a point where the manufacturers are focussing more on productivity in new engine design and their manufacturing. It includes the minimization of costs by several means; the most significant of them is by reducing the number of components, exploiting new materials in the design and fast manufacturing. It is noteworthy to mention here that high speed milling is the most effective way to produce optimum surface finish and geometric accuracy at high metal removal rates. Highly complex components, e.g. compressor bladed disks (blisks), are milled on 5 or 6-axis machines. The productivity in their manufacturing is being achieved by the effective interaction of an advanced CNC control, optimum tools and clamping devices and an effective coolant lubricant system. Up to now, an optimized milling strategy is needed to minimize machining times, optimize aerodynamically defined surfaces and reduce machining costs (Steffens and Wilhelm, 2008). Blisks can be termed as the combination of aerodynamically defined surfaces. According to Bußmann, Kraus and Bayer (2005), Blisks (bladed integrated disks) or IBRs (bladed integrated rotors) are some of the most innovative and challenging components in modern gas turbine engines. Some of the advantages using blisks are that they reduce weight by 20% and improve efficiency, compared with the conventional blade assembled disk. The weight saving is a result of lower rim loads, the elimination of blade roots and disks lugs and the compression of more performance in the same design and weight cover. The weight reduction and the consequent material economization is a step towards productivity enhancement. Productivity issue has become very critical in blisks manufacturing due to the significant ramp up of their forecasted demand within the next twelve years in Europe as well as in USA, for civil and military proposes (see Figure 1). The increasing blisk market is pushing the continuous improvement of manufacturing processes, the development of new manufacturing strategies and, furthermore, the development of process chains (Bußmann & Bayer, 2008).
\n\t\t\tBlisk Market forecast
The process chain development of a complex geometry is defined by its design features. The engineering activities in design are product design, engineering analysis and the design documentation; while the engineering activities in manufacturing are the process planning, the NC part programming, among several other activities. For the last several years, CAD/CAM is being used for the engineering activities in design and manufacturing, as productive tools. In this context, CAD/CAM is not only meant for automating certain activities of design and manufacturing, but also for automating the transition from design to manufacturing (Nasr & Kamrani, 2007). As part of the process plan, the NC part program is generated automatically by CAD/CAM; the automatically program generation takes place only after the manual introduction of a great number of parameters, such as: the tool, the type of machining, the machining strategies, the process parameters, etc. Most of process parameters, such as feeds and speeds, are initially defined based on information generated by the tool supplier and the process constraints, such as the maximum spindle speed provided by the machine supplier. To achieve a better machining program, these parameters are often modified directly on the machine at the workshop. The changes are based on the experience of the tool machine operator, who along the years has become an expert on the machine tool and the machining process. Although valuable information about the final machining process is stored on the machine, at the end this information is not retrieved in an intelligent way to be used in future machining operations. The biggest disadvantage appears when the operator leaves the company, thus valuable implicit knowledge is gone, costing a great loss for the industry.
\n\t\t\tFurthermore, in order to create more accurate NC programs and avoid as possible changes at the workshop the CAM-operator should have on-line knowledge about the manufactured products of the company, and well documented information of successful used cases of machined parts (López de Lacalle Marcaide et al., 2004). According to Sharif Ullah and Harib (2006), manufacturing involves knowledge intensive activities, where the knowledge is often extracted from experimental observations.
\n\t\t\tLike the manufacturing of aero engine components, the automotive assembly system requires data and knowledge for their precise control and on-process quality assurance to enhance productivity further. There are three main factors that are being considered in productivity enhancement. These are time, cost, quality and flexibility in production systems and in their infrastructure; the most significant of them is production monitoring and control. In the past the main emphasis was made on the material and labour productivity which is then diverted towards resource efficiency through many planning strategies, like the material resource planning to influence productivity and the labour productivity enhancement methodologies. In assembly domain, the productivity until now is being improved through many distinct means, particularly virtual assembly techniques to enable fast ramp up and fast programming of the handling and processing equipment. This has given the automotive manufacturers, in particular, a competitive edge in checking the assembly process virtually prior to the actual assembly process. This is one of the areas where automotive industry is investing lot of money to enhance productivity in terms of production ramp up time, production costs and the flexibility in the production setups. This in turn also expanded the role of digital factory in the automotive assembly where the processing, testing and fabrication of assembly lines as well as their visualization are made using interactive digital factory tools (Schenk et al., 2005). In this context, the virtual reality and assembly simulation are combined for better production planning and worker qualification for enhancing productivity in the industry. In the normal production especially in assembly, the generation of unexpected errors which are unforeseen to human experts can be identified prior to the start of the operation on the line. This is due to the fact that many working parameters like dimensional variations of products, fixtures, sensors detection capabilities and robot repeatability are closely coupled with the 3D environment; it is difficult to anticipate all of the error conditions with their likelihood of occurrence and 3-D state in the work-space (Baydar and Saitou, 2001). Through virtual assembly, these errors and deviations can be foreseen and eliminated well in time before the actual assembly or joining takes place. This is in fact provides the manufacturer a large potential for enhancing productivity.
\n\t\t\tThe other technique being employed in automotive industry is AutoID recognition of parts using RFID which fits best even in fast paced complex automotive assembly environments (Gary and Warren, 2008) compared to the conventional low cost bar codes techniques. Bar code has significantly contributed to the productivity for a quite long time but the increasing number of product variety and relevant processing equipment together with advances in database technology has improved the amount, quality, and timeliness of data in the industry (Schuster et al., 2004) in logistics, supply chain management, quality assurance etc. The innovative technologies of today such as Auto-ID and the Electronic Product Code (EPC) with clusters of interactive sensor networks have created larger data streams of greater complexity. It is estimated that the amount of data generated each year is increasing as much as 40% to 60% for many organizations (Park 2004). The above two examples from the assembly domain depict that the manufacturing industry especially the automotive sector is striving hard for the best technological exploitation and resource utilization for enhancing productivity.
\n\t\t\tThese are few but the more actual technologies that have been employed by the automotive manufacturers of today to improve productivity in fragmented form. The state of the art techniques are being used by almost all the automotive manufacturers for productivity enhancement but still the competition is increasing and manufacturers from the automotive industry are striving hard to be highly responsive to differentiated customer demands. By highly responsive means that they should also be highly flexible as well as productive inside so as to meet the individualized demands in an economical way. The area which is not fully explored and where there is still significant untapped potential for productivity enhancement is the intelligent control of production setups. Intelligent control encompasses intelligent selection of resources and parameter settings as well as the exchange of real time data exchange between different actor sensor units as well as the handling systems that play active role in automotive assembly operations. This enables the effective and real time control. For ensuring the real time control in an effective way, smooth flow of comprehensive and precise information throughout the entire process chain is the main key. It offers a solid base for concrete real time decision making as well as online optimization of resources and processes. The up-to-date information enables analysing the current production status of the production system at any definite time. This includes the resources in operations, resources in idle status, material flow and quality assurance for correct planning and control.
\n\t\tThe proposed integrated intelligent methodology (see Figure 2) has an aim to optimize the process chain design in the manufacturing domain and the assembly process control model in the assembly domain through a common knowledge base, the technology data catalogue. Further, the methodology foresees the update of the process model with new process chain parameters and the selection of machine setup, tools and fixtures and other resources.
