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\n\nThe research leading to these results has received funding from the European Community\'s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 285417. The publishing of this book was funded by the EC FP7 Post-Grant Open Access Pilot programme. ',isbn:"978-953-51-3376-6",printIsbn:"978-953-51-3375-9",pdfIsbn:"978-953-51-4699-5",doi:"10.5772/intechopen.68449",price:119,priceEur:129,priceUsd:155,slug:"search-and-rescue-robotics-from-theory-to-practice",numberOfPages:262,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"e1ca88810595580ec90815aab3f1ec9a",bookSignature:"",publishedDate:"August 23rd 2017",coverURL:"https://cdn.intechopen.com/books/images_new/6181.jpg",numberOfDownloads:228679,numberOfWosCitations:29,numberOfCrossrefCitations:46,numberOfCrossrefCitationsByBook:11,numberOfDimensionsCitations:44,numberOfDimensionsCitationsByBook:14,hasAltmetrics:1,numberOfTotalCitations:119,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 10th 2017",dateEndSecondStepPublish:"March 31st 2017",dateEndThirdStepPublish:"June 27th 2017",dateEndFourthStepPublish:"September 25th 2017",dateEndFifthStepPublish:"November 24th 2017",currentStepOfPublishingProcess:1,indexedIn:"1,2,3,4,5,6,7",editedByType:"Authored by",kuFlag:!1,featuredMarkup:'
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\n\nThe research leading to these results has received funding from the European Community\'s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 285417. The publishing of this book was funded by the EC FP7 Post-Grant Open Access Pilot programme.',editors:null,equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1250",title:"Rescue Robot",slug:"rescue-robot"}],chapters:[{id:"56152",title:"Introduction to the Use of Robotic Tools for Search and Rescue",doi:"10.5772/intechopen.69489",slug:"introduction-to-the-use-of-robotic-tools-for-search-and-rescue",totalDownloads:23946,totalCrossrefCites:16,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Modern search and rescue workers are equipped with a powerful toolkit to address natural and man-made disasters. This introductory chapter explains how a new tool can be added to this toolkit: robots. The use of robotic assets in search and rescue operations is explained and an overview is given of the worldwide efforts to incorporate robotic tools in search and rescue operations. Furthermore, the European Union ICARUS project on this subject is introduced. The ICARUS project proposes to equip first responders with a comprehensive and integrated set of unmanned search and rescue tools, to increase the situational awareness of human crisis managers, such that more work can be done in a shorter amount of time. The ICARUS tools consist of assistive unmanned air, ground, and sea vehicles, equipped with victim-detection sensors. The unmanned vehicles collaborate as a coordinated team, communicating via ad hoc cognitive radio networking. To ensure optimal human-robot collaboration, these tools are seamlessly integrated into the command and control equipment of the human crisis managers and a set of training and support tools is provided to them to learn to use the ICARUS system.",signatures:"Geert De Cubber, Daniela Doroftei, Konrad Rudin, Karsten Berns,\nAnibal Matos, Daniel Serrano, Jose Sanchez, Shashank Govindaraj,\nJanusz Bedkowski, Rui Roda, Eduardo Silva and Stephane Ourevitch",downloadPdfUrl:"/chapter/pdf-download/56152",previewPdfUrl:"/chapter/pdf-preview/56152",authors:[{id:"206420",title:"Dr.",name:"Geert",surname:"De Cubber",slug:"geert-de-cubber",fullName:"Geert De Cubber"}],corrections:null},{id:"56037",title:"User-Centered Design",doi:"10.5772/intechopen.69483",slug:"user-centered-design",totalDownloads:22378,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The successful introduction and acceptance of novel technological tools are only possible if end users are completely integrated in the design process. However, obtaining such integration of end users is not obvious, as end‐user organizations often do not consider research toward new technological aids as their core business and are therefore reluctant to engage in these kinds of activities. This chapter explains how this problem was tackled in the ICARUS project, by carefully identifying and approaching the targeted user communities and by compiling user requirements. Resulting from these user requirements, system requirements and a system architecture for the ICARUS system were deduced. An important aspect of the user‐centered design approach is that it is an iterative methodology, based on multiple intermediate operational validations by end users of the developed tools, leading to a final validation according to user‐scripted validation scenarios.",signatures:"Daniela Doroftei, Geert De Cubber, Rene Wagemans, Anibal Matos,\nEduardo Silva, Victor Lobo, Guerreiro Cardoso, Keshav Chintamani,\nShashank Govindaraj, Jeremi Gancet and Daniel Serrano",downloadPdfUrl:"/chapter/pdf-download/56037",previewPdfUrl:"/chapter/pdf-preview/56037",authors:[{id:"82804",title:"Ms.",name:"Daniela",surname:"Doroftei",slug:"daniela-doroftei",fullName:"Daniela Doroftei"},{id:"153104",title:"Prof.",name:"Victor",surname:"Lobo",slug:"victor-lobo",fullName:"Victor Lobo"}],corrections:null},{id:"56050",title:"Unmanned Aerial Systems",doi:"10.5772/intechopen.69490",slug:"unmanned-aerial-systems",totalDownloads:22738,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Unmanned aerial platforms are a means to gather efficiently valuable aerial information to support the crisis manager for further tactical planning and deployment. They can provide continuous support to the coordinators and operators by scanning blocked sectors or establish an communication network. This chapter describes how aerial platforms were tailored to search and rescue (SAR) requirements, including the localisation and tracking of victims. In order to meet the end user demands, complementary platforms are proposed. A small long‐endurance solar aeroplane is used to provide the largest and fastest area coverage at the highest view, and therefore enabling the mapping functionality and potential detection of victims with operation times span up to a day. Complementary to the aeroplane, two rotary‐wing systems were deployed. A large coaxial‐quadrotor was used for outdoor delivery task and detailed close range inspection. Its ability to fly close to the terrain enables a thorough search for victims in a well‐defined sector. A smaller multicopter was used for inspection of the indoor environment. It is able for victim detection in collapsed buildings. Thus, autonomous functionality for precise localisation and positioning was developed to decrease the operator workload.",signatures:"Rudin Konrad, Daniel Serrano and Pascal Strupler",downloadPdfUrl:"/chapter/pdf-download/56050",previewPdfUrl:"/chapter/pdf-preview/56050",authors:[{id:"212085",title:"Mr.",name:"Konrad",surname:"Rudin",slug:"konrad-rudin",fullName:"Konrad Rudin"}],corrections:null},{id:"56080",title:"Unmanned Ground Robots for Rescue Tasks",doi:"10.5772/intechopen.69491",slug:"unmanned-ground-robots-for-rescue-tasks",totalDownloads:24081,totalCrossrefCites:4,totalDimensionsCites:7,hasAltmetrics:0,abstract:"This chapter describes two unmanned ground vehicles that can help search and rescue teams in their difficult, but life-saving tasks. These robotic assets have been developed within the framework of the European project ICARUS. The large unmanned ground vehicle is intended to be a mobile base station. It is equipped with a powerful manipulator arm and can be used for debris removal, shoring operations, and remote structural operations (cutting, welding, hammering, etc.) on very rough terrain. The smaller unmanned ground vehicle is also equipped with an array of sensors, enabling it to search for victims inside semi-destroyed buildings. Working together with each other and the human search and rescue workers, these robotic assets form a powerful team, increasing the effectiveness of search and rescue operations, as proven by operational validation tests in collaboration with end users.",signatures:"Karsten Berns, Atabak Nezhadfard, Massimo Tosa, Haris Balta and\nGeert De Cubber",downloadPdfUrl:"/chapter/pdf-download/56080",previewPdfUrl:"/chapter/pdf-preview/56080",authors:[{id:"212086",title:"Prof.",name:"Karsten",surname:"Berns",slug:"karsten-berns",fullName:"Karsten Berns"}],corrections:null},{id:"56139",title:"Unmanned Maritime Systems for Search and Rescue",doi:"10.5772/intechopen.69492",slug:"unmanned-maritime-systems-for-search-and-rescue",totalDownloads:22742,totalCrossrefCites:4,totalDimensionsCites:10,hasAltmetrics:0,abstract:"The development of maritime unmanned tools for search and rescue operations is not a trivial task. A great part of maritime unmanned systems developed did not target such application, being more focused on environmental monitoring, surveillance or defence. In opposition to these applications, search and rescue operations need to take into account relevant issues such as the presence of people or other vessels on the water. Building upon user requirements and overall integrated components for assisted rescue and unmanned search operations (ICARUS) system architecture, this chapter addresses the development of unmanned maritime systems. It starts with an overview of the approach where a two‐tier solution was adopted to address safety issues and then proceeds to detail each of the developed technologies.",signatures:"Aníbal Matos, Eduardo Silva, José Almeida, Alfredo Martins, Hugo\nFerreira, Bruno Ferreira, José Alves, André Dias, Stefano Fioravanti,\nDaniele Bertin and Victor Lobo",downloadPdfUrl:"/chapter/pdf-download/56139",previewPdfUrl:"/chapter/pdf-preview/56139",authors:[{id:"153104",title:"Prof.",name:"Victor",surname:"Lobo",slug:"victor-lobo",fullName:"Victor Lobo"},{id:"12282",title:"Dr.",name:"Aníbal",surname:"Matos",slug:"anibal-matos",fullName:"Aníbal Matos"}],corrections:null},{id:"56126",title:"Interoperability in a Heterogeneous Team of Search and Rescue Robots",doi:"10.5772/intechopen.69493",slug:"interoperability-in-a-heterogeneous-team-of-search-and-rescue-robots",totalDownloads:22696,totalCrossrefCites:9,totalDimensionsCites:11,hasAltmetrics:1,abstract:"Search and rescue missions are complex operations. A disaster scenario is generally unstructured, time‐varying and unpredictable. This poses several challenges for the successful deployment of unmanned technology. The variety of operational scenarios and tasks lead to the need for multiple robots of different types, domains and sizes. A priori planning of the optimal set of assets to be deployed and the definition of their mission objectives are generally not feasible as information only becomes available during mission. The ICARUS project responds to this challenge by developing a heterogeneous team composed by different and complementary robots, dynamically cooperating as an interoperable team. This chapter describes our approach to multi‐robot interoperability, understood as the ability of multiple robots to operate together, in synergy, enabling multiple teams to share data, intelligence and resources, which is the ultimate objective of ICARUS project. It also includes the analysis of the relevant standardization initiatives in multi‐robot multi‐domain systems, our implementation of an interoperability framework and several examples of multi‐robot cooperation of the ICARUS robots in realistic search and rescue missions.",signatures:"Daniel Serrano López, German Moreno, Jose Cordero, Jose Sanchez,\nShashank Govindaraj, Mario Monteiro Marques, Victor Lobo,\nStefano Fioravanti, Alberto Grati, Konrad Rudin, Massimo Tosa,\nAnibal Matos, Andre Dias, Alfredo Martins, Janusz Bedkowski, Haris\nBalta and Geert De Cubber",downloadPdfUrl:"/chapter/pdf-download/56126",previewPdfUrl:"/chapter/pdf-preview/56126",authors:[{id:"153104",title:"Prof.",name:"Victor",surname:"Lobo",slug:"victor-lobo",fullName:"Victor Lobo"},{id:"212087",title:"Mr.",name:"Daniel",surname:"Serrano",slug:"daniel-serrano",fullName:"Daniel Serrano"}],corrections:null},{id:"56257",title:"Tactical Communications for Cooperative SAR Robot Missions",doi:"10.5772/intechopen.69494",slug:"tactical-communications-for-cooperative-sar-robot-missions",totalDownloads:22551,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter describes how the ICARUS communications (COM) team defined, developed and implemented an integrated wireless communication system to ensure an interoperable and dependable networking capability for both human and robotic search and rescue field teams and crisis managers. It starts explaining the analysis of the requirements and the context of the project, the existing solutions and the design of the ICARUS communication system to fulfil all the project needs. Next, it addresses the implementation process of the required networking capabilities, and finally, it explains how the ICARUS communication system and associated tools have been integrated in the overall mission systems and have been validated to provide reliable communications for real‐time information sharing during search and rescue operations in hostile conditions.",signatures:"José Manuel Sanchez, José Cordero, Hafeez M. Chaudhary, Bart\nSheers and Yudani Riobó",downloadPdfUrl:"/chapter/pdf-download/56257",previewPdfUrl:"/chapter/pdf-preview/56257",authors:[{id:"212088",title:"Mr.",name:"Jose",surname:"Sanchez",slug:"jose-sanchez",fullName:"Jose Sanchez"}],corrections:null},{id:"56086",title:"Command and Control Systems for Search and Rescue Robots",doi:"10.5772/intechopen.69495",slug:"command-and-control-systems-for-search-and-rescue-robots",totalDownloads:22833,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The novel application of unmanned systems in the domain of humanitarian Search and Rescue (SAR) operations has created a need to develop