\n\t\t\tThe intelligent methodology is devised on the following characteristics:
\n\t\t\tHighly knowledge driven platform such as technology data catalogue containing the systematic production parameters and functional correlations and coherencies
Intelligent modelling methods dealing with multi-variant parameter correlations and production control parameters considering their interdependencies
Highly flexible and applicable control methodology taking all technical specifications and functionalities and capable of fast and smooth ramp up of new technologies, processes and ensure direct and effective on-process quality assurance
Schematics for an integrated intelligent methodology
This integrated methodology was practically implemented and demonstrated in two European research projects EU FP6 HYMOULD (http://www.hymould.eu/) and EU FP6 FUTURA (http://www.futura-ip.eu/).
\n\t\t\tThe process chain developer is elaborated further in the case study 1; while the functionalities of the setup configurator and the assembly process modeller are discussed in the case study 2 in the following sections.
\n\t\t\tIntensive, precise and effective information exchange plays a vital role in successful running of the processes and activities in the production system. This information can be exchanged formally within the boundaries of defined mechanisms, such as structured methods and formal processes; or informally; and both horizontally, e.g. cross-functional, and vertically within the organization (Perks, 2000; Van der Bij et al., 2003; Calabrese, 1999). Moreover, management can determine knowledge sharing by implementing formal procedures for guiding information flows; moreover, there are mechanisms which can originate such process (Berends et al., 2006). Nevertheless, sharing knowledge among members of a big organization may be a complex activity. And as long as the knowledge is not shared, can not be exploited by the organization (Choo, 1996).
\n\t\t\t\tTo make this complex activity simpler and enable better exploitation of the knowledge for precise process planning, optimal parameter settings, automatic control program selection and intelligent selection of resources, it is proposed the design and development of a technology data catalogue (TDC) as a main component of the integrated methodology. The main aims of the TDC are collecting, retrieving, structuring, processing and sharing relevant engineering data/information in an intelligent way. The TDC will also provide structured information about the “best-practice” settings of the manufacturing system. Data sources have to be defined and a suitable knowledge representation structure has to be created in order to store the relevant implicit and explicit knowledge generated at the different levels of companies (Minhas et al., 2008).
\n\t\t\t\tThe TDC constitutes the following:
\n\t\t\t\t1) A database with shared terms (concepts, instances, attributes, etc.). The relationship between terms (parameters) will be assured through the axiomatic design theory.
2) Translators will match the conceptual terms coming from different sources ensuring the coherence of the exchange of data between the systems and the TDC. In the literature, translators have already been proposed and successfully tested, e.g. in Goossenaerts and Pelletier (2001).
3) Filters will enable sorting out information that better match the requested technology (Lepratti, 2005; Basson et al., 2004).
4) Characterizer (Berger et al., 2008): required information is selected from different databases and sources, and characterized based on its maturity. Highly mature knowledge is stored in the TDC. The characterization based on maturity considers the standardization, amount of synonyms, visualization, source, etc. (see Figure 3) of the terms and the topics.
Characterization criteria and maturity degree scale
For instance, if there is a technical term, which is considered standard then it gets 3 points on a maturity degree scale. If some synonyms for this standardized technical term are available, then the information quality is higher. If the information was originated at recent date then the information gets more points e.g. 4 points: 2007-2006, 3 points: 2005 -2003, 2 points: 2002 – 2000, 1 point: 1999… Sources can come from theory and practice. If theory is proved through practice, this concept meets the criteria to get 4 points. If the knowledge carries visualization and amount of publications, then the knowledge will get more points compared to the one that was merely originated from theory.
\n\t\t\tThe process chain developer is based on the axiomatic design methodology. Axiomatic design presents many advantages compare with other methodologies like TRIZ and the Taguchi Method (Hu et al. 2000). It provides a good structuring and quantitative modelling for coupled, uncoupled and decoupled design. Moreover, through axiomatic design the process chain can be mathematically modelled which assures precision, and the iterative trial and error process can be minimized which saves a significant amount of time, thus gaining higher productivity. The process chain developer communicates with the technology data catalogue through the knowledge characterizer component to gain parameters for the machine setup such as tools, fixtures, coolants and lubricants.
\n\t\t\t\tFurthermore, the relevant process parameters which are exchanged between the process chain developer and the knowledge characterizer are the feed rates and cutting speeds for specific features and milling operation; these process parameters are extracted from successful past used cases or projects and stored in the technology data catalogue after being classified by the knowledge characterizer. The precise information exchange is enabled and consequently the time for process chain development and the setup time are minimized.
\n\t\t\t\tThe main role of assembly modeller is to extract the assembly process parameters and their values from the knowledge characterizer and then finally generate assembly process control programs. This strategy is adopted to ensure high precision in control programs which in turn eliminates the risk of reworking or using the wrong programs and the consequent malfunctioning of the assembly devices as well as the low product quality. The same concept can be mapped to the manufacturing cell, i.e. machining cell where machine programs will be precisely generated through automatic guidance from the knowledge characterizer. As a result, the time for programming and updating will be reduced to a significant level and likewise the implied costs. Precise programs will also influence the process quality outcomes to the greater extent and part/product rejection rates will be lowered eventually.
\n\t\t\t\tThe assembly process modeller will provide the input to the setup configurator as well as direct control program will be loaded to the assembly cell. The setup configurator after analysing the customer demands configures the assembly cell and set parameters corresponding to the assembly tasks and their control functions being performed in the cell. This enables the configuration/reconfiguration of the cell through software means which enables flexibility. Easy configuration of the cell will enhance productivity in setup time reduction or assembling new components/parts; a step towards fast ramp up. The most salient feature of this integrated methodology is that it simultaneously addresses the time, cost, and quality together with flexible way of adapting production setups and utilizing resources.
\n\t\t\tThe state of the art for productivity enhancement in the manufacturing industry is partly described in the section 2. It was deduced that there is still a need for new manufacturing strategies, as well as, for optimal process chain development. It is necessitated a formal methodology for extracting and then exploiting the useful knowledge from the used cases or projects.
\n\t\t\tThe case study being described here addresses these issues by taking an example of the manufacturing process of bladed integrated disks (blisks). This case study presents a process chain developer able to design an optimized process chain for the production of blisks that will contribute to the enhancement of productivity in the manufacturing domain. The process chain developer is made on the axiomatic design methodology. While the axiomatic design methodology is providing structure to the process chain, the technology data catalogue, main component of the previously described integrated methodology, is providing all data needed for the integrated process chain (see Figure 4). The input data for the process chain developer is coming from the customer needs, i.e. the requested part or design, generally generated as 3D geometry in CAD, and its respective material. The output is the optimized process chain with all process parameters for the manufacturing cell.
\n\t\t\tInteraction between the process chain developer and the TDC
\n\t\t\t\t\tBußmann et al. (2005) affirmed that the optimum blisk manufacturing process, from technical and commercial point of views, depends on material, geometric and aerodynamic parameters; furthermore, they proposed a toolbox-approach that may provide the optimum technology or combination of technologies which may satisfy current and anticipated requirements. Since the disk body involves conventional cutting, surface compactness and finishing, processes where a sufficient amount of experience has been achieved through the production of the conventional blade assembled disk, the toolbox-approach is utilizable specifically for airfoiling.
\n\t\t\t\tTo produce blisk airfoils, three manufacturing processes are commonly used depending on the airfoil size and the resistance of the material to be machined (Bußmann et al., 2005):
\n\t\t\t\tMilling the entire airfoil from the solid; the gas duct area between the airfoils is also milled. This process is applicable for medium-diameter blisks and medium blade counts, and for titanium blisks in the low pressure compressor (LPC) and in the intermediate pressure compressor (IPC) section.