specific multi-Robot Command and Control (RC2) systems. This societal application of robotics requires human-robot interfaces for controlling a large fleet of heterogeneous robots deployed in multiple domains of operation (ground, aerial and marine). This chapter provides an overview of the Command, Control and Intelligence (C2I) system developed within the scope of Integrated Components for Assisted Rescue and Unmanned Search operations (ICARUS). The life cycle of the system begins with a description of use cases and the deployment scenarios in collaboration with SAR teams as end-users. This is followed by an illustration of the system design and architecture, core technologies used in implementing the C2I, iterative integration phases with field deployments for evaluating and improving the system. The main subcomponents consist of a central Mission Planning and Coordination System (MPCS), field Robot Command and Control (RC2) subsystems with a portable force-feedback exoskeleton interface for robot arm tele-manipulation and field mobile devices. The distribution of these C2I subsystems with their communication links for unmanned SAR operations is described in detail. Field demonstrations of the C2I system with SAR personnel assisted by unmanned systems provide an outlook for implementing such systems into mainstream SAR operations in the future.",signatures:"Shashank Govindaraj, Pierre Letier, Keshav Chintamani, Jeremi\nGancet, Mario Nunez Jimenez, Miguel Ángel Esbrí, Pawel Musialik,\nJanusz Bedkowski, Irune Badiola, Ricardo Gonçalves, António\nCoelho, Daniel Serrano, Massimo Tosa, Thomas Pfister and Jose\nManuel Sanchez",downloadPdfUrl:"/chapter/pdf-download/56086",previewPdfUrl:"/chapter/pdf-preview/56086",authors:[{id:"212089",title:"Mr.",name:"Shashank",surname:"Govindaraj",slug:"shashank-govindaraj",fullName:"Shashank Govindaraj"}],corrections:null},{id:"56052",title:"ICARUS Training and Support System",doi:"10.5772/intechopen.69496",slug:"icarus-training-and-support-system",totalDownloads:22393,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The ICARUS unmanned tools act as gatherers, which acquire enormous amount of information. The management of all these data requires the careful consideration of an intelligent support system. This chapter discusses the High-Performance Computing (HPC) support tools, which were developed for rapid 3D data extraction, combination, fusion, segmentation, classification and rendering. These support tools were seamlessly connected to a training framework. Indeed, training is a key in the world of search and rescue. Search and rescue workers will never use tools on the field for which they have not been extensively trained beforehand. For this reason, a comprehensive serious gaming training framework was developed, supporting all ICARUS unmanned vehicles in realistic 3D-simulated (based on inputs from the support system) and real environments.",signatures:"Janusz Będkowski, Karol Majek, Michal Pełka, Andrzej Masłowski,\nAntonio Coelho, Ricardo Goncalves, Ricardo Baptista and Jose\nManuel Sanchez",downloadPdfUrl:"/chapter/pdf-download/56052",previewPdfUrl:"/chapter/pdf-preview/56052",authors:[{id:"63695",title:"Dr.",name:"Janusz",surname:"Bȩdkowski",slug:"janusz-bdkowski",fullName:"Janusz Bȩdkowski"}],corrections:null},{id:"56145",title:"Operational Validation of Search and Rescue Robots",doi:"10.5772/intechopen.69497",slug:"operational-validation-of-search-and-rescue-robots",totalDownloads:22324,totalCrossrefCites:4,totalDimensionsCites:5,hasAltmetrics:0,abstract:"This chapter describes how the different ICARUS unmanned search and rescue tools have been evaluated and validated using operational benchmarking techniques. Two large‐scale simulated disaster scenarios were organized: a simulated shipwreck and an earthquake response scenario. Next to these simulated response scenarios, where ICARUS tools were deployed in tight interaction with real end users, ICARUS tools also participated to a real relief, embedded in a team of end users for a flood response mission. 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\r\n\tAnimal behavior is an animal's response to an action, environment, person, or stimulus after the integration of genetic, sensory, neural, endocrine, and influencer components. The success of the response is an important factor for the survival of living things and the continuation of the species. Learning the behavior is a very important issue that serves as a guide in the adaptation and management of living things. This book, it is aimed to explain the history of behavioral science (Ethology), instinct, domestication, the effects of physiological and biochemical factors, hormones, and the nervous system on animal behavior. Moreover, there will be a comprehensive overview of genetic control of animal behavior, animal learning, offspring care, defense, foraging, sexual behavior, social behavior, migration, sleep, navigation, studies on animal behavior, abnormal animal behavior, and the factors that can cause these behaviors. The book will be an alternative resource for students and educators in biology, veterinary medicine, agriculture, psychology, sociology, and environmental sciences.
",isbn:"978-1-80356-936-9",printIsbn:"978-1-80356-935-2",pdfIsbn:"978-1-80356-937-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"db1dacc9284b2fc73f38fa985a586e15",bookSignature:"Dr. Volkan Gelen and Dr. Abdulsamed Kükürt",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11810.jpg",keywords:"Conditioning, Natural Behaviors, Domestication, Genetics, Environment, Physiology, Sleep Behavior in Animals, Hibernation, Circadian Rhythm, Migration, Parental Care, Reproductive",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 6th 2022",dateEndSecondStepPublish:"June 15th 2022",dateEndThirdStepPublish:"August 14th 2022",dateEndFourthStepPublish:"November 2nd 2022",dateEndFifthStepPublish:"January 1st 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr.Gelen gained his veterinary degree from Kafkas University Veterinary Faculty. 2011, he was rewarded with undergraduate term first place and he received the best poster award at the 8th national veterinary biochemistry congress. Dr. Gelen served as the director of the animal experiments research and application center.",coeditorOneBiosketch:"Dr. Kükürt is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He also served as the director of the animal experiments research and application center.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. 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He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. 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Tau is one of the most common proteins involved in neurodegenerative diseases. In many tauopathy cases, tau protein seeds and forms intracellular fibrillary tangles on itself, one of the pathological hallmarks of Alzheimer diseases [1]. The tangles formations are believed mostly due to altered posttranslational modifications of tau protein, which detaches from microtubules and binds each other forming aggregates. In several parkinsonism-associated movement disorders, including frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), mutations in tau have been identified, and those altered tau are prone to tangles formation [2]. The common involvement of tau protein in a range of neurological disorders makes it one of the most studied proteins. However, despite it has been studied for approximately 30 years since tau is coined as the major component of fibrillary tangles, concrete evidence that detail tauopathy in molecular and cellular levels is still limited [3], and most of the pathological data are obtained from studies using postmortem brain. Therefore, how tau protein and its dynamic changes affect the pathogenesis of various neurodegenerative diseases is still a mystery. Many outstanding questions are being stressed, including which posttranslational modifications are critical for it to gain toxicity, does other neurodegenerative diseases involved proteins interact with tau protein, which brain regions or cell types are most susceptive to the toxicity of tau and how the aggregates cause cellular dysfunction, and which forms of tau during the tangle formation process are toxic. In this process, some widely accepted concepts are being challenged. For example, traditionally, it is believed that hyperphosphorylation of tau induces it to detach from microtubule and increases its toxicity, but recent findings suggest some phosphorylations are protective instead [4, 5]. These findings will be emphasized in the following sections. Apparently, more efforts are needed before we can reach a definitive answer for these questions. Some exciting technological advances promise further exploration of some exist questions and more unexplored fields involving tau protein.
\nTau pathology, namely fibrillary tangles, was observed way before the protein was identified. In fact, it was Alois Alzheimer who first described the heavy burdens of this never reported feature in his demented patient back to 1906 [6]. Seventy years later, tau protein was isolated as a factor that is critical for the re-polymerization of some depolymerized tubulins to form microtubules in vitro [7]. After another 10 years, a series studies confirmed that the tangles observed in AD brain are composed of tau [3, 8, 9, 10]. Since then, tau received significant attention in AD research. Nevertheless, as researchers soon realized tau pathology in a panel of neurological dysfunction, solving the underlying mechanism of tauopathy has been regarded as a unique field of neurobiology.
\nThe expression of tau protein varies in different tissues, but the brain has the most abundant level. In brains, tau is predominately expressed in neurons but can also be detected in glial cells, especially in oligodendrocytes [11]. In neurons, tau proteins are mainly localized in axons, but they are not excluded from dendrites [12]. Functional analyses in vitro demonstrated that tau plays critical roles in both microtubules assembly and maintaining the structural stabilization [7, 13]. But not until recently, researchers are starting to understand the interactions between tau and microtubule in real-time by adopting different newly developed techniques. By fusing a Halo-tag, a dehalogenase modified to bind certain fluorescent ligand; tau could be labeled and monitored in live imaging [14]. With tubulins being labeled with photoactivatable green fluorescent protein (PAGFP), the interactions between tau and tubulins are viewed under total internal reflection fluorescence microscope (TIRF). With such high resolution and relatively short time frame, the live imaging revealed that tau moves on microtubule quickly without direction. In authors’ words, it could “hops on and off” to another microtubule in milliseconds and moves along a microtubule with little dwindle time [14, 15]. In another study, under transmission electron microscope (TEM), it was found that tau could promote the microtubule assemble by laterally crosslinking protofilaments [13]. Moreover, tau showed a preference to bind GDP-tubulin over GTP-tubulin, but the reason behind it is not understood [13].
\nTau is encoded by the gene MAPT (microtubule-associated protein tau), which is located on chromosome 17q21.
On the N terminal side (1–150), it has two N-terminal domains. Each has 29 amino acids, one from 45 to 74 and another from 75 to 103. The physiological functions of N terminal domain are largely unknown, and speculations on that including it could play roles in signal transduction as tau could co-immunoprecipitated with phospholipase C gamma through the binding sites within N terminus [18].
\nThe N terminal side is followed by two proline-rich domains, one from 151 to 198 followed by another from 199 to 243. Studies showed that this region interacts with src kinase family members, such as fyn serving for signal transductions [19, 20]. Furthermore, it was shown that tau could interact with beta and gamma actins, which are the subtypes of actins commonly seen in neurons [21]. A panel of different truncated and or mutated tau was generated to test the interactions of it with actins, and it was found that the proline-rich regions were responsible for this interaction [21].
\nThe proline-rich region is followed by microtubule binding region (244–370), which is composed of four repeated domains and each one of them contains 18 highly conserved amino acids. The microtubule binding region directly binds to tubulin, which plays the most critical role in microtubule interaction [22]. Because the N terminal side does not bind to microtubule and was thought to interact with other proteins, the N terminal side plus the first proline-rich domain is often referred as projection domain of tau. The rest residues, including the second proline-rich domain and microtubule binding domains as well as the C terminal tail, are often referred as microtubule assembly domain [23].
\nBecause the full-length tau has all these N terminal regions (2 N) and C terminal repeats (4R), it is also referred as “2N4R” tau. The rest of other tau isoforms found in brain are the combinations of either lacks one (the second N terminal domain; 1 N) or two N terminal domains (0 N) or does not contain the second microtubule-binding domain (3R). Therefore, isoforms “1N4R”, “0N4R”, “2N3R”, “1N3R,” and “0N3R” are simply denoting the major functional domains of tau [22, 23]. The dominate forms found in human brain are 2N4R and 2N3R. Under physiological conditions, the ratio of isoforms with 4R and 3R is around 1 [24]. While in pathological conditions, the expression of tau isoforms could favor one form, especially 2N4R for most tauopathies. Researchers have long noticed the ratio alterations in disease conditions, but the exact meaning and the reason behind this change are still unknown [25].
\nUnder physiological condition, tau exists in an unfolded state, and 80% of the proteins interact with microtubule in neurons [22, 26]. When tau is not interacting with other proteins, it may curl on its own, and this random curled state is believed important for preventing interactions with other tau proteins by masking the possible interacting sites [27, 28]. The protein itself is bipolar; the N-terminal side is highly negatively charged in normal physiology, while the proline-rich domain and C-terminal end are positively charged, allowing it to interact with the negatively charged C-terminal of tubulins [22, 29]. Various posttranslational modifications could alter its charge. Paired helical filaments (PHFs) are relatively acidic compared to normal full-length tau, which is believed due to the phosphorylation of the amino acid residues [30, 31]. Tau is also very hydrophilic, containing only a small portion of hydrophobic residues [27]. Both the net charge changes and a possible shift from being hydrophilic to hydrophobic are speculated of contributing to its aggregation behavior under pathological conditions [28, 31]. Also, normal tau proteins only exhibit transient secondary structures [27]. Phosphorylation of certain residues may prompt tau to form secondary structures, which is revealed by pseudophosphorylation of all the residues that could be recognized by phospho-tau specific antibodies AT8, AT100, and PHF1 and are shown by the structural changes in nuclear magnetic resonance spectroscopy [32]. But how normal tau proteins are transformed to form aggregates remains a mystery.
\nGiven that tau may exist in various forms and structures, one shall be mindful not to overstate the possible role of tau based on data derived from truncated/engineered tau, which may only have the N terminal side or the C terminal side [18, 33, 34, 35]. Nevertheless, we have gained more understanding of tau and its function from previous works, but better manipulations are needed before we can be comfortable about applying those bench-side results to tauopathies treatment.
\nTauopathies feature a variety of pathological brain defects, such as neurites dystrophy, cell loss of certain brain regions, and brain shrinkage. The patients show associated symptoms like the decline of cognitive function, memory loss, and defects of the visual system. In the postmortem brains of most affected patients, tau aggregations are commonly found.
\nThe fibrillar tangle is the hallmark of tauopathy. The formation process of this aberrant salient could generally be categorized into several stages described as follow:
It is noteworthy that most of these studies used anionic agents like heparin to induce the oligomerization of different recombinant tau isoforms or fragments to test the intrinsic properties and the effects of the modifications in vitro. But to what extent could this artificially induced tau oligomerization reflects the real pathological process is questionable. A recent study showed that heparin-induced recombinant tau tangles have little seeding ability in the wild-type mouse. In contrast, tau tangles isolated from patients have a strong seeding ability, and the pathology could spread quickly to different brain regions, shedding lights on the difference between in vitro generated tau tangles and in situ harvested tau tangles [43].
As mentioned above, tau inclusions are found in different types of cells in different tauopathies. In Alzheimer’s disease (AD), tau inclusions are found in neurons as neurofibrillary tangles (NFT). While in many other tauopathies, the inclusions are found both in neurons and glia cells. Also, the compositions of the inclusions are different. In many tauopathies, the inclusions are mainly composed by 4R tau, while in PiD, 3R tau is the dominant form in the inclusions. In AD, the ratio of 3R/4R is close to 1 albeit the expression favors 2N4R [46]. How the different tau tangles are constructed and what the chemical and physical factors attributing the assembled pattern are still an enigma. Moreover, the locations where the aggregates are first found are also different, following different transmission pathways [46]. Together these indicate that although tau aggregate is the hallmark for all tauopathies, the properties of the inclusions are different and the factors that trigger various pathological changes may also be different [43, 46].
\nNormally, the lifetime of tau is short. It was tested in cultured cells that the lifetime of tau is within 24 hours [49, 50]. It is presumed that tau proteolysis is mainly controlled by proteasomes degradation and in vitro studies also support this notion [51]. Since many endogenous proteolytic enzymes can cleave tau proteins, it is likely there is some coordination which may exist among them and also with the proteasomes [51]. Nevertheless, in tau pathology, the turnover time for tau significantly increased. It has been reported that tau phosphorylation inhibits the protein degradation [52], which could explain its pathogenic link. Recently, studies showed autophagy is involved in the digestion of tau, especially for those bulky inclusions that are probably hard to be digested by the proteasome [53]. It was found hyperphosphorylated tau co-localized with LC3 positive vesicles, a critical autophagy adaptor protein, in postmortem brains of different tauopathies [54]. More importantly, many evidence directly shows that both proteasome and autophagy systems are impaired in tauopathies, likely resulting from the assault of tau aggregation [55, 56].
\nFor proteasome-mediated degradation of tau, different studies have shown that proteasome activities are decreased in tauopathies. Both in a tauopathy animal model or AD brains, isolated tau of sarkosyl-insoluble fraction was co-immunoprecipitated with proteasome subunits [57, 58]. Furthermore, incubating proteasome with fibrillar tau or tau oligomers decreased the activities of the proteasome, whereas when it was incubated with monomer tau, the activities were not affected, demonstrating that pathological tau might cause proteasome dysfunction [57]. It was observed that the ubiquitinated protein levels are increased in a tauopathy model, and PHF tau was also ubiquitinated in both animal models and AD brains [57, 59, 60]. While these results demonstrate a nice correlation between proteasome function and tau degradation, whether the turnover of normal or pathological tau depends on proteasome or not is still unclear [61].
\nFor autophagy, it was observed that the dystrophic neuritis of postmortem AD brains contains huge amounts of autophagic-like vacuoles, which are presumably to be autophagosome or autolysosomes. These observations imply a significant upregulation of autophagy activities preceded by certain stimuli like cytoskeletal dysregulation or oxidative stress, likely causing the neurons to initiate apoptosis and contribute to neurites dystrophy [55, 56, 62]. Dense lysosome proteases staining results in AD brains also indicate defective degradation of major intracellular protein aggregates. Moreover, in the familial AD, presenilin 1 mutation is one of the most common mutations causing the disease. Traditionally, it is believed the pathogenic mechanism is that the expression of presenilin 1 mutations results in the generation of Amyloid-beta, as this molecule constitutes the active domain of γ-Secretase. However, presenilin 1 also plays a critical role in autophagy that functions as an ER chaperon transporting enzyme subunit critical for lysosome protease activation. Deletion of presenilin 1 could abolish autophagy [56]. All these results support the notion that tau aggregation may cause upregulation of autophagy activity.
\nThere are two forms of tauopathy, familial and sporadic. Familial tauopathy is linked with genetic mutations of tau, and sporadic tauopathy is often associated with altered posttranslational modifications. Since the pathogenesis of the two forms is different, so they are discussed separately in the sections below.
\nGenetic mutations of tau can cause familial tauopathies, which are commonly found in frontal temporal dementia (FTD), including a range of clinical conditions like Pick’s disease, corticobasal dementia, and progressive supranuclear palsy [63, 64]. Mutations of tau were first discovered in the late 1990s in inherited FTD families [65], and it was the first known monogenic mutations that could cause FTD [63, 64]. Epidemiological surveys showed MAPT mutations are responsible for 5–20% FTD cases [63]. Since MAPT is localized to chromosome 17 and the subject showed FTD with parkinsonism syndrome, it was named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) to refer tau mutations-associated FTD [66]. More than a hundred tau mutations have been identified, and not all of them are pathogenic. A detailed mutations list and their associated impacts can be found online at Alzforum.org [67]. Tau mutations are rarely found in Alzheimer’s disease (AD) and normally are not considered as a major genetic risk factor for the disease’s familial form. But certain mutations could contribute to the pathogenesis of AD, and some found that mutations’ pathogenicity has not been integrated yet [67, 68].
\nPathogenic tau mutations typically result in either RNA splicing variation causing the ratio change of 3R/4R or a structure change, which will further affect its binding affinity with microtubule and other proteins or promote its self-assembly [66, 67, 69]. The mutation sites cover the whole protein and could also be in the introns affecting the RNA splicing [67]. Some much more common mutations have been selected in generating transgenic models for studying tauopathies [70]. To date, 28 tauopathy mouse models have been reported according to Alzhforum.org and many of which are overexpressing models [67]. Other tauopathy animal models in
Transgenic expression of normal human tau in mouse models with either 3R or 4R forms were unable to induce significant pathological changes [75]. While with strong pan-neuronal promoters could induce more pathological features, this approach also raises a concern of overwhelmed tau expression, which may lead to possible artificial effects by causing heavy burdens on protein degradation systems, which obviously deviated from the progressive pathogenesis that is responsible for the sporadic tauopathy [75, 76, 77]. Notably, a recent study created transgenic mice expressing an N-terminal truncated tau under the control of human tau promoter so to mimic the normal expression level and by which recapitulated some major pathological features of tauopathies [76]. The authors claimed that a similarly truncated tau could be found in postmortem progressive supranuclear palsy brains, which makes this finding quite interesting.
\nIn comparison, expressing disease-linked mutant tau can induce more pronounced pathological effects, and some of the models are widely used in basic or pre-clinical research settings if not in combined with other tauopathy-related protein expression [67, 70, 75, 77]. The most commonly adopted tau mutations in transgenic animal models are P301L, P301S, R406W, and V337 M [59, 77]. All these mutants were found in FTD patients, and their expression showed reduced binding affinity to the microtubule. Importantly, all of them could efficiently induce tau filaments formations in mouse models, although the composition of the filaments may be different for different tau mutations [66, 70]. Among them, three mouse models stand out in terms of their wide usage in basic research, as well as in the pre-clinical tests of drug development. These are P301L, PS19, and rTg4510 (r for regulatable), all of which were developed in the mid-2000s [78, 79, 80]. P301L mice overexpress 2N4R tau with P301L mutation under the pan-neuronal driver Thy1 [78]. PS19 mice overexpress 1N4R tau with P301S mutation driven by mouse prion protein promoter [79], and rTg4510 adopts the tet-off system to overexpress 0N4R tau bearing P301L mutation only in the absence of tetracycline that controlled by Ca2+/calmodulin-dependent protein kinase II (CAMKII) promoter [80]. In general, rTg4510 and PS19 mice show more massive pathology burdens in comparison with to P301L. Although overt tau aggregations were observed in all three types of mice and showed cognitive defects, only rTg4510 and PS19 were reported to induce significant neuronal loss [79, 80]. PS19 mice showed severe hippocampus shrinkage at the age of 9 months, while rTg4510 mice showed gross forebrain atrophy at the age of 10 months [79, 80]. It is noteworthy that human tau expression levels were several times higher than the endogenous mouse tau levels for all three models [78, 79, 80].
\nThese data collectively show that while significant tau aggregates can be induced by expressing mutant tau, the models are different from sporadic tauopathy, especially in terms of studying the pathogenesis and treatment methods for tauopathy with a mouse. Another major concern is related to the modulation of endogenous enzymes at the time of human tau expression, which is an issue difficult to control. Some key features related to general pathogenesis process were missed from the transgenic mice models, including robust tau propagation and significant cell apoptosis [48, 81]. In one study, by injecting insoluble tau to mouse hippocampus, it was found that the seeding and propagation ability of the synthesized insoluble tau are much weaker than the insoluble fraction of isolated tau from the AD in vivo [48]. Together, it shows there is still a long way to go before using these animal models to find a strategy for detour tauopathy.
\nRecent advances in human stem cell research may provide a solution for tauopathy and related research. By grafting human stem cell-derived neuron to express amyloid-beta in mouse brain, a study revealed that the human neurons are more susceptible to the toxicity of amyloid-beta than mouse neurons [81]. This observation proved the discrepancy of cells from the two organisms. Therefore, if the quality of the grafted cells and the surrounding microenvironment represent the physiological conditions in the human brain, shall we also expect human neurons are more susceptible to the toxicity of tau?
\nMost patients who suffer from tauopathies carry wild-type MAPT. Therefore, posttranslational modifications of tau are believed to be the key of tau pathogenesis and have been the major area of tauopathy research for years. Understanding the posttranslational modifications of tau not only helps us to pin down the pathogenic mechanism but also offers a viable path for drug screen by targeting certain enzymes that modifying tau. As mentioned in the above sections, altered posttranslational modifications of tau could render the protein to lose its native unfolded structure and by which to promote aggregate formation. In this process, the modifications also changed the interactions between tau and other proteins in addition to tubulins. So far, 10 types of tau posttranslational modifications have been documented [82], among which phosphorylation and truncation are most found, representing the majority of the modifications, while other modifications (ubiquitylation, oxidation, glycosylation, glycation, nitration, acetylation, and sumoylation) are either not often discussed in this setting or just recently founded. In total, over 100 sites on a tau protein have been proposed that could be modified if not considering the truncation [83].