Joining blade and disk together by linear friction welding (LFW) or inductive high frequency pressure welding (IHFP) and subsequently using adaptive milling to remove expelled material; the gas duct area between the airfoils is also milled. This process is applicable for large-diameter blisks, hollow-blade blisk, blisk with large chamber volumes, where the process is suitable to save raw material costs, and for blisks with few blades; and primary for titanium blisks in the low pressure compressor (LPC) section
Removing material through electrochemical machining (ECM) or precise electrochemical machining (PECM). This process is applicable for medium to small-diameter blisks, high number of blades, and for the hotter sections of the high pressure compressor (HPC) of nickel alloys and nickel powder metallic materials or sintered materials.
Axiomatic design is a methodology created by N. P. Suh Suh (Suh, 1990) that endows designers with the scientific basis for the design of engineering systems. Additionally, axiomatic design enhances creativity, minimize the iterative trial-and-error process, express the process design mathematically and, moreover, determine the best design. Suh defined design as an activity that “involves interplay between what we want to achieve and how we choose to satisfy the need (the what)” and four domains that delineate four different design activities (Suh, 2001): the customer domain, the functional domain, the physical domain, and the process domain (see Figure 5).
\n\t\t\t\tThe customer domain is characterized by attributes or the needs that the customer seeks in a product, or a process or a system; in the functional domain the needs are defined based on functional requirements (FRs) and constraints (Cs); in the physical domain the design parameter (DPs) that satisfy the specified FRs are described; finally, in the process domain manufacturing process variables (PVs) are characterized and a process based on the PVs that can produce the DPs is developed. Constraints (Cs) provide the limits on the acceptable design. The difference between Cs and FRs is that Cs do not have to be independent as the FRs.
\n\t\t\t\tAxiomatic design domains
The axiomatic design starts by the identification and definition of the customer attributes or needs, and then their translation into functional requirements; this involves a mapping process from the customer domain to the functional domain. Then a mapping process between functional domain and the physical domain follows to satisfy the customer needs; this process is also called zigzagging method. This method allows creating hierarchies for FRs, DPs, and PVs in each domain. During the mapping process, there can be found many possible DPs; the key DPs are selected for the design according to two design axioms. The mapping process can be expressed mathematically in terms of vectors; that is, a vector of FRs can be related to a vector of DPs according to the following equation:
\n\t\t\t\twhere [A] is the design matrix that indicates a relation between a DP and a FR.
\n\t\t\t\tThe elements of the matrix are represented with a “0” if there is no effect and with an “X” if there is an effect and later on substitute by other values.
\n\t\t\t\tMoreover, when all Aij are equal to zero except those where i=j then the design matrix is defined as diagonal and the design is called uncoupled design; where each of the FRs can be satisfied independently by means of one DP. And when the upper triangular elements are equal to zero then the design matrix is defined as a lower triangular and the design is called decoupled design; where the independence of FRs can be assured only if the DPs are defined in the right sequence. In any other case, the design matrix is defined as a full matrix and the design called coupled, which is the most undesired design.
\n\t\t\t\t(2)Diagonal matrix/ uncoupled design, (3) triangular matrix/ decoupled design, and (4) full matrix/ coupled design
\n\t\t\tInitially, the process chain developer must identify the customer need or attribute (CA) and then translate them into functional requirements which must be fulfilled by design parameters. As it was described in the last section, blisks are not completely accepted by the customers because their manufacturing costs are still higher than the ones for the blade-disk joints (Steffens and Wilhelm, 2008). Thus, the main customer attribute at this point is defined as the minimization of blisk costs. According to this CA, the first level functional requirement (FR) and the respective design parameter (DP) are decomposed as follows:
\n\t\t\t\tFR1 Reduce blisk manufacturing costs
DP1 Manufacturing process within target costs
Further, blisk manufacturing costs are split into three main categories (Bußmann, et al., 2005): the material costs, the airfoiling process cost and other manufacturing and quality assurance costs. Thus, the next decomposition is as follows:
\n\t\t\t\tFR11 Minimize quality assurance costs
DP11 Steady process to target design specifications
FR12 Minimize airfoiling process costs
DP12 Airfoiling processes optimization
FR13 Minimize material costs
DP13 Optimum material utilization
The design equation representing the interaction between the FRs and DPs is as follows:
\n\t\t\t\twhere [A] is a triangular matrix, thus a decoupled design.
\n\t\t\t\tFor the further decomposition of functional requirements and design parameters, material and process parameters which may have influence on the cost and delivery time of blisks are analysed. These parameters are summarized in the table 1 (Esslinger and Helm, 2003). The material costs are directly correlated to the blisk costs, as pointed in table 1; although they are external costs that can be minimized only by the material supplier, they are partially considered in the development of the process chain since a better utilization of the resources can enhance some reduction of costs. The other material parameter, the material data quality, is being ensured by the knowledge characterizer of the technology data catalogue.
\n\t\t\t\tMaterial parameters | \n\t\t\t\t\t\t\tCost and time of delivery | \n\t\t\t\t\t\t
Material costs | \n\t\t\t\t\t\t\tRelevant | \n\t\t\t\t\t\t
Material data quality | \n\t\t\t\t\t\t\tRelevant | \n\t\t\t\t\t\t
Process parameters | \n\t\t\t\t\t\t\tCost and time of delivery | \n\t\t\t\t\t\t
Process stability | \n\t\t\t\t\t\t\tRelevant | \n\t\t\t\t\t\t
Number of steps and their duration | \n\t\t\t\t\t\t\tRelevant | \n\t\t\t\t\t\t
Availability of process simulation | \n\t\t\t\t\t\t\tRelevant | \n\t\t\t\t\t\t
Correlation between material and process parameters and customers´ demands
Concerning the process parameters, the process stability is correlated in general to the cost and delivery time of blisks and, in particular to the quality assurance costs since a mature process result in less quality discrepancies. The last process parameter, the availability of process simulation, is guaranteed by the use of CAD/CAM tools, which is considered as a constraint in this process chain development. The decomposition of FR11/DP11 (minimize quality assurance costs/ steady process to target design specifications) is defined as follows:
\n\t\t\t\tFR111 Minimize process deviations
DP111 No process adjustments
FR112 Deliver product on time
DP112 Throughout time
FR113 Meet design specifications
DP113 Target surface roughness
where [A] is a triangular matrix, thus a decoupled design
\n\t\t\t\tAs it is illustrated in the table 1, the number of steps and their duration are correlated to the blisk costs, thereby an optimized manufacturing process must be designed. Thus the decomposition of FR12/DP12 (minimize airfoiling process costs/ airfoiling processes optimization) is as follows:
\n\t\t\t\tFR121 Optimize milling process
DP121 Optimized process chain design
FR122 Optimize joining process
DP122 Optimized joining approach
FR123 Optimize ECM/ PECM process
where [A] is a diagonal matrix, thus an uncoupled design.
\n\t\t\t\tAs it was pointed out in the previous section, there are three main airfoiling processes for the blisk manufacturing: milling, joining and electrochemical machining (ECM)/precise electrochemical machining (PECM); this case study is focused on the design of an integrated process chain for milling. And because the milling process enhances better results for medium-size range blisks of titanium alloys (Bußmann, et al., 2005) the first constraint is defined as follows:
\n\t\t\t\tC1: medium-size blisk made of titanium alloys
\n\t\t\t\tBefore the milling process can be carried out, a design in CAD is required. Therefore, a second constraint is also defined.