\nIn one of the pioneer studies aimed to prove that neurofibrillary tangles are made of tau, the researchers found treating the tissue section with phosphatase could dramatically increase the antibody labeling of tau on the tangles [9], and the researchers coined the staining as “atypical phosphorylated” tau. Since then, the “hyperphosphorylated” tau under pathological conditions received a great deal of attention. Many protein kinases have been proposed to play roles in tau phosphorylation, and some of them have been confirmed by in vivo studies [9, 84]. Recent developments have proposed to try out some kinase inhibitors as potential tauopathy therapeutics [85]. For a 2N4R tau protein, it consists of 45 serine residues, 35 threonine residues, 12 histidine residues, and 5 tyrosine residues. Current postulated phosphorylation sites have essentially covered most of the available sites, and indeed many of these residues are found being phosphorylated under physiological conditions. Therefore, the widespread, and likely dynamic, tau phosphorylation appears to serve for certain uncovered functions. Nevertheless, it also indicates that the differences in general phosphorylation and changes of phosphorylation state in certain residues may play a critical role in tauopathies [83, 84]. Moreover, hyperphosphorylated tau could also be detected in other pathological conditions aside from tauopathy. It was found that phosphorylated tau proteins are co-aggregated with alpha-synuclein in Parkinson disease and Lewy bodies dementia [86]. In some reports, phosphorylated tau aggregation can be found in Huntington disease and amyotrophic lateral sclerosis brains [87, 88]. In traumatic brain injury patients, the levels of phosphorylated tau, but not total tau, are significantly increased [89]. Recently, it is also suspected that tau phosphorylation may play a role in type 2 diabetes, rendering the patients incline to have cognitive defects [90]. These data collectively indicate hyperphosphorylation of tau has a strong correlation with a variety of brain pathologies, not just tauopathies.
\nHowever, the scenario of pathogenesis in tau hyperphosphorylation is more than merely the activation of some kinases or down-regulation of some phosphatase. As a matter of fact, different kinases are interacting, regulating, and even competing with each other for acting or interfering on same sites [91, 92], it is conceivable that the dynamics of transferring/removing phosphate groups on tau protein could be complex. Besides, kinases have multiple substrates, and some of them have important roles in normal cell functions [91]. The activities change of a kinase could lead to a domino effect toward the change of cellular activities. Last but not least, not all phosphorylations are toxic as some of them are required for normal tau functions, and certain sites phosphorylation may even serve as a protective effect in tauopathies [4, 5]. Therefore, a systemic dissection of disease-prone tau phosphorylations and their regulation is a pre-requisite before aiming such complex regulation for a therapeutic exploration.
\nTo study the phosphorylations, many antibodies recognizing specific phosphorylated residues on tau have been generated, and a list can be found on Alzforum.org [93]. For analyzing the effect of phosphorylation, recombinant MAPT constructs bearing site-specific mutations to mimic potential phosphorylation status of tau are regularly utilized in tauopathy research, which provides some insights regarding the genotoxic and structural impacts upon modifications [94]. However, even with the recombinant tau with or without pseudo-phosphorylations, it is hard to generate significant polymerization in vitro postulated due to a lack of “nucleation” process, although pseudo-phosphorylated tau may be prone to aggregate [95].
\nIt is well acknowledged that glycogen synthase kinase 3 beta (GSK3β) plays a pivotal role in tau hyperphosphorylation [96, 97]. An early study showed that recombinant tau and microtubule-associated GSK3β that were harvested from bacterial lysates could be co-eluted in immunochromatography with anti-GSK3β and co-immunoprecipitated [98]. A subsequent study found active GSK3β co-localized with tau inclusions in tauopathy brain tissues, and the amount of active GSK3β was significantly increased in the patients [99]. Moreover, in vitro study found active GSK3β could efficiently facilitate tau tangles formation after tau are initially polymerized in the presence of arachidonic acid [100]. It should be noticed that effects of GSK3β in tau-mediated toxicity are unsettled; a report found that overexpression of GSK3β in tauopathy models may not necessarily lead to shortened lifespan or accelerate pathological burden in the animal model [101]. In contrast, results from some studies hinted that activation of GSK3β is critical for exacerbating tauopathy [102, 103]. These observations should be interpreted carefully as the tau models used or compared are not in the same background.
\nGSK3β is a constitutively active protein that can autophosphorylate its tyrosine residues like Tyr 216 to increase the enzyme stability [104]. The activity of GSK3β is mainly regulated by insulin and Wnt signaling pathways [105]. When insulin pathway is activated, protein kinase B/Akt will be activated, which in turns phosphorylate serine 9 on GSK3β and causes its inactivation. In the case of activated Wnt signaling pathway, the inhibition of GSK3β activity would alleviate the degradation of β-catenin, whose nuclear translocation is responsible for the downstream genes activation of the pathway, but the precise mechanism regarding tauopathy modulation is still unknown [106, 107]. Nevertheless, a report showed both pathways are being downregulated in AD [96].
\nIt was postulated that the phosphorylation by GSK3β requires the priming of adjacent proline residue as GSK3β is a member of proline-directed kinase family [84]. So far, more than 40 sites in tau, either serine or threonine, have been reported could be phosphorylated by GSK3β, and some of them are exclusively found in pathological conditions [84]. Among these sites, in vitro study first identified tau could be phosphorylated by GSK3β at the sites S202, S396, and S404 [108]. Since then, different studies reported many different phosphorylation sites with the availability of the corresponded phospho- site-specific antibodies. Some in vitro/in vivo studies later confirmed that frequent phosphorylation sites include S262, S396, and S404 [101, 109]. The phosphorylation of some residues may play important roles in affecting the binding affinity between tau and tubulins or regulating synaptic plasticity [4, 110, 111]. However, it is still unknown which residues are most frequently phosphorylated by GSK3β under different pathological states in contrast to normal condition, and if there is any protective effect by GSK3β phosphorylation against tau from forming the aggregates. Probing these questions is a major challenge but will help our understanding of the role of GSK3β in tau-associated disease conditions.
\nBesides GSK3β, other kinases such as p38, cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), casein kinase (CK), protein kinase A (PKA), and Ca2+ /calmodulin-dependent protein kinase II (CAMKII) have been reported to involve in directing tau phosphorylation [4, 84, 112, 113, 114]. Although the possible phosphorylation sites mediated by these kinases, especially in tauopathy conditions, may be less than GSK3β, it is fair to say that their roles in modulating tau toxicity are less well studied, thus whether the modulations by these kinases are less critical than GSK3β in tauopathy remain to be addressed. Indeed, a recent study found P38γ overexpression could ameliorate excitotoxicity induced by amyloid-beta in a tau-dependent manner. Further experiments showed that the effect was mediated by the phosphorylation of tau S205 through the action of P38γ, and the phosphorylation of this residue could abolish the interaction between tau and Fyn and PSD95, which otherwise could form a complex interacting with NMDA receptor to induce excitotoxicity [4]. This result strongly suggests different kinases may have different roles in tauopathy, and not every up-regulated tau phosphorylations under pathological conditions are for enhancing the toxicity. Given such complex modifications, more studies shall emphasize the difference of activity among these kinases under physiological and pathological conditions, as another recent study showed that ERK1/2 does not phosphorylate tau under physiological condition [115]. Furthermore, since the pathology development in tauopathy usually takes years, whether there is any sequential activation of the kinases appears to be another intriguing issue. Indeed, a recent study examining tau-staining in the postmortem AD brains of different stages showed that N-terminal side of tau is preferentially phosphorylated at early stages [116].
\nProteases including calpain and caspases are involved in tauopathy pathogenesis [117, 118]. They are activated in tauopathies, either directly cleave tau or indirectly cleaving its associated kinases, affecting the structure/function of tau [118, 119, 120, 121]. While less commonly reported, other proteases are suspected to play roles in tauopathy-related protein truncations [122].
\nTwo truncated tau proteins have caught attention in tauopathy, as they are abundant in the postmortem AD brains [123]. In fact, truncated tau could also found in other tauopathies beyond AD. Importantly, researchers used live multiphoton imaging combined with thioflavin S administration and a dye for activated caspases and observed that the tangle formation was preceded by caspases activation in a classic P301L tauopathy mice (tg4510) [124], indicating a close tight between tau cleavage and toxicity. Currently, two truncation sites, E391 and D421, have been characterized and both are on the C-terminus. We also learned that the truncation on D421 is mediated by caspases, mainly by Caspase-3. D421-truncated tau is associated with lysosome in AD brain, indicating that the truncated tau may be favored to be degraded through autophagy or maybe impairing the autophagy system [124]. However, it is still unclear what kind of proteases are responsible for the cleavage at E391, albeit the site was the first-identified cleavage site in tau, and its C-terminal cleavage product appears in PHF core [118, 123, 125, 126, 127, 128]. While various reports have suggested that caspase and calpain are capable of cleaving tau and both present as an early event in pathogenesis and could aggravate tau toxicity [124, 129, 130], an important issue should be solved in studying tau truncation that is whether the aberrant increase of tau truncation is a consequence of tau aggregation or actually the cause that induces tau aggregate formation [124].
\nCalpains are cytosolic calcium-dependent cysteine proteases. In an analysis of a postmortem brain lysates, calpain 1 was found to activate at early stages of AD, close to the stage when GSK-3β and CDK5 were activated [130]. The human genome has two identified calpain family members, calpain 1 and calpain 2. Calpain 1 is mainly expressed by neurons and thus received most attention by researchers concerning neurodegeneration, and calpain 2, on the other hand, is mostly expressed by glial cells. Studies have shown that calpain 1 can cleave p35 to generate p25, which could further induce prolonged activation of CDK5 [120]. Calpain can also cleave GSK3β to generate a C-terminal truncated form, which makes its inhibitory site less likely to be phosphorylated and thus produces a dominant-active GSK3β [121, 131]. Also, calpain can directly process tau and generate small fragments. However, the physiological or pathological impacts of those cleaved calpain products in regarding tauopathy are unclear, and the calpain-mediated tau cleavage site(s) remains elusive [120, 127, 132].
\nAmong the caspases, executive caspases, especially caspase-3, play a critical role in the direct processing of tau at the site D421. As mentioned above, D421-truncated tau can be found in AD brains, and this cleaved form is suspected to facilitate tau aggregate formation and thus enhancing the toxicity [124, 129, 133, 134]. Phosphorylation at S422 could prevent the truncation, which could be mediated by JNK and TTBK-1 [114, 135, 136]. Nevertheless, JNK and TTBK-1 could also phosphorylate tau at the sites other than S422, which complexes the protective scenario [114, 136]. Caspase 3 can also regulate the phosphorylation of tau through cleaving and activates protein kinase B and thereby activates GSK3β [119].
\nBesides caspase-3, other caspases may involve in tauopathy as well. A recent study showed that caspase-2 could cleave tau at the site D314. This truncated tau could not participate in tau aggregation but is existing in the brains of P301L mice by a significant amount. Pseudophoshorylation of this site prevented caspase-2 cleavage and consequently caused memory and cognitive defects of the mice [137].
\nTau lysine residues could be acetylated by certain endogenous acetyltransferase, and such modulations were first demonstrated by p300 and Creb-binding protein (CBP) [138, 139]. Importantly, the insoluble tau protein fraction isolated from postmortem brains of the AD patients could be recognized by an anti-acetylated tau antibody [138]. Since then, tau acetylation studies start to emerge, and up to date, four tau acetylation sites, K174, K274, K280, and K281, have been confirmed in pathological conditions [140]. Acetylation of K280 and K281 reduced tau binding affinity to microtubules in vivo and facilitated tau aggregation in vitro [140, 141]. Moreover, acetylation of K280 exacerbated tau toxicity in a
So far, our understanding of other tau modifications is still limited [82]. Take glycosylation as an example, glycosylation of tau was only found under pathological conditions but not physiological conditions [145], indicating that this type of posttranslational modification has a significant impact toward cell function. However, probed glycosylation sites of tau are limited, and some of the proposed sites might overlap with the known phosphorylation sites, suggesting a potential competition between glycosyltransferase and phosphorylation kinases [145]. The role of glycosylation in tauopathy is unknown [82]. A recent study using
To date, no drug targeting tauopathies has entered the market [147]. Over the past two decades, a dozen representative drugs have been pursued in the clinical trials [148], and these drugs represented the major therapeutic approaches in tauopathy treatment, including tau aggregation inhibitors, tau phosphorylation-related kinase inhibitors, microtubule stabilizers, and immunotherapy against tau. However, since these strategies have yet to show significant benefit, new approaches are being probed, among which a scheme to enhancing protein homeostasis is an intriguing approach [147, 149]. Other alternative approaches including using traditional Chinese medicine are also being pursued [150].
\nFive treatment approaches mentioned above have been scrutinized in clinical trials, and only microtubule stabilization and immunotherapy against tau are still active tau aggregation inhibitors, and phosphorylation kinase inhibitors, including GSK3β inhibitors and CDK5 inhibitors, were once favored, but they showed little efficacy in clinical trials [151].
\nThe direct inhibition of tau aggregation was the major therapeutic strategy being developed and had entered the clinical trials [151]. The development of tau aggregation inhibitor was initiated in the mid-1990s. The first platform to screen the drugs was reported in 1996 with the discovery of phenothiazine, a relatively potent tau aggregation inhibitor in vitro [152]. In this platform, recombinant PHF core tau fragment was incubated in wells, by reciprocal treating the wells with recombinant full-length tau, the protease-resistant tau aggregation could form [152]. By incubating the wells with compounds, the goal was to identify inhibitors that could effectively disrupt tau aggregation through the high-throughput assay, and phenothiazine showed a strong potency [152]. Unfortunately, phenothiazine was found no efficacy in clinical trials, and it was blamed for its poor absorption and was difficult to be transported into the brain [153]. Years later, a renewed platform was designed [153]. In this platform, fibroblasts overexpressing a cocktail of different tau isoforms were incubated in wells. This setting could yield tau aggregations inside the cells, and compounds were tested to compare the labeled tau immunofluorescence as the readout [153]. Although this platform was a lower throughput, it overcame the shortages of the first platform in which cytotoxicity was unknown [153, 154]. With this platform, TRx0237 was later selected to be the lead candidate and went into clinical trials [151]. Unfortunately, the drug did not work in phase 3 as it failed to slow cognitive decline in AD patients [155].
\nBiochemically, the inhibitors could be categorized into two types, covalently and no-covalently tau aggregation inhibitors [156]. However, although they are called “tau” inhibitors, these chemicals are most likely inhibitors to other protein aggregations, and their selectivity is highly questionable [151]. Therefore, a highly selective with high-affinity tau inhibitor is still waiting to be discovered [151, 156].
\nThe aim of immunotherapy is to clear pathological tau through the immune system [157]. It could be achieved either by applying antibodies that could recognize pathological tau or by vaccination to elicit activation of antigen presenting cells and subsequently the B cells and T cells to clear up pathological tau [157, 158]. Ten years have passed since the publication of the first study on tau immunotherapy [159]. In the study, the researchers showed that inoculation of a tau peptide aa R379-L408, which covers two critical phosphorylation sites S396 and S404 that being phosphorylated in P301L tau mice, could successfully elicit endogenous immune system to generate antibodies against tau, and the animal showed ameliorated symptoms of tauopathy-related behavior and decreased tau aggregation [160]. Multiple different antibodies or vaccines aiming at different tau epitopes have been developed since then, and some have entered the early phases of clinical trials [157].
\nMolecular chaperones play important roles in protein homeostasis. It was reported that inhibiting heat shock protein 90 (Hsp90) could inhibit tau toxicity in tauopathy model [160]. The mechanism behind could involve Hsp90 stabilize p35, the activator of CDK5, GSK3β, and tau, inhibiting their degradation [160, 161]. On the other hand, Hsp70 could facilitate protein ubiquitination and degradation by the proteasome [162]. Overexpression of Hsp70 in cells could decrease tau aggregation in vitro [163]. Recently, it is also suggested that targeting co-chaperones of Hsp90 could offer another approach to ameliorate tauopathy [164].
\nSeveral traditional Chinese medicines have been suggested that might be useful for treating tauopathies [150, 165]. Huannao Yicong Decotion was shown to improve learning and memory in rat AD model. Immunolabeling showed the expression levels of GSK3β, CDK5, and TTBK1 in CA1 region of the hippocampus are downregulated in the drug treatment groups [150]. Interestingly, it was also suggested that some traditional Chinese medicines, including Huperzine A and Tianma, could induce upregulation of ubiquitin ligases, indicating that they might facilitate protein degradation through ubiquitin-proteasome pathway [166].
\nIn this chapter, we discussed major basic aspects of tauopathy, from tau normal functions to pathology formation process and from tau genetic mutations to posttranslational modifications. Finally, we discussed currently proposed tauopathy treatment methods. With the findings showing tau proteins are involved in many brain pathology conditions beyond tauopathy and more evidences showing the roles of tau in Alzheimer’s disease are critical, it is expected to receive more basic research attentions in the future [167, 168]. Better animal models tailored for different tauopathy are of pursuit, which will benefit both basic research and clinical drug developments.
\nUniversity research and teaching reactors are fundamentally intended to help prepare nuclear engineering and other students for entry into the nuclear workforce. They introduce students to the disciplined, structured environment of operating a reactor licensed by the Nuclear Regulatory Commission (NRC). They also offer students hands-on experience, provide opportunities to demonstrate the operation of reactors and a variety of the traditional applications of reactors such as neutron activation, and introduce them to the application of nuclear instrumentation, applied principles of health physics, and more. They can be useful to a wide range of people beyond university nuclear engineering students, including those from National Laboratories, utilities, regulators, and others.
The Idaho State University Aerojet General Nucleonics (AGN) model 201 nuclear reactor is an example of a very safe, low-power, solid-core reactor designed with students and teaching in mind. It was developed in the late 1950’s by AGN to satisfy the need of university nuclear engineering departments for a relatively inexpensive, safe, flexible and available reactor with a long design life. The AGN-201’s safety results from,
The small teaching reactors generally preceded the higher-power reactors at universities. As the university’s interest moved to the higher-power reactors, reactors like the AGN-201 s fell into disuse and most were decommissioned. Recently however, there has been a renewed interest in the utility of AGN-201 nuclear reactors [2]. In addition to discussing the potential uses for the AGN-201, this chapter includes discussions of the challenges of replacing obsolete components to facilitate continued operation. To address this issue, Idaho State University teamed with members of the community whose expertise in project management, instrumentation and control, licensing and other subjects complemented the university’s expertise and resources.
A nuclear reactor is an example of the integrated operation of many systems to support the operation of a nuclear core. Simple reactors can be excellent examples of the integrated operation of the core, nuclear instrument systems, the reactor operator or ‘human in the loop’ and control rods and their controls. Although the AGN-201 is a simple reactor, it can be used to measure the operation of the core and understand and gain insight into its operation. It is intended to support teaching, training and research in a wide variety of subjects. For example, human/machine interface studies could even be conducted with the operator to test novel display concepts.
The AGN-201 has a variety of attractive design features. The reactor has direct access to the core via the so-called ‘glory hole’ that runs horizontally through the reactor center. It also has a graphite thermal neutron column at the top of the reactor and beam ports in the radial portion of the graphite reflector. The core is enriched to a nominal 19.5% and given the reactor’s low power, the core should essentially never require replacement [1]. The reactor has extremely low background neutron and gamma flux levels that along with the reactor’s unusually sensitive nuclear instrument systems, facilitate a wide range of measurements including some that might not be possible in other reactors. For example, it is possible to observe individual chains of fissions when the core is just barely subcritical and flux has been allowed to decay to very low levels thus allowing measurement of the prompt neutron decay constant using Rossi’s-α method [3]. Neutron flux near the allowed maximum power level is high enough to usefully activate foils and illustrate reactor physics principles but too low to result in the accumulation of large amounts of fission products.
The AGN-201 provides and supports a number of potential opportunities for demonstrations and tests that complement the theory from the classroom, research and problem solving. A wide range of demonstrations and tests can introduce students to the instrumentation and activities that are conducted by reactor engineers and reactor operators at higher-powered test and research reactors and commercial power reactors. This knowledge can help an instrumentation and control designer or engineer to produce circuits that are more forgiving of noise and to help a technician to differentiate between electronic noise and normal operation of the detector channel and be more successful in reducing noise.
The AGN-201 nuclear reactor is a solid-core reactor with no active cooling system. The core is constructed of nine 25.6-cm diameter fuel disks (see Figure 1). Four of the disks are 4-cm thick, three of the disks are 2-cm thick and two of the disks are 1-cm thick. Each 4-cm thick fuel disk contains 96 g of 235U, each 2-cm thick fuel disk contains 58 g of 235U, and each 1-ck thick fuel disk contains 29 g of 235U. The overall core height is 24 cm. A graphite reflector surrounds the core both radially and axially. The graphite reflector is 20-cm thick and has a density of 1.75 g/cm3. The reactor fuel consists of slightly less than 20 wt. % enriched uranium. The uranium is in the form of 15-micron diameter particles of UO2. The UO2 particles are pressed with 100-micron diameter polyethylene particles. The density of 235U in the UO2-polyethelyene fuel is 61 mg/cm3 and the overall uranium density in the fuel is 305 mg/cm3. The mass ratio of uranium to polyethylene is 1:3.16. The approximate critical mass of the AGN-201 reactor is 665 g 235U [1].
AGN-201 reactor core, reflector, and control rods [
The reactor uses a total of four control rods; two safety rods, one adjustable coarse rod, and one adjustable fine rod. The control rods are made from the same UO2-polyethyelene fuel as the core. To ensure safety, the fueled control rods enter the core from the bottom (see Figure 1) so that gravity, along with compressed springs, ensure rapid removal upon reactor SCRAM. The bottom four fuel disks as well as the lower reflector have holes drilled through them to accommodate the control rods.
In addition to the control rods, the AGN-201 reactor is equipped with a thermal fuse as an ultimate reactor safety shutdown device. The thermal fuse is located just below the core center line (see Figure 1). The fuse is similar in construction to the reactor fuel with two key differences. First, rather than polyethylene, the fuse uses polystyrene. Second, the density of uranium in the fuse material is double the value used in the fuel. The two differences coupled with the location of the fuse results in maximizing the fission rate in the fuse compared to all other locations in the core. In the event of a runaway power transient, heat will be generated in the thermal fuse at a greater rate than any other location in the core. As the fuse temperature rises, it will tend to soften when it reaches 100°C and will melt before any the reactor fuel reaches its melting point of 200°C. The AGN-201 reactor design has the lower portion of the core and reflector held in place by the thermal fuse. In the event of the thermal fuse melting, the lower portion of the core and reflector will move downward approximately 5 cm compared to the upper portion of the core which is stationary since it is supported separate from the thermal fuse. The net result will be a dramatic increase in neutron leakage which will terminate the transient. It must be noted that the thermal fuse is a single use safety device.
The reactor core and a portion of the reflector are contained within a gas tight core tank. The core tank is then located within the remainder of the graphite reflector (see Figure 2). Surrounding the graphite reflector is a 10-cm thick lead shield. The lead shield is primarily used for gamma ray shielding. The reactor core, reflector, and lead shielding are located within the reactor tank. A graphite thermal column is located on the top lead shielding to support experiments and measurements involving thermalized neutrons. The reactor tank is then located within a 200-cm diameter water filled tank. The radial thickness of the water is approximately 55 cm. The water filled tank is used to absorb neutrons that escape from the core.
Reactor tank assembly [
To provide access for experiments, a 2.54-cm diameter hole traverses the reactor tank, lead shielding, graphite reflector, and reactor fuel. The hole through the center of the reactor core is commonly referred to as the “glory hole”. The glory hole aluminum pipe ensures the core, reflector, lead shield, and water remain properly sealed. When not in use, the glory hole is typically open to the air atmosphere. When starting the reactor, a neutron source is placed in the glory hole and when the reactor is shut down and not in use, a cadmium neutron absorber is placed in the glory hole to ensure reactor startup cannot occur. In addition to the glory hole, there are four access ports located in the graphite reflector (see Figure 2). The access ports are 10.16 cm in diameter and penetrate through the reactor tank, lead shielding and graphite reflector. When not in use, the access ports are typically filled with graphite, lead, and wood (to simulate water).
The reactor radial thermal flux profile is provided in Figure 3. The flux profile shows a general Bessel function trend in the core region followed by an exponential drop in the reflector, lead, and water regions. It should be noted that, unlike water reflected thermal reactors, the AGN-201 reactor does not experience an increase in the thermal neutron flux as neutrons enter the reflector. This is primarily due to the difference in neutron scattering properties of water compared to graphite. The flux profile plot demonstrates the effectiveness of the neutron shielding associated with the water shielding tank. The thermal neutron flux at the outer edge of the shielding tank is four orders of magnitude lower than at the center of the reactor.