\n\t\t\t\tC2: 3D-CAD geometry
\n\t\t\t\tThe further decomposition of FR13/DP13 (minimize material costs/optimum material utilization) is as follows:
\n\t\t\t\tFR131 Increase material data quality
DP131 Precise material data from the knowledge characterizer
FR132 Reduce wasted material during machining
DP132 Minimum number of damaged workpieces/ prototypes
where [A] is a triangular matrix, thus a decoupled design.
\n\t\t\t\tHere, the characteristics of titanium alloys that have an influence on the machinability of the alloy (Janssen, 2003); e.g. the low heat conductivity causes thermal load on the tool cutting edge, while the chemical affinity by high temperatures produces welding between the chip and the tool; are taken in consideration for the process chain design. These material characteristics are relevant for increasing the quality of the material data which will be stored in the technology data catalogue (TDC) after its categorization by the knowledge characterizer. The intelligent gaining of precise material data (DP131) is facilitating the design of the process chain and saving setup times.
\n\t\t\t\tA milling approach that integrates a strategy, tools and machines make possible a production time reduction of about 50% (Bußmann et al., 2005), thus the FR121/DP121 (optimize milling process/ optimized process chain design) is decomposed as follows:
\n\t\t\t\tFR1211 Define the milling strategy
DP1211 Feature-based design
FR1212 Determine machine and cutting tool
DP1212 Machine and cutting tool selection from the TDC
FR1213 Generate process parameters
DP1213 Feeds and speeds selection from the TDC
where [A] is a triangular matrix, thus a decoupled design
\n\t\t\t\tOne of the advantages of feature-based designing is that the features can be associated to machining processes which are further related to process resources (machines, tools, fixtures and auxiliary materials), process kinematics (tool access direction), process constraints (interference and spindle power), process parameters (feeds and speeds) and other information, such as time and costs. Thus, enabling the creation of, what in the literature is called, a feature-based manufacturing knowledge repository (Nasr and Kamrani, 2007) and what in this chapter was defined as technology data catalogue and further extended with a knowledge characterizer to assure the precision of the data.
\n\t\t\t\tThe optimized process chain is finally developed taking all relevant process parameters: feed rate and cutting speed for the specific feature and milling operation; these process parameters, stored from successful past used cases or projects, are retrieved from the technology data catalogue (TDC) through the knowledge characterizer. The structuring of knowledge and precise knowledge exchange is enhancing effective optimization of a process chain to produce bladed integrated disks (blisks). This optimal chain development with high precision will eliminate redesigning and the trial and error in the process chain which eventually minimizes time and cost. Consequently, a more productive process chain development is achieved.
\n\t\t\tThe state of the art strategies for making the assembly systems more productive are discussed in the section 2 in fragmented form. It is concluded that the high mass customization has induced the complexities in terms of efficient and intelligent utilization of resources, precise modelling of assembling processes and reliable and effective quality control.
\n\t\t\tThe case study being described here was made on the assembly process of automotive body in white. In this case, the innovative joining process adhesive bonding of car body parts is taken as an example. Adhesive bonding has a strong potential in the car body assembly which has made the joining of different multifunctional materials possible. The objective of this case study is to investigate the possibility of increasing productivity in assembly process with the following targets
\n\t\t\tEfficient resource utilization with the easy and fast ramp up of joining parts in the flexible cell
Precise modelling of the assembly process and automatic updating with the precise knowledge (experienced knowledge from the used cases)
Intelligent selection and parameter settings of assembly setups and using the same setup for multipurpose applications ( Setup cost and time reduction)
Taking adhesive bonding as an example, for joining tasks, the process control sequence and the relevant program is generated by the process modeller after extracting accurate process parameters for the joining process parameters, e.g. adhesive dispensing rate, robot application speed, etc.
\n\t\t\t\tComputation of adhesive positioning with hybrid automata
\n\t\t\t\t\tFigure 6 shows a part of block program that is modelled using the concept of hybrid automata (Henzinger, 1996; Branicky et al., 1998). The intelligence can play its active role in setting up guard conditions in the modelled program. As an example the information about the guard conditions corresponding to the actual process conditions can be extracted from the knowledge characterizer while switching from the discrete steps to the continuous states for calculations such as the position calculations from the monitoring data coming from the sensors to the process model for the actual quality of adhesive bead, i.e. its form and position. The knowledge characterizer will provide the necessary process parameters i.e. dispensing pressure, temperature, robot speed, nozzle valve actuation frequency and its operating timings. This procedure of modelling though hybrid automata helps in eliminating risks and ensures precise process control that can be used in real time situation at the assembly cell level thereby enhancing process reliability and productivity. The process flow diagram (control program) of adhesive bonding station is shown in the following figure 7. The process flow contains many feedback loops and computations after extracting monitoring data from the sensors. These feedback loops are activated using parameters from the knowledge characterizer and the conditions sett by the TDC.
\n\t\t\t\tThe significant task of the process modeller is that it is automatically updates the process model through the real time exchange of data with the knowledge characterizer. It saves setting up time in a case where there is significant change of variants in the cell, which are then to be assembled enabling fast automatic adaptation of control programs. It makes the process modelling and programming activity in the assembly more productive in terms of time and cost. Moreover precise process modelling through extensive knowledge exchange with the knowledge characterizer helps in achieving higher quality, thereby making this activity more productive in terms of process reliability.
\n\t\t\t\tProcess flow diagram (part) for robot guided adhesive bonding application
Flexibility in terms of resource selection and production setup configuration is one of the most influential factors in enhancing productivity. The more is the system flexible, the greater is the system productive, provided the system is subjected to the mass customization. For simplicity, this case study is carried out using the example of multisensory monitoring of adhesive bonding process for demonstrating effective and on-process quality assurance. It enables enhanced process and the resulting product quality.
\n\t\t\tThe investigation for fast adaptation of production setups is made using the case of adaptation of multisensory setup that can be adaptable for different assembly processes in the assembly cell (see Figure 8).
\n\t\t\t\tThe sensors are selected in the network relevant to the joining process by the setup configurator and the controller manages the monitoring data exchange with the main controller for real time process control.
\n\t\t\t\tThe selection of sensors can be made using the following methodologies
\n\t\t\t\tCost functions
Axiomatic design approach (Houshmand M. & Jamshidnezhad B., 2002; Igata, 1996)
Algorithms known from cognitive mapping theory (Zhang et al., 1992)
Schematics of multi-purpose multisensory network
Cost function based evaluation methodology is simpler compared to the other two methodologies, but it has widespread use as it can be employed not only for the static activation of sensors but also for the dynamic activation of sensors in the network. The selection of sensors corresponding to process parameters can be made using the following algebraic equations. From figure 8, if there are n sensors in the networks with n set of characteristics implies:
\n\t\t\t\twhere S1, S2, S3,…….., Sn are the sensors in the network with the characteristics E1, E2, E3…… En respectively and calculation of cost function can be made in the following way:
where W1, W2, W3,……,Wn are the evaluated weights of S1, S2, S3,…….,Sn respectively based on the weights of their characteristics we1, we2,we3,…………….,wen.
Finally the sensors are selected after the sensor weights evaluated corresponding to their suitability for process parameter measurement by the following equations:
\n\t\t\t\twhere M(P1), M(P2),…………., M(Pn) gives the equations of selected sensors suitable for measuring the relevant parameters. The sensors which are not suitable will be given zero weightage, as a result they are automatically eliminated from the equations.