Reactor radial flux profile [
Reactivity control is carried out using four control rods. Two safety rods, each with a reactivity worth of 1.25% Δk/k ($1.68), are operated in a binary fashion. When starting the reactor, the safety rods are driven fully into the core. No intermediate stopping locations are used for the safety rods. When the reactor is SCRAMed, the safety rods are completely removed form the core. The removal mechanism relies on both gravity as well as compressed springs. A single coarse control rod with a reactivity worth identical to the safety rods (1.25% Δk/k ($1.68)) is raised into the core region during reactor startup. Typically, the coarse control rod is driven to its maximum insertion location, although there are scenarios where the coarse control rod is stopped short of the maximum insertion location. Similar to the safety rods, upon reactor SCRAM, the adjustable coarse control rod is rapidly ejected from the core by relying upon gravity and compressed springs. Finally, the fine control rod has a reactivity worth of 0.31% Δk/k ($0.42). The fine control rod is typically driven into the reactor until criticality occurs. Adjustments in the coarse control rod and the fine control rod can then be made to adjust the desired reactor power. Unlike the safety rods and the coarse control rod, the fine control rod is not rapidly ejected from the core when the reactor is SCRAMed. Rather, the fine control rod is driven out of the core at the same rate that it can be driven into the core.
Three monitoring channels are used in the ISU AGN-201 reactor. The three monitoring channel detectors are located within the water filled reactor tank as shown in Figure 4. The AGN-201’s nuclear instrumentation consists of three different nuclear instrument channels and offer students the opportunity to understand the functions performed by separate portions of the circuit as the incoming signal is processed. Students can study the nuclear instrument channels in a laboratory and then observe them at the reactor.
Reactor assembly plan view [
The three channels are comprised of commercial-grade components. They are more accessible than power plant channels to students and others who wish to study them and their operation over a wide range of neutron flux at an actual reactor. Students can study the instrument systems and their theory and design, and then observe the systems in operation at a wide range of neutron flux. Analog and digital designs of nuclear instrument systems, with a variety of neutron detectors, can be evaluated by using the AGN-201. The AGN-201’s nuclear instrumentation consist of the three commonly-found types of nuclear instrument channels that follow the same operating approaches and perform the same functions as the nuclear instrument channels typically found in most reactors. Each channel has a unique but complementary principle of operation. Together, they provide the reactor operators and others with indications of reactor power and the rate of change in power over the entire operating range. Of course they also supply signals for reactor trips.
Channel 1 is the startup, source range, channel and uses a BF3 filled proportional counter. The source range channel illustrates a standard approach that allows the source range channel to display a very low neutron flux in the presence of significant gamma radiation. A proportional-type BF3 neutron detector produces pulses when gamma radiation and neutrons interact with the BF3 that fills the detector. The pulses are amplified and shaped, the lower-amplitude pulses due to gamma interactions within the detector are rejected while the remaining higher-amplitude pulses from neutron interactions are further amplified and displayed. The channel displays count rates from the reactor without a source to well above critical. Channel 1 is designed to initiate a SCRAM signal for low power situations when the count rate falls below the setpoint.
Channel 2 is used to monitor the reactor power using a log scale as well as for indication of the reactor period. The channel 2 detector is a BF3 filled ionization chamber. Channel 2 generates a SCRAM signal when the reactor power falls below 3 x 10−13 W or when the reactor power exceeds 5 W. Additionally channel 2 generates a scram signal if the reactor period is less than 5 seconds. The wide range logarithmic neutron instrument channel (channel 2) illustrates a standard approach that allows the channel to detect and display a current signal that is proportional to power over 7 decades. Channels 1 and 2 rely on different applications of wide-range logarithmic amplifiers. The source range nuclear instrument channel’s wide-range logarithmic amplifier converts the frequency of incoming pulses from neutron interactions to voltage. The wide range logarithmic current channel’s amplifier converts a direct current to a voltage. In both cases, variations in count rate or current level that are due to the normal and expected variations in neutron flux are often misinterpreted as ‘noise’ that can lead to the period meters having too much variation to be useful indicators to the reactor operators, and the period circuits spuriously tripping. Circuit designers frequently assume the neutron signal is relatively constant and do not anticipate the large noise component that is inherent due to sources. The AGN-201 provides the actual variations in neutron flux that drive oscillations in period meters and indications of reactor power and can be used to evaluate the effect of circuit modifications to reduce the amplitudes of the oscillations.
Channel 3 is used to monitor reactor power using a linear scale. The channel 3 detector is a BF3 filled ionization chamber. Channel 3 generates a SCRAM signal when the reactor power exceeds 5 W or whenever the linear rotating switch indicator is less than 5% or greater than 95% of full scale.
Figure 5 shows the SCRAM circuit arrangement for the three monitoring channels. It is important to recognize that the SCRAM circuit arrangement is a single signal SCRAM [4]. If any one of the channels identifies a situation that triggers a SCRAM, the reactor will be SCRAMed. That is, the AGN-201 SCRAM circuit is not a two-out-of-three arrangement.
SCRAM circuit arrangement [
In addition to the monitoring channels, a series of additional interlock circuits are used to prevent reactor startup or to SCRAM the reactor in the event of undesired situations (see Figure 6) [4]. The reactor shielding tank water temperature is monitored to ensure that the maximum allowed excess reactivity is not exceeded. If the reactor water temperature falls below 15°C the reactor excess reactivity is unacceptably large and reactor operation is prevented or discontinued. The reactor shielding tank water level is monitored to ensure sufficient shielding is present. Finally, a seismically activated switch is used to prevent reactor operation or discontinue reactor operation in the case of a seismic event. Similar to the reactor monitoring channels, the interlocks follow a series approach so that if any one of the interlocks is triggered, the reactor will not be allowed to operate.
Interlock circuit [
The reactor is operated from a relatively simple console located in the same room as the reactor. The original console was used for approximately fifty years. In 2020, the original console was replaced with an upgraded console (see Figure 7). The primary motivation for upgrading the console centered on the use of vacuum tubes for the SCRAM circuits in the old console. Obtaining replacement vacuum tubes became very difficult since these items are no longer manufactured in large quantities. The upgraded console uses solid state relays rather than vacuum tubes. In addition to the use of solid-state relays, the upgraded console has all new wiring, instrumentation, switches, and knobs.
Upgraded console installed in 2020 [
While the AGN-201’s core will essentially never be exhausted, support systems such as the instrument systems and their neutron detectors, reactor controls and control rod drives require periodic upgrading. The current financial state of universities and the perceived difficulty in conforming to regulatory requirements tends to encourage using the original 60-year-old tube-based control systems and other equipment until their failure rates leave no choice but to modernize. The cost of the engineering and manufacturing of upgraded instrumentation and equipment by outside firms can be too great for universities. Idaho State University recruited community volunteers with experience in project management and expertise in the design, construction, operation and startup of instrumentation and control, licensing of reactors and other relevant subjects for the university’s second attempt to replace the original tube-based control system. The first attempt involved the design and construction of a complex, multiple-level printed circuit board that could not easily be modified. The second and successful attempt used a breadboard approach of circuit boards with holes that could be used to mount components. The second attempt had very few changes to the design, a likely result of the lifetimes of experience of the community members in designing, repairing and maintaining analog systems. One of the main considerations was if the replacement system was to be analog or digital. The advantages and disadvantages of replacing the existing analog control system with a functionally equivalent analog system or attempting to replace it with a digital system were weighted. A replacement analog functional replacement appeared to be simpler and easier from a regulatory standpoint.
From a lifecycle cost standpoint, the analog system’s lifetime was envisioned to be decades, whereas digital technology is rapidly advancing, and the lifetime of a digital system was envisioned to be a few years. Analog enjoys far superior cyber security than digital, and maintaining cyber security appeared to be an unnecessarily potential burden to the university. It was decided to replace the system under a 10 CFR 50.59 evaluation. The community expert in licensing helped write the 10 CFR 50.59 document and helped ensure applicable codes and standards had been followed. The community member also purchased and donated some of the components. Another community member and two graduate students worked with the community members to document the project in their thesis. One of the community members became the Project Manager and kept the project moving even during the height of the COVID-19 pandemic shutdown. He also reviewed the design and construction and assisted with troubleshooting. The collaboration of community and university personnel worked well to produce and complete the replacement instrumentation and had the time to transfer knowledge. It is anticipated that the same model will be applied to other modernization efforts going forward.
The nuclear instrument systems, convert the neutron flux at the detectors adjacent to the core into instrument readings that the operator interprets to control the core. Each part of the loop can be tested. The neutron flux at neutron detectors is often assumed by designers to be essentially constant at a given power level, whereas from very low to moderate levels of neutron flux, such as found during very low power and shutdown operation, the neutron flux can vary considerably in amplitude in a random manner. The random manner results from the characteristic random nature of the decay of neutron sources that supply the reactor with neutrons at low power and shutdown.
One consequence of the variation in neutron flux is that it appears as an unwanted variation in the display of a channel and might result in inadvertent period trips. Nuclear instrument channel ‘noise’ is generally considered an unwanted (and often misunderstood) variation in a signal. It can be electronic noise that is externally introduced to the circuit and must be minimized so it does not distort the true readings or the ability of the reactor operator to identify the average signal. It can also be due to the normal random decay of a neutron source, where it is a valid part of the signal. It can be very difficult to visually identify if the noise is due to the valid operation of the core, or if it is due to electrical interference.
A statistical test called the ‘Chi-Squared’ test can be applied to data from pulse-type channels such as the startup channel. A Chi-Squared test is often used at power reactors to verify the startup channels and any temporary startup-range neutron detectors used for loading fuel are displaying counts from neutrons rather than noise. The Chi-Squared test will identify if the noise is electronic interference or valid and due to a neutron source, although it will not identify the source of the electric noise.
The AGN-201 offers the opportunity for training and evaluating the nuclear instrument channels with a very low neutron signal, lower than typically encountered at commercial power reactors. The neutron flux at a detector must be low enough that the channels will display changes in signal (jumps) from individual neutron interactions, and the channels must support attaching a scaler-timer. The test is useful when the AGN-201 is shut down and a neutron source is supplying neutrons. If neutron flux is low enough, as it is when the neutron source is inserted, even the channel 2 and 3 ion chambers might be evaluated with the Chi-Squared test. In both cases, a scaler-timer is required to total the counts in a given time interval.
The AGN-201 offers a unique opportunity to explore the variations the current signal of a current neutron instrument channel without the time pressure and limitations on connecting test instruments at a power plant. A properly designed test can demonstrate that current signals from a neutron detector consist of a number of pulses of very small electrical charges, each resulting from the individual disassociation of B10 upon absorbing a neutron.
Teaching-reactors such as the AGN-201 provide the opportunity to measure a wide range of characteristics, and to gain experience and practice in conducting the same measurements that are performed at power reactors during low power physics testing following the loading of the first core, following refueling, and even during power operation to characterize the stability of the reactor. The tests generally involve changing a parameter such as reactor temperature or control rod position, and observing the corresponding change in rate of change in reactor neutron flux. Commercial reactors use a so-called ‘Reactivity Computer’ to infer the change in reactivity from a change in a parameter. The AGN-201 allows students to build, operate and evaluate the operation of analog and digital reactivity computers themselves [5, 6].
The AGN-201 could be used to evaluate and improve test procedures that would be used on future first-of-a-kind reactors, and to train future reactor engineers and other operating staff. In addition to gaining experience and practice in conducting the measurements, students can develop the skills required to write test procedures and to conduct high-quality test programs in a low-risk environment. The AGN-201 can also potentially offer realistic simulations of conditions at other reactors so newly written test procedures can be conducted and improved prior to being used at the reactor. Test engineers, reactor operators and others, including regulators, from other facilities can benefit from the training available at the AGN-201. The AGN-201 can be useful in observing the principles and some of the parameters being tested at other reactors, thereby allowing the test procedures to be validated and problems discovered.
The AGN-201 operates at very low power levels (microwatt range), often termed ‘zero-power’ where its operation closely resembles most other reactors when they are operated at low power levels, below the point of adding sensible nuclear heat. Even at power reactors, many of the core physics measurements that are made following refueling or core alterations occur with the core subcritical or with the reactor just critical on delayed neutrons at low power level. They include monitoring the core during shutdown operation, while core alterations during refueling are being made, during the approach to criticality, and reactor state point measurements and core physics parameter measurements in a suite of ‘low power physics tests.’ Some measurements are made at both low power and at-power, and only a few are restricted to high power operation. The AGN-201 is therefore capable of providing conditions for most of the core physics measurements found at power reactors [7].