This methodology works well when the mature knowledge about the sensors and their characteristics are available in the TDC. The ramp up of newly developed or the sensors with new technology needs an update in the TDC for reliable selection and their parameter settings.
\n\t\t\tIn this chapter, the intelligent integrated methodology for productivity enhancement has been highlighted. The methodology was discussed using two case studies in the production system. The first one was elaborating the innovative process chain optimization of blisks through axiomatic design approach and the intelligent selection of process parameters from the TDC through the knowledge characterizer; and the second one was discussing the parameter settings and adaptation of assembly process control models of a car body in white parts and finally the configuration/ reconfiguration of the adhesive bonding assembly. Moreover, with this integrated methodology is ensured the effective knowledge sharing with the process model from the knowledge characterizer, automatically updating the influential process parameters for enhancing precision in the process model developed through hybrid automata, achievement of better process and the resulting product quality.
\n\t\t\tThe salient advantage of this integrated methodology is that it addresses all the influential factors of productivity simultaneously. It is noteworthy to mention that this methodology revolves around the technology data catalogue as knowledge base for optimization and adaptation purposes and this is possible only if the information of the used cases has a high degree of maturity. Furthermore, if the knowledge is not mature or the used cases are not available then the technology data catalogue and the knowledge characterizer can not be so effective and reliable in precise optimization and adaptation. The authors have noticed these limitations and as a next step this integrated methodology will be extended by using concepts and algorithms known from the self learning theory.
\n\t\tChronic kidney disease (CKD) is a worldwide public health problem whose prevalence is persistently increasing. It is estimated that about 10% of adults in developed countries suffer some degree of kidney damage [1]. Patients with CKD usually develop a progressive kidney damage characterized by glomerular sclerosis and/or tubulointerstitial fibrosis, which eventually leads to end-stage renal disease, the last stage of this condition [2]. The detrimental effect of this process includes the progressive reduction of glomerular filtration rate (GFR) given by an increase in damaged nephrons, which eventually leads to organ failure [3]. CKD has different etiologies, including diabetic nephropathy, hypertensive nephrosclerosis, and glomerulonephritis. However, regardless of the initial cause, the morphological characteristics, such as tubular necrosis and glomerular sclerosis, are similar [4, 5]. This condition induces the partial destruction of nephrons and the progressive failure of renal function [4, 5].
Hypertension is the second cause of end-stage renal disease (ESRD) [6, 7]. Hypertensive nephropathy starts in the glomeruli due to an increase in intraglomerular pressure. These initial events activate and damage mesangial cells, epithelial cells, and podocytes within the glomerulus. In turn, these cells produce vasoactive and pro-inflammatory mediators, which increase cell damage and favor fibrosis, reducing renal blood flow and glomerular filtration rate [8]. The renal corpuscle, formed by Bowman’s capsule and glomerulus, is the fundamental structure in the filtration process. The glomerulus is formed mainly by blood capillaries, podocytes, and the mesangium. The mesangium plays a key role in the structural and functional stability of the glomerulus, allowing it to successfully fulfill its filtering function [9]. The mesangial cells (MCs) constitute 30–40% of the cellular population of the glomerulus, and their function is to support the glomerulus and participate in the maintenance of the opening of its capillaries, regulation of the glomerular filtration rate, and synthesis and degradation of extracellular matrix proteins [9].
The renin-angiotensin system (RAS) is the prototype of a classic systemic endocrine network whose actions in the kidney and adrenal gland include regulation of blood pressure, intravascular volume, and electrolyte balance [10]. The RAS plays an integral role in the homeostatic control of arterial pressure, tissue perfusion, and extracellular volume. This pathway is initiated by the regulated secretion of renin from the kidney, the rate-limiting processing enzyme [11]. RAS begins with the biosynthesis of renin by the juxtaglomerular (JG) cells. Active renin secretion is regulated mainly by (1) the renal baroreceptor mechanism in the afferent arteriole that senses changes in renal perfusion pressure; (2) changes in delivery of NaCl (sensed as changes in Cl concentration) to the macula densa cells of the distal tubule, which lie close to the JG cells and form the JG apparatus; (3) sympathetic nerve stimulation via beta-1 adrenergic receptors; and (4) negative feedback by a direct action of angiotensin II (AngII) on the JG cells [11]. Renin secretion is stimulated by a fall in perfusion pressure or in NaCl delivery and by an increase in sympathetic activity [11, 12]. Angiotensinogen is secreted constitutively by the liver and reacts with renin, ending transformed into the inactive decapeptide angiotensin I (AngI) [11]. AngI is hydrolyzed by angiotensin-converting enzyme (ACE), which removes the C-terminal dipeptide to form AngII, a potent vasoconstrictor [11, 12]. AngII is the primary effector of a variety of RAS-induced physiological and pathophysiological actions [11]. AngII, via the AT1 receptor, stimulates the production of aldosterone by the zona glomerulosa in the adrenal gland [11]. Aldosterone is a major regulator of sodium and potassium ion (Na+ and K+, respectively) balance and thus plays a major role in regulating extracellular volume [11, 12]. It enhances the reabsorption of Na+ and water in the distal tubules and collecting ducts (as well as in the colon and salivary and sweat glands) and thereby promotes K+ (and hydrogen ion) excretion [11, 12].
The vasoconstriction and the increase in blood pressure mediated by AngII represent only part of the pleiotropic actions of this peptide. AngII stimulates aldosterone secretion, cell infiltration, proliferation and migration, thrombosis, superoxide ion production, and other factors involved in nephropathy [8]. When MCs are stimulated with AngII, the synthesis of extracellular matrix is increased and accumulates in the extracellular space [13]. Activated MCs produce more reactive oxygen species (ROS) [14, 15] and synthesize and release more pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and chemokines, such as the macrophage chemoattractant protein (MCP-1) and transforming growth factor β (TGF-β) [13, 15, 16, 17]. In addition, high concentrations of AngII maintained for long periods of time in mice induce an inflammatory response characterized by the expression of pro-inflammatory cytokines such as IL-1β and TNF-α [18], infiltration of macrophages (positive ED-1) [19], tubular overexpression of osteopontin (OPN) [19], and the expression of other pro-inflammatory cytokines, chemokines, and adhesion molecules [8, 20]. AngII also increases the expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX), one of the main enzymes in the generation of ROS, contributing to the onset of oxidative stress (OS), independent of the action of pro-inflammatory cytokines [21, 22]. The sum of these alterations leads to an activation of the transcription factor nuclear factor-NF-κB, which increases the synthesis and release of extracellular matrix protein, such as type IV collagen, laminin, and fibronectin [13, 16], inducing the formation of mesangial nodules with lesions that extend to the interstitial areas, hindering the adequate function of the glomerulus [9, 13, 15, 16]. In summary, intrarenal RAS is an important factor in the pathophysiology of hypertension and hypertensive nephropathy [23].
Two receptors, AngII II receptor type 1 (AT1R) and type 2 (AT2R), both coupled to different G proteins, mediate the actions of AngII. The AT1 receptor activates small G proteins, including Ras, Rac1, RhoA, and the Rho kinase system (ROCK) [24], while the AT2 receptor inhibits RhoA [25]. The Rho family of small GTPases (Rho GTPase) is constituted by monomeric G proteins of 20–40 kDa considered as molecular switches, which cycle between two conformational states, an active state bound to GTP and an inactive state bound to GDP. In mammals, this family is composed of 20 members, of which the most studied are Rac1, Cdc42, and RhoA. The latter being the most studied member of this family [26]. ROCK, an effector downstream of RhoA, is a serine–threonine kinase of around 160 kDa, which in mammals is present in two isoforms, ROCK1 and ROCK2 [27, 28]. ROCK is composed of an amino terminal kinase domain, followed by a super-coiled helix region, which contains the Rho-GTP binding site and a carboxy-terminus, which contains an internal domain rich in cysteine residues [27]. ROCK1 and ROCK2 are highly homologous, sharing an identity of approximately 65% in their amino acid sequences and approximately 92% homology in their amino terminal kinase domain [27, 28].
The RhoA/ROCK pathway has received considerable attention because of its implication in a wide variety of pathophysiological states present in cardiovascular diseases, pulmonary hypertension, Alzheimer’s disease, and glaucoma [27]. The RhoA/ROCK pathway plays an important role in renal pathophysiology, where RhoA/ROCK participates in the regulation of pro-inflammatory cytokines (e.g., TNF-α and IL-1β) [24, 29] and increases the amount of TGF-β and NFκB [27]. On the other hand, great interest has been generated in the use of fasudil, a selective ROCK inhibitor, as regulator in a wide variety of animal models of kidney damage, including unilateral ureteral obstruction, hypertensive glomerulosclerosis, acute renal failure induced by ischemia–reperfusion or by contrast-induced acute kidney injury, and renal failure induced by AngII [27, 30]. Fasudil, a ROCK inhibitor, prevents kidney damage by reducing the expression of extracellular matrix genes, OS, pro-inflammatory cytokines, and macrophage infiltration and inhibiting the cascade of events that leads to these effects. Thus, both RhoA and ROCK could be considered as therapeutic targets to prevent hypertension and kidney damage [24, 27, 29, 31].
Gap junctions (GJs) are conglomerates of intercellular channels that result from docking of two HCs or connexins, each one contributed by one of the cells in contact and formed by six connexins (Cxs). GJs allow direct ion exchange (explaining the electrical coupling), small metabolites (e.g., nicotinamide adenine dinucleotide: NAD+, glucose, lactate, and glutamate), and second messengers (e.g., cyclic adenosine monophosphate [cAMP] and inositol trisphosphate [IP3]) between adjacent cells (explaining metabolic coupling) [32, 33]. There are 21 isoforms of Cxs in humans and 20 in rodents. Each Cx is named according to its approximate molecular weight, and its transmembrane structure identifies four transmembrane domains connected by two extracellular loops and one intracellular loop, which implies that the C and N terminals are in the intracellular space [34]. HCs are fundamental pathways for the exchange of ions and small molecules between the intra- and extracellular compartments. These structures can be opened under physiological and pathophysiological conditions, allowing the release of paracrine and autocrine signaling molecules to the extracellular medium (e.g., adenosine triphosphate [ATP], glutamate, NAD+, and prostaglandin E2 [PGE2]) [35]. Each type of channel formed by the Cxs has unique gate properties, in addition to a characteristic conductance and permeability features [36, 37, 38].
The kidney regulates blood pressure mainly through excretion of Na+ and water, depending on the hormonal action of the RAS and other hormone systems with renal action [39]. However, in order to fulfill this function, the kidney requires the coordinated action of different cell types, including vascular and tubular cells [39]. This intrarenal coordination has not yet been well established, but, since connexins (Cxs) are present in the kidney, the existence of direct communication between the different cell types of the nephron has been proposed to occur through gap junctions (GJs) and/or hemichannels (HCs) [39]. In mammalian kidneys, nine types of Cxs have been detected (Cx26, Cx30.3, Cx31, Cx32, Cx37, Cx40, Cx43, Cx45, and Cx46), which are located in the vasculature or in different segments of the renal tubule, where most likely fulfill different functions [39].
In cortical astrocytes, it has been demonstrated that two pro-inflammatory cytokines, TNF-α and IL-1β, reduce intercellular communication mediated by GJs and increase the permeability of the membrane through HCs formed by Cx43 (Cx43 HCs) [40]. This opposed regulation of Cx43 GJs and HCs also occurs in cultures of proximal tubule cells treated with metabolic inhibitors or pro-inflammatory cytokines, where an increase in the activity of Cx HCs has been demonstrated in response to these stimuli [41, 42]. In pathological conditions such as hypertension, the amount of renal Cxs is altered. For example, in the two-kidney one-clip model (2K1C), an increase in the amount of Cx43 mRNA and protein in the glomerulus was observed [43]. Recently Oliveira et al. showed for the first time that bone marrow mononuclear cell (BMMC) transplantation in clipped kidney of the 2K1C rats significantly increased N-cadherin, E-cadherin, connexin40, and nephrin expression accompanied by improved renal morphology and function and decreased fibrosis [44]. This cell-based therapy, especially using the mononuclear cell fraction, has shown to improve regeneration of multiple tissues under pathological conditions [44]. A recent study provided evidence that both Cx40 and Cx37 participate in endothelial nitric oxide synthase (eNOS) regulation in vivo, where in mice subjected to the 2K1C procedure, the interaction of Cx40 and Cx37 with eNOS was enhanced, resulting in increased nitric oxide (NO) release [45]. Mice lacking Cx40 featured decreased levels of eNOS [45], and in different models of hypertension, Cx37 selectively participates from an altered expression of AT2R [46]. In addition, the amount of Cx43 is increased in inflammatory processes in damaged renal tubules and in interstitial cells in human kidneys [47]. Toubas et al. observed in three different models of CKD (i.e., the transgenic renin [Ren+/+] model, the administration of antibodies against the glomerular basement membrane [α-GMB], and the unilateral obstructive uropathy) an increase in the amount of renal Cx43. Consequently, they postulated that this change in Cx43 was altered by the development of inflammation in the damaged kidney [36]. Therefore, Cx43 is considered a new mediator of renal disease involved in central processes of inflammation and fibrosis, while its inhibition even after the initiation of the disease attenuates renal damage and preserves renal function in animal models of vascular, tubular, and glomerular CKD [48]. Although renal tissue expresses several Cxs, only a few studies have described the involvement of GJs and HCs in kidney damage, and no signaling pathway has been clearly associated with these changes [36, 41, 42]. Therefore, the role of Cx-based channels in normal renal tissue or in the development and progression of kidney damage remains largely unknown.
The main therapies for CKD currently available focus on the control of blood pressure and the optimization of the blockade of the renin-angiotensin system (RAS) [49]. The renal afferent arterioles are primarily responsible for regulating preglomerular resistance, renal blood flow, and GFR. Elevated renal vascular resistance and preglomerular reactivity are observed in AngII-induced hypertension [50]. Although many systemic, neural, paracrine, and autoregulatory mechanisms contribute to afferent arteriolar dynamics, in AngII-dependent hypertension, a direct effect has been observed between the RhoA/ROCK pathway and the endogenous production of AngII [50]. In our studies we have observed that, although treatment with fasudil does not reduce systolic blood pressure (SBP), the establishment of irreversible renal damage is prevented (Figure 1, Table 1), reducing inflammation, OS, and fibrosis, and also kept the amount of Cx43 and phosphorylated myosin phosphatase target subunit-1 (MYPT-1) at normal levels [51] (Figure 2). We have also identified the timepoint when renal damage turns irreversible and, as such, independent of the cause [51]. We considered that kidney damage became irreversible after 4 weeks of treatment with AngII since SBP, inflammation, OS, fibrosis, the amount of Cx43, and phosphorylation status of MYPT-1 remained high even after 2 weeks of AngII withdrawal [51]. On the contrary, these parameters were reversed in animals infused with AngII for 3 or less weeks, which indicates that AngII can generate alterations that can be compensated by kidney tissue that was not affected by AngII and/or recovery thanks to the small regeneration capacity of kidney tissue [51].