The explanations and demonstrations of the theory and measurement techniques of subcritical core physics can be of interest to reactor physicists, instrumentation and control technicians and engineers, operators and managers of nuclear facilities, health physicists and criticality safety personnel. The phenomena of subcritical multiplication of source neutrons requires a ‘multiplying medium,’ neutron source and neutron detector. The common technique that is used at reactors is an ‘inverse multiplication ratio’ or ‘1/M’ plot. The increase in count rate as control rods are moved in steps, and corresponding decrease in ‘1/M’ plot are readily apparent. The plot is typically used to infer the point of criticality, in this case the position of the control rods. The reactivity of the AGN-201’s control rods have been characterized well enough to illustrate the increases in count rate as positive reactivity is added. The demonstration can be relevant for power reactors to illustrate monitoring techniques during core alterations such as fuel loading and about establishing boron dilution warning setpoints. At pressurized water reactors with a soluble boron shim, the source range channels include the ability to establish a setpoint whose warning will help operators stop a dilution that could lead to an inadvertent reactivity change. The count rate at typical alarm setpoints can be low enough that the random variations in neutron production by the source becomes apparent. The resulting variation in source range channel readings, coupled with the requirement for a response time, can make it difficult to establish a setpoint that provides for enough warning but does not have false alarms.
Subcritical measurements to measure the values of parameters that formerly were measured during low power physics testing can save utilities considerable time and money. One is measuring the reactivity worth of control rods by raising and then dropping control rods, which can also be demonstrated in the AGN-201. Control rod drop times are also measured following refueling and other core alterations. The techniques and difficulties in measuring the positions of the controls during the drop, and the response of the nuclear instrumentation can be demonstrated in the AGN-201.
The state-point measurements of a reactor are measurements of parameters whose values define the operating condition, or ‘state’ of the reactor. Examples of parameters include reactor temperature and control rod positions are made to evaluate the reactivity of the reactor, and for comparison with core physics code predictions. Accurate state-point measurements are crucial in assessing the operation of the core and are made when the reactor is first brought critical after a refueling outage, and periodically throughout core life. The technique is simple and involves adjusting parameters such as control rod position, temperature and boron concentration in reactors with soluble neutron poison so the reactor is just critical at a given power level. A careful measurement, where reactor power is essentially constant, provides the best data. The AGN-201 allows operators and reactor engineers to explore their ability to establish just critical conditions, and to compare the measurements of parameters with calculations.
Low power physics measurements are conducted with a critical reactor whose power level is below the point of adding observable sensible nuclear heat, also known as ‘reactors without feedback.’ The measurements include the state-point measurement mentioned earlier, control rod reactivity worth, moderator temperature measurements, core stability measurements using a ‘core oscillator’ with variable, regular changes in reactivity, delayed neutron lifetime, irradiation of metallic foils to determine reactor power and more.
The operation of the AGN-201 is licensed and regulated by the Nuclear Regulatory Commission. The reactor and its conduct of operations are periodically inspected, particularly its documentation, and orderly documentation requires timely, accurate, truthful completion of forms, operating logs and more. Operating a nuclear reactor requires developing the valuable skills of discipline, focus and attention to detail, communication and more. The AGN-201 requires the same attitudes and abilities as higher-power test reactors. The full force of regulations is applied to the AGN-201. The opportunity to operate a nuclear reactor, regardless of size, is a unique experience that can benefit people who choose to put forth the time and effort. Students have opportunities to participate in a disciplined, regulated environment that is required of operators of a nuclear reactor that can shape their outlook on life and work ethic at a pivotal point in their lives. Students and other potential operators are invited to study, pass exams, and be responsible for the operation of a nuclear reactor providing a valuable and unique experience for those considering entering the field of nuclear power.
The Idaho State University AGN-201 reactor is a very safe, low-power, solid-core reactor designed with students and teaching in mind. It was developed in the late 1950’s by AGN to satisfy the need of university nuclear engineering departments for a relatively inexpensive, safe, flexible and available reactor with a long design life. The AGN-201 reactor is well suited for teaching and research activities. The solid-core AGN-201 reactor requires no active cooling system, uses a simple shielding arrangement, and the very low operating power results in trivial burnup providing an operating lifetime exceeding many decades. The AGN-201 reactor is used to help prepare nuclear engineering and other students for entry into the nuclear workforce. The reactor introduces students to the disciplined, structured environment of operating a reactor licensed by the Nuclear Regulatory Commission. The reactor offers students hands-on experience, provides opportunities to demonstrate the operation of reactors and a variety of the traditional applications of reactors such as neutron activation, and introduces them to the application of nuclear instrumentation, applied principles of health physics, and more. With the recently installed reactor console upgrade, the ISU AGN-201 reactor is poised to serve students for many decades to come.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. 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MRI is commonly used once treating brain, prostate cancers, ankle and foot. The Magnetic Resonance Imaging (MRI) images are usually liable to suffer from noises such as Gaussian noise, salt and pepper noise and speckle noise. So getting of brain image with accuracy is very extremely task. An accurate brain image is very necessary for further diagnosis process. During this chapter, a median filter algorithm will be modified. Gaussian noise and Salt and pepper noise will be added to MRI image. A proposed Median filter (MF), Adaptive Median filter (AMF) and Adaptive Wiener filter (AWF) will be implemented. The filters will be used to remove the additive noises present in the MRI images. The noise density will be added gradually to MRI image to compare performance of the filters evaluation. The performance of these filters will be compared exploitation the applied mathematics parameter Peak Signal-to-Noise Ratio (PSNR).",book:{id:"6144",slug:"high-resolution-neuroimaging-basic-physical-principles-and-clinical-applications",title:"High-Resolution Neuroimaging",fullTitle:"High-Resolution Neuroimaging - Basic Physical Principles and Clinical Applications"},signatures:"Hanafy M. Ali",authors:[{id:"213318",title:"Dr.",name:"Hanafy",middleName:"M.",surname:"Ali",slug:"hanafy-ali",fullName:"Hanafy Ali"}]},{id:"46296",doi:"10.5772/57398",title:"Physiological Role of Amyloid Beta in Neural Cells: The Cellular Trophic Activity",slug:"physiological-role-of-amyloid-beta-in-neural-cells-the-cellular-trophic-activity",totalDownloads:5952,totalCrossrefCites:19,totalDimensionsCites:32,abstract:null,book:{id:"3846",slug:"neurochemistry",title:"Neurochemistry",fullTitle:"Neurochemistry"},signatures:"M. del C. Cárdenas-Aguayo, M. del C. Silva-Lucero, M. Cortes-Ortiz,\nB. Jiménez-Ramos, L. 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Forster, Andrew M. Novick, Jamie L. Scholl and Michael J. 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Particularly in the case of motor imagery BCIs, users may need several training sessions before they learn how to generate desired brain activity and reach an acceptable performance. A typical training protocol for such BCIs includes execution of a motor imagery task by the user, followed by presentation of an extending bar or a moving object on a computer screen. In this chapter, we discuss the importance of a visual feedback that resembles human actions, the effect of human factors such as confidence and motivation, and the role of embodiment in the learning process of a motor imagery task. Our results from a series of experiments in which users BCI-operated a humanlike android robot confirm that realistic visual feedback can induce a sense of embodiment, which promotes a significant learning of the motor imagery task in a short amount of time. We review the impact of humanlike visual feedback in optimized modulation of brain activity by the BCI users.",book:{id:"6610",slug:"evolving-bci-therapy-engaging-brain-state-dynamics",title:"Evolving BCI Therapy",fullTitle:"Evolving BCI Therapy - Engaging Brain State Dynamics"},signatures:"Maryam Alimardani, Shuichi Nishio and Hiroshi Ishiguro",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"},{id:"231131",title:"Dr.",name:"Maryam",middleName:null,surname:"Alimardani",slug:"maryam-alimardani",fullName:"Maryam Alimardani"},{id:"231134",title:"Dr.",name:"Shuichi",middleName:null,surname:"Nishio",slug:"shuichi-nishio",fullName:"Shuichi Nishio"}]}],mostDownloadedChaptersLast30Days:[{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:193437,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. Vaccaro",authors:[{id:"91165",title:"Prof.",name:"Vafa",middleName:null,surname:"Rahimi-Movaghar",slug:"vafa-rahimi-movaghar",fullName:"Vafa Rahimi-Movaghar"}]},{id:"63258",title:"Anatomy and Function of the Hypothalamus",slug:"anatomy-and-function-of-the-hypothalamus",totalDownloads:4646,totalCrossrefCites:6,totalDimensionsCites:12,abstract:"The hypothalamus is a small but important area of the brain formed by various nucleus and nervous fibers. Through its neuronal connections, it is involved in many complex functions of the organism such as vegetative system control, homeostasis of the organism, thermoregulation, and also in adjusting the emotional behavior. The hypothalamus is involved in different daily activities like eating or drinking, in the control of the body’s temperature and energy maintenance, and in the process of memorizing. It also modulates the endocrine system through its connections with the pituitary gland. Precise anatomical description along with a correct characterization of the component structures is essential for understanding its functions.",book:{id:"6331",slug:"hypothalamus-in-health-and-diseases",title:"Hypothalamus in Health and Diseases",fullTitle:"Hypothalamus in Health and Diseases"},signatures:"Miana Gabriela Pop, Carmen Crivii and Iulian Opincariu",authors:null},{id:"57103",title:"GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets",slug:"gaba-and-glutamate-their-transmitter-role-in-the-cns-and-pancreatic-islets",totalDownloads:3576,totalCrossrefCites:4,totalDimensionsCites:10,abstract:"Glutamate and gamma-aminobutyric acid (GABA) are the major neurotransmitters in the mammalian brain. Inhibitory GABA and excitatory glutamate work together to control many processes, including the brain’s overall level of excitation. The contributions of GABA and glutamate in extra-neuronal signaling are by far less widely recognized. In this chapter, we first discuss the role of both neurotransmitters during development, emphasizing the importance of the shift from excitatory to inhibitory GABAergic neurotransmission. The second part summarizes the biosynthesis and role of GABA and glutamate in neurotransmission in the mature brain, and major neurological disorders associated with glutamate and GABA receptors and GABA release mechanisms. The final part focuses on extra-neuronal glutamatergic and GABAergic signaling in pancreatic islets of Langerhans, and possible associations with type 1 diabetes mellitus.",book:{id:"6237",slug:"gaba-and-glutamate-new-developments-in-neurotransmission-research",title:"GABA And Glutamate",fullTitle:"GABA And Glutamate - New Developments In Neurotransmission Research"},signatures:"Christiane S. Hampe, Hiroshi Mitoma and Mario Manto",authors:[{id:"210220",title:"Prof.",name:"Christiane",middleName:null,surname:"Hampe",slug:"christiane-hampe",fullName:"Christiane Hampe"},{id:"210485",title:"Prof.",name:"Mario",middleName:null,surname:"Manto",slug:"mario-manto",fullName:"Mario Manto"},{id:"210486",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Mitoma",slug:"hiroshi-mitoma",fullName:"Hiroshi Mitoma"}]},{id:"35802",title:"Cross-Cultural/Linguistic Differences in the Prevalence of Developmental Dyslexia and the Hypothesis of Granularity and Transparency",slug:"cross-cultural-linguistic-differences-in-the-prevalence-of-developmental-dyslexia-and-the-hypothesis",totalDownloads:3625,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"673",slug:"dyslexia-a-comprehensive-and-international-approach",title:"Dyslexia",fullTitle:"Dyslexia - A Comprehensive and International Approach"},signatures:"Taeko N. Wydell",authors:[{id:"87489",title:"Prof.",name:"Taeko",middleName:"N.",surname:"Wydell",slug:"taeko-wydell",fullName:"Taeko Wydell"}]},{id:"58597",title:"Testosterone and Erectile Function: A Review of Evidence from Basic Research",slug:"testosterone-and-erectile-function-a-review-of-evidence-from-basic-research",totalDownloads:1373,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Androgens are essential for male physical activity and normal erectile function. Hence, age-related testosterone deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for erectile dysfunction (ED). This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function. Testosterone affects several organs and is especially active on the erectile tissue. The mechanism of testosterone deficiency effects on erectile function and the results of testosterone replacement therapy (TRT) have been well studied. Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.",book:{id:"5994",slug:"sex-hormones-in-neurodegenerative-processes-and-diseases",title:"Sex Hormones in Neurodegenerative Processes and Diseases",fullTitle:"Sex Hormones in Neurodegenerative Processes and Diseases"},signatures:"Tomoya Kataoka and Kazunori Kimura",authors:[{id:"219042",title:"Ph.D.",name:"Tomoya",middleName:null,surname:"Kataoka",slug:"tomoya-kataoka",fullName:"Tomoya Kataoka"},{id:"229066",title:"Prof.",name:"Kazunori",middleName:null,surname:"Kimura",slug:"kazunori-kimura",fullName:"Kazunori Kimura"}]}],onlineFirstChaptersFilter:{topicId:"18",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82953",title:"Early Visual Areas are Activated during Object Recognition in Emerging Images",slug:"early-visual-areas-are-activated-during-object-recognition-in-emerging-images",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105756",abstract:"Human observers can reliably segment visual input and recognise objects. However, the underlying processes happen so quickly that they normally cannot be captured with fMRI. We used Emerging Images (EI), which contains a hidden object and extends the process of recognition, to investigate the involvement of early visual areas (V1, V2 and V3) and lateral occipital complex (LOC) in object recognition. The early visual areas were located with a retinotopy scan and the LOC with a localiser. The participants (N=8) then viewed an EI, followed by the hidden object’s silhouette (disambiguation), and then, the EI was repeated. BOLD responses before and after disambiguation were compared. The retinotopy parameters were used to back-project the BOLD response onto the visual field, creating spatially detailed maps of the activity change. V1 and V2 (but not V3) showed stronger response after disambiguation, while there was no difference in the LOC. The back-projections revealed no distinct pattern or changes in activity on object location, indicating that the activity in V1 and V2 is not specific for voxels corresponding to the object location. We found no difference before and after disambiguation in the LOC, which may be repetition suppression counteracting the effect of recognition.",book:{id:"11374",title:"Sensory Nervous System - Computational Neuroimaging Investigations of Topographical Organization in Human Sensory Cortex",coverURL:"https://cdn.intechopen.com/books/images_new/11374.jpg"},signatures:"Marleen Bakker, Hinke N. Halbertsma, Nicolás Gravel, Remco Renken, Frans W. Cornelissen and Barbara Nordhjem"},{id:"82931",title:"Neuroinflammation in Traumatic Brain Injury",slug:"neuroinflammation-in-traumatic-brain-injury",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105178",abstract:"Neuroinflammation following traumatic brain injury (TBI) is an important cause of secondary brain injury that perpetuates the duration and scope of disease after initial impact. This chapter discusses the pathophysiology of acute and chronic neuroinflammation, providing insight into factors that influence the acute clinical course and later functional outcomes. Secondary injury due to neuroinflammation is described by mechanisms of action such as ischemia, neuroexcitotoxicity, oxidative stress, and glymphatic and lymphatic dysfunction. Neurodegenerative sequelae of inflammation, including chronic traumatic encephalopathy, which are important to understand for clinical practice, are detailed by disease type. Prominent research topics of TBI animal models and biomarkers of traumatic neuroinflammation are outlined to provide insight into the advances in TBI research. We then discuss current clinical treatments in TBI and their implications in preventing inflammation. To complete the chapter, recent research models, novel biomarkers, and future research directions aimed at mitigating TBI will be described and will highlight novel therapeutic targets. Understanding the pathophysiology and contributors of neuroinflammation after TBI will aid in future development of prophylaxis strategies, as well as more tailored management and treatment algorithms. This topic chapter is important to both clinicians and basic and translational scientists, with the goal of improving patient outcomes in this common disease.",book:{id:"11367",title:"Traumatic Brain Injury",coverURL:"https://cdn.intechopen.com/books/images_new/11367.jpg"},signatures:"Grace Y. Kuo, Fawaz Philip Tarzi, Stan Louie and Roy A. Poblete"},{id:"82876",title:"Oxygen Tissue Levels as an Effectively Modifiable Factor in Alzheimer’s Disease Improvement",slug:"oxygen-tissue-levels-as-an-effectively-modifiable-factor-in-alzheimer-s-disease-improvement",totalDownloads:10,totalDimensionsCites:0,doi:"10.5772/intechopen.106331",abstract:"Despite the advance in biochemistry, there are two substantial errors that have remained for at least two centuries. One is that oxygen from the atmosphere passes through the lungs and reaches the bloodstream, which distributes it throughout the body. Another major mistake is the belief that such oxygen is used by the cell to obtain energy, by combining it with glucose. Since the late nineteenth century, it began to be published that the gas exchange in the lungs cannot be explained by diffusion. Even Christian Bohr suggested that it looked like a cellular secretion. But despite experimental evidence to the contrary and based only on theoretical models, the dogma that our body takes the oxygen it contains inside from the air around it has been perpetuated to this day. The oxygen levels contained in the human body are high, close to 99%, and the atmosphere only contains between 19 and 21%. The hypothesis that there is a supposed oxygen concentrating mechanism has not been experimentally proven to date, after almost two centuries. The mistaken belief, even among neurologists, that our body takes oxygen from the atmosphere is widespread, even though there is no experimental basis to support it, just theoretical models. Our finding that the human body can take oxygen from the water it contains, not from the air around it, like plants, comes to mark a before and after in biology in general, and the CNS is no exception. Therefore, establishing the true origin of the oxygen present within our body and brain will allow us to better understand the physio pathogenesis of neurodegenerative diseases.",book:{id:"11637",title:"Neuropsychology of Dementia",coverURL:"https://cdn.intechopen.com/books/images_new/11637.jpg"},signatures:"Arturo Solís Herrera"},{id:"82859",title:"Impact of Hypoxia on Astrocyte Induced Pathogenesis",slug:"impact-of-hypoxia-on-astrocyte-induced-pathogenesis",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.106263",abstract:"Astrocytes are the most abundant cells of the central nervous system. These cells are of diverse types based on their function and structure. Astrocyte activation is linked mainly with microbial infections, but long-term activation can lead to neurological impairment. Astrocytes play a significant role in neuro-inflammation by activating pro-inflammatory pathways. Activation of interleukins and cytokines causes neuroinflammation resulting in many neurodegenerative disorders such as stroke, growth of tumours, and Alzheimer’s. Inflammation of the brain hinders neural circulation and compromises blood flow by affecting the blood–brain barrier. So the oxygen concentration is lowered, causing brain hypoxia. Hypoxia leads to the activation of nuclear factor kappa B (NFkB) and hypoxia-inducible factors (HIF), which aggravates the inflammatory state of the brain. Hypoxia evoked changes in the blood–brain barrier, further complicating astrocyte-induced pathogenesis.",book:{id:"10744",title:"Astrocytes in Brain Communication and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10744.jpg"},signatures:"Farwa Munir, Nida Islam, Muhammad Hassan Nasir, Zainab Anis, Shahar Bano, Shahzaib Naeem, Atif Amin Baig and Zaineb Sohail"},{id:"82839",title:"Neurophysiology of Emotions",slug:"neurophysiology-of-emotions",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.106043",abstract:"Emotions are automatic and primary patterns of purposeful cognitive-behavioral organizations. They have three main functions: coordination, signaling, and information. First, emotions coordinate organs and tissues, thus predisposing the body to peculiar responses. Scholars have not reached a consensus on the plausibility of emotion-specific response patterns yet. Despite the limitations, data support the hypothesis of specific response patterns for distinct subtypes of emotions. Second, emotional episodes signal the current state of the individual. Humans display their state with verbal behaviors, nonverbal actions (e.g., facial movements), and neurovegetative signals. Third, emotions inform the brain for interpretative and evaluative purposes. Emotional experiences include mental representations of arousal, relations, and situations. Every emotional episode begins with exposure to stimuli with distinctive features (i.e., elicitor). These inputs can arise from learning, expressions, empathy, and be inherited, or rely on limited aspects of the environment (i.e., sign stimuli). The existence of the latter ones in humans is unclear; however, emotions influence several processes, such as perception, attention, learning, memory, decision-making, attitudes, and mental schemes. Overall, the literature suggests the nonlinearity of the emotional process. Each section outlines the neurophysiological basis of elements of emotion.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Maurizio Oggiano"},{id:"82172",title:"Neuroimaging in Common Neurological Diseases Treated by Anticoagulants",slug:"neuroimaging-in-common-neurological-diseases-treated-by-anticoagulants",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.105128",abstract:"Stroke imaging/Cerebral Venous sinus thrombosis/Arterial dissecting disease in Head and Neck regions/Neurocomplication of anticoagulation therapy. Nowsday, anticoagulant drugs are common drugs used in daily practice for patients in neurology clinic. Anticoagulant treatment used for treated symptomatic patients as well as for prophylaxis therapy in asymptomatic patients. The purpose of this chapter based on the review of essential neuroimaging in the most common neurological conditions that benefit from treatment with anticoagulant drugs such as ischemic stroke, cerebral venous sinus thrombosis, and arterial dissecting disease of head and neck arteries and will be enclosed with neuroimaging in case of neurocomplication by anticoagulant therapy.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Pipat Chiewvit"}],onlineFirstChaptersTotal:12},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:126,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:13,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. His research interests include biomaterials, nanomaterials, bioengineering, biosensors, drug delivery systems, and tissue engineering.",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:27,paginationItems:[{id:"83092",title:"Novel Composites for Bone Tissue Engineering",doi:"10.5772/intechopen.106255",signatures:"Pugalanthipandian Sankaralingam, Poornimadevi Sakthivel and Vijayakumar Chinnaswamy Thangavel",slug:"novel-composites-for-bone-tissue-engineering",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biomimetics - Bridging the Gap",coverURL:"https://cdn.intechopen.com/books/images_new/11453.jpg",subseries:{id:"8",title:"Bioinspired Technology and Biomechanics"}}},{id:"82800",title:"Repurposing Drugs as Potential Therapeutics for the SARS-Cov-2 Viral Infection: Automatizing a Blind Molecular Docking High-throughput Pipeline",doi:"10.5772/intechopen.105792",signatures:"Aldo Herrera-Rodulfo, Mariana Andrade-Medina and Mauricio Carrillo-Tripp",slug:"repurposing-drugs-as-potential-therapeutics-for-the-sars-cov-2-viral-infection-automatizing-a-blind-",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Molecular Docking - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82582",title:"Protecting Bioelectric Signals from Electromagnetic Interference in a Wireless World",doi:"10.5772/intechopen.105951",signatures:"David Marcarian",slug:"protecting-bioelectric-signals-from-electromagnetic-interference-in-a-wireless-world",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biosignal Processing",coverURL:"https://cdn.intechopen.com/books/images_new/11153.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}},{id:"82586",title:"Fundamentals of Molecular Docking and Comparative Analysis of Protein–Small-Molecule Docking Approaches",doi:"10.5772/intechopen.105815",signatures:"Maden Sefika Feyza, Sezer Selin and Acuner Saliha Ece",slug:"fundamentals-of-molecular-docking-and-comparative-analysis-of-protein-small-molecule-docking-approac",totalDownloads:29,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Molecular Docking - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11451.jpg",subseries:{id:"7",title:"Bioinformatics and Medical Informatics"}}}]},overviewPagePublishedBooks:{paginationCount:12,paginationItems:[{type:"book",id:"6692",title:"Medical and Biological Image Analysis",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6692.jpg",slug:"medical-and-biological-image-analysis",publishedDate:"July 4th 2018",editedByType:"Edited by",bookSignature:"Robert Koprowski",hash:"e75f234a0fc1988d9816a94e4c724deb",volumeInSeries:1,fullTitle:"Medical and Biological Image Analysis",editors:[{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"7218",title:"OCT",subtitle:"Applications in Ophthalmology",coverURL:"https://cdn.intechopen.com/books/images_new/7218.jpg",slug:"oct-applications-in-ophthalmology",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Michele Lanza",hash:"e3a3430cdfd6999caccac933e4613885",volumeInSeries:2,fullTitle:"OCT - Applications in Ophthalmology",editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza",profilePictureURL:"https://mts.intechopen.com/storage/users/240088/images/system/240088.png",biography:"Michele Lanza is Associate Professor of Ophthalmology at Università della Campania, Luigi Vanvitelli, Napoli, Italy. His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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