Fasudil does not modify the SBP in rats treated with AngII for 4 weeks but prevents the decrease in renal function. (A) Protein (UProt) and creatinine (UCrea) were measured in urine samples to assess renal function from ratio UProt/UCrea. (B) The bars represent the means ± SE of a n ≥ 4 rats per experimental group. The differences between the subgroups of each of the three groups were evaluated by an ANOVA followed by a Tuckey test. ***p < 0.001, **p < 0.01, and * p < 0.05 vs. AngII group.
Groups | Weight (gr) | Proteinuria (mg/day) | Creatinine clearance (ml/min) | FE Na + (%) | FE K+ (%) |
---|---|---|---|---|---|
Ctrl | 482 ± 31 | 2.7 ± 1.1*** | 1.4 ± 0.3*** | 0.2 ± 0.0*** | 12.0 ± 2.7*** |
Ctrl+fasudil | 480 ± 36 | 3.6 ± 1.1*** | 2.1 ± 0.1*** | 0.1 ± 0.0*** | 12.5 ± 0.3*** |
AngII | 364 ± 42 | 214.0 ± 19.0 | 0.7 ± 0.0 | 2.2 ± 0.4 | 162.0 ± 23.0 |
AngII+fasudil | 368 ± 17 | 19 ± 7.2*** | 1.9 ± 0.2*** | 0.5 ± 0.1*** | 30 ± 7.2*** |
Values for weight, proteinuria, creatininuria, creatininemia, creatinine clearance, and fractional excretion (FE) for Na+ and K+ in the experimental groups.
p< 0.001 vs. AngII groups (n≥4/all groups).
The increase in the amounts of phosphorylated MYPT and Cx43 is prevented with fasudil in rats treated with AngII for 6 weeks. Four groups of animals, two control groups (Ctrl and Ctrl+fasudil) and two experimental groups (AngII administered for 6 weeks and AngII+fasudil administered for the last 4 weeks), were studied. Fasudil (100 mg/kg/day) was given in the drinking water. Graphs show phosphorylation of MYPT-1 (A) and the relative amount of Cx43 (B). Under the graph representative pictures of phosphorylated MYPT (p-MYPT), unphosphorylated MYPT and Cx43 positive bands and its loading control (α-tubulin) are shown. The bars represent the means ± SE of n ≥ 4 rats per experimental group. The differences between the subgroups of each of the three groups were evaluated by an ANOVA followed by a Tuckey test. ***p < 0.001 vs. AngII group.
The activity of the RhoA/ROCK pathway has been widely investigated in the pathogenesis of hypertension, where this pathway would fulfill an important role in the regulation of smooth muscle contraction. Other cellular processes such as proliferation, hypertrophy, adhesion, and migration of vascular cells are also mediated by the RhoA/ROCK pathway. These changes could lead to an increase in peripheral vascular resistance, which is one of the critical characteristics of several models of hypertension [52]. Therefore, inhibition of the RhoA/ROCK pathway represents a new approach in the prevention and treatment of hypertension [52]. The protective effect of fasudil in vivo is partly explained by its pleiotropic action in different systems. Therefore, considering that ROCK inhibitors were developed as antihypertensive drugs, it is striking that in our model of rats treated with AngII for 6 weeks, fasudil did not affect SBP, but did reduced the progression of kidney damage [51]. Similar to our observations, several studies have established that fasudil is renoprotective without affecting blood pressure, establishing a controversy regarding the use of fasudil and its antihypertensive action [53, 54, 55, 56]. In view of these results, it would be interesting to develop a line of research that could explain why fasudil does not prevent the increase in SBP, even when it prevents kidney damage.
Hypertensive nephropathy begins in the glomerulus by increasing intraglomerular pressure. These early events activate and damage mesangial cells, epithelial cells, and podocytes in the glomerulus [42]. In turn, these cells produce vasoactive and pro-inflammatory agents, which increase cell damage and promote fibrosis, reducing renal blood flow and glomerular filtration [8]. In afferent arteriolar cells from rats treated with AngII, the activation of NF-κB is mediated by the RhoA/ROCK pathway, and the ROCK/NF-κB axis contributes to the upregulation of angiotensinogen, leading to an increase in the amount of intrarenal AngII [50]. We found that AngII increases the membrane permeability of MES cells, a mesangial glomerular cell line via AT1 receptors, as well as the activation of a RhoA/ROCK-dependent intracellular signaling pathway, followed by the upregulation of three nonselective channels, and the generation of OS and pro-inflammatory cytokines [42]. In MES-13 cells, AngII promotes a feedforward mechanism in which three nonselective channels (Cx43 HCs, Pannexin 1 channels, and P2X7 receptors) maintain or even amplify inflammatory and oxidative responses, causing damage to kidney cells [42].
Xie et al. explored the mechanism of the reduction in the amount of Cx43 induced by RhoA/ROCK signaling in high glucose-treated glomerular mesangial cells (GMCs) [57]. Their results indicate that activated RhoA/ROCK signaling induced Cx43 degradation in GMCs cultured in high glucose via a pathway dependent on F-actin regulation that promoted the association between ZO-1 and Cx43 [57]. Interestingly, we found changes in RhoA/ROCK activity and also found that ROCK inhibitors prevented increases in the amount of Cx43 induced by AngII [51]. Since the expression and activation of RhoA/ROCK and Cx43 HCs, respectively, occur in the same direction, it is likely that they are regulated by the same transduction mechanism and intracellular signaling pathway activated by AngII. Therefore, it was postulated that changes in RhoA/ROCK pathway and Cx43 precede renal damage in this model of hypertensive nephropathy [51]. A comparable response has been found in fibroblasts, and a direct relationship has been demonstrated between the activation of the RhoA/ROCK pathway and the increase in the amount of Cx43. In these cells, the expansion mechanisms in response to stretching involve the release of ATP to the extracellular medium through the RhoA/ROCK pathway and the activation of Cx HCs [58]. In addition, treatment with Y-27632, another inhibitor of the RhoA/ROCK pathway, or with blockers of Cx HCs, such as octanol or carbenoxolone, inhibits the increase of ATP in the extracellular medium and the growth of fibroblast [58]. Nevertheless, this direct relationship is not observed in all cell types. For instance, in corneal epithelial cells, where a RhoA/ROCK-dependent pathway is involved in the formation of Cx43 GJs, inhibition of RhoA/ROCK-dependent pathway results in greater cell–cell communication mediated by Cx43 GJs [59].
Therefore, we propose that blocking AngII-induced damage progression in mesangial cell could be accomplished by inhibiting the RhoA/ROCK as previously demonstrated. Moreover, the effective reduction of initial AngII-induced alterations in cell membrane permeability leading to activation of several metabolic pathways that promote OS and generation of pro-inflammatory cytokines can be accomplished with selective and potent inhibitors of nonselective channels [42, 51].
The differences between the subgroups in each of the three groups were evaluated by an ANOVA followed by a Tuckey test. **p < 0.01, ***p < 0.001 vs. AngII groups (n ≥ 4/all groups).
In conclusion in the hypertensive nephropathy, inflammation, oxidative stress, fibrosis, changes in amount and cell membrane permeability of Cx43 HCs, and activity of the RhoA/ROCK pathway are important in the progression of damage induced by AngII. These alterations are prevented by fasudil, revealing a close relationship between activation of a RhoA/ROCK-dependent pathway and Cx43 in CKD.
The author would like to thank CONICYT, Fondecyt, Universidad Autónoma de Chile, and Pontificia Universidad Católica de Chile. This work was partially supported by a CONICYT Ph.D. fellowship No. 21120081 (Gonzalo I. Gómez) and a FONDECYT grant No. 1150291 (Juan C. Sáez) and ICM-Economía P09-022-F (Juan C. Sáez).
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Gonzalo I. Gómez would like to thank my parents, sister, girlfriend, and teachers for their unconditional support, patience, and belief in me.
chronic kidney diseases
renin-angiotensin system
end-stage renal disease
glomerular filtration rate
mesangial cells
juxtaglomerular cells
angiotensin I
angiotensin-converting enzyme
angiotensin II
interleukin-1β
tumor necrosis factor-α
macrophage chemoattractant protein
transforming growth factor-β
infiltration of macrophages
osteopontin
nicotinamide adenine dinucleotide phosphate oxidase
reactive oxygen species
oxidative stress
angiotensin II receptor type 1
angiotensin II receptor type 2
Rho kinase system
Rho family of small GTPases
nuclear factor-κB
gap junctions
connexins
hemichannels
bone marrow mononuclear cell
two-kidney and one-clip rat model
endothelial nitric oxide synthase
systolic blood pressure
myosin phosphatase target subunit-1
mesangial glomerular cells line
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One distinguished feature of the open source software (OSS) development model is the cooperation and collaboration among the members, which will cause various social networks to emerge. 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This chapter provides theoretical and practical view on different aspects: technical evolution of ICT tools, development and fostering of communication flow, personal aspects of IT communication, with important emphasis on building of trust within virtual teams. The reader can extract from this chapter guidelines for work in collaborative virtual environment, to run effectively either small projects, meetings and lectures or even more complex projects, distributed among several dislocated teams. The chronological overview of the continuous virtual communication in the last 15 years gives also fair suggestions about future evolution for the next decade.",book:{id:"8850",slug:"harnessing-knowledge-innovation-and-competence-in-engineering-of-mission-critical-systems",title:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems",fullTitle:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems"},signatures:"Nikola Vukašinović, Janez Benedičič and Roman Žavbi",authors:[{id:"294317",title:"Dr.",name:"Nikola",middleName:null,surname:"Vukašinović",slug:"nikola-vukasinovic",fullName:"Nikola Vukašinović"},{id:"294322",title:"Prof.",name:"Roman",middleName:null,surname:"Žavbi",slug:"roman-zavbi",fullName:"Roman Žavbi"},{id:"308791",title:"Dr.",name:"Janez",middleName:null,surname:"Benedičič",slug:"janez-benedicic",fullName:"Janez Benedičič"}]},{id:"70099",title:"Knowledge Redundancy Cycles in Complex Mission-Critical Systems",slug:"knowledge-redundancy-cycles-in-complex-mission-critical-systems",totalDownloads:714,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Based on a 20-year, 10-million case study programme of research, 98% of all innovation attempts end in failure. The main aim of the research has been to decode the underpinning, first-principle-driven ‘DNA’ of the 2% of successful attempts. Sitting right at the centre of this DNA is a triad of fundamentals: the need to embrace the dynamics of complex adaptive systems, the need to actively seek out and eliminate compromises and contradictions, and the need for industry domains to periodically unlearn knowledge that has become redundant. The chapter discusses all three of these pillars. Particular attention is paid to the knowledge redundancy topic, where the fact that the life-cycle of knowledge follows distinct, repeating patterns of evolution at meta, macro and micro- hierarchical levels is demonstrated. The research further demonstrates how organizations can use these patterns to objectively identify redundancy ‘pulse-rates’ and thus objectively manage both the acquisition of required new knowledge and the disposal of knowledge that is no longer fit for purpose. The research shows too that a key aspect of this ‘unlearning’ activity demands that organizational leaders acknowledge and accommodate the very human emotions that accompany change initiatives where the things that define a person’s competence become a hazard to the future success of the enterprise.",book:{id:"8850",slug:"harnessing-knowledge-innovation-and-competence-in-engineering-of-mission-critical-systems",title:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems",fullTitle:"Harnessing Knowledge, Innovation and Competence in Engineering of Mission Critical Systems"},signatures:"Darrell Mann",authors:[{id:"297423",title:"Prof.",name:"Darrell",middleName:null,surname:"Mann",slug:"darrell-mann",fullName:"Darrell Mann"}]},{id:"69932",title:"Simplexity: A Hybrid Framework for Managing System Complexity",slug:"simplexity-a-hybrid-framework-for-managing-system-complexity",totalDownloads:726,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Knowledge management, management of mission critical systems, and complexity management rely on a triangular support connection. Knowledge management provides ways of creating, corroborating, collecting, combining, storing, transferring, and sharing the know-why and know-how for reactively and proactively handling the challenges of mission critical systems. Complexity management, operating on “complexity” as an umbrella term for size, mass, diversity, ambiguity, fuzziness, randomness, risk, change, chaos, instability, and disruption, delivers support to both knowledge and systems management: on the one hand, support for dealing with the complexity of managing knowledge, i.e., furnishing criteria for a common and operationalized terminology, for dealing with mediating and moderating concepts, paradoxes, and controversial validity, and, on the other hand, support for systems managers coping with risks, lack of transparence, ambiguity, fuzziness, pooled and reciprocal interdependencies (e.g., for attaining interoperability), instability (e.g., downtime, oscillations, disruption), and even disasters and catastrophes. This support results from the evident intersection of complexity management and systems management, e.g., in the shape of complex adaptive systems, deploying slack, establishing security standards, and utilizing hybrid concepts (e.g., hybrid clouds, hybrid procedures for project management). The complexity-focused manager of mission critical systems should deploy an ambidextrous strategy of both reducing complexity, e.g., in terms of avoiding risks, and of establishing a potential to handle complexity, i.e., investing in high availability, business continuity, slack, optimal coupling, characteristics of high reliability organizations, and agile systems. This complexity-focused hybrid approach is labeled “simplexity.” It constitutes a blend of complexity reduction and complexity augmentation, relying on the generic logic of hybrids: the strengths of complexity reduction are capable of compensating the weaknesses of complexity augmentation and vice versa. The deficiencies of prevalent simplexity models signal that this blended approach requires a sophisticated architecture. In order to provide a sound base for coping with the meta-complexity of both complexity and its management, this architecture comprises interconnected components, domains, and dimensions as building blocks of simplexity as well as paradigms, patterns, and parameters for managing simplexity. The need for a balanced paradigm for complexity management, capable of overcoming not only the prevalent bias of complexity reduction but also weaknesses of prevalent concepts of simplexity, serves as the starting point of the argumentation in this chapter. To provide a practical guideline to meet this demand, an innovative model of simplexity is conceived. This model creates awareness for differentiating components, dimensions, and domains of complexity management as well as for various species of interconnectedness, such as the aligned upsizing and downsizing of capacities, the relevance of diversity management (e.g., in terms of deviations and errors), and the scope of risk management instruments. 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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. 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